|Year : 2020 | Volume
| Issue : 7 | Page : 3-9
COVID-19: Epidemiology and virology
Antariksh Deep1, Aparna Yadav1, Madhu Sharma1, Kundan Mittal2, Anupama Mittal3
1 Department of Microbiology, Pt. B D Sharma, PGIMS, Rohtak, Haryana, India
2 Department of Pediatrics, Pt. B D Sharma, PGIMS, Rohtak, Haryana, India
3 Deputy Civil Surgeon, Rohtak, Haryana, India
|Date of Submission||16-Apr-2020|
|Date of Decision||20-Apr-2020|
|Date of Acceptance||29-Apr-2020|
|Date of Web Publication||29-May-2020|
Prof. Dr. Kundan Mittal
Department of Pediatrics, Pt. B D Sharma, PGIMS, Rohtak, Haryana
Source of Support: None, Conflict of Interest: None
The novel coronavirus (CoV), termed Severe Acute Respiratory Syndrome related CoV-2 (SARS CoV-2), responsible for an outbreak of unusual viral pneumonia in Wuhan city, Hubei province, China is a testimony to the risk the CoVs pose to the public health. In this review, a brief introduction of the human CoVs (hCoV), along with the epidemiology and pathogenesis of the infection caused by the hCoVs, especially the SARS-CoV-2, shall help in the understanding of the COVID-19.
Keywords: COVID-19, cytokines, human coronaviruses, Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome-coronavirus-2
|How to cite this article:|
Deep A, Yadav A, Sharma M, Mittal K, Mittal A. COVID-19: Epidemiology and virology. J Pediatr Crit Care 2020;7, Suppl S1:3-9
|How to cite this URL:|
Deep A, Yadav A, Sharma M, Mittal K, Mittal A. COVID-19: Epidemiology and virology. J Pediatr Crit Care [serial online] 2020 [cited 2021 Sep 23];7, Suppl S1:3-9. Available from: http://www.jpcc.org.in/text.asp?2020/7/7/3/285373
| Introduction|| |
From 18 to 29 December 2019, a cluster of pneumonia cases in Wuhan City, Hubei Province, China were noticed and was laboratory confirmed on January 2, 2020. On January 9, 2020 the Centre for Disease Prevention and Control (CDC), China reported a novel Coronavirus (CoV) to be the causative agent of this peculiar pneumonia. Initially, the cases were limited to the population that had visited the Wuhan “wet market” that was selling the live “game animals.” On February 11, 2020, the World Health Organisation (WHO) named this pneumonia due to the CoV as 'COVID-19. Today, more than 4 months down the line, around 203 countries and one cruise ship have been affected by the COVID-19, thereby resulting in global pandemic. CoVs have been responsible for two major outbreaks before, i.e., Severe Acute Respiratory Syndrome (SARS), in 2002, and Middle East Respiratory Syndrome (MERS), in 2012. SARS, MERS, and COVID-19 are caused due to the bat associated CoVs. In case of SARS and MERS, the transmission is known to take place from bats to human beings via the intermediate hosts such as the palm civets and the dromedary camels. Although nucleotide homology sharing to the extent of 96.2% was observed between the SARS-CoV-2 and RaTG13, a bat CoV found in Rhinolophus affinis bats; however, there are significant differences in the receptor binding domain (RBD) in their S proteins. In the absence of credible data, it is perceived that bamboo rats in the family of Rhizomyidae and civets act might be acting as the intermediate hosts for SARS-CoV-2.,
| Historical Background|| |
Historically, human CoVs (hCoV) can be traced back to 1965, when Tyrell and Bynoe, found a virus in the human embryonic tracheal organ culture that was obtained from an adult patient suffering from common cold, that they named as B814. However, at that time, they could not grow it in tissue culture. Hamre and Procknow also, around the same time could grow a virus in tissue culture and they named it as 229E. McIntosh and colleagues, using the “organ culture” technique also reported the recovery of several ether-sensitive agents from the human respiratory tract, the prototype of which was called as OC43., Tyrell, in late 1960s while working on various human and animal CoVs, observed that on electron microscopy, various viruses such as the infectious bronchitis virus, mouse hepatitis virus, and the transmissible gastroenteritis virus of the swine, were having crown like appearance – “corona” (Latin – Corona, crown) of the surface projections, and named them as CoV, which was later accepted as a new genus of the virus.,, CoVs were not considered highly pathogenic to human beings until 2002, when an outbreak of SARS was reported first from the Guangdong province in China, due to a CoV subsequently getting designated as SARS CoV. A decade later, in 2012, another outbreak was reported to have occurred due to another highly pathogenic CoV in the countries of the middle-eastern region of the Asia, and the etiological agent was designated as MERS-CoV.,
