An Overview of the Epidemiologic, Diagnostic and Treatment Approaches of COVID-19: What do We Know?

Abstract

Background: In late December 2019, a new infectious respiratory disease (COVID-19) was reported in a number of patients with a history of exposure to the Huanan seafood market in China. The World Health Organization officially announced the COVID-19 pandemic on March 11, 2020. Here, we provided an overview of the epidemiologic, diagnostic and treatment approaches associated with COVID-19.

Methods: We reviewed the publications indexed in major biomedical databases by December 20, 2020 or earlier (updated on May 16, 2021). Search keywords included a combination of: COVID-19, Coronavirus disease 2019, SARS-CoV-2, Epidemiology, Prevention, Diagnosis, Vaccine, and Treatment. We also used available information about COVID-19 from valid sources such as WHO.

Results and Conclusion: At the time of writing this review, while most of the countries authorized COVID-19 vaccines for emergency use starting December 8, 2020, there is no a definite cure for it. This review synthesizes current knowledge of virology, epidemiology, clinical symptoms, diagnostic approaches, common treatment strategies, novel potential therapeutic options for control and prevention of COVID-19 infection, available vaccines, public health and clinical implications.

Background

Coronaviruses are a group of viruses that can cause respiratory infection in humans [1]. These viruses were discovered in 1966 by Tyrell and Bynoe, who cultured the viruses from common cold patients [2]. Because of their morphology as sphere-shaped viruses with a core-shell and surface projections similar to a corona (meaning “crown” in Latin), they are named coronaviruses [3, 4]. These viruses are members of the subfamily Coronavirinae in the family Coronaviridae and the order Nidovirales. This subfamily includes four groups: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Figure 1). The Alpha and Betacoronaviruses infect just mammals. Although Gamma and Deltacoronaviruses infect birds, some also may infect mammals [5]. Alpha and Betacoronoviruses are usually associated with human respiratory disease and gastroenteritis disorders in animals. Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe acute respiratory syndrome coronavirus (SARS-CoV) are the most pathogenic viruses which cause the intense respiratory syndrome. The other four human coronaviruses cause mostly mild to severe respiratory illnesses, (i.e. HCoV-229E, HCoV- NL63, HKU1, and HCoV- OC43) [1, 6, 7].

FIGURE 1

On New Year’s Eve 2019, a new, human-infecting coronavirus was reported in some patients with a history of contact with the Huanan seafood market, in Hubei Province, China [8]. This outbreak spurred Chinese scientists to sequence the genome of this virus immediately and raised concern about the link between this virus and wildlife, most likely from bats or pangolins, although a slew of genetic analyses has yet to find definite proof [8, 9]. Using next-generation sequencing, they reported that this virus belongs to B lineage of the Betacoronaviruses and is associated with the SARS-CoV [8, 10]. At first, the virus taxonomy was called 2019-nCoV, but, on February 11, 2020, the International Committee on Taxonomy of Viruses officially renamed the novel coronavirus responsible for the current pandemic of coronavirus disease (aka., COVID‐19), severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) [10]. Therefore, the virus is referred to as SARS-CoV-2, and the associated disease as COVID-19. At the time of last revision for this article (May 16, 2021), more than 162 million cases were reported globally with over 3.3 million deaths from 223 countries, areas or territories, mostly from the United States, India, Brazil, France, Turkey, Russia, United Kingdom, and Italy [11, 12]. As of May 12, 2021, a total of 1,264, 164, 553 vaccine doses have been administered, mostly in developed countries [11, 12]. Given the novelty and the lack of knowledge regarding the current pandemic of COVID-19, here we reviewed the existing evidence on epidemiologic, diagnostic, and treatment approaches of COVID-19.

Virology

The 2002–2004 SARS-CoV is a Betacoronavirus which first emerged in China and infected >8,000 people, leading to 774 deaths in 37 countries around the world [13, 14]. The MERS-CoV was known for the first time in Saudi Arabia in 2012 and resulted in 2,494 definite cases of infection and 858 deaths since September 2012 [15–17]. The receptor which SARS-CoV utilizes for contaminating type II pneumocytes and ciliated bronchial epithelial cells is angiotensin-converting enzyme 2 (ACE2) [18–20], while MERS- CoV employs dipeptidyl peptidase 4 [21] (DPP4) receptor and contaminates type II pneumocytes and unciliated bronchial epithelial cells [22–24]. SARS-CoV and MERS-CoV were spread to individuals from market civets and camels, respectively, and both of them are suspected of originating in bats [25–31]. Figure 2 displays the SARS-CoV-2 genome structure and virion.

FIGURE 2

SARS-CoV-2 is a single-stranded, sense positive RNA virus in length around 26–32 kb with a diameter of 60–140 nm [32]. The membrane of the virus comprises the transmembrane glycoprotein (M), spike glycoprotein (S), envelope protein (E), and a flexible nucleocapsid [33, 34]. Coronaviruses have a minimum of six open reading frames (ORFs). ORF1a/b is the first which contains around two-third of the genome and codes replica proteins. The 3′-end of the genome codes structural proteins with a set of additional proteins that are exclusive for each virus species. Coronavirus cell entrance occurs by binding the S protein to a certain receptor on the cell surface, subsequent fusion is facilitated by the target cell membrane, and finally, the virus nucleocapsid enters the cell for later replication [35]. Some studies indicate that COVID-19 uses ACE2 as its receptor-like SARS-CoV, suggesting that this virus can share a similar life cycle with SARS-CoV [4]. The clinical analysis showed that the S protein of SARS-CoV-2 binds 10- to 20- fold higher affinity than the S protein of SARS-CoV to ACE2. This high affinity may explain the ease by which SARS-CoV-2 can spread among the human populations [36]. Moreover, it has been confirmed that SARS-CoV-2 shares 96% nucleotide identity with the complete genome sequence of the bat coronavirus. However, attempts to recognize intermediate hosts await future research to elucidate [4]. The physicochemical features of SARS-CoV-2 have not been defined completely yet. It is reported that SARS-CoV-2 is sensitive to heat, lipid solvents like 70% ethanol, and UV radiation [37].

In a recently published study, genetic analysis was performed on 103 genomes of SARS-CoV-2 and the results indicated that SARS-CoV-2 developed into main types, L and S. These two types are defined by two single-nucleotide polymorphism (SNP) which demonstrated nearly complete linkage across SARS-CoV-2 strains. Also, the evidence proved that type L (70%) was more prevalent and aggressive than type S, but human interference probably shifted the abundance of L and S type after the outbreak of SARS-CoV-2 [38]. Nevertheless, as highlighted by authors of this study, it is pivotal to further investigate combine genomic and epidemiological data, and chart records of the clinical symptoms of patients infected by SARS-CoV-2.

Epidemiology

Understanding of the epidemiology of COVID-19 is evolving since its first report to the Country Office of WHO in China on December 31, 2019 [39]. The exponentially increasing number of confirmed cases and deaths reported from China and beyond spurred WHO to declare a Public Health Emergency of International Concern on January 30, 2020, which was later upgraded to a declaration of COVID-19 pandemic on March 11, 2020 [40].

Symptoms of SARS-CoV-2 differ in some respects from other betacoronavirus, (e.g. SARS-CoV, MERS-CoV). For example, unlike SARS-CoV and MERS-CoV, SARS-CoV-2 spreads rapidly [41]. Surprisingly, this virus can infect and actively reproduce in the upper respiratory tract given that its close genetic relative, SARS-CoV, lacks this ability [42]. Moreover, whereas COVID-19 patients present intestinal symptoms like diarrhea only a low percentage of SARS-CoV or MERS-CoV patients exhibited these symptoms (Table 1) [43, 44]. However, a recent study in the New England Journal of Medicine [45], concluded that the stability of SARS-CoV-2 is comparable to that of SARS-CoV under clinical conditions. The authors suggest that dissimilarity in the epidemiologic features of these two viruses arise from other aspects such as high viral loads in the respiratory tract and the potential for asymptomatic individuals to shed and transmit the virus to other people. These features facilitate the transmission of the virus during daily activities and interactions between people. Given these characteristics, and to protect the population’s health and slow the rate of transmission of COVID-19, while waiting for vaccines to reach all over the globe, WHO and public health experts are urging several simple mitigation strategies, (e.g. face-covering masks, social distancing, and cleaning hands with an alcohol-based hand rub or washing them with soap and water) to combat COVID-19 pandemic [46–49].

Although understanding COVID-19 transmission risk is in its infancy, as the outbreak progressed, human-to-human spread was identified as the main mode of transmission [50]. The United States Centers for disease Control and Prevention (CDC) report shows that the major route of transmission of this virus is through respiratory droplets generated when an infected individual coughs or sneezes [51]. Additional evidence shows that close social interaction and touching the eyes, nose, or mouth with a contaminated hand, are sources of transmission [50, 52]. Whether transmission may happen via mother-infant or breast milk is not fully known yet [37]. For example, WHO scientific report (June 23rd, 2020) highlighted that the data are not enough to conclude vertical transmission of COVID-19 through breastfeeding [53]. Also, as of May 13, 2021, the United States Center for disease Control and Prevention (CDC) maintains that breast milk is not likely to spread the SARS-CoV-2 to babies [54]. A comprehensive review article published in the International Breastfeeding Journal on September 14, 2020, concluded that breastfeeding must be encouraged, mothers and newborns dyads should be cared for together, and skin-to-skin contact ensured throughout the COVID-19 pandemic [55]. Nevertheless, an earlier study from China concluded that vertical maternal-fetal transmission cannot be ruled out since three of 33 infants (9%; in their study sample) presented with early onset SARS-CoV-2 infection [56]. They suggested that it is critical to screen pregnant women and implement strict infection control procedures, quarantine mothers who are COVID19 positive, and closely monitor neonates at risk of COVID-19 [56]. Moreover, a recent case study concluded that transplacental transmission of SARS-CoV-2 infection is possible during the last weeks of pregnancy [57]. Although future longitudinal studies are warranted to better understand mother-to-child transmission, US CDC recommends sevral precautions while newborn is rooming-in with infected mother in the hospital [54]; they include wearing mask, washing hands with soap, keeping newborn more than 6 feet away from mother as much as possible, and using a physical barrier, (e.g. placing the newborn in an incubator).

As discussed earlier, the number of confirmed cases is increasing exponentially worldwide. As shown in Table 2, according to the WHO, as of May 16, 2021, the top 10 countries that are contributing to the ongoing global pandemic of COVID-19 reported case fatality rate (CFR) between 0.87% in Turkey to 2.99% in Italy, with global CFR of 2.07% (Table 2) [12, 40]. In comparison, the 2002–2004 outbreak of SARS had a CFR of around 10%, while MERS killed 34% of infected people between 2012 and 2019 [58].

Clinical Manifestation

According to the existing evidence, the incubation period for COVID-19 varies from 2 to 14 days with a median of ∼5 days, which is similar to SARS [37, 61–65]. The most important clinical symptoms of the disease are fatigue, fever, and dry cough. Regardless of the atypical symptoms that were reported, fever was cited as the typical sign of COVID-19 infection (Table2) [66]. The disease severity ranges from mild self-restricting flu-like ailment to fulfillment pneumonia, respiratory failure, and death.

