about how long have these symptoms been going on?
and all chest pain should be treated this way especially with your age
and along with a fever
and also needs to be checked your cholesterol blood pressure
and are you having a fever now?
and are you having any of the following symptoms with your chest pain
and are you having a runny nose?
and are you having this chest pain now?
and besides do you have difficulty breathing
and can you tell me what other symptoms are you having along with this?
and does this pain move from your chest?
and drink lots of fluids
and how high has your fever been
and i have a cough too
and i have a little cold and a cough
and i'm really having some bad chest pain today
and is this the right time for your hay fever
and it get the chest pain
and i think i have a little bit of a fever
and i want you to describe where the chest pain is
and she is sorta have the same symptoms
and tell me what symptoms are you having now?
and they're having some fevers as well
and with your history of diabetes
and you know it feels like my chest is like gonna crush
and you know people cough on me all the time
and you're having chest pain
and your symptoms do not go away in five days
and you said this is a pressure in your chest
anyone in the family have a heart problem heart disease heart attack high cholesterol high blood pressure
any other symptoms or problems that you notice with the muscle aches?
any sharp pain on your left side of your chest?
are there other people sick as you at home with your same symptoms?
are you having any difficulty breathing now
are you having any other symptoms?
are you having any shortness of breath?
are you still having the chest pain
because this is flu season
besides the diabetes do you have other problems or important diseases?
but also we shouldn't be put aside for the heart cardiac origin chest pain
but a more important problem now is this chest pain
but if you have the cough
but i have difficulty breathing
but i know lot of people cough on me
but we need to treat every chest pain with the utmost seriousness
but you're breathing all right right now right?
'cause of this chest pain i totally forgot
'cause they're having a cough
does it feel like somebody squeezing your chest
do still feel like shortness of breath
do they complain of being sick similar symptoms?
do you have any blood pressure problem as far as you know?
do you have any other chronic like high blood pressure or anything like that?
do you have any other diseases chronic medical problems like diabetes?
do you have any shortness of breath with that chest pain?
do you have high blood pressure?
do you have some shortness of breath goes with that?
do you know what symptoms she was having?
do your relatives have the same symptoms
do you see the image?
drink plenty of fluids today
have a dry cough a cold and runny nose vomiting diarrhea
however i take tests for the diabetes
however she has symptoms quite similar to mine
how high is your fever?
how' s your blood pressure?
i don't think i have high blood pressure
i feel a pain in the chest here in the front part of the chest
if you continue to have high fevers
if you have a fever of a hundred and two or higher
if you think that your symptoms or problems warrant a better look
i got a fever yesterday
i got a slight fever too
i had a fever yesterday
i had a short sharp pain in my chest
i have a sharp pain here in the chest
i have hay fever though too
i have made on the body around the chest area?
i have some difficulty breathing too
i'll send you an image
i'm having some chest pain today
i'm just having some headaches and some fever today
in my opinion it is flu
in my opinion this is a little flu
i see it going from the center of your chest going up to your neck
is it like some heavy heavy person sitting on your chest?
it all started with the headaches and with the fever about the same time
it hurts in the chest
it hurts in the middle of my chest
it is a pressure like chest pain
it is in my chest
it is in the center of my chest
it is in the center of the chest
it is occurring right in the middle of my chest
it is right in the center of my chest
it sounds like you just may have the garden variety cold or a flu
i've got pain in my chest
i've very concerned of this chest pain
i want you to tell me in describing this chest pain
i will send you an image
i will send you an image on your screen
like high blood pressure or diabetes
like right in the center of the chest
most of the time it is this type of chest pain
my sister has similar symptoms
now for the fever you can take a tachipirina sweet
now i send you an image
now mary how many days have you had the symptoms
now you said you have a chest pain
occasionally i have some chest pain
okay are you having any other symptoms along with this other than just the pain
or if you have high blood pressure
or somebody sitting on your chest?
pretty much the same with the fever and the cough headache and muscle pains
right in the middle of my chest
show me on this image where you feel the pain
since you have a fever
so do you think that some of these symptoms could be related to being pregnant?
so your chest pain started this morning
so your children are having some of the same symptoms?
tell me about your chest pain
the fever increases at night
the fever i've had for the last two days
the fever started to increase last night
the fever started two days ago
the muscle pains with the hay fever
this is doctor porter in the emergency room triage center
well can you tell me a little bit more about your chest pain?
well from my point of view it is a little flu
well i feel a pain in the front of my body here in my chest
well i've been having a strong pain in my chest
well madam from listening to your symptoms it sounds like you've got one of the flu viruses
well when i have that pain in my chest
what kinda pain do you have in your chest?
when this chest pain started?
where do you have the pain in the chest?
where you feel this chest pain eel this chest t
you are probably having chest pain
you feel like tightness on your chest
you know i got diabetes and stuff
you said you're having this chest pain
Rapidly increasing cumulative incidence of coronavirus disease (COVID-19) in the European Union/European Economic Area and the United Kingdom, 1 January to 15 March 2020
The cumulative incidence of coronavirus disease (COVID-19) cases is showing similar trends in European Union/European Economic Area countries and the United Kingdom confirming that, while at a different stage depending on the country, the COVID-19 pandemic is progressing rapidly in all countries.
Based on the experience from Italy, countries, hospitals and intensive care units should increase their preparedness for a surge of patients with COVID-19 who will require healthcare, and in particular intensive care.
On 31 December 2019, a cluster of pneumonia cases of unknown aetiology was reported in Wuhan, Hubei Province, China.
On 9 January 2020, the China Center for Disease Control and Prevention reported the causative agent as being a novel coronavirus now referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Since, the illness resulting from SARS-CoV-2 infection has been named coronavirus disease (COVID-19).
Evidence to date is that ca 80% of individuals with COVID-19 have a mild disease, i.e. a respiratory tract infection with or without pneumonia, and most of these recover.
In ca 14% cases, COVID-19 develops into a more severe disease requiring hospitalisation while the remaining 6% cases experience critical illness requiring intensive care.
The mortality of patients hospitalised due to COVID-19 is ca 4%.
In this study, we assess the trends in the cumulative incidence of COVID-19 in each European Union/European Economic Area (EU/EEA) country and the United Kingdom (UK) and compare them to that of Hubei Province, China.
We also compare the current number of COVID-19 cases in EU/EEA countries and the UK with that in Italy during 31 January–15 March 2020.
COVID-19 cases in EU/EEA countries and the UK
Subsequent to China, COVID-19 underwent further geographical spread and the dynamic of the COVID-19 pandemic in the rest of the world currently follows that of this country.
On 11 March 2020, the Director General of the World Health Organization (WHO) declared COVID-19 a pandemic.
In the 5 March issue of Eurosurveillance 2020, Spiteri et al. reported on the first European confirmed COVID-19 cases according to the WHO case definition.
In the EU/EEA, the first three confirmed cases were reported by France on 24 January 2020 in persons returning from Wuhan, Hubei Province, China.
As at 15 March 2020, COVID-19 cases had been detected in all 30 EU/EEA countries and the United Kingdom (UK), whereby between 31 December 2019 and that date included, 39,768 cases and 1,727 deaths had been reported, with 17,750 cases and 1,441 deaths from Italy alone.
Obtaining cumulative number and cumulative incidence of COVID-19 cases
At the European Centre for Disease Prevention and Control (ECDC), the notified COVID-19 case counts in each country worldwide, obtained from only official sources such as the countries’ Ministry of Health, national and regional health authorities and the WHO, are updated each day at 8:00 a.m.
These data were used for assessing the trends of COVID-19 in EU/EEA and the UK, and comparing them to that in Italy.
As a proxy of the prevalence of active COVID-19 cases, we calculated the 14-day truncated cumulative incidence of COVID-19 cases, thus taking into account the natural course of COVID-19, in each EU/EEA country and the UK, during the 1 January–15 March 2020 period.
We also presented the cumulative number of notified cases of each country as at 15 March 2020 8:00 a.m. compared with that of Italy for the 31 January–15 March 2020 period.
Trends of COVID-19 in EU/EEA countries and the UK
The trends in the 14-day truncated cumulative incidence of COVID-19 cases in EU/EEA countries and the UK generally followed that of Hubei Province (China) (Figure 1).
For the EU/EEA and the UK overall, the cumulative incidence of COVID-19 started to increase around 21 February and then increased sharply around 28 February 2020 (Supplementary material).
This was mostly driven by the rapid increase in the number of reported cases from Italy, but all other EU/EEA countries and the UK showed similar increasing trends of the cumulative incidence of COVID-19 (Supplementary material).
Figure 2 shows the cumulative number of COVID-19 cases, in EU/EEA countries and the UK compared with that in Italy for the 31 January–15 March 2020 period.
It highlights that, as at 15 March 8:00 a.m., 15 other EU/EEA countries and the UK had already reported a total number of cases comparable to that of Italy just 3 weeks prior or less.
Our results indicate that the number of notified cases of COVID-19 is rapidly increasing in the EU/EEA and the UK.
The observed trends in the cumulative incidence of COVID-19 suggest that the pandemic is progressing at a comparable speed in all countries.
This is despite countries being at different stages, variations in national public health responses, and possibly different case definitions in countries and different protocols for selecting patients that must be tested for confirmation of COVID-19, including catch-up testing.
Early March 2020, doctors in the affected regions of Italy described a situation in which ca 10% of patients with COVID-19 required intensive care and media sources reported that hospitals and intensive care units in these regions had already reached their maximum capacity.
Data on admission of COVID-19 cases in a hospital and/or an intensive care unit are currently available at EU/EEA level for only 6% and 1% cases, respectively (data not shown).
They should, however, be collected in a systematic fashion to complement current surveillance data that focus on the number of reported cases and the number of deaths.
A study performed in 2010–11 showed a large variation in the availability of intensive care and intermediate care beds in Europe, ranging from 29.2 in Germany to 4.2 beds per 100,000 population in Portugal.
This means that countries may have more or less resources than Italy (12.5 intensive care and intermediate care beds per 100,000 population in 2010–11).
Modelling scenarios related to healthcare capacity saturation, with estimates for each EU/EEA country and the UK of the prevalence of hospitalised COVID-19 cases associated with a & gt; 90% risk of exceeding intensive care bed capacity, are provided in the sixth update of the ECDC rapid risk assessment on COVID-19.
Since cases have so far clustered in certain regions in EU/EEA countries and the UK, and hospitals and intensive care units usually serve a defined regional catchment population, information about cases and intensive care beds should preferably be made available at the Nomenclature of territorial units for statistics 2 (NUTS-2) level.
The experience from Italy and the current trends in other countries show that the COVID-19 pandemic is progressing rapidly in the EU/EEA and the UK.
Countries, hospitals and intensive care units should thus prepare themselves for a scenario of sustained community transmission of SARS-CoV-2 and an increase in the number of patients with COVID-19 requiring healthcare, and in particular intensive care, such as the one occurring in the affected regions of Italy.
As pointed out in the recent ECDC rapid risk assessment, a rapid, proactive and comprehensive approach is essential to delay the spread of SARS-COV-2, with a shift from a containment to a mitigation approach, as the anticipated rapid increase in the number of cases may not provide decision makers and hospitals enough time to comprehend, accept and adapt their response accordingly if not implemented ahead of time.
The rapid risk assessment also lists the public health measures to mitigate the impact of the pandemic.
There is a short window of opportunity during which countries have the possibility to further increase their control efforts to slow down the spread of SARS-CoV-2 and decrease the pressure on healthcare.
Failing this, it is likely that the healthcare systems of other EU/EEA countries will face a surge of patients that require intensive care within the coming days or weeks.
The outbreak of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has thus far killed over 3,000 people and infected over 80,000 in China and elsewhere in the world, resulting in catastrophe for humans.
Similar to its homologous virus, SARS-CoV, which caused SARS in thousands of people in 2003, SARS-CoV-2 might also be transmitted from the bats and causes similar symptoms through a similar mechanism.
However, COVID-19 has lower severity and mortality than SARS but is much more transmissive and affects more elderly individuals than youth and more men than women.
In response to the rapidly increasing number of publications on the emerging disease, this article attempts to provide a timely and comprehensive review of the swiftly developing research subject.
We will cover the basics about the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease.
Although many questions still require answers, we hope that this review helps in the understanding and eradication of the threatening disease.
The Spring Festival on January 25, 2020 has become an unprecedented and unforgettable memory to all Chinese who were urged to stay indoors for all the holiday and for many weeks after due to the outbreak of a novel viral disease.
The virus is highly homologous to the coronavirus (CoV) that caused an outbreak of severe acute respiratory syndrome (SARS) in 2003; thus, it was named SARS-CoV-2 by the World Health Organization (WHO) on February 11, 2020, and the associated disease was named CoV Disease-19 (COVID-19).
The epidemic started in Wuhan, China, and quickly spread throughout the entire country and to near 50 others all over the world.
As of March 2, 2020, the virus has resulted in over 80,000 confirmed cases of COVID-19, with more than 40,000 patients discharged and over 3,000 patients who died.
WHO warns that COVID-19 is “public enemy number 1” and potentially more powerful than terrorism.
According to PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), in less than two months, over 200 papers have been published on COVID-19 including its virology, epidemiology, etiology, diagnosis, and treatment since the first report on January 7, 2020 that determined the sequence of the virus isolated from multiple patients.
This review attempts to summarize the research progress in the new and swiftly developing subject area.
Whenever possible, we will try to compare COVID-19 with SARS and another CoV-caused disease, Middle East respiratory syndrome (MERS, an outbreak in 2012).
We will also discuss what we have learned so far regarding the prevention and prognosis of the disease as well as some remaining yet urgent questions.
CoVs have been traditionally considered nonlethal pathogens to humans, mainly causing approximately 15% of common colds 4.
However, in this century, we have encountered highly pathogenic human CoVs twice, i.e., SARS-CoV and MERS-CoV, which caused an outbreak originally in China in 2003 and Saudi Arabia in 2012, respectively, and soon spread to many other countries with horrible morbidity and mortality.
Therefore, the current COVID-19 is the third CoV outbreak in the recorded history of humans.
As shown in Fig. ​Fig.1,1, clusters of pneumonia that had unknown origins were first reported from Wuhan on December 31, 2019 to the China National Health Commission.
Seven days later the sequence of the CoV was released.
On January 15, 2020 the first fatal case from Wuhan was reported.
Meanwhile, the epidemic rapidly spread to the neighboring cities, provinces, and countries.
On January 20, the infection of health-care providers was reported, suggesting that human-to-human transmission was possible.
On January 23, the city of Wuhan was locked down with all its public transportation stopped.
On January 24 the first clinical study on the disease reported that, out of 41 patients with confirmed cases, only 21 had direct contact with the Wuhan seafood market that was considered the starting site of the infection from an unknown animal source.
On January 30, WHO declared the outbreak a global health emergency.
By the time of this report, the disease has already spread throughout China and near 50 other countries all over the world (Fig. ​(Fig.2).2).
As the situation is rapidly evolving, the final scope and severity of the outbreak remain to be determined.
On February 11, 2020, a multi-center study on 8,866 patients including 4,021 confirmed COVID-19 patients presented a more updated illustration of the epidemic as follows (https://mp.weixin.qq.com/s/UlBi-HX_rHPXa1qHA2bhdA).
SARS-CoV-2 infected people of all ages, but mainly at the age of 30-65.
Almost half (47.7%) of the infected individuals were over 50 years old, very few were under 20, and only 14 infected individuals were under the age of 10.
SARS-CoV-2 infected more men (0.31/100,000) than women (0.27/100,000).
COVID-19 expanded in clusters mainly in and around Hubei.
COVID-19 took an average of 5 (2-9) days from onset to diagnosis.
The average incubation period was 4.8 (3.0-7.2) days.
The average time from onset to death was 9.5 (4.8-13) days.
The basic reproductive number (R0) was 3.77 (95% CI: 3.51-4.05), and the adjusted R0 was 2.23-4.82.
The number of infected people increased exponentially before 23 Jan. 2020, matching the time of massive transportation before the Spring Festival in China.
The mortality of patients with confirmed cases was 1.44% (95% CI: 1.10-1.86%), and the adjusted mortality of all the patients was 3.06% (95% CI: 2.02-4.59%).
Three major risk factors for COVID-19 were sex (male), age (≥60), and severe pneumonia.
CoVs are a subfamily of large and enveloped viruses containing a single strand of sense RNA.
They can be divided into four genera, i.e., alpha, beta, gamma, and delta, of which alpha- and beta-CoVs are known to infect humans.
The envelope spike (S) glycoprotein binds to its cellular receptors angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4) for SARS-CoV and MERS-CoV, respectively, and then membrane fusion occurs.
The viral RNA genome is released into the cytoplasm; after replication of the viral genome, genomic RNA accompanied by envelope glycoproteins and nucleocapsid proteins forms virion-containing vesicles, which then fuse with the plasma membrane to release the virus.
The first genomic sequence of SARS-CoV-2 was reported on January 10, 2020.
SARS-CoV-2 was found to be a new type of beta-CoV with more than 99.98% genetic identity among 10 sequenced samples collected from the original site of the outbreak, the Huanan Seafood Market in Wuhan.
SARS-CoV-2 is genetically more similar to SARS-CoV than to MERS-CoV.
Through transmission electron microscopy, SARS-CoV-2 particles were found in ultrathin sections of human airway epithelium.
Human ACE2 was found to be a receptor for SARS-CoV-2 as well as SARS-CoV.
However, the S protein of SARS-CoV-2 binds to human ACE2 more weakly than that of SARS-CoV, which is coincident with the fact that SARS-CoV-2 causes less severe infection in patients than SARS-CoV.
SARS-CoV-2 can also form a novel short protein encoded by orf3b and a secreted protein encoded by orf8.
The orf3b of SARS-CoV-2 may play a role in the viral pathogenicity and inhibit the expression of IFNβ; however, orf8 does not contain any known functional domain or motif.
On February 18, 2020, Zhou, et al., reported the cryo-EM structure of the full-length human ACE2 at 2.9 Å resolution in complex with the amino acid transporter B0AT1.
They found that the complex, which had open and closed conformations, was assembled as a dimer and the ACE2-B0AT1 complex can bind two S proteins, which provides evidence for CoV recognition and infection.
B0AT1 may become a therapeutic target for drug screening to suppress SARS-CoV-2 infection.
The origin and intermediate host
It has been known that both SARS-CoV and MERS-CoV originated from bats and were transmitted to humans via civet cats and camels, respectively.
Through a phylogenetic comparison of SARS-CoV-2 with other CoVs, bats were considered the native host of SARS-CoV-2 as the new virus is 96% identical to two SARS-like CoVs from bats called bat-SL-CoVZX45 and bat-SL-CoVZX21.
However, what intermediate host helped the virus cross the species barrier to infect humans remains unknown, and the transmission route is yet to be elucidated.
Ji, et al., proposed snakes as a carrier of the virus from bats to humans which involved homologous recombination within the S protein.
According to a study, researchers in Guangzhou, China, suggested that pangolins - long-snouted, ant-eating mammals often used in traditional Chinese medicine - are the potential intermediate host of SARS-CoV-2 based on 99% genetic homology in a CoV discovered in pangolins and SARS-CoV-2.
However, 1% difference spread all over two genomes is still a big difference; thus, conclusive results for concrete evidence are awaited (Fig. ​(Fig.33).
The physicochemical properties of SARS-CoV-2 are largely not yet known.
SARS-CoV and MERS-CoV can survive in vitro for 48 hours in a dry environment and up to 5 days under 20 °C and 40%-50% humidity.
SARS-CoV-2 may possess similar properties.
It has been reported that SARS-CoV-2 is sensitive to ultraviolet rays and heat at 56 °C for 30 minutes; ether, 75% ethanol, chlorine-containing disinfectant, peracetic acid, chloroform, and other fatty solvents, but not chlorhexidine, can effectively inactivate the virus.
The entire human population generally lacks immunity to SARS-CoV-2 and hence is susceptible to the novel virus.
Currently, no detailed study has been reported regarding the immunological response to SARS-CoV-2.
Thus, we can only refer to previous studies on other CoVs, especially SARS-CoV and MERS-CoV (Fig. ​(Fig.4).4).
In general, after a virus invades the host, it is first recognized by the host innate immune system through pattern recognition receptors (PRRs) including C-type lectin-like receptors, Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I-like receptor (RLR).
Through different pathways, the virus induces the expression of inflammatory factors, maturation of dendritic cells, and synthesis of type I interferons (IFNs) which limit the spreading of the virus and accelerate macrophage phagocytosis of viral antigens.
However, the N protein of SARS-CoV can help the virus escape from the immune responses.
Soon, the adaptive immune response joins the fight against the virus.
T lymphocytes including CD4+ and CD8+ T cells play an important role in the defense.
CD4+ T cells stimulate B cells to produce virus-specific antibodies, and CD8+ T cells directly kill virus-infected cells.
T helper cells produce proinflammatory cytokines to help the defending cells.
However, CoV can inhibit T cell functions by inducing apoptosis of T cells.
The humoral immunity including complements such as C3a and C5a and antibodies is also essential in combating the viral infection.
For example, antibodies isolated from a recovered patient neutralized MERS-CoV.
On the other hand, an overreaction of the immune system generates a large number of free radicals locally that can cause severe damages to the lungs and other organs, and, in the worst scenario, multi-organ failure and even death.
The SARS-CoV-2 infection, featured by clustering onset, is more likely to affect elderly people with comorbidities and pregnant women.
It is common that for people who are exposed to a large number of viruses or whose immune functions are compromised, they have higher chance to be infected than others.
The estimated mean incubation period of SARS-CoV-2 is 1-14 days, mostly 3-7 days based on a study of the first 425 cases in Wuhan.
However, a study on 1,099 cases demonstrates that the incubation period was 3 days on average and ranged from 0 to 24 days.
A more recent study, as described above, demonstrates that the incubation period was 4.8 (3.0-7.2) days based on the demography of 8,866 cases.
It is very important for health authorities to adjust the effective quarantine time based on the most accurate incubation period, thus preventing infected but symptomless people from transmitting the virus to others.
As a common practice, individuals exposed to, or infected by, the virus are usually required to be quarantined for 14 days.
Should the quarantine time be extended to 24 days?
Fever is often the major and initial symptom of COVID-19, which can be accompanied by no symptom or other symptoms such as dry cough, shortness of breath, muscle ache, dizziness, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea, and vomiting.
Some patients experienced dyspnea and/or hypoxemia one week after the onset of the disease.
In severe cases, patients quickly progressed to develop acute respiratory syndrome, septic shock, metabolic acidosis, and coagulopathy.
Patients with fever and/or respiratory symptoms and acute fever, even without pulmonary imaging abnormalities, should be screened for the virus for early diagnosis.
A demographic study in late December of 2019 showed that the percentages of the symptoms were 98% for fever, 76% for dry cough, 55% for dyspnea, and 3% for diarrhea; 8% of the patients required ventilation support.
Similar findings were reported in two recent studies of a family cluster and a cluster caused by transmission from an asymptomatic individual.
Comparably, a demographic study in 2012 showed that MERS-CoV patients also had fever (98%), dry cough (47%), and dyspnea (55%) as their main symptoms.
However, 80% of them required ventilation support, much more than COVID-19 patients and consistent with the higher lethality of MERS than of COVID-19.
Diarrhea (26%) and sore throat (21%) were also observed with MERS patients.
In SARS patients, it has been demonstrated that fever (99%-100%), dry cough (29%-75%), dyspnea (40%-42%), diarrhea (20-25%), and sore throat (13-25%) were the major symptoms and ventilation support was required for approximately 14%-20% of the patients.
By February 14, the mortality of COVID-19 was 2% when the confirmed cases reached 66,576 globally.
Comparably, the mortality of SARS by November 2002 was 10% of 8,096 confirmed cases.
For MERS, based on a demographic study in June 2012, the mortality was 37% of 2,494 confirmed cases.
An earlier study reported that the R0 of SARS-CoV-2 was as high as 6.47 with a 95% confidence interval (CI) of 5.71-7.23, whereas the R0 of SARS-CoV only ranged from 2 to 4.
A comparison of SARS-CoV-2 with MERS-CoV and SARA-CoV regarding their symptoms, mortality, and R0 is presented in Table ​Table1.1.
The above figures suggest that SARS-CoV-2 has a higher ability to spread than MERS-CoV and SARS-CoV, but it is less lethal than the latter two.
Thus, it is much more challenging to control the epidemic of SARS-CoV-2 than those of MERS-CoV and SARS-CoV.
Clustered onset often happens in the same family or from the same gathering or vehicle such as a cruise ship.
Patients often have a history of travel or residence in Wuhan or other affected areas or contact with infected individuals or patients in the recent two weeks before the onset.
However, it has been reported that people can carry the virus without symptoms longer than two weeks and cured patients discharged from hospitals can carry the virus again, which sends out an alarm to increase the time for quarantine.
Patients have normal or reduced number of peripheral white blood cells (especially lymphocytes) at the early stage.
For example, lymphopenia with white blood cell count & lt; 4×109/L including lymphocyte count & lt; 1×109/L, and elevated aspartate aminotransferase levels and viremia were found in 1,099 COVID-19 patients.
The levels of liver and muscle enzymes and myoglobin were increased in the blood of some patients, and C-reactive protein and erythrocyte sedimentation were increased in the blood of most patients.
In patients with severe cases, the level of D-dimer, a fibrin degradation product present in the blood, was elevated, and lymphocyte count was progressively reduced.
Abnormalities in chest radiography are found in most COVID-19 patients and featured by bilateral patchy shadows or ground glass opacity in the lungs.
Patients often develop an atypical pneumonia, acute lung injury, and acute respiratory distress syndrome (ARDS).
When ARDS happens, uncontrolled inflammation, fluid accumulation, and progressive fibrosis severely compromise the gas exchange.
Dysfunction of type-I and type-II pneumocytes decreases the surfactant level and increases surface tension, thus reducing the ability of the lungs to expand and heightening the risk of lung collapse.
Therefore, the worst chest radiographic findings often parallel the most severe extent of the disease.
On February 18, 2020, the first pathological analysis of COVID-19 demonstrated the desquamation of pneumocytes, hyaline membrane formation, and interstitial lymphocyte infiltration, and multinucleated syncytial cells in the lungs of a patient who died of the disease, consistent with the pathology of viral infection and ARDS and similar to that of SARS and MERS patients.
The detection of SARS-CoV-2 RNA via reverse-transcriptase polymerase chain reaction (RT-PCR) was used as the major criteria for the diagnosis of COVID-19.
However, due to the high false-negative rate, which may accelerate the epidemic, clinical manifestations started to be used for diagnosis (which no longer solely relied on RT-PCR) in China on February 13, 2020.
A similar situation also occurred with the diagnosis of SARS.
Therefore, a combination of disease history, clinical manifestations, laboratory tests, and radiological findings is essential and imperative for making an effective diagnosis.
On February 14, 2020, the Feng Zhang group described a protocol of using the CRISPR-based SHERLOCK technique to detect SARS-CoV-2, which detects synthetic SARS-CoV-2 RNA fragments at 20 × 10-18 mol/L to 200 × 10-18 mol/L (10-100 copies per microliter of input) using a dipstick in less than an hour without requiring elaborate instrumentation.
Hopefully, the new technique can dramatically enhance the sensitivity and convenience if verified in clinical samples.
Due to the lack of experience with the novel CoV, physicians can mainly provide supportive care to COVID-19 patients, while attempting a variety of therapies that have been used or proposed before for the treatment of other CoVs such as SARS-CoV and MERS-CoV and other viral diseases (Table ​(Table2).2).
These therapies include current and potential treatments with antiviral drugs, immunosuppressants, steroids, plasma from recovered patients, Chinese medicine, and psychological support.
Even plasma from recovered patients was proposed to be used for treatment.
Pharmaceutical companies are racing to develop antibodies and vaccines against the virus.
SARS-CoV-2 mainly attacks the lungs in the beginning and probably also attacks, to a lesser degree, other organs that express ACE2, such as the gastrointestinal system and the kidneys.
Nevertheless, respiratory dysfunction and failure are the major threat to the patients and the major cause of death.
Thus, respiratory support is critical to relieve the symptoms and save lives and includes general oxygen therapy, high-flow oxygen, noninvasive ventilation, and invasive mechanical ventilation depending on the severity of the disease.
Patients with severe respiratory symptoms have to be supported by extracorporeal membrane oxygenation (ECMO), a modified cardiopulmonary bypass technique used for the treatment of life-threatening cardiac or respiratory failure.
In addition, the maintenance of electrolyte balance, the prevention and treatment of secondary infection and septic shock, and the protection of the functions of the vital organs are also essential for SARS-CoV-2 patients.
It has been known that a cytokine storm results from an overreaction of the immune system in SARS and MERS patients.
Cytokine storm is a form of systemic inflammatory response featured by the release of a series of cytokines including TNFα, IL-1β, IL-2, IL-6, IFNα, IFNβ, IFNγ, and MCP-1.
These cytokines induce immune cells to release a vast number of free radicals which are the major cause of ARDS and multiple organ failure.
Immunosuppression is essential in the treatment of cytokine storms, especially in severe patients.
Corticosteroids and tocilizumab, an anti-IL6 monoclonal antibody, have been used to treat cytokine storm.
Other immunosuppression treatments for cytokine storm include the modulation of T cell-directed immune response; the blockade of IFN-γ, IL-1, and TNF; JAK inhibition; blinatumomab; suppressor of cytokine signaling 4; and HDAC inhibitors.
Steroids, as immunosuppressants, were widely used in the treatment of SARS to reduce the severity of inflammatory damage.
However, steroids at high dosages were not beneficial to severe lung injury in SARS and COVID-19 patients.
Instead, they may cause severe side effects, especially avascular osteonecrosis, dramatically affecting the prognosis.
Nevertheless, short courses of corticosteroids at low-to-moderate doses have been recommended to be used prudently for critically ill COVID-19 patients.
At the time of writing, no effective antiviral therapy has been confirmed.
However, intravenous administration with remdesivir, a nucleotide analog, has been found to be efficacious in an American patient with COVID-19.
Remdesivir is a novel antiviral drug developed by Gilead initially for the treatment of diseases caused by Ebola and Marlburg viruses.
Later, remdesivir also demonstrated possible inhibition of other single stranded RNA viruses including MERS and SARS viruses.
Based on these, Gilead has provided the compound to China to conduct a pair of trials on SARS-CoV-2-infected individuals, and the results are highly anticipated.
In addition, baricitinb, interferon-α, lopinavir/ritonavir, and ribavirin have been suggested as potential therapies for patients with acute respiratory symptoms.
Diarrhea, nausea, vomiting, liver damage, and other adverse reactions can occur following combined therapy with lopinavir/ritonavir.
The interaction of these treatments with other drugs used in the patients should be monitored carefully.
Plasma from recovered patients and antibody generation
The collection of the blood from patients who recovered from a contagious disease to treat other patients suffering from the same disease or to protect healthy individuals from catching the disease has a long history.
Indeed, recovered patients often have a relatively high level of antibodies against the pathogen in their blood.
Antibodies are an immunoglobulin (Ig) produced by B lymphocytes to fight pathogens and other foreign objects and they recognize unique molecules in the pathogens and neutralize them directly.
Based on this, plasma was collected from the blood of a group of patients who recovered from COVID-19 and was injected into 10 seriously ill patients.
Their symptoms improved within 24 hours, accompanied by reduced inflammation and viral loads and improved oxygen saturation in the blood.
However, verification and clarification are necessary to propose the method for large-scale use before specific therapies are not yet developed.
In addition, given the therapeutic effects, some disadvantages associated with the plasma should be considered carefully.
For example, antibodies can overstimulate the immune response and cause cytokine release syndrome, which is potentially a life-threatening toxicity.
The concentration of antibodies in the blood is usually low, and the demand for the plasma is large to treat critically ill patients.
It is difficult to develop and produce specific antibodies rapidly enough to fight against a global epidemic.
Thus, it is more critical and practical to isolate B cells from recovered patients and identify the genetic codes encoding effective antibodies or screen for effective antibodies against essential proteins of the virus.
This way, we can readily scale up the production of the antibodies.
TCM has been used to treat a variety of diseases in China for thousands of years.
However, its effects largely rely on a combination of multiple components in a formula that varies depending on the diagnosis of a disease based on the theories of TCM.
Most of the effective components remain unknown or are vague as it is difficult to extract and verify such components or their optimal combinations.
Currently, due to the lack of effective and specific therapy for COVID-19, TCM has become one of the major alternative treatments for patients with light to moderate symptoms or for those who have recovered from severe stages.
For example, Shu Feng Jie Du capsules and Lian Hua Qing Wen capsules were found to be effective for COVID-19 treatment.
Top cure rates in the treatment of COVID-19 patients were observed in several provinces in China that used TCM in 87% of their patients, including Gansu (63.7%), Ningxia (50%), and Hunan (50%), whereas Hubei province, which used TCM in only approximately 30% of its COVID-19 patients, had the lowest cure rate (13%).
However, this is quite a rough comparison as many other impact factors such as the number and severity of the patients should be included in the evaluation.
On February 18, 2020, Boli Zhang and coworkers published a study to compare western medicine (WM) treatment alone with combined treatment of WM and TCM.
They found that the times needed for body temperature recovery, symptom disappearance, and hospitalization were remarkably shorter in the WM+TCM group than in the WM only group.
Most impressively, the rate for symptomatic worsening (from light to severe) was remarkably lower for the WM+TCM group than for the WM only group (7.4% versus 46.2%) and the mortality was lower in the WM+TCM group than WM only group (8.8% versus 39%).
Nevertheless, the efficacy and safety of TCM still await more well-controlled trials at larger scales and in more centers.
It would also be intriguing to characterize the mechanism of actions and clarify the effective components of TCM treatments or their combinations if possible.
Patients with suspected or confirmed COVID-19 mostly experience great fear of the highly contagious and even fatal disease, and quarantined people also experience boredom, loneliness, and anger.
Furthermore, symptoms of the infection such as fever, hypoxia, and cough as well as adverse effects of the treatments such as insomnia caused by corticosteroids can lead to more anxiety and mental distress.
In the early phase of the SARS outbreak, a range of psychiatric morbidities including persistent depression, anxiety, panic attacks, psychomotor excitement, psychotic symptoms, delirium, and even suicidality were reported.
Mandatory contact tracing and quarantine, as a part of the public health responses to the COVID-19 outbreak, can make people more anxious and guilty about the effects of the contagion, quarantine, and stigma on their families and friends.
Thus, mental health care should be provided to COVID-19 patients, suspected individuals, and people in contact with them as well as the general public who are in need.
The psychological support should include the establishment of multidisciplinary mental health teams, clear communications with regular and accurate updates about the SARS-CoV-2 outbreak and treatment plans and the use of professional electronic devices and applications to avoid close contact with each other.
Effective vaccines are essential for interrupting the chain of transmission from animal reservoirs and infected humans to susceptible hosts and are often complementary to antiviral treatment in the control of epidemics caused by emerging viruses.
Efforts have been made to develop S protein-based vaccines to generate long-term and potent neutralizing antibodies and/or protective immunity against SARS-CoV.
Live-attenuated vaccines have been evaluated in animal models for SARS.
However, the in vivo efficacy of these vaccine candidates in elderly individuals and lethal-challenge models and their protection against zoonotic virus infection have yet to be determined before a clinical study is initiated.
This is probably because SARS died down 17 years ago and no new case has been reported since.
In contrast, sporadic cases and clusters of MERS continue to occur in the Middle East and spread to other regions owing to the persistence of zoonotic sources in endemic areas.
Vaccination strategies have been developed for MERS by using inactivated virus, DNA plasmids, viral vectors, nanoparticles, virus-like particles and recombinant protein subunits and some have been evaluated in animal models.
The development of a safe and effective vaccine against SARS-CoV-2 for non-immune individuals is an urgent and critical task for controlling the ongoing epidemic.
However, it is challenging to overcome the difficulty because of the long period of time (averaged 18 months) needed for vaccine development and the dynamic variations of CoVs.
As a novel disease, COVID-19 has just started to manifest its full clinical course throughout thousands of patients.
In most cases, patients can recover gradually without sequelae.
However, similar to SARS and MERS, COVID-19 is also associated with high morbidity and mortality in patients with severe cases.
Therefore, building a prognosis model for the disease is essential for health-care agencies to prioritize their services, especially in resource-constrained areas.
Based on clinical studies reported thus far, the following factors may affect or be associated with the prognosis of COVID-19 patients (Table ​(Table33):
Age: Age was the most important factor for the prognosis of SARS, which is also true for COVID-19.
COVID-19 mainly happened at the age of 30-65 with 47.7% of those patients being over 50 in a study of 8,866 cases as described above.
Patients who required intensive care were more likely to have underlying comorbidities and complications and were significantly older than those who did not (at the median age of 66 versus 51), suggesting age as a prognostic factor for the outcome of COVID-19 patients.
Sex: SARS-CoV-2 has infected more men than women (0.31/100,000 versus 0.27/100,000), as described above.
Comorbidities and complications: Patients with COVID-19 who require intensive care are more likely to suffer from acute cardiac injury and arrhythmia.
Cardiac events were also the main reason for death in SARS patients.
It has been reported that SARS-CoV-2 can also bind to ACE2-positive cholangiocytes, which might lead to liver dysfunctions in COVID-19 patients.
It is worth noting that age and underlying disease are strongly correlated and might interfere with each other.
Abnormal laboratory findings: The C-reactive protein (CRP) level in blood reflects the severity of inflammation or tissue injury and has been proposed to be a potential prognostic factor for disease, response to therapy, and ultimate recovery.
The correlation of CRP level to the severity and prognosis of COVID-19 has also been proposed.
In addition, elevated lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) may also help predict the outcome.
These enzymes are expressed extensively in multiple organs, especially in the heart and liver, and are released during tissue damage.
Thus, they are traditional markers for heart or liver dysfunctions.
Major clinical symptoms: Chest radiography and temporal progression of clinical symptoms should be considered together with the other issues for the prediction of outcomes and complications of COVID-19.
Use of steroids: As described above, steroids are immunosuppressant commonly used as an adjunctive therapy for infectious diseases to reduce the severity of inflammatory damage.
Since a high dosage of corticosteroids was widely used in severe SARS patients, many survivors suffered from avascular osteonecrosis with life-long disability and poor life quality.
Thus, if needed, steroids should be used at low dosage and for a short time in COVID-19 patients.
Mental stress: As described above, during the COVID-19 outbreak many patients have suffered from extraordinary stress as they often endured long periods of quarantine and extreme uncertainty and witnessed the death of close family members and fellow patients.
It is imperative to provide psychological counseling and long-term support to help these patients recover from the stress and return to normal life.
According to demographic studies so far, COVID-19 seems to have different epidemiological features from SARS.
In addition to replicating in the lower respiratory tract, SARS-CoV-2 can efficiently replicate in the upper respiratory tract and causes mild or no symptoms in the early phase of infection, similar to other CoVs that cause common colds.
Therefore, infected patients at the early phase or incubation period can produce a large amount of virus during daily activities, causing great difficulty for the control of the epidemic.
However, the transmission of SARS-CoV was considered to occur when the patients are severely ill, while most transmission did not happen at the early phase.
Thus, the current outbreak of COVID-19 is much more severe and difficult to control than the outbreak of SARS.
Great efforts are currently underway in China including the lockdown of Wuhan and surrounding cities and continuous quarantine of almost the entire population in hopes of interrupting the transmission of SARS-CoV-2.
Although these actions have been dramatically damaging the economy and other sectors of the country, the number of new patients is declining, indicating the slowdown of the epidemic.
The most optimistic estimate is that the outbreak will end by March and the downswing phase will last for 3-4 months.
However, some other experts are not that optimistic.
Paul Hunter, et al., estimated that COVID-19, which seems substantially more infectious than SARS, will not end in 2020.
Ira Longini, et al., established a model to predict the outcome of the epidemic and suggested that SARS-CoV-2 could infect two-thirds of the global population.
A Canadian group reported that SARS-CoV-2 was detected in both mid-turbinate and throat swabs of patients who recovered and left the hospital 2 weeks earlier, which indicates that the newly identified virus could become a cyclical episode similar to influenza.
However, promising signs have occurred in China based on the declining number of new cases, indicating the current strategies might have been working.
Ebola was originally predicted to cause up to a million cases with half a million deaths.
However, via strict quarantine and isolation, the disease has eventually been put under control.
It is possible, similar to SARS-CoV, that SARS-CoV-2 might become weaker in infectivity and eventually die down or become a less pathogenic virus co-existent with humans.
A comparison of the epidemic of COVID-19 with that of SARS and MERS is provided below (Fig. ​(Fig.55).
SARS-CoV-2 is highly transmittable through coughing or sneezing, and possibly also through direct contact with materials contaminated by the virus.
The virus was also found in feces, which raises a new possibility of feces-to-mouth transmission.
A recent study on 138 cases reported that 41% of the cases were possibly caused by nosocomial infections, including 17 patients with other prior diseases and 40 health-care providers.
Thus, great precaution should be used to protect humans, especially health-care providers, social workers, family members, colleagues, and even bystanders in contact with patients or infected people.
The first line of defense that could be used to lower the risk of infection is through wearing face masks; both the use of surgical masks and N95 respirator masks (series # 1860s) helps control the spread of viruses.
Surgical face masks prevent liquid droplets from a potentially infected individual from traveling through the air or sticking onto surfaces of materials, where they could be passed on to others.
However, only N95 (series # 1860s) masks can protect against the inhalation of virions as small as 10 to 80 nm, with only 5% of the virions being able to penetrate completely; SARS-CoV-2 is similar to SARS-CoV in size and both are approximately 85 nm.
Since particles can penetrate even five surgical masks stacked together, health-care providers in direct contact with patients must wear N95 (series # 1860s) masks but not surgical masks.
In addition to masks, health-care providers should wear fitted isolation gowns in order to further reduce contact with viruses.
Viruses can also infect an individual through the eyes.
On January 22, 2020, a doctor was infected with SARS-CoV-2 although he wore an N95 mask; the virus might have entered his body through his inflammatory eyes.
Thus, health-care providers should also wear transparent face shields or goggles while working with patients.
For the general public in affected or potentially affected areas, it is highly suggested that everybody wash their hands with disinfectant soaps more often than usual, try to stay indoors for self-quarantine and limit contact with potentially infected individuals.
Three feet is considered an appropriate distance for people to stay away from a patient.
These actions are effective methods to lower the risk of infection as well as prevent the spread of the virus.
Although SARS-CoV-2 came as a new virus to the human world, its high homology to SARS-CoV as reported on 7 January 2020 should have caused high alert to China based on her deep memory of the SARS outbreak in 2003.
However, not until 19 January 2020 did the director of the Center of Disease Control of Wuhan comfort the citizens by saying that the novel virus has low contagiousness and limited reproductivity from human to human and that it is not a problem to prevent and contain the disease.
This message remarkably relaxed the alarm of the public, especially when the entire country was preparing for the Spring Festival, and the critical time was missed to contain the disease at its minimal scale in Wuhan.
The disease control agencies in China may take this hard lesson and make critical improvements in the future.
For example, these agencies should be (1) more careful when making public announcements as every word counts to citizens and can change their attitude and decisions; (2) more sensitive and reactive to unusual information from clinics rather than waiting for formal reports from doctors or officials; (3) more restrictive to contain a potential epidemic at its early stage rather than attempting to comfort the public; and (4) more often to issue targeted and effective drills to increase the public's awareness about epidemic diseases and to test and improve the response system of the society periodically.
The outbreak of COVID-19 caused by the novel virus SARS-CoV-2 started in the end of December 2019.
