Coronavirus Disease 2019 (COVID-19): What we know?

Coronavirus Disease 2019 (COVID-19): What we know?

In late December 2019, an outbreak of an unknown disease called pneumonia of unknown cause occurred in Wuhan, Hubei Province, China1. The outbreak has spread substantial to infect 9720 people in China with 213 deaths and to infect 106 people in 19 other countries up to January 31, 2020 (https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200131-  sitrep-11-ncov.pdf). A few days later, the causative agent of this mysterious pneumonia was identified as a novel coronavirus by several independent laboratories2-4. The causative virus has been temporarily named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the relevant infected disease has been named as coronavirus disease 2019 (COVID-19) by the World Health Organization respectively. According to the daily report of the World Health Organization, the epidemic of SARS-CoV-2 so far registered 78630 cases and 2747 deaths in China, spread to 46 other countries that reported a total of 3664 cases by February 27, 2020 (https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200227-  sitrep-38-covid-19.pdf). COVID-19 epidemic has become a global health threat

Coronaviruses are a group of highly diverse, enveloped, positive-sense, single-stranded RNA viruses5. They cause several diseases involving respiratory, enteric, hepatic and neurological systems with vary severity among humans and animals5,6. Human coronavirus (CoV) infections have traditionally caused a low percentage of annual respiratory infections. There are HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1, which cause mild respiratory illness5,7. Over the past two decades, two novel coronaviruses, severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), have emerged and cause severe human diseases8,9. During the epidemic, SARS-CoV infect more than 8000 people worldwide with nearly 800 fatalities, representing its mortality rate around 10%. Whereas MERS-CoV infected over 857 official cases and 334 deaths, making its mortality rate approximately 35%10-12. So far, SARS-CoV-2 is the seventh member of the family of coronaviruses that infects humans. The main symptoms of COVID-19 included fever, fatigue, and cough, which are similar to that of SARS-CoV and MERS-CoV infected cases. There are some overlapping and discrete aspects of the pathology and pathogenesis of these coronaviruses which cause severe diseases in humans13.   Many literatures reported the clinical features, virology, pathology and radiology of COVID-19, but the comprehensive review is few. The purpose of this review is primarily to review the pathogen, clinical features, diagnosis, and treatment of COVID-19, but also to comment briefly on the epidemiology and pathology based on the current evidences

The pathogen

The pathogen that causes COVID-19 is a novel coronavirus that was first identified in the late January 2020, named SARS-CoV-2   (also known as 2019-nCoV)2-4.   SARS-CoV-2 is a novel member of coronaviruses, which are a large group of highly diverse, enveloped, positive-sense, single-stranded RNA viruses5. Recent research reported that SARS-CoV-2 likely originated in bats, based on the similarity of its genetic sequence to that of other coronaviruses14. The intermediate animal host of SARS-CoV-2 between a probable bat reservoir and humans is still unknown15. Although this novel coronavirus has genetic features that are compatible with the family of coronavirus, nevertheless it has distinct gene sequences that are significantly different from previously sequenced coronaviruses(Table 1). The analysis of samples from seven SARS-CoV-2 infected patients suggested that SARS-CoV-2 shares 79.5% sequence identity to SARS-CoV3. Simplot analysis showed that SARS-CoV-2 share 96.2% overall genome sequence identity to RaTG13, which is a short RdRp region from a bat coronavirus3. Phylogenetic analysis revealed that SARS-CoV-2 falls   into the subgenusSarbecovirus of the genus Betacoronavirus and is dist inct fro m SARS-CoV2,4. The envelope spike (S) protein is important for coronavirus16. The S protein mediates receptor binding and membrane fusion and is crucial for determining host tropism and transmission capacity17-19. Generally, the S protein is functionally divided into the S1 domain, responsible for receptor binding, and S2 domain, responsible for cell membrane fusion20. Structure analysis suggested that receptor-binding domain was composed of a core and an external subdomain16. Angiotensin converting enzyme II (ACE2) was known as cell receptor for SARS-CoV21-23. Similar to SARS-CoV, SARS-CoV-2 also use ACE2 as an entry 

receptor in the ACE2-expressing cells3, indicating SARS-CoV-2 may share the same life cycle with SARS-CoV (Figure 1).   The biophysical and structural analysis indicated that S protein of SARS-CoV-2 binds ACE2 with approximately10- to 20- fold higher affinity than S protein of SARS-CoV24. The high affinity of S protein for human ACE2 may facilitate the spread of SARS-CoV-2 in human populations. Meanwhile, SARS-CoV-2 does not use other coronavirus receptors, such as aminopeptidase N and dipeptidyl peptidase 4 (DPP4) to enter cells3.

