Review

Postgrad Med J: first published as 10.1136/postgradmedj-2020-138234 on 20 June 2020. Downloaded from http://pmj.bmj.com/ on March 17, 2021 by guest. Protected by copyright.
Origin, transmission, diagnosis and management of
coronavirus disease 2019 (COVID-19)
Srikanth Umakanthan ,1 Pradeep Sahu,2 Anu V Ranade,3 Maryann M Bukelo,4
Joseph Sushil Rao,5 Lucas Faria Abrahao-Machado,6 Samarika Dahal,7 Hari Kumar,8
Dhananjaya KV9

►► Additional material is ABSTRACT by molecular techniques.11–13 This article aims to

published online only. To view Coronavirus has emerged as a global health threat due to give a detailed insight into the evolution, transmis-
please visit the journal online
(http://dx.doi.org/10.1136/
its accelerated geographic spread over the last two sion and diagnosis of COVID-19. We further discuss
postgradmedj-2020-138234). decades. This article reviews the current state of the challenges encountered in the management of
knowledge concerning the origin, transmission, diagnosis patients with COVID-19 and the current limitations
For numbered affiliations see and management of coronavirus disease 2019 (COVID- in the investigational vaccine. Due to the rapidly
end of article. 19). Historically, it has caused two pandemics: severe evolving nature of COVID-19, the readers are
acute respiratory syndrome and Middle East respiratory requested to update themselves with the nature of
Correspondence to
Dr Srikanth Umakanthan,
syndrome followed by the present COVID-19 that change with this particular type of CoV.
Department of Paraclinical emerged from China. The virus is believed to be acquired
Sciences, Pathology Unit, from zoonotic source and spreads through direct and ORIGIN
Faculty of Medical Sciences, contact transmission. The symptomatic phase manifests
The University of the
Historic perspective
with fever, cough and myalgia to severe respiratory CoV was discovered during the 1960s. The
West Indies, EWMSC, Building
#5, Room 30, Mount Hope, failure. The diagnosis is confirmed using reverse Coronavirus Study Group under the International
Trinidad and Tobago; transcriptase PCR. Management of COVID-19 is mainly by Committee on Taxonomy of Viruses used the prin-
​Srikanth.​Umakanthan@​sta.​ supportive therapy along with mechanical ventilation in ciple of comparative genomics to further assess and
uwi.​edu; severe cases. Preventive strategies form the major role in
​dr.​u.​srikanth@​gmail.​com partition the replicative proteins in open reading
reducing the public spread of virus along with successful frames to identify the factors that differentiate
disease isolation and community containment. CoVat different cluster ranks.14 15 CoV is associated
Received 18 May 2020
Published Online First 8 July Development of a vaccine to eliminate the virus from the with illness of varied intensity. The most severe type
2020 host still remains an ongoing challenge. resulting in large-scale pandemics in the past are the
SARS (in 2002–2003) and Middle East respiratory
syndrome (MERS) (in 2012).16 17

INTRODUCTION Aetiology
Coronavirus (CoV) is derived from the word ‘cor- CoV are RNA viruses of the subfamily Coronavirinae.
ona’ meaning ‘crown’ in Latin.1 It causes a range of They belong to the family Coronaviridae and
human respiratory tract infections varying from the order Nidovirales (nido Latin for ‘nest’). The
mild cold to severe respiratory distress syndrome.2 order Nidovirales is composed of Coronaviridae,
The present novel CoV disease also called as severe Arteriviridae, Mesovirididae and Roniviridae
acute respiratory syndrome (SARS)-CoV-2 and cor- families.10 18 The characteristic features of
onavirus disease 2019 (COVID-19) is an emerging Nidovirales are as follows: they (1) contain very large
global health threat.3 The COVID-19 epidemic genomes for RNA viruses, (2) are highly replicative
started from Wuhan city of China towards the end due to conserved genomic organisation, (3) exhibit
of December 2019 and since then spread rapidly to several unique enzymatic activities and (4) have exten-
Thailand, Japan, South Korea, Singapore and Iran in sive ribosomal frameshifting due to the expression of
the initial months.4–6 This was followed by wide numerous non-structural genes. The Coronaviridae
viral dissemination around the world including family have two subfamilies: Coronavirinae and
Spain, Italy, USA, UAE and the UK.7 The WHO Torovirinae. The subfamily Coronavirinae consist of
declared the COVID-19 outbreak as a pandemic.8 alpha CoV, beta CoV, gamma CoV and delta CoV
As of 6 May 2020, outbreaks and sporadic human based on genomic structure.19
infections have resulted in 3 732 046 confirmed
cases and 261 517 deaths.7 Viral structure
© Author(s) (or their The CoV has posed frequent challenges during its The CoV are enveloped positive single-stranded
employer(s)) 2020. No course ranging from virus isolation, detection, pre- RNA viruses having the largest known viral RNA
commercial re-use. See rights vention to vaccine development.9 CoV belongs to genomes of 8.4–12 kDa in size.20 The viral genomes
and permissions. Published the order Nidovirales and has the largest RNA are made up of 5ʹ and 3ʹ terminal. The 5ʹ terminal
by BMJ.
