Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
All articles are made available under a Creative Commons or similar license. Specific licensing information for individual articles can be found in the PMC source and CORD-19 metadata.
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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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Except for 2 patients who showed no symptoms, six among 26 patients showed clinical deterioration during the hospitalization and needed supplemental oxygen therapy (Supplementary Fig. 2). The others showed little limitation in daily activity during the hospitalization.
While neutrophilia or neutropenia was not common regardless of clinical severity (Fig. 1A and B), lymphopenia (defined as ≤ 1.0 × 109/L) was more common in severe cases (33.3%, 2/6) than mild cases (18.2%, 4/22) during the clinical course (Fig. 1C and D). High levels of C-reactive protein in the blood were more frequently observed in severe cases (Fig. 1E and F) as the clinical course became worse during the 5–7 day period after symptom onset.
We could evaluate viral kinetics by serial RT-PCR of respiratory specimens from 9 patients from the early course of illness. Viral shedding from upper respiratory tract (URT) and lower respiratory tract (LRT) was shown in Fig. 2A and B as cycle threshold (Ct) value, respectively (Supplementary Table 1). Viral shedding was high during the first 5 days of illness and higher in URT than LRT. It decreased after day 7 of illness.
Infiltration on initial chest X-ray was observed in 13 patients (46.4%), but pneumonia was confirmed in most patients who underwent computed tomography (CT) scan initially (16/18, 88.9%) (Table 1). The chest radiographic scores remained relatively stable during the first week of illness. However, around day 7 of illness, the scores began to increase in some patients, suggesting progression of pneumonia (Fig. 2C).
On 29 December 2019, the first four cases of an acute respiratory syndrome of unknown etiology were reported in Wuhan City, Hubei Province, China among people linked to a local seafood market (“wet market”). Research is underway to understand more about transmissibility, severity, and other features associated with COVID-19. It appears that most of the early cases had some sort of contact history with the original seafood market [2, 12–14]. Soon, a secondary source of infection was found to be human-to-human transmission via close contact. There was an increase of infected people with no history of exposure to wildlife or visiting Wuhan, and multiple cases of infection were detected among medical professionals [2, 14–17]. It became clear that the COVID-19 infection occurs through exposure to the virus, and both the immunosuppressed and normal population appear susceptible. Some studies have reported an age distribution of adult patients between 25 and 89 years old. Most adult patients were between 35 and 55 years old, and there were fewer identified cases among children and infants [14, 18]. A study on early transmission dynamics of the virus reported the median age of patients to be 59 years, ranging from 15 to 89 years, with the majority (59%) being male. It was suggested that the population most at risk may be people with poor immune function such as older people and those with renal and hepatic dysfunction.
The COVID-19 has been found to have higher levels of transmissibility and pandemic risk than the SARS-CoV, as the effective reproductive number (R) of COVID-19 (2.9) is estimated to be higher than the reported effective reproduction number (R) of SARS (1.77) at this early stage. Different studies of COVID-19 have estimated the basic reproduction (R0) range to be from 2.6 to 4.71 (Table 4). The average incubation duration of COVID-19 was estimated to be 4.8 ± 2.6, ranging from 2 to 11 days and 5.2 days (95% confidence interval, 4.1 to 7). The latest guidelines from Chinese health authorities stated an average incubation duration of 7 days, ranging from 2 to 14 days. Table 4 summarizes the findings on important indicators from these epidemiological studies.
In China, 11 791 cases were confirmed and 17 988 cases were suspected in 34 provinces as of 24:00, 31 January 2020 (Fig. 4). Studies indicated that the spread of COVID-19 was relatively quick and reported that it had spread to several other countries after its outbreak in China. On 31 January 2020, there were 213 deaths reported globally. Confirmed cases were reported in the following 19 countries outside of China: Australia (9), Canada (3), Cambodia (1), France (6), Finland (1), Germany (5), India (1), Italy (2), Japan (14), Nepal (1), Malaysia (8), the Philippines (1), the Republic of Korea (11), Singapore (13), Sri Lanka (1), Thailand (14), the United States of America (6), United Arab Emirates (4) and Vietnam (5) (Fig. 5).
The study population included 28 hospitalized patients with confirmed COVID-19. The median age of the 28 patients was 40 years (interquartile range, 28–54; range, 20–73), and 15 (53.6%) were men. Of the 28 patients, five (17.9%) had one or more coexisting medical condition and diabetes was most common (Table 1). The most common symptoms at the time of admission for isolation were cough (8, 28.6%) and sore throat (8, 28.6%), followed by fever, myalgia, and headache (7, 25.0%). Diarrhea was present in three patients (10.7%) among initial symptoms. Two cases were asymptomatic when they were confirmed as COVID-19.
We searched MEDLINE, ScienceDirect, Embase, the Cochrane Library, WanFang Database, VIP Database, SinoMed, China National Knowledge Infrastructure (CNKI), the CDC for COVID-19 website (https://www.cdc.gov/coronavirus/2019-ncov/publications.htm), Chinese Scientific Research Academic Exchange Platform for COVID-19 (http://medjournals.cn/2019NCP/index.do), and relevant references for papers related to "ophthalmology and SARS-CoV-2/COVID-19"; published till 12th March 2020. The search strategy was as follows: (SARS-CoV-2 or 2019-nCov or COVID-19 or NCP or coronavirus or "severe acute respiratory syndrome coronavirus 2" [Supplementary Concept] or "COVID-19" [Supplementary Concept]) and (ocular or eye or ophthalm* or ophthalmologist or tear or conjunctiv* or "Conjunctivitis"[Mesh] or "Conjunctivitis, Viral"[Mesh]).
We identified 33 articles in total published by Chinese scholars directly relevant to ophthalmology and SARS-CoV-2/COVID-19. Twenty-seven articles are published in Chinese journals, most articles are reviews, almost all regarding ophthalmic precautions and ocular surface transmission of SARS-CoV-2 infection (Table 1).
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 3):Age: Age was the most important factor for the prognosis of SARS 99, 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 37. 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) 34, 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 37.Comorbidities and complications: Patients with COVID-19 who require intensive care are more likely to suffer from acute cardiac injury and arrhythmia 34. Cardiac events were also the main reason for death in SARS patients 55,65,99. 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 100. It is worth noting that age and underlying disease are strongly correlated and might interfere with each other 55.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 101. The correlation of CRP level to the severity and prognosis of COVID-19 has also been proposed 101. 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 102,103. 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 104. 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 105. 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 66.
Many domestic and wild animals, including camels, cattle, cats, and bats, may serve as hosts for coronaviruses. It is considered that, generally, animal coronaviruses do not spread among humans. However, there are exceptions, such as SARS and MERS, which are mainly spread though close contact with infected people via respiratory droplets from cough or sneezing. With regard to COVID-19, early patients were reported to have some link to the Huanan Seafood Market in Wuhan, China, suggesting that these early infections were due to animal-to-person transmission. However, later cases were reported among medical staff and others with no history of exposure to that market or visiting Wuhan, which was taken as an indication of human-to-human transmission [2, 4, 15–17].
The latest guidelines from Chinese health authorities [23, 43] described three main transmission routes for the COVID-19: 1) droplets transmission, 2) contact transmission, and 3) aerosol transmission. Droplets transmission was reported to occur when respiratory droplets (as produced when an infected person coughs or sneezes) are ingested or inhaled by individuals nearby in close proximity; contact transmission may occur when a subject touches a surface or object contaminated with the virus and subsequently touch their mouth, nose, or eyes; and aerosol transmission may occur when respiratory droplets mix into the air, forming aerosols and may cause infection when inhaled high dose of aerosols into the lungs in a relatively closed environment [23, 43]. In addition to these three routes, one study also indicated the digestive system as a potential transmission route for COVID-19 infection. Since patients had abdominal discomfort and diarrhea symptoms, researchers analyzed four datasets with single-cell transcriptomes of digestive systems and found that ACE2 was highly expressed in absorptive enterocytes from ileum and colon.
Death and severity of COVID-19 are associated with age and comorbidities across the world. Especially in countries with the highest outbreaks, such as China, Italy, and Iran, strategies must be employed to ensure that high-risk groups, such as old people and those with other underlying diseases such as diabetes and cancer, received adequate protection from COVID-19. Therefore, early access to medical care when infected is vital for improving chances of survival. Improving medical supplies to countries such as Iran, which is significantly influenced by US punitive policies, can reduce the deterioration of this politically sensitive situation.
Furthermore, taking detailed and accurate medical history, and scoring CFR alongside RR, may highlight the highest risk areas, and more efficiently direct the intervention to decrease the spread of the virus globally. This may enable the development of point-of-care tools to help clinicians in stratifying patients, based on possible requirements in the level of care to improve probabilities of survival from COVID-19 disease.
According to the findings of the present study, hypertension, cardiovascular diseases, diabetes mellitus, smoking, COPD, malignancy, and chronic kidney disease were among the most prevalent underlying diseases among hospitalized patients with COVID-19, respectively.
No co-exposed person was identified for Case 1. Two contacts were evaluated at low risk of infection, the taxi driver who drove the case from the airport to his home (30-min drive) and the general practitioner who took care of the patient before wearing appropriate personal protection equipment (3-min non-close contact). Seventeen contacts were evaluated at moderate/high risk of infection. Four of them shared the same waiting room in the general practitioner’s office while Case 1 was coughing, seated ca 1–1.5 m away from the case during 5–30 min. The other 13 contacts were the persons sitting in the two seats around Case 1 in the Shanghai–Paris and Paris–Bordeaux flights (Figure). They were considered at moderate risk of exposure despite the fact that Case 1 reported wearing a mask during the whole flight; this was based on the length of one of the flights (> 6 h) and the fact that it was unclear whether or not Case 1 removed his mask during short periods (e.g. meals) and kept the same mask during the whole flights. None of the contacts of the Shanghai–Paris flight were French nationals and their contact tracing was referred to their home countries’ health authorities. All other identified contacts were evaluated at negligible risk of infection because the contacts were short and/or distant in public settings and did not imply face-to-face conversations or because appropriate personal protective equipment (PPE) was worn by the healthcare personnel who took care of the patient, including those involved in the transfer from the general practitioner to the referring hospital.
