COVID-19 Breaking Down A Glob

Mallah et al.
Ann Clin Microbiol Antimicrob

https://doi.org/10.1186/s12941-021-00438-7
(2021) 20:35
Annals of Clinical Microbiology
and Antimicrobials
REVIEW Open Access
COVID‑19: breaking down a global health

crisis
Saad I. Mallah1,2*, Omar K. Ghorab1, Sabrina Al‑Salmi1, Omar S. Abdellatif3,4, Tharmegan Tharmaratnam1,5,
Mina Amin Iskandar1, Jessica Atef Nassef Sefen1, Pardeep Sidhu1, Bassam Atallah6,7, Rania El‑Lababidi6 and
Manaf Al‑Qahtani2,8,9*
Abstract
Coronavirus disease 2019 (COVID-19) is the second pandemic of the twenty-first century, with over one-hundred
million infections and over two million deaths to date. It is a novel strain from the Coronaviridae family, named Severe
Acute Respiratory Distress Syndrome Coronavirus-2 (SARS-CoV-2); the 7th known member of the coronavirus fam‑
ily to cause disease in humans, notably following the Middle East Respiratory syndrome (MERS), and Severe Acute
Respiratory Distress Syndrome (SARS). The most characteristic feature of this single-stranded RNA molecule includes
the spike glycoprotein on its surface. Most patients with COVID-19, of which the elderly and immunocompromised
are most at risk, complain of flu-like symptoms, including dry cough and headache. The most common complications
include pneumonia, acute respiratory distress syndrome, septic shock, and cardiovascular manifestations. Transmis‑
sion of SARS-CoV-2 is mainly via respiratory droplets, either directly from the air when an infected patient coughs or
sneezes, or in the form of fomites on surfaces. Maintaining hand-hygiene, social distancing, and personal protective
equipment (i.e., masks) remain the most effective precautions. Patient management includes supportive care and
anticoagulative measures, with a focus on maintaining respiratory function. Therapy with dexamethasone, remdesivir,
and tocilizumab appear to be most promising to date, with hydroxychloroquine, lopinavir, ritonavir, and interferons
falling out of favour. Additionally, accelerated vaccination efforts have taken place internationally, with several promis‑
ing vaccinations being mass deployed. In response to the COVID-19 pandemic, countries and stakeholders have taken
varying precautions to combat and contain the spread of the virus and dampen its collateral economic damage. This
review paper aims to synthesize the impact of the virus on a global, micro to macro scale.
Keywords: COVID-19, Coronavirus, Pandemic, Global & Public Health, Infectious Diseases
Introduction (SARS-CoV-2), a novel strain from the Coronaviridae

Novel Coronavirus disease 2019 (COVID-19) was family, first isolated in Wuhan (China) after a cluster
crowned as the second pandemic of the twenty-first of outbreaks. SARS-CoV-2 is a positive-sense, single-
century by the World Health Organisation (WHO) on stranded enveloped RNA virus that transmits via res-
March 11th, 2020 [1]. COVID-19 is caused by the Severe piratory droplets and fomites. The virus causes a disease
Acute Respiratory Distress Syndrome Coronavirus-2 spectrum ranging from asymptomatic to severe acute
respiratory distress syndrome (ARDS), and death. Man-
agement of this novel disease remains largely supportive,
*Correspondence: [email protected]; [email protected]
1
School of Medicine, Royal College of Surgeons in Ireland, Bahrain,
with no approved medications available for treatment [2].
Kingdom of Bahrain Only after around two months since the initial case
2
The National Taskforce for Combating the Coronavirus (COVID-19), report in Wuhan, the first one thousand infections were
Bahrain, Kingdom of Bahrain
Full list of author information is available at the end of the article
recorded. Within a short period of time, the infection rate
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Mallah et al. Ann Clin Microbiol Antimicrob (2021) 20:35 Page 2 of 36
had grown exponentially, and as of February 25, 2021, the Chinese Center for Disease Control (China CDC).
over one-hundred and thirteen million infections have This resulted in a Chinese rapid response team dis-
been registered globally, with over two million deaths patched to undertake immediate investigations, and a
(~ 2.2% overall mortality to date, which has been reduced subsequent alert issued to the WHO (Fig. 1) [8, 9]. Since
from the ~ 5% mortality at the start of the outbreak) [3, then, the Wuhan Seafood Market, which was epidemio-
4]. As global leaders and civil servants worldwide enforce logically implicated in the outbreak, was shut down, dis-
life-altering regulations to contain the disease, scientists infected, and investigated [5, 7, 9, 10].
scramble to develop timely vaccines, and with healthcare In early January 2020, all mimicking etiologies such as
providers treating patients on the frontlines and testing the influenza virus, severe acute respiratory syndrome
new treatments, it is now more important than ever for
the research community to disseminate timely, evidence-
based, and up-to-date information about COVID-19
for the public and medical communities alike, both for
current and future reference. Therefore, the aim of this
review is to provide a holistic, comprehensive overview,
both in a retrospective and interim manner, of the rele-
vant epidemiology, pathogenesis, management, potential
therapies and vaccines, global efforts, disease burden, and
preventive measures that have and can be implemented
in the global pursuit of containing COVID-19.
Search strategy and selection criteria

A range of databases and search strategies were adopted
in order to curate a comprehensive overview that
addresses the topic from various angles. The WHO
Global COVID-19 Database, PubMed, Google Scholar,
and medRxiv were mainly searched. Additionally, the
WHO and US CDC webpages were often searched for
guidelines and data. External webpages such as Clini-
calTrials.gov, Our World in Data (OWID), the Oxford
COVID-19 Government Response Tracker (OxCGRT),
governmental and ministerial webpages, and other UN
and Economic related forums and reports were fre-
quently referenced. Alternatives of the ‘COVID-19’ term,
such as ‘2019-nCov’, ‘Novel Coronavirus’, ‘Coronavirus
2019’, ‘SARS-CoV-2’, ‘SARS-2’…etc. were used along-
side the terms relevant to each sub-header. Non-peer
reviewed work was at times referenced due to the excep-
tional nature of the topic at hand. Papers were only refer-
enced if they were primarily written in English or Arabic,
or secondarily referenced in English from a different
language. A diverse list of works were reviewed and dis-
cussed, ranging from case reports to systematic reviews.
Epidemiology
In late December 2019, numerous local healthcare insti-
tutions in Wuhan, Hubei Province, China had reported
several clusters of atypical pneumonia cases (27 cases
total) with signs and symptoms greatly resembling those
of viral pneumonia, seemingly linked to the South China
Seafood City (Huanan Seafood Wholesale Market) [1, 5–
7]. Shortly thereafter, on December 31, 2019, the Wuhan Fig. 1 Epidemiologic timeline of events concerning the COVID-19
pandemic [1, 5, 11–13]
Municipal Health Commission issued a notification to
coronavirus (SARS-CoV), and Middle East respiratory WHO reports a total of 112,224,022 confirmed cases
syndrome coronavirus (MERS-CoV) were excluded, and 2,491,171 confirmed deaths in 236 countries or ter-
and the causative agent recognised as a novel coronavi- ritories worldwide, equating to a resultant overarching
rus, now labelled as “severe acute respiratory syndrome death rate of 2.22% per case of COVID-19 [4]; it is worth
coronavirus 2 (SARS-CoV-2)” by the International Com- mentioning however, that the aforementioned percentage
mittee on Taxonomy of Viruses [7, 9, 14, 15]. It has been is a simplified calculation based on numbers provided by
genomically sequenced for the first time by scientists of WHO, and that earlier estimates of the actual global case
the National Institute of Viral Disease Control and Pre- fatality rate (CFR) vary between 0.3 and 3% [11, 26, 27],
vention [16]. with concrete evidence showing CFR to sharply increase
The initial transmission event(s), also known as ground with age and comorbidities [28], and by territory [11].
zero, are believed to have occurred at the Huanan Sea- Globally, the list of worst-affected countries includes the
food Market in Wuhan, via single or multiple animal- United States (28+ million cases; 500,000+ deaths), India
to-human transmission events, possibly from bats and (11+ million cases; 156,000+ deaths), Brazil (10+ mil-
pangolins captured and sold at the market. The magni- lion cases; 245,000+ deaths), Russia (4+ million cases;
tude of the initial bat-to-human transmission event is 85,000+ deaths), and the United Kingdom [UK] (4+ mil-
not yet known however [7, 16–18]. From those initial lion cases; 121,000+ deaths). [4]. The spread of COVID-
cases infected by zoonotic transmission, Chan et al. [19] 19 has not been proportional to the sizes of the regional
reported subsequent and successive human-to-human populations, which may indicate a range of contributing
transmission to have occurred. Chan et al. [19], reported factors, from containment and screening measures to
a case of a family of six who had travelled to Wuhan population demographics (Fig. 2).
from elsewhere in China, with no history of visiting the During the progression of the outbreak, the situation
market, but with a history of visit for only two of the six in Italy had been particularly concerning, with a CFR
members to a hospital in Wuhan; the first 2 members of 14.44% (95% CI 14.29–14.58) on May 26, 2020 [29].
contracted the virus from the hospital (possibly from an Additionally, it was reported that Italian infection rates
infected person), and then went on to transmit it to the mimic an exponential curve, with unease and doubt
remaining family members [19]. As such, results of Chan regarding whether the Italian healthcare system would be
et al. [19] are consistent with person-to-person transmis- able to cope [30]. Likewise, the outbreak that took place
sion and with travel-related transmission. in Iran had been of particular concern, specifically due to
While there has been some speculation regarding alter- the fact that at least six neighbouring countries (Bahrain,
native origins of the virus, such as it being engineered Iraq, Kuwait, Oman, Afghanistan, and Pakistan) have
in a laboratory and subsequently being released or acci- reported cases of COVID-19 related to travel from Iran
dentally escaping, Anderson et al., (2020) describes that [31].
SARS-CoV-2′s genomic features are highly inconsistent Likewise, the status of the United States had been just
with any laboratory-related scenario of spread/escape, re- as concerning, being the leading nation in cases and
emphasising its natural origins with relation to bats [20]. in deaths, housing over a fifth of the total number of
The emergence of SARS-CoV-2 coincided with the Chi- infected people worldwide. Even conservative estimates
nese Lunar New Year, which is China’s most celebrated reported in early 2020 showed that the outbreak in the
occasion, with millions of people traveling from their United States may push the American healthcare system
residence back to their families and hometowns in other beyond its capacity [32]. Indeed The United States had
provinces and cities [21]. With an estimated cumulative faced a dire shortage in Personal Protective Equipment
number of trips amounting to upwards of 3 billion over (PPEs) and ventilators in March 2020 [33], with a small
the 40-day holiday period, an estimated 5 million people national reserve not equipped for such an unprecedented
had already left Wuhan before the Chinese government demand [34]. An increase in ventilator production how-
implemented a travel ban in late January 2020, making ever soon followed, replenishing the CDC Strategic
containment of the outbreak difficult [21]. In fact, Zhao National Stockpile of Ventilators by September, 2020
et al. [22] found a strong correlation between domes- [35].
tic train-travel from Wuhan to other provinces and the The epicentre of the COVID-19 pandemic has been,
spread of SARS-CoV-2 across China. and continues to be, dynamic in nature. It had begun in
Shortly thereafter, positive cases for SARS-CoV-2 Asia, before transitioning to Europe, then the Americas,
began emerging worldwide, facilitated by air travel; both and back to Europe (UK) with a variant strain [4, 36]. The
Wuhan and Beijing airports had hundreds of flights to WHO had warned that Africa’s increasing infection rates
22 and 54 countries daily, respectively, before the imple- may possibly place it as the next epicentre for the pan-
mented travel bans [23–25]. As of February 25, 2021, the demic [37], but that did not seem to manifest.
Fig. 2 Comparison between prevalence of COVID-19 cases in each continent as a percentage of global cases, and their respective population size
as a percentage of global population [11]
A number of studies have attempted to model the epi- while the majority of countries, such as the United States,
demiological trajectory of the COVID-19 pandemic. Canada, Italy, Iran, Turkey, and the United Kingdom had
Neher et al. (2020), demonstrated that simulation models cases doubling every 2 to 5 days [43]. This of course was
show a small peak in early 2020, followed by a larger peak largely fluctuating as the outbreak progressed.
in winter 2020/2021 in temperate regions of the Northern Over time, variant strains of COVID-19 began to
Hemisphere [38]. In contrast to this, Wilson et al. (2020) appear, often with slightly varying characteristics. The
reported that predictions of infection rates and CFRs new highly transmissible SARS-CoV-2 strain/variant
are highly variable and difficult to establish, given COV- identified in the UK (London and southeast England) in
ID-19’s widespread reach and country-specific infec- December, 2020 (named “VUI-202012/01” or “B.1.1.7”)
tion rates, control efforts, and wildly varying testing and has since spread to many countries, including Ireland,
reporting rates [39]. Indeed, an early predictive model set Denmark [44], India [45], and Italy [46]. Since then, other
forth by the CoronaTracker Community Research Group seemingly related and newly identified variants have been
anticipated the outbreak to peak before February 20, implicated in surges of cases in France, South Africa,
2020, which did not occur [40]. The US Centre for Dis- Israel, Brazil, Japan, and South Korea [44] (REFERENCE
ease Control (CDC) however has been utilising a diverse 1002), creating public unrest and stress on the already-
list of models from various universities and institutes that strained global public health and vaccination efforts to
adopt a range of statistical and machine learning meth- contain COVID-19 [47]. Another novel strain (named
odologies, to a fair degree of accuracy [41]. Furthermore, “501Y.V2”, which shares one mutation with B.1.1.7 [48],
attempts at forecasting epidemiologic dynamics via novel first identified in South Africa [49], has also spread to
markers, such as mean viral loads as indicated by Cycle neighbouring Botswana, as well as distant countries such
threshold values, have surfaced [42]. It is worth mention- as the UK and France [44, 48, 49].
ing, however, that the disease trajectory to date has been
exponential: It took around 3 months for the first 500,000 Virulence
cases to be registered, and a week for the second 500,000. The causative agent of COVID-19 is the SARS-CoV-2,
Likewise, it took two weeks to get from the first million to which has become the 7th known member of the
the second, but three days from the 31st to the 32nd mil- coronavirus family that causes disease in humans. It
lion [3]. As of July 2020, countries such as China, Japan, is a beta-coronavirus that consists of a long single-
Singapore, and most Middle East countries reported a stranded positive-sense RNA molecule, surrounded
doubling number of cases between every 5 to 10 days, by a lipid envelope that anchors many structural viral
glycoproteins, most important of which is the spike gly- mucosal membranes. In about 80% of cases, the virus
coprotein [50]. The virus has been found to be about 80% resides in the upper respiratory tract leading to an innate
similar in genetic sequence to SARS-CoV, with less simi- immune response that is mild and requires conservative
larity to MERS-CoV [18]. An earlier phylogenetic analysis symptomatic therapy. The remaining 20% of cases expe-
of 103 strains of SARS-CoV-2 in China showed that there rience a much severe form of the disease; the virus dif-
are two different types of the virus, an L type and an S fusely invades and destroys lung alveolar cells, leading to
type, with the L type forming the majority (70%) of the a systemic inflammatory response with ‘cytokine storm’,
isolated strains [51]. followed by healing and fibrosis [10, 61]. One study has
The SARS-CoV-2 protein likely to be involved in the suggested that intussusceptive angiogenesis may be a part
pathogenesis of COVID-19 is its spike glycoprotein, of the pathophysiology of COVID-19; this is a unique dis-
which has been shown to interact with host cell targets ease characteristic when compared to other viral illnesses
such as the ACE2 receptor and CD26, and is the same like influenza. However, this association remains to be
viral protein involved in the pathogenesis of SARS [2, 52]. further studied and confirmed [62]. Regarding extra-pul-
The spike glycoprotein consists of two subunits: S1 (for monary manifestations, the virus may disseminate into
ACE2 receptor binding), and S2 (for plasma membrane the blood and affect organs that express ACE2 receptors,
fusion). Upon plasma membrane fusion, the spike pro- such as the lungs, heart, kidneys, and gastrointestinal
tein is cleaved by host proteases, releasing a spike fusion tract [63, 64].
peptide which facilitates viral entry into the host cell [53, Disease severity ranges from asymptomatic to severe,
54]. It has been shown that the SARS-CoV-2 spike glyco- with the latter shown to be associated with older age
protein has a stronger binding affinity to host cell ACE2 and presence of comorbidities [65]. The most com-
receptors than SARS-CoV, and therefore a higher infec- mon symptoms being reported are fever and cough [66].
tious potency [55]. Moreover, the SARS-CoV-2 spike Severe disease involves acute respiratory distress syn-
glycoprotein has been shown to contain a unique cleav- drome (ARDS), which can also be associated with severe
age site not found in other SARS-like coronaviruses [56]. pneumonia. In fact, the most commonly reported cause
The identification of the unique features of SARS-CoV-2 of death is respiratory failure [67]. The pneumonia most
such as its spike glycoprotein, the host cell receptors it commonly presents with bilateral multiple lobular and
binds, and the host proteases that act on the virus could subsegmental areas of ground-glass opacities on CT
be essential in understanding disease pathogenesis, and scan [68]. Non-respiratory complications of COVID-
therefore identifying potential treatment modalities. 19 may include septic shock (reported in 81.2% of non-
The source of SARS-CoV-2 is difficult to confirm, how- survivors in one case series) [69], acute liver injury [70],
ever it most likely originated from bats due to its genetic acute kidney injury [71], ocular problems [72], neuro-
similarity to bat coronaviruses. Zhou et al. (2020) were logical manifestations [73], and resemblances of dis-
the first to display that the SARS-CoV-2 is 96% identical seminated intravascular coagulation (reported in 71%
to the bat coronavirus at the whole-genome level [18], of non-survivors in a case series) [74]. Another compli-
and this figure was similarly reported by Yu et al. (2020), cation of increasing concern is the formation of diffuse
who reported that the virus was 96.11% identical to a bat microvascular thrombi—this has led some health institu-
SARS-like coronavirus strain (RaTG13) [57]. It is also yet tions worldwide to recommend thromboprophylaxis for
to be identified whether virus transmission is directly all COVID-19 patients [75].
from one organism, or through an intermediate host. Several months after the start of the outbreak, a Kawa-
Pangolin coronaviruses were found to be 91.02% identi- saki-like disease had been associated with COVID-19
cal to SARS-CoV-2 at the whole genome level (second presentation; one province in Italy had detected a 30-fold
most identical after RaTG13 bat coronavirus), and there- increase in the incidence of Kawasaki-like disease [76].
fore there is great belief that pangolins may be the inter- Now referred to as multisystem inflammatory syndrome
mediate hosts for virus transmission to humans [58, 59]. in children (MIS-C), the most common associated signs
Another study by Zhu et al. (2020) suggested that bats and symptoms include abdominal pain, vomiting, skin
and minks are the two reservoirs of the virus, with minks rash, diarrhoea, and hypotension, with a majority hav-
being the intermediate hosts [60]. ing gastrointestinal, cardiovascular, and/or dermatologic
or mucocutaneous involvement. The complications are
Pathogenesis often severe, requiring ICU care in the majority of cases
The complete pathogenesis of SARS-CoV-2 is yet to [77].
be fully comprehended. It is believed that the virus is COVID-19 has also been linked with chemosensory
inhaled through respiratory droplets and acquires entry dysfunction; loss of sense of taste and smell has been
into the respiratory tract through the nasopharyngeal widely reported in cases of COVID-19, sometimes
as the only symptom [78, 79]. This has led the WHO Transmission and precautions
to add loss of smell and/or taste to the official list of COVID-19 is transmitted from person-to-person
COVID-19 symptoms [80]. through droplet spread, similar to other subtypes of
When compared to SARS and MERS-CoV from a the coronavirus family. The virus may infect a host by
clinical perspective, COVID-19 shares many of the coming in contact with any mucosal linings, including
clinical features seen in those diseases; however, it mouth, nostrils, and eyes, either directly as respiratory
has been associated with fewer occurrences of gastro- air droplets (suspended in the air when an infected per-
intestinal and upper respiratory tract symptoms [81]. son coughs, sneezes, or talks) or by touching a contami-
Several other complications and underlying pathologic nated surface and then touching a mucosal surface (when
mechanisms continue to be reported as potentially droplets rest on a surface; fomites) [101]. COVID-19′s
associated with COVID-19 (Fig. 3) [77, 82–86]. reproduction number (R0) continues to fluctuate, with
estimates from a meta-analysis ranging from 1.4 to 6.49,
with a mean of 3.28, a median of 2.79; which is higher
Risk factors than that of SARS [102].
The presence of comorbidities has been associated Most worryingly, viral spread can occur through
with a worse COVID-19 prognosis; these specifically infected asymptomatic individuals, referred to as asymp-
include cardiovascular disease, diabetes, respiratory tomatic transmission. This is largely due to the virus’s
disease, and smoking [87, 88]. Elevated levels of blood rather long incubation period, the median of which is
markers such as lactate dehydrogenase, D-dimers, estimated around 5.1 (95% CI 4.5 to 5.8) days, but can
procalcitonin, serum ferritin, and interleukin-6, as extend to over 14 days in some cases. By 11.7 days (95%
well as leucopoenia, were also found to be associ- CI 9.7 to 14.2), 95% of people have been shown to dem-
ated with worse COVID-19 outcomes, and therefore onstrate symptoms of the disease [103].
could potentially be used to monitor disease prognosis In a study exploring aerosol and surface stability,
[89–91]. The cytokine storm induced by SARS-CoV-2 SARS-CoV-2 was found to have a very similar profile to
brings with it a multitude of cytokines; Yang et al. [68] SARS-CoV in terms of stability kinetics [104]. The esti-
found that interferon gamma induced protein (IP10), mated median half-life of SARS-CoV-2 in aerosols is
interleukin-1 receptor antagonist (IL-1ra), and mono- believed to be 1.1 to 1.2 h (95% CI 0.64 to 2.64). Both
cyte chemotactic protein-3 (MCP-3) were significantly viruses were more stable on plastic and stainless steel,
associated with increased COVID-19 severity and pro- with viable viruses still detected after 72 h of contamina-
gression [92]. One case series suggested that throm- tion. The half-life of SARS-CoV-2 on stainless steel and
bocytopenia was significantly associated with death in plastic were 5.6 days and 6.8 days respectively. On copper,
COVID-19 [93]. The use of non-steroidal anti-inflam- no viable SARS-CoV-2 was measured after 4 h, in con-
matory drugs (NSAIDs) during suspected COVID-19 trast to SARS-CoV-1 which was only undetectable after 8
had also been widely discouraged, due to belief that hours [104]. Contrary to this, on cardboard SARS-CoV-2
those drugs may worsen disease outcomes [94]. Recent lasted longer (24 h) than SARS-CoV-1 (8 h) [104]. The
evidence however seems to suggest there may be no estimated median half-life of SARS-CoV-2 in aerosols is
increased risk posed [95]. Other reports hypothesized believed to be 1.1 to 1.2 h (95% CI 0.64 to 2.64) [104].
that ACE inhibitors and nicotine exposure may be Closed-environments are believed to be grounds for a
associated with cardiorespiratory manifestations in superspreading event in the transmission of COVID-19.