In less than two months, it has spread all over China and near 50 other countries globally at the time of this writing.
Since the virus is very similar to SARS-CoV and the symptoms are also similar between COVID-19 and SARS, the outbreak of COVID-19 has created a sense of SARS recurring.
However, there are some remarkable differences between COVID-19 and SARS, which are essential for containing the epidemic and treating the patients.
COVID-19 affects more elderly individuals than youth and more men than women, and the severity and death rate are also higher in elderly individual than in youth.
SARS has higher mortality than COVID-19 (10.91% versus 1.44%).
COVID-19 patients transmit the virus even when they are symptomless whereas SARS patients do so usually when they are severely ill, which causes much greater difficulty to contain the spread of COVID-19 than SARS.
This partially explains why SARS-CoV-2 spread much faster and broader than SARS-CoV.
The regular RNA assay for SARS-CoV-2 can be negative in some COVID-19 patients.
On the other hand, cured patients can be positive for the virus again.
These findings dramatically increase the risk of virus spreading.
Given such rapid progress in research on COVID-19, several critical issues remain to be solved, as follows:
Where did SARS-CoV-2 come from?
Although 96% genetic homolog was found between SARS-CoV-2 and two bat SARS-like CoVs, we still cannot conclude that SARS-CoV-2 is from bats.
What animal was the intermediate species to transmit the virus from the original host, say bats, to humans?
Without knowing answers to #1 and 2, we cannot efficiently cut the transmission, and the outbreak can relapse at any time.
Although molecular modeling and biochemical assays have demonstrated that SARS-CoV-2 binds to ACE2, how exactly does the virus enter the airway cells and cause subsequent pathological changes?
Does the virus also bind ACE2-expressing cells in other organs?
Without clear answers to these questions, we cannot achieve fast and accurate diagnosis and effective treatment.
How long will the epidemic last?
How is the virus genetically evolving during transmission among humans?
Will it become a pandemic worldwide, die down like SARS or relapse periodically like the flu?
It is essential but may take some time to search for answers to the above and many other questions.
However, with whatever expense it may demand, we have no other choice but to stop the epidemic as soon as possible and bring our life back to normal.
Zoonotic origins of human coronaviruses
Mutation and adaptation have driven the co-evolution of coronaviruses (CoVs) and their hosts, including human beings, for thousands of years.
Before 2003, two human CoVs (HCoVs) were known to cause mild illness, such as common cold.
The outbreaks of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) have flipped the coin to reveal how devastating and life-threatening an HCoV infection could be.
The emergence of SARS-CoV-2 in central China at the end of 2019 has thrusted CoVs into the spotlight again and surprised us with its high transmissibility but reduced pathogenicity compared to its sister SARS-CoV.
HCoV infection is a zoonosis and understanding the zoonotic origins of HCoVs would serve us well.
Most HCoVs originated from bats where they are non-pathogenic.
The intermediate reservoir hosts of some HCoVs are also known.
Identifying the animal hosts has direct implications in the prevention of human diseases.
Investigating CoV-host interactions in animals might also derive important insight on CoV pathogenesis in humans.
In this review, we present an overview of the existing knowledge about the seven HCoVs, with a focus on the history of their discovery as well as their zoonotic origins and interspecies transmission.
Importantly, we compare and contrast the different HCoVs from a perspective of virus evolution and genome recombination.
The current CoV disease 2019 (COVID-19) epidemic is discussed in this context.
In addition, the requirements for successful host switches and the implications of virus evolution on disease severity are also highlighted.
Coronaviruses (CoVs) belong to the family Coronaviridae, which comprises a group of enveloped, positive-sensed, single-stranded RNA viruses.
These viruses harbouring the largest genome of 26 to 32 kilobases amongst RNA viruses were termed “CoVs” because of their crown-like morphology under electron microscope.
Structurally, CoVs have non-segmented genomes that share a similar organization.
Approximately two thirds of the genome contain two large overlapping open reading frames (ORF1a and ORF1b), which are translated into the pp1a and pp1ab replicase polyproteins.
The polyproteins are further processed to generate 16 non-structural proteins, designated nsp1~16.
The remaining portion of the genome contains ORFs for the structural proteins, including spike (S), envelope (E), membrane (M) and nucleoprotein (N).
A number of lineage-specific accessory proteins are also encoded by different lineages of CoVs.
Based on the difference in protein sequences, CoVs are classified into four genera (alpha-CoV, beta-CoV, gamma-CoV and delta-CoV), among which the beta-CoV genera contains most HCoVs and is subdivided into four lineages (A, B, C and D).
Phylogenetic evidence has shown that bats and rodents serve as the gene source of most alpha-CoVs and beta-CoVs, while birds are the main reservoir of gamma-CoVs and delta-CoVs.
For thousands of years, CoVs have constantly crossed species barriers and some have emerged as important human pathogens.
To date, seven human CoVs (HCoVs) are known.
Among them HCoV-229E and HCoV-NL63 are alpha-CoVs.
The other five beta-CoVs include HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2.
HCoV-229E, HCoV-OC43, HCoV-HKU1 and HCoV-NL63 usually cause mild symptoms, like common cold and/or diarrhea.
In contrast, SARS-CoV, MERS-CoV and the newly-identified SARS-CoV-2 are highly pathogenic, causing severe lower respiratory tract infection in relatively more patients with a higher chance to develop acute respiratory distress syndrome (ARDS) and extrapulmonary manifestations.
The first HCoV-229E strain, B814, was isolated from the nasal discharge of patients with common cold in mid-1960s.
Since then, more knowledge was accumulated through extensive studies on HCoV-229E and HCoV-OC43, both of which cause self-limiting symptoms.
Indeed, the concept had been widely accepted that infection with HCoVs is generally harmless until the outbreak of SARS.
The SARS outbreak occurred in 2003 is one of the most devastating in current history, infecting over 8,000 people with a crude case fatality of approximately 10%.
Ten years later, the Middle East respiratory syndrome (MERS) outbreak resulted in a persistent epidemic in the Arabian Peninsula with sporadic spreading to the rest of the world.
The 2019 novel HCoV (2019-nCoV), which has subsequently been renamed SARS-CoV-2, is the causative agent of the ongoing epidemic of coronavirus disease 2019 (COVID-19), which has claimed more than 3,120 lives and infected more than 91,000 people as of March 3, 2020.
The alarm has been ringing and the world has to prepare for the coming pandemic of SARS-CoV-2.
All seven HCoVs have a zoonotic origin from bats, mice or domestic animals.
Multiple lines of evidence support an evolutionary origin of all HCoVs from bats, where viruses are well adapted and non-pathogenic but show great genetic diversity.
The COVID-19 epidemic has presented enormous medical, scientific, social and moral challenges to China and the world.
Tracing the zoonotic origins of HCoVs provides a framework to understand the natural history, driving force and restriction factors of species jumping.
This might also guide or facilitate the search for the reservoir, intermediate and amplifying animal host(s) of SARS-CoV-2, with important implications in the prevention of future spillovers.
In this review we present an overview of the zoonotic origins, interspecies transmission and pathogenesis of HCoVs.
Particularly, we highlight and discuss the common theme that parental viruses of HCoVs are typically non-pathogenic in their natural reservoir hosts but become pathogenic after interspecies transmission to a new host.
We also review the trend of HCoV evolution in which the increase in transmissibility often comes with the decrease in pathogenicity.
The outcome of the ongoing SARS-CoV-2 outbreak is also discussed in this context.
Animal CoVs have been known since late 1930s.
Before the first isolation of HCoV-229E strain B814 from the nasal discharge of patients who had contracted common cold, different CoVs had been isolated in various infected animals, including turkey, mouse, cow, pig, cat and dog.
In the past decades, seven HCoVs have been identified.
A brief summary of the history of HCoV discovery in chronological order (Table ​1) would be informative and instructive.
The first HCoV-229E strain was isolated from the respiratory tract of patients with upper respiratory tract infection in the year of 1966, and was subsequently adapted to grow in WI-38 lung cell lines.
Patients infected with HCoV-229E presented with common cold symptoms, including headache, sneezing, malaise and sore-throat, with fever and cough seen in 10~20% cases.
Later in 1967, HCoV-OC43 was isolated from organ culture and subsequent serial passage in brains of suckling mice.
The clinical features of HCoV-OC43 infection appear to be similar to those caused by HCoV-229E, which are symptomatically indistinguishable from infection with other respiratory tract pathogens such as influenza A viruses and rhinoviruses.
Both HCoV-229E and HCoV-OC43 are distributed globally, and they tend to be predominantly transmitted during the season of winter in temperate climate.
Generally, the incubation time of these two viruses is less than one week, followed by an approximately 2-week illness.
According to a human volunteer study, healthy individuals infected with HCoV-229E developed mild common cold.
Only a few immunocompromised patients exhibited severe lower respiratory tract infection.
SARS, also known as “atypical pneumonia”, was the first well documented HCoV-caused pandemic in human history and the etiological agent is SARS-CoV, the third HCoV discovered.
The first case of SARS can be traced back to late 2002 in Guangdong Province of China.
The SARS epidemic resulted in 8,096 reported cases with 774 deaths, spreading across many countries and continents.
Apart from the super-spreaders, it was estimated that each case could give rise to approximately two secondary cases, with an incubation period of 4 to 7 days and the peak of viral load appearing on the 10th day of illness.
Patients infected with SARS-CoV initially present with myalgia, headache, fever, malaise and chills, followed by dyspnea, cough and respiratory distress as late symptoms.
Lymphopenia, deranged liver function tests, and elevated creatine kinase are common laboratory abnormalities of SARS.
Diffuse alveolar damage, epithelial cell proliferation and an increase of macrophages are also observed in SARS patients.
Approximately 20-30% of patients subsequently require intensive care and mechanical ventilation.
In addition to lower respiratory tract, multiple organs including gastrointestinal tract, liver and kidney can also be infected in these severe cases, usually accompanied with a cytokine storm, which might be lethal particularly in immunocompromised patients.
The virus was first isolated from the open lung biopsy of a relative of the index patient who travelled to Hong Kong from Guangzhou.
Since then, tremendous efforts have been dedicated to HCoV research.
HCoV-NL63 was isolated from a 7-month-old child from the Netherlands during late 2004.
It was initially found to be prevalent in young children, the elderly and immunocompromised patients with respiratory illnesses.
Presentation of coryza, conjunctivitis, fever, and bronchiolitis is common in the disease caused by HCoV-NL63.
Another independent study described the isolation of the same virus from a nasal specimen from an 8-month-old boy suffering from pneumonia in the Netherlands.
Although it was identified in Netherlands, it is actually distributed globally.
It has been estimated that HCoV-NL63 accounts for approximately 4.7% of common respiratory diseases, and its peak incidence occurs during early summer, spring and winter.
HCoV-NL63 is associated with obstructive laryngitis, also known as croup.
In the same year, HCoV-HKU1 was isolated from a 71-year-old man who had been hospitalized with pneumonia and bronchiolitis in Hong Kong.
Besides community-acquired pneumonia and bronchiolitis, HCoV-HKU1 was reported to be associated with acute asthmatic exacerbation.
Similar to HCoV-NL63, HCoV-229E and HCoV-OC43, HCoV-HKU1 was found worldwide, causing mild respiratory diseases.
All these four community-acquired HCoVs have been well adapted to humans and are generally less likely to mutate to cause highly pathogenic diseases, though accidents did occur for unknown reasons as in the rare case of a more virulent subtype of HCoV-NL63, which has recently been reported to cause severe lower respiratory tract infection in China.
Generally, when these HCoVs acquire the abilities to transmit efficiently and to maintain themselves continuously within humans, they also become less virulent or pathogenic.
MERS-CoV was first isolated in 2012 from the lung of a 60-year-old patient who developed acute pneumonia and renal failure in Saudi Arabia.
Whereas most of the laboratory-confirmed cases originate from the Middle East, imported cases with occasional secondary spreads to close contacts have been reported in various European countries and Tunisia.
Another secondary outbreak occurred in South Korea in 2015 with 186 confirmed cases.
Clinical manifestations of MERS resemble those of SARS, characterized by progressive acute pneumonia.
Unlike SARS, many patients with MERS also developed acute renal failure, which is thus far unique for MERS among HCoV-caused diseases.
More than 30% of patients present with gastrointestinal symptoms, such as diarrhea and vomiting.
As of February 14, 2020, over 2500 laboratory confirmed cases were reported with a high case fatality of 34.4%, making MERS-CoV one of the most devastating viruses known to humans.
During middle to late December 2019, clusters of pneumonia patients retrospectively known to be associated with SARS-CoV-2 infection were detected in Wuhan, Hubei Province, China.
World Health Organization declared the ongoing outbreak of lower respiratory tract infection caused by SARS-CoV-2 a Public Health Emergency of International Concern and also named the disease COVID-19.
As of March 3, 2020, 90,053 cases have been confirmed worldwide, with a crude case fatality of 3.4%.
Notably, the case fatality in Hubei, China is 4.2%, whereas the one outside of it is 1.2%.
SARS-CoV-2 causes severe respiratory infection like SARS-CoV and MERS-CoV, presented as fever, cough and dyspnea.
Diarrhea is also seen in some patients.
Pneumonia is one of the most severe symptoms and can progress rapidly to acute respiratory distress syndrome.
Although SARS-CoV and SARS-CoV-2 are very similar due to high nucleotide sequence homology of 82%, they cluster into different branches in the phylogenetic tree.
SARS-CoV-2 is apparently less pathogenic but more transmissible compared to SARS-CoV and MERS-CoV.
Asymptomatic subjects infected with SARS-CoV-2 have been reported and might contribute to its rapid spreading around the world.
Comparing and contrasting SARS-CoV-2 with the other six HCoVs reveal similarities and differences of great interest.
First, the incubation period and the duration of the course of HCoV disease are very similar.
In this regard, SARS-CoV-2 follows the general trend of the other six HCoVs.
Second, the severity of symptoms of COVID-19 lies between SARS-CoV and the four community-acquired HCoVs (i.e. HCoV-229E, HCoV-OC43, HCoV-HKU1 and HCoV-NL63).
On one hand, SARS-CoV-2 infection exhibits features that are more commonly seen during infection with community-acquired HCoVs, including the presentation of non-specific, mild or even no symptoms.
On the other hand, a small subset of severe cases of COVID-19 can also be seen as in the case of SARS-CoV infection, although the ratio is a bit lower.
Third, the transmission of SARS-CoV-2 also shows interesting patterns characteristic of both community-acquired HCoVs and SARS-CoV.
On one hand, the transmissibility of SARS-CoV-2 is at least as high as that of community-acquired HCoVs.
On the other hand, it remains to be verified whether the transmissibility of SARS-CoV-2 decreases after passages in humans as in the cases of SARS-CoV and MERS-CoV.
Finally, same as the other HCoVs, SARS-CoV-2 can be detected in fecal samples.
Whether fecal-oral transmission of SARS-CoV-2 plays an important role as in the case of SARS-CoV at least under some circumstance remains to be clarified by future studies.
It is also of particularly great interest to see whether SARS-CoV-2 might exhibit seasonality as in the cases of community-acquired HCoVs.
Nevertheless, the features of SARS-CoV-2 including its transmissibility, pathogenicity and sustainable spreading after passages in humans will be influential on the ultimate fate of the ongoing outbreak of COVID-19.
All four community-acquired HCoVs causing mild symptoms have been well adapted to humans.
From another perspective, it might also be true that humans have been well adapted to these four HCoVs.
In other words, both could be the survivors of ancient HCoV pandemics.
HCoVs that cause severe diseases in humans and humans who developed severe HCoV diseases have been eliminated.
For this to happen, HCoVs have to replicate in humans to sufficient extent to allow the accumulation of adaptive mutations that counteract host restriction factors.
In this sense, the longer the SARS-CoV-2 outbreak persists and the more people that it infects, the greater chance that it will fully adapt to humans.
If it adapts well, its transmission in humans would be difficult to stop by quarantine or other infection control measures.
For many years, the four community-acquired CoVs circulate in human populations, triggering common cold in immunocompetent subjects.
These viruses do not need an animal reservoir.
In contrast, highly pathogenic SARS-CoV and MERS-CoV have not adapted to humans well and their transmission within humans cannot be sustained.
They need to maintain and propagate in their zoonotic reservoirs and seek the chance to spillover to susceptible human targets, possibly via one or more intermediate and amplifying hosts.
SARS-CoV-2 has features that are similar to both SARS-CoV/MERS-CoV and the four community-acquired HCoVs.
It is highly transmissible like community-acquired HCoVs, at least for the time being.
However, it is more pathogenic than community-acquired HCoVs and less pathogenic than SARS-CoV or MERS-CoV.
It remains to be seen whether it will adapt fully to humans and circulate within humans without a reservoir or intermediate animal host.
Before discussing the animal origins of HCoVs, it will serve us well to discuss the definitions and characteristics of evolutionary, natural, reservoir, intermediate and amplifying hosts of HCoVs.
An animal serves as the evolutionary host of an HCoV if it harbours a closely related ancestor sharing high homology at the level of nucleotide sequence.
The ancestral virus is usually well adapted and non-pathogenic in this host.
Likewise, a reservoir host harbours HCoV continuously and for long term.
In both cases, the hosts are naturally infected and are the natural hosts of HCoV or its parental virus.
In contrast, if the HCoV is newly introduced to an intermediate host right before or around its introduction to humans, it is not well adapted to the new host and is often pathogenic.
This intermediate host can serve as the zoonotic source of human infection and play the role of an amplifying host by allowing the virus to replicate transiently and then transmitting it to humans to amplify the scale of human infection.
An HCoV can undergo a dead-end infection if it cannot sustain its transmission within the intermediate host.
On the contrary, HCoVs can also adapt to the intermediate host and even establish long-term endemicity.
In this case, the intermediate host becomes a natural reservoir host.
Epidemiological data revealed retrospectively that the index case of SARS had a contact history with game animals.
Subsequent seroprevalence investigations indicated that animal traders had a higher prevalence of anti-SARS-CoV IgG compared with that of the general population.
Masked palm civets (Paguma larvata) and a racoon dog in live animal markets were first identified to carry SARS-CoV-like viruses that are almost identical to SARS-CoV.
This was indirectly supported by the fact that no further SARS was reported after killing all civets in the markets.
However, it has been reported that masked palm civets from the wild or farms without exposure to the live animal markets were largely negative for SARS-CoV, suggesting that masked palm civets might only serve as the intermediate amplifying host but not the natural reservoir of SARS-CoV.
Notably, since 80% of the different animals in the markets in Guangzhou have anti-SARS-CoV antibodies, the possibilities that multiple species of small mammals might also serve as intermediate amplifying hosts of SARS-CoV cannot be excluded.
All of these appear to be dead-end hosts of SARS-CoV.
Subsequent search for the natural animal host of SARS-CoV unveiled a closely related bat CoV, termed SARS-related Rhinolophus bat CoV HKU3 (SARSr-Rh-BatCoV HKU3), which exists in Chinese horseshoe bats.
These bats are positive for anti-SARS-CoV antibodies and genome sequence of SARSr-Rh-BatCoV HKU3.
This and other bat CoVs share 88-92% nucleotide sequence homology with SARS-CoV.
These studies have laid the foundation for the new concept that bats host emerging human pathogens.
Several SARS-like CoVs (SL-CoVs) have also been identified from bats, but none except for one designated WIV1 can be isolated as live virus.
Human angiotensin converting enzyme 2 (ACE2) is known to be the receptor of SARS-CoV.
WIV1 derived from fecal sample of bats was demonstrated to use bat, civet and human ACE2 as receptor for cell entry.
Intriguingly, sera of convalescent SARS patients were capable of neutralizing WIV1.
Thus far, WIV1 represents the most closely related ancestor of SARS-CoV in bats, sharing 95% nucleotide sequence homology.
Albeit the high homology between these two viruses, it is generally believed that WIV1 is not the immediate parental virus of SARS-CoV and bats are not the immediate reservoir host of SARS-CoV.
Phylogenetic analysis clusters MERS-CoV to the same group as bat CoV-HKU4 and bat CoV-HKU5.
Bat CoV-HKU4 and MERS-CoV utilize the same host receptor, dipeptidyl peptidase 4 (DPP4), for virus entry.
RNA-dependent RNA polymerase sequences of MERS-CoV are phylogenetically closer to counterparts in bat beta-CoVs identified from Europe and Africa.
Up to now, no live MERS-CoV can be found in wild bats.
MERS-CoV and its closest relative bat CoV-HKU25 share only 87% nucleotide sequence homology.
Thus, bats might not be the immediate reservoir host of MERS-CoV.
On the other hand, studies in Middle East have shown that dromedary camels are seropositive for MERS-CoV-specific neutralizing antibodies, same as camels of Middle East origin in multiple African countries.
Live MERS-CoV identical to the virus found in humans was isolated from the nasal swabs of dromedary camels, further indicating that camels serve as the bona fide reservoir host of MERS-CoV.
It is also noteworthy that generally mild symptoms but massive virus shedding were observed in camels experimentally infected with MERS-CoV.
Notably, infected camels shed viruses not only through respiratory route but also through fecal-oral route, which is also the main route for virus shedding from bats.
However, questions still remain since many confirmed cases of MERS have no contact history with camels prior to symptom onset, plausibly ascribed to human-to-human transmission or unknown transmission routes involving unrecognized animal species that harbour MERS-CoV.
SARS-CoV-2 shares 96.2% nucleotide homology with a bat CoV RaTG13 isolated from Rhinolophus affinis bats.
As in the cases of SARS-CoV and MERS-CoV, the sequence divergence between SARS-CoV-2 and RaTG13 is too great to assign parental relationship.
That is to say, bats might not be the immediate reservoir host(s) of SARS-CoV-2 unless almost identical bat CoVs are found in future.
Presumably, the intermediate animal hosts of SARS-CoV-2 should be among the wildlife species sold and killed at the Huanan Seafood Wholesale Market, with which many of the initial cases of COVID-19 were associated, indicative of a probable animal-to-human transmission event.
Several recent studies based on metagenomic sequencing have suggested that a group of endangered small mammals known as pangolins (Manis javanica) could also harbour ancestral beta-CoVs related to SARS-CoV-2.
These novel pangolin CoV genomes share 85-92% nucleotide sequence homology with SARS-CoV-2.
However, they are equally closely related to RaTG13 with about 90% identity at the level of nucleotide sequence.
They cluster into two sub-lineages of SARS-CoV-2-like viruses in the phylogenetic tree, one of which share a more similar receptor binding domain (RBD) with SARS-CoV-2, with 97.4% amino acid sequence identity.
In stark contrast, the RBDs of SARS-CoV-2 and RaTG13 are more divergent, albeit a higher degree of sequence homology genome-wide.
An earlier study on diseased pangolins also reported the detection of viral contigs from lung samples, which turn out to be similarly related to SARS-CoV-2.
This study adopted different assembly methods and manual curation to generate a partial genome sequence comprising about 86.3% of the full-length viral genome.
We cannot exclude the possibility that pangolin is one of the intermediate animal hosts of SARS-CoV-2.
However, currently there is no evidence in support of a direct pangolin origin of SARS-CoV-2 due to the sequence divergence between SARS-CoV-2 and pangolin SARS-CoV-2-related beta-CoVs.
In addition, the distance between SARS-CoV-2 and RaTG13 is even shorter than that between SARS-CoV-2 and pangolin SARS-CoV-2-related beta-CoVs.
The evolutionary pathway of SARS-CoV-2 in bats, pangolins and other mammals remains to be established.
Whereas the highest sequence homology has been found in the RBDs between SARS-CoV-2 and pangolin, SARS-CoV-2-related beta-CoVs, SARS-CoV-2 and RaTG13 share the highest genome-wide sequence homology.
It is highly speculative that the high degree of similarity between the RBDs of pangolin SARS-CoV-2-related beta-CoVs and SARS-CoV-2 is driven by selectivity-mediated convergent evolution.
A counter-proposal is in favour of a recombination between a pangolin SARS-CoV-2-related beta-CoV and RaTG13 in the third wild animal species.
As a driving force in evolution, recombination is widespread among beta-CoVs.
The jury is still out on the immediate zoonotic origin of SARS-CoV-2.
Besides the highly pathogenic HCoVs, the zoonotic origin of HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 have also been studied.
Phylogenetic evidence indicated that both HCoV-NL63 and HCoV-229E might have originated from bat CoVs, while the parental viruses of HCoV-OC43 and HCoV-HKU1 have been found in rodents.
It has been reported that a bat CoV termed ARCoV.2 (Appalachian Ridge CoV) detected in North American tricolored bat displayed close relationship with HCoV-NL63.
On the other hand, HCoV-229E was genetically related to another bat CoV, termed Hipposideros/GhanaKwam/19/2008, which was detected in Ghana, while camelids have also been suspected as its intermediate host.
For clarity, the current knowledge on animal origins of known HCoVs is summarized in Figure ​1 and Table 2.
Phylogenetic analysis has provided evidence for interspecies transmission events of HCoVs in the history.
When HCoV-OC43 crossed species to infect humans from domestic livestock around 1890, a pandemic of respiratory infection was recorded.
The interspecies transmission history of HCoV-229E is less clear.
Bat alpha-CoVs closely related to HCoV-229E have been found.
Between them there is an alpaca alpha-CoV.
Several lines of evidence support the transmission of virus from bats to humans directly.
First, humans but not alpacas might have contact with bats in a shared ecological niche.
Instead, humans have close contact with alpacas.
Second, HCoV-229E-related bat alpha-CoVs are diverse and non-pathogenic in bats, whereas alpaca alpha-CoV caused an outbreak of respiratory disease in infected animals.
Finally, alpaca alpha-CoV has not been found in feral animals.
Thus, the possibility cannot be excluded that alpacas obtain the HCoV-229E-related alpha-CoV from humans.
In fact, bats are the direct source of human pathogenic viruses including rabies virus, Ebola virus, Nipah virus and Hendra virus.
It is therefore not too surprising that bats might transmit HCoV-229E to humans directly.
Alternatively, whereas bat alpha-CoVs serve as the gene pool of HCoV-229E, alpacas and dromedary camels might serve as intermediate hosts that transmit viruses to humans, exactly as in the case of MERS-CoV.
MERS-CoV serves as an excellent example of interspecies transmission from bats to dromedary camels and from dromedary camels to humans.
The evolutionary origin of MERS-CoV from bats is known at its initial identification and has also been strengthened by subsequent findings.
It is obvious that bats provide a rich pool of virus species for interspecies exchange of genetic fragments and interspecies transmission.
Longevity, densely packed colonies, close social interaction and strong ability to fly are all favourable conditions for bats to be an ideal 'virus spreader'.
On the other hand, MERS-CoV has been introduced to dromedary camels for decades.
It is well adapted to these camels that have turned from an intermediate host to a stable and natural reservoir host.
MERS-CoV causes very mild disease and maintains a relatively low mutation rate in these animals.
Its sporadic transmission to humans is an accident and humans remain a dead-end host of MERS-CoV as its transmission cannot be sustained.
In contrast to the role of camels in the transmission of MERS-CoV, the role of pangolins, if there is any, in the transmission of SARS-CoV-2 is different.
Particularly, pangolin beta-CoVs are highly pathogenic in pangolins.
They might be a dead-end host for SARS-CoV-2-related beta-CoVs, similar to civets in the case of SARS-CoV.
Several possibilities for interspecies transmission of SARS-CoV-2 from animals to humans have to be ruled in or ruled out in future studies.
First, bats could be the reservoir host of a SARS-CoV-2-related virus almost identical to SARS-CoV-2.
Humans might share the ecological niche with bats through butchering or coal mining.
Second, pangolins could be one of intermediate amplifying host to which a SARS-CoV-2-related virus had been newly introduced.
Humans contract the virus through butchering and consumption of game meat.
It is possible that many mammals including domestic animals are susceptible to SARS-CoV-2.
A survey of domestic and wild animals for antibodies is warranted.
Third, as mentioned above, recombination and adaptation of SARS-CoV-2 might have occurred in a third species that has contact with both bats and pangolins.
The search for the animal origins of SARS-CoV-2 is still on.
Apart from different types of the animal hosts, three major factors on the viral side are also important in facilitating CoVs to cross species barriers.
First of all, their relatively high mutation rates in RNA replication.
In comparison to other single-stranded RNA viruses, the estimated mutation rates of CoVs could be regarded as “moderate” to “high” with an average substitution rate being ~10-4 substitution per year per site 2, depending on the phase of CoV adaptation to novel hosts.
CoVs have a proof-reading exoribonuclease, deletion of which results in exceedingly high mutability and attenuation or even inviability.
Interestingly, the nucleotide analogue Remdesivir is known to suppress CoV replication through inhibition of this exoribonuclease and the RNA-dependent RNA polymerase.
Remdesivir is one of most promising anti-SARS-CoV-2 agents to be tested in clinical trials.
Nevertheless, mutation rates of CoVs are about a million times higher than those of their hosts.
In addition, mutation rate is often high when CoVs are not well adapted to the host.
Compared to SARS-CoV with a high mutation rate, the mutation rate of SARS-CoV-2 is apparently lower, suggestive of a higher level of adaptation to humans.
Presumably, it has already been adapted to another host close to humans.
In addition to SARS-CoV-2, this also applies to MERS-CoV, which is well adapted to dromedary camels.
Theoretically, it is unlikely that genetic drift would render vaccines and antivirals against SARS-CoV-2 ineffective quickly.
Second, the large RNA genome in CoVs exerts extra plasticity in genome modification for mutations and recombination, thereby increasing the probability for interspecies co-evolution, which is advantageous for the emergence of novel CoVs when the conditions become appropriate.
This is supported by the copious unique open reading frames and protein functions encoded towards the 3′ end of the genome.
Third, CoVs randomly and frequently switch templates during RNA replication through a unique “copy-choice” mechanism.
In a host that serves as the mixing vessel, strand switching occurs frequently during CoV RNA transcription.
Highly homologous full-length and subgenomic RNAs could recombine to generate new CoVs.
Phylogenetic evidence of natural recombination has been found in both HCoV-HKU1 and HCoV-OC43, as well as animal CoVs such as bat SL-CoV and batCoV-HKU9.
Virus-host interaction in relation to transmission
Besides three viral factors stated above, viral interaction with host receptor is another key factor influential on interspecies transmission.
Herein, recombination of SARS-CoV is taken as a typical example, which also showed evidence of positive selection during interspecies transmission events.
Based on the comparative analysis between isolates of human and civet SARS-CoVs, SARS-CoV is thought to undergo rapid adaptation in different hosts, particularly with mutations at the RBD of the S protein.
Generally, the RBD in the S protein of a CoV interacts with the cellular receptor and is intensely selected by the host antibody response.
In SARS-CoV, the RBD is in the 318th to 510th amino acids on the S1 fragment, which binds to the human ACE2 as well as its coreceptors for viral entry.
The RBD of SARS-CoV is capable of recognizing the ACE2 receptors of various animals, including bat, civet, mouse and raccoon dog, allowing interspecies transmission of the virus.
In fact, only 6 amino acid residues were observed to be different from human and civet viral isolates in the RBD and 4 of them locate in the receptor-binding motif for interaction with the ACE2 receptor.
Civet SARS-CoV has K479N and S487T mutations in its RBD, which might increase the affinity of the interaction of spike protein with human ACE2 receptor.
In other words, these two amino acid substitutions might be critical to viral adaption to humans.
It is noteworthy that SARS-CoV-2 shares the same cellular receptor with SARS-CoV.
A 30% difference between SARS-CoV-2 and SARS-CoV in the S1 unit of the S protein implicates that the binding affinity of its S protein with human ACE2 might have altered.
Indeed, a cryo-EM study indicates a 10- to 20-fold higher affinity of this binding than that between human ACE2 and SARS-CoV S protein.
It will also be of interest to determine whether any other coreceptor might be required for SARS-CoV-2 transmission.
Intriguingly, HCoV-NL63 also binds to ACE2 but with a different part of S.
There exist many other HCoV receptors, such as aminopeptidase N for HCoV-229E, and 9-O-acetylated sialic acid for HCoV-OC43.
They might also account for successful adaptation of these CoVs in humans after interspecies transmission from their animal hosts.
In addition to cellular receptors, the outcome of interspecies transmission of HCoVs is also governed by other host dependency and restriction factors.
The divergence of these host proteins between humans and natural reservoir hosts of HCoVs such as bats, dromedary camels and rodents might constitute a barrier to interspecies transmission.
HCoVs have to usurp host dependency factors and subvert host restriction factors for a successful interspecies transmission.
In this regard, molecular determinants in this important area of virus-host interaction remain to be identified and characterized.
An unbiased genome-wide screening of host dependency and restriction factors for SARS-CoV-2 using the state-of-the-art technology of CRISPR might be fruitful.
Emergence of novel HCoVs: back to ground zero
The diversity of bat CoVs provides ample opportunities for the emergence of novel HCoVs.
In this sense, bat CoVs serve as the gene pool of HCoVs.
In addition, rapid mutation and genetic recombination also drive HCoV evolution and serve as two important steps in this process.
For example, the acquisition or loss of novel protein-coding genes has the potential to drastically modify viral phenotypes.
Among SARS-CoV accessory proteins, ORF8 has been thought to be important in adaptation to humans, as SARS-CoV-related bat viruses were isolated but found to encode divergent ORF8 proteins.
A 29-nucleotide deletion characteristic of SARS-CoVs has been found in strains isolated at the beginning of the human epidemic.
This deletion splits ORF8 into ORF8a and ORF8b and is thought to be an adaptive mutation that promotes the switch of hosts.
Besides, SARS-CoV has a possible recombination history with lineages of alpha- and gamma-CoVs, where a large number of smaller recombinant regions were identified in the RNA-dependent RNA polymerase.
Recombination locations were also identified in the nsp9, most of nsp10, and parts of nsp14.
Likewise, it has been shown that the epidemic MERS-CoV experienced recombination events between different lineages, which occurred in dromedary camels in Saudi Arabia.
Besides SARS-CoV and MERS-CoV, recombination events have also been observed in other HCoVs, in which the HCoVs recombine with other animal CoVs in their non-structural genes.
It should also be cautioned that artificial selection can contribute to unintended changes in viral genomes, most likely resulting from relieving viruses from selection pressures exerted, such as by the host immune system.
An example of these effects is the loss of a full-length ORF4 in the HCoV-229E prototype strain, owing to a two-nucleotide deletion.
While intact ORF4 could be observed in bat and camel viruses related to HCoV-229E, the alpaca alpha-CoV displays a single nucleotide insertion, resulting in a frameshift.
Last but not least, the evolution of novel HCoVs is also driven by the selection pressure in their reservoir hosts.
Asymptomatic or only mild symptoms were detected when bats were infected with CoVs, indicating the mutual adaptation between CoVs and bats.
It appeared that bats are well adapted to CoVs anatomically and physiologically.
For example, defects in the activation of pro-inflammatory response in bats efficiently reduce the pathology triggered by CoVs.
Besides, the natural killer cell activity in bats is suppressed due to upregulation of inhibitory natural killer cell receptor NKG2/CD94 and low expression level of major histocompatibility complex class I molecules.
Moreover, the high level of reactive oxygen species (ROS) generated from high metabolic activity of bats could both suppress CoV replication and affects proofreading by exoribonuclease, thus providing the selection pressure for the generation of virus strains highly pathogenic when introduced into a new host.
More pathogenic CoV strains might also evolve by recombination, leading to the acquisition of novel proteins or protein features for host adaptation.
Thus, it is not by chance that three novel HCoVs have emerged in the past two decades.
CoVs are non-pathogenic or cause mild symptoms in their reservoir hosts such as bats and camels.
They replicate robustly without eliciting a strong host immune response.
Herein lie the secrets of why asymptomatic carriers are seen and what causes the severe cases in human infection.
The severe symptoms are mainly due to the hyperactivation of immune response and the cytokine storm wherein the stronger the immune response, the more severe the lung damage.
In contrast, in asymptomatic carriers, the immune response has been de-coupled from CoV replication.
The same strategy of delinking the immune response might have beneficial effects in anti-SARS-CoV-2 therapy.
The interferon response is particularly strong in bats.
Thus, administration of type I interferon at least in the early phase of SARS-CoV-2 infection in humans should be beneficial.
In addition, NLRP3 inflammasome activation in bats is defective.
By this reasoning, inhibition of NLRP3 inflammasome with MCC950 might be useful in the treatment of COVID-19.
The emergence of SARS-CoV-2 follows the general theme by which SARS-CoV and MERS-CoV arose.
Whereas a bat beta-CoV sharing 95% nucleotide homology with SARS-CoV has been found, there also exists a bat-CoV sharing 96% nucleotide homology with SARS-CoV-2.
Whereas civets and other animals in the markets have been found to harbour viruses identical to SARS-CoV, immediate intermediate hosts for SARS-CoV-2 have not been identified.
Pangolin beta-CoVs strikingly homologous to SARS-CoV-2 have been found, indicating that pangolins might serve as one of intermediate hosts or pangolin beta-CoVs could contribute gene fragments to the final version of SARS-CoV-2.
Although questions remain, there is no evidence that SARS-CoV-2 is man-made either deliberately or accidentally.
CoVs have returned to the limelight due to the recent outbreak of SARS-CoV-2.
The study of CoVs in bats and other animals has drastically changed our perception of the importance of zoonotic origins and animal reservoirs of HCoVs in human transmission.
Pervasive evidence has shown that SARS-CoV, MERS-CoV and SARS-CoV-2 have a bat origin and are transmitted to humans via intermediate hosts.
Given that SARS-CoV infection originates from the contact between humans and civets in the markets, closing wet markets and killing civets therein could have effectively ended the SARS epidemic.
By the same reasoning, pangolins should be removed from wet markets to prevent zoonotic transmission, in view of the discovery of multiple lineages of pangolin beta-CoVs closely related to SARS-CoV-2.
However, whether and how SARS-CoV-2 is transmitted to humans through pangolins and other mammals remain to be clarified in future investigations.
On the other hand, MERS-CoV has existed in dromedary camels for a long time.
These camels serve as an important tool for transportation as well as a main source of meat, milk, leather and wool products for the local people.
They are widely distributed across the Middle East and Africa.
It is therefore impossible to sacrifice all camels for the control of MERS, as what was done in wild animal markets in China to prevent the spreading of SARS-CoV and SARS-CoV-2.
To stop the recurrent outbreaks of MERS, a comprehensive approach should be taken to develop effective vaccines against MERS-CoV for camels, in combination with other infection control measures.
As we are not able to eliminate these viruses, new genotypes might emerge to cause outbreaks.
A variety of zoonotic CoVs are circulating in the wild.
Particularly, bat CoVs with zoonotic potential are so diverse.
There are plenty of opportunities that these zoonotic CoVs evolve and recombine, resulting in the emergence of new CoVs that are more transmissible and/or deadly in humans in future.
The culture of eating wild animals in some places of China should be abandoned to reduce unnecessary contact between humans and animals.
With the ordeals of SARS, MERS and COVID-19, a better preparedness and response plan should be in place.
In fact, many viruses have existed in the planet for a very long time.
They stay in their own natural reservoirs until there is a chance for spillover.
Although bats have many features that favours the spreading of viruses, the chance for humans to be in contact with bats and other wildlife species can be minimized if people are educated to stay away from them.
Continuous surveillance in mammals is necessary for better understanding of the ecology of CoVs and their natural hosts, which will prove useful in preventing animal-to-human transmission and future outbreaks.
To conclude, the most effective way to prevent viral zoonosis is for humans to stay away from the ecological niches of the natural reservoirs of the zoonotic viruses.
Several pieces in the puzzle of the zoonotic origin of SARS-CoV-2 are still missing.
First, if bats transmit an ancestral virus of SARS-CoV-2 to pangolins, it will be of interest to see under what circumstances bats and pangolins could share the same ecological niche.
Second, if bats play a more direct role in human transmission, how humans get into contact with bats should be determined.
Third, if a third mammal acts as the true intermediate host, how it interacts with the different species including humans, bats and pangolins has to be clarified.
Finally, since many mammals including domestic animals might be susceptible to SARS-CoV-2, both surveillance and experimental infection should be conducted.
Should it be a bat, a pangolin or another mammal, it is expected that SARS-CoV-2 or its parental viruses that are almost identical will be identified in its natural hosts in future.
Continued investigations in this area will elucidate the evolutionary pathway of SARS-CoV-2 in animals, with important implications in the prevention and control of COVID-19 in humans.
Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020
On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic.
As of March 28, 2020, a total of 571,678 confirmed COVID-19 cases and 26,494 deaths have been reported worldwide.
Reports from China and Italy suggest that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions.
U.S. older adults, including those aged ≥65 years and particularly those aged ≥85 years, also appear to be at higher risk for severe COVID-19–associated outcomes; however, data describing underlying health conditions among U.S. COVID-19 patients have not yet been reported.
As of March 28, 2020, U.S. states and territories have reported 122,653 U.S. COVID-19 cases to CDC, including 7,162 (5.8%) for whom data on underlying health conditions and other known risk factors for severe outcomes from respiratory infections were reported.
Among these 7,162 cases, 2,692 (37.6%) patients had one or more underlying health condition or risk factor, and 4,470 (62.4%) had none of these conditions reported.
The percentage of COVID-19 patients with at least one underlying health condition or risk factor was higher among those requiring intensive care unit (ICU) admission (358 of 457, 78%) and those requiring hospitalization without ICU admission (732 of 1,037, 71%) than that among those who were not hospitalized (1,388 of 5,143, 27%).
The most commonly reported conditions were diabetes mellitus, chronic lung disease, and cardiovascular disease.
These preliminary findings suggest that in the United States, persons with underlying health conditions or other recognized risk factors for severe outcomes from respiratory infections appear to be at a higher risk for severe disease from COVID-19 than are persons without these conditions.
Data from laboratory-confirmed COVID-19 cases reported to CDC from 50 states, four U.S. territories and affiliated islands, the District of Columbia, and New York City with February 12–March 28, 2020 onset dates were analyzed.
Cases among persons repatriated to the United States from Wuhan, China, and the Diamond Princess cruise ship were excluded.
For cases with missing onset dates, date of onset was estimated by subtracting 4 days (median interval from symptom onset to specimen collection date among cases with known dates in these data) from the earliest specimen collection.
Public health departments reported cases to CDC using a standardized case report form that captures information (yes, no, or unknown) on the following conditions and potential risk factors: chronic lung disease (inclusive of asthma, chronic obstructive pulmonary disease [COPD], and emphysema); diabetes mellitus; cardiovascular disease; chronic renal disease; chronic liver disease; immunocompromised condition; neurologic disorder, neurodevelopmental, or intellectual disability; pregnancy; current smoking status; former smoking status; or other chronic disease.
Data reported to CDC are preliminary and can be updated by health departments over time; critical data elements might be missing at the time of initial report; thus, this analysis is descriptive, and no statistical comparisons could be made.
The percentages of patients of all ages with underlying health conditions who were not hospitalized, hospitalized without ICU admission, and hospitalized with ICU admission were calculated.
Percentages of hospitalizations with and without ICU admission were estimated for persons aged ≥19 years with and without underlying health conditions.
This part of the analysis was limited to persons aged ≥19 years because of the small sample size of cases in children with reported underlying health conditions (N = 32).
To account for missing data among these preliminary reports, ranges were estimated with a lower bound including cases with both known and unknown status for hospitalization with and without ICU admission as the denominator and an upper bound using only cases with known outcome status as the denominator.
Because of small sample size and missing data on underlying health conditions among COVID-19 patients who died, case-fatality rates for persons with and without underlying conditions were not estimated.