As reported by WHO [12], 80% of COVID-19 infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. Risk of acquiring virus and severity of COVID-19 differs by sex, age, and other factors such as severe obesity [67, 68]. A study based on publicly released data from 1,212 confirmed patients infected with COVID-19 in Henan of China, showed that a majority of infected cases were among males (55% vs. 45%) [69]. The results highlighted two probable factors that lead to this gender difference including 1) The high expression and distribution of COVID-19 receptor (ACE2) in male patients and 2) The tendency for males to engage in wider social activities than females [69]. Additionally, the reduced vulnerability of women to COVID-19 infections may be related to the protection from sex hormones and X chromosome, which have a key function in immunity [70]. Nevertheless, to explore more precise gender differences of COVID-19, future studies are warranted. A recent retrospective cohort study of 6,916 patients with COVID-19 in the US, found severe obesity as a profound risk for death from COVID-19, particularly in male patients and younger populations [67]. Severe obesity is an intractable problem in the United States and many western nations and little likely can be done in the short-term to reduce its effects on COVID-19 progression except to recognize the increased risk of obesity and target obese patients early for stepped up care.

Presentation of COVID-19 in children presents somewhat differently from adults. Although earlier in the pandemic it was recognized that children have milder symptoms (compared to adults) and are less likely to be hospitalized [71], several studies reported a multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 [72–74]. Available data by the American Academy of Pediatrics shows that, as of May 6, in 46 states of United States, over 3.85 million children have tested positive for COVID-19 since the onset of the pandemic, and children represented 14.0% of all cases in the Unites States by May 6, 2021 [75]. Although children were 0%–0.4% of all COVID-19 deaths, and 19 states reported zero child deaths, the United States CDC’s report highlights that children are at risk for severe COVID-19 and public health authorities and clinicians should continue to track pediatric COVID-19 infection [76].

Strategies in COVID-19 Diagnosis

The United States CDC recommends the collection of specimens for COVID-19 examination from the respiratory tract [70]. Other specimens such as urine or stool can also be collected for diagnostic purposes. Following collection, specimens are tested in the form of reverse transcription-polymerase chain reaction (RT-PCR), which can determine results in 4–6 h [79, 80].

Health providers collect serum samples for COVID-19 that may show virus spreading from the infected lung into the blood circulation, as formerly observed in SARS patients [81]. However, in the first infected case in the United States, it was reported that the stool and respiratory specimens were positive by RT-PCR for COVID-19, while the serum examination was negative [82]. Notably, in some patients, the ground-glass opacity (GGO) variations on CT scan revealed earlier than the positive for RT-PCR test [83, 84]. Thus, repeating sputum or nasopharyngeal swab test are suggested in suspected cases with an initially negative lab result taken from these samples [82, 85–87].

Laboratory Examinations for COVID-19 Infection

In the disease initial phase, the white blood cell (WBC) count in COVID-19 patients can vary [88]. For example, leukopenia, leukocytosis, lymphopenia, and increased aminotransferase levels have been reported previously, although lymphopenia (lymphocyte count of less than 1.5 × 10⁹/L) seems most common [88–93]. It has been proposed that in disease early stage, the total amount of leukocytes is reduced or normal, monocytes amount is normal, and lymphocyte amount is decreased in peripheral blood [94]. Also, prolonged activated thromboplastin time (aPTT), increased muscle enzyme level and C-reactive protein (CRP) have been shown [66]. When the lymphocyte absolute value is less than 0/8 × 109/L, or the amounts of CD8+T and CD4⁺ cells are meaningfully reduced, high attention must be done that mostly suggested re-checking these indicators after 3 days [66]. Some investigations propose that a considerable reduction in the amount of lymphocytes shows that coronavirus targets immune cells and hinders the usual cellular immune function. Impairment in T lymphocytes can be a significant factor that leads to exacerbations of disease [70].

There are additional laboratory analyzes for the COVID-19 infection, such as renal and liver function test, blood gas examination with the increased level of lactic acid used for screening the cases with high-risk of oxygenation disorder, erythrocyte sedimentation rate (ESR), myocardial enzyme, myoglobin, Procalcitonin (PCT) for distinguishing bacterial infection in the lung, coagulation image, D-dimer, inflammatory factors, urine routine test, and anti-acid staining [66].

Bronchoalveolar lavage (BAL) is not recommended for the majority of patients because it increases the risk of infection. BAL can be considered, however, for cases that have noticeable signs of refractory massive atelectasis and airway obstruction that could not be returned by conservative treatments [37].

Some Alternative Diagnostic Methods

COVID-19 diagnostic tests are widely available in a variety of types; however, most countries are still struggling with the management of pandemic [95]. Several novel techniques, including next generation sequencing, loop mediated isothermal amplification, and lateral flow tests are in different stages of validation [96, 97]. Each has benefits and drawbacks, so the best option depends on the intended use. Lateral flow tests designed to detect only infectious cases, can be easily scaled up for decentralized testing, inexpensive, and do not need laboratories [98]. On the other hand, they are less sensitive than RT-PCR, and very susceptible to poor sampling [98, 99]. When it comes to the affordability, accuracy, accessibility, and rapidness of results, no test is flawless. If the COVID-19 pandemic progresses, diagnostic methods may need to be optimized. Risk reduction strategies will aid in ensuring that research outcomes are reliable enough to provide adequate treatment at the patient level, as well as providing sound evidence to inform public health action to interrupt the transmission of the virus [95].

Imaging Examination (CT Imaging)

Radiological analyses play a vital role in the diagnosis and control of COVID-19. As shown in Figure 3, the imaging results change with the patient’s age, disease stage, immunity status, drug interventions. The imaging findings can show the distribution, quantity, shape, and density of the lesions [66].

FIGURE 3

Stage of the Disease Based on CT Image

While chest CT scan results are not specific for COVID-19 diagnosis, CT results have been suggested as the main confirmation of medical diagnosis of this infection [100]. A study that initially performed an RT-PCR test, and in the case of a negative result repeated testing at intervals of 1 day or more, found that chest CT scans had greater sensitivity for diagnosis compared with initial RT-PCR from respiratory specimens ((98% vs. 71%, respectively; p < 0.001) [101]. To date, chest CT scan and RT-PCR remain the most common and available first clinical options in diagnosing COVID-19 infection worldwide [100].

Treatment Approaches for COVID-19 Infection

In the current situation, controlling the infection is the best way to tackle the pandemic of SARS-CoV-2 [102]. Some non-pharmaceutical strategies, including early diagnoses, isolation, and supportive treatments and protective measures, (e.g. wearing masks, improving personal hygiene, and keeping rooms ventilated) can efficiently break the SARS-CoV-2 transmission chain [103].

Analysis of the SARS-CoV-2 RNA genome indicated that this virus has differences in sequence. These differences are typically single nucleotide variations. The preliminary data from samples suggest that SARS-CoV-2 is actively evolving through various mutations which can lead to a major challenge in developing effective drugs and vaccines [106].

At the time of writing this review, no definite cure has been provided for COVID-19. Some drugs, however, are prescribed by health providers, such as nucleoside analogs, lopinavir/ritonavir (LPV/r), umifenovir (Arbidol), neuraminidase inhibitors, remdesivir, DNA synthesis inhibitors (like Disoproxil, tenofovir, and Lamivudine), Hydroxychloroquine/Chloroquine (HCQ/CQ), and favipiravir [107, 108]. There are some positive reports that these antiviral drugs may have clinical efficacy against COVID-19 [109].

For patients with severe signs, antibiotics (Tazobactam sodium, Moxifloxacin, Piperacillin sodium, and Meropenem) and methylprednisolone (1–2 mg per kg weight per day) also have been utilized, according to the physicians’ decision [70]. In low immune function cases, like diabetics, older people, HIV infected persons, individuals with long-term use of immunosuppressive drugs, and pregnant women, early prescribing of antibiotics to inhibit infection may decrease morbidity and mortality [70].

Since the start of the COVID-19 pandemic, corticosteroid use has been the subject of debate.

Previously, it has been recommended that immune-modulating drugs such as corticosteroids be utilized in some special situations, including: in quickly deteriorating chest imaging and ARDS, in encephalitis, hemophagocytic, septic shock, and in apparent wheezing symptoms. Intravenous methylprednisolone (one to two mg/kg/day) usage is suggested for 3–5 days [37, 110].

However, according to the latest evidence corticosteroids do not appear to play a main role in treatment of ARDS [111, 112]. Despite improved cardiopulmonary physiology, routine use of methylprednisolone for persistent ARDS is not recommended [112].

According to a meta-analysis of COVID-19 patients, mortality was higher among patients receiving corticosteroids than among patients who were not receiving corticosteroids [113]. In contrast, a cohort study of 1444 COVID-19 patients found that treating with corticosteroids had no effect on hospital mortality [114]. As a result, corticosteroids seem to be a double-edged sword in the battle against COVID-19 and should be used cautiously, considering the risk–benefit ratio [115].

These recommendations are supported by WHO guidance suggesting that corticosteroid regimens should not be routinely used in the treatment of COVID-19 except in certain scenarios such as treatment of exacerbated asthma attacks, COPD, or septic shock [110, 116].

An Overview of Selected Repurposed Drugs

Remdesivir, a nucleotide analog prodrug, was initially developed by an American biotechnology company Gilead Sciences against the Ebola virus. It has been shown to have potential as an anti-viral drug for SARS-CoV-2. Evidence from a small cohort showed clinical improvement in 68% of patients treated with remdesivir [117]. The United States NIH reported that patients in the remdesivir group showed a 31% faster recovery time compared to those in the placebo group [118]. So, remdesivir could have a considerable impact on healthcare capacity by reducing the length of time in hospital [119, 120].

Previous studies indicate the combination of lopinavir/ritonavir (HIV protease inhibitors) can be helpful for MERS-CoV and SARS-CoV infected cases [121, 122]. While LPV/r has been shown to be effective in patients infected with SARS-CoV [121, 123], but it showed less potent than other antiviral drugs such as remdesivir and Chloroquine [124]. In a study involving 199 COVID-19 patients, LPV/r failed to decrease mortality and viral load [125]. Therefore, it is challenging to determine if the LPV/r can play an effective role in dealing with COVID-19 [126].

Hydroxychloroquine/Chloroquine (HCQ/CQ) are anti-malarial drugs, but also have been suggested as promising agents against the COVID-19 [127]. HCQ/CQ showed in vitro activity for SARS-CoV-2 with an EC50 value of 23.90 and 6.14 μM [128, 129]. However, there are inadequate data to support the use of HCQ/CQ as therapeutic agents in COVID-19. The evidence demonstrated significant virologic clearance in the HCQ group and also the HCQ plus Azithromycin group showed considerably better virus clearance [130, 131]. A recent study on 96,000 patients indicated an increased incidence of ventricular arrhythmias in patients who treated with Hydroxychloroquine or Chloroquine [132]. Likewise, the United States Food and Drug Administration (FDA) has warned against using of HCQ/CQ as a therapeutic agent for COVID-19 because of the risk of Adverse Drug Reactions (ADR) [133]. Additionally, a multicenter, randomized clinical trial among 504 hospitalized patients with suspected or confirmed COVID-19 who were receiving either no supplemental oxygen or a maximum of 4 L per minute of supplemental oxygen, found that the use of Hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care [134]. It is pivotal to know that Hydroxychloroquine has the potential for cardiac toxic effects and overall adverse consequences have been emphasized, especially in people with underlying coexisting conditions that increase the risk of severe COVID-19 [135].

