key: cord-257556-lmws8eed authors: Rafiq, Danish; Batool, Asiya; Bazaz, M. A. title: Three months of COVID‐19: A systematic review and meta‐analysis date: 2020-05-18 journal: Rev Med Virol DOI: 10.1002/rmv.2113 sha: doc_id: 257556 cord_uid: lmws8eed The pandemic of 2019 novel coronavirus (SARS‐CoV‐2019), reminiscent of the 2002‐SARS‐CoV outbreak, has completely isolated countries, disrupted health systems and partially paralyzed international trade and travel. In order to be better equipped to anticipate transmission of this virus to new regions, it is imperative to track the progress of the virus over time. This review analyses information on progression of the pandemic in the past 3 months and systematically discusses the characteristics of SARS‐CoV‐2019 virus including its epidemiologic, pathophysiologic, and clinical manifestations. Furthermore, the review also encompasses some recently proposed conceptual models that estimate the spread of this disease based on the basic reproductive number for better prevention and control procedures. Finally, we shed light on how the virus has endangered the global economy, impacting it both from the supply and demand side. The initial outbreak of the novel coronavirus in December 2019 was centered in Wuhan, Hubei Province of the People's Republic of China. [1] [2] [3] [4] [5] It was initially named as 2019 novel coronavirus, soon after the International Committee of Taxonomy of Viruses (ICTV) named the virus as SARS-CoV-2, 1 because of the previously identified variant-severe acute respiratory syndrome coronavirus (SARS-CoV). The clinical illness it causes is termed as coronavirus disease 2019 . 2 While several other human coronaviruses such as HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1 cause mild respiratory disease, others like the zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV tend to have a higher fatality rate 6 (summarized in Table 1 ). they bear a core shell with surface projections that make them resemble a crown. They were first described by Tyrell and Bynoe in 1966, from patients with the common cold. 9 Four subfamilies of coronaviruses have so far been discovered; • Alpha: Originate from mammals, particularly bats, cause asymptomatic or mildly symptomatic infections • Beta: Originate from mammals, particularly bats, can cause severe disease and fatalities. SARS-CoV-2 belongs to the betacoronaviruses and is closely related to the SARS-CoV virus. 10, 11 SARS-CoV-2 is 96% identical to a bat coronavirus at the wholegenome level. 11 • Gamma and delta: Originate from pigs and birds The genome size of coronaviruses varies between 26 and 32 kb with four major structural genes encoding the membrane glycoprotein (M), spike protein (S), nucleocapsid protein (N), and a small membrane protein (SM) (Figure 2 ). An additional membrane glycoprotein (HE) occurs in the HCoV-OC43 and HKU1 beta-coronaviruses. 12 SARS-CoV-2019 has succeeded in transferring from bats to humans, presumably in the seafood market in Wuhan, China. However, potential intermediate hosts remain to be identified and the precise route of transmission urgently needs to be clarified. Because of the novelty of this virus, experts' understanding of exactly how it spreads is restricted. Major respiratory outbreaks in last century It has also been suggested that the receptor-binding ability of SARS-CoV-2 is 10-20 times stronger than that of SARS-CoV. 15 The patients may move through different stages of illness: • Replicative stage -The virus may take several days to replicate. Initially, it evokes the first line of defence, that is, innate immune response, but this fails to contain the virus resulting in fairly mild symptoms due to direct viral cytopathic effect. • Adaptive immunity stage -The innate immune response is eventually followed by the adaptive immune response which tends to decrease the titer of the virus. Meanwhile, the inflammatory cytokines show augmented levels culminating in tissue damage and consequent clinical deterioration. This explains the sudden deterioration of the patients after being relatively fine for several days. 20 Potentially clinical inferences can be drawn: • Preliminary clinical symptoms are not essentially prognostic of future outcome. • Antiviral therapies need to be given during the replicative stage to work optimally. • It is desirable to deploy any immunosuppressive therapies in the adaptive immune stage to blunt the immunopathologic response. The initial clinical sign of the COVID-19 that allowed its case detection was pneumonia. While some reports suggest gastrointestinal symptoms associated with this disease, others describe asymptomatic infections, particularly among young children. 