The age-wise distribution of cases of COVID-19 varies according to the geographical area of the world. There is not much data available from all sections of the globe at this stage regarding the predominant age group affected. However, according to the data, made available by the Chinese CDC, 73% of the cases were observed to have been in population over 40 years of age. The mortality rate in population <40 years of age has been reported to be around 03%. A significant intervention, i.e., aggressive containment strategies (lockdown and social distancing) that resulted in quarantining of around 11 million population of Wuhan, greatly helped China in containing the total number of cases. Similar strategies of lockdown and social distancing have hence been adopted by countries world over in mitigating the spread of the pandemic.
However, it is very important to take into consideration, various important indices, like transmission rate (reproduction number, R0), incubation period and the case fatality ratio to devise area specific containment strategies. Reproduction number or “R naught” (R0) is an indicator that defines infectiousness/infectivity, i.e., it is the number of persons that an infected individual can further infect. If the R0 of a particular agent is >1, then the disease would spread among people. For, SARS-CoV-2, the mean R0 has been estimated to be around 2.24–3.58. In comparison, the R0 of seasonal influenza varies between 1.1 and 2.3, for SARS CoV between 1 and 2.75, Ebola 1.5–2.5, Polio 5–7, chicken pox between 3.75 and 5.0, HIV/AIDS 2–5, and measles R0 is between 12 and 18.,,
According to the European CDC data, since December 31, 2019 and as of April 14, 2020, globally, a total of 1,924,878 cases of COVID-19 and 119,766 deaths attributable to this condition have been reported (in accordance with the applied case definitions and testing strategies in the affected countries).
The highest number of cases have been reported from the Europe (813,829 cases). The six countries reporting most cases are the United States (571,694), Spain (161,852), Italy (152,271), Germany (120,479), France (93,790), and United Kingdom (78,991) and highest mortality being in the USA.
A total of 284,479 cases have been reported from the Asian countries; the five countries reporting most cases include, China (83,097 cases, and 3343 deaths), Iran (70,029 cases, and 4357 deaths), Turkey (52,167 cases and 1101 deaths), Israel (10,743, and 101 deaths), and South Korea (10,512 cases, and 214 deaths). From India, as of April 14, 2020, a total of 10,363 active cases and 339 deaths have been reported, that are attributable to COVID-19.,
Another important consideration in managing an infectious pandemic is the frontline Healthcare workers (HCWs) providing care to the COVID-19 patients, getting infected. In absence of a reasonably significant number of publications that are available in this regard, as of April 8, 2020, infections in HCWs from 52 countries have been reported to the WHO. However, there is no systematic reporting of HCW COVID-19 infections to WHO. Since, there is no standardized mechanism of reporting such data, therefore this number probably under-represents the true number of COVID-19 infections among HCWs globally. A publication from CDC, China, in March 2020, indicated the prevalence rate of COVID-19 infections among HCWs to be 3.8%. In Italy, a situational report from April 10, 2020 reported 15,314 infections among HCW, representing 11% of all infections at that time.