Epidemiology

Briefly, cases tend to be in clusters which arrive in waves, and develop into larger outbreaks all over the world. The first documented outbreak occurred primarily in Wuhan, China1. According to the daily report of the World Health Organization, the epidemic of SARS-CoV-2 so far registered 78630 cases and 2747 deaths in China, spread to 46 other countries that reported a total of 3664 cases by February 27th, 2020.There are evidences suggest that transmission mode is human to human25,26. The major route of transmission of COVID-19 is droplet and close contact26. Whether infection can occur through the oral or conjunctival routes is unknown, but SARS-CoV-2 has been detected in tears27, which is resemble to SARS-CoV28. Reproductive number (R0) was estimated by some studies. Based on the clinical data of patients in COVID-19 early outbreak, the mean R0 was ranging from 2.20 to 3.58, meaning that each patient has been spreading infection to 2 or 3 other people25,29. It is still too early to develop an accurate R0 estimate or to assess the dynamics of transmission. More research is needed in the future.The mean incubation period is about 5 days, ranging fro m 1-14 days and 95% of patients are likely to experience symptoms within 12.5 days of contact25,30. These data suggest a 14-day medical observation period or quarantine for exposed and close contact persons. However, an asymptomatic carrier was reported and the incubation period was 19 days, suggesting the complicated challenge to contain the outbreak

Clinical features

Most case patients were 30-79 years of age32. The median age is ranging from 49 to 59 years25,26,33,34. There were few cases in children below 15 years of age. More than half the patients were male. Nearly half the cases had one or more coexisting medical conditions, such as hypertension, diabetes and cardiovascular disease25,26,33,34. A large cases study indicated that the case-fatality rate was elevated among those patients with coexisting medical conditions32. The spectrum of clinical presentations of COVID-19 have been reported ranging fro m asymptomat ic infection to severe respiratory failure25,26,30,32-34. The main symptoms include a self-reported fever, fatigue, dry cough, myalgia, and dyspnea. The uncommon symptoms include sputum production, headache, hemoptysis and diarrhea25,26,30,32-34. Although pneumonia is present in most SARS-CoV-2 infected patients, few cases complained of pleuritic chest pain26,33. According to the severit y o f symptoms, patients can be classified as mild, severe, and crit ical t ypes32(Table 2). Mild patients had nonpneumonia or mild pneumonia. Severe patients had several clinical findings, including dyspnea, respiratory frequency ≥  30/min, blood oxygen saturation ≤  93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and/or lung infiltrates >50% within 24 to 48 hours. Critical patients had severe conditions, such as respiratory This article is protected by copyright. All rights reservedfailure, septic shock, and/or multiple organ dysfunction or failure32. If the disease progressed, the median duration period from illness onset to dyspnea was 8.0 days, and to mechanical ventilation was 10.5 days34. Common clinical laboratory findings include leucopenia and lymphopenia25,30,33,34. Lymphopenia is a cardinal feature of COVID-19. Lactate dehydrogenase, and creatinine kinase are all elevated. Half of patients had abnormal liver function, with elevated alanine aminotransferase or aspartate aminotransferase. Most patients had abnormal myocardial zymogram, which showed the elevation of creatine kinase and lactate dehydrogenase. Most patients showed normal serum levels o f procalcitonim, but the C-reactive protein was above the normal range. One third of patients had the elevation of D-dimer25,30,33,34. One study investigated the changes of several cytokines in serum in the COVID-19 patients34. Initial plasma IL1B, IL1RA, IL7, IL8, IL9, IL10, basic FGF, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1A, MIP1B, PDGF, TNFα, and VEGF concentrations were higher in patients than in healthy adults. Plasma levels of IL5, IL12p70, IL15, Eotaxin, and RANTES were similar between patients and healt hy adults. Further comparison between intensive care unit (ICU) and non-ICU patients showed that plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα were higher in ICU patients than non-ICU patients34. These findings suggested that the initiation of the immune response result in the production of chemokines and cytokines, which damage normal host lung.The radio logic manifestations of SARS-CoV-2 infected patients are diverse and progressing rapidly35-38. Two third of patients had at least two affected lobes, nearly half of patients had five affected lobes37,38. The most commo n

manifestations are patchy ground glass opacities (GGO) and patchy consolidation which were mainly distributed in the middle and outer zone of the lung37,38(Figure 2)  . A little fibrous stripe may appear if the condition was improved37. One report suggested that there are four stages defined on CT scan36. In early stage, GGO was the main radiological demonstration distributed in the lower lobes unilaterally or bilaterally. In progressive stage, diffuse and bilateral GGO and consolidation in more than two lobes became the main manifestation. In peak stage, the diffuse GGO and dense consolidation became more prevalent. In absorption stage, extensive GGO could be observed and the consolidation was gradually absorbed

Reference1. 

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