As of March 28, 2020, a total of 122,653 laboratory-confirmed COVID-19 cases (Figure) and 2,112 deaths were reported to CDC.
Case report forms were submitted to CDC for 74,439 (60.7%) cases.
Data on presence or absence of underlying health conditions and other recognized risk factors for severe outcomes from respiratory infections (i.e., smoking and pregnancy) were available for 7,162 (5.8%) patients (Table 1).
Approximately one third of these patients (2,692, 37.6%), had at least one underlying condition or risk factor.
Diabetes mellitus (784, 10.9%), chronic lung disease (656, 9.2%), and cardiovascular disease (647, 9.0%) were the most frequently reported conditions among all cases.
Among 457 ICU admissions and 1,037 non-ICU hospitalizations, 358 (78%) and 732 (71%), respectively occurred among persons with one or more reported underlying health condition.
In contrast, 1,388 of 5,143 (27%) COVID-19 patients who were not hospitalized were reported to have at least one underlying health condition.
Among patients aged ≥19 years, the percentage of non-ICU hospitalizations was higher among those with underlying health conditions (27.3%–29.8%) than among those without underlying health conditions (7.2%–7.8%); the percentage of cases that resulted in an ICU admission was also higher for those with underlying health conditions (13.3%–14.5%) than those without these conditions (2.2%–2.4%) (Table 2).
Small numbers of COVID-19 patients aged & lt; 19 years were reported to be hospitalized (48) or admitted to an ICU (eight).
In contrast, 335 patients aged & lt; 19 years were not hospitalized and 1,342 had missing data on hospitalization.
Among all COVID-19 patients with complete information on underlying conditions or risk factors, 184 deaths occurred (all among patients aged ≥19 years); 173 deaths (94%) were reported among patients with at least one underlying condition.
Among 122,653 U.S. COVID-19 cases reported to CDC as of March 28, 2020, 7,162 (5.8%) patients had data available pertaining to underlying health conditions or potential risk factors; among these patients, higher percentages of patients with underlying conditions were admitted to the hospital and to an ICU than patients without reported underlying conditions.
These results are consistent with findings from China and Italy, which suggest that patients with underlying health conditions and risk factors, including, but not limited to, diabetes mellitus, hypertension, COPD, coronary artery disease, cerebrovascular disease, chronic renal disease, and smoking, might be at higher risk for severe disease or death from COVID-19.
This analysis was limited by small numbers and missing data because of the burden placed on reporting health departments with rapidly rising case counts, and these findings might change as additional data become available.
It is not yet known whether the severity or level of control of underlying health conditions affects the risk for severe disease associated with COVID-19.
Many of these underlying health conditions are common in the United States: based on self-reported 2018 data, the prevalence of diagnosed diabetes among U.S. adults was 10.1%, and the U.S. age-adjusted prevalence of all types of heart disease (excluding hypertension without other heart disease) was 10.6% in 2017.
The age-adjusted prevalence of COPD among U.S. adults is 5.9%, and in 2018, the U.S. estimated prevalence of current asthma among persons of all ages was 7.9%.
CDC continues to develop and update resources for persons with underlying health conditions to reduce the risk of acquiring COVID-19.
The estimated higher prevalence of these conditions among those in this early group of U.S. COVID-19 patients and the potentially higher risk for more severe disease from COVID-19 associated with the presence of underlying conditions highlight the importance of COVID-19 prevention in persons with underlying conditions.
The findings in this report are subject to at least six limitations.
First, these data are preliminary, and the analysis was limited by missing data related to the health department reporting burden associated with rapidly rising case counts and delays in completion of information requiring medical chart review; these findings might change as additional data become available.
Information on underlying conditions was only available for 7,162 (5.8%) of 122,653 cases reported to CDC.
It cannot be assumed that those with missing information are similar to those with data on either hospitalizations or underlying health conditions.
Second, these data are subject to bias in outcome ascertainment because of short follow-up time.
Some outcomes might be underestimated, and long-term outcomes cannot be assessed in this analysis.
Third, because of the limited availability of testing in many jurisdictions during this period, this analysis is likely biased toward more severe cases, and findings might change as testing becomes more widespread.
Fourth, because of the descriptive nature of these data, attack rates among persons with and without underlying health conditions could not be compared, and thus the risk difference of severe disease with COVID-19 between these groups could not be estimated.
Fifth, no conclusions could be drawn about underlying conditions that were not included in the case report form or about different conditions that were reported in a single, umbrella category.
For example, asthma and COPD were included in a chronic lung disease category.
Finally, for some underlying health conditions and risk factors, including neurologic disorders, chronic liver disease, being a current smoker, and pregnancy, few severe outcomes were reported; therefore, conclusions cannot be drawn about the risk for severe COVID-19 among persons in these groups.
Persons in the United States with underlying health conditions appear to be at higher risk for more severe COVID-19, consistent with findings from other countries.
Persons with underlying health conditions who have symptoms of COVID-19, including fever, cough, or shortness of breath, should immediately contact their health care provider.
These persons should take steps to protect themselves from COVID-19, through washing their hands; cleaning and disinfecting high-touch surfaces; and social distancing, including staying at home, avoiding crowds, gatherings, and travel, and avoiding contact with persons who are ill.
Maintaining at least a 30-day supply of medication, a 2-week supply of food and other necessities, and knowledge of COVID-19 symptoms are recommended for those with underlying health conditions.
All persons should take steps to protect themselves from COVID-19 and to protect others.
All persons who are ill should stay home, except to get medical care; should not go to work; and should stay away from others.
This is especially important for those who work with persons with underlying conditions or who otherwise are at high risk for severe outcomes from COVID-19.
Community mitigation strategies, which aim to slow the spread of COVID-19, are important to protect all persons from COVID-19, especially persons with underlying health conditions and other persons at risk for severe COVID-19–associated disease (https://www.cdc.gov/coronavirus/2019-ncov/downloads/community-mitigation-strategy.pdf).
What is already known about this topic?
Published reports from China and Italy suggest that risk factors for severe COVID-19 disease include underlying health conditions, but data describing underlying health conditions among U.S. COVID-19 patients have not yet been reported.
What is added by this report?
Based on preliminary U.S. data, persons with underlying health conditions such as diabetes mellitus, chronic lung disease, and cardiovascular disease, appear to be at higher risk for severe COVID-19–associated disease than persons without these conditions.
What are the implications for public health practice?
Strategies to protect all persons and especially those with underlying health conditions, including social distancing and handwashing, should be implemented by all communities and all persons to help slow the spread of COVID-19.
Emergence of a Novel Coronavirus (COVID-19): Protocol for Extending Surveillance Used by the Royal College of General Practitioners Research and Surveillance Centre and Public Health England
The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) and Public Health England (PHE) have successfully worked together on the surveillance of influenza and other infectious diseases for over 50 years, including three previous pandemics.
With the emergence of the international outbreak of the coronavirus infection (COVID-19), a UK national approach to containment has been established to test people suspected of exposure to COVID-19.
At the same time and separately, the RCGP RSC’s surveillance has been extended to monitor the temporal and geographical distribution of COVID-19 infection in the community as well as assess the effectiveness of the containment strategy.
The aims of this study are to surveil COVID-19 in both asymptomatic populations and ambulatory cases with respiratory infections, ascertain both the rate and pattern of COVID-19 spread, and assess the effectiveness of the containment policy.
The RCGP RSC, a network of over 500 general practices in England, extract pseudonymized data weekly.
This extended surveillance comprises of five components: (1) Recording in medical records of anyone suspected to have or who has been exposed to COVID-19.
Computerized medical records suppliers have within a week of request created new codes to support this.
(2) Extension of current virological surveillance and testing people with influenza-like illness or lower respiratory tract infections (LRTI)—with the caveat that people suspected to have or who have been exposed to COVID-19 should be referred to the national containment pathway and not seen in primary care.
(3) Serology sample collection across all age groups.
This will be an extra blood sample taken from people who are attending their general practice for a scheduled blood test.
The 100 general practices currently undertaking annual influenza virology surveillance will be involved in the extended virological and serological surveillance.
(4) Collecting convalescent serum samples.
We have the opportunity to escalate the data extraction to twice weekly if needed.
Swabs and sera will be analyzed in PHE reference laboratories.
General practice clinical system providers have introduced an emergency new set of clinical codes to support COVID-19 surveillance.
Additionally, practices participating in current virology surveillance are now taking samples for COVID-19 surveillance from low-risk patients presenting with LRTIs.
Within the first 2 weeks of setup of this surveillance, we have identified 3 cases: 1 through the new coding system, the other 2 through the extended virology sampling.
We have rapidly converted the established national RCGP RSC influenza surveillance system into one that can test the effectiveness of the COVID-19 containment policy.
The extended surveillance has already seen the use of new codes with 3 cases reported.
Rapid sharing of this protocol should enable scientific critique and shared learning.
The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is a network of general practices (GPs) with a nationally representative population that provides pseudonymized data for weekly surveillance of infectious diseases.
The disease surveillance program is commissioned by Public Health England (PHE) and covers 37 infectious diseases, including influenza.
The RCGP RSC and PHE have an established collaboration of over 50 years in influenza and respiratory disease surveillance and are now in their 53rd season of surveillance and analysis.
The RCGP RSC extracts pseudonymized data from a nationally representative sample of over 500 urban and nonurban GPs each week covering a population of over 4 million.
Data from these practices are reported online in a weekly return, which includes monitoring weekly rates of influenza-like illness (ILI) and other communicable and respiratory diseases in England.
We also produce an annual report.
The RCGP RSC data set includes all coded data and all prescribed items including vaccine exposure.
The RCGP RSC conducts virology surveillance each influenza season, with 100 GPs participating in the 2019-2020 season (Figure 1).
These virology sampling practices are also recruited to be nationally representative (Figure 1).
GPs take nasopharyngeal swabs from persons showing acute respiratory illness within 7 days of the onset of symptoms.
Nasopharyngeal swabs are taken from children younger than 5 years showing symptoms of acute bronchitis or bronchiolitis.
Additionally, nasopharyngeal samples are taken from anyone 5 years and older showing acute onset of ILI and respiratory synctial virus.
Swabs are tested at the PHE Respiratory Virus Unit for influenza to monitor positivity rates and circulating strains, as well as for measuring vaccine effectiveness.
The RCGP RSC successfully conducted a pilot collecting serological samples from adults and linking them to a patient’s medical records during the 2018-2019 influenza season.
This pilot was in collaboration with the PHE Seroepidemiology Unit and added to the residual blood samples submitted to PHE by National Health Service (NHS) laboratories.
Serology can provide important information about background population immunity, and sentinel networks can provide a mechanism for systematic data collection and linkage to medical records and health outcomes.
The serology pilot has demonstrated the ability of the network to collect serology samples in adults.
With the COVID-19 outbreak, PHE and RCGP RSC have adapted existing influenza surveillance to monitor the spread of COVID-19 in the community, and this protocol sets out the basis for that collaboration.
The primary national strategy for COVID-19 infection is containment, with patients who are at high risk managed via the telephone help system NHS111 and the PHE health protection teams, but the RCGP RSC surveillance is entirely separate.
The RCGP RSC, by extending its established work, will provide virological and serological surveillance to monitor the temporal and geographical distribution of COVID-19 infection in the community, and assess the effectiveness of the containment strategy.
We would not be working in isolation on this research.
We will share the protocol with UK colleagues and the I-MOVE consortium who have recently obtained EU Horizon 2020 funding from the stream “Advancing knowledge for the clinical and public health response to the novel coronavirus epidemic”.
It is anticipated that great efficiencies in project management will result through this collaboration than that obtained from countries acting alone.
The aim of this study is to identify whether there is undetected community transmission of COVID-19, estimate population susceptibility, and monitor the temporal and geographical distribution of COVID-19 infection in the community.
The objectives of this study are as follows:
To monitor the burden of suspected COVID-19 activity in the community through primary care surveillance and clinical coding of possible COVID-19 cases referred into the containment pathway
To provide virological evidence on the presence and extent of undetected community transmission of COVID-19 and monitor positivity rates among individuals presenting ILI or acute respiratory tract infections to primary care
To estimate baseline susceptibility to COVID-19 in the community and estimate both symptomatic and asymptomatic exposure rates in the population through seroprevalence monitoring
To pilot implementation of a scheme for collection of convalescent sera with antibody profiles among recovered cases of COVID-19 discharged to the community
We intend to capture the following.
Clinical workload related to reports of COVID-19 using the codes created to flag cases, those being assessed and where the infection is located are excluded (Figures 2-​-44)
Foreign countries visited in the last 28 days
Existing codes that may have utility (Tables 1-​-3).3).
Many GPs and primary care teams may not realize that important relevant data can be coded.
There is also the potential during any pandemic to monitor the effectiveness of any transmission control measures.
Reliable coding of letters and test results that will show an infection has become either confirmed or excluded
The methods will follow the approach used in the current influenza surveillance system and recent serology study, and includes five components: (1) primary care clinical surveillance; (2) virological surveillance; (3) population serological surveillance; (4) convalescent sera in cases; and (5) data curation.
The NHS uses the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) system of coding, which is normally only updated twice annually.
There was added complexity as some computerized medical record (CMR) suppliers use the Read coding systems (Read clinical terms version 3 – CTv3), which is no longer updated.
Additionally, there were no clinical codes to record COVID-19 in early February 2020.
Therefore, the two main GP system suppliers added the five terms shown in Table 4 as system-wide local codes.
A UK emergency release of SNOMED CT concepts for COVID-19 was also subsequently made available across all CMR systems (Table 4).
The intention is that these will eventually be mapped to the new SNOMED CT concepts as they become available, allowing recording of relevant data (Multimedia Appendix 1).
The key requirements for this release were the ability to code (Table 4) a case of COVID-19, exposure to risk of infection (travel to an area where there may be a higher risk), contact with anyone infected with COVID-19, a report that a person had been tested for COVID-19, and that the disease had been excluded (likely a negative test).
In addition, practices are now able to code any foreign travel undertaken, including the ability to record visits to multiple countries (implemented February 8, 2020).
Figures 2-​-44 show the EMIS web implementation.
Currently, virology samples for influenza surveillance are accompanied by a standard request form.
For COVID-19, we will create a new request form that will record:
Date of onset of symptoms
Diagnosis of any of the following:
Acute bronchitis/bronchiolitis in those younger than five years
Lower respiratory tract infection (LRTI)
History of fever (Y/N); measured (Y/N); if yes, level
Shortness of breath (Y/N), if measured: oxygen saturation and respiratory rate
Recent travel (Y/N); if yes, countries visited in last 14 days
Contact with a named person with confirmed COVID-19 (Y/N) with a free text comment about the level of certainty
These codes will be grouped ontologically into “definite”, “probable”, “possible”, and “not a case” using our standard approach to grouping codes (Table 5), which has been used previously across disease areas.
The RCGP RSC definition for ILI is shown in Multimedia Appendix 2.
Public Presentation of Data Using an Observatory and Dashboards
We will develop an observatory to present data nationally and a dashboard for feedback to practices about their data quality and collection of virology and serology samples.
This is based on coding described in Table 4.
Definite case will be presented on our dashboard as “cases” of COVID-19.
Possible cases will be presented as “Under investigation” (investigating).
“Not a case” will be presented as “Excluded”.
Online data has been established within the initial few weeks in the COVID-19 Observatory (Figure 5), indicating the overall number of patients and rate per 10,000 patients of cases confirmed or under investigation, as well as where the virus is excluded.
We have the option to move to twice weekly surveillance reports with a scope to change this to daily reporting.
We will continue virology sampling from our sentinel practices, rather than discontinuing as seasonal influenza declines.
Additionally, we will recruit more surveillance practices.
The RCGP RSC virology practices will aim to undertake 200-300 nasopharyngeal swabs per week across the RCGP RSC sentinel network, collecting specimens across all age bands.
In addition to the inclusion criteria for influenza virology surveillance (ILI, acute bronchitis/bronchiolitis), participating practices will take nasopharyngeal swab samples from any people showing acute symptoms of LRTI if the onset of symptoms is within 7 days.
RCGP RSC research officers and practice liaison staff will manage practices to achieve a total national sample of 200-300 swabs per week.
This could be increased if PHE modelers require more samples.
Samples from each practice would be spread across the following age groups: & lt; 5 years, 5-17 years, 18-64 years, and 65 years and older
Samples (swabs or serum) collected will be sent via prepaid envelopes addressed to the appropriate PHE laboratory for analysis.
All samples collected will be tested for the presence of influenza and COVID-19.
Additionally, PHE will retrospectively test any influenza virology samples collected between early and mid-February 2020 for COVID-19.
Practices will still follow the PHE protocol for COVID-19 with respect to people at risk of infection who should be signposted down the containment pathway, rather than physically attend their practice.
Direct testing of those who attend surgery remains permitted, but we have also rolled out self-swabbing at home.
Summary of processes are detailed in Multimedia Appendix 3.
Everyone with an ILI or a respiratory illness who contacts a GP (eg, phones for an appointment) should be asked specifically about recent travel to China and other countries flagged in current PHE advice, or if they have had contact with other people with COVID-19.
If these screening enquiries are positive, the patient would be advised to not come to the practice but instead to follow the PHE flow sheet.
This can be by a reception or clinician staff, depending on individual practice protocol.
These calls should be coded into the GP CMR system and can be reported as part of the RCGP RSC weekly return.
We have developed training material to support this coding (Multimedia Appendix 4).
These include prompt cards for:
Practice reception or triage staff: for coding of any patients calling the practice with symptoms of acute respiratory infection with a history of travel to important areas based on PHE advice
Administrative staff or clinicians who code: to encourage consistent coding of results for any suspected cases, including coding of negative results for exclusion
Practices participating in virology surveillance will opportunistically collect blood samples from patients coming into the practice for a routine blood test.
Patients who attend their practice for a routine blood test will be asked to provide an additional sample for serology.
We have conducted initial searches within the RCGP RSC database to look at the number of full blood count (FBC) results and overall rates in adults and children (Figures 6-​-9).9).
An FBC is one of the most common tests performed, and we hope this will give an approximate indication of overall numbers of blood tests performed.
The sampling rate, per 100,000 patients was highest for children 15-17 years of age and 60 year or older in adults, with the lowest rates in children 0-4 years of age and 18-29 years of age in adults (Figures 6-​-99).
We will provide 1000 serology baseline samples across all ages that reflect the varying rates of attendance by age.
Additionally, we will test if we can obtain these all from virology practices to enhance the yield.
A good geographical spread is important, so PHE can advise on areas where serology will most usefully be collected.
This will be followed by 800 samples monthly.
The sample will be stratified with 200 specimens for prepandemic survey (100 for monthly) in the following age groups: & lt; 5 years, 5-17 years, 18-64 years, and 65 years or older.
The younger patients, in many practices younger than 14 years, and in nearly all for children younger than 8 years will require pediatric serology surveillance.
We will develop a new request form for practices to capture recent travel and exposure to COVID-19.
We will pilot a scheme for collecting convalescent serology from people with confirmed cases and who have had an acute virology sample at the time of their infection.
This is to identify a carrier state in patients who have recovered from the virus but may continue shedding the virus.
If there are a small number of cases, this may assist in developing a test kit for patients to take to their own GP and explore its acceptability to patients.
If there are a large number of COVID-19 cases nationally, convalescent samples could be collected from RCGP RSC practices where there are confirmed cases, with the ability to link to the full medical record.
This process may include checking pseudonymized NHS numbers for positive individuals at RCGP RSC practices, checking current PHE guidance regarding considerations of infectiousness for confirmed cases, and offering the patient an appointment following the previously mentioned process.
This needs to be carefully coordinated nationally across the network and may require PHE to ensure individuals are not contacted by multiple agencies.
RCGP RSC could provide a useful structure to channel the initial contact once PHE has made a request.
The RCGP RSC practices participating in the annual influenza virology surveillance have started sampling from patients showing symptoms of a LRTI.
All samples received are being tested for influenza and COVID-19.
The RCGP RSC will explore ways to collect convalescent samples from any patients tested positive for COVID-19 through the extension of the virological surveillance.
From the start, we will be carefully curating data to ensure that it can be used for future studies.
Our clinical data will be linked to virology.
We will curate our data using the Findable, Accessible, Interoperable, Reusable principles.
To facilitate this our data set is listed with Health Data Research UK and the European Health Data Evidence Network.
The statistical methodology is in support of a policy approach to widespread disease outbreak, where so-called nonpharmaceutical interventions (NPIs) are used to respond to an emerging pandemic to produce disease suppression.
This policy aims to reduce contact rates in the population and thereby reduce transmission of the virus.
To implement this the UK government has recently articulated the desire to implement population self-isolation measures.
By targeting the reproduction number (R) (the average number of secondary cases each case generates) and aiming to reduce the R to below 1, the policy seeks to reduce case numbers to low levels or (as seen in previous outbreaks with severe acute respiratory syndrome and Ebola) to eliminate human-to-human transmission.
As the experience from the 2009 H1N1 pandemic has shown, NPIs can be a crucial component of pandemic mitigation.
Key to the focus of our study will be the estimation of peak cases in the population and continual monitoring by data collection and modelling the potential growth and emergence of subsequent peaks in new cases as social distancing measures are relaxed.
There has already been publication of important disease epidemiological measures concerning the outbreak of COVID-19 in mainland China.
A further fundamental measure in pandemic dynamics is the length of time from infection to when a person is infectious to others and the mean duration of infectiousness.
These factors, if estimated accurately, will give good predictions for the likely length of the pandemic, the final number of infected cases.
We intend to apply approximate Bayesian inference (ABC) to (possibly spatially heterogeneous) Susceptible-Exposed- Infectious-Removed (SEIR) stochastic epidemic models.
Such techniques are highly parallelizable and have been successfully applied to many fields including disease transmission modelling.
They are particularly suited to situations where likelihood functions are absent and where more traditional approaches such as Markov chain Monte Carlo are impractical.
Such an approach has been demonstrated to work effectively on the ASPREN surveillance data, a network of sentinel GPs and nurse practitioners who report deidentified information on ILIs and other conditions, where issues such as missing data and the need to model the observation process itself has been successfully addressed.
Furthermore, peaks in new cases have been estimated by distributional methods.
Estimates of the parameters of the SEIR model are tractable on large data sets because of parallelizability, and these methods have been implemented in several R libraries; we intend to use the libraries ABSEIR (deposited on GitHub: https://tinyurl.com/vqu35cj) and abctools (https://tinyurl.com/tfjavz4) to estimate epidemic measures on a weekly basis.
Since we are fitting an SIR-epidemic model in the ABC routine, we anticipate that our results will be robust against weekly case data containing relatively small counts.
For example, see for the ABC methodology applied to the Tristan da Cunha common cold data from 1967, where counts of I (number of infectious cases) and R (number of recovered cases) are in the tens at most.
Finally, in addition to the above methodology we will employ the Kaplan-Meier method with two outcomes (death and recovery) to estimate the case fatality ratio.
This approach is independent of the ABC methodology and will allow comparisons between estimates from the two modelling approaches to judge robustness of results.
RCGP RSC’s surveillance with PHE is defined as Health Protection under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002.
This has been confirmed by PHE’s Caldicott Guardian’s Office.
We do not see any increased risk to practices or practitioners taking part in this surveillance.
Infection prevention and control advice will follow extant national guidance.
Any cases identified will be managed according to the PHE/NHS guidance in force at the time, including advice for identified contacts.
However, our training will include reminders about safe handling of specimens and revision of infection control measures anticipated to be high in our practices.
It is a key part of Regulation 12 about safe care and treatment, periodically inspected by the Care Quality Commission.
Travel History and Clinical Descriptors of the COVID-19 Infections
The RCGP RSC practices have been advised on the clinical coding that has been made available for COVID-19 across all CMR systems.
This includes information on coding of clinical descriptors (Table 4) and any recent travel history.
Establishment of Extended Virology Sampling
The RCGP RSC practices participating in the annual influenza virology surveillance have started sampling from patients showing symptoms of LRTI.
All samples received are being tested for influenza and COVID-19.
This has led to initial early identification of background spread in low-risk patients.
As of March 7, 2020, the surveillance system has detected 2 cases of COVID-19 in low-risk patients with no history of travel through extended virological sampling.
This protocol describes how we have adapted a national influenza surveillance system to monitor community spread of an unexpected infection of COVID-19.
We have rapidly created and incorporated new codes to allow data recording, and are collecting data to monitor the effectiveness of containment strategies.
Through this surveillance, we intend to find out more about the epidemiology of COVID-19 in ambulatory care.
In particular, its rate of spread, both temporal and geographical.
Our testing of low-risk patients will also inform whether the containment strategy that is based on virology testing of high-risk patients and their contacts plus self-isolation is effective.
Containment should slow the spread, and there may be benefits in the management of spread from intense surveillance.
However, there may come a point at which the virus spreads more widely into the population, as has happened in Italy.
Surveillance of low-risk patients should inform when we reach this tipping point and when infection rates start to remit.
The epidemiology of COVID-19 remains emergent.
The registration-based nature of UK primary care means that we will be able to create a complete picture of the cumulative incidence and duration.
The surveillance system should be able to identify areas where COVID-19 spread is taking place that might be suitable for trials of antiviral therapy.
We could also follow up on the effectiveness or any adverse reactions to these medicines or vaccinations.
Finally, early detection of a confirmed COVID-19 case has exemplified the rapid implementation of this enhanced surveillance in the national network.
Safety of practices is our primary concern.
The RCGP RSC has operated for over 50 years and has been involved in collecting samples to monitor disease and vaccine effectiveness through the Hong Kong flu pandemic of 1968/69, the Russian flu of 1977/78, and the 2009 Swine flu pandemic.
We are not aware of any increased risk to practice staff or other patients from involvement in surveillance.
Pandemic preparedness is part of the role of the RCGP RSC.
It is plausible that enhanced coding of information from contacts with the practices in RCGP RSC will reduce the likelihood of people who may be suspected COVID-19 cases being brought to the surgery inadvertently.
Where cases are detected unexpectedly, it is probably helpful for that patient, their contacts, and the practice to know.
The impact on practices has been to close for a day, if a case is found, for deep cleaning and then reopen.
The principal limitations of our system are the number of data points.
We are collecting serology and virology data from 100 sites, which covers a small group of the population.
This has been satisfactory for monitoring influenza, but we are not certain if this is a sufficiently large sample for the COVID-19 outbreak.
Our sites (surveillance practices) are currently fixed, and it could be helpful to be able to rapidly onboard practices in regions where there are more cases.
Currently, we will be reporting weekly.
Our existing system can be enhanced to twice weekly, but maybe daily or hourly data should be our current approach.
Opportunistic sampling for serology in children younger than 10 years might be limited due to the overall reduced rate of blood tests in children.
The extended surveillance using the RCGP RSC-PHE network for the emergent COVID-19 outbreak has been established rapidly.
The model of getting the appropriate informatics to enable capture of the required data has already been a success, with data recording starting the week the codes were created.
In addition, modifying the existing surveillance system to collect population data in a parallel way has also been effective.
However, we are at present unsure as to whether the scale of this surveillance provides sufficient data to drive local containment strategies or if reporting infrequently meets the need of our information age.
Updating the diagnostic criteria of COVID-19 “suspected case” and “confirmed case” is necessary
On 6 February 2020, our team had published a rapid advice guideline for diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infection, and this guideline provided our experience and make well reference for fighting against this pandemic worldwide.
However, the coronavirus disease 2019 (COVID-19) is a new disease, our awareness and knowledge are gradually increasing based on the ongoing research findings and clinical practice experience; hence, the strategies of diagnosis and treatment are also continually updated.
In this letter, we answered one comment on our guideline and provided the newest diagnostic criteria of “suspected case” and “confirmed case” according to the latest Diagnosis and Treatment Guidelines for COVID-19 (seventh version) that issued by the National Health Committee of the People’s Republic of China.
In December 2019, the 2019 novel coronavirus (2019-nCoV) has caused an outbreak, which is now officially named as the coronavirus disease 2019 (COVID-19) and the virus has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
On 11 March 2020, WHO characterized COVID-19 as a pandemic.
In order to fight against the SARS-CoV-2 infection, our team has developed a rapid advice guideline and that has been published online in Military Medical Research on 06 February 2020.
It has attracted a great attention since published.
Note however that COVID-19 is a new disease, our awareness and knowledge is gradually increasing based on the ongoing research findings and clinical practice experience; hence, the strategies of diagnosis and treatment are also continually updated.
For instance the Diagnosis and Treatment Guidelines for COVID-19 issued by the National Health Committee of the People’s Republic of China (http://www.nhc.gov.cn/), among 16 January 2020 to 3 March 2020, has issued a total of seven editions with some contexts being substantively changed.
Now our guideline received a comment by Zhou et al., they introduced a simple scoring proposal based on their clinical experience.
Their work added new evidence for our guideline and also make valuable reference for this pandemic worldwide.
We endorse their significant work and express our thanks.
However, their work also needs update according to the latest Diagnosis and Treatment Guidelines for COVID-19 (Trial seventh version) and recently studies.
According to the seventh edition (3 March 2020), to confirm the suspected case needs to combine any one item of epidemiological history features with two items of clinical manifestations to make a comprehensive analysis, or needs to meet three items of clinical manifestations if without clear epidemiological history:
Epidemiological history: (1) a history of travel or residence in Wuhan city and surrounding areas, or other communities where COVID-19 cases had been reported in the last 14 days before symptom onset; (2) a history of contact with SARS-CoV-2 infectious cases (with positive nucleic acid test); (3) a history of contacting with patients with fever or respiratory symptoms from Wuhan city and surrounding areas, or other communities where COVID-19 had been reported in the last 14 days before symptom onset; (4) a history of contacting with cluster of confirmed cases (≥ 2 cases with fever and/or respiratory symptoms occurred within 2 weeks in small areas, such as home, office, class of school, etc).
Clinical manifestations: (1) fever and/ or respiratory symptoms; (2) with imaging features of COVID-19 infection; (3) total white blood cell counts showing normal, decreased, or reduced lymphocyte count in the early onset stage.
Diagnosing the confirmed case should base on suspected case with any one item of pathogenic or serological evidence as following: (1) real-time PCR test positive for SARS-CoV-2; (2) viral whole genome sequencing showing high homogeneity to the known novel coronaviruses; (3) positive for the specific IgM antibody and IgG antibody to SARS-CoV-2 in serum test; or a change of the SARS-CoV-2-specific IgG antibody from negative to positive, or titer rising ≥4 times in the recovery phase above that in the acute phase.
We can see that the real-time PCR test for nucleic acid in respiratory tract or blood samples was added to the second (18 January 2020) and third (22 January 2020) editions.
The pathogenic detection of blood sample was added to the fourth (27 January 2020) and fifth (8 February 2020) editions; and then the serological evidence was added to the seventh edition.
These modifications based on the researchers continued work that to search for an optimal nucleic acid detection kit for rapid diagnosis, as well as the samples from respiratory tract including blood sampling, which increased the availability of different specimens, and supported bringing the specific antibody positive result into the confirmed criteria.
Besides, there are more and more evidence that remind us to caution with the atypical symptomatic and asymptomatic patients.
Hence, the flow chart of Zhou et al. should be updated, as they classified the person without clinical symptoms as “low risk”.
The score system also needs to be verified in further clinical practice and studies.
To conclude, we hope more direct evidence coming up and call for readers to provide their comments.
For the diagnosis of “suspected case” and “confirmed case”, we suggest to trace and obey the newest guidelines of their home countries.
Our team will also timely update our guideline to offer help.
Bangladesh reports five new deaths due to COVID-19, a daily highest
Yesterday, Bangladesh has confirmed five new deaths due to COVID-19 on the day.
This is the highest number of fatalities in a day due to the virus.
As of yesterday, Bangladesh's Institute of Epidemiology, Disease Control and Research (IEDCR) reported the number of recorded infected cases included 114 active cases and 33 recovered cases who were staying home.
A total of 17 deaths have been recorded.
In an online news briefing, the director of IEDCR, Dr Meerjady Sabrina Flora, said the fatalities included four males and one female.
According to Dr Meerjady, two cases were aged above 60, two between 51 and 60, and one 41-50 years old.
She also said two of the victims were from Dhaka.
The World Health Organization (WHO) declared COVID-19 a pandemic on March 11.
A hospital official told Anadolu Agency, a local news outlet, that one of the deceased was Jalal Saifur Rahman, a director of Bengali Anti-Corruption Commission, who was cared for at the Kuwait Maitree Hospital.
On Saturday, in an online video announcement, Bangladeshi Road Transport and Bridges Minister Obaidul Quader said public transport would be shut down for longer than initially planned, until this coming Saturday.
This public transport shutdown had initially started on March 26 and was planned to end on Saturday, April 4.
Transport of essential goods -- medical, fuel and food -- was still allowed.
The first recorded incidents of COVID-19 infection in Bangladesh were on March 8, in two people who returned from Italy and also the wife of one of them.
As of March 19, these three had already recovered.
National Basketball Association suspends season due to COVID-19 concerns
On Wednesday, the United States' National Basketball Association (NBA) suspended its professional basketball season due to concerns regarding COVID-19.
The NBA's decision followed a Utah Jazz player testing positive for the COVID-19 virus.
The NBA did not release the identity of the player in question in its announcement.
They did say he was not present at Chesapeake Energy Arena in Oklahoma City, where the Utah Jazz were to play against the Oklahoma City Thunder.
" According to its press release, the NBA was ""suspending game play following the conclusion of [Wednesday's] schedule of games until further notice."" "
The Jazz's game was cancelled, as was another NBA game Wednesday between the Sacramento Kings and the New Orleans Pelicans.
Other games scheduled for Wednesday were still held, according to NBC News.
The United States' other major basketball organization, the National Collegiate Athletic Association, which runs college basketball, has cancelled its own tournament, March Madness, for both men's and women's leagues.
According to Johns Hopkins University, as of Wednesday, there were at least 1,279 confirmed cases of COVID-19 in the United States.
CNBC reported there were at least 118,381 cases worldwide.
SARS-CoV-2 surpasses one million infections worldwide
On Thursday, the total number of cases of the SARS-CoV-2 coronavirus infections surpassed one million worldwide, Johns Hopkins University data indicated.
At least 52 thousand deaths were linked to COVID-19, the disease caused by the coronavirus.
The milestone came the same day Malawi confirmed its first coronavirus infections and Zambia had its first coronavirus-related death.
North Korea claimed, as of Thursday, it was one of the few countries remaining free of coronavirus infections.
By yesterday, the World Health Organization reported 1,051,635 confirmed cases, including 79,332 cases in the twenty four hours preceding 10 a.m. Central European Time (0800 UTC) on April 4.
In the United States, over 244 thousand coronavirus cases were recorded, linking to at least 5,900 deaths.
CBS News reported, citing Johns Hopkins University data, there were over 1,000 US deaths on Wednesday caused by coronavirus infections.
Around the world, countries announced stricter measures to inhibit the disease from spreading.
On Thursday, Sergei Sobyanin, the mayor of Moscow, extended the city lockdown to May 1.
Nationally, President Vladimir Putin declared Russians would continue to be paid without going to work until April 30.
The parliament of Portugal voted to extend the national state of emergency by 15 days; the vote passed with 215 votes in favor, ten abstentions, and one vote against.
Saudi Arabia extended curfews in the holy cities of Mecca and Medina to last the entire day; previously, the curfew was only in effect between 3 p.m. and 6 a.m.
Thailand planned to implement a curfew between 10 p.m. and 4 a.m.
The governor of Ohio, Mike DeWine, announced the state had extended its stay-at-home order until May 1.
Stores in Australia lower toilet paper limits per transaction
On Sunday and Saturday evening, Australian store chains Woolworths and Coles lowered their purchase restrictions on toilet paper to two and one package per transaction in all stores on national level, respectively.
ALDI also introduced a one-pack limit, on Monday.
These limitations were posted as messages on the checkouts, and on the chains' Facebook pages.
Buyers were reportedly stocking up due to fears of COVID-19 in case people need to self-isolate.
On Wednesday, Woolworths also limited toilet paper purchases for home delivery to one pack per order.
These changes followed the previous four-pack per transaction restriction introduced by Woolworths and Coles on March 4 and 5 respectively.
" Coles, in its March 8 media release, reported that with the four-pack restriction in place, ""many stores are still selling out within an hour of delivery"", and called the demand ""unprecedented"", while ALDI, in a Facebook post on Tuesday, called it ""unexpected"". "
" Sales went up in a ""sharp increase"" last week, according to a Woolworths spokesperson. "
Costco's store in Canberra also limited the allowed amount to two packs last week.
To further alleviate the shortage, Coles ordered bigger packages from suppliers and increased delivery frequency, Woolworths ordered extra stock, while ALDI made stocks for a planned Wednesday special available early.
Russell Zimmerman, executive director of the Australian Retailers Association, said that retailers try to raise stock, but local council restrictions on the timing of truck-deliveries make it hard.
He expects rising production costs, as suppliers try to meet demand, and fewer specials.
On Tuesday, ALDI announced that following the early release of stock, some stores can't run the Wednesday special.
In a News.com.au report, Dr Gary Mortimer, retail expert from Queensland University of Technology, said the stores fill the stock every night.
He remarked toilet paper is a bulky item, leading to low quantity of stocks in numbers, and, when sold out, leaves vast shelf spaces empty, hardening the feeling of a shortage.
" ""Coles and Woolworths have a view [that] if there was plenty of stuff on the shelf, if product like toilet rolls and sanitiser could be [bought] and are there in quantities, you would probably minimise the panic"" said Russell Zimmerman per ABC News. "
Recycled toilet paper producer Who Gives a Crap said on last Wednesday they'd run out of stock.
Kimberly-Clark, which makes Kleenex Toilet Tissue, and Solaris Paper which makes Sorbent, emphasized they were working 24/7 to maintain the supply, according to the News.com.au report.
Domain.com, a real estate site, reported some property sellers offering free toilet paper to the first bidder on auctions in Melbourne, when fewer auctions were held because of buyers having time off on the long weekend of Labour Day.
The Thursday edition of NT News, a daily printed in Darwin, included an eight-page insert meant to be cut up and used as toilet paper.
The stores were originally reluctant to impose restrictions, according to a report from ABC Australia on March 3 in which they said they had no plans to introduce restrictions on the purchases.
Russell Zimmerman added that other products are also in high demand, including masks, sanitiser, dried goods, handwash and flour.
Similarly, outside of Australia, on Sunday evening online British supermarket Ocado was observed limiting purchases of Andres toilet paper to two 12-roll packs.
US President Trump declares COVID-19 national emergency
On Friday, United States President Donald Trump declared a national emergency in response to the ongoing coronavirus outbreak.
The move came two days after the World Health Organization declared the outbreak, which causes the COVID-19 disease, to be a pandemic.
The move gives the federal government access to around US$50 billion in extra funding to combat the pandemic, according to NBC News.
" The proclamation specifically said ""the COVID-19 outbreak in the United States constitutes a national emergency"" and said the national emergency began on March 1, almost two weeks before the proclamation itself. "
" The United States Department of Health and Human Services declared the outbreak a ""public health emergency"" on January 31. "
Trump did not place the Federal Emergency Management Agency (FEMA) in charge of the government's response to COVID-19, which Politico reported left some experts in disaster management disappointed.
" Politico quoted Tim Manning, formerly a deputy administrator at FEMA, as saying ""FEMA has an important role in coordinating the larger response to the crisis"" and ""[i]f there's an emergency, FEMA needs to be involved."" "
Trump made the decision under provisions of the National Emergencies Act, amongst other governing authorities.
The Trump administration also announced other efforts in response to COVID-19, including waiving the interest it collects on federal student loans and increasing U.S. strategic oil reserve oil purchases.
World Health Organization declares COVID-19 pandemic
On Wednesday, the World Health Organization (WHO) declared the ongoing outbreak of COVID-19 — the disease caused by coronavirus SARS-CoV-2 — to be a pandemic.
" Although the word ""pandemic"" only refers to how widely a disease has spread, not how dangerous specific cases are, the WHO noted the need to drive governments to action: "
" ""All countries can still change the course of this pandemic. "
" If countries detect, test, treat, isolate, trace and mobilize their people in the response,"" said Tedros Adhanom Ghebreyesus, the Director-General of the WHO. "
" ""We are deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction."" "
" According to Dr. Tom Frieden, formerly the director of the United States' Centers for Disease Control and Prevention, the pandemic is ""unprecedented."" "
" He said, in remarks published by CNN in February, ""other than influenza, no other respiratory virus has been tracked from emergence to continuous global spread."" "
" Ghebreyesus expressed a similar view, saying ""we have never before seen a pandemic sparked by a coronavirus."" "
" He continued, ""and we have never before seen a pandemic that can be controlled at the same time."" "
The new status as a pandemic follows the WHO's decision in January to declare the outbreak a public health emergency of international concern.
" The United States' National Institute of Allergy and Infectious Disease's director, Dr. Anthony Fauci, said of the outbreak, ""bottom line, it's going to get worse."" "
As of Thursday, Associated Press reported there were at least 126,000 cases of COVID-19 worldwide, resulting in over 4,600 deaths.
The 2019–20 coronavirus pandemic is an ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The outbreak was identified in Wuhan, China, in December 2019, declared to be a Public Health Emergency of International Concern on 30 January 2020, and recognized as a pandemic on 11 March 2020.
As of 10 April 2020, approximately 1.61 million cases of COVID-19 have been reported in 210 countries and territories, resulting in approximately 97,000 deaths.
About 364,000 people have recovered.
The case fatality rate has been estimated to be 4% in China, while globally ranging from 13.04% in Algeria to .08% in New Zealand.
Common symptoms include fever, cough and shortness of breath.
Complications may include pneumonia and acute respiratory distress syndrome.
The time from exposure to onset of symptoms is typically around five days, but may range from two to fourteen days.
There is no known vaccine or specific antiviral treatment.
Primary treatment is symptomatic and supportive therapy.Recommended preventive measures include hand washing, covering one's mouth when coughing, maintaining distance from other people, and monitoring and self-isolation for people who suspect they are infected.
Authorities worldwide have responded by implementing travel restrictions, quarantines, curfews, workplace hazard controls, and facility closures.
The pandemic has led to severe global socioeconomic disruption, the postponement or cancellation of sporting, religious, political and cultural events, and widespread shortages of supplies exacerbated by panic buying.
Schools and universities have closed either on a nationwide or local basis in 193 countries, affecting approximately 99.4 percent of the world's student population.
Misinformation about the virus has spread online, and there have been incidents of xenophobia and discrimination against Chinese people, other people of East and Southeast Asian descent and appearance, and others from areas with significant virus cases.
Due to reduced travel and closures of heavy industry, there has been a decrease in air pollution and carbon emissions.
Health authorities in Wuhan, China (the capital of Hubei province) reported a cluster of pneumonia cases of unknown cause on 31 December 2019, and an investigation was launched in early January 2020.
The cases mostly had links to the Huanan Seafood Wholesale Market and so the virus is thought to have a zoonotic origin.
The virus that caused the outbreak is known as SARS-CoV-2, a newly discovered virus closely related to bat coronaviruses, pangolin coronaviruses, and SARS-CoV.The earliest known person with symptoms was later discovered to have fallen ill on 1 December 2019, and that person did not have visible connections with the later wet market cluster.
Of the early cluster of cases reported in December 2019, two-thirds were found to have a link with the market.
On 13 March 2020, an unverified report from the South China Morning Post suggested that a case traced back to 17 November 2019, in a 55-year-old from Hubei province, may have been the first.On 26 February 2020, the WHO reported that, as new cases reportedly declined in China but suddenly increased in Italy, Iran, and South Korea, the number of new cases outside China had exceeded the number of new cases within China for the first time.