80% of confirmed COVID-19 cases suffer from only mild to moderate disease, while 13% have severe disease (dyspnea, respiratory frequency ≥30/min, blood oxygen saturation ≤93%, PaO2/FiO2 ratio <300, and/or lung infiltrates >50% of the lung field within 24–48 h). Critical illness (respiratory failure, septic shock, and/or multiple organ dysfunction/failure) is noted in only in <6% of cases. Children are affected less possibly due to lesser number of ACE2 receptors, poorly developed humoral and cellular immune system and more immunoglobulin levels against viruses.
| Coronaviruses: Classification|| |
CoVs cause respiratory and intestinal infections in a large range of animals, including aves and mammals. They are the largest group of RNA viruses belonging to the order Nodovirales, which includes the families, Coronaviridae, Arteriviridae, Mesoniviridae, and Roniviridae. The order Nidovirales comes under the “Realm,” Riboviria. In the family, Coronaviridae, there is a subfamily, Coronavirinae. Based on the phylogenetic and genomic structures, there are four genera in the subfamily coronavirinae, i.e., Alpha CoV, Beta CoV, Gamma CoV, and Delata CoV. Important members of each genus are depicted in the [Figure 1]. Members of the alpha CoVs and beta CoVs can cause infection only in mammals, for example, respiratory tract infections in human beings and gastroenteritis in animals. The majority of the members of the Gamma, and Delta CoVs cause infection in birds, although in few instances, infections in mammals have also been reported [Table 1]. As of today, there are seven different CoVs that are known to infect human beings. Four of these, HCoV-NL63, HCoV-229E, HCoV-OC43, and HKU1, usually cause mild respiratory tract infection in the human beings. Two other HCoVs, i.e., SARS-CoV and MERS-CoV, have caused epidemics in the last two decades. The seventh one, i.e., SARS-CoV-2, is responsible for the current global pandemic.,
| Taxonomy and the Nomenclature of the Severe Acute Respiratory Syndrome-Related Coronavirus|| |
In case of an emerging viral infection/outbreak, while assigning a nomenclature to the viral agent, two agencies work in tandem, i.e., the WHO, and the International Committee on Taxonomy of Viruses (ICTV). The job of assigning a taxonomical status to the viruses, i.e., placing them in subfamily, genus, subgenus, and the species level is delegated by the ICTV to a “Study Group.” In case of the CoVs, Coronaviridae Study Group (CSG), a working group of the ICTV, is responsible for placing the viruses based on phylogenetic relationship. As per the current classification of the CoVs, there are 39 species in 27 subgenera, five genera, and two subfamilies that belong to the family Coronaviridae, suborder Cornidovirineae, order Nidovirales, and realm Riboviria. The CSG has also proposed to adopt the naming convention for individual CoV isolates as: SARS-CoV-2/host/location/isolate/date. According to the ICTV, the species name is italicized, starts with a capital letter and should not be spelt in an abbreviated form. Hence, the species name in the present virus context is “SARS-related CoV.” This convention does not apply while writing the names of the virus. Hence, in the present context, SARS CoV can be abbreviated as SARS-CoV-2.
| Morphology of Severe Acute Respiratory Syndrome-Coronavirus-2 and Genomic Organisation|| |
The virions of CoV are spherical with diameter of around 100–150 nm [Figure 2]. On cryo-electron tomography and cryo-electron microscopy, the most striking feature of the virion are the club-shaped spike projections, emanating from the surface of the virion, giving it the name CoV because of the crown like appearance – “corona” (Latin– Corona, crown). The CoVs have a helically symmetrical nucleocapsid, which is uncommon among the positive sense RNA viruses. The genome is non-segmented, positive sense RNA of the size of around 26–32 kb (29,891 nucleotides and 9860 amino-acids). There are at least six open reading frames (ORFs) in the genome. The first ORFs (ORF1a/b) occupies about two-thirds of the whole genome length [Figure 3]. It encodes 16 non-structural proteins (nsps), the functions of which are summarized in the [Table 2]. Some of the significant ones include, nsp12, that encoded the RNA-dependent RNA polymerase domain, nsp14 encodes the exoribonuclease, that is critical for the maintaining the replication fidelity. The other ORFs occupying the one-third of the genome and present near the 3'-terminus encode for at least four main structural proteins: spike (S: Responsible for crown like appearance), membrane (M formerly known as E1: Large quantity confirming shape of virus), envelope (E: Small quantity), and nucleocapsid (N: Related to viral genomes) proteins. Apart from these, different CoVs encode special structural and accessory proteins, for example, HE protein, 3a/b protein, and 4a/b protein.