Favipiravir is an anti-viral drug that inhibits RNA-dependent RNA polymerase (RdRp). It is used for treating Influenza [136, 137]. The in vitro activity of it was shown against SARS-CoV-2 [129]. Favipiravir has been proved for use in patients with COVID-19 in some countries such as Russia and China [138, 139]. However, favipiravir did not show a noteworthy benefit in infected cases in a trial in Japan [140].

Convalescent Plasma Therapy

In CPT, plasma donated by people who have recovered from COVID-19, the donated plasma is transfused to patients who are ill, so their antibodies will help in overcoming the virus. Studies on patients with COVID-19 showed clinical improvements after CP therapy [141–144]. Recently it has been shown that transfusion of CP is safe and does not have adverse effects on COVID-19 patients also reported a reduction of mortality [145, 146]. The main problem for large-scale plasma therapy is finding donors with high levels of antibody titer (>1:640) [142]. Evidence indicated that neutralizing antibodies reduced quickly after four months of the recovery [147]. This transient immune response recommends that plasma from freshly recovered cases is more efficient for CPT. Still, more investigation is required to know about the concentration and type of neutralizing antibodies in order to protect against the virus [148, 149].

Monoclonal Antibodies for Treating SARS-CoV-2 Infection

Monoclonal antibodies (mAbs) can be obtained from laboratory preparation or by COVID-19 patients. Numerous mAbs are approved by the FDA to treat different disorders such as cancer [148]. Moreover, few monoclonal antibodies are utilized for treating SARS-CoV-2 like tocilizumab [150–152], bevacizumab [153, 154], etc [148].

ACE2, Spike proteins, and their interactions are the key targets for developing novel therapeutic monoclonal antibodies [155–157]. Different neutralizing mAbs are tested against SARS-CoV including m396, CR3022, CR3014, 80R, B1, 68, 201, 5E9, and 1F8, these antibodies could have a critical therapeutic function in SARS-CoV-2 infections [155, 158, 159]. A summary of some of the therapeutic agents that have been applied for COVID-19 treatment was demonstrated in Table 5.

COVID-19 Vaccines

Vaccination is one of the most important strategies and among the safest medical products to prevent infectious diseases from spreading nationally and internationally. The exponentially increased number of patients in the first days of this pandemic triggered intense global research and development activities to use several technologies including protein subunit, viral-vectored, nucleic acid (DNA, RNA), live attenuated and inactivated vaccines with some entering clinical trials to develop a safe and efficient vaccine against this novel disease [160]. According to the up-to-date list by the WHO [161], as of May 14, 2021, more than 180 COVID-19 vaccines were being in the preclinical development and 100 were in clinical development across the globe.

Companies such as BioNTech and Pfizer developed mRNA vaccine BNT162 against COVID-19 [162]. They found the efficacy rate of the vaccine nearly 95%. It has been revealed that two weeks after the first dose, the vaccine started protecting, and the second dose, three weeks later, enhanced the immune response of the volunteers [163]. On December 11, New York-based Pfizer and the German company BioNTech got the first emergency use authorization from the FDA for COVID-19 vaccine [163]. Despite its early vaccination process, on December 19, 2020, the United States CDC reported some people have experienced severe allergic reactions—also known as anaphylaxis—after receiving a COVID-19 vaccine [164]. CDC recommends that “People with a history of severe allergic reactions should be monitored for 30 min after getting the vaccine, while all other people should be monitored for 15 min after getting the vaccine.” [164].

Moderna, an American biotechnology company based in Cambridge, Massachusetts developed the mRNA-1273 vaccine against SARS-CoV-2, which produced by mRNA technology. For mRNA-1273 vaccine, a phase 1 study of eight participants reported in May 2020, showed a higher immunocompatibility similar to those seen in patients formerly infected with COVID-19 [165–170]. On June 11, Moderna announced that the cohort of healthy younger adults ages 18–55 (n = 300) and the sentinel group of older adults ages 55 years and older (n = 300) in the phase 2 study of mRNA-1273 was completed [171]. Moderna has started its phase 3 trial with 30,000 volunteers in conjunction with the Unites States National Institute of Allergy and Infectious Diseases (NIAID) Moderna has declared that the vaccine had an efficacy rate of 94.1% [163, 165–170]. On December 18, 2020, the United States FDA authorized Moderna Vaccine for emergency use in the United States a week after authorizing BNT162 [172]. In addition, the United States-based company Novavax is developing the recombinant vaccine NVX-CoV2373 as a stable, perfusion protein advanced by the nanoparticle technology [173]. They put the genetic code for the spike protein into the genome of yeast or bacterium, so it can produce a large amount of protein [174].

The ChAdOx1 nCoV-19 vaccine that was developed by the University of Oxford containing the full-length sequence of COVID-19 spike protein [175–177] with acceptable safety profile [178], gained authorization for emergency use in the United Kingdom, and 90 year-old Margaret Keenan was the first person to get vaccinated on December 8 [179].

INOVIO has developed the DNA plasmid vaccine as an INO-4800. The company has established such platforms for MERS and SARS viruses [180]. This approach needs a delivery system through electroporation, which will increase the cost of the vaccine [180]. A lately study in The Lancet announced a new effective vaccine for SARS-CoV-2 named PittCoVacc, established by University of Pittsburgh [181]. PittCoVacc utilizes S-protein fragments of SARS-CoV-2 for stimulating the production of antibodies. PittCoVacc is delivered with a method identified as microneedle array, a fingertip-sized patch of 400 small needles. This approach can cause more immune responses than conventional subcutaneous injection and has been proved to be sufficiently safe [182].

On July 11, 2020, Russian President Vladimir Putin announced that Russia had become the first country to approve a COVID-19 vaccine (called “Sputnik V”) [183]. Although some researchers warned about Russian’s rushed decision [183, 184], a most recent interim analysis of the phase 3 trial of Gam-COVID-Vac among adults aged 18 years or older that was published in The Lancet demonstrated 91·6% efficacy against COVID-19 [185]. A summary of developed vaccines is presented in Table 6. A most recent data released on May 15 by Italian scientists shows that COVID-19 infections in adults fell by 80% five weeks after receiving a first dose of Pfizer, Modernaor AstraZeneca vaccines [186]. This might be higher after second dose of the vaccin and awaits further studies to explore.

Serological tests to detect specific antibodies for the SARS-CoV-2 are under development [187]. These tests can help identify individuals who have been infected and developed immunoglobulin M (IgM) and/or immunoglobulin MG (IgG) antibodies that may protect from potential future infection (post-infection immunity) [188, 189] as well as identify those who remain at risk through human leukocyte antigen A [HLA-A], -B, and -C genes [190].

Since IgM antibodies in infected patients may not develop early or at all, this type of antibody test cannot rule out SARS-CoV-2 in an individual. A recent clinical trial of 36 patients with COVID-19 infection and 42 patients with other viral respiratory infections which were published in the Nature Biotechnology reported that the clustered regularly interspaced short palindromic repeats (CRISPR)-based detector essay provides a visual and faster alternative to the United States CDC SARS-CoV-2 real-time RT–PCR assay, with 95% positive predictive agreement and 100% negative predictive agreement [191]. Even with these positive reports concerning antibodies, the majority of scientists believe that most of the antibody tests that were released to the market without appropriate scrutinize and reviews are not accurate enough to confirm whether an individual has been exposed to the virus [192]. Therefore, to understand the full effectiveness of these antibodies, for future large clinical trials and a comprehensive review with governmental agencies are warranted.

Emerging SARS-CoV-2 Variants

On September 2020 Public Health authorities in South East region of England detected a new SARS-CoV-2 variant as a lineage B.1.1.7, aka Variant of Concern 202,012/01 (VOC-202012/01), 20I/501Y.V1, or more commonly known as the British variant or United Kingdom variant [193]. Seventeen mutations in the viral genome occurred in this variation, eight of which are localized in the spike (S) protein of the virus. Two significant characteristics of lineage B.1.1.7 are the N501Y mutation and the 69–70 deletion of the S protein. The 69–70 deletion reduce sensitivity to neutralization by convalescent serum samples [194]. The N501 is one of the six amino acids interacting with ACE-2 [195], and the tyrosine substitution could increase binding affinity to the ACE-2 [196]. These variations have led scientists to be worried about high contagiousness, rapid spread, and possibly augmented mortality.

Variant B.1.351 has appeared in South Africa over the last several months, and similar to the B.1.1.7 raised transmission rates and higher viral load following infection have been reported [197]. Mutations in the S protein are more extended than variant B.1.1.7. Three of these mutations are found in the RBD (E484K, K417N, N501Y). Since RBD is the dominant target for neutralizing antibodies, these mutations might affect the effectiveness of previously approved monoclonal and polyclonal antibodies elicited by vaccination or infection in neutralizing the virus [198, 199].

An additional independent lineage of SARS-CoV-2 (named P.1 variant or 20J/501Y.V3) was identified in Brazil. Variant P.1 is a branch of lineage B.1.1.28 that was initially reported by the Japanese National Institute of Infectious Diseases (NIID) in four travelers from Brazil. It contains three mutations in the spike protein receptor binding domain (E484K, N501Y and K417T) [200]. Existing evidence suggests that some mutations in the P.1 variant can affect its transmissibility and antigenic profile, that may affect the ability of antibodies produced by a previous infection or vaccination [201].

Globally, researchers constantly working hard to gain knowledge and richer understand the variations of virues alluded to above in order to provide information to public health authorities like WHO to prevent more infections and save lives.

Mental Health in the Era of COVID-19

It is critical not to neglect the mental health issues associated with the COVID-19 outbreak. Patients, family members, and healthcare workers who treat viral outbreak patients are all at increased risk of developing mental health problems. For example, the 2002–2003 global SARS epidemic was labeled a “mental health catastrophe” [202]. Health care workers on the front lines of patient care during viral outbreaks experience a whole host of stressors, such as long shifts, difficulty balancing professional and family responsibilities, dealing with inadequate equipment and the fear for personal and family safety, and having to make ethically challenging decisions about the allocation of treatment resources. As a result, healthcare workers are at increased risk of experiencing psychological distress and post-traumatic stress disorder (PTSD) [203]. Additionally, COVID-19 patients, those patients who recovered but still have some symptoms like shortness of breath, high risk populations, (e.g. the elderly, people living with HIV, and those living or receiving care in crowded locations), and people with preexisting medical conditions such as psychiatric or substance use problems are at increased risk for adverse psychosocial consequences [204–206]. Therefore, providing psychosocial support and regularly monitoring mental health needs of those at higher risk necessitate activities that need to be integrated into the general pandemic healthcare system, especially for those nations that are hard hit by this novel disease.

Conclusion

The new coronavirus, termed SARS-CoV-2, causes severe respiratory infection and has been spreading worldwide quickly. Yet, information regarding this novel virus remains inadequate. The main goal of worldwide efforts against COVID-19 in the absence of any approved pharmacological agents is to apply primary preventive measures e.g., face-covering with masks, social distancing, stay at home orders, closing places like theaters, isolation of suspected cases, using PPE in healthcare units, contact tracing and screening persons who might be infected in order to restrict the outbreaks [207, 208]. COVID-19 appears to transmit human-to-human via the same way as other common cold or influenza viruses. Chest CT scan findings and RT-PCR are considered first and available diagnostic approaches of COVID-19. Thin slice chest CT can be helpful in rapid detection, and disease control, playing an essential role in the initial diagnosis and monitor of COVID-19. In terms of laboratory examinations, it has been shown that the total number of lymphocytes in most cases is decreased. This result suggests that COVID-19 may mostly act on lymphocytes, particularly T lymphocytes. The low number of lymphocytes can be used as a reference index in the detection of COVID-19 infections in suspected cases. Therefore, early diagnosis and appropriate symptomatic treatments of critical cases have vital importance.