COVID-19 due to upregulation of ACE-2 receptors In one study in Japan, 110 positive cases among eleven
(which is essential for SARS-COV-2 cell entry), how- clusters were contact traced. The study found that the
ever this remains to be properly studied [96–98]. A odds of a primary case transmitting COVID-19 in a
protective role however has also been suggested due closed-environment was 18.7 times greater compared to
to the drug limiting angiotensin II related pro-inflam- an open-air environment, (95% CI 6.0–57.9). The odds of
matory signalling, as well as limiting breakdown of a superspreading event (defined in this case as transmis-
bradykinin, which would attenuate hypertension and sion to three or more persons), in a closed environment
prevent ventricular apoptosis [99]. In fact, paradoxi- was as high as 29.8 that of an open-air environment (95%
cally, ACE inhibitors suppress TMPRSS2 expression CI 5.8–153.4) [105].
which is an essential co-receptor for SARS-COV-2 cell The association of weather or meteorological factors
entry [99]. Evidence on the effect of NSAIDs and ACE with the spread of COVID-19 has been highly contested
inhibitors on COVID-19 outcomes remains inconclu- in public and scientific discourse. One study from China
sive [100]. found that meteorological factors play an independent
role in COVID-19 transmission. Specifically, that low
ARDS = Acute Respiratory Distress Syndrome DVT = Deep Vein Thrombosis, DIC = Disseminated
Intravascular Coagulopathy, MI = Myocardial Infarction, PE = Pulmonary Embolism, MIS-C =
Multi-inflammatory Syndrome in Children
Fig. 3 Complications reported to be potentially associated with COVID-19 [77, 82–86]
temperatures, low humidity, and a mild diurnal (daytime) and 0.7, and also multiplicatively, wherein the increase
temperature range favours the transmission [106]. On in R ranged between a 50% and 75% advantage [110].
the other hand, another study from China as well, found Additionally, there has been a small shift towards peo-
that after adjustment for relative humidity and ultraviolet ple under their 20 s being more affected by the VOC,
(UV) radiation, temperature had no significant associa- but the mechanism that underlies these differences is
tion with cumulative incidence rate, indicating that trans- not yet understood [110].
mission of the virus would not change with increasing From a sexual transmission standpoint, SARS-
temperature. Furthermore, exposure to UV radiation was CoV-2 has been detected in the semen of patients
not significantly associated with cumulative incidence with COVID-19 and may also be present in the semen
rate after adjusting for temperature and relative humid- of recovering patients. Owing to the fallibility of the
ity either. Relative humidity, maximum temperature, and blood-testis/deferens/epididymis barriers, SARS-
minimum temperature, were likewise not significantly CoV-2 may be seeded to the male reproductive tract,
associated with cumulative incidence rate or the repro- especially in the presence of systemic local inflamma-
duction number of COVID-19 [107]. tion. It has not been proven, however, that COVID-19
Although the main mode of SARS-CoV-2 transmis- can be spread through sexual transmission [111]. Simi-
sion is person-to-person, a number of isolated cases of larly, the virus has also been detected in other non-
animals have been reported to test positive for SARS- respiratory samples such as stool, blood and ocular
CoV-2 following close contact with infected humans. secretions [112, 113].
Preliminary findings suggest that, of the animal species With regards to pregnant women, physiological
investigated so far, cats are the most susceptible species changes in pregnancy and an immunocompromised sta-
to SARS-CoV-2 and can be affected with clinical disease. tus could increase susceptibility [114]. However, evidence
In the laboratory setting, cats were able to transmit infec- suggests no risk of increased maternal–fetal transmis-
tion to other cats. Ferrets also appear to be susceptible sion. In a cohort of 38 pregnant women, Schwartz et al.
to infection but less so to disease and were also able to (2020) [115] reported no evidence of transplacental or
transmit infection to other ferrets. Dogs appear to be intrauterine transfer. The WHO reports that pregnancy
susceptible to infection but appear to be less affected and childbirth do not necessarily aggravate the disease
than ferrets or cats. Egyptian fruit bats were also infected course in the mother [116]. Additionally, the literature is
in the laboratory setting but did not show signs of dis- limited with regards to whether COVID-19 can be trans-
ease or the ability to transmit infection efficiently to mitted in breast milk. In a sample of 6 women, Mullin
other bats. To date, these preliminary findings suggest et al. (2020) [117] were unable to report any findings of
that poultry and pigs are not susceptible to SARS-CoV-2 the virus in maternal breast milk. However, a sympto-
infection [108]. Despite this, there is no evidence to sug- matic mother may transmit the illness if in close contact
gest that infected animals are playing a role in the spread with the neonate. Therefore, social distancing is impor-
of COVID-19. Nevertheless, the WHO advises caution at tant, and following appropriate precautions, pumped
live animal markets and avoiding any direct interaction. breast milk may be fed to the neonate by another car-
Good food safety practices are also recommended espe- egiver. During this process, the mother should ensure
cially when dealing with raw animal products [101]. she follows strict contact precautions, such as wearing
One of the newest COVID variants; B.1.1.7 VOC gloves and a face mask, to reduce the risk of transmis-
(Variant of Concern) 202012/01, first detected in the UK sion, as well as the routine disinfection of surfaces. Note
and predominantly identified in people younger than that breastfeeding should not be discouraged unless the
60 years, has been linked to an increasing incidence of mother is acutely ill [118].
COVID-19, but higher mortality or particularly affected The most important public precaution to contain
groups have not been reported according to the Euro- the outbreak remains to be social distancing [119]. It is
pean Centre for Disease Prevention and Control [109]. advised to remain at home except for necessity, which
Upon further investigation, trends have shown that VOC has prompted the implementation of various travel bans,
202012/01 has clear transmission advantage over the curfews, strict screening procedures, and self-isolation or
non-VOC strain. Epidemiological studies have shown governmental/hospital quarantine [120]. Moreover, mass
that despite the increased transmissibility, the VOC cases gatherings are not advised [121]. The American Acad-
are expected to decline faster than non-VOC cases [110]. emy of Ophthalmology also recommends wearing glasses
An epidemiological study from the Imperial College instead of contact lenses, to decrease eye-touching ten-
of London has quantified the transmission advantage of dencies [122]. Finally, it is advised to keep a minimum of
the VOC in comparison to the non-VOC lineages both 2 m distance between individuals to minimise transmis-
additively as an increase in R that ranged between 0.4 sion [80].
As of April 3 2020, the CDC also recommends wear- Whether COVID-19 is airborne or not has been a
ing cloth face coverings in public settings, especially source of uncertainty during the start of the outbreak.
in areas of significant community-based transmission In fact, 239 scientists submitted signatories appealing to
[123]. There has been much debate regarding the effec- the medical community and relevant national and inter-
tiveness of various forms of face coverings. A meta- national bodies to recognise the potential for airborne
analysis of RCTs found that surgical/medical masks spread of COVID-19, via microscopic respiratory drop-
offered similar protection against viral respiratory lets at a distance of up to several meters [100]. Experi-
infection (including coronavirus) in health-care work- mental data supports the possibility that SARS-COV-2
ers during non-aerosol generating care as N95 respira- may be transmitted via aerosols produced emitted during
tor masks [124]. Another systematic review found that speaking and coughing, which can travel for up to 27 feet.
that cloth face coverings offered limited efficacy com- This so-called airborne transmission has become a worry
pared to medical grade masks, but can be improved as SARS-COV-2 RNA was shown to be recovered from
by using a multi-layer cloth mask made of cotton in air-samples in hospitals; underlining the risk of poor ven-
combination with synthetic cloth material, as well as tilation prolonging the amount of time in which aerosols
by improving the fit, and disinfecting it regularly [125]. will remain airborne and thus an infection risk [129].
Finally, a population modelling study found masks of Despite the presence of such data indicating the possibil-
various efficacy to be useful in preventing both illness in ity of aerosol-based transmission, data on infection rates
health individuals as well as preventing asymptomatic and transmissions in populations during normal daily
transmission. Hypothetical scenarios of near-universal life has proven difficult to reconcile with long-range air-
(80%) adoption of moderately (50%) effective masks in borne/aerosol-based transmission [131].
US states were found to potentially prevent 17–45% of Nonetheless, for the time being, the use of airborne
projected deaths over two months. Even masks of very precautions, specifically the use of the N95 Respirator
low (20%) efficacy were found to be useful if underly- Masks or equivalent, is warranted in aerosol-producing
ing transmission rates were low or decreasing, reduc- procedures as declared by the CDC, under Section 1
ing mortality by up to 24–65% in such scenarios [126]. of their guidelines: [https://www.cdc.gov/coronavirus/
As such, in view of the evidence, universal face cover- 2019- n cov/ h cp/ i nfec t ion- contr o l- recom m enda t ions.
ing/masking has been adopted as a potentially effective html] These procedures include tracheal intubation, non-
public health tool in curtailing community transmis- invasive ventilation, manual ventilation before intuba-
sion [127]. tion, bronchoscopy, administration of high-flow oxygen
These extreme measures are necessary to curb the or nebulized medications, tracheotomy, cardiopulmo-
transmission rates and for individuals to protect them- nary resuscitation, and upper endoscopy, but not naso-
selves and others by decreasing the likelihood of expo- pharyngeal or oropharyngeal specimen collection [132].
sure to those sick or infected, while also decreasing Another precautionary method of interest had been the
transmission by infected individuals. The overwhelming use of hydroxychloroquine in post-exposure prophylaxis.
of healthcare systems would otherwise be an imminent This, however, has not proven to be particularly effective.
risk. Other important measures include maintaining In a randomized trial of hydroxychloroquine as post-
hand hygiene and avoiding touching the face after touch- exposure prophylaxis for COVID-19, the incidence of
ing other surfaces [128]. Studies on symptomatic patients new illness compatible with COVID-19 did not differ sig-
showed that significant environmental contamination by nificantly between those receiving hydroxychloroquine
patients with SARS-CoV-2 through respiratory droplets and participants receiving placebo [133]. Hydroxychloro-
and fecal shedding suggests that the environment is a quine has also completely failed as an effective prophy-
potential medium of transmission and supports the need laxis in a double-blind, placebo-controlled trial among
for strict adherence to environmental and hand hygiene health-care workers [134]. Alternatively, the most prom-
and precaution [129]. ising prophylaxis thus far, is the use of the COVID-19
In addition to the above-mentioned public precau- vaccines [135].
tions, the Recommended Interim Infection Prevention
and Control (IPC) Recommendations for Patients with Screening and diagnosis
Suspected or Confirmed COVID-19 in Healthcare Set- Successful containment of COVID-19 is heavily reliant
tings by the CDC provides an extensive list of preventive on its accurate diagnosis and efficient population screen-
measures for both healthcare professionals and patients ing. Currently, nucleic acid testing to detect SARS-CoV-2
under Section 2 of their guidelines: [https://www.cdc. (RNA genetic identification) is the primary method of
gov/coronavirus/ 2019-ncov/hcp/infection-control-rec- diagnosis. Reverse transcription polymerase chain reac-
ommendations.html] [130]. tion (RT-PCR) kits, using upper or lower respiratory
samples, is considered gold standard [136]. Due to short- planning to board a flight, it was estimated for the base-
age of kits, and fairly high false negative rates, CT scans line scenario that 44% (95% CI 33–56) of them would be
(reported variably with higher sensitivities [137]) have detected by exit screening, no case (95% CI 0–3) would
been considered for use in patients with clinical and develop severe symptoms during travel, another 9% (95%
epidemiologic indications for COVID-19 but a nega- CI 2–16) additional cases would be detected by entry
tive RT-PCR [138, 139]. CT scans may also be benefi- screening, and the remaining 46% (95% CI 36–58) would
cial as a prognostic test to ascertain disease progression not be detected [147]. Overall, viral testing is only one
[138, 139]. COVID-19 patients with pneumonia may aspect of what should be a comprehensive approach to
in fact have lung abnormalities on chest CT (ground- outbreak containment via surveillance, including symp-
glass opacities), but an initially negative RT-PCR [140]. tom-screening and intensive contact tracing [148].
Of note however, up to approximately 50% of patients More innovatively, a study by Qin et al. [149] attempted
with COVID-19 infection may have normal CT scans to create an effective and affordable model to predict new
0–2 days after onset of flu-like symptoms [138]. Addi- cases in a population. Influenced by the current context
tionally, CT findings, which have much lower specificities of the digital age, social media search indexes (SMSI) for
thant viral tests, may overlap with many other viral res- “dry cough”, “fever”, “chest distress”, “coronavirus”, and
piratory illnesses and may be completely absent in many “pneumonia” were tracked and collected from December
positive patients [141]. The former points must thus be 31st, 2019 to February 9th, 2020. SMSI was found to be a
considered when diagnosing patients and interpreting predictor of new suspected COVID-19 confirmed cases,
the results. The American College of Radiology’s recom- and could be detected 6–9 days earlier than the official
mendations echo those of the CDC, which emphasise diagnostic confirmation [149]. This social media-driven
that viral testing (more conventionally, RT-PCR) remains approach could therefore be used by national task forces
the most specific and confirmatory standard test for to estimate the new incidence of disease symptoms in the
COVID-19 [141]. population and prepare accordingly.
Current progress is being made to develop rapid and
accurate point-of-care tests that would reduce the bur- Patient management
den on clinical laboratories and speed up the screening Management of COVID-19 is contingent on disease
process. For instance, the FDA authorized use of a point- severity. In patients with mild disease, the CDC and
of-care test delivering positive results in as little as five WHO recommend home isolation in an effort to allevi-
minutes and negative results in 13 min. The molecular ate the burden on healthcare systems worldwide. Addi-
test identifies a small section of the virus’ genome then tionally, in patients with mild disease, hospitalization is
amplifies it for detection [142]. Antigen testing, specifi- not advised unless signs of rapid deterioration are evi-
cally rapid forms, have also been a centre of attention, dent, such as respiratory distress [132, 150, 151]. Patients
with some countries making them available commer- should be educated about important self-isolation meas-
cially [143]. However, antigen tests are generally consid- ures, such as wearing a face mask at home, disinfecting
ered less sensitive than RT-PCR, but just as specific [144, commonly touched services in co-habited areas, not shar-
145]. As such, a negative test should often be followed up ing washrooms or utensils, and practising social distanc-
by an RT-PCR test, which remains the gold standard for ing. According to the CDC, the decision to discontinue
diagnosing COVID-19 [145]. Other tests that are less fre- home isolation is contingent on both test and non-test
quently used or undergoing testing, utilise loop-mediated based strategies (see: https://www.cdc.gov/coronavirus/
isothermal amplification, lateral flow, and enzyme-linked 2019- n cov/ h cp/ d ispo s ition- i n- h ome- p atie nts. html).
immunosorbent assays [100, 107]. The decision as to which strategy to employ is based on
As for screening, it is an essential tool for risk commu- patient and system-level factors such as co-morbidities,
nication, and thus outbreak containment. Several studies immunogenicity, and the availability of testing resources.
have attempted to estimate the effectiveness of current A non-test-based strategy involves discontinuing home
common screening procedures. Gostic et al. [146] found isolation if at least 24 h have passed since resolution of
that in a growing epidemic, and under best-case assump- fever without the use of anti-pyretic medications, and
tions, the median fraction of infected travellers detected other symptoms (e.g. cough, shortness of breath) have
is only 0.30 (95% confidence interval: 0.10–0.53). The improved. In addition, at least ten days must have passed
total fraction detected was found to be lower for pro- since the appearance of symptom onset. Alternatively,
grams with only one layer of screening, with arrival the test-based strategy additionally involves two negative
screening preferable to departure screening considering results on nasopharyngeal swabs at least ≥ 24 h apart but
possibility of developing symptoms during travel [146]. is generally not recommended (due to prolonged viral
In a simulation of 100 SARS-CoV-2 infected travellers shedding in some cases despite lack of contagiousness)
except in cases of severe immunosuppression or if other- may worsen mortality-related outcomes due to the
wise indicated [152]. increased risk of bleeding—Instead, a prophylactic-
In the case of outpatients with mild to moderate dis- intensity anticoagulation dosage is recommended if no
ease who are at high risk of disease progression, SARS- thrombosis is suspected or confirmed [160, 161]. A high-
CoV-2 neutralizing antibodies (e.g., bamlanivimab plus intensity pharmacologic thromboprophylaxis (interme-
etesevimab or casirivimab plus imdevimab) may be con- diate dose low-molecular-weight heparin) in selected
sidered [153, 154]. intensive care patients may be ideal to balance between
While patients with mild disease may be able to self- the increased risk of bleeding in this critically ill patient
isolate and recover, those with severe disease require population and the overall COVID-19 related pro-
hospitalization. This may include complications of thrombotic state. However, randomized controlled trials
SARS-CoV-2 such as pneumonia, ARDS, and sepsis. In are needed to evaluate this strategy. Generally, it is cru-
response to the COVID outbreak, the CDC has devel- cial to evaluate overall bleeding and thrombosis tenden-
oped a preparedness checklist for hospitals to optimize cies to ensure a personalized management plan informed
management of patients from triage to discharge (See: by the presence of co-morbidities, contraindications (e.g.,
https:// w ww. c dc. g ov/ c oron avirus/ 2 019- n cov/ d ownl bleeding tendencies), and other patient-level factors.
oads/hcp-preparedness-checklist.pdf ], as well as interim-
clinical guidance for management of confirmed cases Management in children
[See: https://www.cdc.gov/coronavirus/2019-ncov/hcp/ The literature suggests that children generally display
clinical-guidance-management-patients.html). milder disease and have a better prognosis than adults
Upon admission after triage, regular vital signs should [162–164]. In a systematic review of 45 studies, Lud-
be monitored to prevent clinical deterioration such as vigsson (2020) concluded that children generally have a
septicaemia and ARDS. Antimicrobial agents should also milder spectrum of disease, and overall, have accounted
be given if a clinical diagnosis of pneumonia is made. In for only 1–5% of all COVID cases, with death being
addition, the use of supplemental oxygen may be war- exceedingly rare [164]. In another study of 2000 children
ranted with high-flow oxygenation and non-invasive pos- from China, Dong et al. [216] reported that only 13%
itive pressure ventilation if hypoxemic respiratory failure of children with COVID-19 were symptomatic [165].
is suspected. More severe cases may warrant the need However, a limitation of this study was that ‘infected’
for invasive mechanical ventilation or ECMO. Antivirals status was based on clinical diagnosis and not labora-
(e.g. remdesivir) and, more importantly, corticosteroids tory confirmation [166]. In another more recent system-
(e.g. dexamethasone) may be warranted in cases of severe atic review of clinical manifestations in children with
disease. More recently, anti-inflammatories such as toci- COVID-19, 1124 RT-PCR-confirmed cases from 38 stud-
lizumab have gained interest. The WHO and US National ies were included. Out of the cases with severity classified
Institute of Health, as well as a wide range of institutions (n = 1117), 14.2% were asymptomatic, 36.3% mild, 46.0%
worldwide, continue to update and publish their recom- moderate, 2.1% severe, and 1.2% were critical. It should
mendations as new evidence appears. (A living WHO be noted however that since the results are from patients
guideline on drugs for COVID-19: https://www.bmj. who presented for medical attention, it is likely that they
com/content/370/bmj.m3379) (The US NIH COVID-19 overestimate the severity of illness in children. Overall,
treatment guidelines: https://www.covid19treatmentguid clinicians should have a high level of clinical suspicion,
elines.nih.gov/whats-new/). since most cases of COVID-19 in children are asympto-
Considering the prevalence of coagulopathies as a matic or mild, and since reported symptoms of fever and
cause of mortality in COVID-19 patients, standard dose respiratory illness were noted to be not as prevalent as
antithrombotic prophylaxis has been recommended in with adult cases [167].
order to circumvent incidences of venous and arterial An asymptomatic state could provide the perfect
thrombotic events in hospitalised patients with mild opportunity for children to be implicated in community-
disease. Full-dose therapeutic low-molecular-weight based transmission as asymptomatic carriers, and be
heparin should also be considered in moderately ill hos- implicated in family cluster outbreaks, thus emphasis-
pitalised patients, and should be considered in the case ing the importance of educating them about maintaining
of patients with mild disease who present with indicators appropriate hygiene, social distancing, and reassurance
of hypercoagulability (e.g. elevated D-Dimer levels) or aimed at mitigating fears regarding the illness. While
confirmed VTE (positive point of care ultrasound or CT children may have a better prognosis than adults, this
angiography) [155–159]. Recent data however suggests does not necessarily mean they are less susceptible to
that in the case of patients with critical illness or those infection with SARS-CoV-2. In fact, Zheng et al. [162]
admitted to the ICU, therapeutic dose anticoagulation reported that while children have more favourable
prognoses, those < 3 years often had critical illness in the controversies regarding the interplay of the virus with
form of pneumonia, which may be due to close contact the cardiovascular system. The first question of whether
with a caregiver or family member [162]. Additionally, patients with chronically up-regulated ACE2 recep-
one retrospective study from. tors, such as those on ACE inhibitors, are more prone
Pediatric cases in Wuhan suggests that children to viral uptake has been a topic of debate. The second
younger than 2 years were most susceptible to SARS- being the need to stop, start, or continue such medica-
CoV-2 from the pediatric population [168]. Thus, in tions and their effect on the progression of the virus.
hospitalized children management should include intra- The ACE-like enzyme appears to partially reverse the
venous fluids, oxygen support, nutritional aid, and effects of its homolog by reverse converting angioten-
maintaining electrolyte balance [164]. In children with sin II to angiotensin 1–7. This will theoretically result in
airway compromise, respiratory distress, or suspected lessening the known vasoconstriction and remodelling
sepsis, airway management and oxygen therapy to tar- effects associated with the renin–angiotensin–aldoster-
get SpO2 > 94% are essential to improve clinical out- one system (RAAS), which is a hypothesis that has been
comes [169]. If mechanical ventilation is unavailable, utilized to explain the benefits of this strategy in animal
bubble continuous positive airway pressure (CPAP) is models [174, 175]. The lack of data and randomized tri-
recommended as an alternative [170]. MIS-C has addi- als on humans have led many prominent cardiovascular
tionally been a major concern in the pediatric popula- societies to advise against changing clinical practice with
tion. Management is often supportive, but may include regard to the use of RAAS inhibition for the sole purpose
anti-inflammatory measures (e.g., administration of of mitigating the pandemic, and instead to continue the
intravenous Immunoglobulins and steroids). Aspirin for standard indication-based utilization. In fact, a case-pop-
concerns regarding coronary artery involvement as well ulation study has demonstrated no increase in risk, and
as thrombotic prophylaxis due to associated hypercoag- even a decreased COVID-19 risk associated with use of
ulable state, may also be considered [171]. See: (https:// RAAS inhibitors in certain populations [176]. However,
www.who.int/publications-detail/clinical-management- the use of RAAS inhibition in general is avoided in the
of-severe-acute-respiratory-infection-when-novel-cor- setting of vasoplegic shock, which continues to apply for
onavirus-(ncov)-infection-is-suspected) for complete those COVID-19 patients who progress to what has been
management of the hospitalized pediatric patients. recently described as stage III (severe) or systemic hyper-
inflammation [89].
