key: cord-279976-juz9jnfk
authors: Xie, Mingxuan; Chen, Qiong
title: Insight into 2019 novel coronavirus — an updated intrim review and lessons from SARS-CoV and MERS-CoV
date: 2020-04-01
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.03.071
sha: 
doc_id: 279976
cord_uid: juz9jnfk

BACKGROUND: The rapid spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus entitled 2019 novel coronavirus (2019-nCoV), has become a global threat. Awareness of the biological features of 2019-nCoV should be updated in time and needs to be comprehensively summarized to help optimize control measures and make therapeutic decisions. METHODS: Based on recently published literatures, official documents and selected up-to-date preprint studies, we reviewed the virology and origin, epidemiology, clinical manifestations, pathology and treatment of 2019-nCoV infection, in comparison with severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV) infection. RESULTS: The genome of 2019-nCoV partially resembled SARS-CoV and MERS-CoV, and indicating a bat origin. The COVID-19 generally had a high reproductive number, a long incubation period, a short serial interval and a low case fatality rate (much higher in patients with comorbidities) than SARS and MERS. Clinical presentation and pathology of COVID-19 greatly resembled SARS and MERS, with less upper respiratory and gastrointestinal symptoms, and more exudative lesions in post-mortems. Potential treatments included remdesivir, chloroquine, tocilizumab, convalescent plasma and vaccine immunization (when possible). CONCLUSION: The initial experience from the current pandemic and lessons from the previous two pandemics can help improve future preparedness plans and combat disease progression.

In late December 2019, a pneumonia outbreak of unknown etiology took place in Wuhan, Hubei province, China, and spread quickly nationwide. Chinese Center for Disease Control and Prevention (CCDC) identified a novel beta-coronavirus called 2019-nCoV, now officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Gorbalenya et al., 2020) , that responsible for the pandemic. This was the third zoonotic coronavirus breakout in the first two decades of 21 st century that allowing human-to-human transmission and raising global health concerns. Chinese government had taken immediate, transparent and extraordinary measures, and reached initial achievements to control the outbreak. As of 11 March 2020, the pandemic in Pubmed, Web of Science, Embase, CNKI, Wanfang, VIP, preprint bioRxiv and medRxiv databases from the earliest available date to 11 March, 2020. Initial search terms were "2019-nCoV" OR "2019 novel coronavirus" OR "SARS-CoV-2" OR "COVID-19" OR "corona virus disease 2019" OR "NCP" OR "Novel coronavirus pneumonia". Further search words were above keywords, "SARS" OR "SARS-CoV" OR "severe acute respiratory syndrome", "MERS" OR "MERS-CoV" OR "middle east respiratory syndrome", in combinations of with "spike protein" OR "genome" OR "reproductive number" OR "incubation period" OR "serial interval" OR "fatality rate" OR "clinical characteristics" OR "pathology" OR "autopsy" OR "treatment". J o u r n a l P r e -p r o o f Moreover, official documents and news released by National Health Commission of P.R. China, CCDC, CDC(USA) and WHO were accessed for up-to-date information on COVID-19. Only the articles in English or Chinese were considered.

In this review, we highlight the pandemic potential and pathological indications of emerging coronavirus, comprehensively and systematically summarize the up-to-date knowledge of the biological characteristics of 2019-nCoV, including virology and origin, epidemiology, clinical manifestations, pathology and treatment. Because of its natural structures and biological features to bind receptors on host cells, the spike protein of 2019-nCoV may played an essential role in disease spreading. We summarized all of the four available pathology studies of COVID-19 biopsy and autopsy, and compared the results with previous two deadly coronavirus diseases.

New therapeutic measures are emerging one after another. Potential effective treatments were remdesivir, chloroquine, tocilizumab, convalescent plasma and vaccine immunization (when possible). Evidence-based medicine should always be advocated to guide our clinical decision.

Coronavirus belongs to the subfamily Orthocoronavirinae in the family of Coronaviridae in the order Nidovirales, which mainly caused infections in respiratory and gastrointestinal tract. The 2019-nCoV is a novel enveloped beta-coronavirus which has a single stranded positive sense RNA genome . Concerning the origin of the virus, several phylogenetic analysis suggested the bat to be the most probable animal reservoir. Based on genome sequencing, 2019-nCoV is about 89% identical to bat SARS-like-CoVZXC21, 82% identical to human SARS-CoV and about 50% to MERS-CoV (Chan et al., 2020; Lu et al., 2020) . As both SARS-CoV and MERS-CoV were transmitted from bats to palm civets or dromedary camels, and finally to humans, there should be another animal representing as an intermediate host between bat and human. Pangolins were suggested as the possible intermediate hosts, because their genome had approximately 85.5%-92.4% similarity to 2019-nCoV, representing two sub-lineages of 2019-nCoV in the phylogenetic tree, one of which (GD/P1L and GDP2S) was extremely closely related to 2019-nCoV (Lam et al., 2020) .