Cases 2 and 3 stayed together and shared the same activities during their stay in Paris, and therefore shared the same contacts from 23 January (date of illness onset for Case 3). Three contacts were evaluated at low risk of infection: the two owners of the apartment rented by the couple and a department store employee with whom Case 2 reported a distant (> 1 m) contact during around 20 min on 22 January. The apartment owner’s child who visited Cases 2 and 3 and was hugged by them was evaluated at moderate/high risk of infection (Figure). All other identified contacts were evaluated at negligible risk of infection, as contacts were short and distant in public settings such as department stores and did not imply face-to-face conversations or because appropriate PPE was worn by the healthcare personnel who took care of the patients.
Follow-up of the identified contacts was initiated according to the COVID-19 procedure (Table). As at 2 February, two contacts have been classified as possible cases since the implementation of the follow-up: A person sitting two seats away from Case 1 during the Paris–Bordeaux flight, and therefore identified as a moderate/high risk contact, developed respiratory symptoms on 27 January and was classified as a possible case on 31 January and was subsequently excluded following negative RT-PCR results. Infection with SARS-CoV-2 was excluded on the same day. A radiology assistant who took care of both Cases 2 and 3 developed respiratory symptoms on 30 January and was classified as a possible case on 2 February. This person had been classified as at negligible risk of exposure, because she wore appropriate PPE during the whole procedure. Infection with SARS-CoV-2 was excluded on 2 February.
Follow-up of the contacts ended on 6 February. No identified contact of the three cases has been confirmed with COVID-19.
Based on the current information, most patients had a good prognosis, while a few patients were in critical condition, especially the elderly and those with chronic underlying diseases. As of 1 March 2020, a total of 79,968 confirmed cases, including 14,475 (18.1%) with severe illness, and 2873 deaths (3.5%) in mainland China had been reported by WHO. Complications included acute respiratory distress syndrome (ARDS), arrhythmia, shock, acute kidney injury, acute cardiac injury, liver dysfunction and secondary infection. The poor clinical outcome was related to disease severity. The disease tends to progress faster in elderly people, with the median number of days from the occurrence of the first symptoms to death shorter among people aged 65 years or more [56, 57]. Similar to H7N9 patients, the elderly male with comorbidities and ARDS showed a higher death risk. Additionally, more than 100 children were infected, with the youngest being 30 h after birth. Neonates and the elderly need more attention and care due to their immature or weak immune system.
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 8. 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 39-41.
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 42. Similar findings were reported in two recent studies of a family cluster and a cluster caused by transmission from an asymptomatic individual 43,44. 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 45.
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 46. For MERS, based on a demographic study in June 2012, the mortality was 37% of 2,494 confirmed cases 47. 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 48, whereas the R0 of SARS-CoV only ranged from 2 to 4 49. A comparison of SARS-CoV-2 with MERS-CoV and SARA-CoV regarding their symptoms, mortality, and R0 is presented in Table 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 6. Thus, it is much more challenging to control the epidemic of SARS-CoV-2 than those of MERS-CoV and SARS-CoV.
Control number of visiting patients
Reducing outpatient visitors will be critical to decrease cross-infection. Patients are asked to make an appointment before going to the hospital.
b)Make good use of online platforms
Online platforms such as the hospital’s official website or WeChat should be well utilized. Online platforms can provide notice for decreasing outpatient visits and updates on COVID-19, help patients distinguish between urgent and non-urgent ocular diseases, recommend safe and self-executing treatments for common nonurgent ocular diseases, remind patients to prepare correct personal protection before coming to the hospital, advise patients with suspicious symptoms such as fever to first visit the screening center before coming to the ophthalmic clinic, and give targeted guidance for common chronic eye diseases during this period.
c)Online ordering and delivery of prescribed medication
Both hospital and patients can benefit from submitting prescriptions online and having patient medication sent to their doorsteps via non-contact delivery.
China and the rest of the world have faced an outbreak of a novel Corona virus. The widespread distribution of this virus has led to a major concern, globally. Human coronaviruses are among the pathogens causing viral respiratory infections, and the recently detected strain called SARS-CoV-2 has caused a big challenge for countries all over the world (15, 16). This is the third contagious Coronavirus leading to an epidemic in the 21st century after MERS and SARS (17). The key problems surrounding this novel virus are as follows: diagnosis, mode of transmission, long incubation period (3 to 14 days), predicting the number of infected cases in the community, and insufficient protection resources due to its pandemic specification (15, 18). The accurate transmission rate of SARS-CoV-2 is unknown, since various factors impact its transmission. Moreover, infection of family clusters and healthcare workers indicate the human to human transmission of the disease and its contagiousness, which makes the condition more complicated (19, 20).
Since SARS-CoV-2 is a newly identified pathogen, there is no pre-existing immunity to it in the human community, also there is no definitive cure to interrupt or reduce its astonishing spread. These ambiguities make the condition more serious for vulnerable members of the community, which include individuals with immune problems, co-existing comorbidity and elderly people. Despite the novelty of the topic, there are a lot of proposed studies about history, transmission route, urgency of responding, pathogenic potential characteristics and prevention strategies but there are still some underlying diseases that have remained unknown (21).
According to the current analysis, hypertension, cardiovascular diseases, diabetes, kidney disease, smoking, and COPDs were among the most prevalent underlying diseases among hospitalized patients with COVID-19.
In terms of pre-existing medical conditions, cardiovascular diseases had the highest prevalence among diseases that put patients at higher risk of SARS-CoV-2 threats. Decreasing the pro-inflammatory cytokines, which leads to a weaker immune function may account for this condition (2, 22). It is worth noting that similar results were found regarding MERS (23). We also found that smokers are more susceptible to Coronavirus infections, especially to the most recent species. Various reasons may justify this happening. It has been mentioned that smokers have unregulated ACE2 in remodeled cell types, which is consistent with results of SARS studies. However, factors such as amount of smoking, the duration of smoking, and the duration of smoking cessation also play a role. In some previous studies on MERS-CoV-2 it has been shown that dipeptidyl peptidase IV (DPP4), which is the specific receptor for this virus, had a higher rate of expression in smokers and COPD patients (24).
Although the results of the current analysis indicate that smoking can be an underlying factor that makes people susceptible to COVID-19 complications, in some studies, especially COVID-19 related studies, no strong evidence has been found regarding the correlation of COPD and smoking with being infected with this new virus. But the important point that must be taken into consideration is that the outcome of SARS-CoV-2 infection is more severe in COPD cases and smokers (25).
As mentioned in the results section, patients with malignancies are more in danger than those without any tumor. Anticancer treatments such as chemotherapy and surgery put this group into an immunosuppressive state and subsequently at higher risk of MERS-CoV-2 infection (26). Among those with malignancies, lung cancer patients seems to be more susceptible, and they must follow guidance on restricting any contact with possible infected zones or individuals for their safety (14).
Possible risk factors for progressive and severe illness may include the above-mentioned factors but are not limited to them; pregnancy and old age are other risky conditions, which should be monitored meticulously. However, there is no clear evidence about the risk of transmission of COVID-19 to the newborn during vaginal delivery or transmission via breastfeeding but care and protection of newborns against possible exposure to infection or contaminated conditions such as maternal breast contamination must be observed. Since MERS-CoV-2 is an emerging virus, no specific treatment is currently available (27, 28), and pathophysiology of this condition is still unknown. Therefore, general prevention measures such as the following should be followed: Washing hands frequently and avoiding touching the eyes, nose, and mouth with contaminated hands, avoiding close contact ,especially with those who have fever, coughing or sneezing, avoiding contact with live animals and consuming raw animal products (29).
There are some responsibilities for health policymakers in this critical condition: Screening of travelers, triage all patients on admission and immediately isolating all suspected and confirmed cases, providing protective gear, preparing local guidance and instructions for people, especially for high risk groups (30, 31).
To the best of our knowledge, this is the first meta-analysis that estimates the prevalence of underlying diseases in patients infected with SARS-CoV-2. Given that most studies on CoVID-19 are in an early stage, and there are some limitations such as small number of studies, and reports being restricted to China and a few other countries, due to the pandemic nature of the disease, specific patterns should be introduced for different groups, including people with underlying diseases, to minimize the harm.
Based on the experiences gained on this disease during this short time, a strong recommendation for all people, clinicians, and policymakers is to guide people to protect themselves to avoid being exposed to SARS-CoV-2, whenever possible (32). Another very important advice to patients with underlying diseases during the epidemics like the one caused by the novel virus is to follow guidance on travel restrictions. These groups must be aware of their high-risk situation and comply with all health guidelines such as hand hygiene, face care, and restricting social interactions. In addition, to reduce the morbidity and complications of COVID-19 in different populations, especially patients with the mentioned underlying diseases, we recommend clinicians and policymakers to launch diagnostic procedures for such individuals first so that proper treatments can be designed and followed to ensure they are protected within epidemic regions (33).
In summary, the results of the current study have shown that in patients with SARS-CoV-2 infection, hypertension, cardiovascular disease, smoking, and diabetes are the most prevalent co-existing disorders. Given that COVID-19 has a relatively long incubation period and during this time the infected person can transmit the virus without showing symptoms, it is strongly recommended that patients with chronic or underlying diseases avoid any close contact with other people in the community, especially in epidemic areas. During the current SARS-CoV-2 pandemic, the statistics reported by different countries regarding associated mortality of those with risk factors, incubation time, and estimated overall mortality have not been consistent and general conclusions should be drawn with caution. It should be noted that the outbreak worsens with decrease in adherence to diagnostic guidelines and prevention strategies, such as avoiding traveling and gathering in public places.