Management in pregnancy The other main controversy that stemmed from the
Currently, a paucity of data exists on COVID-19 and ACE2 receptor binding mechanism is that of cardiac
management during pregnancy. The American College injury observed in COVID-19, particularly in those that
of Obstetricians and Gynecologists (ACOG) recom- progress to severe disease. Epidemiologic data from Shi
mends that management in pregnant individuals should et al. (2020) has not only highlighted the common occur-
be the same as non-pregnant females (see: https://www. rence of such injury but also proved its association with
acog.org/-/media/proje ct/acog/acogorg/files/pdfs/clini higher mortality through regression models [172, 177].
cal-guidance/practice-advisory/covid-19-algorithm.pdf ). What continues to be debated is the etiology of said car-
However, a review of guidelines recommends designat- diac injury; the first theory being inflammatory cytokine
ing an area for COVID-19 positive pregnant patients, or storm-mediated injury rather than an isolated myocar-
those under investigation. Additionally, early discharge dial injury that may be associated with an imbalance in
from hospital (one day for vaginal delivery and two days oxygen supply and demand. The other perspective is a
for cesarean delivery) is encouraged to reduce risk of direct viral injury caused by the viral binding to the ACE2
transmission [118]. However, despite the evidence, there cardiac receptors (leading to myocarditis). In either case,
remains limited literature on the effects of SARS-CoV-2 it seems reasonable to monitor cardiac troponins, par-
on pregnant females, such as its effects on the fetus and ticularly high sensitivity troponin at baseline and then at
on labour, if any; more robust studies are thus warranted. set intervals when elevated in all hospitalized COVID-
19 patients [178]. This is relevant due to the aforemen-
Cardiovascular controversies tioned association of cardiac injury with mortality, as
Cardiovascular disease and injury has been reported well as given the results of a recent meta-analysis of all
as both a co-morbidity associated with severe disease, COVID-19 studies that included troponin measure-
and a complication associated with mortality [87, 172]. ments, highlighting the specific elevation in those with
SARS-CoV-2’s cellular entry via ACE2 receptors has severe infection [179].
implicated the heart, where these receptors have been Several of the potential medications in the treatment
reported to be present [173]. This fact triggers multiple of COVID-19 have QT prolonging potential including
lopinavir/ritonavir, azithromycin, and both chloroquine S glycoprotein-based vaccines should induce the produc-
and hydroxychloroquine [180], and thus risk of torsades tion of antibodies that block receptor binding and viral
de pointes (TdP) and sudden cardiac death. Lack of genome uncoating [187]. It has also been shown that the
clinical data with favipiravir also suggests the need for presence or absence of other viral glycoproteins does
monitoring. QT prolongation after single oral doses of not affect the immunogenicity of the S glycoprotein nor
favipiravir 1200 mg and 2400 mg has not been reported its ability to bind to the ACE2 receptor, further warrant-
with this agent except in one case report, where it was ing the use of this glycoprotein for vaccine development
found to prolong the QT at higher doses [181, 182]. [188]. The possibility of developing a ‘pan-CoV’ vaccine
Below is a suggested protocol for monitoring patients is also being studied, owing to the genetic homogene-
on agents with QT prolonging potential: ity between coronaviruses. However, it has been shown
that different residues exist between SARS-CoV-1 and
1. Discontinue and avoid all other non-critical QT pro- SARS-CoV-2, specifically in the S glycoprotein; therefore,
long agents antibodies produced against SARS-CoV-1 may not be
2. Assess baseline ECG, renal and hepatic function, effective against SARS-CoV-2 [189].
serum potassium and magnesium There are currently 6 vaccines approved for full use,
3. When possible, have an experienced cardiologist/ and 6 others authorized for limited use against COVID-
electrophysiologist measure QTc, and seek pharma- 19 by various countries worldwide [190]. Additionally,
cist input in the setting of acute renal or hepatic fail- there are 21 other vaccines currently in Phase III, 27 in
ure Phase II, and 42 in Phase I [190]. Table 1 elaborates on
4. Assess baseline risk of QT prolongation using the the available details for each of the approved/authorized
Tisdale risk score [183] vaccines. They include inactivated vaccines, recombinant
5. Relative contraindications: history of long QT syn- adenovirus (human and non-human) vaccines, and novel
drome or baseline QTc > 500ms mRNA-based vaccines. Current studies have shown that
6. Ongoing monitoring includes telemetry, laboratory many of these vaccines provide significant protection
studies, and ECG 2–3 h after the second dose and against severe COVID-19 (often up to 100%), and to a
daily thereafter lesser extent, symptomatic COVID-19. Side effect pro-
7. Duration of use of these medications for COVID-19 files tend to be mild to moderate, and acute [191–202].
infection is short (5 to 10 days for acute illness) Both the long-term efficacy and side effects of these vac-
cines remain to be determined, as well as their ability to
prevent transmission (sterilizing immunity).
Vaccination efforts
The ultimate and time-sensitive goal in combating the Novel potential therapies
COVID-19 pandemic is the development of a successful As discussed, current management of COVID-19 is sup-
preventative vaccine. As of 25 February 2021, there are 12 portive, with respiratory failure from ARDS being the
SARS-CoV-2 vaccines that have been approved/author- leading cause of mortality [203]. Although the clinical
ized for full or emergency use in different areas around safety of older medications has been established, includ-
the world, with over 200 million doses administered ing safety profile, side effects, physiology, and drug inter-
worldwide [11, 184]. This experience with the develop- actions, some medications may cause serious adverse
ment of COVID-19 vaccines has been a testimony to the reactions, both known and unclear, in patients with
outcomes that can be achieved with sufficient resources COVID-19 [203].
and international collaboration. Considering the trend of During the viral infection process—including intracel-
major coronavirus pandemics every decade so far in the lular transport, proliferation, and assembling of virions
twenty-first century, such international effort for an opti- in the infected cell—structural and functional proteins,
mised and efficient emergent vaccine production plan is as well as some proteases, play a key part in the virus’s
needed for long-term safeguarding of global health. pathogenesis, suggesting that targeted-therapies against
The current target of SARS-CoV-2 vaccines is the viral SARS-CoV-2 infection could be a promising strategy.
S glycoprotein. In fact, it was also the target for the devel- Some drugs have displayed potent inhibitory effects on
opment of vaccines against other coronaviruses, with the virus in vitro and in vivo; however, not all mecha-
attempts made in the past to develop S glycoprotein- nisms are clear [203]. Considering the seriousness and
based SARS and MERS vaccines [185, 186]. The S glyco- suddenness of the pandemic, over 200 clinical trials on
protein is responsible for both viral binding to the host COVID-19 had commenced in China alone a couple
cell receptor (ACE2 receptor), and host-viral membrane months into the reporting of the outbreak, and have suc-
fusion for viral replication. Therefore, it is believed that cessfully reported that certain targets and their agents
Table 1 Vaccine candidates for COVID-19 as of February 25, 2021 [191–202]

Vaccine name Organization/Institute(s) Manufacturer Comments
BNT162b2 – Pfizer, BioNTech mRNA-based vaccine

95% effective after the second dose
mRNA-1273 Kaiser Permanente Washington Health Moderna mRNA-based vaccine
Research Institute 94.1% effective after the second dose
AZD1222 (Covishield) University of Oxford AstraZeneca Chimpanzee adenovirus vaccine vector
The Jenner Institute 62.1% and 90.0% effective in 2 different
dosing regimens
Sputnik V Gamalaya Research Institute of Epidemi‑ Gamalaya Research Institute of Epidemi‑ Recombinant adenovirus vaccine
ology and Microbiology ology and Microbiology 91.6% effective after the first dose
CoronaVac Sinovac Research and Development Co. Sinovac Formalin-inactivated and alum-adju‑
Ltd vanted vaccine
Ad5-nCoV Tongji Hospital in Wuhan, China CanSino Biologics Recombinant vaccine incorporating
adenovirus type 5 vector
JNJ-78436735 Janssen Vaccines and Prevention B.V Janssen Vaccines and Prevention B.V Non-replicating viral vector vaccine
BBIBP-CoRV Henan Provincial Center for Disease Beijing Institute of Biological Products, Inactivated vaccine
Control and Prevention and Sinopharm
EpiVacCorona Federal Budgetary Research Institution – Peptide vaccine
State Research Center of Virology and
Biotechnology
Covaxin – Bharat Biotech, National Institute of Inactivated vaccine
Virology
CoviVac – Chumakov Federal Scientific Center for Inactivated vaccine
Research and Development of Immune
and Biological Products
– Wuhan Institute of Biological Products Sinopharm Inactivated vaccine
have displayed strong antiviral potential, of which some Dexamethasone

have been permitted to be used in clinical trials [204]. Low-dose Dexamethasone, a potent steroid, is currently
Scientists have suggested multiple existing compounds the most promising potential therapeutic for severe
to undergo clinical trials to determine their efficacy COVID-19. In the RECOVERY trial, 2104 patients were
against COVID-19. The international “SOLIDARITY” randomized to receive dexamethasone for ten days
trial, developed by the WHO, had set to test the effi- and compared with 4321 patients randomised to usual
cacy of five different treatment modalities: (1) standard care alone. Dexamethasone was found to reduce deaths
of care, (2) standard of care plus Remdesivir, (3) stand- by one-third in ventilated patients and by one fifth in
ard of care plus Lopinavir and Ritonavir, (4) standard of patients receiving oxygen only. However, there were
care plus Lopinavir, Ritonavir and Interferon beta, and no statistically significant benefits among patients who
(5) standard of care plus Hydroxychloroquine [205]. On did not require respiratory support [208]—A point that
the other hand, the UK’s national Randomized Evalua- needs to be stressed in order to avert cases of self-treat-
tion of COVID-19 Therapy (RECOVERY) Trial encom- ment, over-treatment, and drug-shortage. These findings
passed several primary and branching treatment arms have encouraged the WHO, NIH, and CDC to recom-
in addition to standard of care; these include the use of mend the use of dexamethasone or alternative gluco-
Lopinavir and Ritonavir, Azithromycin, low-dose corti- corticoids/corticosteroids such as hydrocortisone where
costeroids, convalescent plasma, and Tocilizumab [206]. appropriate [209, 210].
Furthermore, the US National Institute of Health (NIH) Furthermore, a meta-analysis was conducted on 7 ran-
launched the Accelerating COVID-19 Therapeutic Inter- domized clinical trials in 12 different countries, evalu-
ventions and Vaccines (ACTIV) trial, which is set to test ating the efficacy of corticosteroids in 1703 critically ill
in outpatient and inpatients settings, various immune patients with COVID-19. The meta-analysis showed that
modulators, monoclonal antibodies, antithrombotics, dexamethasone reduced 28-day mortality compared to
anti-retrovirals, and convalescent plasma [207]. Data has standard of care or placebo by 36%. On the other hand,
also emerged from independent studies and trials world- hydrocortisone and methylprednisolone did not sig-
wide, which have contributed to the developing interim nificantly reduce mortality [211]. Similarly, a large sys-
clinical consensus. tematic review and network meta-analysis on 85 trials
enrolling 41,669 COVID-19 patients found that corticos- In another RCT, the National Institute of Allergy and
teroids were the only therapeutic to reduce mortality and Infectious Diseases announced the interim results of
morbidity (mechanical ventilation) to a moderate extent their Adaptive COVID-19 Treatment Trial (ACTT;
compared to standard of care—A finding that did not NCT04280705)—A phase 3, randomized, double-blind,
similarly transfer to remdesivir, azithromycin, hydroxy- placebo-controlled trial. The trial involved 1062 patients,
chloroquine, lopinavir/ritonavir, interferon-beta, or toci- and was conducted at 68 sites in the USA, Europe, and
lizumab [212]. Asia. Preliminary results suggested that patients treated
The WHO’s living guidance on COVID-19 therapeu- with Remdesivir had a 31% faster time to recovery
tics, developed in partnership with Magic Evidence (11 days vs 15 days) than those who received placebo
Ecosystem Foundation (MAGIC), is based on a current (p < 0.001). However, the survival benefit of Remdesi-
systematic review and network analysis of all relevant vir (8.0% mortality rate) was not statistically significant
trials. The results report lower mortality rates in critical compared to the placebo group (11.6%; p = 0.059) [220].
or severe COVID-19 patients who are on corticosteroids Recent update from the first stage ACTT-1 further sug-
(specifically, dexamethasone), as well as increased hyper- gests benefits for the use of remdesivir in the setting of
glycaemia. The analysis includes tens of trials with an COVID-19. The trial, which assigned 541 patients to
evidence quality of “low” to “moderate”. Thus, the use of treatment and 521 to placebo, reported a shorter median
dexamethasone in severe/critical COVID-19 patients is recovery time (10 vs 15 days) in patients who received
“strongly” recommended. On the other hand, due to “low remdesivir (rate ratio for recovery, 1.29; 95% CI 1.12 to
quality” data showing increased mortality in non-severe 1.49; P < 0.001). The Kaplan–Meier estimates of mortality
cases of COVID-19 taking corticosteroids, it is “weakly” were also lower for the treatment group, with a hazard
recommended against [213]. ratio of 0.73 (95% CI 0.52 to 1.03) [221].
As such, dexamethasone seems to be a reasonable ther- Furthermore, the SIMPLE trial; an open-label, rand-
apeutic for severe and critical COVID-19 patients who omized, phase III trial in 15 countries primarily com-
require supplemental oxygenation, both invasive and pared clinical improvement of 5-day versus 10-day
non-invasive [213, 214]. treatment duration of Remdesivir in addition to standard
of care, in hospitalised patients with severe COVID-19
Remdesivir (n = 397). The study reported similar outcomes between
Remdesivir (GS-5734), an experimental intravenous drug the 5-day and the 10-day treatment course, which, inter-
originally developed for the treatment of Ebola virus, estingly, was slightly in favor of the 5-day course. An
inhibits viral replication by inhibiting RNA-dependent exploratory analysis of the data, using pooled data from
RNA polymerase [215]. Notably, Remdesivir has dem- both arms, found that more patients were discharged ear-
onstrated antiviral activity in treating MERS and SARS lier when Remdesivir was started early within 10 days of
[216]. The first COVID-19 patient diagnosed in the symptoms onset [222].
United States—A young man in Washington—was given In contrast to the mentioned evidence, recent reports
Remdesivir when his condition worsened; he improved from the WHO SOLIDARITY Trial suggests a lack of
the next day, according to a case report in the New Eng- benefit for Remdesivir. A total of 405 hospitals in 30
land Journal of Medicine [217]. The drug has since then countries participated, with a total of 11,266 randomized
been tested in a number of RCTs globally. Remdesivir is adults, 2750 of which were allocated to Remdesivir. A
currently the only antiviral drug that the CDC does not total of 301/2743 (10.97%) patients expired on Remdesi-
recommend against using [218]. It is recommended by vir, compared to 303/2708 (11.1%) from the control. The
the NIH either as monotherapy or with dexamethasone, death rate ratio or relative risk for Remdesivir was there-
in cases of hospitalized patients who may or may not fore 0.95 (0.81–1.11, p = 0.50), suggesting a lack of ben-
require supplementary oxygenation [214]. WHO guide- efit or hazard. The preprint also reports a meta-analysis
lines however do not find there to be enough evidence as that combines data from 4 trials: SOLIDARITY, ACTT-
of now to recommend its use [213]. 1, and two smaller trials; the Remdesivir versus control
The first double-blind randomized trial conducted with death rate ratio or relative risk was insignificant, at 0.91
Remdesivir (n = 158) versus placebo (n = 79) in severe (95% CI 0.79–1.05) [223].
COVID-19 patients found no significant difference in As for the WHO’s living guidelines on COVID-19 ther-
primary outcome of time to clinical improvement within apeutics, based on MAGIC’s meta-analysis, the results
28-days either in the intention-to-treat analysis or the reported no “important difference” in any clinical out-
per-protocol analysis. Clinically speaking however, the come, including mortality, requirement and duration of
results slightly favoured Remdesivir over placebo in both mechanical ventilation, and serious adverse events. All
analyses [219]. evidence quality was classified as “low” or “very low”,
concluding with a “weak” recommendation against use of tocilizumab group was 1.64 (95% CI 1.14 to 2.35), and
Remdesivir at any COVID-19 severity. 2.01 (95% CI 1.18 to 4.71) for sarilumab as compared to
In the absence of further evidence, Remdesivir remains control [229].
a promising experimental drug in comparison to other In earlier reported trials, a clear benefit was not simi-
investigated therapeutics, with at most a moderate clini- larly observed in the primary outcome [230–232]. In fact,
cal benefit. However, considering concerns of limited in one open-label RCT, it was suggested that tocilizumab
availability, it has been recommended in light of the might even increase mortality and the study was stopped
recent evidence that treatment should be prioritized for early based on the interim analysis [233].
hospitalized patients requiring low-flow supplemental As such, the US CDC’s treatment guidelines now rec-
oxygen, as they seem to derive the most benefit [224]. ommend the use of tocilizumab in combination with dex-
amethasone in certain hospitalized patients who exhibit
Tocilizumab (IL‑6 antagonists) rapid respiratory decompensation due to COVID-19.
Tocilizumab is a recombinant humanized monoclonal Based on the results of the RECOVERY and REMAP-
antibody that targets interleukin 6 (IL-6); a pro-inflam- CAP trials, these patients should be either (1) recently
matory cytokine that induces acute phase reactants (e.g. hospitalized patients who were admitted to the ICU
CRP) [225], and is highly implicated in the resultant within the prior 24 h, requiring invasive or non-inva-
cytokine storm. Since cytokine storms have been estab- sive ventilation, or HFNC, or (2) recently hospitalized
lished as an important pathogenic mechanism of mor- patients not in the ICU with rapidly increasing oxygen
tality in severe COVID-19 [226], the blocking of IL-6 demands (requiring HFNC or non-invasive ventilation)
activity may offer a promising therapeutic target in severe and have significantly increased inflammatory markers
COVID-19. [234].
One retrospective observational cohort study on 544
adults with severe COVID-19 pneumonia compared a Anti‑SARS‑CoV‑2 monoclonal antibodies
non-randomly selected subset of patients who received Monoclonal antibodies, currently undergoing initial
tocilizumab in addition to standard of care (n = 179), stages of testing, have been developed against SARS-
with the rest of the controls (n = 365). The study found CoV-2’s virulence factors. The most prominent of these
that after adjustment for potential confounding factors, tests is the Blocking Viral Attachment and Cell Entry
tocilizumab treatment was associated with reduced risk with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1)
of invasive mechanical ventilation or death (adjusted haz- trial, targeting various components of the virus’s spike
ard ratio: 0.61, 95% CI 0.40–0.92; p = 0.02) [227]. glycoprotein and cell entry mechanisms. 533 patients
The UK RECOVERY trial tested Tocilizumab in admit- were included in the final analysis of Phase II of the study,
ted patients with COVID-19, adopting a randomized, randomized to three main groups: Bamlanivimab mono-
controlled, open-label, platform design. The study found therapy (700, 2800, and 7000 mg), combination treatment
that patients allocated to tocilizumab were more likely to group (bamlanivimab and etesevimab), or placebo. Com-
be discharged alive within 28 days compared to standard pared to placebo, the difference in the change in log viral
of care (54% vs. 47%; rate ratio 1·22; 95% CI 1·12–1·34; load at day 11 from baseline was only significant for the
p < 0·0001). Additionally, among patients not on inva- combination group. As for secondary outcome measures
sive mechanical ventilation at baseline, those allocated to (symptom relief and clinical progression), each treatment
tocilizumab were less likely to reach composite endpoints group had statistically significant differences in outcome
of invasive mechanical ventilation or death (33% vs 38%, for 10 out of 82 of these endpoints. These findings how-
risk ratio: 0.85; 95% CI 0.78–0.93) [228]. ever were restricted to non-hospitalised patients with
Finally, In the international, multifactorial, adaptive mild to moderate COVID-19 illness [154].
platform trial REMAP-CAP (NCT02735707), both toci- Yet-to-be-published results from Phase III of the
lizumab and sarilumab (another IL-6 inhibitor), met BLAZE-1 trial randomized 1,035 participants with mild
predefined criteria for efficacy against COVID-19 in criti- to moderate COVID-19 (but a high risk for disease pro-
cally ill patients receiving organ support in ICU. An anal- gression) to either the bamlanivimab plus etesevimab
ysis of 90-day survival showed improved survival in the arm (n = 518) or to the placebo arm (n = 517). The study
pooled IL-6 receptor antagonist groups (n = 414). When found that participants who received bamlanivimab plus
compared to control group (412), patients receiving Il-6 etesevimab as opposed to placebo had a 5% absolute
antagonists had lower median organ support-free days. reduction and 70% relative reduction in risk for COVID-
The in-hospital mortality in the pooled Il-6 antagonist 19 related hospitalisation or death from any cause
groups was lower than the control group (27% vs 36%)— (p < 0.001). Additionally, there were no deaths in the
Median adjusted odds ratio for in-hospital survival in the intervention arm, compared to 10 deaths in the placebo
arm (p < 0.001). Virus level decline was also greater and azithromycin was added to their treatment; a signifi-
more rapid in the group that received the combination cant reduction in the viral load at day 6 post Azihromy-
antibody therapy as opposed to placebo [234]. cin inclusion compared to control group was observed.
