Introduction

Coronavirus disease 2019 (COVID-19) is a highly contagious viral illness caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has had a catastrophic effect on the
world, resulting in more than 6 million deaths worldwide. After the first cases of this
predominantly respiratory viral illness were reported in Wuhan, Hubei Province, China, in late
December 2019, SARS-CoV-2 rapidly disseminated worldwide. This compelled the World Health
Organization (WHO) to declare it a global pandemic on March 11, 2020.[1]

Even though substantial progress in clinical research has led to a better understanding of SARS-
CoV-2, many countries continue to have outbreaks of this viral illness. These outbreaks are
primarily attributed to the emergence of mutant variants of the virus. Like other RNA viruses,
SARS-CoV-2 adapts with genetic evolution and developing mutations. This results in mutant
variants that may have different characteristics than their ancestral strains. Several variants of
SARS-CoV-2 have been described during the course of this pandemic, among which only a few are
considered variants of concern (VOCs). Based on the epidemiological update by the WHO, 5 SARS-
CoV-2 VOCs have been identified since the beginning of the pandemic:

Alpha (B.1.1.7): First variant of concern, which was described in the United Kingdom (UK) in late
December 2020[2]

Beta (B.1.351): First reported in South Africa in December 2020[2]

Gamma (P.1): First reported in Brazil in early January 2021[2]

Delta (B.1.617.2): First reported in India in December 2020[2]

Omicron (B.1.1.529): First reported in South Africa in November 2021[3]

Despite the unprecedented speed of vaccine development against the prevention of COVID-19 and
robust global mass vaccination efforts, the emergence of new SARS-CoV-2 variants threatens to
overturn the progress made in limiting the spread of this disease. This review aims to
comprehensively describe the etiology, epidemiology, pathophysiology, and clinical features of
COVID-19. This review also provides an overview of the different variants of SARS-CoV-2 and the
guideline-recommended treatment (as of January 2023) for managing this disease.

Etiology

Coronaviruses (CoVs) are positive-sense single-stranded RNA (+ssRNA) viruses with a crown-like
appearance under an electron microscope (coronam is the Latin term for crown) due to the
presence of spike glycoproteins on the envelope.[1] The subfamily Orthocoronavirinae of the
Coronaviridae family (order Nidovirales) classifies into 4 genera of CoVs:
Alphacoronavirus (alphaCoV)

Betacoronavirus (betaCoV)

Deltacoronavirus (deltaCoV)

Gammacoronavirus (gammaCoV)

BetaCoV genus is further divided into 5 sub-genera or lineages.[4] Genomic characterization has
shown that bats and rodents are the probable gene sources of alphaCoVs and betaCoVs. Avian
species seem to be the source of deltaCoVs and gammaCoVs. CoVs have become significant
pathogens of emerging respiratory disease outbreaks. Members of this large family of viruses can
cause respiratory, enteric, hepatic, and neurological diseases in different animal species, including
camels, cattle, cats, and bats.

These viruses can cross species barriers and infect humans as well. Seven human CoVs (HCoVs)
capable of infecting humans have been identified. Some HCoVs were identified in the mid-1960s,
while others were only detected in the new millennium. In general, estimates suggest that 2% of
the population are healthy carriers of CoVs and that these viruses are responsible for about 5% to
10% of acute respiratory infections.[5]

Common human CoVs: HCoV-OC43 and HCoV-HKU1 (betaCoVs of the A lineage), HCoV-229E, and
HCoV-NL63 (alphaCoVs). These viruses can cause common colds and self-limiting upper respiratory
tract infections in immunocompetent individuals. However, in immunocompromised and older
patients, lower respiratory tract infections can occur due to these viruses.