COVID-19 related pediatric disease has an array of symptomatic presentations and outcomes. While the majority of those on the spectrum of the disease will recover well with symptomatic care, this article serves to highlight how myocardial disease, lung pathology, and the substantially higher risk of mortality in certain sub-populations should be kept in the mind. As such, based on our limited data, the authors favor an approach that relies on ensuring potential markers of poorer outcomes, such as evidence of organ dysfunction, evidence of superimposed bacterial infection, and other metrics highlighted in the article, are screened for at an earlier stage. For those children that are deemed sick enough to require admission, the potential need for further investigation for myocardial disease, coagulopathy, and organ damage should be kept in mind.
The data were retrieved from accurate databases including Worldometer 2, WHO 3, the Center of Disease Control and Prevention, and the Morbidity and Mortality Weekly Report series (provided from Center of Disease Control and Prevention), according to the user’s guide of data sources for patient registries. Due to the rapid increase in data, the analysis in this study was performed on the 12th and 23rd of March 2020.
Raw data was mapped according to countries and CFR and RR were compared for countries with ≥ 1,000 cases. All countries with < 1,000 cases are presented in supplementary Table 1. A comparison of CFR with different known viral diseases was performed.
Co-exposed persons are defined as people who shared the same risks of exposure as a possible or confirmed case of COVID-19. Contact and co-exposure identification is done for all identified possible cases. Contacts are traced from the date of onset of clinical symptoms in a case. If the diagnosis of SARS-CoV-2 infection is confirmed in the index case, active surveillance of contacts/co-exposed persons is initiated immediately.
Three levels of risk of infection are defined for contacts/co-exposed persons of a possible/confirmed COVID-19 case (Table). Co-exposed persons of a confirmed case are followed-up according to the same procedure as a moderate-/high-risk contact. The follow-up procedure for the contacts/co-exposed persons differs according to the evaluation of the level of risk of infection (Table).
During the initial implementation phase of the procedure, owing to the limited number of contacts involved, it was decided to also implement an active follow-up for low risk contacts.
Patients are interviewed by the clinicians, with the help of a translator if needed, who recover relevant information on their contacts since onset of clinical symptoms and the nature and intensity of exposure. The involved regional health agencies work closely with the regional entities of Santé publique France (cellules régionales) in order to implement contact tracing and follow-up. Santé publique France coordinates the surveillance at national level in liaison with the national Health Authorities.
On December 31, China announced “it is probing a mystery viral pneumonia outbreak in Wuhan”. Since then, the virus, known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)” is threatening the life of people of at least 140 countries including China (Table 1). On February 11, the World Health Organization (WHO) named the disease caused by SARS-CoV-2 as Coronavirus Disease-19 (COVID-19). COVID-19 patients exhibit flu-like symptoms, such as persistent coughing, fever, shortness of breath, and difficulty breathing, which are similar to the Severe Acute Respiratory Syndrome (SARS), and the Middle East Respiratory Syndrome (MERS).
Because SARS-CoV-2 is a new pathogen, people of all ages have no immunity to it and generally susceptible to infection. Just in about 2.5 months, COVID-19 has been spreading quickly to over 140 countries, infected more than 156,000 people, ranging from newborn to 98 years of age, and killed at least 5,800 patients, mostly in Wuhan, Hubei province of China. Compared with its close related coronavirus family member SARS-CoV and MERS-CoV, which infected 8096 and 2494 people in year 2003 and year 2012, respectively, the outbreak of COVID-19 is much more serious with its high virulence. Although SARS-CoV-2 exhibits a lower fatality rate compared to SARS-CoV and MERS-CoV, the virus has already killed at least 1.8 times more people than SARS-CoV and MERS-CoV combined together (Table 1).
Up to today, China has taken unprecedented public health measures with centralized national medical support, and has achieved significant results in slowing down the spread of the epidemic and blocking the sources of transmission, preventing hundreds of thousands of new cases of pneumonia. While the rate of infection comes down gradually in China, the scales of infection in some other countries are steadily rising. The war against COVID-19 will continue on a global scale. Thus, the knowledge the virus, the mechanism of its infection, the characteristics of the epidemic transmission are essentially important for effective fighting against this deadly disease.
In this special issue, we have 11 reports, which share our understanding of SARS-CoV-2 and COVID-19 from different angles. Zheng indicated that SARS-CoV-2 is an emerging new coronavirus that causes a global threat, and summarized the key events occurred during the early outbreak, the basic characteristics of the pathogen, the signs and symptoms of the infected patients, the possible transmission pathways of the virus, the understanding on the origin and evolution of the virus, as well as the chemotherapeutic options under development 1. Ye et al. overviewed the existing knowledge about 7 human coronavirus (HCoVs), with a focus on the history of their discovery as well as their zoonotic origins and interspecies transmission. They also compared and contrasted the different HCoVs from a perspective of virus evolution and genome recombination 2. Lo et al. reported their experience on the evaluation of SARS-CoV-2 RNA shedding in clinical specimens and clinical features of all 10 patients in Macau, and recommended the assessment of both fecal and respiratory specimens for enhancing diagnostic sensitivity 3.
Because of no specific anti-virus drugs or vaccines are available for the treatment of this sudden and lethal disease, many drugs have been used in the therapy. Yang et al. reported that greater than 85% of COVID-19 patients in China have been receiving Traditional Chinese Medicine (TCM) treatment, and presented the clinical evidence showing the beneficial effect of TCM in the treatment of the patients 4. Zhou and Zhao pointed out the great importance of using therapeutic neutralizing antibodies (NAbs) to control the spread and re-emergence of SARS-CoV-2 and assert that the development of NAbs therefore should be a high priority in near future 5. Yang and Shen discussed the implication of the endocytic pathway and autophagy in viral infection and how novel therapeutic approaches could be developed by targeting these processes for treatment of COVID-19 6.
No one was prepared for this highly infectious and swiftly transmitting disease, creating unprecedented strain on healthcare providers and the overall system. Indeed, the rapid transmission of the COVID-19 has mounted serious challenges to both the patients and the health workers stationed at the epicenter of the outbreak 7. Xiang et al. brought up an issue of high infection rate among health workers in China, mainly due to the lack of experience in handling it in the early stages of the epidemic 8. On the other hand, more than 300 Chinese patients with psychiatric disorders have been with the SARS-CoV-2 since the outbreak of COVID-19 9. Patients, health professionals and the general public are under insurmountable psychological pressure, which may lead to various mental health problems, such as anxiety, fear, depression, and insomnia. Emergency psychological teams have been urgently established at regional and national levels and provided mental health services for those in need as part of the overall deployment of the disease control 7,9.
Understanding the knowledge, attitudes and behaviors of residents towards COVID-19 during the early stage of disease outbreak could help the authority effectively implement preventive and control measures. Zhong et al. conducted an epidemiological survey involving 6,910 residents in China, and the results showed that even during the rapid rise period of the COVID-19 outbreak, most residents had good knowledge of COVID-19 and were optimistic about the epidemic control. To reduce the infection risk, they acted with caution in daily life, and took appropriate preventive measures as recommended by the health authorities 10 . Finally, we bring up a comprehensive review on what we have learned and to be learned by Li et al, who cover the basics about the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease in comparison with SARS and MERS 11.
As the fight to COVID-19 continues, we hope that this special issue will help researchers from various fields to have a better understanding of this dangerous virus and join the urgent fight against this deadly disease. We believe the information provided in this special issue should facilitate the fighting against SARS-CoV-2 and the related COVID-19, a global war that we must win and we will win although with huge expenses, the extent of which remains unclear.
Reviewing published literature, Jiehao et al., in their case series of 10 children with the 2019 novel coronavirus, reported that the age group of patients affected was between three and 131 months with a mean age of 74 months with a male to female ratio of 1:1.5.
Xia et al. noted 65% of the affected patients to be male within their subset of 20 pediatric inpatients with COVID-19 infection. The age range within this group of affected patients was one day to 14 years with a median age of two years. Seventy percent of the affected patients within this subset were under the age of three years. One of the patients had a history of epilepsy as a sequela of previous viral encephalitis and two patients had a history of atrial septal defect (ASD) repair surgery. The authors noted five further patients with a history of congenital or acquired diseases (unspecified within the reported study), which the authors purported to indicate that children with underlying diseases would have a greater susceptibility to COVID-19. Jiehao et al. noted within their study that the mean incubation period in their set of pediatric patients from household exposure to a symptomatic adult case was six and a half days, which they noted to be suggestive of a longer incubation period than what is being reported in adults.
Dong et al., in their pre-publication release data looking at the epidemiology of COVID-19 among children in China, reviewed 2143 cases of which 731 were laboratory confirmed and 1412 were suspected cases. They found the median age among these cases to be seven years with 56.6% of the cases being boys.
Overall, the epidemiological data suggests a slightly higher percentage of affected cases to be male. The age range of affected patients is wide, with concern regarding a higher propensity of illness in patients with pre-existing diseases. This may represent either worse symptoms resulting in a higher rate of testing or may indicate an increased susceptibility to illness with underlying disease.
Xia et al. noted in their study of pediatric COVID-19 cases that eight (80%) patients had a fever, six (60%) had a cough, four (40%) had a sore throat, three (30%) had a stuffy nose, and two (20%) had sneezing and rhinorrhea. None of the patients had diarrhea or dyspnea during the course of their illness.
Xia et al. report the presence of fever, which was defined as axillary temperature over 37.3°C in 12 cases (12/20, 60%), cough in 13 cases (13/20, 65%), diarrhea in three cases (3/20, 15%), nasal discharge in three cases (3/20, 15%), sore throat in one case (1/20, 5%), vomiting in two cases (2/20, 10%), tachypnea in two cases (2/20, 10%), and fatigue in one case (1/20, 5%). They also further noted physical exam findings when assessed by medical personnel to be rales in three cases (3/20, 15%), retraction signs in one case (1/20, 5%), and cyanosis in one case (1/20, 5%).