21 SARS-CoV-2019 may cause lower respiratory symptoms, upper respiratory symptoms, constitutional symptoms, and, less commonly, gastrointestinal symptoms. Most patients show lower respiratory symptoms and constitutional symptoms (eg, cough and fever). • The incidence of fever is variable among studies (ranging from 43% to 98%). This may relate to different strains of virus or different levels of disease severity between several cohorts. Regardless of the frequency, absence of fever in a patient does not exclude COVID-19. • About 80% of patients may have lymphopenia. 22, 23 • Mild thrombocytopenia is very common (but only rarely do platelet counts decline below 100). • Lower platelet count is a marker of poor prognosis. 19 • Also, up to 10% of patients can initially show gastrointestinal symptoms (eg, nausea and diarrhea), followed by dyspnea. 24 • Some patients, especially the elderly, may have "silent hypoxemia" and respiratory failure without dyspnea. 25 • Approximately, 2% of patients may develop pharyngitis or tonsil enlargement. 22 3 | TRANSMISSION AND MANAGEMENT Typical of respiratory viruses like influenza virus, SARS-CoV-2019 can spread through large droplets (with a transmission risk restricted tõ 6 ft from the patient). 26 The droplet containing viral particles (saliva or mucous droplets) can be ejected during coughing, sneezing, laughing, singing, breathing, and talking. If these droplets do not encounter anything along the way, they typically land on the ground or the floor. This transmission via large droplet can be reduced by using a normal surgical-style mask. This mode of transmission is usually overlooked, but it is very important. It works in four chains of reactions: There are currently no reports of intrauterine maternal-fetal transmission, but neonatal transmission can occur. 29 Research thus far has revealed more than 30 agents including natural products, western medicines, and traditional Chinese medicines with potential efficacy against COVID-19. Some promising results have been achieved which are summarized below and listed in Table 2 , but formal randomized clinical trials will be required to prove efficacy and safety. Lopinavir and ritonavir are protease inhibitors that work in conjunction to block viral replication. Ritonavir, being a CYP3A inhibitor, reduces the metabolism of lopinavir, thus boosting its levels. A 4 ug/mL concentration of lopinavir was required for in vitro antiviral activity against SARS while 1ug/mg of lopinavir was enough when used in combination with ribavirin. 30 Both protease inhibitors appear to function synergistically with ribavirin. Combination of all three drugs has been used previously on SARS and MERS. 30 Recently, the combination of lopinavir/ritonavir has not proven impressive, suggesting that a cocktail of ribavirin/lopinavir/ritonavir might be required for efficacy. 20 Nevertheless, lopinavir/ritonavir is advantageous over ribavirin because of its wide availability and an established toxicity profile. Originally developed for Ebola, this drug was the most obvious fit for SARS-CoV-2019 as it has already been tried out for ssRNA viruses like SARS and MERS. 31 Remdesivir is a prodrug whose phosphoramide is cleaved off to leave the active compound GS-44-1524 with a 5 0 OH. Chloroquine, generally used for amebiasis and malaria, is currently being considered for treating COVID-19 in view of its ability to interfere with the cellular receptor ACE2. It also impairs the acidification of endosomes, thereby impeding virus trafficking inside cells. Although chloroquine has been unsuccessful in treatment of SARSinfected mice, 37 recent reports from in vitro data show that chloroquine inhibits SARS-CoV-2 at a 50% inhibitory concentration of 1 uM. This suggests the possibility of achieving therapeutic levels in humans. 38 It is worth mentioning that for SARS, the 50% inhibitory concentration of chloroquine is near to 9 uM, 39 Several other potential drugs include BCR-ABL kinase inhibitor imatinib and Type-II transmembrane serine protease (TMSPSS2) inhibitors. 44 Imatinib inhibits the fusion of virions with the endosomal membrane and as such possesses anti-coronavirus activity. 