Lack of trained personnel, shortage in mechanical ventilators, failure to implement community preventive measures (especially in poor and under war countries), delay in lockdown, quick reopening in some countries, inadequate risk communication (“the exchange of real-time information, advice and opinions between experts and people facing threats to their health, economic or social well-being”) [209] and finally ICU occupancy are thought to be major reasons behind the high mortality associated with COVID-19 in most countries with the highest incident rate [210]. More importantly, it is crucial to adhere to global research ethical standards in developing vaccines, conducting clinical trials, and approving those vaccines to use in the general public. Therefore, to tackle these issues, countries (especially those with the highest number of COVID-19 deaths) need to follow WHO’s guidelines strictly to flatten the mortality curve and save lives. Additionally, WHO translates that knowledge into strategic action that can guide the efforts of all countries when developing context-specific national operational plans [211]. The rapid progress and authorizing three vaccines to be inoculated in the United States and United Kingdom have been almost revolutionary, spurred by the urgent need to blunt the pandemic that is wrecking hovoc on families, society, and economy worldwide.

Constant research is essential to recognize the source of the outbreak and finding the intermediate host for inhibiting future coronavirus outbreaks. Public health authorities must monitor the condition carefully and release surveillance data to better understand the behavior of this novel disease. Although much more remains to be done with many unanswered questions, proactive investment in public health infrastructure and resources is critical, including preventive education, (i.e. social distancing, washing hands, quarantine), vaccine and therapeutic development, providing sensitive and specific diagnostic tests, the availability of well-equipped hospitals for patients with critical conditions, and providing resources in the aftermath of the pandemic to optimize psychological adjustment in survivors.

References

• 1

  Fields BN Knipe DM Howley PM (2013). Fields Virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.

  • Google Scholar

• 2

  Tyrrell DAJ Bynoe ML (1966). Cultivation of Viruses from a High Proportion of Patients with Colds. The Lancet. 287:76–7. 10.1016/s0140-6736(66)92364-6

  • CrossRef
  • Google Scholar

• 3

  Velavan TP Meyer CG (2020). The Covid-19 Epidemic. Trop Med Int Health TM IH25(3):278–80. 10.1111/tmi.13383

  • CrossRef
  • Google Scholar

• 4

  Zhou P Yang XL Wang XG Hu B Zhang L Zhang W et al (2020). A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature579:270–3. 10.1038/s41586-020-2012-7

  • CrossRef
  • Google Scholar

• 5

  Woo PCY Lau SKP Lam CSF Lau CCY Tsang AKL Lau JHN et al (2012). Discovery of Seven Novel Mammalian and Avian Coronaviruses in the Genus Deltacoronavirus Supports Bat Coronaviruses as the Gene Source of Alphacoronavirus and Betacoronavirus and Avian Coronaviruses as the Gene Source of Gammacoronavirus and Deltacoronavirus. J Virol86(7):3995–4008. 10.1128/jvi.06540-11

  • CrossRef
  • Google Scholar

• 6

  Su S Wong G Shi W Liu J Lai ACK Zhou J et al (2016). Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiology24(6):490–502. 10.1016/j.tim.2016.03.003

  • CrossRef
  • Google Scholar

• 7

  Forni D Cagliani R Clerici M Sironi M (2017). Molecular Evolution of Human Coronavirus Genomes. Trends Microbiology25(1):35–48. 10.1016/j.tim.2016.09.001

  • CrossRef
  • Google Scholar

• 8

  Lu R Zhao X Li J Niu P Yang B Wu H et al (2020). Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding. The Lancet395(10224):565–74. 10.1016/s0140-6736(20)30251-8

  • CrossRef
  • Google Scholar

• 9

  Cyranoski D (2020). Did Pangolins Spread the China Coronavirus to People. Nature. 10.1038/d41586-020-00364-2

  • CrossRef
  • Google Scholar

• 10

  Li X Zai J Zhao Q Nie Q Li Y Foley BT et al (2020). Evolutionary History, Potential Intermediate Animal Host, and Cross-Species Analyses of SARS-CoV-2. J Med Virol92:602-611. 10.1002/jmv.25731

  • CrossRef
  • Google Scholar

• 11

  Coronavirus disease (covid-2019). situation reports Available from: [https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200330-sitrep-70-covid-19.pdf?sfvrsn=7e0fe3f8_4]

• 12

  Whorld Health Organization. Coronavirus Disease 2019 (COVID-19). Situation Report – 46 Available from: [https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=96b04adf_4]

  • Google Scholar

• 13

  Peiris J Guan Y Yuen K (2004). Severe Acute Respiratory Syndrome. Nat Med. 10(12):S88–S97. 10.1038/nm1143

  • CrossRef
  • Google Scholar

• 14

  Chan-Yeung M Xu R (2003). SARS: Epidemiology. Respirology(8 Suppl. l) S9–14. 10.1046/j.1440-1843.2003.00518.x

  • CrossRef
  • Google Scholar

• 15

  Zaki AM Van Boheemen S Bestebroer TM Osterhaus ADME Fouchier RAM (2012). Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. N Engl J Med. 367(19):1814–20. 10.1056/nejmoa1211721

  • CrossRef
  • Google Scholar

• 16

  Lee J Chowell G Jung E (2016). A Dynamic Compartmental Model for the Middle East Respiratory Syndrome Outbreak in the Republic of Korea: a Retrospective Analysis on Control Interventions and Superspreading Events. J Theor Biol. 408:118–26. 10.1016/j.jtbi.2016.08.009

  • CrossRef
  • Google Scholar

• 17

  Lee JY Kim YJ Chung EH Kim DW Jeong I Kim Y et al (2015). The Clinical and Virological Features of the First Imported Case Causing MERS-CoV Outbreak in South Korea, 2015. BMC Infectious Diseases. BMC Infect Dis17(1):498. 10.1186/s12879-017-2576-5

  • CrossRef
  • Google Scholar

• 18

  Li W Moore MJ Vasilieva N Sui J Wong SK Berne MA et al (2003). Angiotensin-converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus. Nature426(6965):450–4. 10.1038/nature02145

  • CrossRef
  • Google Scholar

• 19

  Qian Z Travanty EA Oko L Edeen K Berglund A Wang J et al (2013). Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome-Coronavirus. Am J Respir Cel Mol Biol48(6):742–8. 10.1165/rcmb.2012-0339oc

  • CrossRef
  • Google Scholar

• 20

  Asgharpour M Ebrahimi Kalan M Mirhashemi SH Alirezaei A (2019). Lung Cancer Risk and the Inhibitors of Angiotensinconverting Enzyme: A Mini-Review of Recent Evidence. Immunopathol Persa. 5(2):e16. 10.15171/ipp.2019.16

  • CrossRef
  • Google Scholar

• 21

  Serej ZA Kalan AE Mehdipour A Charoudeh HN (2017). Regulation and Roles of CD26/DPPIV in Hematopoiesis and Diseases. Biomed Pharmacother. 91:88–94. 10.1016/j.biopha.2017.04.074

  • CrossRef
  • Google Scholar

• 22

  Lu G Hu Y Wang Q Qi J Gao F Li Y et al (2013). Molecular Basis of Binding between Novel Human Coronavirus MERS-CoV and its Receptor CD26. Nature500(7461):227–31. 10.1038/nature12328

  • CrossRef
  • Google Scholar

• 23

  Raj VS Mou H Smits SL Dekkers DHW Müller MA Dijkman R et al (2013). Dipeptidyl Peptidase 4 Is a Functional Receptor for the Emerging Human Coronavirus-EMC. Nature495(7440):251–4. 10.1038/nature12005

  • CrossRef
  • Google Scholar

• 24

  Scobey T Yount BL Sims AC Donaldson EF Agnihothram SS Menachery VD et al (2013). Reverse Genetics with a Full-Length Infectious cDNA of the Middle East Respiratory Syndrome Coronavirus. Proc Natl Acad Sci. 110(40):16157–62. 10.1073/pnas.1311542110

  • CrossRef
  • Google Scholar

• 25

  Lau SKP Woo PCY Li KSM Huang Y Tsoi H-W Wong BHL et al (2005). Severe Acute Respiratory Syndrome Coronavirus-like Virus in Chinese Horseshoe Bats. Proc Natl Acad Sci. 102(39):14040–5. 10.1073/pnas.0506735102

  • CrossRef
  • Google Scholar

• 26

  Kan B Wang M Jing H Xu H Jiang X Yan M et al (2005). Molecular Evolution Analysis and Geographic Investigation of Severe Acute Respiratory Syndrome Coronavirus-like Virus in palm Civets at an Animal Market and on Farms. Jvi79(18):11892–900. 10.1128/jvi.79.18.11892-11900.2005

  • CrossRef
  • Google Scholar

• 27

  Ithete NL Stoffberg S Corman VM Cottontail VM Richards LR Schoeman MC et al (2013). Close Relative of Human Middle East Respiratory Syndrome Coronavirus in Bat, South Africa. Emerg Infect Dis. 19(10):1697–9. 10.3201/eid1910.130946

  • CrossRef
  • Google Scholar

• 28

  Ge X-Y Li J-L Yang X-L Chmura AA Zhu G Epstein JH et al (2013). Isolation and Characterization of a Bat SARS-like Coronavirus that Uses the ACE2 Receptor. Nature503(7477):535–8. 10.1038/nature12711

  • CrossRef
  • Google Scholar

• 29

  Yang X-L Hu B Wang B Wang M-N Zhang Q Zhang W et al (2016). Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus. J Virol90(6):3253–6. 10.1128/jvi.02582-15

  • CrossRef
  • Google Scholar

• 30

  Hu B Zeng LP Yang XL Ge XY Zhang W Li B et al (2017). Discovery of a Rich Gene Pool of Bat SARS-Related Coronaviruses Provides New Insights into the Origin of SARS Coronavirus. Plos Pathog. 13:e1006698. 10.1371/journal.ppat.1006698

  • CrossRef
  • Google Scholar

• 31

  Lau SKP Li KSM Tsang AKL Lam CSF Ahmed S Chen H et al (2013). Genetic Characterization of Betacoronavirus Lineage C Viruses in Bats Reveals Marked Sequence Divergence in the Spike Protein of pipistrellus Bat Coronavirus HKU5 in Japanese Pipistrelle: Implications for the Origin of the Novel Middle East Respiratory Syndrome Coronavirus. J Virol87(15):8638–50. 10.1128/jvi.01055-13

  • CrossRef
  • Google Scholar

• 32

  Zhu N Zhang D Wang W Li X Yang B Song J et al (2020). A novel coronavirus from patients with pneumonia in China, 2019. New Engl J Med382(8):727–33. 10.1056/NEJMoa2001017

  • CrossRef
  • Google Scholar

• 33

  Bárcena M Oostergetel GT Bartelink W Faas FGA Verkleij A Rottier PJM et al (2009). Cryo-electron Tomography of Mouse Hepatitis Virus: Insights into the Structure of the Coronavirion. Proc Natl Acad Sci. 106(2):582–7. 10.1073/pnas.0805270106

  • CrossRef
  • Google Scholar

• 34

  Neuman BW Adair BD Yoshioka C Quispe JD Orca G Kuhn P et al (2006). Supramolecular Architecture of Severe Acute Respiratory Syndrome Coronavirus Revealed by Electron Cryomicroscopy. Jvi. 80(16):7918–28. 10.1128/jvi.00645-06