|Table 2: Important functions of various nonstructural proteins in coronaviruses|
Click here to view
Important mode virus spread is droplet and contact transmission. Person can get COVID-19 by touching a surface or object that has the virus on it and then touching their own mouth, nose, or possibly their eyesight be possible before symptoms appear. Feco-oral transmission has not been reported so far but virus is also excreted in stool and urine both. In-utero transmission to fetus has also been not reported till today although newborn has been infected with CoV. The infectious period may begin one to 2 days before symptoms appear, but people are likely most infectious during the symptomatic period. The infectious period is now estimated to last 7–12 days in moderate cases and up to 2 weeks on average in severe cases. Incubation period (time between infection and the onset of clinical symptoms of disease) is reported for 2019-nCoV between 2 and 14 days with the average of 5.2 days. CoVs are sensitive to heat and ultraviolet rays. They can be stored for several years at −80°C and inactivated at 56°C for 30 min (the most commonly used method to inactivate SARS-CoV-2 in the laboratory). In addition, 75% ethanol, peracetic acid, and chlorine containing disinfectants can effectively inactivate SARS-CoV-2. Chlorhexidine (also known as chlorhexidine gluconate) also effectively inactivates the virus. Survival time at different temperatures of virus is shown in [Table 3].
| Pathogenesis|| |
The RBDs present on the spike protein of the SARS-CoV-2 bind to the angiotensin-converting-enzyme-2 (ACE-2) receptors present on the heart, lungs, kidneys and the gastrointestinal tissues. Normally, under physiological conditions, the ACE2 receptors are also present on the arterial and venous endothelial cells and the arterial smooth muscle cells present in almost all the body tissues. The ACE2 receptors present on the cardiac tissue and the blood vessels are responsible for the control of the blood pressure [Figure 4].
The binding of SARS-CoV-2 with the ACE2 facilitates the viral entry into the predominant target cells such as the type II pneumocytes, thereby triggering a cascade of inflammation in the lower respiratory tract [Figure 5]. Acute respiratory distress syndrome, which ensues in a subset of the COVID-19 patients is a leading cause of the mortality. There is another less recognized hyperinflammatory condition, that gets triggered by the viral infections and is encountered in around 3.7%–4.3% cases of sepsis. This condition is secondary hemophagocytic lymphohistiocytosis (sHLH), that is, characterized by unremitting fever, hypercytokinemia, cytopenia's, hyperferritinemia and ARDS in around half of the patients. In Wuhan, China, the predictors of mortality, according to a retrospective, multi-center study of 150 confirmed cases of COVID-19, included, elevated ferritin (mean 1297.6 ng/ml in fatal cases vs. 614.0 ng/ml in survivors; P < 0.001) and Interleukin-6 (IL-6) (P < 0.0001) levels.,
|Figure 5: Replication of severe acute respiratory syndrome-related coronavirus-2|
Click here to view
The infection of the host cells triggers the immune response by the antigen presented cells [(APCs) Immune response triggered by SARS-CoV-2 is of two types. During incubation period and nonsevere stage adaptive response is required to eliminate the virus and to prevent further progression of disease. Failure may trigger the inflammatory response and cytokine storm. For this appropriate endogenous immune response, strategies to boost immune response and genetic background HLA type may be helpful. Cytokine Release Syndrome ([Interferons (IFN)-a, IFN-g, IL-1b, IL-6, IL-12, IL-18, IL-33, Tumor necrosis factor (TNF)-a, transforming growth factor b, etc.] and chemokines [CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.]) occurs in severe cases. The APCs present the foreign antigens to the Th1 CD4+ T-helper cells, that leads to release of IL-12, which further stimulate the Th1 cells. In SARS-CoV-2 infection, there is a dysregulated cytokine/chemokine response, which in subset of patients can cause immunopathological lung injury due to the “cytokine release syndrome.” The cytokines through hematogenous dissemination may cause injury at distant sites too. There are increased plasma concentrations of cytokines such as IL1-β, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1α, MIP1 β, PDGFB, TNFα, and VEGFA. In severe case level of following cytokines are increased highly IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1α, and TNFα. Furthermore, there are increased serum levels of the C-reactive protein, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. However, there is a decrease in the concentration of the hemoglobin and the albumin. The SARS-CoV-2 infection can be categorized in three stages and stage I is least manageable; Stage I: Asymptomatic incubation period with or without presence of virus, Stage II: Non-severe symptomatic case with presence of virus, and Stage III: Severe respiratory symptomatic with high virus load.