A Phase I/II randomized trial comparing a combina- Additionally, in patients who had Azithromycin added
tion of casirivimab plus imdevimab to placebo has also to Hydroxychloroquine, a synergistic effect was reported
been conducted. Interim analysis suggests potential [239]. As a single arm study nonetheless, this may have
clinical benefit from the combination therapy for outpa- been the normal course of the disease in this small sam-
tients with mild to moderate COVID-19, who receive the ple size, allowing much room for bias. Another study, a
drug infusion a median of 3 days after symptom onset. randomized parallel-group trial (n = 62), suggested the
In terms of outcomes, 2% (8/434) of participants in the use of hydroxychloroquine could shorten time to clini-
pooled casirivimab plus imdevimab arm, as opposed cal recovery (body temperature and cough), and improve
to 4% (10/231) in the placebo arm, were hospitalised or pneumonia (ChiCTR2000029559) [240]. On the other
required emergency department visits within 28 days of hand, a multicenter, open-label, randomized controlled
treatment. In those specifically at higher risk for hospi- trial (n = 150) found that the administration of hydroxy-
talisation, 3% (4/151) in the combination therapy arm as chloroquine with standard of care did not result in a sig-
opposed to 9% (7/78) in the placebo arm were hospital- nificantly higher probability of negative conversion by
ised or required emergency department visits [235]. day 28 (two negative PCR tests 24 h apart) than stand-
As of recent, the US FDA issued emergency use ard of care alone in patients hospitalized with persis-
authorization for the use of investigational monoclo- tent mild to moderate COVID-19. Additionally, adverse
nal antibody therapy bamlanivimab for the treatment of events were higher in hydroxychloroquine recipients
mild-to-moderate COVID-19 in adult and pediatric out- (ChiCTR2000029868) [241].
patients [236]. Likewise, the US NIH echoed these rec- Overall, there has been much controversy with regards
ommendations, stressing on its use for those at increased to the use of Hydroxychloroquine in both scientific and
risk for disease progression [234]. public discourse. The WHO halted the SOLIDARITY
trial’s Hydroxychloroquine arm following a retrospec-
Hydroxychloroquine tive observational analysis published in The Lancet that
Hydroxychloroquine for a while had been the drug of suggested an association with increased mortality [242,
choice for large-scale use before the emergence of con- 243]. The paper was later retracted due to data integrity
troversial findings, due to its availability, safety record in issues, following announcement of resumption of WHO’s
Malaria patients, and relatively low cost [237]. Chloro- hydroxychloroquine arm of the SOLIDARITY trial on
quine and its derivatives, including hydroxychloroquine the basis of the available interim mortality data [244].
and chloroquine phosphate, have elicited antiviral effects Hydroxychloroquine’s adverse event profile in healthy
on several viruses such as SARS-CoV and Human Coro- has also been looked at in the HyPE study. In a retro-
navirus 229E by interfering with endosomal acidification spective, cross-sectional, web-based survey, data was
[238]. Based on the advantage of known broad-spectrum collected on COVID-19 negative and asymptomatic
activity and supposed safe adverse effects profile, a series healthcare workers (n = 166) who were taking hydroxy-
of RCTs on chloroquine and its derivatives for COVID- chloroquine prophylactically. Overall, a higher incidence
19 treatment advanced rapidly. Therapeutic effects were of adverse events was reported (37.9%) compared to data
observed in aspects of fever reduction, improvements on from studies of patients on long-term hydroxychloro-
CT imaging, and disease progression [238]. In light of the quine therapy, with gastrointestinal bleeding being the
preliminary clinical data, chloroquine had been added most common. This finding was more prominent in those
to the list of trial drugs in the Guidelines for the Diag- under 40 years of age. The self-reported nature of this
nosis and Treatment of COVID-19 published by National study remains a limitation [245].
Health Commission of the People’s Republic of China In line with the growing negative attitudes towards
[237]. Hydroxychloroquine, the RECOVERY (NCT04381936)
Initially, Hydroxychloroquine seemed to be a promis- trial found no significant difference in the primary end-
ing drug in early small trials. An open label non-rand- point of 28-day mortality, or any evidence of beneficial
omized clinical trial conducted in France set out to test effects on hospital stay duration or other outcomes, in
the effects of Hydroxychloroquine and azithromycin. In patients randomised to Hydroxychloroquine (n = 1542)
the study, a total of twenty COVID-19 positive patients vs usual care alone (n = 3132) [246]. In another rand-
received 600 mg of hydroxychloroquine daily, and their omized, double-blind, placebo-controlled trial (n = 423),
viral load measured on a daily basis in a hospital set- the use of Hydroxychloroquine in non-hospitalised adults
ting. Depending on the patients’ clinical presentation, 4-days within symptom onset, did not substantially
reduce symptom severity, but did significantly increase did not have a time to clinical improvement that differed
prevalence of adverse events [247]. from that of the patients assigned to standard care alone
Finally, the WHO SOLIDARITY trial reported that in the intention-to-treat population [251]. Additionally, it
104 (10.98%) of 947 patients on hydroxychloroquine was determined that the viral RNA loads over time did
had expired, compared to 84 (9.27%) of 906 controlled. not differ between the Lopinavir and Ritonavir recipients
The relative risk or death rate ratio was therefore 1.19 and those receiving standard care. Although treatment
(0.89–1.59, p = 0.23)—The highest out of all the other with Lopinavir and Ritonavir did not significantly accel-
investigated drugs in the trial [223]. As for the WHO’s erate clinical improvement, reduce mortality, or dimin-
living guidelines on COVID-19 therapeutics, based on ish throat viral RNA detectability in patients with serious
MAGIC’s meta-analysis, the results reported no “impor- COVID-19 in this study, it is important to note that both
tant difference” in any clinical outcome, including mor- groups were heterogeneous and received various addi-
tality, requirement for mechanical ventilation, admission tional treatments, including other pharmacologic inter-
to hospital, and viral clearance at seven days. However, ventions such as interferon (11%) and glucocorticoids
there were fewer cases of diarrhoea and nausea/vomiting (34%) [252]. However, the median time from symptom
reported in supportive care as opposed to hydroxychr- initiation was 13 days, which may not be ideal to iden-
loquine arm. All evidence quality was classified ranged tify a difference between groups, specifically that the
from “very low” to “moderate”, concluding with a “strong” study was underpowered (recruitment was suspended
recommendation against use of Hydroxychloroquine for early due to Remdesivir being available for clinical trials).
COVID-19 patients at any severity [213]. Additionally, the recruited patients had more severe ill-
In view of the emerging evidence, the FDA revoked ness [251]—It is known to be questionable whether anti-
Hydroxychloroquine and Chloroquine’s emergency use virals would have a significant role in later disease stages.
authorization to treat COVID-19 in certain hospital- On the other hand, in a systematic review and meta-
ized patients, unless a justifiable clinical trial is available analysis of the efficacy and safety of antiviral treatments
and participation is feasible [248]. Several large trials for COVID-19, Lopinavir-Ritonavir combination was the
have also been halted globally, including that of the US only positive outcome with “low-quality evidence” sug-
National Institute of Health [249]. gesting a small decrease in mortality and reduction in
length of hospital and ICU stay for severe COVID-19, in
Lopinavir and ritonavir addition to “moderate-quality evidence” suggesting likely
This drug combination, sold under the brand name Kale- increases in diarrhea, nausea and vomiting. The other
tra, was approved in the US in 2000 to treat HIV infec- drugs, including Hydroxychloroquine, Ribavarin, Inter-
tions. Lopinavir specifically inhibits HIV protease, an feron, Umifenovir, and Favipiravir, were only met with
important enzyme that cleaves a long protein chain “very low-quality evidence” with little or no suggestion of
into peptides during the assembly of new viruses. Since benefit for most treatments and outcomes in both non-
Lopinavir is readily broken down in the human body by severe and severe COVID-19 [253].
our own proteases, it is given with low levels of Ritona- The WHO SOLIDARITY trial recently reported that
vir, another protease inhibitor, that prolongs the effects the relative risk of Lopinavir (co-administered with Rito-
caused by the action of Lopinavir. This combination has navir) was 1.00 (0.79–1.25, p = 0.97) with a mortality of
been shown to inhibit the protease of other viruses as 148/1399 (10.58%), compared to 146/1372 (10.64%) in
well in-vitro, specifically coronaviruses [250]. the control group. Furthermore, the joint mortality com-
Lopinavir and Ritonavir were investigated for their bining SOLIDARITY, RECOVERY, and other smaller tri-
potential to treat patients with SARS in China in 2003. als was 1.02 (95% CI 0.91–1.14) [223]. As such, the use of
Furthermore, shortly after the emergence of MERS, these agents in COVID-19 patients is not supported by
researchers also identified Lopinavir and Ritonavir as the current evidence.
inhibitors of MERS-CoV [237]. However, the first trial As for the WHO’s living guidelines on COVID-19 ther-
of Lopinavir and Ritonavir to treat COVD-19 was not apeutics, based on MAGIC’s meta-analysis, the results
encouraging [251]. This trial was an open-label, individu- reported no “important difference” in any clinical out-
ally randomized, controlled trial, conducted in early 2020 come, including mortality, requirement for mechanical
in Wuhan, China. Of the 199 patients who underwent ventilation, admission to hospital, and viral clearance at
randomization, 99 patients were assigned to the treat- seven days. However, similarly to hydroxychloroquine,
ment group with Lopinavir and Ritonavir twice a day for there were fewer cases of diarrhoea and nausea/vomiting
14 days, in addition to standard care, and 100 patients reported in supportive care as opposed to the lopinavir-
to the control group with standard care alone. Patients ritonavir arm. All evidence quality was classified ranged
assigned to the Lopinavir and Ritonavir treatment group from “very low” to “moderate”, concluding with a “strong”
recommendation against use of lopinavir-ritonavir for the current evidence for the use of these Interferons in
COVID-19 patients at any severity [213]. the treatment of COVID-19 is not sufficient and is rec-
ommended against by the US CDC unless in the context
Interferons
of a clinical trial [260].
Interferons (IFNs) are cytokine proteins that bind to
cell surface receptors and initiate signalling cascades,
which have shown to be effective against many viruses Convalescent plasma
like Hepatitis B and Hepatitis C [254]. Studies evaluat- Treatment via convalescent plasma has also attracted
ing the antiviral activity of types I and II interferons have some attention, with several clinical trials currently
reported that interferon beta is the most potent inter- recruiting [261]. A retrospective, propensity score-
feron in reducing in vitro MERS-CoV replication [254]. matched, case–control study that assessed convalescent
A combination of these drugs are now being tested on plasma therapy in 39 patients with severe or life-threat-
MERS patients in Riyadh, Saudi Arabia, in the placebo- ening COVID-19 reported improved oxygen require-
controlled MIRACLE trial [255]. The study assesses the ments, and survival [262]. One meta-analysis of three
feasibility, efficacy and safety of a combination of Lopi- clinical studies for COVID‐19 in China, showed a statis-
navir/Ritonavir and Interferon Beta-1b in hospitalized tically significant improvement in clinical outcomes of
patients with MERS [256]. patients treated with convalescent plasma (n = 19) com-
The efficacy of this combination with interferon alpha pared with historical controls (n = 10; P < 0.001) [263].
was analysed in a retrospective cross-sectional study An RCT of COVID-19 severe pneumonia assigned
from two hospitals in Anhui, China, on 181 patients 228 patients to receive convalescent plasma and 105 to
with confirmed COVID-19. The analyses suggested that receive placebo. Overall mortality was 10.96% in the
early initiation of lopinavir/ritonavir plus IFN‐α combi- intervention arm and 11.43% in the control group, which
nation therapy was associated with a shortened duration was not statistically significant. No difference was noted
of SARS‐CoV‐2 RNA shedding (HR 1.649 [95% CI 1.162– in the distribution of clinical outcomes according to a
2.339] [257]. 6-point ordinal scale on day 30 either. SARS-CoV-2 anti-
In another RCT (IRCT20100228003449N28) on the bodies titres however tended to be higher in the conva-
efficacy and safety of Interferon Beta-1a in treating severe lescent plasma group at day 2 after intervention, with
COVID-19, a total of 42 patients were randomized into similar adverse events in both groups [264].
the IFN group and 39 patients into the control group. A living Cochrane systematic review (n = 38,160 partic-
Time to clinical response was not significantly differ- ipants of whom 36,081 received plasma) reports uncer-
ence between both groups. However, more patients in tainty regarding convalescent plasma’s ability to decrease
the IFN group were discharged on day 14 compared to all-cause mortality, and little to no difference in improve-
the control group (odds ratio = 2.5; 95% CI 1.05 to 6.37). ment of clinical symptoms [265]. Potentially associ-
Additionally, the 28-day overall mortality was signifi- ated unwanted effects however, also with low evidence,
cantly lower in the IFN group (19%) vs control (43.6%, include death, allergic reactions, thrombotic or cardiac
p = 0.015). Early administration was also found to signifi- events, and respiratory complications [265]. Blood clot-
cantly reduce mortality [258]. ting (due to residually active pro-coagulant factors in
Treatment with nebulized IFN-α2b has been shown to transfused convalescent plasma) has especially been
be promising in a retrospective study of 77 hospitalised brought up as a concern, since COVID-19 patients are
patients with COVID-19. The study showcased a signifi- considered at increased risk [266]. The evidence support-
cantly reduced duration of detectable virus in the upper ing this however remains low, as iterated by the Cochrane
respiratory tract and a parallel reduction in duration of review.
elevated blood levels for inflammatory markers IL-6 and Note that another meta-analysis and systematic review
CRP. This remained true when IFN-α2b was adminis- (n = 35,055) reported that aggregation of mortality data
tered with or without arbidol [259]. from all controlled studies, including RCTs and matched-
However, several of the studies mentioned suffer from controls, indicated that patients transfused with conva-
methodological limitations and relatively small sample lescent plasma exhibited 42% reduction in mortality rate
sizes. On the other hand, the WHO’s SOLIDARITY trial compared to patients receiving standard treatment (20%
reported based on about 4000 patients, that the mortal- vs 28%; OR: 0.58, 95% CI 0.47–0.71, P < 0.001). Further-
ity relative risk for IFN Beta-1a with Lopinavir co-admin- more, an additional dose–response analysis found that
istration was 1.16 (95% CI 0.96–1.39, p = 0.11), and 1.12 the aggregate mortality rate of COVID-19 patients trans-
(95% CI 0.83–1.51) without Lopinavir co-administration; fused early-on with higher-titre convalescent plasma was
all of which point to lack of significant benefit. As such, lesser than that of patients transfused with lower titre.
Overall, more information will be needed from clinical countries, such as China, Russia, India, the US, and the
trials before recommending this approach, thus remain- UK, have been directly involved with the production of
ing as a last resort in compassionate use. vaccines [190]. Multiple other countries have instead
led randomized controlled trials testing their safety and
Global health response efficacy. In terms of vaccination rates, as of February
The global response to the COVID-19 pandemic has 25, 2021, Israel, the United Arab Emirates, US, UK, and
widely varied, including complete lockdowns, social dis- Chile have had the highest total number of vaccination
tancing measures, and population screening policies— doses per 100 people [270]. However, this list continues
or none of the above (Fig. 4). The outbreak continues to vary throughout the pandemic. Global equitable access
to exert pressure beyond capacity on countries globally, to vaccines has also been a major concern, which pro-
revealing in some instances a lack of preparation and pelled the WHO’s COVAX initiative for accelerated equi-
infrastructure to protect the public and healthcare prac- table access to vaccines worldwide [271].
titioners, as was seen by the shortage in emergency medi-
cal supplies [267]. COVID-19 has proven to be difficult to China and the border Asian region
control as compared to previous outbreaks due to a large On December 1, 2019, the first symptomatic patient
number of cluster transmissions or superspreader events, was identified with SARS-CoV-2 in the Huanan Sea-
relatively limited health resources, and the unavail- food Market in Wuhan of the Hubei province in China;
ability of rapid testing kits [268, 269]. As seen in Fig. 4, the epicentre of the pandemic [6]. On January 23, 2020,
countries that enforced public health measures early on weeks after SARS-CoV-2 was identified, the Hubei
during the progression of their national outbreak, were province underwent a lockdown. Other provinces fol-
better able to control the spread of the virus compared to lowed suit on February 11, 2020 due to an increase in
other countries who had not done so. Additionally, vac- the number of cases nationally [273, 274], which began
cine roll-out responses have been widely variable. Several to decline on March 15, 2020 [275]. The lockdown on
Fig. 4 Comparison between the number of COVID-19 cases per million when public health containment initiatives were taken by the five
countries (Mauritania, Uganda, Laos, Vietnam, and Gambia) with the lowest number of cases per million and the five countries (Italy, Spain,
Switzerland, Belgium, Portugal) with the largest number of cases per million, in the first 30 days since their first confirmed case [11, 272]. Countries
with a population of less than one million or with exceptional circumstances (civil war) were excluded [11, 272]
Wuhan is theorised to have delayed the spread to other Middle East and North Africa region
areas in China by 2.91 days and decreased the number The majority of the region implemented mitigation strat-
of cases by 33.3%. Additionally, it is thought to have egies, as described below [289]. Iran, the epicentre of the
reduced worldwide spread by 77% with a two to three region, began its efforts against COVID-19 on February
weeks delay in the spread [273, 276]. 19, 2020 with the formation of the COVID-19 National
Other areas in the Asian region responded quickly, Committee. Partial restrictions were enforced, such as
using strategies that were refined after the 2003 SARS cancellation of congregational prayers. Neighbouring
and 2009 H1N1 Influenza outbreaks. South Korea countries also suspended flights to and from Iran on Feb-
responded by distribution of test kits early on, by Feb- ruary 25, 2020 [31, 290]. As of February 2021, Iran has
ruary 7, and implementing restrictive measures by closed all schools, placed a stricter travel ban and a night
February 23, a month after their first case. Addition- traffic ban. They have also introduced a national vaccine
ally, they established 600 screening sites nationally [11, campaign [291]. Additionally, Saudi Arabia began taking
277]. South Korea’s CFR as of February 25, 2020 is 1.8% actions before their first case with the suspension of pil-
[11]. Taiwan also increased its laboratory capacity by grimage visits [11, 292]. Following a short-lived return to
building a national program to include 27 laboratories normal by July of 2020, a lockdown was brought back in
in the country, and currently boasts a CFR of 1.04% February 2021 to suppress a rise in cases [293]. Similarly,
[11, 278]. Meanwhile, Singapore announced an orange Jordan enforced one of the strictest complete lockdowns
alert 15 days after their first case. In January 2021, they globally [294]. On October 1, 2020, schools and univer-
announced the use of the Moderna vaccines, in addi- sities were shut down due to a cluster of cases linked to
tion to implementing tighter restrictions on travels the student population. By February 7, 2021, schools had
from South Africa after reports of a new variant [279]. gradually begun re-opening. Additionally, Jordan was the
As of February 25, 2021, their CFR is less than 0.01% first country in the world to begin vaccinating refugees
[11]. Hong Kong, on the other hand, responded before and asylum seekers in its territories [295].
the appearance of their first case [280, 281]. It is note- The Eastern Mediterranean Region makes up 6% of
worthy that these countries have an elderly population cumulative cases worldwide, and 6% of the deaths over-
that forms only 10 to 14% of the country, which may all [287]. Under-testing and lack of funding has been one
have contributed to their greater success in containing of the major points of struggle. Many countries, such as
COVID-19 when compared to other countries [269]. Iraq, attempted to increase their testing by opening new
Nonetheless, Japan, which has the largest elderly laboratories [296]. The WHO’s regional office has also
population (26%), boasted a relatively low number of received support through an increase in PPE and labora-
cases in comparison to Italy, which has the second tory supplies in Dubai and other countries. Financially,
largest elderly population (23%). The reason behind $71 million in funds has been secured (Kuwait—$41 M;
the difference between Japan and Italy’s total number Saudi Arabia—$10 M) [289, 292, 297]. The WHO has
of cases is yet to be determined but has been theorised also donated over 55 tons of health supplies to Syria
to be due to a lower frequency of testing [282]. Due to [298]. Another issue that has surfaced in the region is the
Japan’s initially limited testing capacities, the authori- spread of COVID-19 among migrant workers’ camps, as
ties had opted to depend on mitigation measures [283, seen in Bahrain, and the wider GCC. The public health
284]. However, on January 19, 2021, Japan launched a policies have been widely dynamic, changing throughout
COVID-19 Robot testing system, and began mass ran- the pandemic as new evidence appeared. Countries like
dom PCR testing in cities [285]. As such, on February Bahrain for instance cancelled their mandatory 10-day
25, 2021, Japan had done 60.31 tests per 1000 people quarantine and tracing bracelets for all travellers, as only
[11]. Japan has currently implemented a state of emer- 0.2% of arrivals were positive after the 10 days, which was
gency starting from February 2, 2021 up until March 7, considered not significant enough to continue the meas-
2021 in order to mitigate the “3rd wave” of COVID-19 ure [299]. Bahrain then began a nationwide vaccination
that began in November 2020 [285, 286]. program, which placed it as one of the top three inter-
As of February 2021, the countries with the highest nationally throughout the period of December 2020 and
cases in the region are India, Indonesia and Sri Lanka January 2021in terms of population vaccination rates
[285, 287]. The region as a whole, excluding China, [300].
houses 16.99% of global COVID-19 cases, and 18.06%
of the global deaths [11, 287, 288].
Europe and the UK
During March of 2020, Europe became the global epi-
centre of COVID-19 cases, and only began to see a
reduction in its cases around June 2020. As of Septem- ending date of March 2021. This reactive response may
ber 22, 2020, Europe made up 14.38% of cases worldwide, have been as a result of the spike that was brought by the
ranking fourth out of the continents [11, 298]. The situ- reopening of education institutions gradually in June.
ation began in Italy, which rapidly deteriorated starting By doing so, the UK authorities risked raising the repro-
from January 23, 2020, leading to a relatively high CFR. ductive number above 1 [308]. On November 8, 2020,
On January 30, all travels to China were banned, followed Scotland elevated their restriction to a level 5, meaning
by severe mitigation policies (National Red Zone) which individuals are only allowed to go out for an emergency.
were put in place from March to May 2020. By Febru- Following this, a few travel restrictions were placed again,
ary 21, 2020, Travellers departing from Italy had spread such as a 14-days quarantine for travellers coming from
COVID-19 to 21 other countries [301]. Italy began its certain countries (e.g. Spain) starting from December 12,
reopening phase around May, 2020, easing out the sev- 2020. This continued into 2021, with travellers required
eral month-long restrictions. [302] Different areas in Italy to quarantine and take two NP swabs before ending the
seemed to report varying CFRs; studying the different quarantine if they are arriving from COVID-19 hotspots.
containment strategies in each area and their correlation, On January 8, 2021, the UK hits its highest number of
if any, with the reported CFR, would be worthwhile [301]. cases per day, at 68,053, with the death toll peaking on
As of February 25, 2021, Italy had a cumulative testing January 20, 2021, at 1,820 death [309]. Additionally, once
rate of 648.8 tests per thousand people, bringing down its the UK had identified the presence of a variant of con-
CFR from 14.4% during September of 2020, to 3.4% as of cern in the country, known as B.1.351, which originated
February, 2021 [11, 303]. from South Africa, the government decided that it would
As of February 21, 2021, Europe ranks second (34%) perform additional testing and sequencing in eight differ-
after North America (45%) in percentage of cumulative ent areas in England. While this is less than one in every
cases [287]. The CFR of different countries in this region 10 samples from people who test positive for COVID-19,
greatly vary, with Iceland having the lowest CFR (0.5%) the UK is the second highest country in Europe to test
and Bulgaria the highest (4.1%). Other countries fall and sequence the variant of COVID-19. As a result, they
in between this range, such as Germany with 2.9%, and have carried out almost half of the COVID-19 genome
Italy with 3.4% [11].The difference between the CFRs can sequence globally. [Wise J. Covid-19: The E484K muta-
be attributed to many factors. In terms of age, an estab- tion and the risks it poses.] On February 22, 2021, the
lished co-morbidity, a comparison between the average government of the UK announced that they will lift all
age of the populations in Germany (46 years) and Italy lockdown restrictions by June 21, 2021, with educational
(63 years) may point towards a correlation. Another institutes reopening on March 8, 2021. In terms of test-
potential factor is the capacity of the respective health- ing, the UK began testing door-to-door on all households
care systems, with Germany’s ICUs providing 29 beds starting from February 1, 2021 [309].
per 100,000 people, compared to Italy with 12 beds per
100,000 people, and Spain with 10 beds. Additionally, the North and South America
timing of the response may be a main differentiating fac- On June 1, 2020, North America ranked first for number
tor, as some public health measures were enforced rela- of COVID-19 cases and second for total death rate. The
tively late into the spread of COVID-19 [304]. Iceland for USA, encountering its first case of COVID-19 on Febru-
instance, with a relatively low CFR, had started imple- ary 26, 2020, started to reinforce testing and public health
menting random testing (population screening) before measures a month later, influenced by the severity of the
their first confirmed case. Patients with a negative result predicted death count of up to 2.2 million if restrictive
in quarantine were re-tested, which contributed to 54% measures were to not be implemented. Consequently, the
of the confirmed cases [305]. outbreak in late February of 2020 in Washington was not
Initially, the United Kingdom (UK) opted for a herd- detected and mitigated in a timely manner. One of the
immunity approach; however, mitigation strategies were largest set-backs that the healthcare system in the USA
implemented on March 18, 2020, when the daily new had faced included shortage of emergency supplies, such
COVID-19 cases reached 407 per day [11, 306, 307]. The as masks, protective equipment and detection kits [11,
UK, at 382.1 deaths per million cases, has exceeded Italy’s 305]. However, the public health responses in the US have
death toll at 298.1 deaths per million cases (As of Febru- varied widely between different states. For instance, dur-
ary 25, 2021) [11]. However, the UK still remains lower on ing the Month of March 2021, states such as California,
the scale in comparison to the USA, which is at 2,090.9 New York, and Los Angeles, had broad public face mask
deaths per million cases. Around August of 2020, the UK requirements enforced both indoors and outdoors. States
began easing up lockdown measures, before resuming like Minnesota however enforced masks inside pub-
stricter measures on November 5, 2020, announcing an lic buildings/businesses only. On the other hand, many
other states, including Texas, Missouri, and Montana, did public health measures in place [318]. Currently, both
not have any face-mask mandates [310]. This variation Brazil and Mexico place second and third within the
extended similarly to travel restrictions and stay-at-home region of America for number of cases, respectively.
orders [310]. The Biden-Harris administration’s “plan to
beat COVID-19” includes giving all citizens access to free
testing, investing in vaccines to be distributed for free to Australia and New Zealand
all American citizens, and implementing a public-setting Australia saw its first case of COVID-19 on January 25,
mask requirement nationwide [311]. Additionally, on 2020, and implemented travel bans to China, Iran and
January 21, 2021, the United States decided to reverse Italy on February 1, February 29, and March 10, respec-
its decision to withdraw from the WHO, in order to tively. It is estimated that the travel ban on China reduced
strengthen its plan for combating COVID-19 [312]. As of the potential number of cases and deaths by 87% [319].