Other human CoVs: SARS-CoV and MERS-CoV (betaCoVs of the B and C lineage, respectively).
These viruses are considered more virulent and capable of causing epidemics with respiratory and
extra-respiratory manifestations of variable clinical severity.[1]

SARS-CoV-2 is a novel betaCoV belonging to the same subgenus as the severe acute respiratory
syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-
CoV), which have been previously implicated in SARS-CoV and MERS-CoV epidemics with mortality
rates up to 10% and 35%, respectively.[6] It has a round or elliptic and often pleomorphic form and
a diameter of approximately 60 to 140 nm. Like other CoVs, it is sensitive to ultraviolet rays and
heat.[6]

The inactivation temperature of SARS-CoV-2 is being researched. A stainless steel surface held at
an air temperature of 54.5°C (130 °F) results in the inactivation of 90% of SARS-CoV-2 in
approximately 36 minutes.[7] It resists lower temperatures, even those below 0°C. However, lipid
solvents can effectively inactivate these viruses, including ether (75%), ethanol, chlorine-
containing disinfectant, peroxyacetic acid, and chloroform (except for chlorhexidine).
Although the origin of SARS-CoV-2 is currently unknown, it is widely postulated to have a zoonotic
transmission.[1] Genomic analyses suggest that SARS-CoV-2 probably evolved from a strain found
in bats. The genomic comparison between the human SARS-CoV-2 sequence and known animal
coronaviruses revealed high homology (96%) between the SARS-CoV-2 and the betaCoV RaTG13 of
bats (Rhinolophus affinis).[8] Similar to SARS and MERS, it has been hypothesized that SARS-CoV-2
advanced from bats to intermediate hosts, such as pangolins and minks, and then to humans.[9]
[10]

SARS-CoV-2 Variants

A globally dominant D614G variant was eventually identified and associated with increased
transmissibility but without the ability to cause severe illness.[11] Another variant was attributed
to transmission from infected farmed mink in Denmark but was not associated with increased
transmissibility.[10] Since then, multiple variants of SARS-CoV-2 have been described, of which a
few are considered variants of concern (VOCs) due to their potential to cause enhanced
transmissibility or virulence. The United States Centers for Disease Control and Prevention (CDC)
and the WHO have independently established a classification system for distinguishing the
emerging variants of SARS-CoV-2 into variants of concern(VOCs) and variants of interest(VOIs).

SARS-CoV-2 Variants of Concern (VOCs)

Alpha (B.1.1.7 lineage)

In late December 2020, the Alpha variant, or GRY (formerly GR/501Y.V1), was reported in the UK
based on whole-genome sequencing of samples from patients who tested positive for SARS-CoV-2.
[12][13]

The variant was also identified using a commercial assay characterized by the absence of the S
gene (S-gene target failure, SGTF) in PCR samples. The B.1.1.7 variant includes 17 mutations in the
viral genome. Of these, 8 mutations (Δ69-70 deletion, Δ144 deletion, N501Y, A570D, P681H, T716I,
S982A, D1118H) are in the spike (S) protein. N501Y shows an increased affinity of the spike protein
to ACE 2 receptors, enhancing the viral attachment and subsequent entry into host cells.[14][15]
[16]

This alpha variant was reportedly 43% to 82% more transmissible, surpassing preexisting variants
of SARS-CoV-2 to emerge as the dominant SARS-CoV-2 variant in the UK.[15]

An initial matched case-control study reported no significant difference in the risk of

hospitalization or associated mortality with the B.1.1.7 lineage variant compared to other existing
variants. However, subsequent studies have reported that people infected with B.1.1.7 lineage
variant had increased disease severity compared to those infected with other circulating variants.
[17][13]
A large matched cohort study in the UK reported that the mortality hazard ratio of patients
infected with the B.1.1.7 lineage variant was 1.64 (95% confidence interval 1.32 to 2.04, P<0.0001)
compared to patients with previously circulating strains.[18]

Another study reported that the B 1.1.7 variant was associated with increased mortality compared
to other SARS-CoV-2 variants (HR= 1.61, 95% CI 1.42-1.82).[19] The risk of death was reportedly
greater (adjusted hazard ratio 1.67, 95% CI 1.34-2.09) among individuals with confirmed B.1.1.7
infection compared to individuals with non-B.1.1.7 SARS-CoV-2.[20]