  • CrossRef
  • Google Scholar

• 35

  Tortorici MA Veesler D (2019). Structural Insights into Coronavirus Entry. Adv Virus Res. 105:93–116. 10.1016/bs.aivir.2019.08.002

  • CrossRef
  • Google Scholar

• 36

  Wrapp D Wang N Corbett KS Goldsmith JA Hsieh C-L Abiona O et al (2020). Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. Science367(6483):1260–3. 10.1126/science.abb2507

  • CrossRef
  • Google Scholar

• 37

  Chen ZM Fu JF Shu Q Chen YH Hua CZ Li FB et al (2020). Diagnosis and Treatment Recommendations for Pediatric Respiratory Infection Caused by the 2019 Novel Coronavirus. World J Pediatr16:240–6. 10.1007/s12519-020-00345-5

  • CrossRef
  • Google Scholar

• 38

  Tang X Wu C Li X Song Y Yao X Wu X et al (2020). On the Origin and Continuing Evolution of SARS-CoV-2. Natl Sci Revnwaa036. 10.1093/nsr/nwaa036

  • CrossRef
  • Google Scholar

• 39

  Rolling updates on coronavirus disease (covid-19). Available from: [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen]

• 40

  Coronavirus disease (covid-2019) situation reports [internet]. Available from: [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/]

• 41

  Fani M Teimoori A Ghafari S (2020). Comparison of the COVID-2019 (SARS-CoV-2) Pathogenesis with SARS-CoV and MERS-CoV Infections. Future Virol. 10.2217/fvl-2020-0050

  • CrossRef
  • Google Scholar

• 42

  Cyranoski D (2020). Profile of a Killer: the Complex Biology Powering the Coronavirus Pandemic. Nature. 581(7806):22–6. 10.1038/d41586-020-01315-7

  • CrossRef
  • Google Scholar

• 43

  Peiris JSM Yuen KY Osterhaus ADME Stöhr K (2003). The Severe Acute Respiratory Syndrome. N Engl J Med. 349(25):2431–41. 10.1056/nejmra032498

  • CrossRef
  • Google Scholar

• 44

  Rothan HA Byrareddy SN (2020). The Epidemiology and Pathogenesis of Coronavirus Disease (COVID-19) Outbreak. J Autoimmun109:102433. 10.1016/j.jaut.2020.102433

  • CrossRef
  • Google Scholar

• 45

  van Doremalen N Bushmaker T Morris DH Holbrook MG Gamble A Williamson BN et al (2020). Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. New Engl J Med382(16):1564–67. 10.1056/NEJMc2004973

  • CrossRef
  • Google Scholar

• 46

  Hellewell J Abbott S Gimma A Bosse NI Jarvis CI Russell TW et al (2020). Feasibility of Controlling COVID-19 Outbreaks by Isolation of Cases and Contacts. Lancet Glob Health8(4):e488–96. 10.1016/S2214-109X(20)30074-7

  • CrossRef
  • Google Scholar

• 47

  Niu Y Xu F (2020). Deciphering the Power of Isolation in Controlling COVID-19 Outbreaks. Lancet Glob Health. 8(4):e452–e453. 10.1016/s2214-109x(20)30085-1

  • CrossRef
  • Google Scholar

• 48

  Organization WH (2020). Rational Use of Personal Protective Equipment (PPE) for Coronavirus Disease (COVID-19): Interim Guidance. World Health Organization, 192020.

  • Google Scholar

• 49

  World Health Organization. Coronavirus disease (COVID-19) advice for the public Available from: [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public]

• 50

  Novel coronavirus situation report -2. January 22 (2020). Available from: [https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200122-sitrep-2-2019. -ncov.pdf]

  • Google Scholar

• 51

  Control CfD (2020). Prevention: Coronavirus Disease 2019 (COVID-19): Standard Operating Procedure (SOP) for Triage of Suspected COVID-19 Patients in Non-US Healthcare Settings: Early Identification and Prevention of Transmission during Triage. Centers Dis Control Prev (Us) 2020: Centers Dis Control Prev (Us).

  • Google Scholar

• 52

  Shereen MA Khan S Kazmi A Bashir N RJJoAR S (2020). COVID-19 Infection: Origin, Transmission, and Characteristics of Human Coronaviruses.

  • Google Scholar

• 53

  World Health Organization (2020). Breastfeeding and COVID-19- Scientific Brief- 23. Available from: [https://www.who.int/publications/i/item/10665332639].

  • Google Scholar

• 54

  Breastfeeding and caring for newborns. Available from: [https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html#:∼:text=Current%20evidence%20suggests%20that%20breast.,nutrition%20for%20most%20babies.]

• 55

  Lubbe W Botha E Niela-Vilen H Reimers P (2020). Breastfeeding during the COVID-19 Pandemic - a Literature Review for Clinical Practice. Int Breastfeed J. 15:82. 10.1186/s13006-020-00319-3

  • CrossRef
  • Google Scholar

• 56

  Zeng L Xia S Yuan W Yan K Xiao F Shao J et al (2020). Neonatal Early-Onset Infection with SARS-CoV-2 in 33 Neonates Born to Mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 174:722. 10.1001/jamapediatrics.2020.0878

  • CrossRef
  • Google Scholar

• 57

  Vivanti AJ Vauloup-Fellous C Prevot S Zupan V Suffee C (2020). Do Cao J, Benachi A, De Luca D: Transplacental Transmission of SARS-CoV-2 Infection. Nat Commun. 11(1):3572. 10.1038/s41467-020-17436-6

  • CrossRef
  • Google Scholar

• 58

  Mahase E (2020). Coronavirus: Covid-19 Has Killed More People Than SARS and MERS Combined, Despite Lower Case Fatality Rate. In.: Br Med J Publishing Group. m641. 10.1136/bmj.m641

  • CrossRef
  • Google Scholar

• 59

  Tsang TK Wu P Lin Y Lau EHY Leung GM Cowling BJ (2020). Effect of Changing Case Definitions for COVID-19 on the Epidemic Curve and Transmission Parameters in mainland China: a Modelling Study. The Lancet Public Health. 5(5):e289–e296. 10.1016/s2468-2667(20)30089-x

  • CrossRef
  • Google Scholar

• 60

  Global Surveillance for Covid-19 Disease Caused by Human Infection with the 2019 Novel Coronavirus. [file:///C:/Users/Ebi/Downloads/WHO-2019-nCoV-SurveillanceGuidance-2020.4-eng.pdf]

  • Google Scholar

• 61

  Lauer SA Grantz KH Bi Q Jones FK Zheng Q Meredith HR et al (2020). The Incubation Period of Coronavirus Disease 2019 (COVID-19) from Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med172:577-582. 10.7326/m20-0504

  • CrossRef
  • Google Scholar

• 62

  Singhal T (2020). A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 87(4):281–6. 10.1007/s12098-020-03263-6

  • CrossRef
  • Google Scholar

• 63

  Lauer SA Grantz KH Bi Q Jones FK Zheng Q Meredith HR et al (2020). The Incubation Period of Coronavirus Disease 2019 (COVID-19) from Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med172(9):577–82. 10.7326/m20-0504

  • CrossRef
  • Google Scholar

• 64

  Linton N Kobayashi T Yang Y Hayashi K Akhmetzhanov A Jung S-m. et al (2020). Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data. J Clin Med. 9(2):538. 10.3390/jcm9020538

  • CrossRef
  • Google Scholar

• 65

  Park M Cook AR Lim JT Sun Y Dickens BL (2020). A Systematic Review of COVID-19 Epidemiology Based on Current Evidence. J Clin Med. 9(4):967. 10.3390/jcm9040967

  • CrossRef
  • Google Scholar

• 66

  Jin Y-H Cai L Cheng Z-S Cheng H Deng T Fan Y-P et al (2020). A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV) Infected Pneumonia (Standard Version). Mil Med Res7(1):4. 10.1186/s40779-020-0233-6

  • CrossRef
  • Google Scholar

• 67

  Tartof SY Qian L Hong V Wei R Nadjafi RF Fischer H et al (2020). Obesity and Mortality Among Patients Diagnosed with COVID-19: Results from an Integrated Health Care Organization. Ann Intern Med. 173:773-781. 10.7326/M20-3742

  • CrossRef
  • Google Scholar

• 68

  Liu K Chen Y Lin R Han K (2020). Clinical Features of COVID-19 in Elderly Patients: A Comparison with Young and Middle-Aged Patients. J Infect. 80(6):e14–e18. 10.1016/j.jinf.2020.03.005

  • CrossRef
  • Google Scholar

• 69

  Wang P Lu J Jin Y Zhu M Wang L Chen S (2020). Epidemiological Characteristics of 1212 COVID-19 Patients in Henan, China. medRxiv. 10.1101/2020.02.21.20026112v2

  • CrossRef
  • Google Scholar

• 70

  Ji D Zhang D Chen Z Xu Z Zhao P Zhang M et al (2020). Clinical Characteristics Predicting Progression of COVID-19. 10.2139/ssrn.3539674

  • CrossRef
  • Google Scholar

• 71

  Wang E (2020). Brar KJTJoA, Practice CIi: COVID-19 in Children: an Epidemiology Study from China.

  • Google Scholar

• 72

  Shulman ST (2020). Pediatric Coronavirus Disease-2019-Associated Multisystem Inflammatory Syndrome. J Pediatr Infect Dis Soc. 9(3):285–6. 10.1093/jpids/piaa062

  • CrossRef
  • Google Scholar

• 73

  Feldstein LR Rose EB Horwitz SM Collins JP Newhams MM Son MBF et al (2020). Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med383(4):334–46. 10.1056/NEJMoa2021680

  • CrossRef
  • Google Scholar

• 74

  Riollano-Cruz M Akkoyun E Briceno-Brito E Kowalsky S Posada R Sordillo EM et al Multisystem Inflammatory Syndrome in Children (MIS-C) Related to COVID-19: A New York City Experience. N/a(n/a).

  • Google Scholar

• 75

  American Academy of Pediatrics. Children and COVID-19. State-Level Data Report Available from: [https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/]

  • Google Scholar

• 76

  Kim LJMM Report MW (2020). Hospitalization Rates and Characteristics of Children Aged 18 Years Hospitalized with Laboratory-Confirmed COVID-19—COVID-NET, 14 States, March 1–July 25, 2020. MMWR Morb Mortal Wkly Rep69(32):1081–88. 10.15585/mmwr.mm6932e3

  • CrossRef
  • Google Scholar

• 77

  Cascella M Rajnik M Cuomo A Dulebohn SC Di Napoli R (2021). Features, Evaluation and Treatment Coronavirus (COVID-19). In: StatPearls [internet]. Treasure Island (FL):StatPearls Publishing.

  • Google Scholar

• 78

  Wu Z McGoogan JM (2020). Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention. Jama.