February 25, 2021, the USA has a CFR of 1.8% and has The country has performed 54.81 tests per 1,000 people,
performed 2.73 test per 1,000 people [11]. with one confirmed case per 202.4 tests, exceeding the
Canada entered a state of emergency on March 17, test ratio performed by South Korea and Iceland, both of
2020, a week after its first case, and expanded its ICU which were considered high in their respective regions
capacities in preparation [313]. However, the authori- [11]. As of February 25, 2021, Australia’s CFR is at 3.1%.
ties in Canada did not broaden the traveling restric- Since December 23, 2020, the country has been on lock-
tions accordingly nor enforced testing of all passengers down due to the surge of cases [320].
on arrival; hence, out of the initial 118 cases, 30% came New Zealand saw its first case on February 28, 2020
from Iran, 18.2% from the US and 13.1% from Europe and closed its borders on March 19, 2020 with a recorded
[314]. Canada likewise faced a shortage of PPE and medi- 5.81 cases per million people. The country eventually
cal resources [315]. Canada has also remained on a strict entered a strict lockdown on March 25, 2020 [321]. They
lockdown up until June 25, 2020, before starting to ease have performed 191.75 tests per 1,000 people, with one
up and reopen certain businesses. However, a few regions confirmed case per 3,079.0 tests, placing themselves at
continued to extend their lockdowns up until October 7, the top for the least number of positive cases per tests
2020. On January 5, 2021, Canada enforced COVID-19 by the end of September, 2020 [11]. Overall, New Zea-
testing for all air travellers. With the easing of the restric- land adopted a proactive approach and implemented
tions, Canada’s 7-day average for new daily cases reached strict policies early on, which may have contributed to
9,626.86 by January 9, 2021. As a result, on January 12, the relatively low CFR of 1.70% [11, 321]. As of February
2021, Ontario imposed a stay-at-home order, permit- 2021, New Zealand has managed to avoid being severally
ting people to go out shopping for necessities only and impacted by COVID-19 and has maintained an almost
for exercising. In addition, travel restrictions were placed COVID-19-free status via adoption of an elimination
against the US and UK. This is planned to continue until strategy as opposed to mitigation and suppression [322].
the end of March 2021 [316]. As of February 25, 2021,
Canada managed to reduce the 7-day average of new
daily COVID-19 cases down to an average of 2,986.43 per Africa
day, and now has a CFR of 2.5% [11]. In Africa, the regional CDC began its emergency
On the other hand, South America has had varying response on January 27, 2020, quickly implementing
responses throughout the continent, with Paraguay pro- mitigation and containment measures to control any
moting strict mitigation strategies, and Chile and Colom- potential spread of the disease. By March 20, 2020, they
bia establishing a consistent testing policy along with were already seeing a reduction in their average daily
other strict measures [317]. The South American region case growth. With the extra time that the continent had,
stands out due to the wide inequalities in income and the they prepared for a continent-wide response, in which
lack of equal access to healthcare services [318]. In the they increased their labs from 2 to 43 by mid-March.
region, the only country that has not implemented any Additionally, they received funding and medical supplies
suppression strategies or strict policies is Brazil. This has from various NGOs. Finally, the African Union (AU)
overwhelmed their healthcare system, with a CFR that announced that they would start a COVID-19 Respond
had reached 7.0% in May, dropping to 2.4% by February Fund which would support Africa CDC in accelerating
25, 2021 [11]. As a continent, South America constitutes COVID-19 testing [318]. This has been well-reflected in
18.4% of the cumulative confirmed deaths from COVID- the outcomes, as Africa makes up only 3% of the COVID-
19 (February 25, 2021) [11]. The biggest challenges faced 19 cases worldwide, and 3% of the deaths as of February
in the region included limited healthcare resources, and 23, 2020, despite forming around 17% of the world popu-
lack of consistent compliance by the population to the lation (Fig. 5) [11, 287].
Fig. 5 A comparison of the Case Fatality Rate (CFR) and the Recovery Rate in the five countries (Mauritania, Uganda, Laos, Vietnam, and Gambia)
with the lowest number of cases per million in the first 30 days since their first confirmed case, to the five countries (Italy, Spain, Switzerland,
Belgium, Portugal) with the largest number of cases per million in the first 30 days since their first confirmed case [11]
Innovative COVID‑19 coping responses [332]. Nonetheless, it is important to point out that
Several forms of adaptations in various sectors have been severe disease in children has regardless been reported as
adopted worldwide to cope with the changes brought low in prevalence globally—As such, closure of schools is
forth by the COVID-19 pandemic. Telemedicine for argued for in order to prevent transmission from children
instance was introduced in multiple countries to avert to the adults and elderly they are in contact with who may
the risks of in-person medical visits; these include Sin- be more at risk for severe disease [333]. The responses to
gapore (March 8), Australia (March 11), Saudi Ara- the COVID-19 pandemic have been both reactionary and
bia (March 12), UK (March 17) and the USA (March proactive, with policies remaining dynamic throughout.
17) [323–325]. In addition, virtual education has been Overall, as theoretical concepts are applied and tested
adopted in most countries worldwide, in order to avoid in a novel setting, global health responses to COVID-19
disruption of student learning after closure of campuses continue to pose a challenge for all stakeholders involved,
[326, 327]. In addition, various innovative forms of “con- both within public and scientific circles.
tact-less” processes, such as payment and delivery, have
been introduced by institutions to decrease risk of virus Global economic burden
transmission [328, 329]. However, as of the end of May The outbreak of SARS-CoV-2 has resulted in a global
2020, many countries began studying the option of re- economic slowdown, as demonstrated by the 2020 crash
opening and easing restrictions to varying extents, which of global financial markets due to the disruption of inter-
sparked both public and scientific controversy, and con- national business activities [334]. The pandemic has dis-
tinues to be a point of contention. For instance, accord- rupted international trade, as the global supply chain
ing to Kim et al. (2020), school closures have mitigated systems used by organizations and oil-producing coun-
COVID-19 spread in Korea and re-opening them could tries to conduct business at the global level have been ter-
result in doubling the cases [330]. On the other hand, the minated as a result of precautionary measures taken by
efficacy of school closures as a means to reduce the num- states to reduce the spread of the virus. In effect, the value
ber of new COVID-19 cases is considered insignificant of international trade is deteriorating. The World Trade
in countries like Taiwan, due to already low transmission Organization (WTO) estimates the volume of global
rate and the minimal number of new cases in the younger trade to have declined by an overall of 9.2% in 2020, due
population [331]. Sweden has also been argued as a case to the pandemic’s economic shock [335]. According to
against the closure of schools, considering that despite the UNCTAD, global trade began a strong recovery in Q4
schools remaining open nationwide a low incidence of of 2020 due to an 8% growth in goods trade [336]. The
severe Covid-19 among schoolchildren was observed recovery of international trade is projected to stall in the
first quarter of 2021 (1.5% fall in the trade of goods rela- hours in 2020, equivalent to 250 million full-time jobs
tive to Q4 of 2020) due to continuous disruptions in the [343]. According to the ILO estimates the working hours
travel sector and the trade of services caused by virus lost in 2020 were four times greater than during the 2009
surges [336]. The UN DESA expects global trade activity financial crisis, translating into a global employment loss
to remain below pre−pandemic levels until 2022 [336]. of 114 million jobs, increasing global unemployment by
An overall 6.9% rebound in the cross-border trade of 33 million and reducing the global labour income by a
goods and services is projected in 2021, subject to the total of USD3.7 trillion [343]. The ILO and IMF forecast
wide rollout of vaccines, the lift of movement restrictions under a baseline, pessimistic and optimistic scenarios
and uncertainties over the pandemic clearing up [337]. that global working hours in 2021 would fall by 3.0%,
According to the World Bank, the global economy 4.6% and 1.3% respectively, depending on the epidemio-
faced in 2020 the deepest recession since 1945, with logical situation [343]. Companies in impacted indus-
a 4.3% contraction in global GDP and a 6.2% decline in tries express their willingness to retain their employees
global GDP per capita [338, 339]. The global GDP is pro- if a time estimate is provided by the WHO, pertaining
jected to expand by 4% in 2021 and 3.8% in 2022 (global to when the outbreak will end. Currently, no confirmed
GDP remains 5.3% and 4.4% below pre-pandemic lev- time estimate exists [344].
els respectively) [338]. The cumulative estimated cost Although the incomes of world states declined, govern-
of SARS-CoV-2 on the global economic output in 2020 ments are required to increase the budgetary allocations
and 2021 is USD8.5 trillion and USD22 trillion between for their health sectors to combat the COVID-19 out-
2020 and 2025 [340, 341]. The economic implications of break. The increase in government spending on health-
the COVID-19 outbreak and the global economic growth care is to facilitate hospitals, ICU units, isolation centers,
commence into recovery depends on the path of the equip medical facilities, procure the relevant drugs and
virus, duration of the pandemic and the success of vac- testing kits, and accommodate citizens’ evacuated from
cines. In addition to agreements made by governments abroad [345]. This shortage between government rev-
and pharmaceutical companies on vaccines’ distribu- enue and spending is an economic challenge that hin-
tion mechanism.283 The International Monetary Fund ders the healthcare response to the pandemic’s outbreak.
(IMF) anticipates that a wide rollout of effective vacci- The virus outbreak in Italy reduced the state’s revenues
nation could stimulate a 5.5% economic growth in 2021, from the tourism sector (accounts for 14% of GDP), cre-
with economic recovery rates varying across countries ating a financial deficit. The financial deficit situation
depending on policy response effectiveness, vaccination hindered the capacity of the Italian government to sup-
speed, medical interventions, monetary policy initiatives port its healthcare sector with sufficient resources and
and structural economic characteristics [340]. Although, funds, resulting in the spread of the outbreak [346]. In
new SARS-CoV-2 variants pose risks causing uncer- addition, the action of global governments reprioritiz-
tainty on the global economic recovery in 2021. As such ing their budgets to support their health sectors with the
the United Kingdom, previously expected to economi- necessary funds to combat the pandemic would result
cally rebound in the first quarter of 2021, faces a GDP in a shortage in budgets allocated to other fundamental
contraction of 4%, following lockdown 3.0 caused by the sectors, primarily education. The World Bank estimates
spread of the B.1.1.7 variant [342]. The IMF projects in the per capita education spending in all world countries
a downside scenario, that the economic global growth shrunk by 5.7 percent in the second half of 2020 [347].
would only recover to 1.6% in 2021 and 2.5% in 2022, if While there is no verified global estimate of the finan-
new COVID-19 cases remain high around the world and cial funds required to control the outbreak, WHO has
the vaccine rollout process is disrupted by logistical hur- requested USD 675 million to combat COVID-19 [348].
dles, new virus strains or public reluctance to vaccination On June 26, 2020, the WHO announced that developing
[340]. Negative global growth in 2021 remains a possibil- COVID-19 tests, treatments, and vaccines will require
ity under a pessimistic scenario, in which financial stress USD31.3 billion over the next one year. The requested
is widespread [340]. financing will enable the delivery of 500 million tests
As a result of the deep global economic recession, and 245 million courses of treatment to low and middle-
the World Bank estimates that in 2020, between 119 income countries over the next 12–18 months [349]. The
and 124 million people worldwide were pushed into WHO indicated in August 2020, that ensuring global
extreme poverty, due to the COVID-19 pandemic [338]. access to SARS-CoV-2 vaccine will require over US$100
The number of COVID-19 induced poor is estimated to billion [350].
increase between 143 and 163 million in 2021 [338]. The The decline in state revenue caused by the virus out-
International Labour Organization (ILO) revealed that break, limited resources, and medical infrastructure pre-
the COVID-19 pandemic led to an 8.8% loss in working vents developing states from independently financing
the combat of the virus. Private financial inflows into the associated with the pandemic [352]. Moving forward and
economies of developing countries has dropped in 2020 in order to minimize the global recessionary gaps coun-
by a number of US$700 billion in comparison to the lev- tries are advised to adopt collective international stimu-
els of 2019. This exceeds the impact of the Global Finan- lus measures rather than independent actions. In this
cial Crisis in 2008 by 60 percent, resulting in setbacks respect, the G20 and as part of an international coordi-
and reductions in global development of infrastructure nated action, announced the investment of USD11 tril-
creating a situation in which states would become more lion in the global economy to address financial losses
vulnerable to future crises particularly regarding health caused by the virus outbreak [363, 364].
such as in the case of a future pandemic [351]. The pan- Worldwide governments encounter social and eco-
demic has also caused a decline in African states export nomic pressures to re-open economic activities, in order
revenues, followed by depreciation in local currencies. to account for increasing poverty rates and financial
A depreciation in exchange rates increases local infla- losses. The World Tourism Organization (UNWTO)
tion rates of foreign currency debt, which intensifies revealed that the global tourism sector has lost a total of
the situation of debt distress. Although governments USD1.1 trillion in 2020 due to the COVID-19 outbreak
are required to increase healthcare spending to combat [365]. Accordingly, several countries began in May 2020
the pandemic, African governments may be required to to announce exit strategies for the COVID-19 pandemic,
implement financial tightening measures to manage eco- involving the relaxation of containment measures. Coun-
nomic inflation [352]. Developing countries depend on tries which re-open their economies however may be
donations from donor states, international organizations, required to reimplement lockdown restrictions due to
and NGOs to attain the necessary funds to support their the resurgence of subsequent waves of COVID-19. The
health care sectors in combating the COVID-19 out- Authorities in France, UK, Ireland, Spain, Italy, Germany,
break. In this respect, the WHO introduced a crowdfund Canada and China re-imposed restrictive lockdown
requesting the support of public and private donors for measures during the end of 2020, due to cases surge and
its COVID-19 response [353]. The World Bank also allo- the spread of new virus strains [366]. Governments con-
cated USD14 billion to aid developing countries’ COVID- tinue to examine the implementation of policies which
19 response [354] and USD12 billion to finance their would allow for the economy to reopen while avoiding a
purchase and distribution of vaccines [354, 355]. How- surge in COVID-19 new cases. Only returning employ-
ever, the United States, which funded 15% of the WHO’s ees aged 20–49, who encounter low fatality rates and
2018–2019 budget, announced on April 14, 2020, the the lowest risk of requiring hospitalization, back to the
suspension of its funding to the organisation. The US was workplace is a proposed policy in countries where the
due to pay USD58 million to the WHO in 2020 [356]. The healthcare system no longer has critical congestion. The
US reversed its withdrawal decision, restoring its funding risk of new waves of infections remains high nonethe-
to the WHO in January 2021 [357]. less as a large fraction of the population is not immune to
To avoid the spread of the pandemic the WHO has the virus. According to a report by the Imperial College
urged developing states to implement containment pro- COVID-19 Response Team (Ferguson et al. 2020), SARS-
cedures [358]. However, governments may resist imple- CoV-2 infection fatality rate in the age groups 20–29,
menting containment precautions, since countries that 30–39, 40–49 is 0.03%, 0.08% and 0.15%, respectively.
have imposed lock-downs and curfews have experi- The corresponding probabilities of requiring hospitaliza-
enced economic repercussions, caused by the decline in tion are 1.2%, 3.2% and 4.9% [367].
volume of trade [359]. The United States for instance, Other governments including Germany, Chile, and the
whose economy contracted by 32.9% in the second quar- USA proposed restarting the economy through issuing
ter of 2020, did not implement containment measures immunity passports, which certifies that an individual
in a timely fashion, due to its forecasted impacts on the has been infected by SARS-CoV-2 and has developed
national economy [360–362]. If implemented for the long antibodies to the virus. Following the rollout of COVID-
term, the economic consequences of containment meas- 19 vaccines, the International Air Transport Association
ures will be more intense on developing African states, (IATA) and several governments began issuing a digital
considering their greater dependence on trade. The vaccine passport for individuals who vaccinated against
United Nations Economic Commission for Africa esti- the virus, receiving all required doses [368]. Holders of
mates that Africa’s GDP growth rate declines from 3.2% vaccination passports could be allowed to resume eco-
to 1.8% in 2020, pushing tens of millions in Sub-Saharan nomic and financial activities, while being exempt from
Africa into extreme poverty through 2021. The continent physical restrictions. However, considerable scientific,
is expected to require at least USD100 billion as a fiscal practical, ethical and legal issues are posed by vaccination
stimulus to address the healthcare and economic needs passports [367].
The global supply side of advanced pharmaceutical of USD323.1 billion in 2020, and one million job loss in
ingredients and pharmaceuticals was also disrupted by the American healthcare sector{Blumenthal, 2020 #202.
the virus outbreak. The closure of Chinese factories dur- Expenses will rise as a result of the demand to provide
ing the start of the pandemic resulted in a shortage of raw equipment to protect medical staff dealing with infected
components used by international drug companies to patients, as well as increased costs of employee upkeep.
develop essential vitamins and antibiotics. This shortage Under specific conditions, the financial losses of the
in the global supply of vital drugs may reflect negatively health sector will be cushioned by government fund-
on the health of patients with diseases other than SARS- ing aimed at combating the COVID-19 pandemic [374].
CoV-2. Additionally, measures taken by states to pre- However, government funding will not fully cover the
serve their national stocks of vital medications during the financial losses that will be incurred by healthcare firms
outbreak resulted in an increased shortage of its global or the full cost of treating those infected [375]. The
supply. For instance, the Indian government banned the Spanish government, for instance, has taken measures
pharmaceutical industry’s export of 26 drugs, antibiotics, to monopolize all private health industries and place it
and pharmaceutical ingredients, starting March 3, 2020; under the disposition of the national healthcare sector.
according to the India Brand Equity Foundation, one- The government did not set a time frame for provid-
fifth of the global exports of generic drugs in 2019 was ing financial reimbursement to private healthcare firms
supplied by India (worth USD19 billion of drug exports) [283].
[369]. On June 29, 2020, the United States’ government Nonetheless, the value of the financial budget that gov-
purchased 500,000 doses of the antiviral drug Remdesivir, ernments are required to allocate to support their health
accounting for 100% of Gilead Sciences’ global produc- sectors in combating the pandemic outbreak differs from
tion of the drug in July, and 90% of the projected global one country to another, depending on the current status
stock in August and September 2020. Governments’ of its health sector and the extent of its development and
focus on marginalized advantages results in a global com- preparedness to cope with a pandemic. The fragile health
petition to secure access to SARS-CoV-2 drugs, which systems of some developing countries are a result of their
increases their global prices. As a result, a shortage in the limited economic capacity, poor governance, and inter-
global supply of Remdesivir is expected between July and nal conflicts. This creates a situation in which the state’s
September 2020 [370]. health and economic resources are insufficient in com-
Additionally, the rollout of COVID-19 vaccines was bating the COVID-19 outbreak, while also continuing to
complicated by global economic inequalities. Several combat the outbreak of other pre-existing epidemics in
high-income countries and due to their purchasing the country. Yemen for instance, while facing the novel
power secured enough doses to vaccinate its entire popu- SARS-CoV-2, must also deal with the Cholera epidemic
lation multiple times in 2021, with 95% of world vaccines and other communicable diseases (diphtheria, dengue
in January 2021 being administered in ten countries only fever and measles). Yemen has recorded 2 million sus-
[371]. The excess demand of vaccines by wealthy states, pected cases of Cholera as of January 2020 [376]. Yem-
exceeding the market supply of vaccines by pharma- en’s inflated economy, decreased government revenues,
ceutical companies, results in a shortage for developing and its limited public healthcare system where only 50%
and low-income countries. Estimates predict 90% of the of health facilities are functioning at full capacity, makes
population in 67 countries will be deprived from receiv- it incapable of combating multiple diseases at the same
ing the COVID-19 vaccine in 2021 [371]. The shortage of time [377]. The WHO requested a fund worth US$179
vaccine supply to world states was intensified by the EU million from donor states to aid Yemen with the essen-
decision to control the foreign exports of vaccines pro- tial medical equipment to combat the COVID-19 out-
duced within the bloc [372]. According to the UN, vac- break [378]. Furthermore, countries’ allocation of most
cination policies lead to a rapid increase in the price of of its health budgets towards combating COVID-19 has
vaccines, resulting in countries such as South Africa pay- also led to a shortfall in budgets allocated for combating
ing 2.5 times higher price than the EU for the AstraZen- Malaria in sub-Saharan Africa where mass insecticide-
eca/Oxford vaccine [372, 373]. treated net campaigns have been suspended [379].