There may be substantial underreporting of cases, particularly among those with milder symptoms.
By 26 February, relatively few cases had been reported among youths, with those 19 and under making up 2.4% of cases worldwide.The United Kingdom's chief scientific adviser, Patrick Vallance, estimated that 60% of the British population would need to become infected before effective herd immunity could be achieved.
Cases refers to the number of people who have been tested for COVID-19, and whose test has been confirmed positive according to official protocols.
As of 23 March, no country had tested more than 3% of its population, and many countries have had official policies not to test those with only mild symptoms, such as Italy, the Netherlands, Spain, and Switzerland.
A study published on 16 March found that in China, up to 23 January, an estimated 86% of COVID-19 infections had not been detected, and that these undocumented infections were the infection source for 79% of documented cases.
A statistical analysis published 30 March estimated that numbers of infections in Italy were considerably greater than the reported cases.
The initial estimates of the basic reproduction number (R0) for COVID-19 were 1.4 to 2.4.
A study published by the US Center for Disease Control and Prevention has concluded that it may be 5.7.
Most people with COVID-19 recover.
For those who do not, the time from development of symptoms to death has been between 6 and 41 days, with the most common being 14 days.
As of 10 April 2020, approximately 97,000 deaths had been attributed to COVID-19.
In China, as of 5 February about 80% of deaths were in those over 60, and 75% had pre-existing health conditions including cardiovascular diseases and diabetes.Official tallies of deaths from the COVID-19 pandemic generally refer to dead people who tested positive for COVID according to official protocols.
The number of true fatalities from COVID-19 may be much higher, as it may not include people who die without testing - e.g. at home, in nursing homes, etc.
Partial data from Italy found that the number of excess deaths during the pandemic exceeded the official COVID death tally by a factor of 4-5x.
" A spokeswoman for the U.S. Centers for Disease Control and Prevention (CDC) acknowledged ""We know that [the stated death toll] is an underestimation"", a statement corroborated by anecdotal reports of undercounting in the U.S. Such underestimation often occurs in pandemics, such as the 2009 H1N1 swine flu epidemic.The first confirmed death was in Wuhan on 9 January 2020. "
The first death outside mainland China occurred on 1 February in the Philippines, and the first death outside Asia was in France on 14 February.
By 28 February, outside mainland China, more than a dozen deaths each were recorded in Iran, South Korea, and Italy.
By 13 March, more than forty countries and territories had reported deaths, on every continent except Antarctica.Several measures are commonly used to quantify mortality.
These numbers vary by region and over time, and are influenced by the volume of testing, healthcare system quality, treatment options, time since initial outbreak, and population characteristics such as age, sex, and overall health.The death-to-case ratio reflects the number of deaths divided by the number of diagnosed cases within a given time interval.
Based on Johns Hopkins University statistics, the global death-to-case ratio is 6.0% (97,039/1,617,204) as of 10 April 2020.
The number varies by region.
In China, estimates for the death-to-case ratio decreased from 17.3% (for those with symptom onset 1–10 January 2020) to 0.7% (for those with symptom onset after 1 February 2020).Other measures include the case fatality rate (CFR), which reflects the percent of diagnosed people who die from a disease, and the infection fatality rate (IFR), which reflects the percent of infected (diagnosed and undiagnosed) who die from a disease.
These statistics are not timebound and follow a specific population from infection through case resolution.
A number of academics have attempted to calculate these numbers for specific populations.
The University of Oxford's Centre for Evidence-Based Medicine estimates that the infection fatality rate for the pandemic as a whole is between 0.1% and 0.39%.
The upper estimate of this range is consistent with the results from the first random testing for COVID-19 in Germany, and a statistical study analysing the impact of testing on CFR estimates.
The WHO asserts that the pandemic can be controlled.
The peak and ultimate duration of the outbreak are uncertain and may differ by location.
" Maciej Boni of Penn State University stated, ""Left unchecked, infectious outbreaks typically plateau and then start to decline when the disease runs out of available hosts. "
" But it's almost impossible to make any sensible projection right now about when that will be"". "
" The Chinese government's senior medical adviser Zhong Nanshan argued that ""it could be over by June"" if all countries can be mobilized to follow the WHO's advice on measures to stop the spread of the virus. "
" On 17 March, Adam Kucharski of the London School of Hygiene & amp; Tropical Medicine stated that SARS-CoV-2 ""is going to be circulating, potentially for a year or two"". "
" According to the Imperial College study led by Neil Ferguson, physical distancing and other measures will be required ""until a vaccine becomes available (potentially 18 months or more)"". "
" William Schaffner of Vanderbilt University stated, ""I think it's unlikely that this coronavirus—because it's so readily transmissible—will disappear completely"" and it ""might turn into a seasonal disease, making a comeback every year"". "
The virulence of the comeback would depend on herd immunity and the extent of mutation.
Symptoms of COVID-19 can be relatively non-specific and infected people may be asymptomatic.
The two most common symptoms are fever (88%) and dry cough (68%).
Less common symptoms include fatigue, respiratory sputum production (phlegm), loss of the sense of smell, shortness of breath, muscle and joint pain, sore throat, headache, chills, vomiting, hemoptysis, diarrhea, or cyanosis.The WHO states that approximately one person in six becomes seriously ill and has difficulty breathing.
The U.S. Centers for Disease Control and Prevention (CDC) lists emergency symptoms as difficulty breathing, persistent chest pain or pressure, sudden confusion, difficulty waking, and bluish face or lips; immediate medical attention is advised if these symptoms are present.Further development of the disease can lead to severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock and death.
Some of those infected may be asymptomatic, with no clinical symptoms but with test results that confirm infection, so researchers have issued advice that those with close contact to confirmed infected people should be closely monitored and examined to rule out infection.
Chinese estimates of the asymptomatic ratio range from few to 44%.
The usual incubation period (the time between infection and symptom onset) ranges from one to 14 days; it is most commonly five days.As an example of uncertainty, the estimate of the fraction of people with COVID-19 who lost their sense of smell was initially 30% and later fell to 15%.
Some details about how the disease is spread are still being determined.
The disease is believed to be primarily spread during close contact and by small droplets produced during coughing, sneezing, or talking; with close contact being within 1 to 2 metres (3 to 6 feet).
Studies have found that an uncovered coughing can lead to droplets travelling up to 4.5 metres (15 feet) to 8.2 metres (27 feet).
Some have proposed that the virus may also be transmitted by small droplets that stay for more prolonged periods in the air, that may be generated during speech.Respiratory droplets may also be produced during breathing out, including when talking, though the virus is not generally airborne.
The droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs.
Some medical procedures such as intubation and cardiopulmonary resuscitation (CPR) may cause respiratory secretions to be aerosolized and thus result in airborne spread.
It may also spread when one touches a contaminated surface, including skin, and then touches their eyes, nose, or mouth.
While there are concerns it may spread by faeces, this risk is believed to be low.
The Government of China denied the possibility of faecal-oral transmission of SARS-CoV-2.The virus is most contagious during the first three days after onset of symptoms, although spread may be possible before symptoms appear and in later stages of the disease.
People have tested positive for the disease up to three days before onset of symptoms suggesting transmission is possible before developing significant symptoms.
Only few reports of laboratory-confirmed asymptomatic cases exist, but asymptomatic transmission has been identified by some countries during contact tracing investigations.
The European Centre for Disease Prevention and Control (ECDC) states that while it is not entirely clear how easily the disease spreads, one person generally infects two to three others.The virus survives for hours to days on surfaces.
Specifically, the virus was found to be detectable for up to three days on plastic (polypropylene) and 304 stainless steel, for one day on cardboard, and for up to four hours on copper.
This, however, varies based on the humidity and temperature.Pets and other animals have tested positive for COVID-19.
There is no evidence animals can pass the virus on to humans, though British authorities advise washing one's hands after contact with animals, like after contact with other surfaces infected people could have touched.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus, first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan.
All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature.Outside the human body, the virus is killed by household soap, which dissolves its protective envelope.SARS-CoV-2 is closely related to the original SARS-CoV.
It is thought to have a zoonotic origin.
Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains.
It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13).
In February 2020, Chinese researchers found that there is only one amino acid difference in certain parts of the genome sequences between the viruses from pangolins and those from humans.
Whole-genome comparison to date has found at most 92% of genetic material shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.
Infection by the virus can be provisionally diagnosed on the basis of symptoms, though confirmation is ultimately by reverse transcription polymerase chain reaction (rRT-PCR) of infected secretions or CT imaging.
A study comparing PCR to CT in Wuhan has suggested that CT is significantly more sensitive than PCR, though less specific, with many of its imaging features overlapping with other pneumonias and disease processes.
" As of March 2020, the American College of Radiology recommends that ""CT should not be used to screen for or as a first-line test to diagnose COVID-19"". "
The WHO has published several RNA testing protocols for SARS-CoV-2, with the first issued on 17 January.
The test uses real-time reverse transcription polymerase chain reaction (rRT-PCR).
The test can be done on respiratory or blood samples.
Results are generally available within a few hours to days.
Generally this test is carried out on a nasopharyngeal swab though a throat swab may also be used.A number of laboratories and companies are developing serological tests, which detect antibodies.
As of 6 April 2020, none of these has been proved sufficiently accurate to be approved for widespread use.
In the US a serological test developed by Cellex has been approved for emergency use by certified laboratories only.
Characteristic imaging features on radiographs and computed tomography (CT) of people who are symptomatic include asymmetric peripheral ground glass opacities and absent pleural effusions.
The Italian Radiological Society is compiling an international online database of imaging findings for confirmed cases.
Due to overlap with other infections such as adenovirus, imaging without confirmation by PCR is of limited specificity in identifying COVID-19.
A large study in China compared chest CT results to PCR and demonstrated that though imaging is less specific for the infection, it is faster and more sensitive, suggesting its consideration as a screening tool in epidemic areas.
Artificial intelligence-based convolutional neural networks have been developed to detect imaging features of the virus with both radiographs and CT.
Strategies for preventing transmission of the disease include maintaining overall good personal hygiene, washing hands, avoiding touching the eyes, nose, or mouth with unwashed hands, and coughing or sneezing into a tissue and putting the tissue directly into a waste container.
Those who may already have the infection have been advised to wear a surgical mask in public.
Physical distancing measures are also recommended to prevent transmission.Many governments have restricted or advised against all non-essential travel to and from countries and areas affected by the outbreak.
However, the virus has reached the stage of community spread in large parts of the world.
This means that the virus is spreading within communities, and some community members don't know where or how they were infected.Health care providers taking care of someone who may be infected are recommended to use standard precautions, contact precautions, and eye protection.Contact tracing is an important method for health authorities to determine the source of an infection and to prevent further transmission.
The use of location data from mobile phones by governments for this purpose has prompted privacy concerns, with Amnesty International and over 100 other organizations issuing a statement calling for limits on this kind of surveillance.
Various mobile apps have been implemented or proposed for voluntary use, and as of April 7, 2020, over a dozen expert groups were working on privacy-friendly solutions, such as using Bluetooth to log a user's proximity to other cellphones.
Users then receive a message if they've been in close contact with someone who has tested positive for COVID-19.Misconceptions are circulating about how to prevent infection; for example, rinsing the nose and gargling with mouthwash are not effective.
There is no COVID-19 vaccine, though many organizations are working to develop one.
Hand washing is recommended to prevent the spread of the disease.
The CDC recommends that people wash hands often with soap and water for at least twenty seconds, especially after going to the toilet or when hands are visibly dirty; before eating; and after blowing one's nose, coughing, or sneezing.
This is because outside the human body, the virus is killed by household soap, which bursts its protective bubble.
CDC further recommended using an alcohol-based hand sanitizer with at least 60% alcohol by volume when soap and water are not readily available.
The WHO advises people to avoid touching the eyes, nose, or mouth with unwashed hands.
Surfaces may be decontaminated with a number of solutions (within one minute of exposure to the disinfectant for a stainless steel surface), including 62–71% ethanol, 50–100% isopropanol, 0.1% sodium hypochlorite, 0.5% hydrogen peroxide, and 0.2–7.5% povidone-iodine.
Other solutions, such as benzalkonium chloride and chrohexidine gluconate, are less effective.
The CDC recommends that if a COVID case is suspected or confirmed at a facility such as an office or day care, all areas such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and ATM machines used by the ill persons, should be disinfected.
Health organizations recommended that people cover their mouth and nose with a bent elbow or a tissue when coughing or sneezing, and disposing of any tissue immediately.
Surgical masks are recommended for those who may be infected, as wearing a mask can limit the volume and travel distance of expiratory droplets dispersed when talking, sneezing, and coughing.
The WHO has issued instructions on when and how to use masks.
" According to Stephen Griffin, a virologist at the University of Leeds, ""Wearing a mask can reduce the propensity [of] people to touch their faces, which is a major source of infection without proper hand hygiene.""Masks have also been recommended for use by those taking care of someone who may have the disease. "
The WHO has recommended the wearing of masks by healthy people only if they are at high risk, such as those who are caring for a person with COVID-19, although they also acknowledge that wearing masks may help people avoid touching their face.
Several countries have started to encourage the use of face masks by members of the public.
In the U.S., the CDC recommends wearing non-medical face mask made out of cloth.China has specifically recommended the use of disposable medical masks by healthy members of the public, particularly when coming into close contact (1 metre (3 ft) or less) with other people.
Hong Kong recommends wearing a surgical mask when taking public transport or staying in crowded places.
Thailand's health officials are encouraging people to make cloth facemasks at home and wash them daily.
The Czech Republic and Slovakia banned going out in public without wearing a mask or covering one's nose and mouth.
On 16 March, Vietnam requested everyone to wear a face mask when going to public areas in order to protect themselves and others.
The Austrian government mandated that everyone entering a grocery store must wear a face mask.
Israel has asked all residents to wear face masks when in public.
Taiwan, which has been producing ten million masks per day since mid-March, required passengers on trains and intercity buses to wear face masks on 1 April.
Panama has made it obligatory to wear a face mask whenever going outside, while also recommending the manufacture of a homemade face mask for those who cannot purchase face masks.
Face masks have also been widely used in Japan, South Korea, Malaysia, and Singapore.
Social distancing (also known as physical distancing) includes infection control actions intended to slow the spread of disease by minimizing close contact between individuals.
Methods include quarantines; travel restrictions; and the closing of schools, workplaces, stadiums, theatres, or shopping centres.
Individuals may apply social distancing methods by staying at home, limiting travel, avoiding crowded areas, using no-contact greetings, and physically distancing themselves from others.
Many governments are now mandating or recommending social distancing in regions affected by the outbreak.
The maximum gathering size recommended by US government bodies and health organizations was swiftly reduced from 250 people (if there was no known COVID-19 spread in a region) to 50 people, and later to 10 people.
" On 22 March 2020, Germany banned public gatherings of more than two people.Older adults and those with underlying medical conditions such as diabetes, heart disease, respiratory disease, hypertension, and compromised immune systems face increased risk of serious illness and complications and have been advised by the CDC to stay home as much as possible in areas of community outbreak.In late March 2020, the WHO and other health bodies began to replace the use of the term ""social distancing"" with ""physical distancing"", to clarify that the aim is to reduce physical contact while maintaining social connections, either virtually or at a distance. "
" The use of the term ""social distancing"" had led to implications that people should engage in complete social isolation, rather than encouraging them to stay in contact with others through alternative means.Some authorities have issued sexual health guidelines for use during the pandemic. "
These include recommendations to only have sex with someone you live with, who does not have the virus or symptoms of the virus.
Self-isolation at home has been recommended for those diagnosed with COVID-19 and those who suspect they have been infected.
Health agencies have issued detailed instructions for proper self-isolation.Many governments have mandated or recommended self-quarantine for entire populations living in affected areas.
The strongest self-quarantine instructions have been issued to those in high risk groups.
Those who may have been exposed to someone with COVID-19 and those who have recently travelled to a country or region with widespread transmission have been advised to self-quarantine for 14 days from the time of last possible exposure.
Strategies in the control of an outbreak are containment or suppression, and mitigation.
Containment is undertaken in the early stages of the outbreak and aims to trace and isolate those infected as well as introduce other measures of infection control and vaccinations to stop the disease from spreading to the rest of the population.
When it is no longer possible to contain the spread of the disease, efforts then move to the mitigation stage: measures are taken to slow the spread and mitigate its effects on the healthcare system and society.
A combination of both containment and mitigation measures may be undertaken at the same time.
Suppression requires more extreme measures so as to reverse the pandemic by reducing the basic reproduction number to less than 1.Part of managing an infectious disease outbreak is trying to decrease the epidemic peak, known as flattening the epidemic curve.
This decreases the risk of health services being overwhelmed and provides more time for vaccines and treatments to be developed.
Non-pharmaceutical interventions that may manage the outbreak include personal preventive measures, such as hand hygiene, wearing face-masks, and self-quarantine; community measures aimed at physical distancing such as closing schools and cancelling mass gathering events; community engagement to encourage acceptance and participation in such interventions; as well as environmental measures such surface cleaning.More drastic actions aimed at containing the outbreak were taken in China once the severity of the outbreak became apparent, such as quarantining entire cities and imposing strict travel bans.
Other countries also adopted a variety of measures aimed at limiting the spread of the virus.
South Korea introduced mass screening and localized quarantines, and issued alerts on the movements of infected individuals.
Singapore provided financial support for those infected who quarantined themselves and imposed large fines for those who failed to do so.
Taiwan increased face mask production and penalized hoarding of medical supplies.Simulations for Great Britain and the United States show that mitigation (slowing but not stopping epidemic spread) and suppression (reversing epidemic growth) have major challenges.
Optimal mitigation policies might reduce peak healthcare demand by 2/3 and deaths by half, but still result in hundreds of thousands of deaths and health systems being overwhelmed.
Suppression can be preferred but needs to be maintained for as long as the virus is circulating in the human population (or until a vaccine becomes available, if that comes first), as transmission otherwise quickly rebounds when measures are relaxed.
Long-term intervention to suppress the pandemic causes social and economic costs.
There are no specific antiviral medications approved for COVID-19, but development efforts are underway, including testing of existing medications.
Taking over-the-counter cold medications, drinking fluids, and resting may help alleviate symptoms.
Depending on the severity, oxygen therapy, intravenous fluids, and breathing support may be required.
The use of steroids may worsen outcomes.
Several compounds that were previously approved for treatment of other viral diseases are being investigated for use in treating COVID-19.
" The WHO also stated that some ""traditional and home remedies"" can provide relief of the symptoms caused by SARS-CoV-19. "
Increasing capacity and adapting healthcare for the needs of COVID-19 patients is described by the WHO as a fundamental outbreak response measure.
The ECDC and the European regional office of the WHO have issued guidelines for hospitals and primary healthcare services for shifting of resources at multiple levels, including focusing laboratory services towards COVID-19 testing, cancelling elective procedures whenever possible, separating and isolating COVID-19 positive patients, and increasing intensive care capabilities by training personnel and increasing the number of available ventilators and beds.
There are various theories about where the very first case (the so-called patient zero) may have originated.
The first known case of the novel coronavirus may trace back to 1 December 2019 in Wuhan, Hubei, China.
Within a month, the number of coronavirus cases in Hubei gradually increased.
These were mostly linked to the Huanan Seafood Wholesale Market, which also sold live animals, and one theory is that the virus came from one of these kinds of animals; or, in other words, has a zoonotic origin.A pneumonia cluster of unknown cause was observed on 26 December and treated by the doctor Zhang Jixian in Hubei Provincial Hospital, who informed the Wuhan Jianghan CDC on 27 December.
" On 30 December, a group of doctors at Wuhan Central Hospital alerted their colleagues of a ""SARS-like coronavirus"". "
Eight of these doctors, including Li Wenliang, were admonished by the police for spreading false rumours, and another, Ai Fen, was reprimanded by her superiors for raising the alarm.
The Wuhan Municipal Health Commission later released a public notice on 31 December and informed the WHO.
Enough cases of unknown pneumonia had been reported to health authorities in Wuhan to trigger an investigation in early January.During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days.
In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail interchange.
On 20 January, China reported nearly 140 new cases in one day, including two people in Beijing and one in Shenzhen.
Later official data shows that 6,174 people had already developed symptoms by 20 January 2020.As of 26 March, the United States has overtaken China and Italy with the highest number of confirmed cases in the world.As of 9 April 2020, more than 1.61 million cases have been reported worldwide; more than 97,000 people have died and more than 364,000 have recovered.
Around 200 countries and territories have had at least one case.
Due to the pandemic in Europe, many countries in the Schengen Area have restricted free movement and set up border controls.
National reactions have included containment measures such as quarantines (known as stay-at-home orders, shelter-in-place orders, or lockdown) and curfews.As of 2 April, nearly 300 million people, or about 90% of the population, are under some form of lockdown in the United States, more than 50 million people are in lockdown in the Philippines, about 59 million people are in lockdown in South Africa, and 1.3 billion people are in lockdown in India.
On 26 March, 1.7 billion people worldwide were under some form of lockdown, which increased to 2.6 billion people two days later—around a third of the world's population.
The first confirmed case of COVID-19 has been traced back to 1 December 2019 in Wuhan; one unconfirmed report suggests the earliest case was on 17 November.
Doctor Zhang Jixian observed a cluster of pneumonia cases of unknown cause on 26 December, upon which her hospital informed Wuhan Jianghan CDC on 27 December.
Initial genetic testing of patient samples on 27 December 2019 indicated the presence of a SARS-like coronavirus.
A public notice was released by Wuhan Municipal Health Commission on 31 December.
The WHO was informed on the same day.
" As these notifications occurred, doctors in Wuhan were warned by police for ""spreading rumours"" about the outbreak. "
" The Chinese National Health Commission initially claimed that there was no ""clear evidence"" of human-to-human transmission. "
" In late January, the Chinese government launched a radical campaign later described by the Chinese Communist Party general secretary Xi Jinping as a ""people's war"" to contain the spread of the virus. "
" In what has been described as ""the largest quarantine in human history"", a cordon sanitaire was announced on 23 January stopping travel in and out of Wuhan, which was extended to a total of 15 cities in Hubei, affecting a total of about 57 million people. "
Private vehicle use was banned in the city.
Chinese New Year (25 January) celebrations were cancelled in many places.
The authorities also announced the construction of a temporary hospital, Huoshenshan Hospital, which was completed in 10 days.
Another hospital was built afterwards, Leishenshan Hospital, to handle additional patients.
In addition to newly constructed hospitals, China also converted 14 other facilities in Wuhan, such as convention centers and stadiums, into temporary hospitals.On 26 January, the government instituted further measures to contain the COVID-19 outbreak, including issuing health declarations for travellers and extending the Spring Festival holiday.
Universities and schools around the country were also closed.
The regions of Hong Kong and Macau instituted several measures, particularly in regard to schools and universities.
Remote working measures were instituted in several Chinese regions.
Travel restrictions were enacted in and outside of Hubei.
Public transport was modified, and museums throughout China were temporarily closed.
" Control of public movement was applied in many cities, and it has been estimated that about 760 million people (more than half the population) faced some form of outdoor restriction.After the outbreak entered its global phase in March, Chinese authorities took strict measures to prevent the virus from ""importing"" from other countries. "
For example, Beijing has imposed a 14-day mandatory quarantine for all international travellers entering the city.On 23 March, mainland China only one case had transmitted domestically in the five days prior, in this instance via a traveller returning to Guangzhou from Istanbul.
On 24 March 2020, Chinese Premier Li Keqiang reported that the spread of domestically transmitted cases has been basically blocked and the outbreak has been controlled in China.
The same day travel restrictions were eased in Hubei, apart from Wuhan, two months after the lockdown was imposed.The Chinese Ministry of Foreign Affairs announced on 26 March 2020 that entry for visa or residence permit holders would be suspended from 28 March onwards, with no specific details on when this policy will end.
Those who wish to enter China will have to apply for visas in Chinese embassies or consulates.
The Chinese government encouraged businesses and factories to re-open on 30 March, and provided monetary stimulus packages for firms.The State Council declared a day of mourning to begin with a national three-minute moment of silence on 10:00 4 April, coinciding with Qingming Festival, although the central government asked families to pay their respects online in observance of physical distancing as to avoid a renewed COVID-19 outbreak.
COVID-19 was confirmed to have spread to South Korea on 20 January 2020 from China.
The nation's health agency reported a significant increase in confirmed cases on 20 February, largely attributed to a gathering in Daegu of a new religious movement known as the Shincheonji Church of Jesus.
Shincheonji devotees visiting Daegu from Wuhan were suspected to be the origin of the outbreak.
As of 22 February, among 9,336 followers of the church, 1,261 or about 13% reported symptoms.South Korea declared the highest level of alert on 23 February 2020.
On 28 February, more than 2,000 confirmed cases were reported in Korea, rising to 3,150 on 29 February.
All South Korean military bases were quarantined after tests confirmed that three soldiers were positive for the virus.
Airline schedules were also affected and therefore they were changed.South Korea introduced what was considered the largest and best-organized programme in the world to screen the population for the virus, and isolate any infected people as well as tracing and quarantining those who contacted them.
Screening methods included mandatory self-reporting of symptoms by new international arrivals through mobile application, drive-thru testing for the virus with the results available the next day, and increasing testing capability to allow up to 20,000 people to be tested every day.
South Korea's programme is considered to be a success in controlling the outbreak despite not quarantining entire cities.The South Korean society was initially polarized on President Moon Jae-in's response to the crisis.
Many Koreans signed petitions either calling for the impeachment of Moon over what they claimed to be government mishandling of the outbreak, or praising his response.
On 23 March, it was reported that South Korea had the lowest one-day case total in four weeks.
On 29 March it was reported that beginning 1 April all new overseas arrivals will be quarantined for two weeks.
Per media reports on 1 April, South Korea has received requests for virus testing assistance from 121 different countries.
Iran reported its first confirmed cases of SARS-CoV-2 infections on 19 February in Qom, where, according to the Ministry of Health and Medical Education, two people died later that day.
Early measures announced by the government included the cancellation of concerts and other cultural events, sporting events, and Friday prayers, and closures of universities, higher education institutions, and schools.
Iran allocated five trillion rials to combat the virus.
President Hassan Rouhani said on 26 February 2020 that there were no plans to quarantine areas affected by the outbreak, and only individuals would be quarantined.
Plans to limit travel between cities were announced in March, although heavy traffic between cities ahead of the Persian New Year Nowruz continued.
Shia shrines in Qom remained open to pilgrims until 16 March 2020.Iran became a centre of the spread of the virus after China during February.
Amidst claims of a cover-up of the extent of the outbreak in Iran, more than ten countries had traced their cases back to Iran by 28 February, indicating that the extent of the outbreak may be more severe than the 388 cases reported by the Iranian government by that date.
The Iranian Parliament was shut down, with 23 of its 290 members reported to have had tested positive for the virus on 3 March.
On 12 March, the Human Rights Watch urged the Iranian prison authorities to unconditionally release the human rights defenders detained for peaceful dissent, and to also temporarily release all the eligible prisoners.
It stated that there is a greater risk of the virus to spread in closed institutions like detention centres, which also lack adequate medical care.
On 15 March, the Iranian government reported 100 deaths in a single day, the most recorded in the country since the outbreak began.
At least 12 sitting or former Iranian politicians and government officials had died from the disease by 17 March.
By 23 March, Iran was experiencing 50 new cases every hour and one new death every ten minutes due to coronavirus.
According to a WHO official, there may be five times more cases in Iran than what is being reported.
It is also suggested that U.S. sanctions on Iran may be affecting the country's financial ability to respond to the viral outbreak.
The UN High Commissioner for Human Rights has demanded economic sanctions to be eased for nations most affected by the pandemic, including Iran.
The outbreak was confirmed to have spread to Italy on 31 January, when two Chinese tourists tested positive for SARS-CoV-2 in Rome.
Cases began to rise sharply, which prompted the Italian government to suspend all flights to and from China and declare a state of emergency.
An unassociated cluster of COVID-19 cases was later detected, starting with 16 confirmed cases in Lombardy on 21 February.On 22 February, the Council of Ministers announced a new decree-law to contain the outbreak, including quarantining more than 50,000 people from 11 different municipalities in northern Italy.
" Prime Minister Giuseppe Conte said, ""In the outbreak areas, entry and exit will not be provided. "
" Suspension of work activities and sports events has already been ordered in those areas.""On 4 March, the Italian government ordered the full closure of all schools and universities nationwide as Italy reached 100 deaths. "
All major sporting events, including Serie A football matches, were to be held behind closed doors until April, but on 9 March, all sport was suspended completely for at least one month.
On 11 March, Prime Minister Conte ordered stoppage of nearly all commercial activity except supermarkets and pharmacies.On 6 March, the Italian College of Anaesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) published medical ethics recommendations regarding triage protocols that might be employed.
On 19 March, Italy overtook China as the country with the most coronavirus-related deaths in the world after reporting 3,405 fatalities from the pandemic.
On 22 March, it was reported that Russia had sent nine military planes with medical equipment to Italy.
As of 5 April, there were 128,948 confirmed cases, 15,887 deaths, and 21,815 recoveries in Italy, with the majority of those cases occurring in the Lombardy region.
A CNN report indicated that the combination of Italy's large elderly population and inability to test all who have the virus to date may be contributing to the high fatality rate.
The United Kingdom's response to the virus first emerged as one of the most relaxed of the affected countries, and until 18 March 2020, the British government did not impose any form of social distancing or mass quarantine measures on its citizens.
As a result, the government received criticism for the perceived lack of pace and intensity in its response to concerns faced by the public.On 16 March, Prime Minister Boris Johnson made an announcement advising against all non-essential travel and social contact, suggesting people work from home where possible and avoid venues such as pubs, restaurants, and theatres.
On 20 March, the government announced that all leisure establishments such as pubs and gyms were to close as soon as possible, and promised to pay up to 80% of workers' wages to a limit of £2,500 per month to prevent unemployment in the crisis.On 23 March, the Prime Minister announced tougher social distancing measures, banning gatherings of more than two people and restricting travel and outdoor activity to that deemed strictly necessary.
Unlike previous measures, these restrictions were enforceable by police through the issuing of fines and the dispersal of gatherings.
" Most businesses were ordered to close, with exceptions for businesses deemed ""essential"", including supermarkets, pharmacies, banks, hardware shops, petrol stations, and garages. "
On 20 January, the first known case of COVID-19 was confirmed in the Pacific Northwest state of Washington in a man who had returned from Wuhan on 15 January.
The White House Coronavirus Task Force was established on 29 January.
On 31 January, the Trump administration declared a public health emergency, and placed restrictions on entry for travellers from China.
On 28 January 2020, the Center for Disease Control—the leading public health institute of the U.S. government—announced they had developed their own testing kit.
Despite doing so, the United States had a slow start in testing, which obscured the true extent of the outbreak at the time.
Testing was marred by defective test kits produced by the federal government in February, a lack of federal government approval for non-government test kits (by academia, companies and hospitals) until the end of February, and restrictive criteria for people to qualify for a test until early March (a doctor's order was required thereafter).
By 27 February, The Washington Post reported fewer than 4,000 tests had been conducted in the United States.
By 13 March, The Atlantic reported that less than 14,000 tests had been conducted.
" On 22 March, the Associated Press reported: ""Many people who have symptoms and a doctor's order have waited hours or days for a test.""After the first death in the United States was reported in Washington state on 29 February, Governor Jay Inslee declared a state of emergency, an action that was soon followed by other states. "
Schools in the Seattle area cancelled classes on 3 March, and by mid-March, schools across the country were shutting down.On 6 March 2020, the United States was advised of projections for the impact of the new coronavirus on the country by a group of epidemiologists at Imperial College London.
On the same day President Trump signed the Coronavirus Preparedness and Response Supplemental Appropriations Act, which provided $8.3 billion in emergency funding for federal agencies to respond to the outbreak.
Corporations imposed employee travel restrictions, cancelled conferences, and encouraged employees to work from home.
Sports events and seasons were cancelled.On 11 March, Trump announced travel restrictions for most of Europe, excluding the United Kingdom, for 30 days, effective 13 March.
The following day, he expanded the restrictions to include the United Kingdom and Ireland.
On 13 March, he declared a national emergency, which made federal funds available to respond to the crisis.
Beginning on 15 March, many businesses closed or reduced hours throughout the U.S. to try to reduce the spread of the virus.
By 17 March, the epidemic had been confirmed in all 50 states and in the District of Columbia.On 23 March, it was reported that New York City had 10,700 cases of the coronavirus, more than the total number of cases in South Korea.
On 25 March, the governor said that social distancing seemed to be working, as estimates of case doubling slowed from 2.0 days to 4.7 days.
As of 28 March, there were 32,308 confirmed cases in New York City, and 672 people had died from the virus.On 26 March, the United States was reported to have more confirmed coronavirus infection cases than any other country in the world, including China and Italy.As of 8 April, 400,335 cases have been confirmed in the United States, and 12,841 people have died.
Per media reports on 30 March, U.S. President Trump has decided to extend social distancing guidelines until 30 April.
On the same day, the USNS Comfort, a hospital ship with about 1000 beds, made anchor in New York.
On 3 April, the U.S. had a record 884 deaths due to the coronavirus in a 24-hour period.
In the state of New York the cases have exceeded 100,000 people on 3 April.The White House has been criticized for downplaying the threat and controlling the messaging by directing health officials and scientists to coordinate public statements and publications related to the virus with the office of Vice-President Mike Pence.
Overall approval of Trump's management of the crisis has been polarized along partisan lines.
Some U.S. officials and commentators criticized the U.S. reliance on importation of critical materials, including essential medical supplies, from China.
An analysis of air travel patterns was used to map and predict patterns of spread and was published in The Journal of Travel Medicine in mid-January 2020.
Based on 2018 information from the International Air Transport Association, Bangkok, Hong Kong, Tokyo, and Taipei had the largest volume of travellers from Wuhan.
Dubai, Sydney, and Melbourne were also reported as popular destinations for people travelling from Wuhan.
Bali was reported as least able among the 20 most popular destination cities in terms of preparedness, while cities in Australia were considered most able.Australia released its Emergency Response Plan for Novel Coronavirus (COVID-19) on 7 February.
It stated that much was yet to be discovered about COVID-19, and that Australia would emphasize border control and communication in its response to the pandemic.
On 21 March, a human biosecurity emergency was declared in Australia.
Owing to the effective quarantine of public transport in Wuhan and Hubei, several countries have planned to evacuate their citizens and diplomatic staff from the area, primarily through chartered flights of the home nation, with Chinese authorities providing clearance.
Canada, the United States, Japan, India, Sri Lanka, Australia, France, Argentina, Germany, and Thailand were among the first to plan the evacuation of their citizens.
Pakistan has said that it will not be evacuating any citizens from China.
On 7 February, Brazil evacuated 34 Brazilians or family members in addition to four Poles, a Chinese person, and an Indian citizen.
The citizens of Poland, China, and India deplaned in Poland, where the Brazilian plane made a stopover before following its route to Brazil.
Brazilian citizens who went to Wuhan were quarantined at a military base near Brasília.
On the same day, 215 Canadians (176 from the first plane, and 39 from a second plane chartered by the U.S. government) were evacuated from Wuhan to CFB Trenton to be quarantined for two weeks.
On 11 February, another plane of 185 Canadians from Wuhan landed at CFB Trenton.
Australian authorities evacuated 277 citizens on 3 and 4 February to the Christmas Island Detention Centre, which had been repurposed as a quarantine facility, where they remained for 14 days.
A New Zealand evacuation flight arrived in Auckland on 5 February; its passengers (including some from Australia and the Pacific) were quarantined at a naval base in Whangaparoa, north of Auckland.
On 15 February, the United States announced that it would evacuate Americans aboard the cruise ship Diamond Princess.
On 21 February, a plane carrying 129 Canadian passengers who had been evacuated from Diamond Princess landed in Trenton, Ontario.
In early March, the Indian government began evacuating its citizens from Iran.On 14 March a South African Airways aircraft chartered by the South African Government repatriated 112 South African citizens.
Medical screening was performed prior to departure, and four South Africans who were showing signs of coronavirus were left behind to mitigate risk.
Only South Africans who tested negative were repatriated.
Test results cleared all the South Africans, including the flight crew, pilots, hotel staff, police and soldiers involved in the humanitarian mission who, as a precautionary measure, all remained under observation and in quarantine for a 14-day period at The Ranch Resort.
On 20 March, the United States began to partially withdrawal its troops from Iraq due to the pandemic.
On 5 February, the Chinese foreign ministry stated that 21 countries (including Belarus, Pakistan, Trinidad and Tobago, Egypt, and Iran) had sent aid to China.
Some Chinese students at American universities joined together to help send aid to virus-stricken parts of China, with a joint group in the greater Chicago area reportedly managing to send 50,000 N95 masks to hospitals in the Hubei province on 30 January.The humanitarian aid organization Direct Relief, in coordination with FedEx, sent 200,000 face masks along with other personal protective equipment, including gloves and gowns, by emergency airlift to the Wuhan Union Hospital by 30 January.
" On 5 February, Bill and Melinda Gates announced a $100 million donation to the WHO to fund vaccine research and treatment efforts along with protecting ""at-risk populations in Africa and South Asia"". "
Interaksyon reported that the Chinese government donated 200,000 masks to the Philippines on 6 February, after Senator Richard Gordon shipped 3.16 million masks to Wuhan.
On 19 February, the Singapore Red Cross announced that it would send $2.26 million worth of aid to China.
Japan donated one million face masks to Wuhan, Turkey dispatched medical equipment, Russia sent more than 13 tonnes of medical supplies to Wuhan, Malaysia announced a donation of 18 million medical gloves to China, Germany delivered various medical supplies including 10,000 Hazmat suits, and the United States donated 17.8 tons of medical supplies to China and promised an additional $100 million in financial support to affected countries.After cases in China seemed to stabilize, the country has been sending aid to various nations hit by the pandemic.
In March, China, Cuba and Russia sent medical supplies and experts to help Italy deal with its coronavirus outbreak.
Businessman Jack Ma sent 1.1 million testing kits, 6 million face masks, and 60,000 protective suits to Addis Ababa, Ethiopia for distribution by the African Union.
He later sent 5,000 testing kits, 100,000 face masks and 5 ventilators to Panama.
Ma also donated medical supplies to Canada.The Netherlands, Spain, Turkey, Georgia, and the Czech Republic expressed their concerns over Chinese-made masks and test kits.
For instance, Spain withdrew 58,000 Chinese-made coronavirus testing kits with an accuracy rate of just 30%, meanwhile, the Netherlands recalled 600,000 Chinese face masks which were defective.
Belgium recalled 100,000 unusable masks, thought to be from China, but were in fact from Colombia.
On the other hand, Chinese aid has been well-received in parts of Latin America and Africa.On 2 April, the World Bank launched emergency support operations for developing countries.
The WHO has commended the efforts of Chinese authorities in managing and containing the epidemic.
" The WHO noted the contrast between the 2002–2004 SARS outbreak, where Chinese authorities were accused of secrecy that impeded prevention and containment efforts, and the current crisis where the central government ""has provided regular updates to avoid panic ahead of Lunar New Year holidays"". "
" On 23 January, in reaction to the central authorities' decision to implement a transportation ban in Wuhan, WHO representative Gauden Galea remarked that while it was ""certainly not a recommendation the WHO has made"", it was also ""a very important indication of the commitment to contain the epidemic in the place where it is most concentrated"" and called it ""unprecedented in public health history"".On 30 January, following confirmation of human-to-human transmission outside China and the increase in the number of cases in other countries, the WHO declared the outbreak a Public Health Emergency of International Concern (PHEIC), the sixth PHEIC since the measure was first invoked during the 2009 swine flu pandemic. "
" WHO Director-General Tedros Adhanom said that the PHEIC was due to ""the risk of global spread, especially to low- and middle-income countries without robust health systems. "
" In response to the implementations of travel restrictions, Tedros stated that ""there is no reason for measures that unnecessarily interfere with international travel and trade"" and that the ""WHO doesn't recommend limiting trade and movement."" "
" On 5 February, the WHO appealed to the global community for a $675 million contribution to fund strategic preparedness in low-income countries, citing the urgency to support those countries which ""do not have the systems in place to detect people who have contracted the virus, even if it were to emerge"". "
" Tedros further made statements declaring that ""we are only as strong as our weakest link"" and urged the international community to ""invest today or pay more later"".On 11 February, the WHO in a press conference established COVID-19 as the name of the disease. "
" On the same day, Tedros stated that UN Secretary-General António Guterres had agreed to provide the ""power of the entire UN system in the response"". "
" A UN Crisis Management Team was activated as a result, allowing coordination of the entire United Nations response, which the WHO states will allow them to ""focus on the health response while the other agencies can bring their expertise to bear on the wider social, economic and developmental implications of the outbreak"". "
" On 14 February, a WHO-led Joint Mission Team with China was activated to provide international and WHO experts on the ground in China to assist in the domestic management and evaluate ""the severity and the transmissibility of the disease"" by hosting workshops and meetings with key national-level institutions and to conduct field visits to assess the ""impact of response activities at provincial and county levels, including urban and rural settings"".On 25 February, the WHO declared that ""the world should do more to prepare for a possible coronavirus pandemic,"" stating that while it was still too early to call it a pandemic, countries should nonetheless be ""in a phase of preparedness"". "
" In response to a developing outbreak in Iran, the WHO sent a Joint Mission Team there to assess the situation.On 28 February, WHO officials said that the coronavirus threat assessment at the global level would be raised from ""high"" to ""very high"", its highest level of alert and risk assessment. "
" Mike Ryan, executive director of the WHO's health emergencies program, warned in a statement that ""This is a reality check for every government on the planet: Wake up. "
" This virus may be on its way and you need to be ready,"" urging that the right response measures could help the world avoid ""the worst of it"". "
" Ryan further stated that the current data did not warrant public health officials to declare a global pandemic, saying that such a declaration would mean ""we're essentially accepting that every human on the planet will be exposed to that virus."" "
On 11 March, the WHO declared the coronavirus outbreak a pandemic.
" The Director-General said that the WHO was ""deeply concerned both by the alarming levels of spread and severity, and by the alarming levels of inaction"".The WHO has faced significant criticism for what is seen as inadequate handling of the pandemic, including the late declaration of a public health emergency and the classification of the virus as a pandemic. "
The backlash included a petition for the WHO Director-General Tedros Adhanom to tender his resignation, signed by 733,000 people as of 6 April.
On 26 March 2020, dozens of UN human rights experts emphasized respecting the rights of every individual during the COVID-19 pandemic.
The expert group stated that everyone is entitled to life-saving interventions and the government holds this responsibility.
The group stressed that the lack of resources or health insurance should never serve as a justification for discrimination against a specific group.
The experts underscored that every individual has the right to health, including people with disabilities, belonging to minority groups, older people, internally displaced people, the homeless, those living in extremely poor conditions, people in detention, as well as refugees and other unspecified groups in need of government support.
International governmental organizations are addressing the economic and social impacts of the COVID-19 crisis.
The Organisation for Economic Co-operation and Development has launched a platform to provide timely and comprehensive information on policy responses in countries around the world, as well as viewpoints and advice.
From policies to strengthen health systems and the world economy to addressing the effects of lockdown and restrictions on travel, the digital hub includes a Country Policy Tracker, and aims to help countries learn from each other and to facilitate a co-ordinated global response to the coronavirus challenge.