  • Google Scholar

• 79

  Center for Disease Control and Prevention. Testing for COVID-19 Available from: [https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/testing.html]

• 80

  Patel A Jernigan DB (2020). Initial Public Health Response and Interim Clinical Guidance for the 2019 Novel Coronavirus Outbreak - United States, December 31, 2019-February 4, 2020Morbidity and Mortality Weekly Report. MMWR Morb Mortal Wkly Rep. 69(5):140–6. 10.15585/mmwr.mm6905e1

  • CrossRef
  • Google Scholar

• 81

  Hung IFN Cheng VCC Wu AKL Tang BSF Chan KH Chu CM et al (2004). Viral Loads in Clinical Specimens and SARS Manifestations. Emerg Infect Dis10(9):1550–7. 10.3201/eid1009.040058

  • CrossRef
  • Google Scholar

• 82

  Holshue ML DeBolt C Lindquist S Lofy KH Wiesman J Bruce H et al (2020). First Case of 2019 Novel Coronavirus in the United States. New Engl J Med.

  • Google Scholar

• 83

  Kanne JP (2020). Chest CT Findings in 2019 Novel Coronavirus (2019-nCoV) Infections from Wuhan, China: Key Points for the Radiologist. Radiological Soc North America. 295:16-17. 10.1148/radiol.2020200241

  • CrossRef
  • Google Scholar

• 84

  Ai T Yang Z Hou H Zhan C Chen C Lv W et al (2020). Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 296(2):E32–e40. 10.1148/radiol.2020200642

  • CrossRef
  • Google Scholar

• 85

  Li Y Xia L (2020). Coronavirus Disease 2019 (COVID-19): Role of Chest CT in Diagnosis and Management. Am J Roentgenology. 214(6):1280–6. 10.2214/ajr.20.22954

  • CrossRef
  • Google Scholar

• 86

  Caruso D Zerunian M Polici M Pucciarelli F Polidori T Rucci C et al (2020). Chest CT Features of COVID-19 in Rome, Italy. Radiology296:E79. 10.1148/radiol.2020201237

  • CrossRef
  • Google Scholar

• 87

  Zhou S Wang Y Zhu T Xia L (2020). CT Features of Coronavirus Disease 2019 (COVID-19) Pneumonia in 62 Patients in Wuhan, China. Am J Roentgenology. 214(6):1287–94. 10.2214/ajr.20.22975

  • CrossRef
  • Google Scholar

• 88

  Huang C Wang Y Li X Ren L Zhao J Hu Y et al (2020). Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. The Lancet395(10223):497–506. 10.1016/s0140-6736(20)30183-5

  • CrossRef
  • Google Scholar

• 89

  Zhao Q Meng M Kumar R Wu Y Huang J Deng Y et al (2020). Lymphopenia Is Associated with Severe Coronavirus Disease 2019 (COVID-19) Infections: A Systemic Review and Meta-Analysis. Int J Infect Dis96:131-135. 10.1016/j.ijid.2020.04.086

  • CrossRef
  • Google Scholar

• 90

  Fan BE Chong VCL Chan SSW Lim GH Lim KGE Tan GB et al (2020). Hematologic Parameters in Patients with COVID‐19 Infection. Am J Hematol95(6):E131–E134. 10.1002/ajh.25774

  • CrossRef
  • Google Scholar

• 91

  Bermejo-Martin JF Almansa R Menéndez R Mendez R Kelvin DJ Torres A (2020). Lymphopenic Community Acquired Pneumonia as Signature of Severe COVID-19 Infection. J Infect. 80(5):e23–e24. 10.1016/j.jinf.2020.02.029

  • CrossRef
  • Google Scholar

• 92

  Henry BM (2020). COVID-19, ECMO, and Lymphopenia: a Word of Caution. Lancet Respir Med. 8(4):e24. 10.1016/s2213-2600(20)30119-3

  • CrossRef
  • Google Scholar

• 93

  Tan L Wang Q Zhang D Ding J Huang Q Tang Y-Q et al (2020). Lymphopenia Predicts Disease Severity of COVID-19: a Descriptive and Predictive Study. Signal Transduction Targeted Therapy5(1):1–3. 10.1038/s41392-020-0159-1

  • CrossRef
  • Google Scholar

• 94

  Wang D Hu B Hu C Zhu F Liu X Zhang J et al (2020). Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. Jama. 323(11):1061–9. 10.1001/jama.2020.1585

  • CrossRef
  • Google Scholar

• 95

  Peeling RW Olliaro PL Boeras DI Fongwen N (2021). Scaling up COVID-19 Rapid Antigen Tests: Promises and Challenges. Lancet Infect Dis. 10.1016/s1473-3099(21)00048-7

  • CrossRef
  • Google Scholar

• 96

  Zhu X Wang X Han L Chen T Wang L Li H et al (2020). Multiplex Reverse Transcription Loop-Mediated Isothermal Amplification Combined with Nanoparticle-Based Lateral Flow Biosensor for the Diagnosis of COVID-19. Biosens Bioelectron166:112437. 10.1016/j.bios.2020.112437

  • CrossRef
  • Google Scholar

• 97

  Carter LJ Garner LV Smoot JW Li Y Zhou Q Saveson CJ et al (2020). Assay Techniques and Test Development for COVID-19 Diagnosis. ACS Publications6:591-605. 10.1021/acscentsci.0c00501

  • CrossRef
  • Google Scholar

• 98

  Dinnes J Deeks J Adriano A (2020). Cochrane COVID-19 Diagnostic Test Accuracy Group. Rapid Point-of-care Antigen Molecular-based Tests Diagnosis Sars-cov-2 Infection Cochrane Database Syst Rev8.

  • Google Scholar

• 99

  Crozier A Rajan S Buchan I McKee M (2021). Put to the Test: Use of Rapid Testing Technologies for Covid-19. bmj. 372:n208. 10.1136/bmj.n208

  • CrossRef
  • Google Scholar

• 100

  Zu ZY Jiang MD Xu PP Chen W Ni QQ Lu GM et al (2020). Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology. 296:E15. 10.1148/radiol.2020200490

  • CrossRef
  • Google Scholar

• 101

  Fang Y Zhang H Xie J Lin M Ying L Pang P et al (2020). Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology296:E115. 10.1148/radiol.2020200432

  • CrossRef
  • Google Scholar

• 102

  Sun P Lu X Xu C Sun W Pan B (2020). Understanding of COVID-19 Based on Current Evidence. J Med Virol. 92(6):548-551. 10.1002/jmv.25722

  • CrossRef
  • Google Scholar

• 103

  GuanWJ N (2020). Clinical characteristics of 2019 novel coronavirus infection in China. bio Rxiv preprint first posted online Feb. 6.

  • Google Scholar

• 104

  She J Jiang J Ye L Hu L Bai C Song Y (2020). 2019 Novel Coronavirus of Pneumonia in Wuhan, China: Emerging Attack and Management Strategies. Clin translational Med. 9(1):1–7. 10.1186/s40169-020-00271-z

  • CrossRef
  • Google Scholar

• 105

  Management of persons with covid-19. Available from: [https://www.covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/]

• 106

  Nguyen TM Zhang Y Pandolfi PP (2020). Virus against Virus: a Potential Treatment for 2019-nCov (SARS-CoV-2) and Other RNA. viruses. Nat Publishing Group. 30:189-190. 10.1038/s41422-020-0290-0

  • CrossRef
  • Google Scholar

• 107

  Wang M Cao R Zhang L Yang X Liu J Xu M et al (2020). Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) In Vitro. Cell Res30:269–71. 10.1038/s41422-020-0282-0

  • CrossRef
  • Google Scholar

• 108

  Lu H (2020). Drug Treatment Options for the 2019-new Coronavirus (2019-nCoV). Bioscience Trends. 16:69-71. 10.5582/bst.2020.01020

  • CrossRef
  • Google Scholar

• 109

  Yao TT Qian JD Zhu WY Wang Y Wang GQ (2020). A Systematic Review of Lopinavir Therapy for SARS Coronavirus and MERS Coronavirus–A Possible Reference for Coronavirus Disease-19 Treatment Option. J Med Virol. 92:556-563. 10.1002/jmv.25729

  • CrossRef
  • Google Scholar

• 110

  Organization WH (2020). Clinical Management of Severe Acute Respiratory Infection when Novel Coronavirus ( 2019-nCoV) Infection Is Suspected: Interim Guidance. New York: World Health Organization, 28.

  • Google Scholar

• 111

  Ruan S-Y Lin H-H Huang C-T Kuo P-H Wu H-D Yu C-J (2014). Exploring the Heterogeneity of Effects of Corticosteroids on Acute Respiratory Distress Syndrome: a Systematic Review and Meta-Analysis. Crit Care. 18(2):1–9. 10.1186/cc13819

  • CrossRef
  • Google Scholar

• 112

  Steinberg KP Hudson LD Goodman RB Hough CL Lanken PN Hyzy R et al National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network (2006). Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. New Engl J Med. 354(16):1671–84. 10.1056/NEJMoa051693

  • CrossRef
  • Google Scholar

• 113

  Cano EJ Fuentes XF Campioli CC O’Horo JC Saleh OA Odeyemi Y et al (2020). Impact of Corticosteroids in COVID-19 Outcomes: Systematic Review and Meta-Analysis. Chest.

  • Google Scholar

• 114

  Albani F Fusina F Granato E Capotosto C Ceracchi C Gargaruti R et al (2021). Corticosteroid Treatment Has No Effect on Hospital Mortality in COVID-19 Patients. Scientific Rep11(1):1–6. 10.1038/s41598-020-80654-x

  • CrossRef
  • Google Scholar

• 115

  Monreal E de la Maza SS Sainz de la Maza S Natera-Villalba E Beltrán-Corbellini Á Rodríguez-Jorge F et al (2021). High versus Standard Doses of Corticosteroids in Severe COVID-19: a Retrospective Cohort Study. Eur J Clin Microbiol Infect Dis40(4):761–9. 10.1007/s10096-020-04078-1

  • CrossRef
  • Google Scholar

• 116

  Arabi YM Mandourah Y Al-Hameed F Sindi AA Almekhlafi GA Hussein MA et al (2018). Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med197(6):757–67. 10.1164/rccm.201706-1172oc

  • CrossRef
  • Google Scholar

• 117

  Grein J Ohmagari N Shin D . Original: Compassionate Use of Remdesivir for Patients with Severe Covid-19.

  • Google Scholar

• 118

  Nih clinical trial of investigational vaccine for covid-19 begins. Available from: [https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins]

• 119

  Chakraborty R Parvez S (2020). COVID-19: An Overview of the Current Pharmacological Interventions, Vaccines, and Clinical Trials. Biochem Pharmacol. 180:114184. 10.1016/j.bcp.2020.114184

  • CrossRef
  • Google Scholar

• 120

  Sheahan TP Sims AC Leist SR Schäfer A Won J Brown AJ et al (2020). Comparative Therapeutic Efficacy of Remdesivir and Combination Lopinavir, Ritonavir, and Interferon Beta against MERS-CoV. Nat Commun11(1):1–14. 10.1038/s41467-019-13940-6

  • CrossRef
  • Google Scholar

• 121

  Chu CM Cheng V Hung I Wong M Chan K Chan K et al (2004). Role of Lopinavir/ritonavir in the Treatment of SARS: Initial Virological and Clinical Findings. Thorax59(3):252–6. 10.1136/thorax.2003.012658

  • CrossRef
  • Google Scholar

• 122

  Arabi YM Alothman A Balkhy HH Al-Dawood A AlJohani S (2018). Al Harbi S, Kojan S, Al Jeraisy M, Deeb AM, Assiri AM: Treatment of Middle East Respiratory Syndrome with a Combination of Lopinavir-Ritonavir and Interferon-Β1b (MIRACLE Trial): Study Protocol for a Randomized Controlled Trial. Trials. 19(1):81. 10.1186/s13063-017-2427-0

  • CrossRef
  • Google Scholar

• 123

  Chan K Lai S Chu C Tsui E Tam C Wong M et al (2003). Treatment of Severe Acute Respiratory Syndrome with Lopinavir/ritonavir: a Multicentre Retrospective Matched Cohort Study. Hong Kong Med J9:399-406.