| Conclusion|| |
COVID 19 is one of seventh CoV which infects human beings. It is similarity with SARS-CoV and MERS viruses. Mainly it is transmitted through droplets and contacts. COVID 19 causes more fatality in older age and person with associated comorbid conditions. High level of cytokines is related to mortality and poor outcome. The development of SARS-CoV-2 depends on the interaction between the virus and immune system of human body. Various viral factors include virus type, mutation, viral load, viral titer, and viability of the virus invitro. Various immune system-related factors include genetics (such as HLA genes), age, gender, nutritional status, neuroendocrine-immune regulation, and physical status.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al
. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020:395;514-23. [Doi: 10.1016/S0140-6736(20)30154-9].
Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558-70.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al
. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. Pediatr Infect Dis J 2005;24:S223-7, discussion S226.
Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 1966;121:190-3.
McIntosh K, Dees JH, Becker WB, Kapikian AZ, Chanock RM. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc Natl Acad Sci U S A 1967;57:933-40.
McIntosh K, Becker WB, Chanock RM. Growth in suckling-mouse brain of “IBV-like” viruses from patients with upper respiratory tract disease. Proc Natl Acad Sci U S A 1967;58:2268-73.
Witte KH, Tajima M, Easterday BC. Morphologic characteristics and nucleic acid type of transmissible gastroenteritis virus of pigs. Arch Gesamte Virusforsch 1968;23:53-70.
Tyrrell DA, Almeida JD, Cunningham CH, Dowdle WR, Hofstad MS, McIntosh K, et al
. Bingham RW. Intervirology 1975;5:76-82. doi: 10.1159/000149883.
Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019;17:181-92.
Zhong NS, Zheng BJ, Li YM, Poon, Xie ZH, Chan KH, et al
. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003. Lancet 2003;362:1353-8.
Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far. Pathogens 2020;9. pii: E231.
Zhao S, Lin Q, Ran J, Musa SS, Yang G, Wang W, et al
. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int J Infect Dis 2020;92:214-7.
Guerra FM, Bolotin S, Lim G, Heffernan J, Deeks SL, Li Y, et al
. The basic reproduction number (R0) of measles: A systematic review. Lancet Infect Dis 2017;17:e420-8.
Marangi L, Mirinaviciute G, Flem E, Scalia Tomba G, Guzzetta G, Freiesleben de Blasio B, et al
. The natural history of varicella zoster virus infection in Norway: Further insights on exogenous boosting and progressive immunity to herpes zoster. PLoS One 2017;12:e0176845.
Perlman S, McIntosh K. Coronaviruses, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In: Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 9th
ed. Philadelphia (USA): Elsevier; 2020. p. 2072-80.
Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1-23.
Liu Z, Xiao X, Wei X, Li J, Yang J, Tan H, et al
. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol 2020;92:595-601.
Lefkowitz EJ, Dempsey DM, Hendrickson RC, Orton RJ, Siddell SG, Smith DB. Virus taxonomy: The database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res 2018;46:D708-D717. doi:10.1093/nar/gkx932
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020;5:536-44.
Masters P, Perman S. Coronaviridae. In: Knipe DM, Howley PM, editors. Field's Virology. 6th
ed. Philadelphi (USA): Lippincott Williams and Wilkins; 2013;825-58.
Beniac DR, Andonov A, Grudeski E, Booth TF. Architecture of the SARS coronavirus prefusion spike. Nat Struct Mol Biol 2006;13:751-2.
Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020;92:418-23.
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. On behalf of the HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. [Doi.org/10.1016/S0140-6736(20)30628-0].
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020. p. 1-3.
Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev 2020: nwaa041. [Doi: 10.1093/nsr/nwaa041/5804736].
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]