The Chinese government has been criticized by the United States, UK Minister for the Cabinet Office Michael Gove, and Brazil President Jair Bolsonaro's son Eduardo Bolsonaro for its handling of the pandemic, which began in the Chinese province of Hubei.
A number of provincial-level administrators of the Communist Party of China (CPC) were dismissed over their handling of the quarantine efforts in Central China, a sign of discontent with the political establishment's response to the outbreak in those regions.
Some commentators believe that this move was intended to protect Chinese Communist Party general secretary Xi Jinping from the public's anger over the coronavirus outbreak.
Some Chinese officials, e.g. Zhao Lijian rejected an earlier acknowledgement of the coronavirus outbreak starting in Wuhan, in favour of conspiracy theories about the COVID-19 originating from the U.S. or Italy.
" The U.S. administration of Donald Trump has referred to the coronavirus as ""Chinese virus"" or ""Wuhan virus"" saying that China's ""censorship supercharged a virus that has now turned into a global pandemic"", which has in turn been criticized by some critics as racism and ""distract[ing] from his administration's failure to contain the disease"". "
" The Daily Beast obtained a U.S. government cable outlining a communications stratagem with apparent origins in the National Security Council, with the strategy being quoted as ""Everything is about China. "
" We're being told to try and get this messaging out in any way possible, including press conferences and television appearances.""Outlets such as Politico, Foreign Policy, and Bloomberg have claimed that China's efforts to send aid to virus-stricken countries is part of a propaganda push for global influence. "
" EU foreign policy chief Josep Borrell warned that there is ""a geo-political component including a struggle for influence through spinning and the 'politics of generosity'"". "
" Borrell also said that ""China is aggressively pushing the message that, unlike the US, it is a responsible and reliable partner."" "
China has also called for the US to lift its sanctions off of Syria, Venezuela and Iran, while reportedly sending aid to the latter two countries.
Jack Ma's donation of 100,000 masks to Cuba was blocked by US sanctions on 3 April.
US authorities have also been accused of diverting aid meant for other nations to their own country.
And there have been mask-related disputes reported between other countries, such as Germany, Austria and Switzerland; and the Czech Republic and Italy.
In addition, Turkey seized hundreds of ventilators destined for Spain.
In early March, the Italian government criticized the European Union's lack of solidarity with coronavirus-affected Italy.
" Maurizio Massari, Italy's ambassador to the EU, said that ""Only China responded bilaterally. "
" Certainly, this is not a good sign of European solidarity."" "
On 22 March, after a phone call with Italian Prime Minister Giuseppe Conte, Russian president Vladimir Putin arranged the Russian army to send military medics, special disinfection vehicles, and other medical equipment to Italy.
" Italy's La Stampa newspaper cited an anonymous ""high-level political source"" that 80 percent of Russia's aid was ""useless or of little use to Italy"". "
" The source accused Russia of embarking on a ""geopolitical and diplomatic"" charm offensive. "
The President of Lombardy, Attilio Fontana, and Italian Foreign Minister Luigi Di Maio dismissed the media reports and expressed their gratitude.
Russia also sent a cargo plane with medical aid to the United States.
" Kremlin spokesman Dmitry Peskov said that ""when offering assistance to US colleagues, [Putin] assumes that when US manufacturers of medical equipment and materials gain momentum, they will also be able to reciprocate if necessary."" "
" The planned NATO ""Defender 2020"" military exercise in Germany, Poland, and the Baltic states, the largest NATO war exercise since the end of the Cold War, will be held on a reduced scale. "
" The Campaign for Nuclear Disarmament's general secretary Kate Hudson criticized the Defender 2020 exercise: ""In the current public-health crisis, it jeopardizes the lives not only of the troops from the US and the many European countries participating but the inhabitants of the countries in which they are operating.""The Iranian government has been heavily affected by the virus, with around two dozen parliament members infected as well as fifteen other current or former political figures. "
Iran's President Hassan Rouhani wrote a public letter to world leaders asking for help on 14 March 2020, saying that his country is struggling to fight the outbreak due to lack of access to international markets as a result of the United States sanctions against Iran.The outbreak has prompted calls for the United States to adopt social policies common in other wealthy countries, including universal health care, universal child care, paid family leave, and higher levels of funding for public health.
Political analysts anticipated it may negatively affect Donald Trump's chances of re-election in the 2020 presidential election.Diplomatic relations between Japan and South Korea worsened due to the pandemic.
" South Korea criticized Japan's ""ambiguous and passive quarantine efforts"" after Japan announced anybody coming from South Korea will be placed in two weeks' quarantine at government-designated sites. "
The South Korean society was initially polarized on President Moon Jae-in's response to the crisis.
Many Koreans signed petitions either calling for the impeachment of Moon over what they claimed to be government mishandling of the outbreak, or praising his response.The pandemic has allowed countries to pass emergency legislation in response.
Some commentators have expressed concerns that it could allow governments to strengthen their grip on power.
In Hungary, its parliament voted to allow the prime minister, Viktor Orbán, to rule by decree indefinitely, suspend parliament as well as elections and punish those deemed to have spread false information about the virus and the government's handling of the crisis.
The coronavirus outbreak has been blamed for several instances of supply shortages, stemming from globally increased usage of equipment to fight the outbreaks, panic buying, and disruption to factory and logistic operations.
The United States Food and Drug Administration has issued warnings about shortages of drugs and medical equipment due to increased consumer demand and supplier disruption.
Several localities also witnessed panic buying that led to shelves being cleared of grocery essentials such as food, toilet paper, and bottled water, inducing supply shortages.
The technology industry in particular has been warning about delays to shipments of electronic goods.
According to WHO director-general Tedros Adhanom, the demand for personal protection equipment has risen 100-fold.
This demand has led to the increase in prices of up to twenty times the normal price and also induced delays on the supply of medical items for four to six months.
It has also caused a shortage of personal protective equipment worldwide, with the WHO warning that this will endanger health workers.
In Australia, the pandemic provided a new opportunity for daigou shoppers to sell Australian products into China.
The activity has created a shortage of baby formula in some supermarkets and was subsequently banned by the Australian government.Despite the high prevalence of COVID-19 cases in Northern Italy and the Wuhan region, and the ensuing high demand for food products, both areas have been spared from acute food shortages.
Measures by China and Italy against the hoarding and illicit trade of critical products have been successful, avoiding acute food shortages that were anticipated in Europe as well as in North America.
Northern Italy with its significant agricultural production has not seen a large reduction, but prices may increase according to industry representatives.
Empty food shelves were only encountered temporarily, even in Wuhan city, while Chinese government officials released pork reserves to assure sufficient nourishment of the population.
Similar laws exist in Italy requiring food producers to keep reserves for such emergencies.
Damage to the global economy has been felt in China: according to a media report on 16 March, the economy in China was very hard hit in the first two months of 2020 due to the measures taken by the government to curtail virus spread, and retail sales plunged 20.5%.
As mainland China is a major economy and manufacturing hub, the viral outbreak has been seen to pose a major destabilizing threat to the global economy.
Agathe Demarais of the Economist Intelligence Unit has forecast that markets will remain volatile until a clearer image emerges on potential outcomes.
In January 2020, some analysts estimated that the economic fallout of the epidemic on global growth could surpass that of the 2002–2004 SARS outbreak.
One estimate from an expert at Washington University in St. Louis gave a $300+ billion impact on the world's supply chain that could last up to two years.
" The Organization of the Petroleum Exporting Countries (OPEC) reportedly ""scrambled"" after a steep decline in oil prices due to lower demand from China. "
Global stock markets fell on 24 February due to a significant rise in the number of COVID-19 cases outside mainland China.
On 27 February, due to mounting worries about the coronavirus outbreak, various U.S. stock indexes including the NASDAQ-100, the S & amp;P 500 Index, and the Dow Jones Industrial Average posted their sharpest falls since 2008, with the Dow falling 1,191 points, the largest one-day drop since the financial crisis of 2007–08.
All three indexes ended the week down more than 10%.
On 28 February, Scope Ratings GmbH affirmed China's sovereign credit rating, but maintained a Negative Outlook.
Stocks plunged again based on coronavirus fears, the largest fall being on 16 March.
Many consider an economic recession to be likely.
Economist Mohamed El-Erian praised central banks' and states' timely emergency measures.
Central banks are reacting more quickly than they did to the 2008 financial crash.
Tourism is one of the worst affected sectors due to travel bans, closing of public places including travel attractions, and advice of governments against any travel all over the world.
As a consequence, numerous airlines have cancelled flights due to lower demand, including British Airways, China Eastern Airlines, and Qantas, while British regional airline Flybe collapsed.
The impact on the cruise line industry was at a level never seen before.
Several train stations and ferry ports have also been closed.
The epidemic coincided with the Chunyun, a major travel season associated with the Chinese New Year holiday.
A number of events involving large crowds were cancelled by national and regional governments, including annual New Year festivals, with private companies also independently closing their shops and tourist attractions such as Hong Kong Disneyland and Shanghai Disneyland.
Many Lunar New Year events and tourist attractions have been closed to prevent mass gatherings, including the Forbidden City in Beijing and traditional temple fairs.
In 24 of China's 31 provinces, municipalities and regions, authorities extended the New Year's holiday to 10 February, instructing most workplaces not to re-open until that date.
These regions represented 80% of the country's GDP and 90% of exports.
Hong Kong raised its infectious disease response level to the highest and declared an emergency, closing schools until March and cancelling its New Year celebrations.The retail sector has been impacted globally, with reductions in store hours or temporary closures.
Visits to retailers in Europe and Latin America declined by 40%.
North America and Middle East retailers saw a 50–60% drop.
This also resulted in a 33–43% drop in foot traffic to shopping centres in March compared to February.
Shopping mall operators around the world imposed additional measures, such increased sanitation, installation of thermal scanners to check the temperature of shoppers, and cancellation of events.According to a United Nations Economic Commission for Latin America estimate, the pandemic-induced recession could leave between 14 and 22 million more people in extreme poverty in Latin America than would have been in that situation without the pandemic.
In January and February 2020, during the height of the epidemic in Wuhan, about 5 million people in China lost their jobs.
Many of China's nearly 300 million rural migrant workers have been stranded at home in inland provinces or trapped in Hubei province.In March 2020, more than 10 million Americans lost their jobs and applied for government aid.
The coronavirus outbreak could cost 47 million jobs in the United States and unemployment rate may hit 32%, according to estimates by the Federal Reserve Bank of St. Louis.The lockdown in India has left tens of millions of Indian migrant workers (who are paid through daily wages) unemployed.The survey from the Angus Reid Institute found that 44% of Canadian households have experienced some type of unemployment.Nearly 900,000 workers lost their jobs in Spain since it went into lockdown in mid-March 2020.
During the second half of March, 4 million French workers applied for temporary unemployment benefits and 1 million British workers applied for a universal credit scheme.Almost half a million companies in Germany have sent their workers on a government-subsidized short-time working schemes known as Kurzarbeit.
The German short-time work compensation scheme has been adopted by France and Britain.
The performing arts and cultural heritage sectors have been profoundly affected by the pandemic, impacting organizations' operations as well as individuals—both employed and independent—globally.
Arts and culture sector organizations attempted to uphold their (often publicly funded) mission to provide access to cultural heritage to the community, maintain the safety of their employees and the public, and support artists where possible.
By March 2020, across the world and to varying degrees, museums, libraries, performance venues, and other cultural institutions had been indefinitely closed with their exhibitions, events and performances cancelled or postponed.
In response there were intensive efforts to provide alternative services through digital platforms.Another recent and rapidly accelerating fallout of the disease is the cancellation of religious services, major events in sports, and other social events, such as music festivals and concerts, technology conferences, and fashion shows.
The film industry has also experienced disruption.The Vatican announced that Holy Week observances in Rome, which occur during the last week of the Christian penitential season of Lent, have been cancelled.
Many dioceses have recommended older Christians to stay at home rather than attending Mass on Sundays; some churches have made church services available via radio, online live streaming or television while others are offering drive-in worship.
With the Roman Catholic Diocese of Rome closing its churches and chapels and St. Peter's Square emptied of Christian pilgrims, other religious bodies also cancelled services and limited public gatherings in churches, mosques, synagogues, temples and gurdwaras.
Iran's Health Ministry announced the cancellation of Friday prayers in areas affected by the outbreak and shrines were later closed, while Saudi Arabia banned the entry of foreign pilgrims as well as its residents to holy sites in Mecca and Medina.
The pandemic has caused the most significant disruption to the worldwide sporting calendar since the Second World War.
Most major sporting events have been either cancelled or postponed, including the 2019–20 UEFA Champions League, 2019–20 Premier League, UEFA Euro 2020, 2019–20 NBA season, and 2019–20 NHL season.
" The outbreak disrupted plans for the 2020 Summer Olympics, which were originally scheduled to start at the end of July; the International Olympic Committee announced on 24 March that the event will be ""rescheduled to a date beyond 2020 but not later than summer 2021"".Casinos and other gaming venues worldwide have closed and live poker tournaments have been either postponed or cancelled. "
This has led many gamblers to move online, with many online gambling sites reporting significant increases in their rates of new sign-ups.The entertainment industry has also been affected, with various music groups suspending or cancelling concert tours.
Many large theatres such as those on Broadway also suspended all performances.
" Some artists have explored ways to continue to produce and share work over the internet as an alternative to traditional live performance, such as live streaming concerts or creating web-based ""festivals"" for artists to perform, distribute, and publicize their work. "
Online, numerous coronavirus-themed Internet memes have spread as many turn to humour and distraction amid uncertainty.
Since the outbreak of COVID-19, heightened prejudice, xenophobia, and racism have been noted toward people of Chinese and East Asian descent, and against people from hotspots in Europe, the United States and other countries.
Incidents of fear, suspicion, and hostility have been observed in many countries, particularly in Europe, East Asia, North America, and the Asia-Pacific region.
Reports from February (when the majority of the cases had still been confined to China) have documented racist sentiments expressed in various groups worldwide of Chinese people deserving the virus or receiving what has been claimed as justified retribution.
Some countries in Africa have also seen a rise in anti-Chinese sentiment.
Many residents of Wuhan and Hubei have reported discrimination based on their regional origin.
There has been support for the Chinese, both on and offline, and towards those in virus-stricken areas.
Following the progression of the outbreak to new hotspot countries, people from Italy, the first country in Europe to experience a serious outbreak of COVID-19, could also be subjected to suspicion and xenophobia.Citizens in countries including Malaysia, New Zealand, Singapore, and South Korea initially signed petitions lobbying to ban Chinese people from entering their countries in an effort to stop the disease.
In Japan, the hashtag #ChineseDontComeToJapan trended on Twitter.
Chinese people as well as other Asians in the United Kingdom and the United States have reported increasing levels of racist abuse, as well as assaults.
" U.S. president Donald Trump has faced criticism for referring to the coronavirus as the ""Chinese Virus"", a term considered by critics to be racist and anti-Chinese. "
Protesters in Ukraine attacked buses carrying Ukrainian and foreign evacuees from Wuhan to Novi Sanzhary.
Students who come from Northeast India, which shares a border with China, and study in major Indian cities have reportedly experienced harassment related to the coronavirus outbreak.
" The Bharatiya Janata Party's State unit president in West Bengal Dilip Ghosh stated that the Chinese had destroyed nature and ""that's why the God took revenge against them."" "
" The remarks were later condemned by the Chinese consulate in Kolkata, calling it ""erroneous"".In China, xenophobia and racism agains non-Chinese residents has been inflamed by the pandemic, with foreigners described as ""foreign garbage"" and targeted for ""disposal"". "
Many newspapers with paywalls have removed them for some or all of their coronavirus coverage.
Many scientific publishers made scientific papers related to the outbreak available with open access.
Some scientists chose to share their results quickly on preprint servers such as bioRxiv.
Emerging infectious disease – Infectious disease of emerging pathogen, often novel in its outbreak range or transmission mode
Globalization and disease – Overview of globalization and disease transmission
List of epidemics and pandemics – A list of death tolls due to infectious disease
Wildlife smuggling and zoonoses – Health risks associated with the trade in exotic wildlife
Laboratory testing for the respiratory coronavirus disease 2019 (COVID-19) and the associated SARS-CoV-2 virus includes methods that detect the presence of virus and those that detect antibodies produced in response to infection.
The presence of viruses in samples is confirmed by RT-PCR, which detects the coronavirus' RNA.
This test is specific and is designed to only detect the RNA of the SARS-CoV-2 virus.
It is used to confirm very recent or active infections.
Detection of antibodies (serology) can be used both for diagnosis and population surveillance.
Antibody tests show how many people have had the disease, including those whose symptoms were too minor to report or who were asymptomatic.
An accurate mortality rate of the disease and the level of herd immunity in the population can be determined from the results of this test.
Due to limited testing, as of March 2020 no countries had reliable data on the prevalence of the virus in their population.
By 23 March, no country had tested more than 3% of their population, and there are massive variations in how much testing has been done across countries.
This variability is also likely to be significantly affecting reported case fatality rates, which are likely to be significantly over-estimated in some countries.
Using real-time reverse transcription polymerase chain reaction (rRT-PCR) the test can be done on respiratory samples obtained by various methods, including nasopharyngeal swab or sputum sample.
Results are generally available within a few hours to 2 days.
The RT-PCR test performed with throat swabs is only reliable in the first week of the disease.
Later on the virus can disappear in the throat while it continues to multiply in the lungs.
For infected people tested in the second week, alternatively sample material can then be taken from the deep airways by suction catheter or coughing up material (sputum) can be used.
One of the early PCR tests was developed at Charité in Berlin in January 2020 using real-time reverse transcription polymerase chain reaction (rRT-PCR), and formed the basis of 250,000 kits for distribution by the World Health Organization (WHO).
The United Kingdom had also developed a test by 23 January 2020.The South Korean company Kogenebiotech developed a clinical grade, PCR-based SARS-CoV-2 detection kit (PowerChek Coronavirus) on 28 January 2020.
" It looks for the ""E"" gene shared by all beta coronaviruses, and the RdRp gene specific to SARS-CoV-2.In China, BGI Group was one of the first companies to receive emergency use approval from China's National Medical Products Administration for a PCR-based SARS-CoV-2 detection kit.In the United States, the Centers for Disease Control and Prevention (CDC) is distributing its 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel to public health labs through the International Reagent Resource. "
One of three genetic tests in older versions of the test kits caused inconclusive results due to faulty reagents, and a bottleneck of testing at the CDC in Atlanta; this resulted in an average of fewer than 100 samples a day being successfully processed throughout the whole of February 2020.
Tests using two components were not determined to be reliable until 28 February 2020, and it was not until then that state and local laboratories were permitted to begin testing.
The test was approved by the Food and Drug Administration under an Emergency Use Authorization.US commercial labs began testing in early March 2020.
As of 5 March 2020 LabCorp announced nationwide availability of COVID-19 testing based on RT-PCR.
Quest Diagnostics similarly made nationwide COVID-19 testing available as of 9 March 2020.
No quantity limitations were announced; specimen collection and processing must be performed according to CDC requirements.
In Russia, the COVID-19 test was developed and produced by the State Research Center of Virology and Biotechnology VECTOR.
On 11 February 2020 the test was registered by the Federal Service for Surveillance in Healthcare.On 12 March 2020, Mayo Clinic was reported to have developed a test to detect COVID-19 infection.On 13 March 2020, Roche Diagnostics received FDA approval for a test which could be performed within 3.5 hours in high volume, thus allowing one machine to do approximately 4,128 tests in a 24-hour period.
On 19 March 2020, the FDA issued emergency use authorization (EUA) to Abbott Laboratories for a test on Abbott's m2000 system; the FDA had previously issued similar authorization to Hologic, LabCorp, and Thermo Fisher Scientific.
On 21 March 2020, Cepheid similarly received EUA from the FDA for a test that takes about 45 minutes.
The FDA has approved a test that uses isothermal nucleic acid amplification technology instead of PCR.
Since this does not require a series of alternating temperature cycles this method can deliver positive results in as little as five minutes and negative results in 13 minutes.
There are currently about 18,000 of these machines in the U.S. and Abbott expects to ramp up manufacturing to deliver 50,000 tests per day.A test which uses a monoclonal antibody which specifically binds to the nucleocapsid protein (N protein) of the novel coronavirus is being developed in Taiwan, with the hope that it can provide results in 15 to 20 minutes just like a rapid influenza test.
" A March 2020 literature review concluded that ""chest radiographs are of little diagnostic value in early stages, whereas CT [computed tomography] findings may be present even before symptom onset."" "
Typical features on CT include bilateral multilobar ground-glass opacificities with a peripheral, asymmetric and posterior distribution.
Subpleural dominance, crazy paving and consolidation develop as the disease evolves.
A study comparing PCR to CT in Wuhan at the point of origin of the current pandemic has suggested that CT is significantly more sensitive than PCR, though less specific, with many of its imaging features overlapping with other pneumonias and disease processes.
" As of March 2020, the American College of Radiology recommends that ""CT should not be used to screen for or as a first-line test to diagnose COVID-19"".As of March 2020, the CDC recommends PCR for initial screening. "
Part of the immune response to infection is the production of antibodies including IgM and IgG.
These can be used to detect infection in individuals starting 7 days or so after the onset of symptoms, to determine immunity, and in population surveillance.Assays can be performed in central laboratories (CLT) or by point-of-care testing (PoCT).
The high-throughput automated systems in many clinical laboratories will be able to perform these assays but their availability will depend on the rate of production for each system.
For CLT a single specimen of peripheral blood is commonly used, although serial specimens can be used to follow the immune response.
For PoCT a single specimen of blood is usually obtained by skin puncture.
Unlike PCR methods an extraction step is not needed before assay.On March 26, 2020, the FDA named 29 entities that provided notification to the agency as required and are now therefore able to distribute their antibody tests.
As of April 7, 2020, only a single test has been approved by the FDA under an emergency use authorization.In late March 2020, Euroimmun Medical Laboratory Diagnostics and Epitope Diagnostics received European approvals for their test kits, which can detect IgG and IgA antibodies against the virus in blood samples.
The testing capacity is several hundred samples within hours and therefore much faster than the conventional PCR assay of viral RNA.
The antibodies are usually detectable 14 days after the onset of the infection.In early April, the UK found none of the antibody test kits it purchased were sufficiently good to use.
" Hong Kong has set up a scheme where suspected patients can stay home, ""emergency department will give a specimen tube to the patient"", they spit into it, send it back and get a test result a while after.The British NHS has announced that it is piloting a scheme to test suspected cases at home, which removes the risk of a patient infecting others if they come to a hospital or having to disinfect an ambulance if one is used.In drive-through testing for COVID-19 for suspected cases, a healthcare professional takes sample using appropriate precautions. "
Drive-through centers have helped South Korea do some of the fastest, most-extensive testing of any country.In Germany, the National Association of Statutory Health Insurance Physicians said on 2 March, that it had a capacity for about 12,000 tests per day in the ambulatory setting and 10.700 had been tested in the prior week.
Costs are borne by the health insurance when the test is ordered by a physician.
According to the president of the Robert Koch Institute, Germany has an overall capacity for 160,000 tests per week.
As of 19 March drive in tests were offered in several large cities.
As of 26 March 2020 the total number of tests performed in Germany was unknown, because only positive results are reported.
" A first lab survey revealed that as of calendar week 12/2020 a total of at least 483,295 samples were tested up to and including week 12/2020 and 33,491 samples (6.9%) tested positive for SARS-CoV-2.In Israel, researchers at Technion and Rambam Hospital developed and tested a method for testing samples from 64 patients simultaneously, by pooling the samples and only testing further if the combined sample is found to be positive.In Wuhan a makeshift 2000-sq-meter emergency detection laboratory named ""Huo-Yan"" (Chinese: 火眼, or ""Fire Eye"" in English) was opened on 5 February 2020 by BGI, which can process over 10,000 samples a day. "
With the construction overseen by BGI-founder Wang Jian and taking 5-days, modelling has show cases in Hubei would have been 47% higher and the corresponding cost of the tackling the quarantine would have doubled if this testing capacity hadn't come on line.
The Wuhan Laboratory has been promptly followed by Huo-Yan labs in Shenzhen, Tianjin, Beijing, and Shanghai, in a total of 12 cities across China.
By 4 March 2020 the daily throughput totals were 50,000 tests per day.Open source, multiplexed designs released by Origami Assays have been released that can test as many as 1122 patient samples for COVID19 using only 93 assays . These balanced designs can be run in small laboratories without the need for robotic liquid handlers.
By March, shortages and insufficient amounts of reagent has become a bottleneck for mass testing in the EU and UK and the US.
This has led some authors to explore sample preparation protocols that involve heating samples at 98 °C (208 °F) for 5 minutes to release RNA genomes for further testing.On 31 March it was announced United Arab Emirates was now testing more of its population for Coronavirus per head than any other country, and was on track to scale up the level of testing to reach the bulk of the population.
" This was through a combination of drive-through capability, and purchasing a population-scale mass-throughput laboratory from Group 42 and BGI (based on their ""Huo-Yan"" emergency detection laboratories in China). "
Constructed in 14 days, the lab is capable of conducting tens of thousands RT-PCR tests per day and is the first in the world of this scale to be operational outside of China.
Different testing recipes targeting different parts of the coronavirus genetic profile were developed in China, France, Germany, Hong Kong, Japan, and the United States.
The World Health Organization adopted the German recipe for manufacturing kits sent to low-income countries without the resources to develop their own.
The German recipe was published on 17 January 2020; the protocol developed by the United States Centers for Disease Control was not available until 28 January, delaying available tests in the U.S.China and the United States had problems with the reliability of test kits early in the outbreak, and these countries and Australia were unable to supply enough kits to satisfy demand and recommendations for testing by health experts.
In contrast, experts say South Korea's broad availability of testing helped reduce the spread of the novel coronavirus.
Testing capacity, largely in private sector labs, was built up over several years by the South Korean government.
On 16 March, the World Health Organization called for ramping up the testing programmes as the best way to slow the advance of COVID-19 pandemic.High demand for testing due to wide spread of the virus caused backlogs of hundreds of thousands of tests at private U.S. labs, and supplies of swabs and chemical reagents became strained.
In March 2020 China reported problems with accuracy in their test kits.
" In the United States, the test kits developed by the CDC had ""flaws;"" the government then removed the bureaucratic barriers that had prevented private testing.Spain purchased test kits from Chinese firm Shenzhen Bioeasy Biotechnology Co Ltd, but found that results were inaccurate. "
The firm explained that the incorrect results may be a result of a failure to collect samples or use the kits correctly.
The Spanish ministry said it will withdraw the kits that returned incorrect results, and would replace them with a different testing kit provided by Shenzhen Bioeasy.80% of test kits the Czech Republic purchased from China gave wrong results.Slovakia purchased 1.2 million test kits from China which were found to be inaccurate.
" Prime Minister Matovič suggested these be dumped into the Danube.Ateş Kara of the Turkish Health Ministry said the test kits Turkey purchased from China had a ""high error rate"" and did not ""put them into use.""The UK purchased 3.5 million test kits from China but in early April 2020 announced these were not usable. "
Testing, followed with quarantine of those who tested positive and tracing of those with whom the SARS-CoV-2 positive people had had contact, resulted in positive outcomes.
Researchers working in the Italian town of Vò, the site of the first COVID-19 death in Italy, conducted two rounds of testing on the entire population of about 3,400 people, about ten days apart.
About half the people testing positive had no symptoms, and all discovered cases were quarantined.
With travel to the commune restricted, this eliminated new infections completely.
With aggressive contact tracing, inbound travel restrictions, testing, and quarantining, the 2020 coronavirus pandemic in Singapore has proceeded much more slowly than in other developed countries, but without extreme restrictions like forced closure of restaurants and retail establishments.
Many events have been cancelled, and Singapore did start advising residents to stay at home on 28 March, but schools reopened on time after holiday break on 23 March.
Several other countries have also managed the pandemic with aggressive contact tracing, inbound travel restrictions, testing, and quarantining, but with less aggressive lock-downs, such as Iceland and South Korea.
A statistical study has found that countries that have tested more, relative to the number of deaths, have much lower case fatality rates, probably because these countries are better able to detect those with only mild or no symptoms.
WHO recommends that countries that do not have testing capacity and national laboratories with limited experience on COVID-19 send their first five positives and the first ten negative COVID-19 samples to one of the 16 WHO reference laboratories for confirmatory testing.
Out of the 16 reference laboratories, 7 are in Asia, 5 in Europe, 2 in Africa, 1 in North America and 1 in Australia.
In the following chart, the column “Positive as % of tests” is influenced by the country's testing policy.
A country that only tests people admitted to hospitals will have a higher positive as % of tests than a country that tests all citizens, whether or not they are showing symptoms, other things being equal.
Hand washing (or handwashing), also known as hand hygiene, is the act of cleaning one's hands for the purpose of removing soil, grease, microorganisms, or other unwanted substances.
" Hand washing with soap consistently at certain ""critical moments"" during the day prevents the spread of many diseases, for example diarrhoea and cholera, which are transmitted through fecal–oral route. "
People can also become infected with respiratory diseases such as influenza or the common cold, for example, if they do not wash their hands before touching their eyes, nose, or mouth (i.e., mucous membranes).
The five critical moments during the day where washing hands with soap is important include: before and after defecation, after cleaning a child's bottom or changing nappies, before feeding a child, before eating and before and after preparing food or handling raw meat, fish, or poultry.
If water and soap are not available, hands can be cleaned with ash.The World Health Organization recommends washing hands:
Before, during, and after preparing food.
Before and after caring for a sick person.
After changing the diapers or cleaning up a child who has used the toilet.
After blowing your nose, coughing or sneezing.
After touching animal, animal feed, or animal waste.
Medical hand hygiene refers to hygiene practices related to medical procedures.
Hand washing before administering medicine or medical care can prevent or minimize the spread of disease.
The main medical purpose of washing hands is to cleanse the hands of pathogens (bacteria, viruses, or other microorganisms that can cause disease) and chemicals which can cause harm or diseases.
This is especially important for people who handle food or work in the medical field, but also an important practice for the general public.
Hand washing has many health benefits, including minimizing the spread of influenza, coronavirus, and other infectious diseases; preventing infectious causes of diarrhea; decreasing respiratory infections;
and reducing infant mortality rate at home birth deliveries.
A 2013 study showed that improved hand washing practices may lead to small improvements in the length growth in children under five years of age.
In developing countries, childhood mortality rates related to respiratory and diarrheal diseases can be reduced by introducing simple behavioral changes, such as hand washing with soap.
This simple action can reduce the rate of mortality from these diseases by almost 50%.
Interventions that promote hand washing can reduce diarrhoea episodes by about a third, and this is comparable to providing clean water in low income areas.
48% of reductions in diarrhoea episodes can be associated with hand washing with soap.Hand washing with soap is the single most effective and inexpensive way to prevent diarrhea and acute respiratory infections (ARI), as automatic behavior performed in homes, schools, and communities worldwide.
Pneumonia, a major ARI, is the number one cause of mortality among children under five years old, taking the lives of an estimated 1.8 million children per year.
Diarrhea and pneumonia together account for almost 3.5 million child deaths annually.
According to UNICEF, turning hand washing with soap before eating and after using the toilet into an ingrained habit can save more lives than any single vaccine or medical intervention, cutting deaths from diarrhea by almost half and deaths from acute respiratory infections by one-quarter.
Hand washing is usually integrated together with other sanitation interventions as part of water, sanitation and hygiene (WASH) programmes.
Hand washing also protects against impetigo which is transmitted through direct physical contact.
A small detrimental effect of hand washing is that frequent hand washing can lead to skin damage due to drying of the skin.
A 2012 Danish study found that excessive hand washing can lead to an itchy, flaky skin condition known as hand eczema or hand dermatitis, which is especially common among health-care workers.
Too frequent hand washing is also seen as one of the symptoms of obsessive-compulsive disorder (OCD).
There are five critical times during the day where washing hands with soap is important to reduce fecal-oral transmission of disease: after using the bathroom (urination, defecation), after cleaning a child's bottom (changing nappies), before feeding a child, before eating and before/after preparing food or handling raw meat, fish, or poultry.
Other occasions when correct handwashing technique should be practiced in order to prevent the transmission of disease include before and after treating a cut or wound; after sneezing, coughing, or blowing your nose; after touching animal waste or handling animals; and after touching garbage.
In many countries, there is a low rate of hand washing with soap.
A study of hand washing in 54 countries in 2015 found that on average, 38.7% of households practiced hand washing with soap.A 2014 study showed that Saudi Arabia had the highest rate of 97 percent; the United States near the middle with 77 percent; and China with the lowest rate of 23 percent.Several behaviour change methodologies now exist to increase uptake of the behaviour of hand washing with soap at the critical times.Group hand washing for school children at set times of the day is one option in developing countries to engrain hand washing in children's behaviors.
" The ""Essential Health Care Program"" implemented by the Department of Education in the Philippines is an example of at scale action to promote children's health and education. "
Deworming twice a year, supplemented with washing hands daily with soap, brushing teeth daily with fluoride, is at the core of this national program.
It has also been successfully implemented in Indonesia.
Removal of microorganisms from skin is enhanced by the addition of soaps or detergents to water.
The main action of soaps and detergents is to reduce barriers to solution, and increase solubility.
Water alone is an inefficient skin cleanser because fats and proteins, which are components of organic soil, are not readily dissolved in water.
Cleansing is, however, aided by a reasonable flow of water..
Solid soap, because of its reusable nature, may hold bacteria acquired from previous uses.
A small number of studies which have looked at the bacterial transfer from contaminated solid soap have concluded transfer is unlikely as the bacteria are rinsed off with the foam.
" The CDC still states ""liquid soap with hands-free controls for dispensing is preferable"". "
Antibacterial soaps have been heavily promoted to a health-conscious public.
To date, there is no evidence that using recommended antiseptics or disinfectants selects for antibiotic-resistant organisms in nature.
However, antibacterial soaps contain common antibacterial agents such as triclosan, which has an extensive list of resistant strains of organisms.
So, even if antibiotic resistant strains aren't selected for by antibacterial soaps, they might not be as effective as they are marketed to be.
Besides the surfactant and skin-protecting agent, the sophisticated formulations may contain acids (acetic acid, ascorbic acid, lactic acid) as pH regulator, antimicrobially active benzoic acid and further skin conditioners (aloe vera, vitamins, menthol, plant extracts).A comprehensive analysis from the University of Oregon School of Public Health indicated that plain soaps are as effective as consumer-grade anti-bacterial soaps containing triclosan in preventing illness and removing bacteria from the hands.
Hot water that is comfortable for washing hands is not hot enough to kill bacteria.
Bacteria grow much faster at body temperature (37 °C).
However, warm, soapy water is more effective than cold, soapy water at removing natural oils which hold soils and bacteria.
Contrary to popular belief however, scientific studies have shown that using warm water has no effect on reducing the microbial load on hands.
A hand sanitizer or hand antiseptic is a non-water-based hand hygiene agent.
In the late 1990s and early part of the 21st century, alcohol rub non-water-based hand hygiene agents (also known as alcohol-based hand rubs, antiseptic hand rubs, or hand sanitizers) began to gain popularity.
Most are based on isopropyl alcohol or ethanol formulated together with a thickening agent such as Carbomer (polymer of acrylic acid) into a gel, or a humectant such as glycerin into a liquid, or foam for ease of use and to decrease the drying effect of the alcohol.
Adding diluted hydrogen-peroxide increases further the antimicrobial activity.Hand sanitizers containing a minimum of 60 to 95% alcohol are efficient germ killers.
Alcohol rub sanitizers kill bacteria, multi-drug resistant bacteria (MRSA and VRE), tuberculosis, and some viruses (including HIV, herpes, RSV, rhinovirus, vaccinia, influenza, and hepatitis) and fungi.
Alcohol rub sanitizers containing 70% alcohol kill 99.97% (3.5 log reduction, similar to 35 decibel reduction) of the bacteria on hands 30 seconds after application and 99.99% to 99.999% (4 to 5 log reduction) of the bacteria on hands 1 minute after application.Hand sanitizers are most effective against bacteria and less effective against some viruses.
Alcohol-based hand sanitizers are almost entirely ineffective against norovirus (or Norwalk) type viruses, the most common cause of contagious gastroenteritis.Enough hand antiseptic or alcohol rub must be used to thoroughly wet or cover both hands.
The front and back of both hands and between and the ends of all fingers are rubbed for approximately 30 seconds until the liquid, foam or gel is dry.
Finger tips must be washed well too, rubbing them in both palms.The US Center for Disease Control and Prevention recommends hand washing over hand sanitizer rubs, particularly when hands are visibly dirty.
The increasing use of these agents is based on their ease of use and rapid killing activity against micro-organisms; however, they should not serve as a replacement for proper hand washing unless soap and water are unavailable.
Frequent use of alcohol-based hand sanitizers can cause dry skin unless emollients and/or skin moisturizers are added to the formula.
The drying effect of alcohol can be reduced or eliminated by adding glycerin and/or other emollients to the formula.
In clinical trials, alcohol-based hand sanitizers containing emollients caused substantially less skin irritation and dryness than soaps or antimicrobial detergents.
Allergic contact dermatitis, contact urticaria syndrome or hypersensitivity to alcohol or additives present in alcohol hand rubs rarely occur.
The lower tendency to induce irritant contact dermatitis became an attraction as compared to soap and water hand washing.
Despite their effectiveness, non-water agents do not cleanse the hands of organic material, but simply disinfect them.
It is for this reason that hand sanitizers are not as effective as soap and water at preventing the spread of many pathogens, since the pathogens still remain on the hands.
Alcohol-free hand sanitizer efficacy is heavily dependent on the ingredients and formulation, and historically has significantly under-performed alcohol and alcohol rubs.
More recently, formulations that use benzalkonium chloride have been shown to have persistent and cumulative antimicrobial activity after application, unlike alcohol, which has been shown to decrease in efficacy after repeated use, probably due to progressive adverse skin reactions.
Many people in low-income communities cannot afford soap and use ash or soil instead.
Ash or soil may be more effective than water alone, but may be less effective than soap.
One concern is that if the soil or ash is contaminated with microorganisms it may increase the spread of disease rather than decrease it.
Like soap, ash is also a disinfecting agent because in contact with water, it forms an alkaline solution.
WHO recommended ash or sand as alternative to soap when soap is not available.
Correct handwashing technique recommended by the US Centers for Disease Control for prevention of transmission of disease includes the following steps:
Wet hands with warm or cold running water.
Running water is recommended because standing basins may be contaminated, while the temperature of the water does not seem to make a difference.
Lather hands by rubbing them with a generous amount of soap, including the backs of hands, between fingers, and under nails.
Soap lifts germs from the skin, and studies show that people tend to wash their hands more thoroughly when soap is used rather than water alone.
Scrub for at least 20 seconds.
Scrubbing creates friction, which helps remove germs from skin, and scrubbing for longer periods removes more germs.
Rinse well under running water.
Rinsing in a basin can recontaminate hands.
Dry with a clean towel or allow to air dry.
Wet and moist hands are more easily recontaminated.The most commonly missed areas are the thumb, the wrist, the areas between the fingers, and under fingernails.
Artificial nails and chipped nail polish may harbor microorganisms.
Moisturizing lotion is often recommended to keep the hands from drying out; dry skin can lead to skin damage which can increase the risk for the transmission of infection.
" Various low-cost options can be made to facilitate hand washing where tap-water and/or soap is not available e.g. pouring water from a hanging jerrycan or gourd with suitable holes and/or using ash if needed in developing countries.In situations with limited water supply (such as schools or rural areas in developing countries), there are water-conserving solutions, such as ""tippy-taps"" and other low-cost options. "
A tippy-tap is a simple technology using a jug suspended by a rope, and a foot-operated lever to pour a small amount of water over the hands and a bar of soap.
Effective drying of the hands is an essential part of the hand hygiene process, but there is some debate over the most effective form of drying in public washrooms.
A growing volume of research suggests paper towels are much more hygienic than the electric hand dryers found in many washrooms.
In 2008, a study was conducted by the University of Westminster, London, and sponsored by the paper-towel industry the European Tissue Symposium, to compare the levels of hygiene offered by paper towels, warm-air hand dryers and the more modern jet-air hand dryers.
After washing and drying hands with the warm-air dryer, the total number of bacteria was found to increase on average on the finger pads by 194% and on the palms by 254%.
Drying with the jet-air dryer resulted in an increase on average of the total number of bacteria on the finger pads by 42% and on the palms by 15%.
After washing and drying hands with a paper towel, the total number of bacteria was reduced on average on the finger pads by up to 76% and on the palms by up to 77%.The scientists also carried out tests to establish whether there was the potential for cross contamination of other washroom users and the washroom environment as a result of each type of drying method.
The jet-air dryer, which blows air out of the unit at claimed speeds of 180 m/s (650 km/h; 400 mph), was capable of blowing micro-organisms from the hands and the unit and potentially contaminating other washroom users and the washroom environment up to 2 metres away.
Use of a warm-air hand dryer spread micro-organisms up to 0.25 metres from the dryer.
Paper towels showed no significant spread of micro-organisms.In 2005, in a study conducted by TÜV Produkt und Umwelt, different hand drying methods were evaluated.
The following changes in the bacterial count after drying the hands were observed:
Many different hand dryer manufacturers exist, and hand driers have been compared against drying with paper towels.
Hand washing using hand sanitizing wipes is an alternative during traveling in the absence of soap and water.
Alcohol-based hand sanitizer should contain at least 60% alcohol.
Medical hand-washing became mandatory long after Hungarian physician Ignaz Semmelweis discovered its effectiveness (in 1846) in preventing disease in a hospital environment.
There are electronic devices that provide feedback to remind hospital staff to wash their hands when they forget.
One study has found decreased infection rates with their use.
Medical hand-washing is for a minimum of 15 seconds, using generous amounts of soap and water or gel to lather and rub each part of the hands.
Hands should be rubbed together with digits interlocking.
If there is debris under fingernails, a bristle brush may be used to remove it.
Since germs may remain in the water on the hands, it is important to rinse well and wipe dry with a clean towel.
After drying, the paper towel should be used to turn off the water (and open any exit door if necessary).
This avoids re-contaminating the hands from those surfaces.
" The purpose of hand-washing in the health-care setting is to remove pathogenic microorganisms (""germs"") and avoid transmitting them. "
The New England Journal of Medicine reports that a lack of hand-washing remains at unacceptable levels in most medical environments, with large numbers of doctors and nurses routinely forgetting to wash their hands before touching patients, thus transmitting microorganisms.
One study showed that proper hand-washing and other simple procedures can decrease the rate of catheter-related bloodstream infections by 66 percent.The World Health Organization has published a sheet demonstrating standard hand-washing and hand-rubbing in health-care sectors.
The draft guidance of hand hygiene by the organization can also be found at its website for public comment.
A relevant review was conducted by Whitby et al.
Commercial devices can measure and validate hand hygiene, if demonstration of regulatory compliance is required.
" The World Health Organization has ""Five Moments"" for washing hands: "
after exposure to blood/body fluids
before an aseptic task, and
" after patient care.The addition of antiseptic chemicals to soap (""medicated"" or ""antimicrobial"" soaps) confers killing action to a hand-washing agent. "
Such killing action may be desired prior to performing surgery or in settings in which antibiotic-resistant organisms are highly prevalent.To 'scrub' one's hands for a surgical operation, it is necessary to have a tap that can be turned on and off without touching it with the hands, some chlorhexidine or iodine wash, sterile towels for drying the hands after washing, and a sterile brush for scrubbing and another sterile instrument for cleaning under the fingernails.
All jewelry should be removed.