  • Google Scholar

• 124

  De Wilde AH Jochmans D Posthuma CC Zevenhoven-Dobbe JC Van Nieuwkoop S Bestebroer TM et al (2014). Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture. Antimicrob Agents Chemother. 58(8):4875–84. 10.1128/aac.03011-14

  • CrossRef
  • Google Scholar

• 125

  Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX et al (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 382(18):1708–20. 10.1056/NEJMoa2002032

  • CrossRef
  • Google Scholar

• 126

  No clinical benefit from use of lopinavir-ritonavir in hospitalised covid-19 patients studied in recovery Available from: [https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery]

• 127

  Dong L Hu S Gao J (2020). Discovering Drugs to Treat Coronavirus Disease 2019 (COVID-19). DD&T. 14(1):58–60. 10.5582/ddt.2020.01012

  • CrossRef
  • Google Scholar

• 128

  Yao X Ye F Zhang M Cui C Huang B Niu P (2020). In Vitro antiviral Activity 551 and Projection of Optimized Dosing Design of Hydroxychloroquine for the 552 Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 553 (SARS-CoV-2). Clin Infect Dis. 71:732-739. 10.1093/cid/ciaa237

  • CrossRef
  • Google Scholar

• 129

  Wang M Cao R Zhang L Yang X Liu J Xu M et al (2020). Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) In Vitro. Cel Res30(3):269–71. 10.1038/s41422-020-0282-0

  • CrossRef
  • Google Scholar

• 130

  Gautret P Lagier J-C Parola P Hoang VT Meddeb L Mailhe M et al (2020). Vieira VE: Herv ́e Tissot Dupont, St ́ephane Honor ́e, Philippe Colson, Eric Chabriere, Bernard La Scola, Jean-Marc Rolain, Philippe Brouqui, Didier Raoult, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents

  • Google Scholar

• 131

  Arshad S Kilgore P Chaudhry ZS Jacobsen G Wang DD Huitsing K et al (2020). Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. Int J Infect Dis97:396-403. 10.1016/j.ijid.2020.06.099

  • CrossRef
  • Google Scholar

• 132

  Watson J Adler A Amaravadi A (2020). Open Letter to MR Mehra, SS Desai, F Ruschitzka, and an Patel, Authors of “Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: a Multinational Registry Analysis”. Lancet. 31180–6.

  • Google Scholar

• 133

  Fda cautions against use of hydroxychloroquine or chloroquine for covid-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems Available from: [https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or]

• 134

  Cavalcanti AB Zampieri FG Rosa RG Azevedo LCP Veiga VC Avezum A et al (2020). Hydroxychloroquine with or without Azithromycin in Mild-To-Moderate Covid-19. New Eng J Med. 383(21):2041–52. 10.1056/NEJMoa2019014

  • CrossRef
  • Google Scholar

• 135

  Magagnoli J Narendran S Pereira F Cummings T Hardin JW Sutton SS et al (2020). Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-192020.

  • Google Scholar

• 136

  Furuta Y Komeno T Nakamura T (2017). Favipiravir (T-705), a Broad Spectrum Inhibitor of Viral RNA Polymerase. Proc Jpn Acad Ser. B: Phys Biol Sci. 93(7):449–63. 10.2183/pjab.93.027

  • CrossRef
  • Google Scholar

• 137

  Jin Z Smith LK Rajwanshi VK Kim B Deval J (2013). The Ambiguous Base-Pairing and High Substrate Efficiency of T-705 (Favipiravir) Ribofuranosyl 5′-Triphosphate towards Influenza A Virus Polymerase. PloS one. 8(7):e68347. 10.1371/journal.pone.0068347

  • CrossRef
  • Google Scholar

• 138

  Clinical symptoms China Approves Favipiravir (Avigan). As An Experimental Drug To Treat Coronavirus Available from: [https://www.thailandmedical.news/news/china-approves-favipiravir-avigan–as-an-experimental-drug-to-treat-coronavirus]

• 139

  RUSSIAN DIRECT INVESTMENT FUND (2020). Russian Ministry of Health Approves the First Covid-19 Drug Avifavir Produced by Jv of Rdif and Chemrar.

  • Google Scholar

• 140

  Results from Trial of Antiviral Favipiravir in Patients with Asymptomatic or Mild Covid-19 Conducted at Fujita Health university. Available from: []

  • Google Scholar

• 141

  Chen L Xiong J Bao L Shi Y (2020). Convalescent Plasma as a Potential Therapy for COVID-19. Lancet Infect Dis. 20(4):398–400. 10.1016/s1473-3099(20)30141-9

  • CrossRef
  • Google Scholar

• 142

  Zhang L Zhai H Ma S Chen J Gao Y (2020). Efficacy of Therapeutic Plasma Exchange in Severe COVID-19 Patients. Br J Haematol. 190:e181-e183. 10.1111/bjh.16890

  • CrossRef
  • Google Scholar

• 143

  Fda G (2020). Investigational-covid-19-convalescent-plasma-emergency-inds. US Food Drug Adm 2020. Available from: https://www fda gov/vaccines-blood.

  • Google Scholar

• 144

  Roback JD Guarner J (2020). Convalescent Plasma to Treat COVID-19. Jama. 323(16):1561–2. 10.1001/jama.2020.4940

  • CrossRef
  • Google Scholar

• 145

  Joyner MJ Bruno KA Klassen SA Kunze KL Johnson PW Lesser ER et al (2020). Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. in Mayo Clinic Proceedings: 2020. Elsevier

  • Google Scholar

• 146

  Coronavirus india. Rush for Plasma Therapy as Covid-19 Cases Rise. Available from: [https://www.bbc.com/news/world-asia-india-53387607]

  • Google Scholar

• 147

  Cao W-C Liu W Zhang P-H Zhang F Richardus JH (2007). Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery. N Engl J Med. 357(11):1162–3. 10.1056/nejmc070348

  • CrossRef
  • Google Scholar

• 148

  Lotfi M Hamblin MR Rezaei N (2020). COVID-19: Transmission, Prevention, and Potential Therapeutic Opportunities. Clinica Chim Acta. 508:254-266. 10.1016/j.cca.2020.05.044

  • CrossRef
  • Google Scholar

• 149

  Duan K Liu B Li C Zhang H Yu T Qu J et al (2020). The Feasibility of Convalescent Plasma Therapy in Severe COVID-19 Patients: a Pilot Study. medRxiv.

  • Google Scholar

• 150

  Somers EC Eschenauer GA Troost JP Golob JL Gandhi TN Wang L et al (2020). Tocilizumab for Treatment of Mechanically Ventilated Patients with COVID-19. medRxiv10.1093/cid/ciaa954

  • CrossRef
  • Google Scholar

• 151

  Kaly L Rosner I (2012). Tocilizumab - A Novel Therapy for Non-organ-specific Autoimmune Diseases. Best Pract Res Clin Rheumatol. 26(1):157–65. 10.1016/j.berh.2012.01.001

  • CrossRef
  • Google Scholar

• 152

  Kreft H Jetz W (2007). Global Patterns and Determinants of Vascular Plant Diversity. Proc Natl Acad Sci. 104(14):5925–30. 10.1073/pnas.0608361104

  • CrossRef
  • Google Scholar

• 153

  Ferrara N Hillan KJ Gerber H-P Novotny W (2004). Discovery and Development of Bevacizumab, an Anti-VEGF Antibody for Treating Cancer. Nat Rev Drug Discov. 3(5):391–400. 10.1038/nrd1381

  • CrossRef
  • Google Scholar

• 154

  Fanelli V Ranieri VM (2015). Mechanisms and Clinical Consequences of Acute Lung Injury. Ann ATS. 12(Suppl. 1):S3–S8. 10.1513/annalsats.201407-340mg

  • CrossRef
  • Google Scholar

• 155

  Shanmugaraj B Siriwattananon K Wangkanont K Phoolcharoen W (2020). Perspectives on Monoclonal Antibody Therapy as Potential Therapeutic Intervention for Coronavirus Disease-19 (COVID-19). Asian Pac J Allergy Immunol. 38(1):10–8. 10.12932/AP-200220-0773

  • CrossRef
  • Google Scholar

• 156

  Chen X Li R Pan Z Qian C Yang Y You R et al (2020). Human Monoclonal Antibodies Block the Binding of SARS-CoV-2 Spike Protein to Angiotensin Converting Enzyme 2 Receptor. Cell Mol Immunol17:647–9. 10.1038/s41423-020-0426-7

  • CrossRef
  • Google Scholar

• 157

  Tian X Li C Huang A Xia S Lu S Shi Z et al (2020). Potent Binding of 2019 Novel Coronavirus Spike Protein by a SARS Coronavirus-specific Human Monoclonal Antibody. Emerging Microbes & Infections9(1):382–5. 10.1080/22221751.2020.1729069

  • CrossRef
  • Google Scholar

• 158

  Zhang L Liu Y (2020). Potential Interventions for Novel Coronavirus in China: A Systematic Review. J Med Virol. 92(5):479–90. 10.1002/jmv.25707

  • CrossRef
  • Google Scholar

• 159

  Wang C Li W Drabek D Okba NM van Haperen R Osterhaus AD et al (2020). A Human Monoclonal Antibody Blocking SARS-CoV-2 Infection. Nat Commun11(1):1–6. 10.1038/s41467-020-16452-w

  • CrossRef
  • Google Scholar

• 160

  Lurie N Saville M Hatchett R Halton J (2020). Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 382(21):1969–73. 10.1056/nejmp2005630

  • CrossRef
  • Google Scholar

• 161

  World Health Organization. Draft Landscape of COVID-19 Candidate Vaccines. Available from: [https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines]

  • Google Scholar

• 162

  BioNTech and Pfizer get German approval for Covid-19 vaccine trial. Available from: [https://www.clinicaltrialsarena.com/news/biontech-pfizer-covid-19-vaccine-trial/]

• 163

  Coronavirus vaccine tracker. Available from: [https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html]

• 164

  COVID-19 Vaccines and Severe Allergic Reactions. Available from: [https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/allergic-reaction.html]

• 165

  Phase 3 clinical trial of investigational vaccine for COVID-19 begins. Available from: [https://www.nih.gov/news-events/news-releases/phase-3-clinical-trial-investigational-vaccine-covid-19-begins]

• 166

  When Will a Coronavirus Vaccine Be Ready? Available from: [https://www.theguardian.com/world/2020/apr/06/when-will-coronavirus-vaccine-be-ready]

  • Google Scholar

• 167

  Moderna Charts Fast Track of SARS-CoV-2 Vaccine to Clinical Trials. Available from: [https://www.clinicalomics.com/topics/patient-care/moderna-charts-fast-track-of-sars-cov-2-vaccine-to-clinical-trials/]

  • Google Scholar

• 168

  Meet the Company that Has Just Begun Testing a Coronavirus Vaccine in the United States Available from: [https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/allergic-reaction.html]

  • Google Scholar

• 169

  clinicaltrials: Safety and immunogenicity study of 2019-ncov vaccine (mrna-1273) for prophylaxis of sars-cov-2 infection (covid-19) (2020).