genome.10 It is known to be acquired from constitutes a major part of the genome and contains
To cite: Umakanthan S, Sahu a zoonotic source and typically spreads through open reading frames, which encodes proteins respon-
P, Ranade AV, et al. contact and droplet transmission. The infected per- sible for viral replication. The 3ʹ terminal contains
Postgrad Med J son presents with non-specific clinical features the five structural proteins, namely the spike protein
2020;96:753–758. requiring virological detection and confirmation (S), membrane protein (M), nucleocapsid protein
Umakanthan S, et al. Postgrad Med J 2020;96:753–758. doi:10.1136/postgradmedj-2020-138234 753
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Postgrad Med J: first published as 10.1136/postgradmedj-2020-138234 on 20 June 2020. Downloaded from http://pmj.bmj.com/ on March 17, 2021 by guest. Protected by copyright.
(N), envelope protein (E) and the haemagglutinin-esterase (HE) HCoV-OC43, HCoV-HKU1) to severe acute respiratory distress
protein.21 22 The S protein mediates an attachment and fusion syndrome (ARDS).16 33–35
between the virus and host cell membrane and also between the Initial cases reported in Wuhan, China, are considered to be an
infected and adjacent uninfected cells. They are the major inducers acquired infection from a zoonotic source from Huanan wholesale
for neutralising antibodies in a vaccine. The N protein forms RNA seafood market which sold poultry, snake, bats and other farm
complexes that aid in virus transcription and assembly. The animals.36 37 To isolate the possible virus reservoir,
M protein is the most abundant structural protein and also defines a comprehensive genetic sequence analysis was undertaken among
the viral envelope shape. The E protein is the most enigmatic and different animal species.9 15 The results suggested that 2019-nCov is
the smallest of the major structural protein, which is highly a recombinant virus between the bat CoV and an unknown origin
expressed within the infected cell during viral replication cycle. CoV. A study revealed, based on relative synonymous codon usage
The HE protein is responsible for receptor binding and host (RSCU) on variety of animal species showed that bats are the most
specificity.20 23 probable wildlife reservoir of 2019-nCov.10 This homologous
recombination has proved previously in classical swine fever virus,
SARS and MERS hepatitis B virus, hepatitis C virus, HIV and dengue virus.38
SARS was first recognised in Guangdong province, China, in
November 2002. It advanced among 30 countries, infecting Modes of spread
79 000 people by 2003 with a fatality of 9.5%. SARS-CoV was Human-to-human transmission occurs through common routes
traced and isolated from Himalayan palm civets found in such as direct transmission, contact transmission and airborne
a livestock market in Guangdong, China.16 24 The zoonotic transmissions through aerosols and during medical procedures
origin of SARS was also discovered in racoon dogs, ferret badgers (figure 1). Cough, sneeze, droplet inhalation, contact with oral,
and in humans working at the same market. These market ani- nasal and eye mucous membranes are the common modes of
mals were therefore intermediate hosts that increased the trans- spread. Viral shedding occurs from respiratory tract, saliva, faeces
mission of virus to humans.15 24 and urine resulting in other sources of virus spread.37 39 40 The
Thereon, in 2012, Jeddah, Saudi Arabia, a patient presented viral load is higher and of longer duration in patients with severe
with respiratory illness consistent with pneumonia along with COVID-19.41 Spread of COVID-19 from patients to health
features of renal failure.25 The patient’s sputum analysis was workers and flight attenders who were in close contact with the
done by reverse transciptase (RT-PCR) using pan-CoV primers infected patients are also reported.42