This procedure requires washing the hands and forearms up to the elbow, usually 2–6 minutes.
Long scrub-times (10 minutes) are not necessary.
When rinsing, water on the forearms must be prevented from running back to the hands.
After hand-washing is completed, the hands are dried with a sterile cloth and a surgical gown is donned.
To reduce the spread of germs, it is better to wash the hands or use a hand antiseptic before and after tending to a sick person.
For control of staphylococcal infections in hospitals, it has been found that the greatest benefit from hand-cleansing came from the first 20% of washing, and that very little additional benefit was gained when hand cleansing frequency was increased beyond 35%.
Washing with plain soap results in more than triple the rate of bacterial infectious disease transmitted to food as compared to washing with antibacterial soap.Comparing hand-rubbing with alcohol-based solution with hand washing with antibacterial soap for a median time of 30 seconds each showed that the alcohol hand-rubbing reduced bacterial contamination 26% more than the antibacterial soap.
But soap and water is more effective than alcohol-based hand rubs for reducing H1N1 influenza A virus and Clostridium difficile spores from hands.Interventions to improve hand hygiene in healthcare settings can involve education for staff on hand washing, increasing the availability of alcohol-based hand rub, and written and verbal reminders to staff.
There is a need for more research into which of these interventions are most effective in different healthcare settings.
In developing countries, hand washing with soap is recognized as a cost-effective, essential tool for achieving good health, and even good nutrition.
However, a lack of reliable water supply, soap or hand washing facilities in people's homes, at schools and at the workplace make it a challenge to achieve universal hand washing behaviors.
For example, in most of rural Africa hand washing taps close to every private or public toilet are scarce, even though cheap options exist to build hand washing stations.
However, low hand washing rates rather can also be the result of engrained habits rather than due to a lack of soap or water.
The promotion and advocacy of hand washing with soap can influence policy decisions, raise awareness about the benefits of hand washing and lead to long-term behavior change of the population.
For this to work effectively, monitoring and evaluation are necessary.
" A systematic review of 70 studies found that community-based approaches are effective at increasing hand washing in LMICs, while social marketing campaigns are less effective.One example for hand washing promotion in schools is the ""Three Star Approach"" by UNICEF that encourages schools to take simple, inexpensive steps to ensure that students wash their hands with soap, among other hygienic requirements. "
When minimum standards are achieved, schools can move from one to ultimately three stars.
Building hand washing stations can be a part of hand washing promotion campaigns that are carried out in order to reduce diseases and child mortality.
Global Hand washing Day is another example of an awareness-raising campaign that is trying to achieve behavior change.As a result of the 2019-20 coronavirus pandemic, UNICEF promoted the adoption of a handwashing emoji.
Few studies have considered the overall cost effectiveness of hand washing in developing countries in relationship to DALYs averted.
However, one review suggests that promoting hand washing with soap is significantly more cost-effective than other water and sanitation interventions.
" The importance of hand washing for human health – particularly for people in vulnerable circumstances like mothers who had just given birth or wounded soldiers in hospitals – was first recognized in the mid 19th century by two pioneers of hand hygiene: the Hungarian physician Ignaz Semmelweis who worked in Vienna, Austria and Florence Nightingale, the English ""founder of modern nursing"". "
At that time most people still believed that infections were caused by foul odors called miasmas.
In the 1980s, foodborne outbreaks and healthcare-associated infections led the United States Centers for Disease Control and Prevention to more actively promote hand hygiene as an important way to prevent the spread of infection.
The outbreak of swine flu in 2009 and the COVID-19 pandemic in 2020 led to increased awareness in many countries of the importance of washing hands with soap to protect oneself from such infectious diseases.
" For example, posters with ""correct hand washing techniques"" were hung up next to hand washing sinks in public toilets and in the toilets of office buildings and airports in Germany. "
" The phrase ""washing one's hands of"" something, means declaring one's unwillingness to take responsibility for the thing or share complicity in it. "
It originates from the bible passage in Matthew where Pontius Pilate washed his hands of the decision to crucify Jesus Christ, but has become a phrase with a much wider usage in some English communities.
In Shakespeare's Macbeth, Lady Macbeth begins to compulsively wash her hands in an attempt to cleanse an imagined stain, representing her guilty conscience regarding crimes she had committed and induced her husband to commit.
It has also been found that people, after having recalled or contemplated unethical acts, tend to wash hands more often than others, and tend to value hand washing equipment more.
" Furthermore, those who are allowed to wash their hands after such a contemplation are less likely to engage in other ""cleansing"" compensatory actions, such as volunteering. "
Religions prescribe hand washing for both hygienic and symbolic purposes.Symbolic hand washing, using water but no soap to wash hands, is a part of ritual hand washing featured in many religions, including Bahá'í Faith, Hinduism, tevilah and netilat yadayim in Judaism, Lavabo in Christianity, and Wudhu in Islam.Religions also prescribe hygienic hand washing, especially after certain actions.
Hinduism, Judaism and Islam mandate washing of hands after using the toilet.
And, Hinduism, Buddhism, Sikhism, Judaism and Islam mandate washing of hands before and after every meal.
Impact of the 2019–20 coronavirus pandemic on education
The 2019–20 coronavirus pandemic has affected educational systems worldwide, leading to the widespread closures of schools and universities.
As of 8 April 2020, approximately 1.716 billion learners have been affected due to school closures in response to COVID-19.
According to UNESCO monitoring, 188 countries have implemented nationwide closures and 5 have implemented local closures, impacting about 99.4% of the world's student population.
On 23 March 2020, Cambridge International Examinations (CIE) released a statement announcing the cancellation of Cambridge IGCSE, Cambridge O Level, Cambridge International AS & amp; A Level, Cambridge AICE Diploma, and Cambridge Pre-U examinations for the May/June 2020 series across all countries.
International Baccalaureate exams have also been cancelled.School closures impact not only students, teachers, and families, but have far-reaching economic and societal consequences.
School closures in response to COVID-19 have shed light on various social and economic issues, including student debt, digital learning, food insecurity, and homelessness, as well as access to childcare, health care, housing, internet, and disability services.
The impact was more severe for disadvantaged children and their families, causing interrupted learning, compromised nutrition, childcare problems, and consequent economic cost to families who could not work.In response to school closures, UNESCO recommended the use of distance learning programmes and open educational applications and platforms that schools and teachers can use to reach learners remotely and limit the disruption of education.
Efforts to stem the spread of COVID-19 through non-pharmaceutical interventions and preventive measures such as social-distancing and self-isolation have prompted the widespread closure of primary, secondary, and tertiary schooling in over 100 countries.Previous outbreaks of infectious diseases have prompted widespread school closings around the world, with varying levels of effectiveness.
Mathematical modelling has shown that transmission of an outbreak may be delayed by closing schools.
However, effectiveness depends on the contacts children maintain outside of school.
School closures may be effective when enacted promptly.
If school closures occur late relative to an outbreak, they are less effective and may not have any impact at all.
Additionally, in some cases, the reopening of schools after a period of closure has resulted in increased infection rates.
As closures tend to occur concurrently with other interventions such as public gathering bans, it can be difficult to measure the specific impact of school closures.During the 1918-1919 influenza pandemic in the United States, school closures and public gathering bans were associated with lower total mortality rates.
Cities that implemented such interventions earlier had greater delays in reaching peak mortality rates.
Schools closed for a median duration of 4 weeks according to a study of 43 US cities' response to the Spanish Flu.
School closures were shown to reduce morbidity from the Asian flu by 90% during the 1957–58 outbreak, and up to 50% in controlling influenza in the US, 2004–2008.Multiple countries successfully slowed the spread of infection through school closures during the 2009 H1N1 Flu pandemic.
School closures in the city of Oita, Japan, were found to have successfully decreased the number of infected students at the peak of infection; however closing schools was not found to have significantly decreased the total number of infected students.
Mandatory school closures and other social distancing measures were associated with a 29% to 37% reduction in influenza transmission rates.
Early school closures in the United States delayed the peak of the 2009 H1N1 Flu pandemic.
" Despite the overall success of closing schools, a study of school closures in Michigan found that ""district level reactive school closures were ineffective.""During the swine flu outbreak in 2009 in the UK, in an article titled ""Closure of schools during an influenza pandemic"" published in the Lancet Infectious Diseases, a group of epidemiologists endorsed the closure of schools in order to interrupt the course of the infection, slow further spread and buy time to research and produce a vaccine. "
Having studied previous influenza pandemics including the 1918 flu pandemic, the influenza pandemic of 1957 and the 1968 flu pandemic, they reported on the economic and workforce effect school closure would have, particularly with a large percentage of doctors and nurses being women, of whom half had children under the age of 16.
They also looked at the dynamics of the spread of influenza in France during French school holidays and noted that cases of flu dropped when schools closed and re-emerged when they re-opened.
They noted that when teachers in Israel went on strike during the flu season of 1999–2000, visits to doctors and the number of respiratory infections dropped by more than a fifth and more than two fifths respectively.
For schools and childcare facilities, the U.S. Centers for Disease Control and Prevention recommends short-term closure to clean or disinfect if an infected person has been in a school building regardless of community spread.
When there is minimal to moderate community transmission, social distancing strategies can be implemented such as cancelling field trips, assemblies, and other large gatherings such as physical education or choir classes or meals in a cafeteria, increasing the space between desks, staggering arrival and dismissal times, limiting nonessential visitors, and using a separate health office location for children with flu-like symptoms.
When there is substantial transmission in the local community, in addition to social distancing strategies, extended school dismissals may be considered.
On 26 January, China instituted measures to contain the COVID-19 outbreak which included extending the Spring Festival holiday to contain the outbreak.
Universities and schools around the country closed.
On 23 February, Iran's Ministry of Health announced the closure of universities, higher educational institutions and schools in several cities and provinces.
On 3 March, UNESCO released the first global numbers on school closures and affected students.
It reported that 13 countries had enacted preventive measures including the temporary closure of schools and universities, impacting 290.5 million students around the world.
In reaction, UNESCO called on countries to support affected students and families and facilitate large-scale inclusive distance learning programmes.
On 4 March, the Italian government ordered the full closure of all schools and universities nationwide as Italy reached 100 deaths.
In doing so, Italy became one of 22 countries on three continents which had announced or implemented school closures.
On 5 March, the majority of learners affected by COVID-19 emergency measures were located in China, with 233 million learners affected, followed by Japan at 16.5 million and Iran at 14.5 million.
" By 10 March, one in five students worldwide was ""staying away from school due to the COVID-19 crisis"" while another one in four was barred from higher education institutions. "
On 13 March, governments in 49 countries announced or implemented school closures, including 39 countries which closed schools nationwide and 22 countries with localised school closures.
By 16 March, this figure increased from 49 to 73 countries according to UNESCO.
By 19 March, 50% of students worldwide were affected by school closures, corresponding to nationwide closures in 102 countries and local closures in 11 countries affecting 850 million children and youth.
By 20 March, over 70% of the world's learners were impacted by closures, with 124 country-wide school closures.
On 23 March, all Nigerian school were found to have been closed down by Nigerian government, markets as well as companies were closed down and children were forbidden by parents to step out of their homes.
On 26 March, all New Zealand schools and universities have been closed down across the country.
The government has imposed a two-week holiday, allowing schools to transition to forms of distant teaching as soon as possible.
Universities have closed for one week, but resumed with online teaching afterwards.
Other school services remain open, but teaching is restricted to distant learning.
By 27 March, nearly 90 percent of the world's student population was out of class.
Regions with schools remaining open included Taiwan, Singapore, Australia, Sweden, and some U.S. states.
By 29 March, more than 1.5 billion children and other students were affected by nationwide school closures.
Others were disrupted by localized closures.
Until April 6, holidays were extended in all secondary schools of Turkmenistan.
An order signed by the Ministry of Education as a preventative measure aims to prevent the spread of respiratory diseases in connection with the WHO coronavirus pandemic.
10 countries have localised schools closures, UNESCO estimates 473,933,356 learners are potentially at risk (pre-primary to upper-secondary education) and 77,938,904 learners are potentially at risk in tertiary education.
Note: Figures correspond to total number of learners enrolled at pre-primary, primary, lower-secondary, and upper-secondary levels of education [ISCED levels 0 to 3], as well as at tertiary education levels [ISCED levels 5 to 8] who could be affected should localised closures become countrywide.
Enrolment figures based on latest UNESCO Institute of Statistics data.
School closures in response to the COVID-19 pandemic have shed a light on numerous issues affecting access to education, as well as broader socio-economic issues.
As of March 12, more than 370 million children and youth are not attending school because of temporary or indefinite country wide school closures mandated by governments in an attempt to slow the spread of COVID-19.
As of 29 March, nearly 90% of the world's learners were impacted by closures.Even when school closures are temporary, it carries high social and economic costs.
The disruptions they cause affect people across communities, but their impact is more severe for disadvantaged children and their families including interrupted learning, compromised nutrition, childcare problems and consequent economic cost to families who cannot work.
Working parents are more likely to miss work when schools close in order to take care of their children, incurring wage loss in many instances and negatively impacting productivity.
Localised school closures place burdens on schools as parents and officials redirect children to schools that are open.
Women often represent a large share of health-care workers and often cannot attend work because of childcare obligations that result from school closures.
This means that many medical professionals are not at the facilities where they are most needed during a health crisis.
Lack of access to technology or fast, reliable internet access can prevent students in rural areas and from disadvantaged families.
Lack of access to technology or good internet connectivity is an obstacle to continued learning, especially for students from disadvantaged families.
In response to school closures caused by COVID-19, UNESCO recommends the use of distance learning programmes and open educational applications and platforms that schools and teachers can use to reach learners remotely and limit the disruption of education.To aid in slowing the transmission of COVID-19, hundreds of libraries have temporarily closed.
In the United States, numerous major cities announced public library closures, including Los Angeles, San Francisco, Seattle, and New York City, affecting 221 libraries.
For students without internet at home, this increases the difficulty of keeping up with distance learning.
School closures puts a strain on parents and guardians to provide childcare and manage distance learning while children are out of school.
In the absence of alternative options, working parents often leave children alone when schools close and this can lead to risky behaviours, including increased influence of peer pressure and substance abuse.
Many children worldwide rely on free or discounted meals at schools.
When schools close, nutrition is compromised.Nutrition plays a critical role in cognitive development and academic performance for children.In Washington State, around 45% of the states 1.1 million students enrolled in traditional public and charter schools qualify for subsidised school meals.
At least 520,000 students and their families may be affected by food insecurity as a result of school closures.School lunch programmes are the second-biggest anti-hunger initiative in the United States after food stamps.
Every year, nearly 30 million children rely on schools to provide free or low-cost meals including breakfast, lunch, snacks, and even dinner.In Alabama, where state-wide school closures as of 18 March have affected over 720,000 students, the state Superintendent announced that staff in schools disproportionately affected by poverty would create meal distribution networks to provide food for students who rely on school lunches.
School closures negatively impact student learning outcomes.
Schooling provides essential learning and when schools close, children and youth are deprived opportunities for growth and development.
The disadvantages are disproportionate for under-privileged learners who tend to have fewer educational opportunities beyond school.Student drop-out rates tend to increase as an effect of school closures due to the challenge of ensuring all students return to school once school closures ends.
This is especially true of protracted closures.Schools are hubs of social activity and human interaction.
When schools are closed, many children and youth miss out of on social contact that is essential to learning and development.When schools close parents are often asked to facilitate the learning of children at home and can struggle to perform this task.
This is especially true for parents with limited education and resources.
Potential impacts of school closures and reliance on distance learning are not addressed in federal acts of legislation at this time.
Formal education — as opposed to informal education or non-formal education — tends to refer to schools, colleges, universities and training institutions.
A 1974 report by the World Bank defined formal education as the following:Formal education: the hierarchically structured, chronologically graded ‘education system’, running from primary school through the university and including, in addition to general academic studies, a variety of specialised programmes and institutions for full-time technical and professional training.The majority of data collected on the number of students and learners impacted by COVID-19 has been calculated based on the closure of formal education systems.
The UNESCO Institute for Statistics provides figures on students impacted by COVID-19 corresponding to the number of learners enrolled at pre-primary, primary, lower-secondary, and upper-secondary levels of education [ISCED levels 0 to 3], as well as at tertiary education levels [ISCED levels 5 to 8].
Early childhood educational programmes are usually designed for children below the age of 3 and may refer to preschools, nursery schools, kindergartens, and some day care programmes.
While many primary and secondary schools have closed around the world due to COVID-19, measures impacting early childhood educational programmes have varied.
In some countries and territories, preschools and day cares are considered necessary services and have not closed in tandem with broader school closure measures.In the United States, the Washington State Department of Children, Youth, and Families encouraged child care and early learning centres to stay open.
Some school districts may offer alternative child care options, prioritising the children of first responders and healthcare workers.
The governor of Maryland mandated that specific child care services remain open for the children of emergency personnel while Washington State and California have left it to the discretion of care providers.
California Governor Gavin Newsom explained his state's position, saying “We need our child care facilities, our daycare centers, to operate to absorb the impact of these school closures.”
" Colorado has encouraged the development of ""tool kits"" for parents to use at home to emulate the lessons children would have received in their early learning programmes.In Japan, Prime Minister Shinzo Abe closed all schools throughout the country until April 8, however, children's daycare facilities were excluded. "
In early March, five adults associated with a nursing facility for preschool children in Kobe tested positive for coronavirus.
After testing over one hundred children at the facility, a preschool student was found to be carrying the virus.
Primary or elementary education typically consists of the first four to seven years of formal education.
The International Baccalaureate Organization (IBO) canceled the examinations for its Diploma Programme and Career-related Programme candidates scheduled between 30 April and 22 May 2020, reportedly affecting more than 200,000 students worldwide.
" The IBO stated that it would award candidates their diplomas or certificates based on ""their coursework"" and ""the established assessment expertise, rigor, and quality control already built into the programme."" "
Tertiary education, also known as higher education, refers to the non-compulsory educational levels that follow completion of secondary school or high school.
Tertiary education is normally taken to include undergraduate and postgraduate education, as well as vocational education and training.
Individuals who complete tertiary education generally receive certificates, diplomas, or academic degrees.
Undergraduate education is education conducted after secondary education and prior to post-graduate education, for which the learner is typically awarded a bachelor's degree.
" Students enrolled in higher education programmes at colleges, universities, and community colleges are often refereed to in countries such as United States as ""college students.""The closure of colleges and universities has widespread implications for students, faculty, administrators, and the institutions themselves. "
Colleges and universities across the United States have been called upon to issue refunds to students for the cost of tuition and room and board.
" In the United States of America, Colleges and universities operate as ""mini-cities"" which generate significant revenue for cities, states, and regions. "
For example, Princeton University contributed $1.58 billion USD to the New Jersey economy and students spent about $60 million in off-campus spending.
" College and university closures have a domino effect on economies with far-reaching implications.According to Linda Bilmes of the Harvard Kennedy School, ""local hotels, restaurants, cafes, shops, car rental agencies and other local businesses obtain a significant share of annual revenue from graduation week and college reunions... "
" these communities will suffer a lot of economic damage if the colleges remain closed at that time.""Small towns which rely on college students to support the local economy and provide labour to local businesses are especially impacted by school closures and the exodus of students from campus. "
In Ithaca, New York, Cornell University students spent at least $4 million a week in Tompkins county.
" In the wake of Cornell's decision to keep students home following spring break and transition to virtual instruction, the Mayor of Ithaca called for ""immediate and forceful federal action — we will see a horrific economic impact as a result of Cornell University closing."" "
UNESCO is sharing 10 recommendations during this period:
Examine the readiness and choose the most relevant tools: Decide on the use high-technology and low-technology solutions based on the reliability of local power supplies, internet connectivity, and digital skills of teachers and students.
This could range through integrated digital learning platforms, video lessons, MOOCs, to broadcasting through radios and TVs.
Ensure inclusion of the distance learning programmes: Implement measures to ensure that students including those with disabilities or from low-income backgrounds have access to distance learning programmes, if only a limited number of them have access to digital devices.
Consider temporarily decentralising such devices from computer labs to families and support them with internet connectivity.
Protect data privacy and data security: Assess data security when uploading data or educational resources to web spaces, as well as when sharing them with other organisations or individuals.
Ensure that the use of applications and platforms does not violate students’ data privacy.
Prioritize solutions to address psychosocial challenges before teaching: Mobilize available tools to connect schools, parents, teachers, and students with each other.
Create communities to ensure regular human interactions, enable social caring measures, and address possible psychosocial challenges that students may face when they are isolated.
Plan the study schedule of the distance learning programmes: Organise discussions with stakeholders to examine the possible duration of school closures and decide whether the distance learning programme should focus on teaching new knowledge or enhance students’ knowledge of prior lessons.
Plan the schedule depending on the situation of the affected zones, level of studies, needs of students needs, and availability of parents.
Choose the appropriate learning methodologies based on the status of school closures and home-based quarantines.
Avoid learning methodologies that require face-to-face communication.
Provide support to teachers and parents on the use of digital tools: Organise brief training or orientation sessions for teachers and parents as well, if monitoring and facilitation are needed.
Help teachers to prepare the basic settings such as solutions to the use of internet data if they are required to provide live streaming of lessons.
Blend appropriate approaches and limit the number of applications and platforms: Blend tools or media that are available for most students, both for synchronous communication and lessons, and for asynchronous learning.
Avoid overloading students and parents by asking them to download and test too many applications or platforms.
Develop distance learning rules and monitor students’ learning process: Define the rules with parents and students on distance learning.
Design formative questions, tests, or exercises to monitor closely students’ learning process.
Try to use tools to support submission of students’ feedback and avoid overloading parents by requesting them to scan and send students’ feedback
Define the duration of distance learning units based on students’ self-regulation skills: Keep a coherent timing according to the level of the students’ self-regulation and metacognitive abilities especially for livestreaming classes.
Preferably, the unit for primary school students should not be more than 20 minutes, and no longer than 40 minutes for secondary school students.
Create communities and enhance connection: Create communities of teachers, parents, and school managers to address sense of loneliness or helplessness, facilitate sharing of experience and discussion on coping strategies when facing learning difficulties.
290 million students out of school due to COVID-19: UNESCO releases first global numbers and mobilizes response, UNESCO.
Workplace hazard controls for COVID-19
Workplace hazard controls for COVID-19 are the application of occupational safety and health methodologies for hazard controls to the prevention of coronavirus disease 2019 (COVID-19).
The proper hazard controls in the workplace depend on the worksite and job task, based on a risk assessment of sources of exposure, disease severity in the community, and risk factors of individual workers who may be vulnerable to contracting COVID-19.
According to the U.S. Occupational Safety and Health Administration (OSHA), lower exposure risk jobs have minimal occupational contact with the public and other coworkers, for which basic infection prevention measures are recommended, including hand washing, encouraging workers to stay home if they are sick, respiratory etiquette, and maintaining routine cleaning and disinfecting of the work environment.
Medium exposure risk jobs include those that require frequent or close contact with people who are not known or suspected with COVID-19, but may be infected due to ongoing community transmission or international travel.
This includes workers who have contact with the general public such as in schools, high-population-density work environments, and some high-volume retail settings.
Hazard controls for this group, in addition to basic infection prevention measures, include ventilation using high-efficiency air filters, sneeze guards, and having personal protective equipment available in case a person with COVID-19 is encountered.
OSHA considers healthcare and mortuary workers exposed to known or suspected person with COVID-19 to be at high exposure risk, which increases to very high exposure risk if workers perform aerosol-generating procedures on, or collect or handle specimens from, known or suspected person with COVID-19.
Hazard controls appropriate for these workers include engineering controls such as negative pressure ventilation rooms, and personal protective equipment appropriate to the job task.
COVID-19 outbreaks can have several effects within the workplace.
Workers may be absent from work due to becoming sick, needing to care for others, or from fear of possible exposure.
Patterns of commerce may change, both in terms of what goods are demanded, and the means of acquiring these goods (such as shopping at off-peak hours or through delivery or drive-through services).
Lastly, shipments of items from geographic areas severely affected by COVID-19 may be interrupted.An infectious disease preparedness and response plan can be used to guide protective actions.
Plans address the levels of risk associated with various worksites and job tasks, including sources of exposure, risk factors arising from home and community settings, and risk factors of individual workers such as old age or chronic medical conditions.
They also outline controls necessary to address those risks, and contingency plans for situations that may arise as a result of outbreaks.
Infectious disease preparedness and response plans may be subject to national or subnational recommendations.
Objectives for response to an outbreak include reducing transmission among staff, protecting people who are at higher risk for adverse health complications, maintaining business operations, and minimizing adverse effects on other entities in their supply chains.
The disease severity in the community where the business is located affects the responses taken.
The hierarchy of hazard controls is a framework widely used in occupational safety and health to group hazard controls by effectiveness.
Where COVID-19 hazards cannot be eliminated, the most effective controls are engineering controls, followed by administrative controls, and lastly personal protective equipment.
Engineering controls involve isolating employees from work-related hazards without relying on worker behavior, and can be the most cost-effective solution to implement.
Administrative controls are changes in work policy or procedures that require action by the worker or employer.
Personal protective equipment (PPE) is considered less effective than engineering and administrative controls, but can help prevent some exposures.
All types of PPE must be selected based upon the hazard to the worker, properly fitted as applicable (e.g., respirators), consistently and properly worn, regularly inspected, maintained, and replaced, as necessary, and properly removed, cleaned, and stored or disposed of to avoid contamination.
According to the U.S. Occupational Safety and Health Administration (OSHA), lower exposure risk jobs have minimal occupational contact with the public and other coworkers.
Basic infection prevention measures recommended for all workplaces include frequent and thorough hand washing, encouraging workers to stay home if they are sick, respiratory etiquette including covering coughs and sneezes, providing tissues and trash receptacles, preparing for telecommuting or staggered shifts if needed, discouraging workers from using others' tools and equipment, and maintaining routine cleaning and disinfecting of the work environment.
Prompt identification and isolation of potentially infectious individuals is a critical step in protecting workers, customers, visitors, and others at a worksite.
The U.S. Centers for Disease Control and Prevention (CDC) recommends that employees who have symptoms of acute respiratory illness are to stay home until they are free of fever, signs of a fever, and any other symptoms for at least 24 hours without the use of fever-reducing or other symptom-altering medicines, and that sick leave policies are flexible, permit employees to stay home to care for a sick family member, and that employees are aware of these policies.
According to OSHA, medium exposure risk jobs include those that require frequent or close contact within six feet (1.8 m) of people who are not known or suspected COVID-19 patients, but may be infected with SARS-CoV-2 due to ongoing community transmission around the business location, or because the individual has recent international travel to a location with widespread COVID-19 transmission.
These include workers who have contact with the general public such as in schools, high-population-density work environments, and some high-volume retail settings.Engineering controls for this and higher risk groups include installing high-efficiency air filters, increasing ventilation rates, installing physical barriers such as clear plastic sneeze guards, and installing a drive-through window for customer service.Administrative controls for this and higher risk groups include encouraging sick workers to stay at home, replacing face-to-face meetings with virtual communications, establishing staggered shifts, discontinuing nonessential travel to locations with ongoing COVID-19 outbreaks, developing emergency communications plans including a forum for answering workers’ concerns, providing workers with up-to-date education and training on COVID-19 risk factors and protective behaviors, training workers who need to use protecting clothing and equipment how to use it, providing resources and a work environment that promotes personal hygiene, requiring regular hand washing, limiting customers' and the public's access to the worksite, and posting signage about hand washing and other COVID-19 protective measures.Depending on the work task, workers with at least medium exposure risk may need to wear personal protective equipment including some combination of gloves, a gown, a face shield or face mask, or goggles.
Workers in this risk group rarely require use of respirators.
If a person becomes sick on an airplane, proper controls to protect workers and other passengers include separating the sick person from others by a distance of 6 feet, designating one crew member to serve the sick person, and offering a face mask to the sick person or asking the sick person to cover their mouth and nose with tissues when coughing or sneezing.
Cabin crew should wear disposable medical gloves when tending to a sick traveler or touching body fluids or potentially contaminated surfaces, and possibly additional personal protective equipment if the sick traveler has fever, persistent cough, or difficulty breathing.
Gloves and other disposable items should be disposed of in a biohazard bag, and contaminated surfaces should be cleaned and disinfected afterwards.For commercial shipping, including cruise ships and other passenger vessels, hazard controls include postponing travel when sick, and self-isolating and informing the onboard medical center immediately if one develops a fever or other symptoms while on board.
Ideally, medical follow-up should occur in the isolated person's cabin.For schools and childcare facilities, CDC recommends short-term closure to clean or disinfect if an infected person has been in a school building regardless of community spread.
When there is minimal to moderate community transmission, social distancing strategies can be implemented such as canceling field trips, assemblies, and other large gatherings such as physical education or choir classes or meals in a cafeteria, increasing the space between desks, staggering arrival and dismissal times, limiting nonessential visitors, and using a separate health office location for children with flu-like symptoms.
When there is substantial transmission in the local community, in addition to social distancing strategies, extended school dismissals may be considered.For law enforcement personnel performing daily routine activities, the immediate health risk is considered low by CDC.
Law enforcement officials who must make contact with individuals confirmed or suspected to have COVID-19 are recommended to follow the same guidelines as emergency medical technicians, including proper personal protective equipment.
If close contact occurs during apprehension, workers should clean and disinfect their duty belt and gear prior to reuse using a household cleaning spray or wipe, and follow standard operating procedures for the containment and disposal of used PPE and for containing and laundering clothes.
OSHA considers certain healthcare and mortuary workers to be at high or very high categories of exposure risk.
High exposure risk jobs include healthcare delivery, support, laboratory, and medical transport workers who are exposed to known or suspected COVID-19 patients.
These become very high exposure risk if workers perform aerosol-generating procedures on, or collect or handle specimens from, known or suspected COVID-19 patients.
Aerosol-generating procedures include intubation, cough induction procedures, bronchoscopies, some dental procedures and exams, or invasive specimen collection.
High exposure risk mortuary jobs include workers involved in preparing the bodies of people who had known or suspected cases of COVID-19 at the time of their death; these become very high exposure risk if they perform an autopsy.Additional engineering controls for these risk groups include isolation rooms for patients with known or suspected COVID-19, including when aerosol-generating procedures are performed.
Specialized negative pressure ventilation may be appropriate in some healthcare and mortuary settings.
Specimens should be handled with Biosafety Level 3 precautions.
The World Health Organization (WHO) recommends that incoming patients be separated into distinct waiting areas depending on whether they are a suspected COVID-19 case.In addition to other PPE, OSHA recommends respirators for those who work within 6 feet of patients known to be, or suspected of being, infected with SARS-CoV-2, and those performing aerosol-generating procedures.
In the United States, NIOSH-approved N95 filtering facepiece respirators or better must be used in the context of a comprehensive, written respiratory protection program that includes fit-testing, training, and medical exams.
Other types of respirators can provide greater protection and improve worker comfort.The WHO does not recommend coveralls, as COVID-19 is a respiratory disease rather than being transmitted through bodily fluids.
WHO recommends only a surgical mask for point-of-entry screening personnel.
For those who are collecting respiratory specimens from, caring for, or transporting COVID-19 patients without any aerosol-generating procedures, WHO recommends a surgical mask, goggles, or face shield, gown, and gloves.
If an aerosol-generating procedure is performed, the surgical mask is replaced with an N95 or FFP2 respirator.
Given that the global supply of PPE is insufficient, WHO recommends minimizing the need for PPE through telemedicine, physical barriers such as clear windows, allowing only those involved in direct care to enter a room with a COVID-19 patient, using only the PPE necessary for the specific task, continuing use of the same respirator without removing it while caring for multiple patients with the same diagnosis, monitoring and coordinating the PPE supply chain, and discouraging the use of masks for asymptomatic individuals.
WHEREAS on March 4, 2020, I proclaimed a State of Emergency to exist in California as a result of the threat of COVID-19;
and WHEREAS in a short period of time, COVID-19 has rapidly spread throughout California, necessitating updated and more stringent guidance from federal, state, and local public health officials;
and WHEREAS for the preservation of public health and safety throughout the entire State of California, I find it necessary for all Californians to heed the State public health directives from the Department of Public Health.
NOW, THEREFORE, I, GAVIN NEWSOM, Governor of the State of California, in accordance with the authority vested in me by the State Constitution and statutes of the State of California, and in particular, Government Code sections 8567, 8627, and 8665 do hereby issue the following Order to become effective immediately:
IT IS HEREBY ORDERED THAT:
1) To preserve the public health and safety, and to ensure the healthcare delivery system is capable of serving all, and prioritizing those at the highest risk and vulnerability, all residents are directed to immediately heed the current State public health directives, which I ordered the Department of Public Health to develop for the current statewide status of COVID-19.
Those directives are consistent with the March 19, 2020, Memorandum on Identification of Essential Critical Infrastructure Workers During COVID-19 Response, found at: https://covid19.ca.gov/.
ORDER OF THE STATE PUBLIC HEALTH OFFICER
To protect public health, I as State Public Health Officer and Director of the California Department of Public Health order all individuals living in the State of California to stay home or at their place of residence except as needed to maintain continuity of operations of the federal critical infrastructure sectors, as outlined at https://www.cisa.gov/critical-infrastructure-sectors.
In addition, and in consultation with the Director of the Governor's Office of Emergency Services, I may designate additional sectors as critical in order to protect the health and well-being of all Californians.
Pursuant to the authority under the Health and Safety Code 120125, 120140, 131080, 120130(c), 120135, 120145, 120175 and 120150, this order is to go into effect immediately and shall stay in effect until further notice.
The federal government has identified 16 critical infrastructure sectors whose assets, systems, and networks, whether physical or virtual, are considered so vital to the United States that their incapacitation or destruction would have a debilitating effect on security, economic security, public health or safety, or any combination thereof.
I order that Californians working in these 16 critical infrastructure sectors may continue their work because of the importance of these sectors to Californians' health and well-being.
This Order is being issued to protect the public health of Californians.
The California Department of Public Health looks to establish consistency across the state in order to ensure that we mitigate the impact of COVID-19.
Our goal is simple, we want to bend the curve, and disrupt the spread of the virus.
The supply chain must continue, and Californians must have access to such necessities as food, prescriptions, and health care.
When people need to leave their homes or places of residence, whether to obtain or perform the functions above, or to otherwise facilitate authorized necessary activities, they should at all times practice social distancing.
2) The healthcare delivery system shall prioritize services to serving those who are the sickest and shall prioritize resources, including personal protective equipment, for the providers providing direct care to them.
3) The Office of Emergency Services is directed to take necessary steps to ensure compliance with this Order.
4) This Order shall be enforceable pursuant to California law, including, but not limited to, Government Code section 8665.
IT IS FURTHER ORDERED that as soon as hereafter possible, this Order be filed in the Office of the Secretary of State and that widespread publicity and notice be given of this Order.
This Order is not intended to, and does not, create any rights or benefits, substantive or procedural, enforceable at law or in equity, against the State of California, its agencies, departments, entities, officers, employees, or any other person.
IN WITNESS WHEREOF I have hereunto set my hand and caused the Great Seal of the State of California to be affixed this 19th day of March 2020.
FROM: Katherine Maher, Wikimedia Foundation CEO
TO: All Wikimedia Foundation staff
SUBJECT LINE: [Covid-19] Lightening the load and preparing for the future
SEND DATE/TIME: 14 March, 2020, 00:24 UTC
LICENSING: CC0: No rights reserved
We find ourselves in remarkable circumstances this month.
The COVID-19 epidemic is something that makes clear our global human interconnectedness and the responsibilities we have to one another.
We don’t have precedent for its challenges, but we do know that our best response relies on the sort of global empathy, cooperation, and community building that sits at the heart of this organization.
The camaraderie and care we have seen among all of our colleagues over email, calls, and chats is a remarkable validation of the incredible humans we are fortunate enough to work with.
I couldn’t be more grateful and proud to count you all as colleagues.
Last week, someone shared with me their appreciation for our work.
They reminded me how meaningful it is for the world to be able to turn to Wikipedia right now, and what a powerful symbol it is for this critical resource to remain online and available to all.
Your work makes this possible, whether you keep the sites stay up or our colleagues paid or our communities safe.
The world needs the information that Wikipedia provides, now more than ever.
This is a moment in which not only what we do, but how we do it, will make a meaningful impact on the world.
Because of the importance of this mission and your role in it, we will be making some significant adjustments to how we work together, starting this coming week.
Adjustments to our work and schedules
As Robyn mentioned previously, the c-team met last night to discuss our approach and schedule for the coming days and months.
In that conversation, we considered what we thought would be an appropriate response to what we’re facing and the best way to keep the organization sustainable during this time.
Overwhelmingly we wanted to remove stress and support our mission for the long term.
If you need to dial back, that’s okay.
For all staff, contractors, and contract workers:
our daily working expectations will be about 4 hours a day, or 20 hours a week until further notice.
We’re not declaring a holiday - if you are able to work more normal hours, the mission can use you.
However, the world is unpredictable right now, and whether you need to care for loved ones, get groceries, or go to the doctor, your well-being is our priority.
We are not tracking your time.
If you are sick, do not work.
This should go without saying, but we’re saying it.
No sick days or PTO required - just tell your manager and help your team revise calendars and schedules to make sure key areas of work are covered.
(If you are diagnosed positive for COVID-19, please let Bryan within T & amp;C Ops know so T & amp;C can help with support and make sure your situation gets appropriate attention from management).
Hourly folks will be fully paid.
We have already said, and are recommitting to honor our commitments to our contractors and hourly staff colleagues.
Everyone will be paid on the basis of their usual hours worked during normal circumstances.
This includes if you are sick and unable to work.
If you want to work, we support you.
Many people use work as a way of channeling their stress with the world around us.
What we do can be incredibly rewarding, especially during times like this.
Again, this is about your self-care.
Our ask is that you communicate with your manager, so we know what to expect and can adjust accordingly.
Some work is considered essential.
There are some things that we must keep doing.
The SRE, HR Ops, Trust & amp; Safety, and Fundraising teams (among others) do critical work that may need additional support.
We’ll begin a process with all departments to assess current objectives and shift our focus to supporting what’s essential for our mission.
There’s plenty to do for all of us, we just will all focus on the most essential projects.
Slowing now won’t hurt later.
We do not plan to go “double-time to catch up” once the pandemic has passed.
You will not be expected to work extra hours to meet deadlines which are now unrealistic.
We accept that circumstances have changed, and will work to set new targets and timelines where appropriate.
What happens with the APP (Annual Planning)?
To adjust to our new reality and daily working hour expectations, we intend to adjust the timeline for the delivery of our 2020-2021 Annual Plan.
Our intention is to propose an extension of our 2019-2020 plan that allows more time for budgeting to allow employees to prioritize critical work, self-care, and care for loved ones while accommodating those who need or wish to work a reduced schedule over the next few weeks.
This timeline extension greatly reduces current planning workloads and pressure across the whole organization.
We will introduce our proposal to the Board next week and will update delegates and teams on the next steps as soon as we have confirmation.
Thank you to the APP team for your leadership in this.
Office status, exposure, and cleaning
Last week, we learned that one of our SF-based colleagues may have been exposed to the COVID-19 virus.
However, out of an abundance of caution, we employed an antiviral cleaning crew to disinfect all surfaces in the San Francisco office.
They utilized a hospital-grade anti-viral solution to disinfect every surface, as well as the lobby and elevator banks accessing our floor.
The building is employing its own duty-of-care protocol utilizing products that support the safety of their tenants.
We feel comfortable that the office will be well-prepared for when we decide to return.
Our DC office is located in a WeWork, which has shared its COVID-19 protocol with us and all DC-based staff members.
As of last week, our DC office moved to a fully remote setup in line with the guidance shared with San Francisco.
As some of our NYC-based colleagues know, we have also been in discussion about leasing a location in Brooklyn.
These discussions are continuing but may be delayed.
Some of our colleagues are working remotely for the first time.
Our long-time remote colleagues know that it can be an adjustment, and wanted to offer you some advice:
Limit the length of meetings to at most one or two hour increments.
If longer sessions are required, consider how they can be broken up over the course of several days.
Clearly define the meeting, have an agenda, and send reading materials in advance.
Make video the default, with tools like Google Docs and Zoom to facilitate live collaboration and connection.
Have a lead to facilitate every meeting, someone to monitor the chat for questions and track the speaker list, and someone to help take notes (or do collaborative note-taking).
Send an email to tech support if you need a comfortable headset.
Use your wellness reimbursement for snacks.
Join the #remoties channel in Slack to talk with your colleagues about distributed work
The HR Operations team is looking into webinar-based ergonomics guidance to support the increase in distributed work across the Foundation.
This past week we asked all community grant recipients to cancel Wikimedia-funded public events, such as editathons, until the WHO declares the pandemic to be over.
We let them know that we understood that our request for cancellations and other restrictions could make it impossible to complete their agreed-upon grant activities and that no one would be penalized for having to delay or modify those goals.
This coming week we will follow up with additional guidance on Wikimania and other regional and thematic community conferences.
The general sentiment from around the global community seems to be both sadness at the disruption but relief at the clarity and ability to focus on their own communities, Wikimedia and otherwise.
Going forward, the CRT is working to set up a page on Meta-Wiki to provide a space for the community to monitor the impact and follow our communications with them.
Staying in touch around COVID-19 related issues
We’ll be sending an invitation to your calendars for next Thursday, 14:00 UTC/07:00 PT for a special staff meeting.
We’ll use this time to share additional updates, answer your questions and spend some time connecting with each other.
We’re in this together and here to help however we can.
In the meantime, you can continue to find the information from this email, and all other essential COVID-19 related information, on Office Wiki.
The CRT will keep these pages updated and all the information in one place.
We are also working to maintain regular communications with staff who reside in countries that are currently significantly affected.
If you have any questions about travel, events, a major workstream, or coverage challenge, or anything else you may need help with, please don’t hesitate to notify and work with the CRT.
We’re here to help provide support and liaise as needed.
If you have a confidential or sensitive matter, please email Bryan Judan - Director of HR International Global Operations.
None of these changes should be seen as an abandonment of our work and obligations.
Rather, they are a recognition that at this moment, our work and obligations will likely need to adapt in a way we have not in the past.
These are the steps we believe are necessary to support this one another so that we can continue to work, provide our movement with the support they need, and the world with the service they rely on.
Our planned work will be there waiting for us when the time comes.
For now, it is time to support one another and create space for the important work that will be coming in the weeks and potentially months ahead.
We need all of you to make that happen, and so we need you all to take care of yourself and your families so that you can be at your best when the need arises.
Now, please -- wash your hands and don’t touch your face!
Katherine, the CRT (Amanda K, Amy V, Bryan J, Doreen D, Gregory V, Jaime V, Joel L, Lynette L, Ryan M, and Tony S), and the rest of the Leadership Team (Grant I, Heather W, Jaime V, Janeen U, Lisa S, Robyn A, Ryan M, and Toby N).
The SARS-CoV-2 virus is the cause of COVID-19 (coronavirus disease 2019), a contagious respiratory disease that was first identified in December 2019, in Wuhan, Hubei, China.
The disease is a type of coronavirus, the same family that includes SARS, MERS, and some varieties of the common cold.
It was declared a pandemic by the World Health Organization (WHO) on 11 March 2020.
While much about COVID-19 is still unknown, preliminary data suggests that it is more virulent and contagious than the seasonal flu, and less virulent but more contagious than SARS and MERS.
Older people and those with underlying conditions are the most at risk of serious complications including death.
Due to the spread of the disease, you are advised not to travel unless necessary, to avoid being infected, quarantined, or stranded by changing restrictions and cancelled flights.