Other research suggested 2019-nCoV was the recombinant virus of bat coronavirus and J o u r n a l P r e -p r o o f snake coronavirus, by comparison in conjunction with relative synonymous codon usage bias among different animal species (Ji et al., 2020) . The truth is yet to be discovered.

The spike surface glycoprotein of coronavirus plays an essential role in binding to receptors on host cells and determines host tropism. Spike protein(S-protein) of 2019-nCoV is reported to bind with angiotensin-converting enzyme 2 (ACE2), the same receptor of SARS-CoV to invade host cells; whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4) as the primary receptor . The amino acid sequence Another research team also discovered an "RRAR" furin recognition site by an insertion in the S1/S2 protease cleavage site in 2019-nCoV, instead of a single arginine in SARS-CoV. After quantifying the kinetics mediating the interaction via surface plasmon resonance, ACE2 is calculated to bind to 2019-nCoV ectodomain with ~15 nM affinity, which is approximately 10-to 20-fold higher affinity than ACE2 binding to SARS-CoV (Wrapp et al., 2020) . In all, the binding affinity between 2019-nCoV S-protein and ACE2 is comparable or even stronger than SARS-CoV S-protein and ACE2. This may explain the rapid development and strong ability of human-to-human transmission in COVID-19.

The pandemic escalated exponentially at the beginning of 2020, which might only be the tip of the iceberg due to delayed case reporting and deficiency in testing kits . The onset of first cluster cases were reported an exposure history to the J o u r n a l P r e -p r o o f Huanan seafood(wild animal) wholesale market in Wuhan. However, phyloepidemiologic analyses suggested that Huanan market was not the origin of 2019-nCoV. The virus was imported from elsewhere and boosted in the crowded market (Yu et al., 2020) . The proportion of infected cases without an exposure history and in health care workers gradually increased. All of the evidence indicated the human-to-human transmission ability of 2019-nCoV, which may already be spread silently between people in Wuhan before the cluster of cases from Huanan market was discovered in late December. Person-to-person transmission may occur mainly through droplet or contact transmission. According to Guan's latest pilot study, 2019-nCoV was detected positive in the gastrointestinal tract specimens (stool and rectal swabs) as well as in saliva and urine, and even in esophageal erosion and bleeding site of severe peptic ulcer patients . Four important epidemiological parameters of 2019-nCoV were reviewed in comparison with those of SARS-CoV and MERS-CoV(shown in Table 1 ).

representing the average number of new infections generated by an infectious person in a totally naïve population. For R0˃1, the number of infected is likely to increase; for R0 ˂1, transmission is likely to decline and die out. The reproductive number updated along with the development of the outbreak and interventions. R0 was estimated to be around 3 for SARS (Bauch et al., 2005) and ˂1 for MERS (Bauch and Oraby, 2013) . The preliminary R0 of 2019-nCoV was reported as 2.24-3.58 . Several research groups reported estimated R0 of the outbreak depending on distinct estimation methods and the validity of underlying assumptions. Liu et al. (2020) reviewed all of the 12 references of an estimated R0 ranged from 1.4 to 6.49, with a mean of 3.28 and a median of 2.79. In clinical studies, a 425-case study by 22 January 2020, reported an R0 of approximately 2.2(95%CI, 1.4-3.9) , while another 4021-case study by 26 January 2020, estimated 3.77(95%CI, 3.51-4.05) . The discrepancy may be due to sample number and different stages of the pandemic.

Incubation period is defined as the interval from initial exposure to an infectious agent to onset of any symptoms or signs it causes. A long incubation period may lead to a high rate of asymptomatic and subclinical infection. The first prediction of mean incubation period was 5.2 days (95%CI, 4.1-7.0 days), with the 95th percentile of the distribution at 12.5 days, based on 2019-nCoV exposure histories of the first 425 cases in Wuhan . A 4021-case study reported 4.75 days (interquartile range: J o u r n a l P r e -p r o o f 3.0-7.2 days) . Another 88-exported-case study calculated the mean incubation period to be 6.4 days (95%CI, 5.6-7.7 days), using known travel histories to and from Wuhan and symptom onset dates (Backer et al., 2020) . All these literatures lay the foundation to set 14 days as the medical observation period if any exposure occurred. A latest study collected 1099 cases from 552 hospitals in 31 provinces in China and declared a median incubation period of 3.0 days, ranging from 0 to surprisingly 24.0 days. An adjustments in screening and control policies may be needed. The 2019-nCoV generally has a longer incubation time than SARS-CoV (4.0 days, 95% CI 3.6-4.4 days) (Lessler et al., 2009 ) and MERS-CoV (range 4.5-5.2 days) (Park et al., 2018) .