revealing the viral RNA to be MERS-CoV.26 As of July 2013, 91
patients were infected with MERS-CoV and had a high fatality Virus–host interaction
rate of 34%. Bats and Arabian dromedary camels were identified Extensive structural analyses revealed atomic-level interactions
as potential hosts for MERS-CoV. Intermediate host reservoir between the CoV and the host. Cross-species and human-to-
species were also seen in goats, sheep and cows.27 28 human transmission of COVID-19 is mainly dependent on spike
protein receptor-binding domain and its host receptor ACE2.23 43
High expression of ACE2 was identified in lung (type II alveolar
Novel CoV
cells), oesophagus, ileum, colon, kidney (proximal convoluted
In view of taxonomical classification, SARS-CoV-2 (COVID-19)
tubules), myocardium, bladder (urothelial cells) and also recently
is one among many other viruses in the species, SARS-related
the oral mucosa. ACE2 receptors provide entry of the virus into the
CoV. However, SARS-CoV and SARS-CoV-2 vary in terms of
host cells and also subsequent viral replication. The main factors
disease spectrum, modes of transmission and also diagnostic
involved in viral pathogenesis of 2019-nCov are spike 1 subunit
methods.9 28 The recent report on a cluster cases having respira-
protein, priming by transmembrane protease serine-2 (essential for
tory illness in Wuhan, Central China, was followed by a global
entry and viral replication), ACE2 receptor–2019-nCov interaction
spread of the disease in a very short duration of time. The samples
and downregulation of ACE2 protein. These factors contribute to
(oral and anal swabs, blood and broncho-alveolar fluid lavage)
atrophy, fibrosis, inflammation and vasoconstriction resulting in
from patients admitted to the intensive care unit of Wuhan
host tissue injury.43–45
Jinyintan Hospital were sent to Wuhan Institute of Virology. Pan-
CoV PCR primers were used and these samples were positive for
CoV.1–3 29 This was followed by metagenomics analysis and CLINICAL PRESENTATION AND DIAGNOSIS
genomic sequencing study. The results revealed that this virus Demographics
was identical (79.6%) to the genetic sequence of SARS- Based on numerous studies published, the median age was 56 years
CoVBJ01 leading the WHO to call it novel CoV-2019 (2019- (range 55–65 years) and males were predominately affected due to
nCoV).30 31 high ACE2 concentrations in them. The median onset of illness
was 8 days (range 5–13 days).46 47 Due to limited comorbid data
availability, it is important to correlate with previously proven
TRANSMISSION AND PATHOGENESIS susceptible factors to SARS and MERS-CoV infection, which
Zoonosis includes smoking, hypertension, diabetes, cardiovascular disease
CoVs are widespread among birds and mammals with cements and/or chronic illness.16 24 25 Based on the National Health
bats forming the major evolutionary reservoir and ecological Institute analysis in Italy, the average mortality age for patients
drivers of CoV diversity.32 CoV causes a large variety of diseases suffering from COVID-19 was 81 years.48 In China, the case
in pigs, cows, chicken, dogs and cats. The major diseases caused fatality rate (CFR) increased with age and showed CFR of 18%
by CoVs in animals are transmissible gastroenteritis virus, porcine for patients above 80 years.49 This striking target to the elderly
epidemic diarrhoea virus, porcine hemagglutinating encephalo- population is attributed to underlying chronic disorders and
myelitis virus and murine hepatitis virus. In humans, alpha and declined immune function. Declined immune function has been
beta CoV have caused a variety of illness ranging from mild-self- linked to cytokine storm syndrome (elevated circulating inflam-
limiting respiratory infections (HCoV-229E, HCoV-NL63, matory cytokines) and hyper-inflammation syndrome. These

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Figure 1 Modes of transmission.