The COVID-19 outbreak results in a negative financial Political contexts also factor into the economic
outlook for global non-profit public healthcare sectors. capacity of countries to provide sufficient financial
The revenues of global health sectors are likely to decline support to their healthcare sector. For example, Iran’s
in comparison to 2019, as a result of hospitals halting fragile healthcare system coupled with the economic
certain profitable medical services and elective surgical lockdown it experiences due to politically-driven sanc-
procedures in order to divert focus on cases linked to tions imposed by the UN and US, may have likely
COVID-19. Hospitals in the US have an estimated loss hindered the capacity of the Iranian government to
support its health sector with the necessary funds for Declarations
clinical, laboratory, and pharmaceutical equipment to
Ethics approval and consent to participate
efficiently combat the outbreak [326]. Not applicable.
Consent for publication

Not applicable.
Conclusion
The spread of COVID-19 has taken the world by sur- Competing interests
None declared.
prise, and unlike most health crises of the recent decades,
impacted the routine lives of all humans in all walks of Author details
life. Governments and national task forces continue to 1
School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom
work with public health experts to contain the spread of Bahrain. 2 The National Taskforce for Combating the Coronavirus (COVID-19),
Bahrain, Kingdom of Bahrain. 3 Department of Political Science, Faculty of Arts
of the virus on a national level, through implementa- and Science, University of Toronto, Toronto, Canada. 4 G7 and G20 Research
tion of screening, quarantine, and community-based Groups, Munk School of Global Affairs and Public Policy, University of Toronto,
Toronto, Canada. 5 School of Medicine, RCSI University of Medicine and Health
laws and protocols—despite the grave forecasted conse-
Sciences, Dublin, Ireland. 6 Department of Pharmacy Services, Cleveland Clinic
quences on the economy. Multidisciplinary groups of sci- Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates. 7 Cleveland
entists meanwhile are working on developing improved Clinic Lerner College of Medicine of Case Western Reserve University, Cleve‑
land, OH, USA. 8 Department of Medicine, Royal College of Surgeons in Ireland,
diagnostic tests, efficient health equipment, and effec-
Bahrain, Kingdom of Bahrain. 9 Department of Infectious Diseases, Royal Medi‑
tive vaccines. Healthcare workers, despite the personal cal Services, Bahrain Defence Force Hospital, Riffa, Kingdom of Bahrain.
risks associated with the global shortage in PPE, con-
Received: 29 October 2020 Accepted: 26 April 2021
tinue work on the frontlines to manage patients as per
the published literature and official guidelines, focusing
on sustaining respiratory function and preventing septic
infections, coagulopathy, and cardiac morbidities—topics
that clinical researchers continue to investigate in rela- References
tion to COVID-19. The WHO continues to coordinate 1. World Health Organisation. WHO announces COVID-19 outbreak a
on an international level and disseminate evidence-based pandemic. Geneva: World Health Organization; 2020.
2. Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the
information and awareness. National efforts, essen- ongoing Wuhan outbreak and modeling of its spike protein for risk of
tial workers, and communities at large, are cooperating human transmission. Sci China Life Sci. 2020;63(3):457–60.
with the aforementioned bodies, and each other, to see 3. Worldometers. Coronavirus Cases - Statistics and Charts. 2020. https://
www.worldometers.info/coronavirus/coronavirus-cases/#case-growth-
an end to this global health crisis. Although no end date outchina.
can be predicted as of yet, once this pandemic is over- 4. World Health Organisation. WHO Coronavirus Disease (COVID-19)
come through the collective global efforts, it will leave Dashboard. 2020. https://covid19.who.int/.
5. World Health Organisation. Novel coronavirus-China. 2020.
a significant residual impact behind, and many lessons 6. Huang C, Wang Y, Li X, et al. Clinical features of patients
to be learnt by all stakeholders involved—communities, infected with 2019 novel coronavirus in Wuhan China. Lancet.
governments, and health systems—As we move forward 2020;395(10223):497–506.
7. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with
to deal with the next pandemic or global health crisis to pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–33.
threaten human existence, in what will hopefully be a 8. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak
more proactive, systematic, and efficient global response. of global health concern. Lancet. 2020;395(10223):470–3.
9. Hui DS, Azhar E, Madani TA, et al. The continuing 2019-nCoV epidemic
Acknowledgements threat of novel coronaviruses to global health The latest 2019 novel
Not applicable coronavirus outbreak in Wuhan China. Int J Infect Dis. 2020;91:264–6.
10. Zahedipour F, Hosseini SA, Sathyapalan T, et al. Potential effects of
Authors’ contributions curcumin in the treatment of COVID-19 infection. PTR. 2020;5:78.
SIM was lead author of the project, and MA the senior supervisor. SIM, OGK, 11. Roser M, Ritchie H, Ortiz-Ospina E, Hasell J. Coronavirus Pandemic
SA, TT, OA, PS, MAI, JANS, and BA were all involved in drafting one or multiple (COVID-19). 2020. https://ourworldindata.org/coronavirus.
sections of the review paper. SIM, OGK, SA, and OA were involved in the crea‑ 12. Gorbalenya AEBS, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, et al.
tion and design of tables and figures. SIM, TT, RE, and MA were involved in the The species severe acute respiratory syndrome-related coronavirus:
editing of the manuscript and provided intellectual contributions. MA and RE classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol.
were involved in the review and provided expert feedback on the content. All 2020;5(4):536.
authors read and approved the final manuscript. 13. World Health Organisation. Timeline: WHO’s COVID-19 response. 2020.
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/
Funding interactive-timeline/.
Funding for Open-Access publication was provided by the Royal College of 14. Surveillances V. The epidemiological characteristics of an outbreak of
Surgeons in Ireland, Bahrain. 2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC
Weekly. 2020;2(8):113–22.
Availability of data and materials 15. Gorbalenya AE, Baker SC, Baric RS, et al. The species severe acute
Not applicable. respiratory syndrome-related coronavirus: classifying 2019-nCoV and
naming it SARS-CoV-2. Nat Microbiol. 2020;5(4):536–44.
16. Tan W, Zhao X, Ma X, et al. A novel coronavirus genome identified in 41. Prevention CfDCa. COVID-19 Forecasts: Cases. 2020. https://www.cdc.
a cluster of pneumonia cases—Wuhan, China 2019–2020. China CDC gov/coronavirus/2019-ncov/cases-updates/forecasts-cases.html.
Weekly. 2020;2(4):61–2. 42. Abdulrahman A, Mallah S, AlAwadhi AI, Perna S, Janahi E, AlQahtani M.
17. Riou J, Althaus CL. Pattern of early human-to-human transmission of Association between RT-PCR Ct values and COVID-19 new daily cases: a
Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to Janu‑ multicenter cross-sectional Study. medRxiv. 2020.
ary 2020. Eurosurveillance. 2020;25(4):2000058. 43. Routley N. Infection trajectory: see which Countries are flattening their
18. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak asso‑ COVID-19 curve. 2020. https://www.visualcapitalist.com/infection-traje
ciated with a new coronavirus of probable bat origin. Nature. ctory-flattening-the-covid19-curve/.
2020;579(7798):270–3. 44. ASSESSMENT RR. Risk related to the spread of new SARS-CoV-2 variants
19. Chan JFW, Yuan S, Kok KH, et al. A familial cluster of pneumo‑ of concern in the EU/EEA–first update. 2021.
nia associated with the 2019 novel coronavirus indicating 45. Yadav PD, Nyayanit DA, Sahay RR, et al. Isolation and characterization
person-to-person transmission: a study of a family cluster. Lancet. of VUI-202012/01, a SARS-CoV-2 variant in travellers from the United
2020;395(10223):514–23. Kingdom to India. J Travel Med. 2021;88:65.
20. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal 46. Loconsole D, Sallustio A, Accogli M, et al. Genome sequence of a
origin of SARS-CoV-2. Nat Med. 2020;26(4):450–2. SARS-CoV-2 VUI 202012/01 strain identified from a patient returning
21. Chen S, Yang J, Yang W, Wang C, Bärnighausen T. COVID-19 control from London, England, to the Apulia Region of Italy. Microbiol Resour
in China during mass population movements at New Year. Lancet. Announc. 2021;10(4):e01487-e1520.
2020;395(10226):764–6. 47. van Oosterhout C, Hall N, Ly H, Tyler KM. COVID-19 evolution during
22. Zhao S, Zhuang Z, Ran J, et al. The association between domestic train the pandemic—implications of new SARS-CoV-2 variants on disease
transportation and novel coronavirus (2019-nCoV) outbreak in China control and public health policies. Virulence. 2021;12(1):507–8.
from 2019 to 2020: a data-driven correlational report. Travel Med Infect 48. Tang JW, Tambyah PA, Hui DS. Emergence of a new SARS-CoV-2 variant
Dis. 2020;33:101568. in the UK. J Infect. 2020.
23. Bogoch II, Watts A, Thomas-Bachli A, Huber C, Kraemer MUG, Khan K. 49. Tang JW, Toovey OTR, Harvey KN, Hui DDS. Introduction of the
Potential for global spread of a novel coronavirus from China. J Travel South African SARS-CoV-2 variant 501Y.V2 into the UK. J Infect. 2021:
Med. 2020;27:2. S0163–4453(21)00030-X.
24. Rodríguez-Morales AJ, MacGregor K, Kanagarajah S, Patel D, Schlagen‑ 50. Heaton NS, Randall G. Multifaceted roles for lipids in viral infection.
hauf P. Going global—travel and the 2019 novel coronavirus. Travel Trends Microbiol. 2011;19(7):368–75.
Med Infect Dis. 2020;33:101578. 51. Tang X, Wu C, Li X, et al. On the origin and continuing evolution of
25. Wilson ME, Chen LH. Travellers give wings to novel coronavirus (2019- SARS-CoV-2. Natl Sci Rev. 2020.
nCoV). Oxford: Oxford University Press; 2020. 52. Vankadari N, Wilce JA. Emerging COVID-19 coronavirus: glycan shield
26. World Health Organization. Coronavirus disease 2019 (COVID-19): situa‑ and structure prediction of spike glycoprotein and its interaction with
tion report, 30. 2020. human CD26. Emerg Microbes Infect. 2020;9(1):601–4.
27. Cao Y, Hiyoshi A, Montgomery S. COVID-19 case-fatality rate and demo‑ 53. Baglivo M, Baronio M, Natalini G, et al. Natural small molecules as
graphic and socioeconomic influencers: worldwide spatial regression inhibitors of coronavirus lipid-dependent attachment to host cells: a
analysis based on country-level data. BMJ Open. 2020;10(11):e043560. possible strategy for reducing SARS-COV-2 infectivity? Acta Biomed.
28. Surveillances V. The epidemiological characteristics of an outbreak of 2020;91(1):161–4.
2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC 54. Wang Q, Qiu Y, Li J-Y, Zhou Z-J, Liao C-H, Ge X-Y. A unique protease
weekly. 2020;2(8):113–22. cleavage site predicted in the spike protein of the novel pneumonia
29. CEBM: The Centre for Evidence-Based Medicine. Global Covid-19 Case coronavirus (2019-nCoV) potentially related to viral transmissibility. Virol
Fatality Rates. 2020. https://www.cebm.net/covid-19/global-covid-19- Sin. 2020;5:1–3.
case-fatality-rates/. 55. Priya P, Shanker A. Coevolutionary forces shaping the fitness of SARS-
30. Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet. CoV-2 spike glycoprotein against human receptor ACE2. Infect Genet
2020;8:94. Evol. 2021;87:104646.
31. Zhuang Z, Zhao S, Lin Q, et al. Preliminary estimation of the novel coro‑ 56. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E.
navirus disease (COVID-19) cases in Iran: a modelling analysis based on The spike glycoprotein of the new coronavirus 2019-nCoV contains a
overseas cases and air travel data. Int J Infect Dis. 2020;94:29–31. furinlike cleavage site absent in CoV of the same clade. Antiviral Res.
32. Ferguson N, Laydon D, Nedjati Gilani G, et al. Report 9: Impact of non- 2020;176:5.
pharmaceutical interventions (NPIs) to reduce COVID19 mortality and 57. Yu H, Wang X, Li J, et al. Genomic analysis of a 2019-nCoV strain in the
healthcare demand. 2020. first COVID-19 patient found in Hangzhou, Zhejiang, China. Zhonghua
33. Emanuel EJ, Persad G, Upshur R, et al. Fair allocation of scarce medical yu Fang yi xue za zhi [Chin J Prevent Med]. 2020; 54: E026.
resources in the time of Covid-19. New Engl J Med. 2020;8:25. 58. Lam TT-Y, Shum MH-H, Zhu H-C, et al. Identification of 2019-nCoV
34. Ranney ML, Griffeth V, Jha AK. Critical supply shortages—the Need for related coronaviruses in Malayan pangolins in southern China. BioRxiv.
Ventilators and personal protective equipment during the Covid-19 2020.
Pandemic. New Engl J Med. 2020;2:69. 59. Zhang T, Wu Q, Zhang Z. Probable pangolin origin of 2019-nCoV associ‑
35. Kobokovich A. Ventilator Stockpiling and Availability in the US. Center ated with outbreak of COVID-19. Curr Biol. 2020;20:299.
for Health Security, 2020. 60. Zhu H, Guo Q, Li M, et al. Host and infectivity prediction of Wuhan 2019
36. Van Oosterhout C, Hall N, Ly H, Tyler KM. COVID-19 evolution during the novel coronavirus using deep learning algorithm. BioRxiv. 2020.
pandemic–Implications of new SARS-CoV-2 variants on disease control 61. Wu Z, McGoogan JM. Characteristics of and important lessons from the
and public health policies. New York: Taylor & Francis; 2021. coronavirus disease 2019 (COVID-19) outbreak in China: summary of a
37. World Health Organization. WHO Director-General’s opening remarks report of 72 314 cases from the Chinese Center for Disease Control and
at the media briefing on COVID-19–17 April 2020. 2020. https://www. Prevention. JAMA. 2020;323(13):1239–42.
who.int/dg/speeches/detail/who-director-general-s-opening-remarks- 62. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular
at-the-media-briefi ng-on-covid-19---17-april-2020. endothelialitis, thrombosis, and angiogenesis in Covid-19. New Engl J
38. Neher RA, Dyrdak R, Druelle V, Hodcroft EB, Albert J. Potential impact Med. 2020.
of seasonal forcing on a SARS-CoV-2 pandemic. Swiss Med Weekly. 63. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-
2020;150:1112. CoV-2 infection–a review of immune changes in patients with viral
39. Wilson N, Kvalsvig A, Barnard LT, Baker MG. Case-fatality risk estimates pneumonia. Emerg Microb Infect. 2020;9(1):727–32.
for COVID-19 calculated by using a lag time for fatality. Emerg Infect 64. Letko M, Marzi A, Munster V. Functional assessment of cell entry and
Dis. 2020;26(6):1339. receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.
40. Binti Hamzah FA, Hau C, Nazri H, et al. CoronaTracker: World-wide Nat Microbiol. 2020;5(4):562–9.
COVID-19 Outbreak Data Analysis and Prediction. 2020.
65. Jin H, Liu J, Cui M, Lu L. Novel coronavirus pneumonia emergency in 91. Henry BM, De Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic,
Zhuhai: impact and challenges. J Hosp Infect. 2020;104(4):452–3. biochemical and immune biomarker abnormalities associated with
66. Guan W-j, Ni Z-y, Hu Y, et al. Clinical characteristics of 2019 novel coro‑ severe illness and mortality in coronavirus disease 2019 (COVID-19): a
navirus infection in China. MedRxiv. 2020. meta-analysis. Clin Chem Lab Med. 2020;58(7):1021–8.
67. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality 92. Yang Y, Shen C, Li J, et al. Exuberant elevation of IP-10, MCP-3 and IL-1ra
due to COVID-19 based on an analysis of data of 150 patients from during SARS-CoV-2 infection is associated with disease severity and
Wuhan China. Intens Care Med. 2020;46(5):846–8. fatal outcome. MedRxiv. 2020.
68. Yang W, Cao Q, Qin L, et al. Clinical characteristics and imaging manifes‑ 93. Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with
tations of the 2019 novel coronavirus disease (COVID-19): a multi- severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis.
center study in Wenzhou city, Zhejiang China. J Infect. 2020;15:78. Clinica Chimica Acta. 2020;87:22.
69. Du Y, Tu L, Zhu P, et al. Clinical features of 85 fatal cases of COVID-19 94. Day M. Covid-19: ibuprofen should not be used for managing symp‑
from Wuhan. A retrospective observational study. Am J Respir Critic toms, say doctors and scientists. British Medical Journal Publishing
Care Med. 2020;201(11):1372–9. Group; 2020.
70. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic 95. Wong AY, MacKenna B, Morton CE, et al. Use of non-steroidal anti-
human coronavirus infections. Liver Int. 2020;40(5):998–1004. inflammatory drugs and risk of death from COVID-19: an OpenSAFELY
71. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteris‑ cohort analysis based on two cohorts. Ann Rheum Dis. 2021.
tics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: 96. Olds JL, Kabbani N. Is nicotine exposure linked to cardiopulmonary
a descriptive study. Lancet. 2020;395(10223):507–13. vulnerability to COVID‐19 in the general population? FEBS J. 2020.
72. Seah I, Agrawal R. Can the coronavirus disease 2019 (COVID-19) affect 97. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and
the eyes? A review of coronaviruses and ocular implications in humans angiotensin receptor blockers may increase the risk of severe COVID-19.
and animals. Ocul Immunol Inflamm. 2020;28(3):391–5. J Travel Med. 2020.
73. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized 98. Javanmard SH, Heshmat-Ghahdarijani K, Vaseghi G. Angiotensin-con‑
patients with coronavirus disease 2019 in Wuhan China. JAMA Neurol. verting-enzyme inhibitors (ACE inhibitors) and angiotensin II receptor
2020;77(6):683–90. blocker (ARB) use in COVID-19 prevention or treatment: a paradox.
74. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are Infect Control Hosp Epidemiol. 2021;42(1):118–9.
associated with poor prognosis in patients with novel coronavirus 99. Wang JJ, Edin ML, Zeldin DC, Li C, Wang DW, Chen C. Good or bad:
pneumonia. J Thromb Haemost. 2020;18(4):844–7. application of RAAS inhibitors in COVID-19 patients with cardiovascular
75. Campbell CM, Kahwash R. Will complement inhibition be the new comorbidities. Pharmacol Ther. 2020;8:107628.
target in treating COVID-19–related systemic thrombosis? Circulation. 100. Smart L, Fawkes N, Goggin P, et al. A narrative review of the potential
2020;141(22):1739–41. pharmacological influence and safety of ibuprofen on coronavirus
76. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki- disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of
like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an expectation and reality. Inflammopharmacology. 2020;25:1–12.
observational cohort study. Lancet. 2020;12:497. 101. Centers for Disease Control and Prevention. Coronavirus Disease 2019
77. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19–associated multisys‑ (COVID-19)—Transmission. 2020.
tem inflammatory syndrome in children—United States, March–July 102. Liu Y, Gayle AA, Wilder-Smith A, Rocklöv J. The reproductive number of
2020. Morb Mortal Wkly Rep. 2020;69(32):1074. COVID-19 is higher compared to SARS coronavirus. J Travel Med. 2020.
78. Gane SB, Kelly C, Hopkins C. Isolated sudden onset anosmia in COVID- 103. McAloon C, Collins Á, Hunt K, et al. Incubation period of COVID-19: a
19 infection. A novel syndrome. Rhinology. 2020;58(3):299–301. rapid systematic review and meta-analysis of observational research.
79. Kumar L, Kahlon N, Jain A, Kaur J, Singh M, Pandey A. Loss of smell and BMJ Open. 2020;10(8):e039652.
taste in COVID-19 infection in adolescents. Int J Pediatr Otorhinolaryn‑ 104. Van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface
gol. 2021;142:110626. stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med.
80. World Health Organization. Coronavirus. 2020. https://www.who.int/ 2020;382(16):1564–7.
health-topics/coronavirus#tab=tab_3. 105. Nishiura H, Oshitani H, Kobayashi T, et al. Closed environments facilitate
81. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteris‑ secondary transmission of coronavirus disease 2019 (COVID-19).
tics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: medRxiv. 2020.
a descriptive study. Lancet. 2020;395(10223):507–13. 106. Liu J, Zhou J, Yao J, et al. Impact of meteorological factors on the
82. BMJ Best Practice. Coronavirus disease 2019 (COVID-19)—Complica‑ COVID-19 transmission: a multi-city study in China. Sci Total Environ.
tions. 2020. 2020: 138513.
83. European Centre for Disease Prevention and Control. Clinical charac‑ 107. Yao Y, Pan J, Liu Z, et al. No Association of COVID-19 transmission with
teristics of COVID-19. 2020. https://www.ecdc.europa.eu/en/covid-19/ temperature or UV radiation in Chinese cities. Eur Respir J. 2020;55:5.
latest-evidence/clinical. 108. World Organisation for Animal Health. Questions and Answers on the
84. Varatharaj A, Thomas N, Ellul MA, et al. Neurological and neuropsychi‑ COVID-19. 2020. https://www.oie.int/en/scientific-expertise/specific-
atric complications of COVID-19 in 153 patients: a UK-wide surveillance information-and-recommendations/questions-and-answers-on-2019n
study. Lancet Psychiatry. 2020. ovel-coronavirus/.
85. Zhao Q, Fang X, Pang Z, Zhang B, Liu H, Zhang F. COVID-19 and cutane‑ 109. European Center for Disease Control and Prevention. Rapid increase of
ous manifestations: a systematic review. J Eur Acad Dermatol Venereol. a SARS-CoV-2 variant with multiple spike protein mutations observed
2020;54:65. in the United Kingdom—20 December 2020. ECDC: Stockholm; 2020.
86. Rey JR, Caro-Codón J, Poveda Pineda D, Merino JL, Iniesta ÁM, López- 110. Volz E, Mishra S, Chand M, et al. Transmission of SARS-CoV-2 Lineage
Sendón JL. Arterial thrombotic complications in hospitalized patients B. 1.1. 7 in England: Insights from linking epidemiological and genetic
with COVID-19. Revista Española de Cardiología. 2020. data. medRxiv. 2021: 2020.12. 30.20249034.
87. Stein R. COVID‐19: risk groups, mechanistic insights, and challenges. Int 111. Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results
J Clin Pract. 2020. of semen tests among men with coronavirus disease 2019. JAMA Netw
88. Vardavas CI, Nikitara K. COVID-19 and smoking: a systematic review of Open. 2020;3(5):e208292.
the evidence. Tobacco Induced Dis. 2020;18:78. 112. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of
89. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of clinical specimens. JAMA. 2020;323(18):1843–4.