Dong et al. characterized, in looking at their data of 2143 pediatric patients with laboratory diagnosed and/or clinically suspicious cases of COVID-19 infection, the severity of illness as asymptomatic, mild (predominantly upper respiratory tract infectious symptoms with no frank respiratory distress), moderate (presence of pneumonia, frequent fever and cough but with no obvious hypoxemia), severe (presence of dyspnea with central cyanosis, oxygen saturation <92% with other hypoxia manifestations) and critical (acute respiratory distress syndrome (ARDS), respiratory failure, shock, encephalopathy, myocardial injury, heart failure, coagulation dysfunction, and organ dysfunction). With these clinical parameters, they found 4.4% of cases to be asymptomatic, 50.9% of cases to be mild, and 38.8% of the cases to be in the moderate range accounting for 94.1% of all cases. They also noted the proportion of severe and critical cases to be inversely proportional to the age range, with the age group of less than one year old having 10.6% of the severe and/or critical cases.
Chest radiographs revealed a unilateral patchy infiltrate in four (40%) of 10 patients with COVID-19 reported by Jiehao et al.. Xia et al. further looked to examine the chest CT findings at various stages of the COVID 19 process. At the early stage of the disease, they noted six patients presented with unilateral pulmonary lesions (6/20, 30%), 10 with bilateral pulmonary lesions (10/20, 50%), and one pediatric patient and three neonates had no abnormalities on chest CT (4/20, 20%). Sub-pleural lesions with localized inflammatory infiltration were found in all children. Ten patients (10/20, 50%) were noted to have “halo sign” consolidation, 12 patients (12/20, 60%) had ground-glass opacities, four patients (4/20, 20%) had “fine mesh shadows,” and tiny nodules were detected in three patients (3/20, 15%). No patients were noted to have signs of pleural effusion and lymphadenopathy on CT scan.
Jiehao et al. noted within their laboratory findings: median white blood cell count (WBC) 7.35×109/L, C-reactive protein (CRP) 7.5 mg/L, procalcitonin (PCT) 0.07 ng/dL, creatine kinase-myocardial band (CK-MB) 23 U/L, alanine aminotransferase (ALT) 18.5 U/L, aspartate aminotransferase (AST) 27.7 U/L, urea 3.1 mmol/L, creatinine 35.5 μmol/L, lactate dehydrogenase (LDH) 25 U/L, and D-dimer 0.45 μg/mL; influenza virus A and B were negative. The study also showed that all patients had 2019-nCoV RNA detected in nasopharyngeal and throat swabs within four to 48 hours after the onset of symptoms and 2019-nCoV RNA in nasopharyngeal or throat swabs was no longer detectable within six to 22 days (with a mean of 12 days) after the onset of illness. Six of these patients had fecal samples tested, and 5 (83.3%) were positive for 2019-nCoV RNA. The authors also noted with concern that the five patients still had 2019-nCoV RNA detected in feces within 18-30 days after illness onset at the time of publication of their findings. Five patients also had serum and urine samples tested and were negative for 2019-nCoV RNA.
For Xia et al. (per their reference ranges used), WBC was normal (5.5-12.2) in 14 cases (14/20, 70%), decreased (<5.5) in four cases (4/20, 20%), and increased (>12.2) in two cases (2/20, 10%); ALT increased (>40 IU/L) in five cases (5/20, 25%),CK‐MB increased in 15 cases (15/20, 75%), and PCT (>0.05) increased in 16 cases (16/20, 80%). Eight patients were co-infected with other pathogens (8/20, 40%), including influenza viruses A and B, mycoplasma, respiratory syncytial virus (RSV), and cytomegalovirus (CMV). Further, four cases had abnormal electrocardiogram (EKG) events, including atrial arrhythmia, first-degree atrioventricular (AV) block, atrial and ventricular premature beats, and incomplete right bundle branch block.
Elevations in CK-MB and EKG changes are of particular concern, as they may be indicative of myocarditis as a potential complication of COVID-19. Lippi et al., in their electronic data review (which was not specific for pediatric patients), also noted the cardiac Troponin I value significantly increased in patients with severe COVID-19 infection.
Jiehao et al. noted the mean number of secondary symptomatic cases in the household exposure setting was 2.43, which is indicative of the basic reproductive number for pediatric COVID-19 cases and proof of direct transmission. Xia et al. noted within their subset of 20 cases that 13 pediatric patients (13/20, 65%) had an identified history of close contact with COVID‐19 diagnosed family members, again supporting proof of direct transmission.
A particular source of concern is the paucity of data on the vertical transmission potential of COVID-19 pneumonia in pregnant women. Chen et al. retrospectively reviewed the medical records for nine pregnant women with laboratory-confirmed COVID-19. The evidence of intrauterine vertical transmission through testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples was assessed. Breastmilk samples were also collected and tested from patients after the first lactation.
They reported that within this subset of patients nine live-births delivered via cesarian section were recorded. No neonatal asphyxia was observed in the newborn babies. All nine newborns had a one-minute Apgar score of eight to nine and a five-minute Apgar score of nine to 10. Six patient’s amniotic fluid, cord blood, neonatal throat swab, and mother’s breastmilk samples were tested for SARS-CoV-2, and all samples tested negative for the virus. They noted within this subset of patients that the clinical characteristics of the disease were similar in pregnant and non-pregnant adults and that they did not note any evidence of intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy.
At the time of publication of this article, the U.S. Food and Drug Administration (FDA) currently has no approved medications to treat patients with COVID-19. As such, management algorithms, particularly for the pediatric patient, are based at least in part on clinical opinion. Partially based on the data reviewed above and partially upon the opinion of the authors of the article, looking specifically at pediatric COVID-19, we recommend the investigation and management pathway as displayed in Figure 1.
The epidemic of unknown acute respiratory tract infection broke out first in Wuhan, China, since 12 December 2019, possibly related to a seafood market. Several studies suggested that bat may be the potential reservoir of SARS-CoV-2 [9, 10]. However, there is no evidence so far that the origin of SARS-CoV-2 was from the seafood market. Rather, bats are the natural reservoir of a wide variety of CoVs, including SARS-CoV-like and MERS-CoV-like viruses [11–13]. Upon virus genome sequencing, the COVID-19 was analyzed throughout the genome to Bat CoV RaTG13 and showed 96.2% overall genome sequence identity, suggesting that bat CoV and human SARS-CoV-2 might share the same ancestor, although bats are not available for sale in this seafood market. Besides, protein sequences alignment and phylogenetic analysis showed that similar residues of receptor were observed in many species, which provided more possibility of alternative intermediate hosts, such as turtles, pangolin and snacks.
Human-to-human transmission of SARS-CoV-2 occurs mainly between family members, including relatives and friends who intimately contacted with patients or incubation carriers. It is reported that 31.3% of patients recent travelled to Wuhan and 72.3% of patients contacting with people from Wuhan among the patients of non-residents of Wuhan. Transmission between healthcare workers occurred in 3.8% of COVID-19 patients, issued by the National Health Commission of China on 14 February 2020. By contrast, the transmission of SARS-CoV and MERS-CoV is reported to occur mainly through nosocomial transmission. Infections of healthcare workers in 33–42% of SARS cases and transmission between patients (62–79%) was the most common route of infection in MERS-CoV cases [17, 18]. Direct contact with intermediate host animals or consumption of wild animals was suspected to be the main route of SARS-CoV-2 transmission. However, the source(s) and transmission routine(s) of SARS-CoV-2 remain elusive.
Over the past few decades, a large number of people have been affected with the 3 epidemics caused by coronavirus family (SARS-2003, MERS-2012, and COVID-2019) in the world. Nevertheless, there is substantial genetic dissimilarity between pathogens of the three previous epidemics, in particular MERS with COVID-19. In the previous epidemics, initial hotspots of diseases were Middle East, Saudi Arabia (MERS) and China and animal to human, and then human to human transmissions of pathogens were reported in other countries (1,2).
For COVID-19, as suggested by epidemiological evidence in China (at the time of writing this paper), this outbreak began from a seafood and live animal shopping center in Wuhan, Hubei Province on December 12, 2019. However, similar to two previous epidemics, the current epidemic also switched to human to human transmission immediately, and swept through most regions in China even faster than the previous pandemics (3).
Recent epidemics of viral respiratory diseases in the world have started from China (except for MERS that originated in Saudi Arabia), and there are several possible reasons for this. From an economic perspective, China has emerged as one of the leading countries in the production of various commodities, especially in the past decade, and given the enormous volume of trade, tourism and military transactions with other countries, there was no doubt that the virus would spread to other parts of the world (4).
China has already acknowledged the possibility of a new virus epidemic in the future and has consequently stressed the importance of formulating a policy to improve the healthcare system and preparedness after the two previous epidemics. This country rearranged its health plan in the wake of MERS epidemic in 2012, establish a new web-based service for quick alarming in case of an emerging disease with unknown origin through common surveillance system. In the wake of conditions ensuing SARS epidemic and severe criticisms levelled by international institutions regarding delayed provision and sharing of data by China government, this country has started extensive collaborations with international institutions from the early days of the recent epidemic, and established a publicly available database of line list of cases through coordinating with Johns Hopkins University (5).
Moreover, China scaled up public health measures and quarantined many cities, bearing the grave economic consequences of this action to prevent the spread of the disease to other parts of the world. Although, China has been struggling with tough conditions in the previous month, reduction in the number of incidence cases and interruption of transmission indicate its successful measures to control the recent epidemic and highlight the importance of timely and appropriate decisions through activating human and material resources for addressing a serious global threat (6).