Avoid crowded places whenever possible.
This is not just to protect you, but also those you come in contact with.
As it happens, you probably aren't missing much by staying home, as many attractions around the world are closing their doors to avoid spreading the disease.
If you do need to travel, take precautions as you would for other infections: wash your hands frequently, avoid touching your face, cough and sneeze into your elbow or a tissue, and avoid contact with sick people.
Before traveling, read up on the extensive and fast-changing array of travel restrictions that have been imposed around the world.
After travel, monitor your health and consider self-isolation for two weeks to avoid transmitting the disease to others.
Transportation from long-distance passenger flights to local buses has been curtailed or completely shut down in many countries due to low demand or government orders.
Many international and regional borders are closed.
If you are away from home, and especially if you are in another country, consider returning home as soon as possible; this may get even more difficult as restrictions continue to change.
In some cases it may simply not be possible, even if you're healthy and meet the legal requirements for entry.
If you can't find a way back to your country, contact your nearest embassy or consulate for assistance.
They may be able to organize an evacuation, identify non-regularly scheduled flights, or give you an emergency loan to pay for transport.
In case they can't, make preparations in case you need to stay where you are for an extended period.
If you do find a way back home, be prepared that it may be expensive, inconvenient, and have unusual restrictions (such as no checked baggage).
As of early April 2020, the number of confirmed cases of COVID-19 is approaching one million.
Though the disease started in mainland China, it has spread around the world and China has fewer confirmed cases and deaths than several other countries.
Europe is the new epicenter of the pandemic.
All but a handful of countries have reported at least one case, with the highest numbers of reported cases in the United States, Spain, Italy, Germany, France, mainland China, Iran, and the United Kingdom.
Local transmission is established in many countries in all major inhabited regions of the world except some Pacific island nations.
(See updates from the WHO.)
The full extent of the spread is uncertain, due in part to limited testing.
Many countries are experiencing a severe shortage of test kits, and the authorities have not been able to test everybody who is at high risk, so the real number of cases is probably much higher than the official one.
Countries also differ in their testing and reporting practices, so comparisons of the number of reported cases do not tell the full story of how the epidemic has progressed in different areas.
The virus is transmitted through respiratory droplets and through objects.
The coronavirus is a relatively large virus, meaning it is not truly airborne: it will settle down in respiratory droplets.
Staying two metres (six feet) away from other people is usually enough to prevent transmission through this route.
Transmission from objects can happen, for example, if someone sneezes, touches a doorknob, and then other people touch the doorknob and then touch their faces.
The SARS-CoV-2 virus may last on cardboard for up to 24 hours and on plastic for up to 3 days.
Transmission via the fecal–oral route may also be possible.
Evidence suggests that COVID-19 is contagious even without symptoms, though to what extent is still being investigated.
Common symptoms include a fever, dry cough, and fatigue.
Other less common symptoms include shortness of breath, a sore throat, headache, muscle pain, or sputum production.
Some patients have very mild symptoms, similar to a cold.
Serious complications include pneumonia, acute respiratory distress syndrome, and multi-organ failure leading to disability or death.
About 80% of infections result in mild symptoms, while the remaining may result in hospitalization.
Case fatality rate is estimated at 1-3% of infected individuals, most of whom are elderly with underlying health conditions.
The fatality rate is much higher for those over 70 but significantly lower for those under 40.
Those most at risk of COVID-19 infection and serious complications are the elderly and those with weakened immune systems or underlying health conditions like cardiovascular disease, diabetes, hypertension, chronic respiratory disease, and cancer.
Not many cases are reported in children and most of these are mild or moderate, though a significant fraction do get pneumonia.
Occupationally, health care workers have higher risk compared to others with clusters of disease among workers and in health care settings.
The time between being exposed to the virus and the emergence of symptoms (incubation period) is typically between 2 and 14 days, though there has been one reported case in China where symptoms appeared 27 days after exposure.
As of February 2020, the period of infectiousness is unknown, but is likely most significant when people are symptomatic.
There is evidence of transmission from people who don't have symptoms, although to what extent is still being investigated.
It is unclear whether it is possible to be reinfected with the virus after recovering from it the first time around.
Long-term effects for people who have recovered remain unclear, but there is evidence of reduced lung capacity in some recovered patients.
Testing for the virus usually consists of a swab inserted through the nose or a throat swab which is analysed in a laboratory for the virus.
" The current ""gold standard"" test involves extracting the genetic material from the sample and analysing it for known genetic markers of the virus. "
There is no established test assessing for the virus or antibodies in the blood, although tests are being developed.
There is no test to establish immunity to the virus.
Many governments around the world have advised their citizens not to travel unnecessarily amid the pandemic.
Lots of airlines and package holidays are making it easy for you by waiving cancellation and change fees.
Particularly avoid cruise ship travel.
Older travelers and those with underlying health conditions are most at risk and should avoid travel that puts them at risk, such as long plane flights, visits to crowded places, and especially cruises, even outside of severely affected areas.
In affected areas, most experts recommend a practice known as social distancing.
This means minimising contact with others by keeping a distance of six feet or two meters from them and avoiding gathering together in groups.
Some areas permit small groups; others prohibit all group gatherings.
Measures you are encouraged to take include working from home whenever possible, avoiding crowds and avoiding leaving your home unless absolutely necessary.
If you must go out, try to stay at least 2 meters (6 feet) away from other people.
In many places these measures are required.
Follow hygiene practices like for flu prevention.
Frequently wash your hands with soap and warm water, and then dry your hands on a clean towel.
As coronaviruses are enveloped viruses, washing your hands with soap kills the virus by disrupting the mostly fat-based viral envelope.
Effective hand washing requires rubbing your hands for at least 20 seconds.
Drying your washed hands physically removes some germs from your skin (so don't skip that step, and don't share towels).
If soap and water are not available, then use a & gt;60% alcohol-based hand sanitizer.
Alcohol is a quick germ-killer, but it's not quite instant, so this still requires the same 20 seconds of rubbing your hands together, making sure that every single scrap of skin gets wet, and then you have to wait about another minute, for the alcohol to completely dry.
Avoid touching your eyes, nose and mouth with your hands.
Most people touch their faces every few minutes, all day long.
Try to do this less, and try to wash your hands before touching your face.
Also, try to avoid touching surfaces you don't have to touch in the first place, at least with your bare hands.
Cough and sneeze into your elbow or a tissue, and then immediately throw away the tissue and wash your hands.
Don't stand or sit near people who might be sick.
Stay at least one meter – and ideally two meters (six feet) – away.
As a quick way to eyeball this distance, imagine that you and the other person both reached your hands towards each other.
Could you touch the other person's hand without taking a step towards that person?
If the answer is yes, then you're too close.
Clean objects and surfaces that a lot of people touch, such as doorknobs, phones, and television remotes with regular household cleaner.
Disinfect the surfaces with a suitable disinfectant, such as diluted household bleach.
Stay home when you are sick, and avoid contact with other people until your symptoms are gone.
Do not share personal items that come into contact with saliva, such as toothbrushes, eating utensils, drinks, water bottles, and towels.
The practice of serving yourself from a common plate with your own chopsticks, common in China, should be avoided.
Greet people without touching them.
Avoid hugs, kisses, handshakes, fist bumps, and any other contact.
If it's impossible to avoid contact, then wash your hands both before and after.
It won't protect you from the coronavirus, but it will partially protect you from the flu, which remains a greater risk than COVID-19 in many areas.
This also saves you from unnecessary worry if you get the flu and think it might be the coronavirus.
If you are elderly or otherwise in a high-risk group and can be vaccinated for pneumonia, get that vaccination.
It won't protect you from viral pneumonia from COVID-19, but some COVID-19 patients have died of bacterial pneumonia that attacked their weakened lungs, so a pneumonia vaccination could save your life.
Wearing masks is recommended for those who are suspected of carrying of disease and those who are in close contact with those infected.
For those who are asymptomatic, the WHO does not recommend masks, though some national governments do.
Wearing a mask of some kind is required in some countries and cities in an effort to reduce community transmission.
There are worldwide shortages of surgical masks.
If you do wear a mask, make sure to use it correctly.
The mask should cover your nose and mouth and fit without gaps.
Wash your hands before putting on the mask and avoid touching the mask while wearing it.
If you do touch it, wash your hands immediately afterwards.
When the mask becomes damp, discard and replace it.
Remove it from the back, throw it away, and then wash your hands.
Remember that masks are not a substitute for good hygiene: continue to wash your hands frequently.
Don't stock up on masks if you don't need them.
Mask shortages mean that healthcare workers are having trouble getting a hold of masks, which puts everyone at risk.
That includes N95 respirators, which are not recommended for the general public – these are specialist equipment which must be fitted to be optimally effective.
Leave them for healthcare workers.
Avoid crowded areas, especially enclosed areas without much air circulation, such as conferences, performances, shopping malls, public transportation, and religious services.
Events which involve a large scale gathering of people, from religious pilgrimages to music concerts, are being canceled worldwide, in an effort to contain the spread of the virus.
Tourist attractions, businesses, and transportation may be closed, especially in affected countries.
Some canceled events, especially performances, sporting events, and classes, are being moved online, which means you can experience them without traveling.
At petrol/gas stations, use gloves or wipe down the handle with a disinfectant wipe if you can.
After filling up, clean your hands with hand sanitizer.
The U.S. and Canadian governments recommend avoiding travel by cruise ship.
Infections spread easily on board, and medical care is limited.
Amid a cruise ship outbreak, quarantines and docking are challenging partly due to the large number of people aboard.
Even cruise ships without confirmed cases have been denied permission to dock due to virus fears, and in the high-profile case of the Diamond Princess in Japan, hundreds of people were infected on the ship.
If you believe you may be infected, call a hospital or local emergency medical services instead of going in person to avoid infecting others.
Mention your symptoms and travel history.
Wear a medical mask and follow the instructions of authorities and doctors.
See also: Flight and health
On a plane, follow the same hygiene practices as anywhere else: wash hands frequently, or use alcohol-based hand sanitizer if it's not convenient to leave your seat, and avoid touching your face.
Researchers have found that passengers in window seats have less risk of contact with sick people.
Try to book a window seat, and avoid moving around the cabin during the flight.
After washing your hands and before sitting down, use disinfectant wipes to wipe down the area around your seat.
Wipe hard surfaces, and if your seat is leather you can wipe that too.
Don't wipe a cloth seat, as the moisture can make transmission easier.
When using disinfectant wipes, follow the instructions on the packaging.
And remember, viruses enter through your mouth, nose, and eyes – wiping down the area doesn't hurt, but it's not a substitute for proper hygiene.
Wash your hands and avoid touching your face.
And use a tissue to touch the touch screen or other controls.
When using the lavatory, use paper towels to turn off the faucet and open the door, then throw them away.
Airlines in affected areas are taking steps to reduce transmission and keep passengers safe.
For instance, these may include cleaning facilities more frequently, allowing flight attendants to wear masks, and serving prepackaged instead of freshly heated meals.
If a group of passengers is connecting from an area with a severe outbreak, the flight attendants may be able to seat them away from the rest of the passengers (and if you were recently in a high-risk area, consider telling the flight attendants for this reason).
You may be prohibited from changing seats on the flight.
This is so that, if someone on the flight turns out to be infected, the authorities can track down the people who were sitting near them for testing or quarantine.
COVID-19 is treated by relieving symptoms and preventing complications.
There is no vaccine or specific treatment for the novel coronavirus.
Research into a vaccine or specific antiviral drug is underway.
There are a variety of trials using HIV medications and other novel antiviral medications for treatment of COVID-19.
Mild symptoms may be relieved by taking paracetamol (acetaminophen).
If you are infected with COVID-19, countries will isolate you until several consecutive tests for COVID-19 are negative.
If you have been in close contact with someone infected with COVID-19, many countries will quarantine you for 14 days since the last exposure and monitor you for signs and symptoms.
Some countries will also test you even if you don't have symptoms.
In many countries, the healthcare system has been stretched to the point of not being able to handle the sheer number of patients, and there is a chance you may be refused treatment due to the lack of available medical staff, supplies or equipment.
Many countries have shut down or severely limited flights, ships, and border crossings, especially to and from affected areas.
Even more countries have imposed restrictions on arriving travelers, either barring entry (maybe with an exception for local citizens and permanent residents) or requiring you to be quarantined, typically for 14 days.
" Even if a mandatory quarantine is not imposed, you may be asked to ""self-quarantine"" by staying at home and not interacting with other people. "
The most severe restrictions are on travellers who have recently been to affected areas, but increasingly many countries are applying them to incoming travellers overall.
Some countries have even prohibited all or almost all foreigners from entry or limited the ability of local citizens and residents to leave.
What are the affected areas?
Well, this is a fast-changing situation, and each country/region/organization has its own list of what areas are subject to restrictions.
The city of Wuhan is on every list and the rest of mainland China is on most.
Other areas that are often included: France, Germany, Hong Kong, Iran, Italy, Japan, Macau, Singapore, South Korea, Spain, Taiwan, the United Kingdom, the United States, the Schengen Area as a whole, and sometimes various others.
Some countries have imposed restrictions based on citizenship or residency from severely affected areas.
A detailed list of entry restrictions is maintained by the IATA.
It doesn't cover all the restrictions, but it's still useful.
Keep up to date—the outbreak and the travel restrictions are changing rapidly.
For travel in the near future, consider making refundable reservations in case the changing situation forces you to change your plans.
Avoid buying tickets with a connection in an affected area – even changing planes can make you subject to restrictions.
Flights may get canceled with little notice, either due to the disease's spread and ever-changing entry restrictions, or simply because fewer people are flying and airlines are having trouble filling seats.
You might also be delayed for hours upon arrival waiting for temperature checks and related procedures and paperwork, or even get quarantined for two weeks.
Be prepared for the possibility of disruption to your travel plans, especially if traveling internationally.
Even if you're nowhere near affected areas there's a risk that you'll have to stay at the destination longer than planned if you've shared a building or vessel with an infected person.
For example, in late February an Italian doctor on vacation in Costa Adeje (Canary Islands) was diagnosed with COVID-19, and as a result all the guests in the hotel he stayed at were quarantined.
Lockdowns and other internal restrictions
Some countries and regions, especially severely affected ones, are implementing emergency lockdowns and restrictions on people's movements and activities, even for those who haven't recently been abroad.
These include the temporary reintroduction of some border controls, restrictions on travel within the country, closing or limiting service at restaurants and other establishments, banning large public events, and in the most severe cases prohibiting people from leaving the house except for essential reasons.
Beyond government restrictions, individual establishments are shutting their doors and cancelling events to try to reduce the spread of the virus.
In China, there are extensive restrictions on transportation and activity, which vary widely by province, city, and even by district or village.
Many governments recommend against traveling to China at this time.
If you have no choice, do your research and get up-to-date information about the local situation wherever you are going.
People who have traveled to Hubei face particularly severe restrictions.
Examples of restrictions that you may encounter in some parts of China (this is not an exhaustive list):
14-day quarantine, self-quarantine, or COVID-19 test upon arrival from other parts of China or from other countries, at your expense
questions about your travel and medical history (lying can get you years in prison)
mandatory registration using an online or paper form
requirement to wear a face mask in public
people who have been outside of China within 14 days not allowed into public places like malls
shops only accept mobile payments, not cash
restaurants, transportation and other establishments refusing service to non-Chinese citizens
many forms of transportation reduced or shut down
mandatory real-name registration for public transit cards
access in and out of a town, village, or city completely blocked
non-resident visitors prohibited from entering apartment complexes
only allowed to go outside once every two days to get supplies
businesses, activities, and attractions closed
businesses need local government permission to re-open
restaurants (if they are even open) require a minimum distance between customers
selling substandard face masks has a maximum sentence of life imprisonment
As of mid-March 2020, Europe is the epicenter of the epidemic, and many European countries have closed their borders to international travel - only border commuters and freight are allowed to cross.
Also businesses other than food stores and pharmacies are closed, and public transport has been reduced or stopped.
In the worst affected countries including Italy, Spain and France, lockdowns like in China in January, have been implemented.
As well the EU has closed its outer borders.
COVID-19 is prevalent also in North America.
The borders between Canada, the U.S., and Mexico are closed to non-essential travel, and in many areas bans on big gatherings are in effect (this means places like restaurants are closed, and events are canceled).
Numerous state, county, and municipal jurisdictions have issued stay-at-home orders that require all nonessential businesses to close.
With lots of flights canceled, warnings issued, and restrictions imposed, flying in the time of coronavirus can be a challenge.
Some routes are not possible.
Others will require more inconvenient connections than usual—multiple stops and long waits between flights.
In some cases that means more expensive tickets.
On the other hand, the good news is that many flights are cheaper than usual due to decreased demand, and there's a decent chance you'll get an empty seat next to you.
Build in extra time for your connections, especially if transferring from an international flight to a domestic flight and especially if your itinerary involves a country that's seriously affected.
Screenings, temperature checks, extra paperwork, and the associated waiting around can add minutes or hours before you're allowed to continue on your journey.
You may find it harder than usual to buy a ticket to or from a destination subject to warnings and restrictions.
This is a real concern if you're trying to get out of an affected area.
For instance, most aggregators are not selling tickets from China to the United States (presumably to avoid falling afoul of restrictions and being on the hook for a passenger's flight out).
To buy a ticket for an itinerary like this, you may have to contact the airline or use a lesser-known aggregator.
Another possibility is to buy two separate tickets (for instance, a ticket from China to Cambodia and a second ticket from Cambodia to the U.S.), but be careful you won't get quarantined or lose your luggage in between.
Connecting flights can be a problem.
The risk of getting stuck in the connection city is higher than usual right now, due to delays for screening and testing as well as extensive cancellations.
Connecting in an affected area may lead to entry restrictions later on, and if you've been in an affected area recently some countries won't even let you change planes.
On certain itineraries there is a risk of getting quarantined somewhere along the way.
So book a direct flight if you can, and if not, think carefully about where to connect.
In uncertain times, plans can change.
Many embassies and consulates have evacuated nonessential staff, and some have shut down operations completely.
Emergency assistance should still be available, though it's possible you may have to contact a further-away consulate if your local one has shut down.
If you have been stranded due to the pandemic, your nearest consulate may be able to help you find a flight home, arrange an emergency loan so you can buy a ticket, or provide an emergency passport.
At the very least they can keep you informed about the local situation and notify you about recently introduced travel requirements and restrictions.
Ordinary consular services such as visa and passport processing may be suspended or restricted to urgent need, depending on the location and the consulate.
" Although some people call the disease ""Wuhan pneumonia"" (武汉(漢)肺炎/武肺), ""Wuhan disease"", or ""Chinese virus"", the use of these terms is considered racist in China and by many people of Chinese origin. "
" It is still common to refer the disease as ""Wuhan pneumonia"" or ""Chinese virus"" in places like Hong Kong and Taiwan. "
" To be safe, use location-neutral terms when referring to the disease, such as ""COVID-19"", ""novel coronavirus"", or just ""the virus"" or ""the pandemic"". "
Particularly in developing countries where law enforcement are poorly trained, enforcement of curfew, lockdown or stay-at-home orders are often brutal, often using forces not proportionate against crowds.
Comply with these orders, and avoid crowds in public.
As a result of the coronavirus pandemic, xenophobia has risen in many countries, primarily but not exclusively targeting people perceived to be Chinese.
There has been a worldwide spike in racist incidents targeting people of East Asian origin, including in major cities such as New York, London and San Francisco.
In Hong Kong, Sinophobia, which was already high to begin with, has intensified as a result of the pandemic, with the result that many shops and restaurants are now denying service to mainland Chinese customers and banning Mandarin speakers from their premises (with the exception of Taiwanese).
Levels of xenophobia have also risen in East Asia, with some restaurants and other businesses in Japan and China refusing service to foreign customers.
In China, there have been incidents of foreigners being refused rooms by hotel staff, and foreign residents, particularly black people, being kicked out of their apartments on short notice by their landlords.
Sources for further information on the coronavirus outbreak include:
The US government Centers for Disease Control and Prevention
European Centre for Disease Prevention and Control (daily updates)
United Kingdom government, - Foreign and Commonwealth Office advice for Travellers
An online map and dashboard from the John Hopkins University Center for Systems Science and Engineering with live updates
Partial lists of entry restrictions from IATA and The New York Times
A variety of misinformation and conspiracy theories about the virus are being promoted online and even by some government officials, so be careful which sources you check for information.
Ensure that all information and advice you receive has been backed by reputable doctors and scientists.
In a crisis, it's natural to want to keep following the latest updates, but it may be better for your mental health to moderate the amount of news that you look at, and stick to reliable news sources.
If you normally watch the news twice per day then stick to this schedule and do something else, rather than having the 24-hour news on continuously.
b'Angiotensin-converting enzyme 2 (ACE2) is an enzyme attached to the outer surface (cell membranes) of cells in the lungs, arteries, heart, kidney, and intestines.
ACE2 counters the activity of the related angiotensin-converting enzyme (ACE) by reducing the amount of angiotensin-II and increasing Ang(1-7) making it a promising drug target for treating cardiovascular diseases.ACE2 also serves as the entry point into cells for some coronaviruses.
The human version of the enzyme is often referred to as hACE2.
Angiotensin-converting enzyme 2 is a zinc containing metalloenzyme located on the surface of endothelial and other cells.
ACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.
ACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in lungs and other tissues.
The extracellular domain of ACE2 is cleaved from the transmembrane domain by another enzyme known as sheddase, and the resulting soluble protein is released into the blood stream and ultimately excreted into urine.
ACE2 is present in most organs: ACE2 is attached to the cell membrane of mainly lung type II alveolar cells, enterocytes of the small intestine, arterial and venous endothelial cells and arterial smooth muscle cells in most organs.
ACE2 mRNA expression is also found in the cerebral cortex, striatum, hypothalamus, and brainstem.
The primary function of ACE2 is to act as a counter balance to ACE.
ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin II.
ACE2 in turn cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator angiotensin (1-7), (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH).
ACE2 can also cleave a number of other peptides including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.
ACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.
As a transmembrane protein, ACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63; SARS-CoV (the virus that causes SARS); and SARS-CoV-2 (the virus that causes COVID-19).
More specifically, the binding of the spike S1 protein of SARS-CoV and SARS-CoV2 to the enzymatic domain of ACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells.
This entry process also requires priming of the S protein by the host serine protease TMPRSS2, the inhibition of which is under current investigation as a potential therapeutic.This has led some to hypothesize that decreasing the levels of ACE2, in cells, might help in fighting the infection.
However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.
"A systematic review and meta-analysis published on July 11, 2012, found that ""use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls."""
"Moreover, ""the risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure."
"Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."""
Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for acute lung injury, and appeared to improve pulmonary hemodynamics and oxygen saturation in piglets with a lipopolysaccharide-induced acute respiratory distress syndrome.
The half-life of rhACE2 in human beings is about 10 hours and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours.
Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic renin-angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome.
b'Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIV1), also sometimes called SARS-like coronavirus WIV1, is a strain of Severe acute respiratory syndrome-related coronavirus (SARSr-CoV) isolated from Chinese rufous horseshoe bats (Rhinolophus sinicus).
Like all coronaviruses, virions consist of single-stranded positive-sense RNA enclosed within an envelope.
The discovery confirms that bats are the natural reservoir of SARS-CoV.
Phylogenetic analysis shows the possibility of direct transmission of SARS from bats to humans without the intermediary Chinese civets, as previously believed.
"b'COVID-19 apps are mobile software applications designed to aid contact tracing in response to the 2019-20 coronavirus pandemic, i.e. the process of identifying persons (""contacts"") who may have been in contact with an infected individual."
Numerous applications were developed or proposed, with official government support in some territories and jurisdictions.
Several frameworks for building contact tracing apps have been developed.
Privacy concerns have been raised, especially about systems that are based on tracking the geographical location of app users.
Less intrusive alternatives include the use of Bluetooth signals to log a user's proximity to other cellphones.
On 10 April 2020, Google and Apple jointly announced that they would integrate functionality to support such Bluetooth-based apps directly into their Android and iOS operating systems.
In China, the Chinese government, in conjunction with Alipay, has deployed an app that allows citizens to check if they have been in contact with people that have COVID-19.
It is in use across more than 200 Chinese cities.In Singapore, an app called TraceTogether is being used.
"The app was developed by local IT community, released as open source and will be handed over to the government.North Macedonia launched ""StopKorona!"", a Bluetooth-based app to trace exposure with potentially infected persons and provide a fast response to healthcare authorities."
The app was developed by the Ministry of Communication and Technology and Ministry of Health.
As of 14 April 2020, the app was awaiting approval by the Google Play Store and Apple App Store.
"On 12 April, the government stated that the contact tracing app was in an advanced stage of development, and would be available for deployment within weeks.A similar app is planned in Ireland, and in France (""StopCovid"")."
Both Australia and New Zealand are considering apps based on Singapore's TraceTogether app and BlueTrace protocol.Russia intends to introduce a geofencing app for patients diagnosed with COVID-19 living in Moscow, designed to ensure they do not leave home.
Ross Anderson, professor of security engineering at Cambridge University, listed a number of potential practical problems with app-based systems, including false positives and the potential lack of effectiveness if takeup of the app is limited to only a small fraction of the population.
"Addressing concerns about the spread of misleading or harmful ""coronavirus"" apps, Apple set limits on which types of organizations could add coronavirus-related apps to its App Store, limiting them to only ""official"" or otherwise reputable organizations."
Google and Amazon have implemented similar restrictions.
Privacy campaigners voiced their concern regarding the implications of mass surveillance using coronavirus apps, in particular about whether surveillance infrastructure created to deal with the coronavirus pandemic will be dismantled once the threat has passed.
Amnesty International and over 100 other organizations issued a statement calling for limits on this kind of surveillance.
The organisations declared eight conditions on governmental projects:
"surveillance would have to be ""lawful, necessary and proportionate"";"
extensions of monitoring and surveillance would have to have sunset clauses;
the use of data would have to be limited to COVID-19 purposes;
data security and anonymity would have to be protected and shown to be protected based on evidence;
digital surveillance would have to avoid exacerbating discrimination and marginalisation;
any sharing of data with third parties would have to be defined in law;
there would have to be safeguards against abuse and the rights of citizens to respond to abuses;
"meaningful participation by all ""relevant stakeholders"" would be required, including that of public health experts and marginalised groups.The German Chaos Computer Club (CCC) and Reporters Without Borders (Reporter ohne Grenzen) (RSF) also issued checklists."
The proposed Google/Apple plan intends to address the problem of persistent surveillance by removing the tracing mechanism from their device operating systems once it is no longer needed.
Some countries used network-based location tracking instead of apps, eliminating both the need to download an app and the ability to avoid tracking.
In Israel, network-based tracking was approved.
Network-based solutions that have access to raw location data have significant potential privacy problems.
However, not all systems with central servers need to have access to personal location data; a number of privacy-preserving systems have been created that use central servers only for intercommunication (see section below).
In South Korea, a non-app-based system was used to perform contact tracing.
Instead of using a dedicated app, the system gathered tracking information from a variety of sources including mobile device tracking data and card transaction data, and combined these to generate notices via text messages to potentially-infected individuals.
In addition to using this information to alert potential contacts, the government has also made the location information publicly available, something permitted because of far-reaching changes to information privacy laws after the MERS outbreak in that country.
This information is available to the public via a number of apps and websites.Countries including Germany considered using both centralized and privacy-preserving systems.
As of 6 April 2020, the details had not yet been released.
Privacy-preserving contact tracing is a well-established concept, with a substantial body of research literature dating back to at least 2013.As of 7 April 2020, over a dozen expert groups were working on privacy-friendly solutions, such as using Bluetooth Low Energy (BLE) to log a user's proximity to other cellphones.
However, PEPP-PT is a co-ordination effort which contains both centralised and decentralised approaches, and is not a single protocol.Decentralised protocols include Decentralized Privacy-Preserving Proximity Tracing (DP-PPT/DP-3T), Temporary Contact Numbers (TCN, fka Contact Event Numbers, CEN), Privacy Sensitive Protocols and Mechanisms for Mobile Contact Tracing (PACT) and others.
In these protocols, identifiable personal data never leaves the device, and all matching happens on-device.
The Privacy Group at MIT Media Lab has been developing SafePaths, a platform for using privacy-preserving techniques when collecting and using location or path intersection data to track the spread of COVID-19.
"It is based on research from the whitepaper ""Apps Gone Rogue: Maintaining Personal Privacy in an Epidemic"" released in March 2020.Another similar effort is the SafeTrace platform by Enigma MPC, a company developing privacy technologies that was also originally founded at the MIT Media Lab."
SafeTrace utilizes secure hardware technologies to allow users to share sensitive location and health data with other users and officials, without compromising the privacy of that data.
On 5 April 2020, the global TCN Coalition was founded by groups that had coalesced around what was essentially the same approach and largely overlapping protocols, with the goal to reduce fragmentation, and enable global interoperability of tracing and alerting apps, a key aspect of achieving widespread adoption.
On 9 April 2020, the Singaporean government announced that it had open-sourced the BlueTrace protocol used by its official government app.
On 10 April 2020, Google and Apple, the companies that control the Android and iOS mobile platforms, announced an initiative for contact tracing, which they claimed would preserve privacy, based on a combination of Bluetooth Low Energy technology and privacy-preserving cryptography.
They also published specifications of the core technologies used in the system.
According to Apple and Google, the system is intended to be rolled out in three stages:
rollout of tools to enable governments to create official privacy-preserving coronavirus tracing apps
integration of this functionality directly into iOS and AndroidGoogle and Apple plan to address the take-up and persistent surveillance problems by first distributing the system through operating system updates, and later removing it in the same way once the threat has passed.
b'COVID-19 drug development is the research process to develop a preventative vaccine or therapeutic prescription drug that would alleviate the severity of 2019-20 coronavirus disease (COVID-19).
The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.
"In March, the WHO initiated the ""SOLIDARITY Trial"" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy."
A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.Vaccine and drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound.
Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery.
It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug.
Development of a COVID-19 vaccine or therapeutic antiviral drug begins with matching a chemical concept to the potential prophylactic mechanism of the future vaccine or antiviral activity in vivo.
New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery to specify a vaccine or antiviral candidate.
These have promising activity against a biological target related to COVID-19 disease.
At the beginning of vaccine or drug development, little is known about the safety, toxicity, pharmacokinetics, and metabolism of the NCE in humans.
It is the function and obligation of drug development to assess all of these parameters prior to human clinical trials to prove safety and efficacy.
"A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial (""first-in-human"" [FIH] or First Human Dose [FHD], previously also known as ""first-in-man"" [FIM])."
In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility.
Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale.
They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations.
Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC).Many aspects of drug development focus on satisfying the regulatory requirements of drug licensing authorities.
These generally constitute tests designed to determine the major toxicities of a novel compound prior to first use in humans.
"The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, with plans to establish a ""vaccine bank"" of new vaccines for implementation if another coronavirus outbreak occurs."
Clinical trial programs involve three, multiple-year stages toward product approval, and a fourth, post-approval stage for ongoing safety monitoring of the vaccine or drug therapy:
Phase I trials, usually in healthy volunteers, determine safety and dosing.
Phase II trials are used to establish an initial reading of efficacy and further explore safety in small numbers of people having the disease targeted by the NCE.
Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of people with the COVID-19 infection.
If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage to begin marketing.
Phase IV trials are post-approval trials that may be a condition attached by the FDA, also called post-market surveillance studies.
In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).
"In the United States, this process is called a ""new drug application"" or NDA."
"A clinical trial design in progress may be modified as an ""adaptive design"" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment."
The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II-III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II-III clinical trials.
"The high failure rates associated with pharmaceutical development are referred to as an ""attrition rate"", requiring decisions during the early stages of drug development to ""kill"" projects early to avoid costly failures."
One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market as about US$1.8 billion and $870 million, respectively.
A median cost estimate of 2015-16 trials for development of 10 anti-cancer drugs was $648 million.
In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%.
Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate.
Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April.
Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments.
The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments.
In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19.
For an already-approved drug (such as hydroxychloroquine for malaria), Phase III-IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection.
As of early April 2020, 103 candidate therapeutics were in preclinical or a stage of Phase I-IV development, with trial results for 29 drug candidates expected during April.
"In March, the World Health Organization (WHO) launched the coordinated ""Solidarity trial"" in 10 countries to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness."
Do any of the drugs reduce mortality?
Do any of the drugs reduce the time a patient is hospitalized?
Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website.
After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19.
The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website.
A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy.
"A similar web-based study to Solidarity, called ""Discovery"", was initiated in March across seven countries by INSERM (Paris, France).During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management."
"Numerous candidate drugs under study as ""supportive"" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below."
Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, are also excluded.
Drug candidates in Phase I-II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval.
Hydroxychloroquine is more commonly available than chloroquine in the United States.
Although several countries use chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID-19, as of March 2020 the drug has not been formally approved through clinical trials in the United States.
Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19, although these agencies and the US CDC noted contraindications for people with heart disease or diabetes.
Both drugs have extensive interactions with prescription drugs, affecting the therapeutic dose and disease mitigation.
Some people have allergic reactions to these drugs.On 12 April, a preliminary clinical trial conducted at a hospital in Brazil was stopped when several people given high doses of chloroquine for COVID-19 infection developed irregular heart rates, causing 11 deaths.
"Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was ""clearly effective""."
Of 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.
In a study conducted in Wuhan on 240 patients with pneumonia half were given favipiravir and half received umifenovir.
"The term ""preclinical research"" is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a vaccine, antiviral or monoclonal antibody therapy, such as experiments to determine effective doses and toxicity, before a candidate compound is advanced for safety and efficacy evaluation in humans."
Some antibiotics may be repurposed as COVID-19 treatments:
In March 2020, the main protease of the SARS-CoV-2 virus was identified as a target for post-infection drugs.
This enzyme is essential to the host cell to reproduce the ribonucleic acid of the virus.
To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease.
As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID-19.
A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID-19.
b'Drug repositioning (also known as drug repurposing, re-profiling, re-tasking or therapeutic switching) is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed.
This is one line of scientific research which is currently being pursued to develop safe and effective COVID-19 treatments.
Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.SARS-CoV-2 has about 66 druggable proteins, each of which has multiple ligand binding sites.
Analyzing those binding sites provide the reasonable project of developing effective antiviral drug against COVID-19 proteins.
Of the most important SARS-CoV-2 target proteins are papain-like protease, RNA dependent RNA polymerase, helicase, S protein, and ADP ribophosphatase.
Hussein A A, et al studied several candidate compounds which then optimized and analyzed for their skeleton similarity with the highest similar approved drugs in order to accelerate a potent anti-SARS-CoV-2 drug development in his preclinical study to be recommended in a clinical study design.
Chloroquine is an anti-malarial medication that is also used against some auto-immune diseases.
On 18 March, the WHO announced that chloroquine and the related hydroxychloroquine would be among the four drugs studied as part of the Solidarity clinical trial.
New York governor Andrew Cuomo announced that New York State trials of chloroquine and hydroxychloroquine would begin on 24 March.On 28 March, the FDA authorized the use of hydroxychloroquine sulfate and chloroquine phosphate under an Emergency Use Authorization (EUA).
The treatment has not been approved by the FDA's clinical trials process and is authorized under the EUA only as an experimental treatment for emergency use in patients who are hospitalized but are not able to receive treatment in a clinical trial.
"The CDC has said that ""the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection"" are not yet established."
"Doctors have said they are using the drug when ""there's no other option""."
A Turkish research team in Istanbul is conducting a small study on the use of chloroquine in combination with zinc, vitamin A, vitamin C and vitamin D.
Large studies are underway at Duke University and the University of Oxford.
NYU Langone Medical School is conducting a trial on the safety and efficacy of preventative use of hydroxychloroquine.
"Chinese clinical trials in Wuhan and Shenzhen claimed to show favipiravir was ""clearly effective""."
35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.
In a study conducted in Wuhan on 240 patients with pneumonia, half were given favipiravir and half received umifenovir.
The Italian Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.
On 2 April, Germany announced that it would purchase the drug from Japan for its stockpile, and use the military to deliver the drug to university hospitals, where the drug will be used to treat COVID-19 patients.
According to the South China Morning Post, Shinzo Abe has made overtures to the Trump administration about purchasing the drug.The drug may be less effective in severe cases of illness where the virus has already multiplied.
It may not be safe for use by pregnant women or those trying to conceive.
"One study of lopinavir/ritonavir (Kaletra), a combination of the antivirals lopinavir and ritonavir, concluded that ""no benefit was observed""."
The drugs were designed to inhibit HIV from replicating by binding to the protease.
A team of researchers at the University of Colorado are trying to modify the drugs to find a compound that will bind with the protease of SARS-CoV-2.There are criticisms within the scientific community about directing resources to repurposing drugs specifically developed for HIV/AIDS.
The WHO included lopinavir/ritonavir in the international Solidarity trial.
Remdesivir was created and developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections . Gilead Sciences subsequently discovered that Remdesivir had antiviral activity in vitro against multiple filo-, pneumo-, paramyxo-, and corona- viruses .
One issue with antiviral treatment is the development of resistance through mutations that can lead to more severe disease and transmission.
Some early pretrial studies suggest remdesivir may have a high genetic barrier to resistance.There are several clinical trials underway, including two conducted by Cleveland University Hospitals; one for people with moderate illness and another for those with more severe illness.
There are three ongoing clinical trials of intravenous vitamin C for people who are hospitalized and severely ill with COVID-19; two placebo controlled (China, Canada) and one with no control (Italy).
New York State began trials for the antibiotic azithromycin on 24 March 2020.
Japan's National Center for Global Health and Medicine (NCGM) is planning a clinical trial for Teijin's Alvesco (ciclesonide), an inhaled corticosteroid for asthma, for the treatment of pre-symptomatic patients infected with the novel coronavirus.
A form of angiotensin-converting enzyme 2, a Phase II trial is underway with 200 patients to be recruited from severe, hospitalized cases in Denmark, Germany, and Austria to determine the effectiveness of the treatment.
Researchers from the Montreal Heart Institute in Canada are currently studying the role of colchicine in reducing inflammation and pulmonary complications in patients suffering from mild symptoms of COVID-19.
The study, named COLCORONA, is recruiting 6000 adults aged 40 and over who were diagnosed with COVID-19 and experience mild symptoms not requiring hospitalization.
Women who are pregnant or breastfeeding or who do not have an effective contraceptive method are not eligible.
Several anticoagulants are being tested in Italy.
Low-molecular-weight heparin is being widely used to treat patients, prompting the Italian Medicines Agency to publish guidelines on its use.
A multicenter study on 300 patients researching the use of enoxaparin sodium at prophylaxis and therapeutic dosages was announced in Italy on April 14.
Since SARS-CoV-2 is a virus, considerable scientific attention has been focused on repurposing approved anti-viral drugs that were developed for prior outbreaks such as MERS, SARS, and West Nile virus.
Ribavirin: ribavirin was recommended for COVID-19 treatment according to Chinese 7th edition guidelines
Umifenovir: umifenovir was recommended for COVID-19 treatment according to Chinese 7th edition guidelines
Some antibiotics that have been identified as potentially repurposable as COVID-19 treatments:
Tocilizumab (Anti-IL-6 receptor): Approved by China.
Also trials in Italy and China. and see Tocilizumab#COVID-19.
It is unclear yet whether conditions arising during pregnancy including diabetes, cardiac failure, hypercoagulability or hypertension might represent additional risk factors for pregnant people as they do for nonpregnant people.From the limited data available, vertical transmission during the third trimester probably does not occur, or only occurs very rarely.
There is no data yet on early pregnancy.
Little evidence exists to permit any solid conclusions about the nature of COVID-19 infection in pregnancy.
A case series of 43 women from New York who tested positive for COVID-19 showed similar patterns to non-pregnant adults: 86% had mild disease, 9.3% had severe disease and 4.7% developed critical disease.
Fetal distress was reported in two.
None of the women developed severe COVID-19 pneumonia or died.
All of them had live birth pregnancies and no severe neonatal asphyxia was observed.
The samples of breast milk, amniotic fluid, cord blood and neonatal throat swab were tested for SARS-CoV-2, and all results were negative.In another study on 15 pregnant women, majority of the patients presented with fever and cough, while laboratory tests yielded lymphocytopenia in 12 patients.
Computed tomography findings of these patients were consistent with previous reports of non-pregnant patients, consisting of ground-glass opacities at early stage.
Follow-up images after delivery showed no progression of pneumonia.Media reports indicate that over 100 women with COVID-19 might have delivered, and in March 2020, no maternal deaths were reported.
Their guidelines thus advise that any pregnant person admitted to hospital with a COVID-19 infection should receive at least 10 days of prophylactic low-molecular-weight heparin after being discharged from the hospital.
There are no data yet concerning the implications of COVID-19 infections for labour.
One infant girl born to a mother with COVID-19 had elevated IgM levels two hours after birth, suggesting that she had been infected in utero and supporting the possibility of vertical transmission in some cases.
A small study involving 6 confirmed COVID-19 mothers showed no indication of SARS-COV-19 in their newborns' throats or serum but antibodies were present in neonatal blood sera samples, including IgM in two of the infants.
This is not usually passed from mother to fetus so further research is required to know whether the virus crossed the placenta or whether placentas of women in the study were damaged or abnormal.
Since COVID-19 shows similarities to SARS-CoV and MERS-CoV, it is likely that their effect on pregnancy are similar.
Four of seven had first trimester miscarriage, two of five had fetal growth restriction in the second trimester, and four of five had preterm birth.
None of the newborns were infected with SARS-CoV.
A report of ten cases of MERS- CoV infection in pregnancy in Saudi Arabia showed that the clinical presentation is variable, from mild to severe infection.
The outcome was favorable in a majority of the cases, but the infant death rate was 27%.A recent review suggested that COVID-19 appeared to be less lethal to mothers and infants than SARS and MERS but that there may be an increased risk of preterm birth after 28 weeks' gestation.
The World Health Organization and Centers for Disease Control and Prevention of the United States advises pregnant women to do the same things as the general public to avoid infection, such as covering cough, avoid interacting with sick people, cleaning hands with soap and water or sanitizer.
A survey conducted in Shanghai among pregnant women in different trimesters of pregnancy identified a strong demand for online access to health information and services.
People expecting their first baby were more willing to have online consultation and guidance than who had previously given birth.The RCOG and RCM recommend that in-person appointments be deferred by 7 days after the start of symptoms of COVID-19 or 14 days if another person in the household has symptoms.
Fever subsequently developed in three asymptomatic patients.
One patient who had tested negative subsequently became symptomatic postpartum and tested positive three days after the initial negative test.
The doctors conducting the screening recommended that in order to reduce infection and allocate PPE, due to high numbers of patients presenting as asymptomatic, universal screening of pregnant patients should be conducted.
They also suggest that people with suspected or confirmed COVID-19 should have continuous electronic fetal monitoring.
The use of birthing pools is not recommended for suspected or confirmed cases of COVID-19 due to the risk of infection via faeces.
In the UK, official recommendations state that precautionary separation of a mother and a healthy baby should not be undertaken lightly and that they should be kept together in the postpartum period where neonatal care is not required.Literature from China recommended separation of infected mothers from babies for 14 days.
In the US there is also the recommendation that newborns and mothers should be temporarily separated until transmission-based precautions are discontinued, and that where this is not possible the newborn should be kept 2 metres away from the mother.
b'COVID-19 surveillance involves monitoring the spread of the coronavirus disease in order to establish the patterns of disease progression.
The World Health Organization (WHO) recommends active surveillance, with focus of case finding, testing and contact tracing in all transmission scenarios.