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort 113. Colavita FLD, Carletti F, et al. SARS-CoV-2 isolation from ocular secre‑
study. Lancet. 2020. tions of a patient with COVID-19 in Italy with prolonged viral RNA
90. Lippi G, Plebani M. Procalcitonin in patients with severe coronavi‑ detection. Ann Intern Med. 2020;2:M20-1176.
rus disease 2019 (COVID-19): a meta-analysis. Clinica Chimica Acta. 114. Luo Y, Yin K. Management of pregnant women infected with COVID-19.
2020;505:190. Lancet Infect Dis. 2020;20(5):513–4.
115. Schwartz DA. An analysis of 38 pregnant women with COVID-19, their 138. Kanne JP, Little BP, Chung JH, Elicker BM, Ketai LH. Essentials for radiolo‑
newborn infants, and maternal-fetal transmission of SARS-CoV-2: gists on COVID-19: an update—radiology scientific expert panel.
maternal coronavirus infections and pregnancy outcomes. Archiv Radiological Society of North America; 2020.
Pathol Lab Med. 2020. 139. Naguib M, Moustafa F, Salman MT, Saeed NK, Al-Qahtani M. The use of
116. World Health Organisation. Key considerations for repatriation and radiological imaging alongside reverse transcriptase PCR in diagnos‑
quarantine of travellers in relation to the outbreak of novel coronavirus ing novel coronavirus disease 2019: a narrative review. Fut Microbiol.
2019-nCoV. 2020. https://www.who.int/ith/Repatriation_Quarantine_ 2020;15(10):897–903.
nCoV-key-considerations_HQ-final11Feb.pdf?ua=1. 140. Fang Y, Zhang H, Xie J, et al. Sensitivity of chest CT for COVID-19: com‑
117. Mullins E, Evans D, Viner R, O’Brien P, Morris E. Coronavirus in parison to RT-PCR. Radiology. 2020;296(2):E115–7.
pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol. 141. American College of Radiology. ACR Recommendations for the use of
2020;55(5):586–92. Chest Radiography and Computed Tomography (CT) for Suspected
118. Narang K, Ibirogba ER, Elrefaei A, et al. SARS-CoV-2 in pregnancy: a com‑ COVID-19 Infection. 2020. https://www.acr.org/Advocacy-and-Econo
prehensive summary of current guidelines. J Clin Med. 2020;9(5):1521. mics/ACR-Position-Statements/Recommendations-for-Chest-Radio
119. Centers for Disease Control and Prevention. Coronavirus Disease 2019 - graphy-and-CT-for-Suspected-COVID19-Infection.
Social Distancing. 2020. https://www.cdc.gov/coronavirus/2019-ncov/ 142. Abott. Detect COVID-19 in as Little as 5 Minutes. 2020. https://www.
prevent-getting-sick/social-distancing.html. abbott.com/corpnewsroom/product-and-innovation/detect-covid-19-
120. Travel.state.gov. COVID-19 Traveler Information. 2020. https://travel. in-as-little-as-5-minutes.html.
state.gov/content/travel/en/traveladvisories/ea/covid-19-information. 143. Bahrain News Agency. MOH announces the availability of the COVID-19
html rapid antigen test in pharmacies across the Kingdom. 2021. https://
121. Centers for Disease Control and Prevention. Get your mass gatherings www.bna.bh/en/MOHannouncestheavailabilityoftheCOVID19rapida
or large community events ready. 2020. https://www.cdc.gov/coron ntigentestinpharmaciesacrosstheKingdom.aspx?cms=q8FmFJgiscL2fwI
avirus/2019-ncov/community/large-events/mass-gatherings-ready-for- zON1%2BDrjnpd2dLAJj10eK6GkPGpo%3D.
covid-19.html. 144. Abdulrahman A, Mustafa F, AlAwadhi AI, Alansari Q, AlAlawi B,
122. Mukamal R. Eye care during the coronavirus pandemic. Am Acad AlQahtani M. Comparison of SARS-COV-2 nasal antigen test to naso‑
Opthalmol. 2020. pharyngeal RT-PCR in mildly symptomatic patients. medRxiv. 2020.
123. Centers for Disease Control and Prevention. Considerations for Wearing 145. Centers for Disease Control. Interim Guidance for Antigen Testing for
Cloth Face Coverings. 2020. https://www.cdc.gov/coronavirus/2019- SARS-CoV-2. 2020. https://www.cdc.gov/coronavirus/2019-ncov/lab/
ncov/prevent-getting-sick/cloth-face-cover.html. resources/antigen-tests-guidelines.html.
124. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95 146. Gostic K, Gomez AC, Mummah RO, Kucharski AJ, Lloyd-Smith JO.
respirators for preventing COVID-19 in healthcare workers: A systematic Estimated effectiveness of symptom and risk screening to prevent the
review and meta-analysis of randomized trials. Influenza Other Respir spread of COVID-19. Elife. 2020;9:e55570.
Viruses. 2020;14(4):365–73. 147. Quilty BJ, Clifford S, Flasche S, Eggo RM. Effectiveness of airport screen‑
125. Sharma SK, Mishra M, Mudgal SK. Efficacy of cloth face mask in preven‑ ing at detecting travellers infected with novel coronavirus (2019-nCoV).
tion of novel coronavirus infection transmission: a systematic review Eurosurveillance. 2020;25(5):2000080.
and meta-analysis. J Educ Health Prom. 2020;9:87. 148. Centers for Disease Control. Overview of Testing for SARS-CoV-2
126. Eikenberry SE, Mancuso M, Iboi E, et al. To mask or not to mask: Mod‑ (COVID-19). 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/
eling the potential for face mask use by the general public to curtail the testing-overview.html.
COVID-19 pandemic. Infect Dis Modell. 2020;5:293–308. 149. Qin L, Sun Q, Wang Y, et al. Prediction of number of cases of 2019 novel
127. Sunjaya AP, Jenkins C. Rationale for universal face masks in public coronavirus (COVID-19) using social media search index. Int J Environ
against COVID‐19. Respirology. 2020. Res Public Health. 2020;17(7):2365.
128. Organization WH. WHO guidelines on hand hygiene in health care: first 150. Organization WH. Coronavirus disease (COVID-19) technical guidance:
global patient safety challenge clean care is safer care. Geneva: World patient management. 2020.
Health Organization; 2009. 151. Banskota S, Healy M, Goldberg EM. 15 smartphone apps for older adults
129. Ong SWX, Tan YK, Chia PY, et al. Air, surface environmental, and personal to use while in isolation during the COVID-19 pandemic. West J Emerg
protective equipment contamination by severe acute respiratory syn‑ Med. 2020;21(3):514–25.
drome coronavirus 2 (SARS-CoV-2) from a symptomatic patient. JAMA. 152. Centers for Disease Control. Discontinuation of Transmission-Based
2020;323(16):1610–2. Precautions and Disposition of Patients with SARS-CoV-2 Infection in
130. Prevention CfDCa. Interim infection prevention and control recommen‑ Healthcare Settings. 2021. https://www.cdc.gov/coronavirus/2019-
dations for healthcare personnel during the coronavirus disease 2019 ncov/hcp/disposition-hospitalized-patients.html.
(COVID-19). 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/ 153. Centers for Disease Control. Therapeutic management of adults with
infection-control-recommendations.html?CDC_AA_refVal=https%3A% COVID-19. 2021. https://www.covid19treatmentguidelines.nih.gov/
2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Finfection-contr therapeutic-management/.
ol%2Fcontrol-recommendations.html. 154. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as mono‑
131. Klompas M, Baker MA, Rhee C. Airborne transmission of SARS-CoV-2: therapy or in combination with etesevimab on viral load in patients
theoretical considerations and available evidence. JAMA. 2020. with mild to moderate COVID-19: a randomized clinical trial. JAMA.
132. Control CfD, Prevention. Infection control guidance for healthcare 2021;325(7):632–44.
professionals about coronavirus (COVID-19). 2020. 155. Atallah B, Mallah SI, AlMahmeed W. Anticoagulation in COVID-19. Eur
133. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of Heart J. 2020.
hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J 156. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagu‑
Med. 2020;383(6):517–25. lant therapy during the COVID-19 pandemic: interim clinical guidance
134. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxy‑ from the anticoagulation forum. J Thromb Thrombol. 2020;8:1.
chloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis 157. Health NIo. Antithrombotic therapy in patients with COVID-19. 2020.
among health care workers: a randomized clinical trial. JAMA Intern 158. Kreuziger LB, Lee AYY, Garcia D, et al. COVID-19 and VTE/anticoagula‑
Med. 2021;181(2):195–202. tion: frequently asked questions. 2021. https://www.hematology.org/
135. Organization WH. An international randomised trial of candidate vac‑ covid-19/covid-19-and-vte-anticoagulation.
cines against COVID-19. 2020. 159. National Institute of Health. Full-dose blood thinners decreased need
136. Udugama B, Kadhiresan P, Kozlowski HN, et al. Diagnosing COVID-19: for life support and improved outcome in hospitalized COVID-19
the disease and tools for detection. ACS Nano. 2020;14(4):3822–35. patients. 2021. https://www.nih.gov/news-events/news-releases/full-
137. Kim H, Hong H, Yoon SH. Diagnostic performance of CT and reverse dose-blood-thinners-decreased-need-life-support-improved-outco
transcriptase polymerase chain reaction for coronavirus disease 2019: a me-hospitalized-covid-19-patients.
meta-analysis. Radiology. 2020;296(3):E145–55.
160. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 185. Yang Z, Kong W, Huang Y, et al. A DNA vaccine induces SARS
2021 guidelines on the use of anticoagulation for thromboprophylaxis coronavirus neutralization and protective immunity in mice. Nature.
in patients with COVID-19. Blood Adv. 2021;5(3):872–88. 2004;428(6982):561–4.
161. National Institute of Health. NIH ACTIV Trial of blood thinners pauses 186. Widjaja I, Wang C, van Haperen R, et al. Towards a solution to MERS: pro‑
enrollment of critically ill COVID-19 patients. 2020. https://www.nih. tective human monoclonal antibodies targeting different domains and
gov/news-events/news-releases/nih-activ-trial-blood-thinners-pauses- functions of the MERS-coronavirus spike glycoprotein. Emerg Microb
enrollment-critically-ill-covid-19-patients. Infect. 2019;8(1):516–30.
162. Zheng F, Liao C, Fan Q, et al. Clinical characteristics of children with 187. Du L, He Y, Zhou Y, Liu S, Zheng B-J, Jiang S. The spike protein of SARS-
coronavirus disease 2019 in Hubei China. Curr Med Sci. 2020;52:1–6. CoV—a target for vaccine and therapeutic development. Nat Rev
163. Lu X, Zhang L, Du H, et al. SARS-CoV-2 infection in children. N Engl J Microbiol. 2009;7(3):226–36.
Med. 2020;382(17):1663–5. 188. Kim MH, Kim HJ, Chang J. Superior immune responses induced by
164. Ludvigsson JF. Systematic review of COVID-19 in children shows intranasal immunization with recombinant adenovirus-based vaccine
milder cases and a better prognosis than adults. Acta Paediatr. expressing full-length Spike protein of Middle East respiratory syn‑
2020;109(6):1088–95. drome coronavirus. PLoS ONE. 2019;14(7):e0220196.
165. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in 189. Burton DR, Walker LM. Rational vaccine design in the time of COVID-19.
China. Pediatrics. 2020;145:6. Cell Host Microbe. 2020;27(5):695–8.
166. Cruz AT, Zeichner SL. COVID-19 in children: initial characterization of the 190. Corum J, Grady D, Wee S-L, Zimmer C. Coronavirus vaccine tracker. The
pediatric disease. Pediatrics. 2020;145:6. New York Times 2020.
167. de Souza TH, Nadal JA, Nogueira RJ, Pereira RM, Brandão MB. Clinical 191. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-
manifestations of children with COVID-19: a systematic review. Pediatr 1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403–16.
Pulmonol. 2020;2:79. 192. Chen W. A Phase III clinical trial for inactivated novel coronavirus pneu‑
168. Peng H, Gao P, Xu Q, et al. Coronavirus Disease 2019 in children monia (COVID-19) vaccine (Vero cells). Wuhan Institute of Biological
characteristics, antimicrobial treatment, and outcomes. J Clin Virol. Products: Chinese Clinical Trials Registry; 2020. p. 19.
2019;2020:104425. 193. Halperin SA, Zhu F, angley JM. Phase III Trial of A COVID-19 Vaccine of
169. Organization WH. Oxygen therapy for children: a manual for health Adenovirus Vector in Adults 18 Years Old and Above (NCT04526990).
workers. 2016. 2021. https://clinicaltrials.gov/ct2/show/NCT04526990.
170. Ekhaguere OA, Mairami AB, Kirpalani H. Risk and benefits of bubble 194. Kuzubov VI. Study of the Safety, Reactogenicity and Immunogenicity of
continuous positive airway pressure for neonatal and childhood res‑ "EpiVacCorona" Vaccine for the Prevention of COVID-19 (EpiVacCorona).
piratory diseases in low-and middle-income countries. Paediatr Respir 2021. https://clinicaltrials.gov/ct2/show/NCT04527575.
Rev. 2019;29:31–6. 195. Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy
171. Centers for Disease Control. Information for Healthcare Providers about of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-
Multisystem Inflammatory Syndrome in Children (MIS-C). 2021. https:// 19 vaccine: an interim analysis of a randomised controlled phase 3 trial
www.cdc.gov/mis-c/hcp/. in Russia. Lancet. 2021;397(10275):671–81.
172. Shi S, Qin M, Shen B, et al. Cardiac injury in patients with corona virus 196. Palacios R. Clinical Trial of Efficacy and Safety of Sinovac’s Adsorbed
disease 2019. JAMA Cardiol. 2020;5:78. COVID-19 (Inactivated) Vaccine in Healthcare Professionals (PROFIS‑
173. Tikellis C, Thomas M. Angiotensin-converting enzyme 2 (ACE2) is a key COV). 2021. https://clinicaltrials.gov/ct2/show/record/NCT04456595?
modulator of the renin angiotensin system in health and disease. Int J view=record.
Pept. 2012;2012:78. 197. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy
174. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med.
from severe acute lung failure. Nature. 2005;436(7047):112–6. 2020;383(27):2603–15.
175. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting 198. Products CFSCfRaDoIaB. The control of the first batch of CoviVac vac‑
enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. cine will be completed in the second half of March. Sciences RAo; 2021.
2005;11(8):875–9. 199. Technology P. Bharat Biotech’s Covid-19 vaccine shows interim efficacy
176. de Abajo FJ, Rodríguez-Martín S, Lerma V, et al. Use of renin–angio‑ of 81%. 2021. https://www.pharmaceutical-technology.com/news/
tensin–aldosterone system inhibitors and risk of COVID-19 requiring bharat-biotech-vaccine-efficacy/#:~:text=Indian%20firm%20Bharat%
admission to hospital: a case-population study. Lancet. 2020;5:78. 20Biotech%20has,demonstrated%20clinical%20effi cacy%20of%2081%
177. Clerkin KJ, Fried JA, Raikhelkar J, et al. COVID-19 and cardiovascular 25.
disease. Circulation. 2020;141(20):1648–55. 200. Vaccines J, BV P. A study of Ad26. COV2. S for the prevention of SARS-
178. Atallah B, Mallah SI, AbdelWareth L, AlMahmeed W, Fonarow GC. A CoV-2-mediated COVID-19 in adult participants (ENSEMBLE). ClinicalTri‑
marker of systemic inflammation or direct cardiac injury: should cardiac als gov: NCT04505722 2020.
troponin levels be monitored in COVID-19 patients? Eur Heart J Q Care 201. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the
Clin Outcomes. 2020. ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim
179. Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with analysis of four randomised controlled trials in Brazil, South Africa, and
coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. the UK. Lancet. 2021;397(10269):99–111.
Progress Cardiovasc Dis. 2020. 202. Xia S. A randomized, double-blind, placebo parallel-controlled phase I/II
180. CredibmeMeds. Combined list of drugs that prolong QT and/or cause clinical trial for inactivated Novel Coronavirus Pneumonia vaccine (Vero
torsades de pointes (TDP). 2020. cells). 2021. http://www.chictr.org.cn/showprojen.aspx?proj=52227.
181. Chinello P, Petrosillo N, Pittalis S, et al. QTc interval prolongation during 203. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider
favipiravir therapy in an Ebolavirus-infected patient. CA USA: Public cytokine storm syndromes and immunosuppression. Lancet.
Library of Science San Francisco; 2017. 2020;395(10229):1033.
182. Kumagai Y, Murakawa Y, Hasunuma T, et al. Lack of effect of favipiravir, 204. Duan Y, Zhu H-L, Zhou C. Advance of promising targets and agents
a novel antiviral agent, on QT interval in healthy Japanese adults. Int J against 2019-nCoV in China. Drug Discov Today. 2020.
Clin Pharmacol Ther. 2015;53(10):866–74. 205. Kupferschmidt K, Cohen J. WHO launches global megatrial of the four
183. Szekely Y, Lichter Y, Shrkihe BA, Bruck H, Oster HS, Viskin S. Chloroquine- most promising coronavirus treatments. Science. 2020;22:58.
induced torsades de pointes in a patient with coronavirus disease 2019. 206. Trial R. This national clinical trial aims to identify treatments that may be
Heart Rhythm. 2020. beneficial for people hospitalised with suspected or confirmed COVID-
184. Craven J. COVID-19 vaccine tracker. 2021. https://www.raps.org/news- 19. 2021. https://www.recoverytrial.net/.
and-articles/news-articles/2020/3/covid-19-vaccine-tracker?fbclid= 207. National Institutes of Health. COVID-19 Therapeutics Prioritized for Test‑
IwAR3_zdwmwEyo9RcbPDpz2_RzMBiNDTDsnYJ9jPZzst4nw1qmp5Yw ing in Clinical Trials. 2021. https://www.nih.gov/research-training/medic
RZ3Znjk. al-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-
clinical-trials#activ2.
208. Trial CIotR. Low-cost dexamethasone reduces death by up to one third 236. Food U, Administration D. Coronavirus (COVID-19) update: FDA author‑
in hospitalised patients with severe respiratory complications of COVID- izes monoclonal antibodies for treatment of COVID-19.
19 — RECOVERY Trial (2020). 2020. 237. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of
209. National Institute of Health. COVID-19 Treatment Guidelines. 2020. chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell
210. World Health Organisation. Corticosteroids for COVID-19. 2020. https:// discovery. 2020;6(1):1–4.
www.who.int/publications/i/item/WHO-2019-nCoV-Corticoste 238. Zhou D, Dai S-M, Tong Q. COVID-19: a recommendation to examine the
roids-2020.1. effect of hydroxychloroquine in preventing infection and progression. J
211. Sterne JA, Murthy S, Diaz JV, et al. Association between administration Antimicrob Chemother. 2020.
of systemic corticosteroids and mortality among critically ill patients 239. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithro‑
with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330–41. mycin as a treatment of COVID-19: results of an open-label non-rand‑
212. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: omized clinical trial. Int J Antimicrob Agents. 2020;105:949.
living systematic review and network meta-analysis. BMJ. 2020;370:54. 240. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients
213. Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline with COVID-19: results of a randomized clinical trial. MedRxiv. 2020.
on drugs for covid-19. BMJ. 2020;370:74. 241. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with
214. National Institutes of Health. Therapeutic management of adults with mainly mild to moderate coronavirus disease 2019: open label, ran‑
COVID-19. 2021. https://www.covid19treatmentguidelines.nih.gov/ domised controlled trial. BMJ. 2020;369:124.
therapeutic-management/. 242. Organization WH. Solidarity” clinical trial for COVID-19 treatments. World
215. Prevention CfDCa. Information for clinicians on investigational thera‑ Health Organization (WHO) Situation reports Geneva: WHO. https://
peutics for patients with COVID-19. 2020. https://www.cdc.gov/coron www.who int/emergencies/diseases/novel-coronavirus-2019/global-
avirus/2019-ncov/hcp/therapeutic-options.html/. research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-
216. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease covid-19-treatments 2020. Accessed 5 Apr 2020
2019 (COVID-19). Drug Discov Ther. 2020;14(1):58–60. 243. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or
217. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel corona‑ chloroquine with or without a macrolide for treatment of COVID-19: a
virus in the United States. N Engl J Med. 2020;382(10):929–36. multinational registry analysis. Lancet. 2020.
218. National Institute of Health. COVID-19 Treatment guidelines. potential 244. Robinson J. World Health Organization resumes hydroxychloroquine
antiviral drugs under evaluation for the treatment of COVID-19. 2020. arm of COVID-19 SOLIDARITY trial. Pharm J. 2020;5:78.
https://www.covid19treatmentguidelines.nih.gov/whats-new/. 245. Nagaraja BS, Ramesh KN, Dhar D, et al. HyPE study: hydroxychloroquine
219. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID- prophylaxis-related adverse events’ analysis among healthcare workers
19: a randomised, double-blind, placebo-controlled, multicentre trial. during COVID-19 pandemic: a rising public health concern. J Public
Lancet. 2020;2:89. Health. 2020.
220. Health NIo. NIH clinical trial shows Remdesivir accelerates recovery 246. University O. Maternal use of hydroxychloroquine is associated with
from advanced COVID-19. Bethesda: National Institutes of Health; 2020. a reduced risk of recurrent anti-SSA/Ro-antibody–associated cardiac
221. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of manifestations of neonatal lupus. 2020.
Covid-19—preliminary report. New Engl J Med. 2020. 247. Boulware DR, Skipper CP, Pastick K, et al. Hydroxychloroquine in non‑
222. Sciences G. Gilead announces results from phase 3 trial of investiga‑ hospitalized adults with early COVID-19. Ann Intern Med. 2020.
tional antiviral remdesivir in patients with severe COVID‐19. 248. US Food and Drug Administration. FDA cautions against use of
223. Pan H, Peto R, Karim QA, et al. Repurposed antiviral drugs for COVID-19; hydroxychloroquine or chloroquine for COVID-19 outside of the
interim WHO SOLIDARITY trial results. medRxiv. 2020. hospital setting or a clinical trial due to risk of heart rhythm problems.
224. Davis MR, McCreary EK, Pogue JM. That escalated quickly: remdesivir’s 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cauti
place in therapy for COVID-19. Infect Dis Ther. 2020;52:1–12. ons-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-
225. DrugBank. Tocilizumab. 2021. https://go.drugbank.com/drugs/DB062 hospital-setting-or.
73. 249. National Institutes of Health. NIH halts clinical trial of hydroxychloro‑
226. Hojyo S, Uchida M, Tanaka K, et al. How COVID-19 induces cytokine quine. 2020. https://www.nih.gov/news-events/news-releases/nih-
storm with high mortality. Inflamm Regener. 2020;40(1):1–7. halts-clinical-trial-hydroxychloroquine.
227. Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients 250. Chan JFW, Yao Y, Yeung ML, et al. Treatment with lopinavir/ritona‑
with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. vir or interferon-β1b improves outcome of MERS-CoV infection in
2020;2(8):e474–84. a nonhuman primate model of common marmoset. J Infect Dis.