  • Google Scholar

• 170

  Kirby T (2020). Development of Potential COVID-19 Vaccines Continues to Accelerate. The Lancet Microbe. 1(3):e109. 10.1016/s2666-5247(20)30070-7

  • CrossRef
  • Google Scholar

• 171

  Philippidis A (2020). Moderna's COVID-19 Vaccine Speeds to Phase III Trial after More Positive Data. Mary Ann Liebert, Inc 140 Huguenot Street, 3rd Floor New Rochelle, NY.

  • Google Scholar

• 172

  U.S. Food and Drug Administration. Moderna COVID-19 Vaccine. Available from: [https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccine]

  • Google Scholar

• 173

  Novavax Identifies Coronavirus Vaccine Candidate; Accelerates Initiation of First-In-Human Trial to Mid-may. Available from: [https://ir.novavax.com/news-releases/news-release-details/novavax-identifies-coronavirus-vaccine-candidate-accelerates]

  • Google Scholar

• 174

  Novavax Advances Development of Novel Covid-19 Vaccine. Available from: [https://ir.novavax.com/news-releases/news-release-details/novavax-advances-development-novel-covid-19-vaccine]

  • Google Scholar

• 175

  COVID-19 vaccine trial. Oxford University to Recruit 500 Volunteers. Available from: [https://ahmedabadmirror.indiatimes.com/news/world/covid-19-vaccine-trial-oxford-university-to-recruit-500-volunteers/articleshow/74864262.cms]

  • Google Scholar

• 176

  University of oxford: New study reveals Oxford coronavirus vaccine produces strong immune response (2020).

  • Google Scholar

• 177

  A Study of a Candidate COVID-19 Vaccine (COV001). Available from: [https://clinicaltrials.gov/ct2/show/NCT04324606]

  • Google Scholar

• 178

  Folegatti PM Ewer KJ Aley PK Angus B Becker S Belij-Rammerstorfer S et al (2020). Safety and Immunogenicity of the ChAdOx1 nCoV-19 Vaccine against SARS-CoV-2: a Preliminary Report of a Phase 1/2, Single-Blind, Randomised Controlled Trial. Lancet396(10249):467–78. 10.1016/S0140-6736(20)31604-4

  • CrossRef
  • Google Scholar

• 179

  UK starts virus campaign with a shot watched round the world (2020). Available from: []

  • Google Scholar

• 180

  Khuroo MS Khuroo M Khuroo MS Sofi AA Khuroo NS . COVID-19 Vaccines: A Race against Time in the Middle of Death and Devastation!. J Clin Exp Hepatol. 10:610-621. 10.1016/j.jceh.2020.06.003

  • CrossRef
  • Google Scholar

• 181

  Kim E Erdos G Huang S Kenniston TW Balmert SC Carey CD et al (2020). Microneedle Array Delivered Recombinant Coronavirus Vaccines: Immunogenicity and Rapid Translational Development. EBioMedicine55:102743. 10.1016/j.ebiom.2020.102743

  • CrossRef
  • Google Scholar

• 182

  Zhang J Xie B Hashimoto K (2020). Current Status of Potential Therapeutic Candidates for the COVID-19 Crisis. Brain Behav Immun. 87:59-73. 10.1016/j.bbi.2020.04.046

  • CrossRef
  • Google Scholar

• 183

  Callaway E (2020). Russia’s Fast-Track Coronavirus Vaccine Draws Outrage over Safety. Nature. 10.1038/d41586-020-03209-0

  • CrossRef
  • Google Scholar

• 184

  ‘New York Times. This Is All beyond Stupid.’ Experts Worry about Russia’s Rushed Vaccine. Available from: [https://www.nytimes.com/2020/08/11/health/russia-covid-19-vaccine-safety.html?auth=login-facebook]

  • Google Scholar

• 185

  Logunov DY Dolzhikova IV Shcheblyakov DV Tukhvatulin AI Zubkova OV Dzharullaeva AS et al (2021). Safety and Efficacy of an rAd26 and rAd5 Vector-Based Heterologous Prime-Boost COVID-19 Vaccine: an Interim Analysis of a Randomised Controlled Phase 3 Trial in Russia. The Lancet397:671-681. 10.1016/S0140-6736(21)00234-8

  • CrossRef
  • Google Scholar

• 186

  Italian Study Shows Covid-19 Infections, Deaths Plummeting after Jabs Available from: [https://www.reuters.com/business/healthcare-pharmaceuticals/italian-study-shows-covid-19-infections-deaths-plummeting-after-jabs-2021-05-15/]

  • Google Scholar

• 187

  The U.S. Food and Drug Administration (FDA). Important Information on the Use of Serological (Antibody) Tests for COVID-19-Letter to Health Care Providers. Available from: [https://www.fda.gov/medical-devices/letters-health-care-providers/important-information-use-serological-antibody-tests-covid-19-letter-health-care-providers]

  • Google Scholar

• 188

  Kirkcaldy RD King BA Brooks JT (2020). COVID-19 and Postinfection Immunity. JAMA. 323(22):2245–6. 10.1001/jama.2020.7869

  • CrossRef
  • Google Scholar

• 189

  Dijkstra JM Hashimoto K (2020). Expected Immune Recognition of COVID-19 Virus by Memory from Earlier Infections with Common Coronaviruses in a Large Part of the World Population. F1000Res. 9(285):285. 10.12688/f1000research.23458.2

  • CrossRef
  • Google Scholar

• 190

  Nguyen A David JK Maden SK Wood MA Weeder BR Nellore A et al (2020). Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2. J Virol.94(13):94. 10.1128/JVI.00510-20

  • CrossRef
  • Google Scholar

• 191

  Broughton JP Deng X Yu G Fasching CL Servellita V Singh J et al (2020). CRISPR-Cas12-based Detection of SARS-CoV-2. Nat Biotechnol.38:870–4. 10.1038/s41587-020-0513-4

  • CrossRef
  • Google Scholar

• 192

  Mallapaty S (2020). Will Antibody Tests for the Coronavirus Really Change Everything?Nature. 580:571–2. 10.1038/d41586-020-01115-z

  • CrossRef
  • Google Scholar

• 193

  Galloway SE Paul P MacCannell DR Johansson MA Brooks JT MacNeil A et al (2021). Emergence of SARS-CoV-2 B.1.1.7 Lineage - United States, December 29, 2020-January 12, 2021. MMWR Morb Mortal Wkly Rep70(3):95–9. 10.15585/mmwr.mm7003e2

  • CrossRef
  • Google Scholar

• 194

  Kemp S Harvey W Datir R Collier D Ferreira I Carabelii A et al (2020). Recurrent Emergence and Transmission of a SARS-CoV-2 Spike Deletion ΔH69/V70. bioRxiv

  • Google Scholar

• 195

  Starr TN Greaney AJ Hilton SK Ellis D Crawford KHD Dingens AS et al (2020). Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. Cell182(5):1295–310. e1220. 10.1016/j.cell.2020.08.012

  • CrossRef
  • Google Scholar

• 196

  Chan CE Seah SG Massey S Torres M Lim AP Wong SK et al (2020). San Wong P, Lim JH, Loh GS: The Fc-Mediated Effector Functions of a Potent SARS-CoV-2 Neutralizing Antibody, SC31, Isolated from an Early Convalescent COVID-19 Patient, Are Essential for the Optimal Therapeutic Efficacy of the Antibody. bioRxiv. 10.1101/2020.10.26.355107

  • CrossRef
  • Google Scholar

• 197

  Tegally H Wilkinson E Giovanetti M Iranzadeh A Fonseca V Giandhari J et al (2020). Emergence and Rapid Spread of a New Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Lineage with Multiple Spike Mutations in South Africa. medRxiv. 10.1101/2020.12.21.20248640

  • CrossRef
  • Google Scholar

• 198

  Greaney AJ Loes AN Crawford KH Starr TN Malone KD Chu HY et al (2021). Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. Cell Host Microbe29(3):463–76.e6. 10.1016/j.chom.2021.02.003

  • CrossRef
  • Google Scholar

• 199

  Wibmer CK Ayres F Hermanus T Madzivhandila M Kgagudi P Lambson BE et al (2020). SARS-CoV-2 501Y. V2 Escapes Neutralization by South African COVID-19 Donor plasma. BioRxiv

  • Google Scholar

• 200

  Naveca F da Costa C Nascimento V Souza V Corado A Nascimento F et al (2021). SARS-CoV-2 Reinfection by the New Variant of Concern (VOC) P1. Amazonas. Brazilvirological org [Preprint] Available at: https://virological Available at: org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596

  • Google Scholar

• 201

  Voloch CM Ronaldo da Silva F de Almeida LG Cardoso CC Brustolini OJ Gerber AL (2020). de C Guimarães AP, Mariani D, da Costa RM, Ferreira OC: Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil. medRxiv.

  • Google Scholar

• 202

  Mak IWC Chu CM Pan PC Yiu MGC Ho SC Chan VL (2010). Risk Factors for Chronic post-traumatic Stress Disorder (PTSD) in SARS Survivors. Gen Hosp Psychiatry. 32(6):590–8. 10.1016/j.genhosppsych.2010.07.007

  • CrossRef
  • Google Scholar

• 203

  Gardner PJ Moallef P (2015). Psychological Impact on SARS Survivors: Critical Review of the English Language Literature. Can Psychology/Psychologie canadienne. 56(1):123–35. 10.1037/a0037973

  • CrossRef
  • Google Scholar

• 204

  Pfefferbaum B North CS (2020). Mental Health and the Covid-19 Pandemic. N Engl J Med. 383(6):510–2. 10.1056/nejmp2008017

  • CrossRef
  • Google Scholar

• 205

  Rajkumar RP (2020). COVID-19 and Mental Health: A Review of the Existing Literature. Asian J Psychiatry. 52:102066. 10.1016/j.ajp.2020.102066

  • CrossRef
  • Google Scholar

• 206

  Sun S Hou J Chen Y Lu Y Brown L Operario D (2020). Challenges to HIV Care and Psychological Health during the COVID-19 Pandemic Among People Living with HIV in China. AIDS Behav. 24(10):2764–5. 10.1007/s10461-020-02903-4

  • CrossRef
  • Google Scholar

• 207

  Health NIo (2020). COVID-19 Treatment Guidelines. Potential Antivir Drugs under Eval Treat COVID-19 Accessed. 26.

  • Google Scholar

• 208

  World Health Organization. Contact Tracing in the Context of COVID-19. Available from: []

  • Google Scholar

• 209

  Abrams EM Greenhawt M (2020). Risk Communication during COVID-19. J Allergy Clin Immunol Pract. 8(6):1791–4. 10.1016/j.jaip.2020.04.012

  • CrossRef
  • Google Scholar

• 210

  News WC (2020). Front-line Healthcare Workers Say Lack of Training, protection Puts Them at Risk for COVID-19.

  • Google Scholar

• 211

  World Health Organization. Strategy and Planning. Available from: []

  • Google Scholar

• 212

  Zhang W (2020). Imaging Changes of Severe COVID-19 Pneumonia in Advanced Stage. Intensive Care Med. 46:841–3. 10.1007/s00134-020-05990-y

  • CrossRef
  • Google Scholar

• 213

  Cansino Biologics’ Ad5-Ncov the First Covid-19 Vaccine to Phase Ii Clinical Trials Available from: [https://www.trialsitenews.com/cansino-biologics-ad5-ncov-the-first-covid-19-vaccine-to-phase-ii-clinical-trials/]

  • Google Scholar