45 ple. 47 The interpretation of the results is given in Table 3 . The presence of SARS-CoV-2 viral proteins (antigens) in a sample from the respiratory tract of a person can also be detected within Considering P as the total population, it is assumed that the susceptible population (S) is stably decreasing at a protection rate (α) and moving to compartment (S q ) that represents the quarantined individuals. Those who are not quarantined and come in contact with infected persons belong to the compartment exposed (E) depending upon the transmission rate (β). An exposed individual, if protected from being infected (eg, by using protection of face mask or hand sanitizers) will move back to the susceptible (S) compartment at the safety rate (μ). The exposed individuals can get infected and move either to infectious and symptomatic (I) or infectious but not yet symptomatic/presymptomatic to (A) compartment depending upon the average latent time (γ − 1 1 ) and (γ −1 2 ), respectively. The infected individuals can be detected and then hospitalized at a rate δ. From compartment (H), the patients can also move to the compartment recovery (R) at cure rate Λ(t) or die at mortality rate κ 1 (t). However, the recovered persons are added back to the susceptible compartment (S) at a rate θ. It is important to mention that a percentage of people, though less, die in presymptomatic phase before being hospitalized. They also add to the death compartment at rate κ 2 (t). The SEIR model described above can be modeled by a set of ordinary differential equations (ODEs) given as follows: These nonlinear coupled ODEs can be solved using an explicit/ implicit time stepping integrating scheme like the regular fourth-order Runge-Kutta scheme. 56 In the past 3 months, various mathematical models have estimated • Later an updated estimation risk has been shown 59 that included calculating the time-dependent contact and diagnosis rates. from a period of January 1, 2020 to February 7, 2020. • The authors have argued that the estimation of R o mainly depends on the estimation technique involved and the modeling assumptions used. • Both deterministic and stochastic models were included in the study. • The study showed that the maximum-likelihood (ML) value of basic reproductive number (R 0 ) was 2.28 at an early stage on the ship for the COVID-19 outbreak. • It was shown that if (R 0 ) value was reduced by 25% and 50%, the • The value of (R 0 ) was estimated using the next-generation matrix approach which came out to be 2.30 for reservoir to person and 3.58 for person to person. of COVID-19 is presented in this study along with some useful insights from these models. • Also, a Susceptible-Exposed-Infected (SEI) model framework was presented, and auxiliary strategies were described to prevent the COVID-19 outbreak. The study showed that exposure time plays a significant role in spreading the disease. • The data were used for estimation of basic reproduction number using a Susceptible Infected Recovered Dead (SIRD) framework. • The estimated average value of R 0 was~2.6 based on confirmed cases. The plot for the estimated value of the (R 0 ) obtained by the above-mentioned studies is shown in Figure 4 . The plot shows a high reproductive number at the beginning of the outbreak in China with the maximum peak in mid-January 2020. However, with passage of time, social distancing, self-quarantine, health care measures, and governmental actions had a substantial effect in containing the outbreak which is evident from the estimates of the (R 0 ) in the months of February and March, 2020. It is pertinent to mention that the estimates of the basic reproductive number mentioned in the above studies can be poor due to insufficient data, and different estimation techniques can result in different forecasts. However, further collection of data with robust modeling can result in close estimates. Viral spread has borne out experts' downside fears, with consequences of possible containment measures, disrupted supply chains, and spill overs from the real economy to monetary markets. 75 This overview provides the basic, biomedical, and translational research communities some key insights on COVID-19. We believe that the focus of future studies still lies in the progress of effective drugs in general and development of SARS-CoV-2 vaccines in particular. While uncertainty lingers, credible, coordinated, and coherent policy responses would deliver the best chance at limiting the fallout from this human tragedy. Time alone can tell how the virus is going to affect our lives, but future outbreaks of pathogens of zoonotic origin and viruses are likely to continue. As such, besides curbing this epidemic, efforts should be implemented to devise inclusive measures to avert future outbreaks of zoonotic origin. Though the virus has reshaped the geopolitical globalization, multilateralism and integration of countries are indispensable. Without a doubt, we must move toward policy making and greater coordination to combat the current health crisis. 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Three months of COVID-19: A systematic review and meta-analysis The authors declare no conflicts of interest. Danish Rafiq and Asiya Batool collected the data and wrote the manuscript, M. A. Bazaz analyzed the data and helped in critical analysis and proof reading of the manuscript. Not required. https://orcid.org/0000-0002-9232-4875