Number of COVID-19 cases has risen substantially in the world compared to SARS and MERS, and it would probably take longer to halve the disease cases; meaning that control measures would have to be in place for a longer period of time. WHO has announced that Coronavirus epidemic is progressively increasing in three countries, including Italy, South Korea, and Iran. The shared string that links these three countries is the pandemic of MERS in 2013, which was transmitted through close human-to-human contacts (7). This study was carried out to review different epidemiological and clinical aspects of the new emerging disease along with specific measures by countries in the community level.
10-month-old boy presented with fever for 3 hours and was admitted to the Fever Clinic of the Beijing Haidian Hospital. His parents and sister were confirmed with COVID-19 2 days before. They contracted it after having dinner with a family friend who had recently returned from Wuhan. Physical examination showed fever with a peak body temperature of 38℃ that returned to normal by itself. Laboratory examination showed normal leukocyte (9.32 × 109/L) and neutrophil (1.93 × 109/L) counts, increased differential count of lymphocytes (68.8%), and an elevated C-reactive protein level (11 mg/L).
The patient had been admitted to the Fever Clinic 2 weeks before because of influenza A infection as evidenced by a weakly positive nucleic acid test result. Subsequently, the patient underwent isolated medical observation before his family was diagnosed with COVID-19. During the medical observation, the nucleic acid test presented weakly positive for influenza A again, and CT showed diffuse ground-glass opacities in both lungs. A deep learning (DL)-based computer-aided diagnostic system for pneumonia, which was trained with CT scans of patients with COVID-19, suggested this patient to have pneumonia, with the lesion volume accounting for 13.3% of the whole lungs (Fig. 1). Later, throat swab specimens from the patient were tested with rRT-PCR for SARS-CoV-2. After two consecutive negative results, a third SARS-CoV-2 rRT-PCR test confirmed the infection.
Genetic differences between SARS, MERS, and COVID-19 epidemics
The animal reservoir of the virus has not yet been identified, but genomic of COVID-19 is so similar to bat coronavirus (98%), reinforcing the presumption that the virus was transmitted by an animal in the shopping center in Wuhan. With regard to genomic similarity, the virus differs from its predecessors, namely SARS (79%) and MERS (50%). As indicated by genetic data, CVOID-19 pathogen is classified as a member of the beta-coronavirus genus, and can bind to the angiotensin-converting enzyme 2 receptor in humans (1,2).
Transmission and Incubation period
Human to human transmission via either respiratory droplets or close contacts was initially proposed as the main routes of transmission of the pathogen based on experience gained in the previous two epidemics caused by coronaviruses (MERS-CoV and SARS-CoV)(8). According to the world Health Organization (WHO) report, 2019-nCoV is a unique virus that causes respiratory disease, which spreads via oral and nasal droplets. Moreover, the pathogen of COVID-19 can float in the air in the form of aerosols and cause infection in healthy people (9). Evidence of a study in Singapore revealed higher loads of virus in confirmed cases of COVID-19 in early stages of the disease, which decreased dramatically over time (10).
There is a limited number of evidence on oral-fecal transmissibility of the pathogen. However, COVID-19 RNA was found in fecal specimens of 2 to 10% of confirmed patients with gastrointestinal symptoms such as diarrhea (11,12), so fecal-oral transmission should be taken into account as a probable route through case investigation.
Incubation period (the time from infection to the onset of symptoms) for the new pathogen varies from 2 to 14 days in human to human transmission (13). Furthermore, median incubation period was reported as 5-6 days (ranged from 0-14 days) in WHO report (14). Studies that were conducted on those who had traveled to Wuhan and Guangdong mean incubation period of 4.8 (±2.6) days was reported. In some other studies the mean incubation period was reported to be 6.4 days (15,16), while another study in China reported longer incubation times up to 24 days (13).
An important question about COVID-19, which has raised much concern among health care providers, health policy makers and the general population, is the degree of transmissibility or contagiousness of the coronavirus (infectivity). In general, epidemiologists use mathematical formulas with clear and acceptable assumptions to calculate the infectivity index. For this purpose, "basic reproduction number" termed R0 is used, and it indicates the expected number of cases directly infected by one contagious case in a population that everyone is supposed to be susceptible. For viral pathogens in MERS and SARS epidemics, the index was approximated to be 2, indicating that each infected person could infect two people on average in an effective contact. However, for COVID-19, the calculated value in a study was slightly higher and the index value based on data calculated in Wuhan, China was 2.2 (95% CI, 1.4 to 3.9) (17) and it shows that the infectivity of COVID-19 is higher than previous epidemics originated by coronavirus (18). In other studies, R0 has been reported with different values, the lowest of which corresponds to the WHO report of 1.95 (1.4-2.5) (19) and the highest value is 6.47 (95% CI 5.71–7.23) (20). A review study estimated an average R0 for COVID-19 of 3.28 with a median of 2.79 and an IQR of 1.16 (21). As an explanation for variety of the calculated indices is that different calculation methods were used and calculations were done at different times of epidemics.
As previously noted, certain assumptions have been made in calculation of this index. Initial reports on a family in one of the provinces of China show that all six-members of a family, aged 10-66 years were infected within a short period after one member returned from Wuhan (8). As a conclusion, this index is changing over time, and its reduction may reflect effectiveness of preventive measures, so that reaching a value less than one (less than one new case per effective contact with an infected person and transmission) implies that the epidemic is controlled in the community (6).
An important concern in the recent pandemic is the capability of the pathogen to establish and induce infection with different clinical manifestations in human. According to WHO report, about 82 percent of COVID-19 patients have mild symptoms and were recovered immediately. As of 20 February, there were 18264 (24%) recovered cases in China and recovery and mortality rates of the disease among severe cases in Guangdong were 26.4 % and 13.4%, respectively. Median time for onset of symptoms to recovery in mild and severe cases was 2 and 3-6 weeks, respectively. Furthermore, time interval between onset and developing severe symptoms such as hypoxia was one week (22).
In case studies that were conducted outside of mainland China, time of onset of symptom(s) to recovery was 22.2 days (95% confidence interval 18-83). Moreover, average time of onset of symptom(s) to death varies from 20.2 (95% confidence interval 15.1-29.9) to 22.3 days (95% confidence interval 18-82) (23,24). Results of a case-series study on six infants (45-days to one-year) infected with COVID-19 in China indicated mild symptoms of the disease in this age group with no need for further intensive care (25). According to WHO report, COVID-19 disease among children seems to be rare with mild symptoms, about 2.4% of total cases were reported in children and adolescents (aged under 19 years), while older cases aged over 60 years and those with a background of chronic diseases were at higher risk of developing severe disease and death (22).
Even though age is an important deterministic factor for severity of symptoms, other risk factors such as having a history of underlying diseases and/or co-infection with other infections like Influenza virus and Klebsiella may accelerate the progress of symptoms and lead to poor prognosis of the disease (26). However, findings from a study in Singapore shows that infected patients with no history of underlying diseases may also develop severe disease and need for intensive care (4).
The virulence of a disease is usually measured on the basis of indicators such as mortality rate and disability. Compared with the previous two epidemics (SARS and MERS), the case fatality rate was lower and approximately 2% in COVID-19, and only less than 15% of patients would seek hospital services. However, the case fatality rate of SARS and MERS was 10% and 34%, respectively (18). Results of a study in China revealed the overall case fatality rate of 2.3% for COVID-19 (27) and some studies reported case fatality rate of 0.9% in Beijing (28). In another study, Jung and colleagues reported a confirmed case fatality risk of 5.3% to 8.4% for COVID-19(23). However, due to the rapid spread of COVID-19, there is a higher number of death cases in the recent pandemic (N=3043, up to 02 March 2020) compared to SARS and MERS (N=1871) (29).
There is a poor prognosis for the disease in middle and older aged patients (28). In a study on 44672 confirmed cases in China, case fatality rate was highest in the group of over 80 years (14.77%), followed by the age group between 70 to 80 years (7.96%) and no mortality was reported in age group below 10 years (30). Even though death outcome is uncommon in young people, a few deaths are reported in this age group in China and Iran.
Availability of and access to healthcare facilities has likely contributed to increase in death outcome. As a probable explanation for the difference between fatality rate in Wuhan (3%) and other provinces (0.7%) in China, death rates are likely affected by shortage in health resources due to increasing number of patient who had sought diagnosis and treatment services in the early phase of the epidemic in Wuhan (31).
Exploring and understanding the immunogenicity of COVID-19 is essential for developing the most effective treatment regimens and vaccine. However, evidence on immunogenicity of COVID-19 is limited. Study on B-cell and T-cells epitopes revealed that SARS-CoV and the virus causing COVID-19 had identical proteins (32). A few clinical trials have evaluated the efficacy of new vaccines in MERS-CoV and SARS-CoV. Results of these studies in Phase-1 showed some degree of efficacy and one of these studies has been certified to begin Phase-2 (33,34).
Absence of clinical symptoms, respiratory lesions in CT scan and two negative RT-PCR tests in two consecutive days are introduced as criteria of discharge from hospital or quarantine center in China (35). However, recent studies reported several cases of COVID-19 with clinical manifestations of the disease along with a positive test after discharging from hospital (36,37). False positive and false negative results have been reported in RT-PCR test (10,38); hence, hospitals in China have considered additional antibody test (negative IgM and positive IgG results) as a recovery criteria and discharge requirement (39). In conclusion, recurrence of COVID-19 in recovered cases highlights the necessity for development of a more effective vaccine.
Pathogen of COVID-19 has been detected in upper and lower respiratory tracts in initial assessments. Moreover, viral RNA has been detected in fecal and blood samples in later studies. According to WHO guideline, laboratory diagnosis of COVID-19 is based on a positive RT-PCR test. Target gene for diagnosis may be different by country. Accordingly, target genes for screening and confirmatory assays by RT-PCR are ORF1ab and N in Chinese laboratory protocol, while RdRP, E and N are checked in Germany. Furthermore, three targets in N gene are considered in the US protocol (40).