Beta (B.1.351 lineage)

The Beta variant, or GH501Y.V2 with multiple spike mutations, resulted in the second wave of
COVID-19 infections and was first detected in South Africa in October 2020.[21]

The B.1.351 variant includes 9 mutations (L18F, D80A, D215G, R246I, K417N, E484K, N501Y,
D614G, and A701V) in the spike protein, of which 3 mutations (K417N, E484K, and N501Y) are
located in the receptor binding domain (RBD) and increase its binding affinity for the ACE
receptors.[22][14][23]

SARS-CoV-2 501Y.V2 (B.1.351 lineage) was reported in the US at the end of January 2021.

This variant had an increased risk of transmission and reduced neutralization by monoclonal
antibody therapy, convalescent sera, and post-vaccination sera.[24]

Gamma (P.1 lineage)

The Gamma variant, or GR/501Y.V3, was identified in December 2020 in Brazil and was first
detected in the US in January 2021.[25]

This B.1.1.28 variant harbors ten mutations in the spike protein (L18F, T20N, P26S, D138Y, R190S,
H655Y, T1027I V1176, K417T, E484K, and N501Y). Three mutations (L18F, K417N, E484K) are
located in the RBD, similar to the B.1.351 variant.[25]

Delta (B.1.617.2 lineage)

The Delta variant was initially identified in December 2020 in India and was responsible for the
deadly second wave of COVID-19 infections in April 2021 in India. In the United States, this variant
was first detected in March 2021.[2]

The B.1.617.2 variant harbors ten mutations ( T19R, (G142D*), 156del, 157del, R158G, L452R,
T478K, D614G, P681R, D950N) in the spike protein.

Omicron (B.1.1.529 lineage)

The Omicron variant was first identified in South Africa on 23 November 2021 after an uptick in
the number of cases of COVID-19.[26]

Omicron was quickly recognized as a VOC due to more than 30 changes to the spike protein of the
virus and the sharp rise in the number of cases observed in South Africa.[27] The reported
mutations include T91 in the envelope, P13L, E31del, R32del, S33del, R203K, G204R in the
nucleocapsid protein, D3G, Q19E, A63T in the matrix, N211del/L212I, Y145del, Y144del, Y143del,
G142D, T95I, V70del, H69del, A67V in the N-terminal domain of the spike, Y505H, N501Y, Q498R,
G496S, Q493R, E484A, T478K, S477N, G446S, N440K, K417N, S375F, S373P, S371L, G339D in the
receptor-binding domain of the spike, D796Y in the fusion peptide of the spike, L981F, N969K,
Q954H in the heptad repeat 1 of the spike as well as multiple other mutations in the non-
structural proteins and spike protein.[28]

Many subvariants of Omicron, such as BA.1, BA.2, BA.3, BA.4, and BA.5, have been identified.[3]

Transmission of SARS-CoV-2

The primary mode of transmission of SARS-CoV-2 is via exposure to respiratory droplets carrying
the infectious virus from close contact or direct transmission from presymptomatic, asymptomatic,
or symptomatic individuals harboring the virus.[1]

Airborne transmission with aerosol-generating procedures has also been implicated in the spread
of COVID-19. Data implicating airborne transmission of SARS-CoV-2 in the absence of aerosol-
generating procedures is present; however, this mode of transmission has not been universally
acknowledged.

Fomite transmission from contamination of inanimate surfaces with SARS-CoV-2 has been well
characterized based on many studies reporting the viability of SARS-CoV-2 on various porous and
nonporous surfaces. Under experimental conditions, SARS-CoV-2 was stable on stainless steel and
plastic surfaces compared to copper and cardboard surfaces, with the viable virus being detected
up to 72 hours after inoculating the surfaces with the virus.[29] The viable virus was isolated for up
to 28 days at 20°C from nonporous surfaces such as glass and stainless steel. Conversely, recovery
of SARS-CoV-2 on porous materials was reduced compared with nonporous surfaces.[30] In
hospital settings, the SARS-CoV-2 has been detected on floors, computer mice, trash cans, sickbed
handrails, and in the air (up to 4 meters from patients).[31] The Centers for Disease Control and
Prevention (CDC) has stated that individuals can be infected with SARS-CoV-2 via contact with
surfaces contaminated by the virus, but the risk is low and is not the main route of transmission of
this virus.