syndromes are triggered by viral infections and are also predictors less than 300 and/or lung infiltrates more than 50% of the lung
of fatality in patients with COVID-19.50 51 Children are less field within 24–48 hours) and critical (respiratory failure, septic
affected due to higher antibodies, lower prior exposure to the shock and/or multi-organ dysfunction/failure).12 52 Many of the
virus and relatively low levels of inflammatory cytokines in their elderly patients who had severe illness had evidence of chronic
systems. underlying illness such as cardiovascular disease, lung disease,
kidney disease or malignant tumours.53
Signs and symptoms
Clinical features varied from mild illness to severe or fatal illness. Laboratory evaluation and confirmation
The most common symptoms of COVID-19 were non-specific and Laboratory findings most consistent with COVID-19 were lym-
mainly included fever, cough and myalgia. Other minor symptoms phocytopenia, elevated C reactive protein and elevated erythro-
were sore throat, headache, chills, nausea or vomiting, diarrhoea, cyte sedimentation rate. Lymphocytopenia is due to necrosis or
ageusia and conjunctival congestion. The COVID-19 was clinically apoptosis of lymphocytes. The severity of lymphocytopenia
classified into mild to moderate disease (non-pneumonia and reflects the severity of COVID-19.54–56 Procalcitonin was com-
pneumonia), severe disease (dyspnoea, respiratory frequency monly elevated and was associated with coinfection in majority of
over 30/min, oxygen saturation less than 93%, PaO2/FiO2 ratio reported paediatric cases.57 58
Umakanthan S, et al. Postgrad Med J 2020;96:753–758. doi:10.1136/postgradmedj-2020-138234 755
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Detection of COVID-19 is based on virological detection Role of vaccines
by RT-PCR using swabs (nasopharynx, oropharynx), sputum Vaccine development is underway for COVID-19, but there are
and faeces, chest radiograph and dynamic monitoring of various limitations. This includes (1) the place for phase 3 vaccine
inflammatory mediators (eg, cytokines).59–61 Faecal speci- trials are to be conducted in the locality of the ongoing transmission
mens detected for COVID-19 nucleic acid was equally accu- of disease, (2) vaccine manufactures need to work closely with
rate as of pharyngeal swab specimens.60 Patients with biotechnology companies to develop effective vaccines which prob-
COVID-19 showed high blood levels of cytokines and che- ably takes a minimum of 12–18 months and (3) regulators should
mokines such as interleukin (IL)-7, IL-8, IL-9, IL-10, granu- evaluate safety with a range of virus strains in more than one animal
locyte-colony stimulating factor, granulocyte-macrophage model.78–80
colony-stimulating factor ,tumour necrosis factor alpha and The investigational vaccine has been currently developed using
VEGFA.50 62 63 mRNA as its genetic platform using prior studies related to SARS
and MERS.16 24 The basis of effective vaccine is immune targeted
and involves identifying of B cell and Tcell epitopes derived from
Radiological findings the spike (S) and nucleocapsid (N) proteins among 120 available
Most standard patterns observed on chest CT were ground-glass SARS-CoV-2 genetic sequences.24 Effective vaccination would
opacity, ill-defined margins, smooth or irregular interlobular play a vital role in reducing the viral spread and eliminate the
septal thickening, air bronchogram, crazy-paving pattern and virus from the host.81
thickening of the adjacent pleura. Chest CT is considered to be
a sensitive routine imaging tool for COVID-19.64–66
CONCLUSION
COVID-19 has presented itself as a global pandemic in a short
MANAGEMENT time period resulting in rapid curve shift of infected patients,
At the initial presentation of cluster infection, many cases were increasing death rates, huge global economic burden and wide-
treated with antiviral therapy, antibacterial therapy and glucocor- spread mobilisation of medical resource across the globe. Being
ticoids. Observation forms the mainstay for those who have mild a novel disease, COVID-19 has presented itself as a mystery
illness. Moderately ill patients with underlying chronic illness, infection to the medical field, also requiring tremendous
immunocompromised conditions and pregnancy require research and insights about the nature of the virus, and posing
hospitalisation.67 68 frequent challenges for a successful vaccine outcome. The
The anti-malarial drugs, hydroxychloroquine and chloroquine, approach to this disease requires active loco-regional to inter-
showed promising results in early in vitro study.69 However, the national collaboration with regards to disease containment,
most robust and recent study in patients with COVID-19 have not preventive strategies and treatment approach.
shown unequivocal evidence of benefits for the treatment with
hydroxychloroquine or chloroquine.70–72 In fact, the largest ana-
lysis to date of the risks and benefits of treating COVID-19 patients
with these anti-malarial drugs was unable to confirm a benefit of Main messages
hydroxychloroquine or chloroquine, when used alone or with
a macrolide, on in-hospital outcomes for COVID-19.70 Besides, ► This article reviews the current state of knowledge concerning the
this study of 96 000 hospitalised patients on six continents found origin, transmission, diagnosis and management of coronavirus
that those who received the drugs had a significantly higher risk of disease 2019 (COVID-19).
death and an increased frequency of ventricular arrhythmias com- ► It traces the origin of coronavirus as it emerged and differentiates the
pared with those who did not use it.70 COVID-19 with specific features from SARS and MERS.
► We give a detailed insight into the modes of transmission, clinical
manifestations, diagnosis and management. Also, it highlights the
recent trends on vaccine development.
Treatment of systemic complications in COVID-19
Extracorporeal membrane oxygenation is an excellent choice for
patients with ARDS progressing to respiratory failure. Other
modes of treatment include high-flow nasal oxygen and endotra-
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61 Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 ► False
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3099:30086–4. ► True
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