RT-PCR is an expensive test and no access to diagnostic facility during COVID-19 pandemic advocates conducting new researches on other diagnostic approaches such as Chest CT. However, results of recent studies in China demonstrate low specificity for this diagnostic approach (41). As a critical point in diagnostic studies, accuracy of a new test is compared to the gold standard. This comparison resulted in lower values of diagnostic accuracy for the new test. On the other hand, the sensitivity and specificity of a test depend on the severity of cases, which may vary between different populations according to their type of surveillance system (42). In the mentioned study that compared CT scan with RT-PCR as a gold standard, sensitivity of CT scan was appropriate (41). However, the study population consisted of suspected cases and generalizability of the findings is questionable (43). Furthermore, the large number of hospitalized cases due to false positive results by CT scan may increase the risk of transmission to healthy people. On the other hand, RT-PCR test may be subject to some limitations, especially in the earlier phase of an epidemic, as the specialists should be trained for running related procedures and interpretation of results. Moreover, false negative results due to either low quality of specimen in use or inadequate number of organisms in the samples are introduced as main challenges (44). Results of a recent study on rapid IgM-IgG combined test revealed some limitation for RT-PCR test as a standard diagnostic method for COVID-19. The following limitations were indicated for RT-PCR test: long turnaround times, complex operation, and need for quality controlled laboratories, expensive equipment and trained specialists (38).
Surveillance The outbreak surveillance is the anticipation, early warning, prompt detection and response to unusual increase in the number of cases. Establishing a surveillance system for a new epidemic is believed to be a core intervention in controlling the disease (45). Surveillance system data provides reliable information for epidemiologists to identify weak chains of transmission and facilitates evidence-based decisions by policymakers both inside and outside the healthcare service. Moreover, updating and sharing interpretations of data with media, especially in earlier phase of an epidemic, will aid community engagement and participation in control activities and prevention of spreading rumors. Although, it may be too soon to compare the effectiveness of surveillance systems for COVID-19 epidemic in different countries, it seems that the Chinese surveillance system is highly effective as it ensures timely detection, recording, tracking, updating and sharing information on media for an outbreak with unknown origin and high burden of cases (4).
In a large number of countries, the initial focus of the surveillance system for CIVID-19 is examination of all suspected cases with symptoms of the disease (mostly fever) and all people with a travel history to China or visiting Chinese travelers or citizens it the previous two weeks. However, this type of screening program mainly relies on fever cases and those with direct flights from China, so it misses pre-symptomatic cases as well as infected travelers who are arriving from regions with high burden of disease via indirect flights, which could be a source of infection in COVID-19-free countries (46).
In a communicable disease outbreak, essential data are usually collected in parallel from different available information sources in the country including data of weekly outpatient visits to health care centers and hospital referrals with a chief complaint of fever, data of weekly inpatient fever cases and deaths with unknown origin (45). Furthermore, increase in the number of cases and deaths due to pneumonia may raise an alarm in COVID-19 free areas.
A prerequisite for establishing a surveillance system is to provide basic laboratory facilities, particularly at "point of care" (10). This system should be constantly monitored and evaluated using sensitive indicators to ensure the quality of case detection, diagnosis and management.
Detection of primary confirmed cases with poor prognosis in early phase of the epidemic without any link to confirmed cases from other regions emphasis on the insensitivity of a national and local surveillance systems and low performance of control activities against the disease in community level. In this case, it should be immediately addressed and capability and capacity of the surveillance system should be checked.
Examples of surveillance systems in different countries (
National authorities are actively looking for cases in all provinces of China and efforts for finding additional cases inside and outside of Wuhan City have been expanded. Moreover, active and reactive case detection along with tracing close contacts have been started in medical institutions.
The Department of Disease Control in Thailand scaled up the Emergency Operations Center to Level 3 to closely monitor the ongoing situation in both national and international levels. This country has started a screening program to check for fever in all travelers who arrived from Wuhan through direct flights in airports.
Japan’s Ministry of Health requested local health governments to be aware of the respiratory illnesses in Wuhan using the existing surveillance system for serious infectious illnesses with unknown etiology. It has strengthened surveillance for undiagnosed severe acute respiratory illnesses. Quarantine and screening measures have been intensified for travelers from Wuhan at the points of entry. Furthermore, National Institute of Infectious Disease (NIID) established an in-house PCR assay for COVID-19.
Contact tracing and other epidemiological investigation are ongoing in the Republic of Korea to prevent the spread of the disease. The government has scaled up the national alert level from Blue (Level 1) to Yellow (Level 2 of the 4-level national crisis management system). Surveillance of pneumonia cases has been strengthened in health facilities nationwide and quarantine and screening measures have been enhanced for travelers from Wuhan at the points of entry.
The US centers for disease control and prevention (CDC) activated its Emergency Response System to provide ongoing support against COVID-19. Screening of passengers on direct and indirect flights from Wuhan China to the 3 main ports of entry in the United States has begun and will expand to Atlanta and Chicago in the coming days. CDC deployed a team to support ongoing investigation in the state of Washington and tracing close contacts following the first reported case of COVID-19.
Clinical Case Management
Diagnosis of COVID-19 based on clinical manifestations is complicated and initial symptoms of the disease are usually nonspecific. A large number of patients present to clinics and health centers with mild common cold symptoms such as dry cough, sore throat, low-grade fever or body aches. Patients usually go to the emergency departments if the symptoms of the clinical manifestations worsen after a few days. Because of the wide spectrum of clinical symptoms, research on biomarkers and clinical criteria predicting prognosis is of high priority to enable differentiating cases that require further interventions in the early phase of the disease (10).
No approved drug regimen has been introduced to treat infected cases so far, antiviral treatments are used to alleviate the disease symptoms. Studies on Remedesevir, as an antiviral agent, revealed its in vitro activity against the COVID-19 virus and its safety was proven in Ebola trials. Another proposed treatment is Chloroquine, an old drug for treatment of malaria, with apparent effectiveness and acceptable safety against COVID-19 associated pneumonia (48,49). Evaluating the efficacy of anti-influenza drugs such as Umifenovir and Oseltamivir against COVID-19 virus is interesting but lacks any biological plausibility. Using monoclonal antibodies has been suggested as an attractive choice among inactive prophylactic methods; however, its effectiveness has not been proven in other viral respiratory diseases and influenza, yet (50,51).
Steroids and methylprednisolone seem to be widely used in the recent pandemic. However, in case of MERS, it has been shown that the drug prolongs the presence of the virus and WHO does not recommend its use for COVID-19, except for patients with acute respiratory distress syndrome (ARDS) (52,53).
The effectiveness of other medicines and regimens such as Chloroquine, Vitamin C, and Chinese medicine, as well as Lopinavir/Ritonavir combination therapy and Remedesevir are being evaluated in China. Even though randomized clinical trials are important for improving prognosis and interrupting transmission of disease, researchers and healthcare providers should concentrate on alleviation of the disease among subgroups of patients and in different phases of the disease (54).
In addition, since the emerging virus has become a serious global concern, there is a need for rapid development of a vaccine. There are a few vaccine candidates developed in response to outbreak. However, an effective anti-viral medication or a vaccine that has been evaluated for safety and efficacy against COVID-19 is not available yet, and most vaccines are still in the preclinical testing stage (55,56,57).
Special intervention in community level
So after the rise of an emerging disease, goverments have a special responsibility to balance between civil liberties and special measures for protecting susceptible populations (46). However, three components of "scientific", "voluntary" and civil liberty should be considered as guiding principles for decision-making and operating each special protective measure at the community level. Through their experiences in previous communicable disease epidemics, US public health authorities found that enhanced screening programs, monitoring healthy people and quarantine at the community level were not effective measures against progressive spreading of disease. Therefore, specific regulations and waivers were declared to prevent traveling to mainland china and flights to and from China were temporarily suspended. Passengers and US citizens with a history of traveling to China during the previous month were encouraged to stay home and self-quarantine for up to 14 days. However, these interventions and recommendations were deemed insufficint, so public health experts warned about expanding transmission throughout the country in the coming weeks as a consequence of population movements and large scale spread of the disease all over the world (46,58).
Even though children are important sources of influenza virus transmission in the community, initial data analysis on COVID-19 indicated that children were mainly infected from adults rather than the other way around. However, clinical attack rates are low in children and teenagers (0-19) (59), so this age-group may contribute to continuous transmission in the communty. Therefore, countries with high prevalnece of the disease, such as China, Iran, Italy, South korea and Japan, closed or postponed the start of school and extended holidays.
Other special measures considered for control of the pandemic at community level include: cancellin mass gatherings, religious services, tourism, cultural and sport events, concerts and other events. In the mentioned countries, healthcare authorities issued travel ban to and from affected areas and allowed non-essential personnel and employees to work from home.
Special interventions for healthcare providers
Healthcare authorities are responsible for predicting and supplying the essential protective equipment for general population as well as healthcare providers. By ensuring their availability through effective supply chain management, they gain public trust. They also have to plan for deploying healthcare perssonel from less affected areas to epidemic regions (10). With this method, a large number of medical staff and nurses were voluntarily deployed to Wuhan, China (60).
According to primary reports from China and Singapre, working with protective equipment for a long time is cumbersome for healthcare providers and they are under tremendous stress due to probability of being infection and transmitting the disease to their families through close contact (57). The high rates of hospital infection in the recent pandemic emphasizes the importance of regular examination for symptoms among healthcare providers who are in close contact with confirmed patients in order to isolate them in case of positive laboratory test.
A suspected case in which the result of SARS-COV-2 Real Time PCR performed at Regional reference laboratories is doubtful or not conclusive or the result of a pan-coronavirus test is positive.