Epidemiologic data from several case studies have reported that patients with SARS-CoV-2
infection have the live virus in feces implying possible fecal-oral transmission.[32]

A meta-analysis that included 936 neonates from mothers with COVID-19 showed vertical
transmission is possible but occurs in a minority of cases.[33]

Go to:

Epidemiology

COVID-19 was the third leading cause of death in the United States (USA) in 2020 after heart
disease and cancer, with approximately 375,000 deaths.[34]
Individuals of all ages are at risk of contracting this infection. However, patients aged ≥60 and
patients with underlying medical comorbidities (obesity, cardiovascular disease, chronic kidney
disease, diabetes, chronic lung disease, smoking, cancer, solid organ or hematopoietic stem cell
transplant patients) have an increased risk of developing severe COVID-19 infection.

According to the CDC, age remains the strongest predictor of poor outcomes and severe illness in
patients with COVID-19. Data from the National Vital Statistics System (NVSS) at CDC states that
patients with COVID-19 aged 50 to 64 years have a 25 times higher risk of death when compared
to adults infected with this illness and aged less than 30 years. In patients 65 to 74 years old, this
risk increases to 60 times. In patients older than 85, the risk of death increases to 340 times.
According to the CDC, these data include all deaths in the United States throughout the pandemic,
from February 2020 to July 1, 2022, including deaths among unvaccinated individuals.

The percentage of COVID-19 patients requiring hospitalization was 6 times higher in those with
preexisting medical conditions than those without medical conditions (45.4% vs. 7.6%) based on
an analysis by Stokes et al. of confirmed cases reported to the CDC from January 22 to May 30,
2020.[35] The study also reported that the percentage of patients who succumbed to this illness
was 12 times higher in those with preexisting medical conditions than those without (19.5% vs
1.6%).[35]

Data regarding the gender-based differences in COVID-19 suggests that male patients have a
higher risk of severe illness and increased mortality due to COVID-19 compared to female patients.
[36][37] Results from a retrospective cohort study from March 1 to November 21, 2020, evaluating
the mortality rate in 209 United States of America (USA) acute care hospitals that included 42604
patients with confirmed SARS-CoV-2 infection, reported a higher mortality rate in male patients
(12.5%) compared to female patients (9.6%).[38]

Racial and ethnic minority groups have been reported to have a higher percentage of COVID-19-
related hospitalizations than White patients based on a recent CDC analysis of hospitalizations
from an extensive administrative database that included approximately 300,000 COVID-19
patients hospitalized from March 2020 to December 2020. This high percentage of COVID-19-
related hospitalizations among racial and ethnic groups was driven by a higher risk of exposure to
SARS-CoV-2 and an increased risk of developing severe COVID-19 disease.[39] A meta-analysis of
50 studies from USA and UK researchers noted that people of Black, Hispanic, and Asian ethnic
minority groups are at increased risk of contracting and dying from COVID-19 infection.[40]

COVID-19-related death rates were the highest among Hispanic persons.[34] Another analysis by
the CDC evaluating the risk of COVID-19 among sexual minority adults reported that underlying
medical comorbidities which increase the risk of developing severe COVID-19 were more prevalent
in sexual minority individuals than heterosexual individuals within the general population and
within specific racial/ethnic groups.[41]

Go to:

Pathophysiology

Structurally and phylogenetically, SARS-CoV-2 is similar to SARS-CoV and MERS-CoV and is

composed of 4 main structural proteins: spike (S), envelope (E) glycoprotein, nucleocapsid (N), and
membrane (M) protein. It also contains 16 nonstructural proteins and 5-8 accessory proteins.[42]