Serial interval is the interval from illness onset in a primary case to illness onset in the secondary case. The mean serial interval was estimated at 7.5 days(95% CI, 5.3-19days) using contact tracing data from early Wuhan cases in 2019-nCoV pandemic, which was shorter than the 8.4-day mean serial interval reported for SARS (Lipsitch et al., 2003) and 12.6-day for MERS (Cowling et al., 2015) . Another estimation of the mean serial interval from 26 infector-infectee pairs was surprisingly 2.6 days, which was shorter than the median incubation period, suggesting a substantial proportion of secondary transmission before illness onset (Nishiura et al., 2020) .

The CFR in early studies of COVID-19 involving relatively small samples of confirmed cases in Wuhan, varied from 4.3% to 14.6% Huang et al., 2020; , but that may not be able to reflect the truth. The CFR in Wuhan was undoubtedly higher than CFR outside of Wuhan. The reported CFR ranged 1.4%-3.06% in large nationwide case studies .

Prognosis factors such as male, elderly patients aged≥ 60 years, underlying disease, severe pneumonia at baseline and a delay from onset to diagnosis >5 days substantially elevated the CFRs . CFRs in patients with cardiovascular disease, diabetes, hypertension and respiratory disorders were as high as 10.5%, 7.3%, 6.0% and 6.3%, respectively. According to WHO announcement, SARS accounted for 8096 cases and 774 death, with a CFR of 9.6% (WHO, 2004 

Clinical presentation of COVID-19 greatly resembled viral pneumonia such as SARS and MERS. Most cases are mild cases(81%), whose symptoms were usually self-limiting and recovery in two weeks (Wu and McGoogan, 2020) . Severe patients progressed rapidly with acute respiratory distress syndrome (ARDS) and septic shock, eventually ended in multiple organ failure.

General information of four inpatient case studies with relatively comprehensive data were summarized in supplementary table 1. The 2019-nCoV was more likely to infect elderly men with comorbidities. Males were more susceptible to 2019-nCoV infection, same as SARS-CoV and MERS-CoV studies (Badawi and Ryoo, 2016) , due to X chromosome and sex hormones' role on innate and adaptive immunity (Jaillon et al., 2019) . Chronic underlying diseases (mainly hypertension, cardio-cerebrovascular diseases and diabetes) may increase the risk of 2019-nCoV infection , which is similar to MERS-CoV infection (Badawi and Ryoo, 2016) . Smoking may be a negative prognostic indicator for COVID-19 Guan et al., 2020) .

Clinical information of the above four selected inpatient case studies were summarized in supplementary table 2. Onset of symptoms were usually mild and nonspecific, presenting by fever, dry cough and shortness of breath. Very few COVID-19 patients had prominent upper respiratory tract and gastrointestinal symptoms (eg, diarrhea) Huang et al., 2020) , compared to 20-25% of patients with MERS-CoV or SARS-CoV infection developed diarrhea (Assiri et al., 2013) . However, only 43.8% of COVID-19 patients had an initial presentation of fever, and developed to 87.9% following hospitalization , compared to as high as 99% and 98% frequent in SARS-CoV and MERS-CoV infection (Badawi and Ryoo, 2016) . Those patients without fever or even asymptomatic may be left un-quarantined as silent infection source, if the surveillance methods focused heavily J o u r n a l P r e -p r o o f on fever detection. Moreover, the onset of symptoms may help physicians identifying patients with poor prognosis. Patients admitted to the ICU were more likely to report pharyngeal pain, dyspnea, dizziness, abdominal pain and anorexia .

In terms of laboratory findings, a substantial decrease in the total number of lymphocytes could be used as an index in the diagnosis of 2019-nCoV infection, indicating a consumption of immune cells and an impairment to cellular immune function . Non-survivors developed more severe lymphopenia over time . Initial proinflammatory plasma cytokine concentrations were higher in COVID-19 patients than in healthy adults. ICU patients had even higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα compared to non-ICU patients . There were numerous differences in laboratory findings between patients admitted to the ICU and those not, including higher white blood cell and neutrophil counts, higher levels of D-dimer, creatine kinase, and creatine in ICU patients .