The 2019-nCoV causes an ongoing outbreak of lower respiratory tract disease called novel coronavirus pneumonia (NCP) by the Chinese government initially. The disease name was subsequently recommended as COVID-19 by the World Health Organization. Meanwhile, 2019-nCoV was renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses. As of February 24, 2020, more than 80,000 confirmed cases including more than 2,700 deaths have been reported worldwide, affecting at least 37 countries. The WHO has declared this a global health emergency at the end of January 2020. The epicenter of this ongoing outbreak is in the city of Wuhan in Hubei Province of central China and the Huanan seafood wholesale market was thought to be at least one of the places where SARS-CoV-2 from an unknown animal source might have crossed the species barrier to infect humans.
A pioneering study conducted in the city of Shenzhen near Hong Kong by a group of clinicians and scientists from the University of Hong Kong has provided the first concrete evidence for human-to-human transmission of SARS-CoV-2. This is an excellent example of how a high-quality clinical study can make a major difference in policy setting. Several important clinical features of COVID-19 have also been documented in this study. First, an attack rate of 83% within the family context is alarmingly high, indicating the high transmissibility of SARS-CoV-2. Second, the clinical manifestations of COVID-19 in this family range from mild to moderate, with more systematic symptoms and more severe radiological abnormalities seen in older patients. Generally, COVID-19 appears to be less severe than SARS. Third, an asymptomatic child was found to have ground-glass opacities in his lung and SARS-CoV-2 RNA in his sputum sample. This finding of asymptomatic virus shedding raises the possibility for transmission of SARS-CoV-2 from asymptomatic carriers to others, which is later confirmed by others. Finally, the presentation of diarrhea in two young adults from the same family also suggests the possibility for gastrointestinal involvement in SARS-CoV-2 infection and fecal–oral transmission. The study has set the stage for the control and management of COVID-19. The work was completed timely and the investigators showed great courage and leadership in a very difficult time when the Chinese authority failed to recognize widespread person-to-person transmission of SARS-CoV-2 before January 20, 2020.
Several interesting papers on SARS-CoV-2 and COVID-19 have been published in the past few weeks to report on the evolutionary reservoir, possible intermediate host and genomic sequence of SARS-CoV-2 as well as clinical characteristics of COVID-19 [6, 7]. In view of these findings and the urgent needs in the prevention and control of SARS-CoV-2 and COVID-19, in this commentary we highlight the most important research questions in the field from our personal perspectives.
The first question concerns how SARS-CoV-2 is transmitted currently in the epicenter of Wuhan. In order to minimize the spreading of SARS-CoV-2, China has locked down Wuhan and nearby cities since January 23, 2020. The unprecedented control measures including suspension of all urban transportation have apparently been successful in preventing further spreading of SARS-CoV-2 to other cities. However, the number of confirmed cases in Wuhan continued to rise. It is therefore crucial to determine whether the rise is due to a large number of infected individuals before the lock down and/or failure in the prevention of widespread intra-familial, nosocomial or community transmission. Based on the number of exported cases from Wuhan to cities outside of mainland China, it was predicted that there might be more than 70,000 individuals infected with SARS-CoV-2 on January 25, 2020 in Wuhan. This should be determined experimentally in Wuhan as discussed below and it will reveal whether the real numbers of infected people and asymptomatic carriers are indeed underestimated severely. In addition to viral RNA detection, measurement of IgM and IgG antibodies as well as antigens would be very helpful. Several representative residential areas should be selected for detailed analysis so that a big picture can be deduced. The analysis should include all healthy and diseased individuals within the area with the aim of identifying people who have recovered from an infection or are having an active infection. The ratio of asymptomatic carriers should also be determined. The analysis should also be extended to detect RNA and antigen of influenza viruses. The activity of seasonal flu in Wuhan also reached a peak at the beginning of 2020. It will be of interest to see whether the flu season had ended and how many people having a fever now are actually infected with influenza virus. Precision control measures for SARS-CoV-2 should be tailor-designed for high-risk groups based on the results of this analysis. Differentiating people having a flu and preventing them from infecting with SARS-CoV-2 in a hospital setting might also be critical.
The second question is how transmissible and pathogenic is SARS-CoV-2 in tertiary and quaternary spreading within humans. Continued transmission of SARS-CoV-2 in Wuhan suggests that tertiary and quaternary spreading has occurred. Compared to the primary and secondary spreading during which SARS-CoV-2 was transmitted from animal to human and from human to human, has the transmission rate increased and has the pathogenicity decreased? Alternatively, is the virus less transmissible after several passages in humans? Retrospective analysis of all confirmed cases in Wuhan should be very informative. The answers to the above questions hold the key to the outcome of the outbreak. If the transmission is weakened, the outbreak may ultimately come to an end at which SARS-CoV-2 is eradicated from humans. On the contrary, if effective transmission can be sustained, the chance is increased that SARS-CoV-2 will become another community-acquired human coronavirus just like the other four human coronaviruses (229E, OC43, HKU1 and NL63) causing common cold only. The basic reproductive number (R0) of SARS-CoV-2 has been estimated to be 2.68, resulting in an epidemic doubling time of about 6.4 days. Other estimates of R0 could go up to 4, higher than that of SARS-CoV, which is lower than 2. Determining the real R0 will shed light on whether and to what extent infection control measures are effective.
The third question relates to the importance of asymptomatic and presymptomatic virus shedding in SARS-CoV-2 transmission. Asymptomatic and presymptomatic virus shedding posts a big challenge to infection control [1, 2]. In addition, patients with mild and unspecific symptoms are also difficult to identify and quarantine. Notably, the absence of fever in SARS-CoV-2 infection (12.1%) is more frequent than in SARS-CoV (1%) and Middle East respiratory syndrome coronavirus (MERS-CoV; 2%) infection. In light of this, the effectiveness of using fever detection as the surveillance method should be reviewed. However, based on previous studies of influenza viruses and community-acquired human coronaviruses, the viral loads in asymptomatic carriers are relatively low. If this is also the case for SARS-CoV-2, the risk should remain low. Studies on the natural history of SARS-CoV-2 infection in humans are urgently needed. Identifying a cohort of asymptomatic carriers in Wuhan and following their viral loads, clinical presentations and antibody titers over a time course will provide clues as to how many of the subjects have symptoms in a later phase, whether virus shedding from the subjects is indeed less robust, and how often they might transmit SARS-CoV-2 to others.
The fourth question relates to the importance of fecal–oral route in SARS-CoV-2 transmission. In addition to transmission via droplets and close contact, fecal–oral transmission of SARS-CoV has been shown to be important in certain circumstances. Gastrointestinal involvement of SARS-CoV-2 infection and isolation of SARS-CoV-2 from fecal samples of patients are in support of the importance of fecal–oral route in SARS-CoV-2 transmission. Although diarrhea was rarely seen in studies with large cohorts [6, 7], the possibility of SARS-CoV-2 transmission via sewage, waste, contaminated water, air condition system and aerosols cannot be underestimated, particularly in cases such as the Diamond Princess cruise ship with 3,700 people, among whom at least 742 have been confirmed to be infected with SARS-CoV-2 plausibly as the result of a superspreading event. Further investigations are required to determine the role of fecal–oral transmission in these cases and within the representative residential areas selected for detailed epidemiological studies in Wuhan as discussed earlier.
The fifth question concerns how COVID-19 should be diagnosed and what diagnostic reagents should be made available. RT-PCR-based SARS-CoV-2 RNA detection in respiratory samples provides the only specific diagnostic test at the initial phase of the outbreak. It has played a very critical role in early detection of patients infected with SARS-CoV-2 outside of Wuhan, implicating that widespread infection of the virus had occurred in Wuhan at least as early as the beginning of 2020. This has also pushed the Chinese authority to acknowledge the severity of the situation. Due to difficulties in sampling and other technical issues in this test, at one point in early February clinically diagnosed patients with typical ground glass lung opacities in chest CT were also counted as confirmed cases in order to have the patients identified and quarantined as early as possible. ELISA kits for detection of IgM and IgG antibodies against N and other SARS-CoV-2 proteins have also been available more recently. This has made specific diagnosis of ongoing and past infection possible. Particularly, seroconversion for IgM antibodies normally occurs a few days earlier than that of IgG. ELISA reagents for detection of SARS-CoV-2 antigens such as S and N are still in urgent need, and would provide another test highly complementary to viral RNA detection.
The sixth question concerns how COVID-19 should be treated and what treatment options should be made available. COVID-19 is a self-limiting disease in more than 80% of patients. Severe pneumonia occurred in about 15% of cases as revealed in studies with large cohorts of patients. The gross case fatality is 3.4% worldwide as of February 25, 2020. This rate is 4.4% for patients in Wuhan, 4.0% for patients in Hubei and 0.92% for patients outside of Hubei. The exceedingly high fatality in Wuhan might be explained by the collapse of hospitals, a large number of undiagnosed patients, suboptimal treatment or a combination of these. Up to date, we still do not have any specific anti-SARS-CoV-2 agents but an anti-Ebola drug, remdesivir, may hold the promise. As a nucleotide analog, remdesivir was shown to be effective in preventing MERS-CoV replication in monkeys. Severity of disease, viral replication, and lung damage were reduced when the drug was administered either before or after infection with MERS-CoV. These results provide the basis for a rapid test of the beneficial effects of remdesivir in COVID-19. Other antiviral agents worthy of further clinical investigations include ribavirin, protease inhibitors lopinavir and ritonavir, interferon α2b, interferon β, chloroquine phosphate, and Arbidol. However, we should also bear in mind the side effects of these antiviral agents. For example, type I interferons including interferon α2b and interferon β are well known for their antiviral activity. Their beneficial effects at an early phase of infection are well expected. However, administration at a later stage carries the risk that they might worsen the cytokine storm and exacerbate inflammation. Notably, steroids have been experimentally used widely in the treatment of SARS and are still preferred by some Chinese physicians in the treatment of COVID-19. It is said to be capable of stopping the cytokine storm and preventing lung fibrosis. However, the window in which steroids might be beneficial to patients with COVID-19 is very narrow. In other words, steroids can only be used when SARS-CoV-2 has already been eliminated by human immune response. Otherwise, SARS-CoV-2 replication will be boosted leading to exacerbation of symptoms, substantial virus shedding, as well as increased risk for nosocomial transmission and secondary infection. In this regard, it will be of interest to determine whether the report of fungal infection in the lungs of some patients in Wuhan might be linked to misuse of steroids. Nevertheless, the screening of new pharmaceuticals, small-molecule compounds and other agents that have potent anti-SARS-CoV-2 effects will successfully derive new and better lead compounds and agents that might prove useful in the treatment of COVID-19.