The surface spike (S) glycoprotein, which resembles a crown, is located on the outer surface of the
virion. It undergoes cleavage into an amino (N)-terminal S1 subunit, which facilitates the
incorporation of the virus into the host cell. The carboxyl (C)-terminal S2 subunit contains a fusion
peptide, a transmembrane domain, and a cytoplasmic domain responsible for virus-cell membrane
fusion.[43][44] The S1 subunit is further divided into a receptor-binding domain (RBD) and an N-
terminal domain (NTD), which facilitates viral entry into the host cell and serves as a potential
target for neutralization in response to antisera or vaccines.[45]

The RBD is a fundamental peptide in the pathogenesis of infection as it represents a binding site
for the human angiotensin-converting enzyme 2 (ACE2) receptors. Inhibition of the renin-
angiotensin-aldosterone system (RAAS) does not increase the risk of hospitalization for COVID-19
and severe disease.[46]

SARS-CoV-2 gains entry into the host cells by binding the SARS-CoV-2 spike or S protein (S1) to the
ACE2 receptors in the respiratory epithelium. ACE2 receptors are also expressed by other organs
such as the upper esophagus, enterocytes from the ileum, myocardial cells, proximal tubular cells
of the kidney, and urothelial cells of the bladder.[47] The viral attachment process is followed by
priming the spike protein S2 subunit by the host transmembrane serine protease 2 (TMPRSS2) that
facilitates cell entry and subsequent viral replication.[48]

In the early phase of the infection, viral replication results in direct virus-mediated tissue damage.
In the late phase, the infected host cells trigger an immune response by recruiting T lymphocytes,
monocytes, and neutrophils. Cytokines such as tumor necrosis factor-α (TNF α), granulocyte-
macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), ), IL-1β,
IL-8, IL-12 and interferon (IFN)-γ are released. In severe COVID-19 illness, a 'cytokine storm' is
seen. This is due to the over-activation of the immune system and high levels of cytokines in
circulation. This results in a local and systemic inflammatory response.[49][50]
Effect of SARS-CoV-2 on the Respiratory System

Increased vascular permeability and subsequent development of pulmonary edema in patients

with severe COVID-19 are explained by multiple mechanisms.[51][52][53] These mechanisms
include:

Endotheliitis as a result of direct viral injury and perivascular inflammation leading to

microvascular and microthrombi deposition

Dysregulation of RAAS due to increased binding of the virus to the ACE2 receptors

Activation of the kallikrein-bradykinin pathway, the activation of which enhances vascular

permeability

Enhanced epithelial cell contraction causes swelling of cells and disturbance of intercellular
junctions

The binding of SARS-CoV-2 to the Toll-Like Receptor (TLR) induces the release of pro-IL-1β, which
mediates lung inflammation until fibrosis.[54]

Effect of SARS-CoV-2 on Extrapulmonary Organ Systems

Although the respiratory system is the principal target for SARS-CoV-2, other major organ systems
such as the gastrointestinal tract (GI), hepatobiliary, cardiovascular, renal, and central nervous
systems may also be affected. SARS-CoV-2–induced organ dysfunction is likely due to a
combination of mechanisms, such as direct viral toxicity, ischemic injury caused by vasculitis,
thrombosis, immune dysregulation, and renin-angiotensin-aldosterone system (RAAS)
dysregulation.[55]

Cardiac involvement in COVID-19 is common and likely multifactorial. ACE2 receptors exhibited by
myocardial cells may cause direct cytotoxicity to the myocardium leading to myocarditis.
Proinflammatory cytokines such as IL-6 can also lead to vascular inflammation, myocarditis, and
cardiac arrhythmias.[56]