228. Horby PW, Pessoa-Amorim G, Peto L, et al. Tocilizumab in patients 2015;212(12):1904–13.
admitted to hospital with COVID-19 (RECOVERY): preliminary results of 251. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospi‑
a randomised, controlled, open-label, platform trial. Medrxiv. 2021. talized with severe Covid-19. New Engl J Med. 2020.
229. Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor 252. Baden LR, Rubin EJ. Covid-19—the search for effective therapy. Mass
antagonists in critically Ill patients with Covid-19–preliminary report. Medical Soc; 2020.
medRxiv. 2021: 2021.01. 07.21249390. 253. Liu W, Zhou P, Chen K, et al. Efficacy and safety of antiviral treatment for
230. Hermine O, Mariette X, Tharaux P-L, et al. Effect of tocilizumab vs COVID-19 from evidence in studies of SARSCoV-2 and other acute viral
usual care in adults hospitalized with COVID-19 and moderate or infections: a systematic review and meta-analysis. CMAJ. 2020.
severe pneumonia: a randomized clinical trial. JAMA Intern Med. 254. Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19
2021;181(1):32–40. treatment. Rev Panam Salud Publica. 2020;44:e40.
231. Rosas IO, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients 255. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy
with severe Covid-19 pneumonia. New Engl J Med. 2021. of remdesivir and combination lopinavir, ritonavir, and interferon beta
232. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocili‑ against MERS-CoV. Nat Commun. 2020;11(1):1–14.
zumab in patients hospitalized with Covid-19. N Engl J Med. 256. Arabi YM, Asiri AY, Assiri AM, et al. Treatment of Middle East respiratory
2020;383(24):2333–44. syndrome with a combination of lopinavir/ritonavir and interferon-β1b
233. Veiga VC, Prats JA, Farias DL, et al. Effect of tocilizumab on clinical out‑ (MIRACLE trial): statistical analysis plan for a recursive two-stage group
comes at 15 days in patients with severe or critical coronavirus disease sequential randomized controlled trial. Trials. 2020;21(1):1–8.
2019: randomised controlled trial. BMJ. 2021;372:25. 257. Zuo Y, Liu Y, Zhong Q, Zhang K, Xu Y, Wang Z. Lopinavir/ritonavir and
234. Health NIo. The COVID-19 Treatment Guidelines Panel’s Statement on interferon combination therapy may help shorten the duration of
the Emergency Use Authorization of Convalescent Plasma for the Treat‑ viral shedding in patients with COVID‐19: a retrospective study in two
ment of COVID-19. September; 2020. designated hospitals in Anhui, China. J Med Virol. 2020.
235. National Institutes of Health. Anti-SARS-CoV-2 Monoclonal Antibodies. 258. Davoudi-Monfared E, Rahmani H, Khalili H, et al. A randomized clinical
2021. https://www.covid19treatmentguidelines.nih.gov/anti-sars-cov- trial of the efficacy and safety of interferon β-1a in treatment of severe
2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/. COVID-19. Antimicrob Agents Chemother. 2020;64:9.
259. Zhou Q, Chen V, Shannon CP, et al. Interferon-α2b treatment for COVID- 284. Looi M-K. Covid-19: Japan declares state of emergency as Tokyo
19. Front Immunol. 2020;11:1061. cases soar. British Medical Journal Publishing Group; 2020.
260. National Institutes of Health. COVID-19 Treatment Guidelines - Inter‑ 285. Abdellatif OS, Behbehani A, Landin M. Global Governmental
ferons (Alfa, Beta). 2020. https://www.covid19treatmentguidelines.nih. Response to COVID-19 in accordance to WHO guidelines—Actions
gov/immunomodulators/interferons/. taken by Japan to prevent the spread of COVID-19 as of February 15,
261. ClinicalTrials.gov. Search of: convalescent plasma | Recruiting Studies 2021. UN Compliance Research Group; 2021.
| COVID-19 - List Results - ClinicalTrials.gov. 2020. https://clinicaltrials. 286. Karako K, Song P, Chen Y, Tang W, Kokudo N. Overview of the charac‑
gov/ct2/results?term=convalescent+plasma&cond=COVID-19& teristics of and responses to the three waves of COVID-19 in Japan
Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=. during 2020–2021. BioScience Trends. 2021.
262. Liu ST, Lin H-M, Baine I, et al. Convalescent plasma treatment of severe 287. World Health Organisation. Weekly epidemiological update—23
COVID-19: a propensity score–matched control study. Nat Med. February 2021. 2021. https://www.who.int/publications/m/item/
2020;54:1–6. weekly-epidemiological-update ---23-february-2021.
263. Chen B, Xia R. Early experience with convalescent plasma as immuno‑ 288. Africa CDC. Outbreak Brief 34: COVID-19 Pandemic—8 September
therapy for COVID‐19 in China: Knowns and unknowns. Vox Sanguinis. 2020 2020. https://africacdc.org/download/outbreak-brief-34-covid-
2020. 19-pandemic-8-september-2020/.
264. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial 289. Karamouzian M, Madani N. COVID-19 response in the Middle East
of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. and North Africa: challenges and paths forward. Lancet Global
2021;384(7):619–29. Health. 2020.
265. Chai KL, Valk SJ, Piechotta V, et al. Convalescent plasma or hyperim‑ 290. Abdi M. Coronavirus disease 2019 (COVID-19) outbreak in
mune immunoglobulin for people with COVID-19: a living systematic Iran: actions and problems. Infect Control Hosp Epidemiol.
review. Cochrane Database Syst Rev. 2020;10:87. 2020;41(6):754–5.
266. Sanfilippo F, La Rosa V, Oliveri F, Astuto M. Convalescent plasma for 291. Abdellatif OS, Behbehani A, Landin M. Global Governmental Response
COVID-19: the risk of pulmonary embolism should not be underesti‑ to COVID-19 in accordance to WHO guidelines - Actions taken by Iran
mated! Crit Care. 2020;24(1):1–2. to prevent the spread of COVID-19 as of February 15, 2021. UN Compli‑
267. Wang X, Wu W, Song P, He J. An international comparison analysis of ance Research Group; 2021.
reserve and supply system for emergency medical supplies between 292. Algaissi AA, Alharbi NK, Hassanain M, Hashem AM. Preparedness and
China, the United States, Australia, and Canada. BioScience Trends. response to COVID-19 in Saudi Arabia: building on MERS experience. J
2020. Infect Public Health. 2020;5:98.
268. Swerdlow DL, Finelli L. Preparation for possible sustained transmission 293. Abdellatif OS, Behbehani A, Landin M. Global Governmental Response
of 2019 novel coronavirus: lessons from previous epidemics. JAMA. to COVID-19 in accordance to the World Health Organization - Actions
2020;323(12):1129–30. taken by the Kingdom of Saudi Arabia to curb the spread of COVID-19
269. Petersen E, Gökengin AD. SARS-CoV-2 epidemiology and control, differ‑ as of February 22, 2021. UN Compliance Research Group. 2021.
ent scenarios for Turkey. Turk J Med Sci. 2020;50:509–14. 294. Suleiman A, Bsisu I, Guzu H, et al. Preparedness of Frontline Doctors in
270. Ritchie H, Ortiz-Ospina E, Beltekian D, et al. Coronavirus (COVID-19) Jordan Healthcare Facilities to COVID-19 Outbreak. Int J Environ Res
Vaccinations—statistics and research. 2021. https://ourworldindata.org/ Public Health. 2020;17:9.
covid-vaccinations. 295. Abdellatif OS, Behbehani A. Global Governmental Response to COVID-
271. World Health Organisation. COVAX: Working for Global Equitable Access 19 in accordance to WHO guidelines. UN Compliance Research Group;
to COVID-19 vaccines. 2020. 2021.
272. Blavatnik School of Government UoO. Coronavirus government 296. Al-Malkey MK, Al-Sammak MA. Incidence of the COVID-19 in Iraq–Impli‑
response tracker. 2020. cations for travellers. Travel Med Infect Dis. 2020.
273. Tian H, Liu Y, Li Y, et al. The impact of transmission control measures 297. Al-Mandhari A, Samhouri D, Abubakar A, Brennan R. Coronavirus
during the first 50 days of the COVID-19 epidemic in China. medRxiv. Disease 2019 outbreak: preparedness and readiness of countries in the
2020: 2020.01.30.20019844. Eastern Mediterranean Region. https://coronavirus1science.com/item/
274. Chang R, Wang H, Zhang S, et al. Phase-and epidemic region-adjusted 6166e6044a2114454e136505bc74865c1c52e8da . 2020.
estimation of the number of coronavirus disease 2019 cases in China. 298. Organization WH. Coronavirus disease (COVID-19): situation report, 150.
Front Med. 2020;8:1–11. 2020.
275. Shim E, Tariq A, Choi W, Lee Y, Chowell G. Transmission potential and 299. Ministry of Health-Kingdom of Bahrain. The National Medical Task Force
severity of COVID-19 in South Korea. Int J Infect Dis. 2020. for Combatting the Coronavirus: 10 day quarantine upon arrival to be
276. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on lifted, compulsory COVID-19 testing for all incoming passengers will
the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. remain intact. 2020. https://www.moh.gov.bh/COVID19/Details/4340.
2020;368(6489):395–400. 300. Rahman MM. The Covid-19 Pandemic: Vulnerability of Migrant workers
277. Choi JY. Covid-19 in South Korea. Postgraduate Med J. 2020. in the GCC States. 2020.
278. Cheng H-Y, Li S-Y, Yang C-H. Initial rapid and proactive response for 301. Signorelli C, Scognamiglio T, Odone A. COVID-19 in Italy: impact of
the COVID-19 outbreak—Taiwan’s experience. J Formos Med Assoc. containment measures and prevalence estimates of infection in the
2020;119(4):771. general population. Acta Bio-medica. 2020;91(3S):175–9.
279. Abdellatif OS, Behbehani A. Global Governmental Response to COVID- 302. Capalbo C, Aceti A, Simmaco M, et al. The exponential phase of the
19 in accordance to WHO guidelines—Actions taken by Singapore to Covid-19 pandemic in central italy: an integrated care pathway. Int J
prevent the spread of COVID-19 as of February 16, 2021. UN Compli‑ Environ Res Public Health. 2020;17(11):3792.
ance Research Group. 2021. 303. Medicine CCfEB. Global Covid-19 Case Fatality Rates. 2020. https://
280. Wong SY, Kwok KO, Chan FK. What can countries learn from www.cebm.net/covid-19/global-covid-19-case-fatality-rates/.
Hong Kong’s response to the COVID-19 pandemic? CMAJ. 304. Undela K, Gudi S. Assumptions for disparities in case-fatality rates of
2020;192(19):E511–5. coronavirus disease (COVID-19) across the globe. Eur Rev Med Pharma‑
281. Sesagiri Raamkumar A, Tan SG, Wee HL. Measuring the outreach efforts col Sci. 2020;24:9.
of public health authorities and the public response on facebook dur‑ 305. Sen-Crowe B, McKenney M, Elkbuli A. COVID-19 response and contain‑
ing the COVID-19 Pandemic in Early 2020: cross-country comparison. J ment strategies in the US, South Korea, and Iceland: lessons learned
Med Internet Res. 2020;22(5):e19334. and future directions. Am J Emerg Med. 2020.
282. Iwasaki A, Grubaugh ND. Why does Japan have so few cases of COVID- 306. Hunter DJ. Covid-19 and the stiff upper lip—the pandemic response in
19? EMBO Mol Med. 2020;12(5):e12481. the United Kingdom. N Engl J Med. 2020;382(16):e31.
283. Tanne JH, Hayasaki E, Zastrow M, Pulla P, Smith P, Rada AG. Covid-19: 307. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features,
how doctors and healthcare systems are tackling coronavirus world‑ evaluation and treatment coronavirus (COVID-19). Statpearls: StatPearls
wide. BMJ. 2020;368:25. Publishing; 2020.
308. O’Dowd A. Covid-19: Papers justifying government’s plans to reopen 335. World Trade Organisation. Trade Policy Review Body. Overview of
schools are “inconclusive,” say union bosses. British Medical Journal Developments in the International Trading Environment: Annual Report
Publishing Group; 2020. by the Director-General. 2020. https://www.wto-ilibrary.org/trade-
309. Abdellatif OS, Behbehani A, Landin M. Global Governmental Response monitoring/overview-of-developments-in-the-international-trading-
to COVID-19 in accordance to the World Health Organization. UN environment-annual-report-by-the-director-general-2020_afdeeebf-en.
Compliance Research Group; 2021. 336. United Nations: UNCTAD. Global Trade Update. 2021.
310. MultiState. COVID-19 Policy Tracker. 2021. https://www.multistate.us/ 337. United Nations. World economic situation and prospects 2021: Chap‑
issues/covid-19-policy-tracker. ter 2. 2021.
311. House TW. COVID-19: The Biden-Harris plan to beat COVID-19. 2020. 338. Bank W. Global Economic Prospects, January 2021. 2021.
312. House TW. National Security Memorandum on United States Global 339. World Bank. Global Economic Prospectus | June 2020, 2020.
Leadership to Strengthen the International COVID-19 Response and to 340. International Monetary Fund. WORLD ECONOMIC OUTLOOK UPDATE.
Advance Global Health Security and Biological Preparedness. 2021. 2021.
313. Tuite AR, Greer AL, De Keninck S, Fisman DN. Risk for COVID-19 resur‑ 341. Affairs UNDoEaS. World Economic Situation and Prospects as of mid-
gence related to duration and effectiveness of physical distancing in 2020 2020.
Ontario, Canada. Ann Intern Med. 2020. 342. May B. Research Briefing | Global - New virus variants, new economic
314. Zhao N, Liu Y, Smaragiassi A, Bernatsky S. Tracking the origin of early risks. Oxford Economics; 2021.
COVID-19 cases in Canada. Int J Infect Dis. 2020. 343. Organization IL. ILO Monitor: Covid-19 and the world of work. Switzer‑
315. Adisesh A, Durand-Moreau Q, Patry L, Straube S. COVID-19 in Canada land: International Labour Organization Geneva; 2020.
and the use of personal protective equipment. Occup Med. 2020;5:78. 344. Analytica O. More airlines will fail amidst the COVID-19 outbreak. Emer‑
316. Abdellatif OS, Behbehani A, Landin M, Safadi M. Global governmental ald Expert Briefings; (oxan-es).
response to COVID-19 in accordance to WHO guidelines. UN Compli‑ 345. Kandel N, Chungong S, Omaar A, Xing J. Health security capacities in
ance Research Group; 2021. the context of COVID-19 outbreak: an analysis of International Health
317. González-Bustamante B. Evolution and early government responses to Regulations annual report data from 182 countries. Lancet. 2020.
COVID-19 in South America. World Development; 2020. 346. Khan N, Naushad M, Akbar A, Faisal S, Fahad S. Critical review of COVID-
318. Garcia PJ, Alarcón A, Bayer A, et al. COVID-19 Response in Latin America. 2019 in Italy and Impact on Its Economy.
Am J Trop Med Hyg. 2020. 347. Al-Samarrai S, Gangwar M, Gala P. The impact of the COVID-19 pan‑
319. Costantino V, Heslop DJ, MacIntyre CR. The effectiveness of full and demic on education financing. World Bank; 2020.
partial travel bans against COVID-19 spread in Australia for travellers 348. Makoni M. Africa prepares for coronavirus. Lancet. 2020;395(10223):483.
from China. medRxiv. 2020. 349. World Health Organisation. ACT-Accelerator Update—26 June 2020;
320. Abdellatif OS, Behbehani A, Landin M. Global Governmental Response News Release. 2020. https://www.who.int/news-room/detail/26-06-
to COVID-19 in accordance to WHO guidelines. UN Compliance 2020-act-accelerator-update.
Research Group; 2021. 350. World Health Organisation. COVID-19 Virtual Press conference—10
321. Bandyopadhyay G, Meltzer A. Let’s Unite Against COVID-19-A New August 2020 2020.
Zealand Perspective. Irish J Psychol Med. 2020;78:1–10. 351. OECD. The impact of the coronavirus (COVID-19) crisis on development
322. Geoghegan JL, Moreland NJ, Le Gros G, Ussher JE. New Zealand’s finance. 2020. https://www.oecd.org/coronavirus/policy-responses/
science-led response to the SARS-CoV-2 pandemic. Nat Immunol. the-impact-of-the-coronavirus-covid-19-crisis-on-development-finan
2021;22(3):262–3. ce-9de00b3b/#blocknotes-d7e1933.
323. Fisk M, Livingstone A, Pit SW. Telehealth in the context of COVID-19: 352. Analytica O. Africa may seek COVID-19 debt service reprieve. Emerald
changing perspectives in Australia, the United Kingdom, and the Expert Briefings; (oxan-es).
United States. J Med Internet Res. 2020;22(6):e19264. 353. Usher AD. WHO launches crowdfund for COVID-19 response. The
324. Smith AC, Thomas E, Snoswell CL, et al. Telehealth for global emergen‑ Lancet. 2020;395(10229):1024.
cies: Implications for coronavirus disease 2019 (COVID-19). J Telemed 354. Djalante R, Shaw R, DeWit A. Building resilience against biological
Telecare. 2020;135:6567. hazards and pandemics: COVID-19 and its implications for the Sendai
325. Webster P. Canada and COVID-19: learning from SARS. The Lancet. Framework. Prog Disaster Sci. 2020;100:80.
2020;395(10228):936–7. 355. Lucero-Prisno DE III, Ogunkola IO, Imo UF, Adebisi YA. Who Will Pay for
326. Takian A, Raoofi A, Kazempour-Ardebili S. COVID-19 battle during the the COVID-19 Vaccines for Africa? Am J Trop Med Hyg. 2021;201:506.
toughest sanctions against Iran. Lancet. 2020;395(10229):1035. 356. Mateusz P SZ. U.S. Suspends Funding for the World Health Organisation.
327. Zhang W, Wang Y, Yang L, Wang C. Suspending classes without stop‑ Polish Institute of International Affairs; 2020.
ping learning: China’s education emergency management policy in the 357. Gostin LO, Friedman EA, Wetter S. How the Biden administration can
COVID-19 outbreak. J Risk Financ Manag. 2020;13(3):55. reinvigorate global health security, institutions, and governance. Am J
328. Kim JJ, Kim I, Hwang J. A change of perceived innovativeness for Int Law. 2021;115:74–9.
contactless food delivery services using drones after the outbreak of 358. Nyarko OO, Hardy YOI, Opoku G, Konadu SO. Coronavirus disease 2019
COVID-19. Int J Hosp Manag. 2021;93:102758. (COVID-19): preparedness of africa. Afr J Curr Med Res. 2020.
329. Puriwat W, Tripopsakul S. Explaining an adoption and continuance 359. Wango G, Wairire G, Kimamo C. Patterns of development of COVID-19
intention to use contactless payment technologies: during the COVID- in Low-And Middle-Income Countries: Suggested Psychological Inter‑
19 pandemic. Emerg Sci J. 2021;5(1):85–95. vention Strategies. Press; 2020.
330. Kim S, Kim Y-J, Peck KR, Jung E. School opening delay effect on 360. Janice Hopkins T, Hayasaki E, Zastrow M, Pulla P, Smith P, Acer Garcia R.
transmission dynamics of Coronavirus disease 2019 in Korea: Based Covid-19: how doctors and healthcare systems are tackling coronavirus
on mathematical modeling and simulation study. J Kor Med Sci. worldwide. BMJ. 2020;368:14.
2020;35:13. 361. Somerville P. Modelling the coronavirus pandemic to guide policy in
331. Esposito S, Principi N. School closure during the coronavirus disease real time.
2019 (COVID-19) pandemic: an effective intervention at the global 362. US Department of Commerce - Bureau of Economic Analysis. Gross
level? JAMA Pediatrics. 2020. Domestic Product, Second Quarter 2020 (Advance Estimate) and
332. Ludvigsson JF, Engerström L, Nordenhäll C, Larsson E. Open schools, Annual Update. 2020.
Covid-19, and child and teacher morbidity in Sweden. New Engl J Med. 363. International Monetary Fund. G-20 Surveillance Note: G-20 Leaders’
2021. Summit, November 21–22, 2020—Riyadh Summit, Virtual Meeting,
333. Hyde Z. COVID-19, children, and schools: overlooked and at risk. Med J 2020.
Aust. 2020;213(10):444–6. 364. Baldwin R, Mauro BWd. Mitigating the COVID economic crisis: act fast
334. McKibbin WJ, Fernando R. The global macroeconomic impacts of and do whatever it takes. VoxEuorg. 2020.
COVID-19: Seven scenarios. 2020. 365. McCartney G, Pinto J, Liu M. City resilience and recovery from COVID-19:
the case of Macao. Cities. 2021;112:103130.
366. Ontario Agency for Health Protection and Promotion (Public Health 375. Thunstrom L, Newbold S, Finnoff D, Ashworth M, Shogren JF. The ben‑
Ontario). Resurgence of COVID-19, lockdown measures and impact: a efits and costs of flattening the curve for COVID-19.
rapid scan. 2020. 376. Dureab F, Al-Awlaqi S, Jahn A. COVID-19 in Yemen: preparedness meas‑
367. Ichino A, Calzolari G, Mattozzi A, Rustichini A, Zanella G, Anelli M. Transi‑ ures in a fragile state. Lancet Public Health. 2020.
tion steps to stop COVID-19 without killing the world economy. VoxEU 377. Al-Awlaqi S, Dureab F, Annuzaili D, Al-Dheeb N. COVID-19 and conflict:
Org. 2020;25:2. The devastating impact of withdrawing humanitarian support on uni‑
368. Juniac Ad, Careen N. IATA Media Update on COVID-19, 2020. versal health coverage in Yemen. Public Health Pract. 2020;54:100015.
369. Analytica O. G20 COVID-19 spending will not alleviate doubts. Emerald 378. Devi S. Fears of “highly catastrophic” COVID-19 spread in Yemen. Lancet.
Expert Briefings; (oxan-es). 2020;395(10238):1683.
370. Wise J. Remdesivir: US purchase of world stocks sparks new “hunger 379. World Health Organisation. The potential impact of health service
games,” warn observers. British Medical Journal Publishing Group; 2020. disruptions on the burden of malaria: a modelling analysis for countries
371. Rights UNH. Human rights and access to COVID-19 vaccines. Office of in sub-Saharan Africa. 2020.
the High Commissioner 2020.
372. Baraniuk C. How to vaccinate the world against covid-19. BMJ.
2021;372:22. Publisher’s Note
373. Landgren K, al. e. Monthly Forecast. Security Council Report. 2021. Springer Nature remains neutral with regard to jurisdictional claims in pub‑
374. Ozili PK, Arun T. Spillover of COVID-19: impact on the Global Economy. lished maps and institutional affiliations.
2020.
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COVID‑19: breaking down a global health

Introduction (SARS-CoV-2), a novel strain from the Coronaviridae

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Table 1 Vaccine candidates for COVID-19 as of February 25, 2021 [191–202]

BNT162b2 – Pfizer, BioNTech mRNA-based vaccine

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