Typical chest CT manifestation of COVID-19 pneumonia were initially small subpleural ground glass opacities that grew larger with crazy-paving pattern and consolidation. After two weeks of growth, the lesions were gradually absorbed leaving extensive opacities and subpleural parenchymal bands in recovery patients. However, Guan et al. ( 2020) demonstrated that patients with normal radiologic findings on initial presentation consisted of 23.9% and 5.2% of severe and non-severe cases respectively, which add the complexity to disease control. (Nicholls et al., 2003) . Thrombi were seen in all six autopsies of SARS-CoV infected patients, with even huge thrombus formation in part of pulmonary vessels. Coagulation function disorders were reported in most of the severe COVID-19 patients, by elevated levels of D-Dimer and prolonged prothrombin time, some of whom ended in disseminated intravascular coagulation Huang et al., 2020; . This may explain some sudden death of clinical recovery patients and serve as an indication for disease severity. In an autopsy study, the only one patient without usage of corticosteroids demonstrated increased CD3+ lymphocyte than five other specimen treated by corticosteroids (Pei et al., 2005) . It suggested an inhibition of immune system similarities. The human monoclonal antibody could efficiently neutralize SARS-CoV and inhibit syncytia formation between S-protein and ACE2 expressing cells (Sui et al., 2004) . Appropriate modification of the monoclonal antibody may be effective for treatment of COVID-19. What's more, potential therapies targeting the renin-angiotensin system, to increase ACE2 expression and inhibit ACE may be There are no effective antiviral treatment for coronavirus infection, even the strong candidates as lopinavir/ritonavir and abidol exhibited no remarkable effect on clinical improvement, day 28 mortality or virus clearance (Chen et al., 2020) . Expectation and attention were shifted to "remdesivir" which may be the most potential wide-spectrum drug for antiviral treatment of 2019-nCoV. Remdesivir is an adenosine analogue, which incorporates into novel viral RNA chains and results in pre-mature termination.

It is currently under clinical development for the treatment of Ebola virus infection (Mulangu et al., 2019) . Wang et al. (2020b) revealed that remdesivir were highly effective and safe in the control of 2019-nCoV infection in Vero E6 cells and Huh-7 cells. A successful appliance of remdesivir on the first 2019-nCoV infected case in the United States when the his clinical status was getting worsen, were recently released (Holshue et al., 2020) . Animal experiments also showed superiority of remdesivir over lopinavir/ritonavir combined with interferon-β, by reducing MERS-CoV titers of infected mice and improving the lung tissue damage (Sheahan et al., 2020) . The effectiveness and safety of remdesivir can be expected by the clinical trial lead by Dr Bin Cao.

The 2019-nCoV infection is associated with a cytokine storm triggered by over-activated immune system Xu et al., 2020b) , similar to SARS and MERS. The aberrant and excessive immune responses lead to a long-term lung function and structure damage in patients survived from ICU. Ongoing trials of IL-6 antagonist tocilizumab, which shown effective against cytokine release syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia, may be expanded to restore T cell counts and treat severe 2019-nCoV infection (Le et al., 2018) . The available observational studies and meta-analysis of corticosteroid treatment suggested impaired antibody response, increased mortality and secondary infection rates in influenza, increased viraemia and impaired virus clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors (Zumla et al., 2020) . Therefore, corticosteroid should not be recommended for treatment of 2019-nCoV, or use on severe patient with special caution. A review (Nichol et al., 2003) .

In conclusion, it still remains a challenging task to fight the 2019-nCoV of unknown origin and mysterious biological features, and to control an outbreak of COVID-19 with such a high R0, a long incubation period and a short serial interval, by limited treatment and prevention measures. Lessons learned from the MERS and SARS outbreaks can provide valuable insight into how to handle the current pandemic. The successful public health outbreak response tactics of Chinese government, such as hand hygiene, wearing masks, isolation, quarantine, social distancing, and community containment, can be copied by other countries according to their national situation. As the pandemic is still ongoing and expanding, experiences and research literatures from China and other countries will increase. The 2019-nCoV should be monitored of any possible gene variation of antigenic drift or antigenic conversion, to avoid another round of outbreak. Another lessons from this pandemic will be awe for nature and love for life. Funding Source: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical Approval: The ethical approval or individual consent was not applicable.

All authors declare no conflict of interest. All authors don't have any financial and personal relationships with other people or organizations that could influence our work. 

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CRRT(%) 7 9 1.5 0.8