Acute coronary syndrome (ACS) is a well-recognized cardiac manifestation of COVID-19. It is likely

due to multiple factors, including proinflammatory cytokines, worsening of preexisting severe
coronary artery disease, coronary plaque destabilization, microthrombogenesis, and reduced
coronary blood flow.[57]
SARS-CoV-2 has a significant effect on the hematological and hemostatic systems as well. The
mechanism of leukopenia, one of the most common laboratory abnormalities encountered in
COVID-19, is unknown. Several hypotheses have been postulated that include ACE 2 mediated
lymphocyte destruction by direct invasion by the virus, lymphocyte apoptosis due to
proinflammatory cytokines, and possible invasion of the virus in the lymphatic organs.[58]

Thrombocytopenia is common in COVID-19 and is likely due to multiple factors, including virus-
mediated suppression of platelets, autoantibodies formation, and coagulation cascade activation,
resulting in platelet consumption.[59]

Thrombocytopenia and neutrophilia are considered a hallmark of severe illness.[55] Although it is

well known that COVID-19 is associated with a state of hypercoagulability, the exact mechanisms
that lead to the activation of the coagulation system are unknown and likely attributed to the
cytokine-induced inflammatory response. The pathogenesis of this associated hypercoagulability is
multifactorial. The hypercoagulability is probably induced by direct viral-mediated damage or
cytokine-induced injury of the vascular endothelium leading to the activation of platelets,
monocytes, and macrophages, with increased expression of von Willebrand factor and Factor VIII
that results in the generation of thrombin and formation of a fibrin clot.[59][60]

Other mechanisms that have been proposed include possible mononuclear phagocyte-induced
prothrombotic sequelae, derangements in the renin-angiotensin system (RAS) pathways, and
complement-mediated microangiopathy.[59]

Go to:

History and Physical

Clinical Manifestations of COVID-19

The median incubation period for SARS-CoV-2 is estimated to be 5.1 days, and most patients will
develop symptoms within 11.5 days of infection.[61]

The clinical spectrum of COVID-19 varies from asymptomatic or paucisymptomatic forms to clinical
illness characterized by acute respiratory failure requiring mechanical ventilation, septic shock,
and multiple organ failure.

It is estimated that 17.9% to 33.3% of infected patients will remain asymptomatic.[62][63]

Most symptomatic patients present with fever, cough, and shortness of breath. Less common
symptoms include sore throat, anosmia, dysgeusia, anorexia, nausea, malaise, myalgias, and
diarrhea. Stokes et al. reported that among 373,883 confirmed symptomatic COVID-19 cases in the
USA, 70% experienced fever, cough, and shortness of breath, 36% reported myalgia, and 34%
reported headache.[35]

A large meta-analysis evaluating clinicopathological characteristics of 8697 patients with COVID-19

in China reported laboratory abnormalities that included lymphopenia (47.6%), elevated C-
reactive protein levels (65.9%), elevated cardiac enzymes (49.4%), and abnormal liver function
tests (26.4%). Other laboratory abnormalities included leukopenia (23.5%), elevated D-dimer
(20.4%), elevated erythrocyte sedimentation rate (20.4%), leukocytosis (9.9%), elevated
procalcitonin (16.7%), and abnormal renal function (10.9%).[64]

A meta-analysis of 212 published studies with 281,461 individuals from 11 countries/regions

reported that severe disease course was noted in about 23% of the patients, with a mortality rate
of about 6% in patients infected with COVID-19.[65]

An elevated neutrophil-to-lymphocyte ratio (NLR), an elevated derived NLR ratio (d-NLR), and an
elevated platelet-to-lymphocyte ratio indicate a cytokine-induced inflammatory storm.[66]

Based on the severity of the presenting illness, which includes clinical symptoms, laboratory and
radiographic abnormalities, hemodynamics, and organ function, the National Institutes of Health
(NIH) issued guidelines that classify COVID-19 into 5 distinct types.[NIH COVID-19 Treatment
Guidelines]

Asymptomatic or Presymptomatic Infection: Individuals with positive SARS-CoV-2 test without any
clinical symptoms consistent with COVID-19.

Mild illness: Individuals who have symptoms of COVID-19, such as fever, cough, sore throat,
malaise, headache, muscle pain, nausea, vomiting, diarrhea, anosmia, or dysgeusia but without
shortness of breath or abnormal chest imaging.