COVID-19 surveillance is expected to monitor epidemiological trends, rapidly detect new cases, and based on this information, provide epidemiological information to conduct risk assessment and guide disease preparedness.
Syndromic surveillance is done based on the symptoms of an individual that corresponds to COVID-19.
As of March 2020, the WHO recommends the following case definitions:
"Probable case : ""A suspect case for whom testing for the COVID-19 virus is inconclusive"" OR ""a suspect case for whom testing could not be performed for any reason""."
"Confirmed case: ""A person with laboratory confirmation of COVID-19 infection, irrespective of clinical signs and symptoms""."
Direct physical contact with a probable or confirmed case;
Direct care for a patient with probable or confirmed COVID-19 disease without using proper personal protective equipment;
"Other situations as indicated by local risk assessments"".WHO recommends reporting of probable and confirmed cases of COVID-19 infection within 48 hours of identification."
The countries should report on a case-by-case basis as far as possible, but in case of limitation in resources, aggregate weekly reporting is also possible.
Some organizations have created crowdsourced apps for syndromic surveillance, where people can report their symptoms to help researchers map areas with concentration of COVID-19 symptoms.
Virological surveillance is done by using molecular tests for COVID-19.
WHO has published resources for laboratories on how to perform testing for COVID-19.
In the European Union, laboratory confirmed cases of COVID-19 are reported within 24 hours of identification.
At least 24 countries have established digital surveillance of their citizens.
The digital surveillance technologies include apps, location data and electronic tags.
The Center For Disease Control and Prevention in USA tracks the travel information of individuals using airline passenger data.
In Hong Kong, authorities are requiring a bracelet and an app for all travellers.
A GPS app is used to track the locations of individuals in South Korea to ensure against quarantine breach, sending alerts to the user and to authorities if people leave designated areas.
In Singapore, individuals have to report their locations with photographic proof.
Thailand is using an app and SIM cards for all travelers to enforce their quarantine.
Human rights organizations have criticized some of these measures, asking the governments not to use the pandemic as a cover to introduce invasive digital surveillance.
b'A COVID-19 vaccine is a hypothetical vaccine against coronavirus disease 2019 (COVID-19).
Although no vaccine has completed clinical trials, there are multiple attempts in progress to develop such a vaccine.
In late February 2020, the World Health Organization (WHO) said it did not expect a vaccine against SARS-CoV-2, the causative virus, to become available in less than 18 months.
Five vaccine candidates were in Phase I safety studies in April.
COVID-19 was identified in December 2019.
A major outbreak spread around the world in 2020, leading to considerable investment and research activity to develop a vaccine.
Many organizations are using published genomes to develop possible vaccines against SARS-CoV-2.
Stated in April, imperatives of the CEPI initiative for vaccine development are speed, manufacturing capacity, deployment at scale, and global access.
In April, CEPI scientists reported that 10 different technology platforms were under research and development during early 2020 to create an effective vaccine against COVID-19.
Major platform targets advanced into Phase I safety studies include:
nucleic acid (DNA and RNA) (Phase I developer and vaccine candidate: Moderna, mRNA-1273)
viral vector (Phase I developer and vaccine candidate: CanSino Biologics, adenovirus type 5 vector)
As reported by CEPI scientists in April, 115 total vaccine candidates are in early stages of development, with 78 confirmed as active projects (79, according to the Milken Institute), and 37 others announced, but with little public information available (presumed to be in planning or being designed).
A Phase I-II trial conducts preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, and at multiple sites, while determining more precise, effective doses.
Phase III trials typically involve more participants, including a control group, and test effectiveness of the vaccine to prevent the disease, while monitoring for adverse effects at the optimal dose.
"Of 79 vaccine candidates in active development (confirmed as of early April 2020), 74 were not yet in human evaluation (still in ""preclinical"" research)."
Around 24 January 2020 in Australia, the University of Queensland announced that it is investigating the potential of a molecular clamp vaccine that would genetically modify viral proteins in order to stimulate an immune reaction.
Around 24 January 2020 in Canada, the International Vaccine Centre (VIDO-InterVac) at the University of Saskatchewan announced the commencement of work on a vaccine, aiming to start human testing in 2021.
Vaccine development projects were announced at the Chinese Center for Disease Control and Prevention on 26 January 2020, and the University of Hong Kong on 28 January.
Around 29 January 2020, Janssen Pharmaceutical Companies, led by Hanneke Schuitemaker, announced that it had begun work on developing a vaccine.
Janssen is co-developing an oral vaccine with its biotechnology partner, Vaxart.
On 18 March 2020, Emergent BioSolutions announced a manufacturing partnership with Vaxart to develop the vaccine.
On 8 February 2020, the laboratory OncoGen in Romania published a paper on the design of a vaccine with similar technology to the one used for cancer neoantigen vaccination therapy.
On 25 March the head of the research institute announced that they had finalized the synthesis of the vaccine and were beginning the tests.
On 27 February 2020, a Generex subsidiary company, NuGenerex Immuno-Oncology, announced they were beginning a vaccine project to create an Ii-Key peptide vaccine against COVID-19.
"They wanted to produce a vaccine candidate that could be tested in humans ""within 90 days."""
On 5 March 2020, Washington University in St. Louis announced its projects to develop a vaccine.
On 5 March 2020, the United States Army Medical Research and Materiel Command at Fort Detrick and the Walter Reed Army Institute of Research in Silver Spring, both in western Maryland, announced they were working on a vaccine.
Around 10 March 2020, Emergent Biosolutions announced that it had teamed with Novavax Inc.
in the development and manufacture of a vaccine.
The partners further announced plans for preclinical testing and a Phase I clinical trial by July 2020.
On 12 March 2020, India's Health Ministry announced they are working with 11 isolates, and that even on a fast track it would take at least around one-and-a-half to two years to develop a vaccine.
On 12 March 2020, Medicago, a biotechnology company in Quebec City, Quebec, reported development of a coronavirus-like particle under partial funding from the Canadian Institutes for Health Research.
The vaccine candidate is in laboratory research, with human testing planned for July or August 2020.
"Earlier that week, The Guardian reported that the US President Donald Trump had offered CureVac ""'large sums of money' for exclusive access to a Covid-19 vaccine"", against which the German government protested."
On 17 March 2020, American pharmaceutical company Pfizer announced a partnership with German company BioNTech to jointly develop a mRNA-based vaccine.
mRNA-based vaccine candidate BNT162, currently in pre-clinical testing with clinical trials expected to begin in April 2020.
In Italy on 17 March 2020, Takis Biotech, an Italian biotech company announced they will have pre-clinical testing results in April 2020 and their final vaccine candidate could begin human testing by fall.
In France on 19 March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) announced a US$4.9 million investment in a COVID-19 vaccine research consortium involving the Institut Pasteur, Themis Bioscience (Vienna, Austria), and the University of Pittsburgh, bringing CEPI's total investment in COVID-19 vaccine development to US$29 million.
CEPI's other investment partners for COVID-19 vaccine development are Moderna, Curevac, Inovio, Novavax, the University of Hong Kong, the University of Oxford, and the University of Queensland.
On 20 March 2020, Russian health officials announced that scientists have begun animal testing of six different vaccine candidates.
Imperial College London researchers announced on 20 March 2020 that they are developing a self-amplifying RNA vaccine for COVID-19.
The vaccine candidate was developed within 14 days of receiving the sequence from China.
In late March, the Canadian government announced C$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian companies and universities, such as the Medicago and University of Saskatchewan initiatives.
"Around the same time, the Canadian government announced C$192 million specifically for developing a COVID-19 vaccine, with plans to establish a national ""vaccine bank"" of several new vaccines that could be used if another coronavirus outbreak occurs."
"On 2 April 2020, researchers at the University of Pittsburgh School of Medicine reported on testing of PittCoVacc, a possible COVID-19 vaccine in mice, stating that ""MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses [in the mice] that were evident beginning 2 weeks after immunization."""
In Canada on 16 April 2020, the University of Waterloo School of Pharmacy announced design of a DNA-based vaccine candidate as a possible nasal spray.
Using bacteriophages, the DNA will be designed to replicate inside human bacteria to produce harmless virus-like particles, which may stimulate the immune system to produce antibodies against the SARS-CoV-2 virus.
In March 2020, the US government, industry, and three universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google.
Some vaccines have heterologous effects, also called non-specific effects.
That means they can have benefits beyond the disease they prevent.
A further randomized trial in Australia is seeking to enrol 4,170 healthcare workers.
It is possible vaccines in development will not be safe or effective.
Early research to assess vaccine efficacy using COVID-19-specific animal models, such as ACE2-transgenic mice, other laboratory animals, and non-human primates, indicate a need for biosafety-level 3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.
Vaccines against SARS and MERS have been tested in non-human animal models.
As of 2020, there is no cure or protective vaccine for SARS that has been shown to be both safe and effective in humans.
According to research papers published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS was a priority for governments and public health agencies around the world.There is also no proven vaccine against MERS.
When MERS became prevalent, it was believed that existing SARS research may provide a useful template for developing vaccines and therapeutics against a MERS-CoV infection.
As of March 2020, there was one (DNA based) MERS vaccine which completed phase I clinical trials in humans, and three others in progress, all of which are viral-vectored vaccines, two adenoviral-vectored (ChAdOx1-MERS, BVRS-GamVac), and one MVA-vectored (MVA-MERS-S).
Social media posts have promoted a conspiracy theory claiming the virus behind COVID-19 was known and that a vaccine was already available.
The patents cited by various social media posts reference existing patents for genetic sequences and vaccines for other strains of coronavirus such as the SARS coronavirus.
b'Coronaviruses are a group of related viruses that cause diseases in mammals and birds.
In humans, coronaviruses cause respiratory tract infections that can range from mild to lethal.
Mild illnesses include some cases of the common cold (which has other possible causes, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19.
Symptoms in other species vary: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea.
There are yet to be vaccines or antiviral drugs to prevent or treat human coronavirus infections.
Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria.
They are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry.
The genome size of coronaviruses ranges from approximately 26 to 32 kilobases, one of the largest among RNA viruses.
They have characteristic club-shaped spikes that project from their surface, which in electron micrographs create an image reminiscent of the solar corona from which their name derives.
Coronaviruses were first discovered in the 1930s when an acute respiratory infection of domesticated chickens was shown to be caused by infectious bronchitis virus (IBV).
In the 1940s, two more animal coronaviruses, mouse hepatitis virus (MHV) and transmissible gastroenteritis virus (TGEV), were isolated.Human coronaviruses were discovered in the 1960s.
The earliest ones studied were from human patients with the common cold, which were later named human coronavirus 229E and human coronavirus OC43.
They were first imaged by Scottish virologist June Almeida at St. Thomas Hospital in London.
Other human coronaviruses have since been identified, including SARS-CoV in 2003, HCoV NL63 in 2004, HKU1 in 2005, MERS-CoV in 2012, and SARS-CoV-2 in 2019.
Most of these have involved serious respiratory tract infections.
The name was first used in 1968 by an informal group of virologists in the journal Nature to designate the new family of viruses.
The name refers to the characteristic appearance of virions (the infective form of the virus) by electron microscopy, which have a fringe of large, bulbous surface projections creating an image reminiscent of a crown or of a solar corona.
This morphology is created by the viral spike peplomers, which are proteins on the surface of the virus.
Coronaviruses are large pleomorphic spherical particles with bulbous surface projections.
The envelope of the virus in electron micrographs appears as a distinct pair of electron dense shells.The viral envelope consists of a lipid bilayer where the membrane (M), envelope (E) and spike (S) structural proteins are anchored.
The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.
Coronaviruses contain a positive-sense, single-stranded RNA genome.
The genome size for coronaviruses ranges from 26.4 to 31.7 kilobases.
The genome size is one of the largest among RNA viruses.
The open reading frames 1a and 1b, which occupy the first two-thirds of the genome, encode the replicase/transcriptase polyprotein.
The replicase/transcriptase polyprotein self cleaves to form nonstructural proteins.The later reading frames encode the four major structural proteins: spike, envelope, membrane, and nucleocapsid.
Interspersed between these reading frames are the reading frames for the accessory proteins.
The number of accessory proteins and their function is unique depending on the specific coronavirus.
Infection begins when the viral spike (S) glycoprotein attaches to its complementary host cell receptor.
After attachment, a protease of the host cell cleaves and activates the receptor-attached spike protein.
Depending on the host cell protease available, cleavage and activation allows the virus to enter the host cell by endocytosis or direct fusion of the viral envelop with the host membrane.On entry into the host cell, the virus particle is uncoated, and its genome enters the cell cytoplasm.
The host ribosome translates the initial overlapping open reading frame of the virus genome and forms a long polyprotein.
The polyprotein has its own proteases which cleave the polyprotein into multiple nonstructural proteins.
A number of the nonstructural proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC).
The main replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp).
It is directly involved in the replication and transcription of RNA from an RNA strand.
The other nonstructural proteins in the complex assist in the replication and transcription process.
The exoribonuclease nonstructural protein, for instance, provides extra fidelity to replication by providing a proofreading function which the RNA-dependent RNA polymerase lacks.One of the main functions of the complex is to replicate the viral genome.
RdRp directly mediates the synthesis of negative-sense genomic RNA from the positive-sense genomic RNA.
This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA.
The other important function of the complex is to transcribe the viral genome.
RdRp directly mediates the synthesis of negative-sense subgenomic RNA molecules from the positive-sense genomic RNA.
This is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs.
The replicated positive-sense genomic RNA becomes the genome of the progeny viruses.
The mRNAs are gene transcripts of the last third of the virus genome after the initial overlapping reading frame.
These mRNAs are translated by the host's ribosomes into the structural proteins and a number of accessory proteins.
RNA translation occurs inside the endoplasmic reticulum.
The viral structural proteins S, E, and M move along the secretory pathway into the Golgi intermediate compartment.
There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid.
Progeny viruses are then released from the host cell by exocytosis through secretory vesicles.
The interaction of the coronavirus spike protein with its complement host cell receptor is central in determining the tissue tropism, infectivity, and species range of the virus.
The SARS coronavirus, for example, infects human cells by attaching to the angiotensin-converting enzyme 2 (ACE2) receptor.
The scientific name for coronavirus is Orthocoronavirinae or Coronavirinae.
Coronaviruses belong to the family of Coronaviridae, order Nidovirales, and realm Riboviria.
Genus Betacoronavirus; type species: Murine coronavirus
Species: Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Human coronavirus HKU1, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2), Tylonycteris bat coronavirus HKU4, Middle East respiratory syndrome-related coronavirus, Hedgehog coronavirus 1 (EriCoV)
Species: Beluga whale coronavirus SW1, Infectious bronchitis virus
The most recent common ancestor (MRCA) of all coronaviruses is estimated to have existed as recently as 8000 BCE, although some models place the common ancestor as far back as 55 million years or more, implying long term coevolution with bat and avian species.
The most recent common ancestor of the alphacoronavirus line has been placed at about 2400 BCE, the betacoronavirus line at 3300 BCE, the gammacoronavirus line at 2800 BCE, and the deltacoronavirus line at about 3000 BCE.
The large number of host bat and avian species, and their global range, has enabled extensive evolution and dissemination of coronaviruses.Many human coronavirus have their origin in bats.
More recently, alpaca coronavirus and human coronavirus 229E diverged sometime before 1960.
MERS-CoV emerged in humans from bats through the intermediate host of camels.
MERS-CoV, although related to several bat coronavirus species, appears to have diverged from these several centuries ago.
The most closely related bat coronavirus and SARS-CoV diverged in 1986.
A possible path of evolution, of SARS coronavirus and keen bat coronaviruses, suggests that SARS related coronaviruses coevolved in bats for a long time.
In the 1790s, equine coronavirus diverged from the bovine coronavirus after a cross-species jump.
Later in the 1890s, human coronavirus OC43 diverged from bovine coronavirus after another cross-species spillover event.
It is speculated that the flu pandemic of 1890 may have been caused by this spillover event, and not by the influenza virus, because of the related timing, neurological symptoms, and unknown causative agent of the pandemic.
Human coronavirus OC43 besides causing respiratory infections is also suspected of playing a role in neurological diseases.
In the 1950s, the human coronavirus OC43 began to diverge into its present genotypes.
Phylogentically, mouse hepatitis virus (Murine coronavirus), which infects the mouse's liver and the central nervous system, is related to human coronavirus OC43 and bovine coronavirus.
Human coronavirus HKU1, like the aforementioned viruses, also has its origins in rodents.
Coronaviruses vary significantly in risk factor.
Some can kill more than 30% of those infected, such as MERS-CoV, and some are relatively harmless, such as the common cold.
Coronaviruses can cause colds with major symptoms, such as fever, and a sore throat from swollen adenoids.
Coronaviruses can cause pneumonia (either direct viral pneumonia or secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or secondary bacterial bronchitis).
The human coronavirus discovered in 2003, SARS-CoV, which causes severe acute respiratory syndrome (SARS), has a unique pathogenesis because it causes both upper and lower respiratory tract infections.Six species of human coronaviruses are known, with one species subdivided into two different strains, making seven strains of human coronaviruses altogether.
Four of these coronaviruses continually circulate in the human population and produce the generally mild symptoms of the common cold in adults and children worldwide: -OC43, -HKU1, HCoV-229E, -NL63.
Coronaviruses cause about 15% of commons colds.
The majority of colds are caused by rhinoviruses.
The four mild coronaviruses have a seasonal incidence occurring in the winter months in temperate climates.
There is no preference towards a particular season in tropical climates.
Four human coronaviruses produce symptoms that are generally mild:
The virus was officially named the SARS coronavirus (SARS-CoV).
More than 8,000 people were infected, about ten percent of whom died.
In September 2012, a new type of coronavirus was identified, initially called Novel Coronavirus 2012, and now officially named Middle East respiratory syndrome coronavirus (MERS-CoV).
The World Health Organization issued a global alert soon after.
The WHO update on 28 September 2012 said the virus did not seem to pass easily from person to person.
However, on 12 May 2013, a case of human-to-human transmission in France was confirmed by the French Ministry of Social Affairs and Health.
In addition, cases of human-to-human transmission were reported by the Ministry of Health in Tunisia.
Two confirmed cases involved people who seemed to have caught the disease from their late father, who became ill after a visit to Qatar and Saudi Arabia.
Despite this, it appears the virus had trouble spreading from human to human, as most individuals who are infected do not transmit the virus.
The final name for the virus is Middle East respiratory syndrome coronavirus (MERS-CoV).
The only U.S. cases (both survived) were recorded in May 2014.In May 2015, an outbreak of MERS-CoV occurred in the Republic of Korea, when a man who had traveled to the Middle East, visited four hospitals in the Seoul area to treat his illness.
This caused one of the largest outbreaks of MERS-CoV outside the Middle East.
As of December 2019, 2,468 cases of MERS-CoV infection had been confirmed by laboratory tests, 851 of which were fatal, a mortality rate of approximately 34.5%.
In December 2019, a pneumonia outbreak was reported in Wuhan, China.
On 31 December 2019, the outbreak was traced to a novel strain of coronavirus, which was given the interim name 2019-nCoV by the World Health Organization (WHO), later renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses.
Some researchers have suggested the Huanan Seafood Wholesale Market may not be the original source of viral transmission to humans.As of 17 April 2020, there have been at least 153,822 confirmed deaths and more than 2,240,191 confirmed cases in the coronavirus pneumonia pandemic.
The Wuhan strain has been identified as a new strain of Betacoronavirus from group 2B with approximately 70% genetic similarity to the SARS-CoV.
The virus has a 96% similarity to a bat coronavirus, so it is widely suspected to originate from bats as well.
The pandemic has resulted in travel restrictions and nationwide lockdowns in several countries.
Coronaviruses have been recognized as causing pathological conditions in veterinary medicine since the 1930s.
Except for avian infectious bronchitis, the major related diseases have mainly an intestinal location.
Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds.
They also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry.
In chickens, the infectious bronchitis virus (IBV), a coronavirus, targets not only the respiratory tract but also the urogenital tract.
The virus can spread to different organs throughout the chicken.
Economically significant coronaviruses of farm animals include porcine coronavirus (transmissible gastroenteritis coronavirus, TGE) and bovine coronavirus, which both result in diarrhea in young animals.
Feline coronavirus: two forms, feline enteric coronavirus is a pathogen of minor clinical significance, but spontaneous mutation of this virus can result in feline infectious peritonitis (FIP), a disease associated with high mortality.
Similarly, there are two types of coronavirus that infect ferrets: Ferret enteric coronavirus causes a gastrointestinal syndrome known as epizootic catarrhal enteritis (ECE), and a more lethal systemic version of the virus (like FIP in cats) known as ferret systemic coronavirus (FSC).
There are two types of canine coronavirus (CCoV), one that causes mild gastrointestinal disease and one that has been found to cause respiratory disease.
Mouse hepatitis virus (MHV) is a coronavirus that causes an epidemic murine illness with high mortality, especially among colonies of laboratory mice.
Sialodacryoadenitis virus (SDAV) is highly infectious coronavirus of laboratory rats, which can be transmitted between individuals by direct contact and indirectly by aerosol.
Some strains of MHV cause a progressive demyelinating encephalitis in mice which has been used as a murine model for multiple sclerosis.
Significant research efforts have been focused on elucidating the viral pathogenesis of these animal coronaviruses, especially by virologists interested in veterinary and zoonotic diseases.
Porcine coronavirus (transmissible gastroenteritis coronavirus of pigs, TGEV).
Bovine coronavirus (BCV), responsible for severe profuse enteritis in of young calves.
Feline coronavirus (FCoV) causes mild enteritis in cats as well as severe Feline infectious peritonitis (other variants of the same virus).
the two types of canine coronavirus (CCoV) (one causing enteritis, the other found in respiratory diseases).
Turkey coronavirus (TCV) causes enteritis in turkeys.
Ferret enteric coronavirus causes epizootic catarrhal enteritis in ferrets.
Ferret systemic coronavirus causes FIP-like systemic syndrome in ferrets.
Rabbit enteric coronavirus causes acute gastrointestinal disease and diarrhea in young European rabbits.
Porcine epidemic diarrhea virus (PED or PEDV), has emerged around the world.
b'Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Common symptoms include fever, cough, and shortness of breath.
Other symptoms may include fatigue, muscle pain, diarrhea, sore throat, loss of smell, and abdominal pain.
The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days.
While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure.
As of 17 April 2020, more than 2.24 million cases have been reported across 210 countries and territories, resulting in more than 153,000 deaths.
More than 568,000 people have recovered.The virus is primarily spread between people during close contact, often via small droplets produced by coughing, sneezing, or talking.
While these droplets are produced when breathing out, they usually fall to the ground or onto surfaces rather than being infectious over long distances.
People may also become infected by touching a contaminated surface and then touching their eyes, nose, or mouth.
The virus can survive on surfaces up to 72 hours.
It is most contagious during the first three days after the onset of symptoms, although spread may be possible before symptoms appear and in later stages of the disease.The standard method of diagnosis is by real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.
The use of masks is recommended for those who suspect they have the virus and their caregivers.
Recommendations for mask use by the general public vary, with some authorities recommending against their use, some recommending their use, and others requiring their use.
Currently, there is no vaccine or specific antiviral treatment for COVID-19.
Local transmission of the disease has been recorded in most countries across all six WHO regions.
Those infected with the virus may be asymptomatic or develop flu-like symptoms such as fever, cough, fatigue, and shortness of breath.
Emergency symptoms include difficulty breathing, persistent chest pain or pressure, confusion, difficulty waking, and bluish face or lips; immediate medical attention is advised if these symptoms are present.
Less commonly, upper respiratory symptoms such as sneezing, runny nose or sore throat may be seen.
Gastrointestinal symptoms such as nausea, vomiting and diarrhoea have been observed in varying percentages.
Some cases in China initially presented only with chest tightness and palpitations.
In some, the disease may progress to pneumonia, multi-organ failure, and death.
This is called the incubation period.
The incubation period for COVID-19 is typically five to six days but may range from two to 14 days.
97.5% of people who develop symptoms will do so within 11.5 days of infection.Reports indicate that not all who are infected develop symptoms.
The role of these asymptomatic carriers in transmission is not yet fully known; however, preliminary evidence suggests that they may contribute to the spread of the disease.
The proportion of infected people who do not display symptoms is currently unknown and being studied, with the Korea Centers for Disease Control and Prevention (KCDC) reporting that 20% of all confirmed cases remained asymptomatic during their hospital stay.
China's National Health Commission began including asymptomatic cases in its daily cases on 1 April; of the 166 infections on that day, 130 (78%) were asymptomatic at the time of testing.
Both sputum and saliva can carry large viral loads.
Loud talking releases more droplets than normal talking.
A study in Singapore found that an uncovered cough can lead to droplets travelling up to 4.5 meters (15 feet).
Though the virus is not generally airborne, the National Academy of Science has suggested that bioaerosol transmission may be possible and air collectors positioned in the hallway outside of people's rooms yielded samples positive for viral RNA.
Some medical procedures such as intubation and cardiopulmonary resuscitation (CPR) may cause respiratory secretions to be aerosolised and thus result in airborne spread.
While there are concerns it may spread via feces, this risk is believed to be low.The virus is most contagious when people are symptomatic; while spread may be possible before symptoms emerge, the risk is low.
The European Centre for Disease Prevention and Control (ECDC) says while it is not entirely clear how easily the disease spreads, one person generally infects two to three others.The virus survives for hours to days on surfaces.
Specifically, the virus was found to be detectable for one day on cardboard, for up to three days on plastic (polypropylene) and stainless steel (AISI 304), and for up to four hours on 99% copper.
This, however, varies depending on the humidity and temperature.
Soap and detergent are also effective if correctly used; soap products degrade the virus' fatty protective layer, deactivating it, as well as freeing them from skin and other surfaces.
Other solutions, such as benzalkonium chloride and chlorhexidine gluconate (a surgical disinfectant), are less effective.In a Hong Kong study, saliva samples were taken a median of two days after the start of hospitalization.
In five of six patients, the first sample showed the highest viral load, and the sixth patient showed the highest viral load on the second day tested.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus, first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan.
All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature.
Outside the human body, the virus is killed by household soap, which bursts its protective bubble.SARS-CoV-2 is closely related to the original SARS-CoV.
The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in the type II alveolar cells of the lungs.
"The virus uses a special surface glycoprotein called a ""spike"" (peplomer) to connect to ACE2 and enter the host cell."
Acute cardiac injury was found in 12% of infected people admitted in hospital in Wuhan, China, and is more frequent in severe disease.
Rates of cardiovascular symptoms is high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injury may also be related to ACE2 receptors in the heart.
ACE2 receptors are highly expressed in the heart and are involved in heart function.
A high incidence of thrombosis (31%) and venous thromboembolism (25%) have been found in ICU patients with COVID-19 infections and may be related to poor prognosis.Autopsies of people who died of COVID-19 have found diffuse alveolar damage (DAD), and lymphocyte-containing inflammatory infiltrates within the lung.
Although SARS-COV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, patients with severe COVID-19 have symptoms of systemic hyperinflammation.
In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in COVID-19 patients.
Lymphocytic infiltrates have also been reported at autopsy.
The WHO has published several testing protocols for the disease.
The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).
The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used.
Results are generally available within a few hours to two days.
Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value.
Chinese scientists were able to isolate a strain of the coronavirus and publish the genetic sequence so laboratories across the world could independently develop polymerase chain reaction (PCR) tests to detect infection by the virus.
As of 4 April 2020, antibody tests (which may detect active infections and whether a person had been infected in the past) were in development, but not yet widely used.
The Chinese experience with testing has shown the accuracy is only 60 to 70%.
The FDA in the United States approved the first point-of-care test on 21 March 2020 for use at the end of that month.Diagnostic guidelines released by Zhongnan Hospital of Wuhan University suggested methods for detecting infections based upon clinical features and epidemiological risk.
Bilateral multilobar ground-glass opacities with a peripheral, asymmetric and posterior distribution are common in early infection.
Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.
Few data are available about microscopic lesions and the pathophysiology of COVID-19.
The main pathological findings at autopsy are:
Macroscopy: pleurisy, pericarditis, lung consolidation and pulmonary oedema
Four types of severity of viral pneumonia can be observed:
mild pneumonia: pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation
severe pneumonia: diffuse alveolar damage (DAD) with diffuse alveolar exudates.
DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.
healing pneumonia: organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis
Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction
Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene and avoiding touching the eyes, nose or mouth with unwashed hands.
The CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available.
Proper hand hygiene after any cough or sneeze is encouraged.
The CDC has recommended the use of cloth face coverings in public settings, in part to limit transmission by asymptomatic individuals.Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel and cancelling large public gatherings.
Distancing guidelines also include that people stay at least 6 feet (1.8 m) apart.
"There is no medication known to be effective at preventing COVID-19.As a vaccine is not expected until 2021 at the earliest, a key part of managing COVID-19 is trying to decrease the epidemic peak, known as ""flattening the curve""."
The CDC also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one's nose, coughing or sneezing.
It further recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available.For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production.
In these formulations, the antimicrobial activity arises from ethanol or isopropanol.
"Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is ""not an active substance for hand antisepsis""."
Glycerol is added as a humectant.
People are managed with supportive care, which may include fluid therapy, oxygen support, and supporting other affected vital organs.
The CDC recommends that those who suspect they carry the virus wear a simple face mask.
Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.
Personal hygiene and a healthy lifestyle and diet have been recommended to improve immunity.
Supportive treatments may be useful in those with mild symptoms at the early stage of infection.The WHO and Chinese National Health Commission have published recommendations for taking care of people who are hospitalised with COVID-19.
Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.
As of April 2020, there is no specific treatment for COVID-19.
For symptoms, some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use.
Precautions must be taken to minimise the risk of virus transmission, especially in healthcare settings when performing procedures that can generate aerosols, such as intubation or hand ventilation.
For healthcare professionals caring for people with COVID-19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions and airborne precautions.The CDC outlines the guidelines for the use of personal protective equipment (PPE) during the pandemic.
The recommended gear is: PPE gown, respirator or facemask, eye protection, and medical gloves.When available, respirators (instead of facemasks) are preferred.
N95 respirators are approved for industrial settings but the FDA has authorised the masks for use under an Emergency Use Authorisation (EUA).
They are designed to protect from airborne particles like dust but effectiveness against a specific biological agent is not guaranteed for off-label uses.
When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.
Most cases of COVID-19 are not severe enough to require mechanical ventilation or alternatives, but a percentage of cases are.
The type of respiratory support for individuals with COVID-19 related respiratory failure is being actively studied for people in hospital, with some evidence that intubation can be avoided with a high flow nasal cannula or bi-level positive airway pressure.
Whether either of these two leads to the same benefit for people who are critically ill is not known.
Some doctors prefer staying with invasive mechanical ventilation when available because this technique limits the spread of aerosol particles compared to a high flow nasal cannula.Severe cases are most common in older adults (those older than 60 years, and especially those older than 80 years).
Many developed countries do not have enough hospital beds per capita, which limits a health system's capacity to handle a sudden spike in the number of COVID-19 cases severe enough to require hospitalisation.
One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.
In China, approximately 30% of people in hospital with COVID-19 are eventually admitted to ICU.
Mechanical ventilation becomes more complex as acute respiratory distress syndrome (ARDS) develops in COVID-19 and oxygenation becomes increasingly difficult.
Ventilators capable of pressure control modes and high PEEP are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax.
High PEEP may not be available on older ventilators.
Research into potential treatments started in January 2020, and several antiviral drugs are in clinical trials.
Remdesivir appears to be the most promising.
Although new medications may take until 2021 to develop, several of the medications being tested are already approved for other uses or are already in advanced testing.
Antiviral medication may be tried in people with severe disease.
The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.The FDA has granted temporary authorisation to convalescent plasma as an experimental treatment in cases where the person's life is seriously or immediately threatened.
It has not undergone the clinical studies needed to show it is safe and effective for the disease.
In February 2020, China launched a mobile app to deal with the disease outbreak.
Users are asked to enter their name and ID number.
The app is able to detect 'close contact' using surveillance data and therefore a potential risk of infection.
Every user can also check the status of three other users.
If a potential risk is detected, the app not only recommends self-quarantine, it also alerts local health officials.Big data analytics on cellphone data, facial recognition technology, mobile phone tracking and artificial intelligence are used to track infected people and people whom they contacted in South Korea, Taiwan and Singapore.
In March 2020, the Israeli government enabled security agencies to track mobile phone data of people supposed to have coronavirus.
The measure was taken to enforce quarantine and protect those who may come into contact with infected citizens.
Also in March 2020, Deutsche Telekom shared aggregated phone location data with the German federal government agency, Robert Koch Institute, in order to research and prevent the spread of the virus.
Russia deployed facial recognition technology to detect quarantine breakers.
"Italian regional health commissioner Giulio Gallera said he has been informed by mobile phone operators that ""40% of people are continuing to move around anyway""."
German government conducted a 48 hours weekend hackathon with more than 42.000 participants.
Also the president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.
Individuals may experience distress from quarantine, travel restrictions, side effects of treatment or fear of the infection itself.
"BBC quoted Rory O'Connor in saying, ""Increased social isolation, loneliness, health anxiety, stress and an economic downturn are a perfect storm to harm people's mental health and wellbeing."""
The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold.
Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover.
Pregnant women may be at higher risk for severe infection with COVID-19 based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.In some people, COVID-19 may affect the lungs causing pneumonia.
In those most severely affected, COVID-19 may rapidly progress to acute respiratory distress syndrome (ARDS) causing respiratory failure, septic shock or multi-organ failure.
Complications associated with COVID-19 include sepsis, abnormal clotting and damage to the heart, kidneys and liver.
Clotting abnormalities, specifically an increase in prothrombin time, have been described in 6% of those admitted to hospital with COVID-19, while abnormal kidney function is seen in 4% of this group.
Approximately 20-30% of people who present with COVID-19 demonstrate elevated liver enzymes (transaminases).
According to the same report, the median time between onset of symptoms and death was ten days, with five being spent hospitalised.
However, patients transferred to an ICU had a median time of seven days between hospitalisation and death.
In a study of early cases, the median time from exhibiting initial symptoms to death was 14 days, with a full range of six to 41 days.
In a study by the National Health Commission (NHC) of China, men had a death rate of 2.8% while women had a death rate of 1.7%.
Histopathological examinations of post-mortem lung samples show diffuse alveolar damage with cellular fibromyxoid exudates in both lungs.
Viral cytopathic changes were observed in the pneumocytes.
The lung picture resembled acute respiratory distress syndrome (ARDS).
In 11.8% of the deaths reported by the National Health Commission of China, heart damage was noted by elevated levels of troponin or cardiac arrest.
According to March data from the United States, 89% of those hospitalised had preexisting conditions.Availability of medical resources and the socioeconomics of a region may also affect mortality.
Estimates of the mortality from the condition vary because of those regional differences, but also because of methodological difficulties.
The under-counting of mild cases can cause the mortality rate to be overestimated.
However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated.
Smokers were 1.4 times more likely to have severe symptoms of COVID-19 and approximately 2.4 times more likely to require intensive care or die compared to non-smokers.Concerns have been raised about long-term sequelae of the disease.
The Hong Kong Hospital Authority found a drop of 20% to 30% in lung capacity in some people who recovered from the disease, and lung scans suggested organ damage.
This may also lead to post-intensive care syndrome following recovery.
As of March 2020, it was unknown if past infection provides effective and long-term immunity in people who recover from the disease.
Immunity is seen as likely, based on the behaviour of other coronaviruses, but cases in which recovery from COVID-19 have been followed by positive tests for coronavirus at a later date have been reported.
These cases are believed to be worsening of a lingering infection rather than re-infection.
The virus is thought to be natural and have an animal origin, through spillover infection.
The actual origin is unknown, but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission.
A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, revealed the earliest date of onset of symptoms as 1 December 2019.
Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.
Several measures are commonly used to quantify mortality.
These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since initial outbreak and population characteristics such as age, sex and overall health.
In late 2019, WHO assigned the emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID-19 without lab-confirmed SARS-CoV-2 infection.The death-to-case ratio reflects the number of deaths divided by the number of diagnosed cases within a given time interval.
Based on Johns Hopkins University statistics, the global death-to-case ratio is 6.9% (153,822/2,240,191) as of 17 April 2020.
The number varies by region.Other measures include the case fatality rate (CFR), which reflects the percent of diagnosed individuals who die from a disease, and the infection fatality rate (IFR), which reflects the percent of infected individuals (diagnosed and undiagnosed) who die from a disease.
These statistics are not time bound and follow a specific population from infection through case resolution.
While not all infected people develop antibodies, the presence of antibodies may provide information about how many people have been infected.
In the epicentre of the outbreak in Italy, Castiglione d'Adda, a small village of 4600, 80 (1.7%) are already dead.
In Gangelt, the disease was spread by Carnival festivals, and spread to younger people, causing a relatively lower mortality, and not all COVID-19 deaths may have been formally classified as such.
Furthermore, the German health system has not been overwhelmed.
In the Netherlands, about 3% may have antibodies, as assessed from blood donors.
69 (0.004% of the population) have been confirmed to have died from COVID-19.
The impact of the pandemic and its mortality rate are different for men and women.
Mortality is higher in men in studies conducted in China and Italy.
The highest risk for men is in their 50s, with the gap between men and women closing only at 90.
In China, the death rate was 2.8 percent for men and 1.7 percent for women.
The exact reasons for this sex-difference is not known, but genetic and behavioural factors could be a reason.
Sex-based immunological differences, lesser prevalence of smoking in women and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men.
In Europe, 57% of the infected individuals were men and 72% of those died with COVID-19 were men.
As of April 2020, the US government is not tracking sex-related data of COVID-19 infections.
Research has shown that viral illnesses like Ebola, HIV, influenza and SARS affect men and women differently.
A higher percentage of health workers, particularly nurses, are women, and they have a higher chance of being exposed to the virus.
"The World Health Organization announced on 11 February 2020 that the official name of the disease would be ""COVID-19""."
WHO chief Tedros Adhanom Ghebreyesus explained that CO stands for corona, VI for virus, D for disease, and 19 for when the outbreak was first identified: 31 December 2019.
The name had been chosen to avoid references to a specific geographical location (e.g. China), animal species or group of people, in line with international recommendations for naming aimed at preventing stigmatisation.The virus that causes COVID-19 is named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
"The WHO additionally uses ""the COVID-19 virus"" and ""the virus responsible for COVID-19"" in public communications."
"Both the disease and virus are commonly referred to as ""coronavirus""."
"During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as ""coronavirus"" and ""Wuhan coronavirus""."
In January 2020, WHO recommended 2019-nCov and 2019-nCoV acute respiratory disease as interim names for the virus and disease in accordance with 2015 guidance against using locations in disease and virus names.
The official names COVID-19 and SARS-CoV-2 were issued on 11 February 2020.
Due to capacity limitations in the standard supply chains, some digital manufacturers are printing healthcare material such as nasal swabs and ventilator parts.
In one example, when an Italian hospital urgently required a ventilator valve, and the supplier was unable to deliver in the timescale required, a local startup reverse-engineered and printed the required 100 valves overnight.
After the initial outbreak of COVID-19, conspiracy theories, misinformation and disinformation emerged regarding the origin, scale, prevention, treatment and other aspects of the disease and rapidly spread online.
Humans appear to be capable of spreading the virus to some other animals.
The study failed to find evidence of viral replication in pigs, ducks, and chickens.
No medications or vaccine is approved to treat the disease.
International research on vaccines and medicines in COVID-19 are underway by government organisations, academic groups and industry researchers.
"In March, the World Health Organization initiated the ""SOLIDARITY Trial"" to assess treatment effects of four existing antiviral compounds with the most promise of efficacy."
There is no available vaccine, but various agencies are actively developing vaccine candidates.
Previous work on SARS-CoV is being utilised because SARS-CoV and SARS-CoV-2 both use the ACE2 receptor to enter human cells.
There are three vaccination strategies being investigated.
First, researchers aim to build a whole virus vaccine.
The use of such a virus, be it inactive or dead, aims to elicit a prompt immune response of the human body to a new infection with COVID-19.
A second strategy, subunit vaccines, aims to create a vaccine that sensitises the immune system to certain subunits of the virus.
In the case of SARS-CoV-2, such research focuses on the S-spike protein that helps the virus intrude the ACE2 enzyme receptor.
A third strategy is that of the nucleic acid vaccines (DNA or RNA vaccines, a novel technique for creating a vaccination).
Experimental vaccines from any of these strategies would have to be tested for safety and efficacy.On 16 March 2020, the first clinical trial of a vaccine started with four volunteers in Seattle.
The vaccine contains a harmless genetic code copied from the virus that causes the disease.Antibody dependent enhancement has been suggested as a potential challenge for vaccine development for SARS-COV-2, but this is controversial.
There are more than 300 active clinical trials underway as of April 2020.
Seven trials were evaluating already approved treatments for malaria, including four studies on hydroxychloroquine or chloroquine.
Repurposed antiviral drugs make up most of the Chinese research, with nine phase III trials on remdesivir across several countries due to report by the end of April.
A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April 2020.Several existing antiviral medications are being evaluated for treatment of COVID-19, including remdesivir, chloroquine and hydroxychloroquine, lopinavir/ritonavir and lopinavir/ritonavir combined with interferon beta.
There is tentative evidence for efficacy by remdesivir, as of March 2020.
Clinical improvement was observed in patients treated with compassionate-use remdesivir.
Phase III clinical trials are being conducted in the US, China and Italy.Chloroquine, previously used to treat malaria, was studied in China in February 2020, with preliminary results.
However, there are calls for peer review of the research.
Korean and Chinese Health Authorities recommend the use of chloroquine.
However, the Wuhan Institute of Virology, while recommending a daily dose of one gram, notes that twice that dose is highly dangerous and could be lethal.
On 28 March 2020, the FDA issued an emergency use authorisation for hydroxychloroquine and chloroquine at the discretion of physicians treating people with COVID-19.The Chinese 7th edition guidelines also include interferon, ribavirin or umifenovir for use against COVID-19.
Preliminary data indicate that high doses of ribavirin are necessary to inhibit SARS-CoV-2 in vitro.
Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.Studies have demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2 via interaction with the ACE2 receptor.
The studies of chloroquine and hydroxychloroquine with or without azithromycin have major limitations that have prevented the medical community from embracing these therapies without further study.Oseltamivir does not inhibit SARS-CoV-2 in vitro and has no known role in COVID-19 treatment.
Cytokine storm can be a complication in the later stages of severe COVID-19.
There is evidence that hydroxychloroquine may have anti-cytokine storm properties.Tocilizumab has been included in treatment guidelines by China's National Health Commission after a small study was completed.
It is undergoing a phase 2 non randomised test at the national level in Italy after showing positive results in people with severe disease.
Combined with a serum ferritin blood test to identify cytokine storms, it is meant to counter such developments, which are thought to be the cause of death in some affected people.
The interleukin-6 receptor antagonist was approved by the FDA based on retrospective case studies for treatment of steroid refractory cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.
To date, there is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS.
Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID-19 to people who need them is being investigated as a non-vaccine method of passive immunisation.
This strategy was tried for SARS with inconclusive results.
Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2.
Other mechanisms however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible.
Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.
Production of convalescent serum, which consists of the liquid portion of the blood from recovered patients and contains antibodies specific to this virus, could be increased for quicker deployment.
Coronavirus diseases, a group of closely related syndromes
Li Wenliang, a doctor at Central Hospital of Wuhan, who later contracted and died of COVID-19 after raising awareness of the spread of the virus.