The seventh question is whether inactivated vaccines are a viable option for SARS-CoV-2. The chance that SARS-CoV-2 will become endemic in some areas or even pandemic has increased in view of its high transmissibility, asymptomatic and presymptomatic virus shedding, high number of patients with mild symptoms, as well as the evidence for superspreading events. Thus, vaccine development becomes necessary for prevention and ultimate eradication of SARS-CoV-2. Inactivated vaccines are one major type of conventional vaccines that could be easily produced and quickly developed. In this approach, SARS-CoV-2 virions can be chemically and/or physically inactivated to elicit neutralizing antibodies. In the case of SARS-CoV and MERS-CoV, neutralizing antibodies were successfully and robustly induced by an inactivated vaccine in all types of animal experiments, but there are concerns about antibody-dependent enhancement of viral infection and other safety issues. While inactivated vaccines should still be tested, alternative approaches include live attenuated vaccines, subunit vaccines and vectored vaccines. All of these merit further investigations and tests in animals.
The eighth question relates to the origins of SARS-CoV-2 and COVID-19. To make a long story short, two parental viruses of SARS-CoV-2 have now been identified. The first one is bat coronavirus RaTG13 found in Rhinolophus affinis from Yunnan Province and it shares 96.2% overall genome sequence identity with SARS-CoV-2. However, RaTG13 might not be the immediate ancestor of SARS-CoV-2 because it is not predicted to use the same ACE2 receptor used by SARS-CoV-2 due to sequence divergence in the receptor-binding domain sharing 89% identity in amino acid sequence with that of SARS-CoV-2. The second one is a group of betacoronaviruses found in the endangered species of small mammals known as pangolins, which are often consumed as a source of meat in southern China. They share about 90% overall nucleotide sequence identity with SARS-CoV-2 but carries a receptor-binding domain predicted to interact with ACE2 and sharing 97.4% identity in amino acid sequence with that of SARS-CoV-2. They are closely related to both SARS-CoV-2 and RaTG13, but apparently they are unlikely the immediate ancestor of SARS-CoV-2 in view of the sequence divergence over the whole genome. Many hypotheses involving recombination, convergence and adaptation have been put forward to suggest a probable evolutionary pathway for SARS-CoV-2, but none is supported by direct evidence. The jury is still out as to what animals might serve as reservoir and intermediate hosts of SARS-CoV-2. Although Huanan seafood wholesale market was suggested as the original source of SARS-CoV-2 and COVID-19, there is evidence for the involvement of other wild animal markets in Wuhan. In addition, the possibility for a human superspreader in the Huanan market has not been excluded. Further investigations are required to shed light on the origins of SARS-CoV-2 and COVID-19.
The ninth question concerns why SARS-CoV-2 is less pathogenic. If the reduced pathogenicity of SARS-CoV-2 is the result of adaptation to humans, it will be of great importance to identify the molecular basis of this adaptation. The induction of a cytokine storm is the root cause of pathogenic inflammation both in SARS and COVID-19. SARS-CoV is known to be exceedingly potent in the suppression of antiviral immunity and the activation of proinflammatory response. It is therefore intriguing to see how SARS-CoV-2 might be different from SARS-CoV in interferon-antagonizing and inflammasome-activating properties. It is noteworthy that some interferon antagonists and inflammasome activators encoded by SARS-CoV are not conserved in SARS-CoV-2. Particularly, ORF3 and ORF8 in SARS-CoV-2 are highly divergent from ORF3a and ORF8b in SARS-CoV that are known to induce NLRP3 inflammasome activation. ORF3 of SARS-CoV-2 is also significantly different from the interferon antagonist ORF3b of SARS-CoV. Thus, these viral proteins of SARS-CoV and SARS-CoV-2 should be compared for their abilities to modulate antiviral and proinflammatory responses. The hypothesis that SARS-CoV-2 might be less efficient in the suppression of antiviral response and the activation of NLRP3 inflammasome should be tested experimentally.
Much progress has been made in the surveillance and control of infectious diseases in China after the outbreak of SARS-CoV in 2003. Meanwhile, virological research in the country has also been strengthened. The new disease report and surveillance system did function relatively well during the 2009 pandemic of swine flu. New viral pathogens such as avian influenza virus H7N9 and severe-fever-with-thrombocytopenia syndrome bunyavirus have also been discovered in recent years [11, 12], indicating the strength and vigor of Chinese infectious disease surveillance and virological research. However, the ongoing outbreak of SARS-CoV-2 has not only caused significant morbidity and mortality in China, but also revealed major systematic problems in control and prevention of infectious diseases there. Unfortunately, many of the lessons from the 2003 outbreak have not been learned. Importantly, disease control professionals, practicing physicians and scientists are disconnected in the fight against SARS-CoV-2 and COVID-19. In addition, important decisions were not made by experts in the field. Hopefully, these issues will be dealt with swiftly and decisively during and after the outbreak.
Above we have discussed the two possibilities that this outbreak will unfold. If SARS-CoV-2 is not eliminated from humans through quarantine and other measures, it can still be eradicated by vaccination. If it attenuates to become another community-acquired human coronavirus causing mild respiratory tract disease resembling the other four human coronaviruses associated with common cold, it will not be a disaster either. Before SARS-CoV-2 attenuates further to a much less virulent form, early diagnosis and improved treatment of severe cases hold the key to reduce mortality. We should remain vigilant, but there are grounds for guarded optimism. Redoubling our research efforts on SARS-CoV-2 and COVID-19 will solidify the scientific basis on which important decisions are made.
The 2019 coronavirus disease (COVID-19) epidemic in China is a global health threat, and is by far the largest outbreak of atypical pneumonia since the severe acute respiratory syndrome (SARS) outbreak in 2003. Within weeks of the initial outbreak the total number of cases and deaths exceeded those of SARS. The outbreak was first revealed in late December 2019 when clusters of pneumonia cases of unknown etiology were found to be associated with epidemiologically linked exposure to a seafood market and untraced exposures in the city of Wuhan of Hubei Province. Since then, the number of cases has continued to escalate exponentially within and beyond Wuhan, spreading to all 34 regions of China by 30 January 2020. On the same day, the World Health Organization (WHO) declared the COVID-19 outbreak a public health emergency of international concern.
COVID-19, similarly to SARS, is a beta-coronavirus that can be spread to humans through intermediate hosts such as bats, though the actual route of transmission is still debatable. Human-to-human transmission has been observed via virus-laden respiratory droplets, as a growing number of patients reportedly did not have animal market exposure, and cases have also occurred in healthcare workers. Transmissibility of COVID-19 as indicated by its reproductive number has been estimated at 4.08, suggesting that on average, every case of COVID-19 will create up to 4 new cases. The reporting rate after 17 January 2020 has been considered to have increased 21-fold in comparison to the situation in the first half of January 2020. The average incubation period is estimated to be 5.2 days, with significant variation among patients, and it may be capable of asymptomatic spread. Symptoms of infection include fever, chills, cough, coryza, sore throat, breathing difficulty, myalgia, nausea, vomiting, and diarrhea. Older men with medical comorbidities are more likely to get infected, with worse outcomes. Severe cases can lead to cardiac injury, respiratory failure, acute respiratory distress syndrome, and death. The provisional case fatality rate by WHO is around 2%, but some researchers estimate the rate to range from 0.3% to 0.6%.
Since the outbreak, response efforts by the China government have been swift, and three weeks into the epidemic, in an unprecedented move to retard the spread of the virus, a lockdown was imposed on Wuhan on 23 January, with travel restrictions. Within days, the quarantine was extended to additional provinces and cities, affecting more than 50 million people in total. Many stayed at home and socially isolated themselves to prevent being infected, leading to a “desperate plea”. There have also been accounts of shortages of masks and health equipment. The ongoing COVID-19 epidemic is inducing fear, and a timely understanding of mental health status is urgently needed for society. Previous research has revealed a profound and wide range of psychosocial impacts on people at the individual, community, and international levels during outbreaks of infection. On an individual level, people are likely to experience fear of falling sick or dying themselves, feelings of helplessness, and stigma. During one influenza outbreak, around 10% to 30% of general public were very or fairly worried about the possibility of contracting the virus. With the closure of schools and business, negative emotions experienced by individuals are compounded. During the SARS outbreak, many studies investigated the psychological impact on the non-infected community, revealing significant psychiatric morbidities which were found to be associated with younger age and increased self-blame. Those who were older, of female gender, more highly educated, with higher risk perceptions of SARS, a moderate anxiety level, a positive contact history, and those with SARS-like symptoms were more likely to take precautionary measures against the infection.
Currently, there is no known information on the psychological impact and mental health of the general public during the peak of the COVID-19 epidemic. This is especially pertinent with the uncertainty surrounding an outbreak of such unparalleled magnitude. Based on our understanding, most of the research related to this outbreak focuses on identifying the epidemiology and clinical characteristics of infected patients, the genomic characterization of the virus, and challenges for global health governance. However, there are no research articles examining the psychological impact on COVID-19 on the general population in China.
Therefore, this present study represents the first psychological impact and mental health survey conducted in the general population in China within the first two weeks of the COVID-19 outbreak. This study aims to establish the prevalence of psychiatric symptoms and identify risk and protective factors contributing to psychological stress. This may assist government agencies and healthcare professionals in safeguarding the psychological wellbeing of the community in the face of COVID-19 outbreak expansion in China and different parts of the world.