Moderate illness: Individuals with clinical symptoms or radiologic evidence of lower respiratory
tract disease and oxygen saturation (SpO2) ≥94% on room air.

Severe illness: Individuals who have SpO2 less than 94% on room air, a ratio of partial pressure of
arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of less than 300, marked tachypnea
with a respiratory frequency of greater than 30 breaths/min, or lung infiltrates that are greater
than 50% of total lung volume.

Critical illness: Individuals with acute respiratory failure, septic shock, or multiple organ
dysfunction. Patients with severe COVID-19 illness may become critically ill with the development
of acute respiratory distress syndrome (ARDS). This tends to occur approximately one week after
the onset of symptoms.

ARDS is characterized by a severe new-onset respiratory failure or worsening of an already

identified respiratory picture. The diagnosis requires bilateral opacities (lung infiltrates >50%), not
fully explained by effusions or atelectasis. The Berlin definition classifies ARDS into 3 types based
on the degree of hypoxia, with the reference parameter being PaO2/FiO2 or P/F ratio:[67]
Mild ARDS: 200 mm Hg <PaO2/FiO2 ≤300 mm Hg in patients not receiving mechanical ventilation
or in those managed through noninvasive ventilation (NIV) by using positive end-expiratory
pressure (PEEP) or a continuous positive airway pressure (CPAP) ≥5 cm H2O.

Moderate ARDS: 100 mm Hg <PaO2/FiO2 ≤200 mm Hg

Severe ARDS: PaO2/FiO2 ≤100 mm Hg

When PaO2 is unavailable, a ratio of SpO2/FiO2 ≤315 suggests ARDS. A multicenter prospective
observational study that analyzed 28-day mortality in mechanically ventilated patients with ARDS
concluded that COVID-19 patients with ARDS had features similar to other ARDS cohorts, and the
risk of 28-day mortality increased with ARDS severity.[68]

Extrapulmonary Manifestations

Acute kidney injury (AKI) is the most frequently encountered extrapulmonary manifestation of
COVID-19 and is associated with an increased mortality risk.[69] A large multicenter cohort study
of hospitalized patients with COVID-19 that involved 5,449 patients admitted with COVID-19
reported that 1993 (36.6%) patients developed AKI during their hospitalization, of which 14.3% of
patients required renal replacement therapy (RRT).[70]

Myocardial injury manifesting as myocardial ischemia/infarction (MI) and myocarditis are well-
recognized cardiac manifestations in patients with COVID-19. Single-center retrospective study
analysis of 187 patients with confirmed COVID-19 reported that 27.8% of patients exhibited
myocardial injury indicated by elevated troponin levels. The study also noted that patients with
elevated troponin levels had more frequent malignant arrhythmias and a higher mechanical
ventilation frequency than patients with normal troponin levels.[71] A meta-analysis of 198
published studies involving 159698 COVID-19 patients reported that acute myocardial injury and a
high burden of pre-existing cardiovascular disease were significantly associated with higher
mortality and ICU admission.[72]

Lymphopenia is a common laboratory abnormality in most patients with COVID-19. Other

laboratory abnormalities include thrombocytopenia, leukopenia, elevated ESR levels, C-reactive
protein (CRP), lactate dehydrogenase (LDH), and leukocytosis.

COVID-19 is also associated with a hypercoagulable state, evidenced by the high prevalence of
venous thromboembolic events. COVID-19 is associated with markedly elevated D-dimer and
fibrinogen levels and prolonged prothrombin time (PT) and partial thromboplastin time (aPTT).[71]
[55]

GI symptoms (such as diarrhea, nausea, vomiting), anorexia, and abdominal pain are common. A
meta-analysis reported that the weighted pool prevalence of diarrhea was 12.4% (95% CI, 8.2% to
17.1%), nausea or vomiting was 9% (95% CI, 5.5% to 12.9%), loss of appetite was 22.3% (95% CI,
11.2% to 34.6%) and abdominal pain was 6.2% (95% CI, 2.6% to 10.3%). The study also reported
that the mortality rate among patients with GI symptoms was similar to the overall mortality rate.
[73] Cases of acute mesenteric ischemia and portal vein thrombosis have also been described.[74]

An acute increase in aspartate transaminase (AST) and alanine transaminase (ALT) is noted in 14%
to 53% of patients with COVID-19 infection.[75]

Guillain-Barré syndrome (GBS) cases from Northern Italy have also been reported.[76][77]

Acral lesions resembling pseudo chilblains (40.4%) are the most common cutaneous manifestation
noted in patients with COVID-19.[78]

Other cutaneous manifestations include erythematous maculopapular rash (21.3%), vesicular

rashes (13%), urticarial rashes (10.9%), vascular rashes (4%) resembling livedo or purpura, and
erythema multiforme-like eruptions (3.7%).[78]

Go to:

Evaluation

Diagnostic Testing in COVID-19

A nasopharyngeal swab for SARS-CoV-2 nucleic acid using a real-time PCR assay is the standard
diagnostic test.[NIH COVID-19 Treatment Guidelines] Commercial PCR assays have been
authorized by the USA Food and Drug Administration (FDA) for the qualitative detection of SARS-
CoV-2 virus using specimens obtained from nasopharyngeal swabs as well as other sites such as
oropharyngeal, anterior/mid-turbinate nasal swabs, nasopharyngeal aspirates, bronchoalveolar
lavage (BAL) and saliva.

The sensitivity of PCR testing depends on multiple factors, including the specimen's adequacy,
time from exposure, and specimen source.[79] However, the specificity of most commercial FDA-
authorized SARS-CoV-2 PCR assays is nearly 100%, provided there is no cross-contamination during
specimen processing. SARS-CoV-2 antigen tests are less sensitive but have a faster turnaround
time than molecular PCR testing.[80]

Despite the numerous antibody tests designed to date, serologic testing has limitations in
specificity and sensitivity, and results from different tests vary. According to the NIH guidelines,
diagnosing acute SARS-CoV-2 infection based on serologic testing is not recommended. They also
stated that there is insufficient evidence to recommend for or against using serologic testing to
assess immunity, even if it is used to guide clinical decisions about COVID-19 vaccines/monoclonal
antibodies.[NIH COVID-19 Treatment Guidelines]

Other Laboratory Assessment

Complete blood count (CBC), a comprehensive metabolic panel (CMP) that includes renal and liver
function testing, and a coagulation panel should be performed in all hospitalized patients.

Additional tests, such as ESR, C-reactive protein (CRP), ferritin, lactate dehydrogenase, and
procalcitonin, can be considered in hospitalized patients. However, their prognostic significance in
COVID-19 is not clear.

A D-dimer level is required as it guides the use of therapeutic versus prophylactic doses of
anticoagulation.

Imaging ModalitiesThiss viral illness commonly manifests as pneumonia, so radiological imaging

such as chest x-rays, lung ultrasounds, and chest computed tomography (CT) are often obtained.
However, there are no guidelines regarding the timing and choice of pulmonary imaging in
patients with COVID-19.

When obtained, the chest X-ray usually shows bilateral multifocal alveolar opacities. Pleural
effusions can also be demonstrated. The most common CT chest findings in COVID-19 are
multifocal bilateral ground glass opacities with consolidation changes, usually in a patchy
peripheral distribution.[81]

Radiologic imaging is not a sensitive method for detecting this disease. A retrospective study of 64
patients with documented COVID-19 reported that 20% had no abnormalities on chest
radiographs during the illness.[82] A chest CT is more sensitive than a radiograph but is not
specific. No finding on radiographic imaging can completely rule in or rule out COVID-19 illness.
Therefore the American College of Radiology (ACR) advises against the routine use of chest CT for
screening or diagnosis of COVID-19.[ACR Position Statement for Diagnosis of COVID-19]

Go to:

Treatment / Management

According to the National Institutes of Health (NIH), the 2 main processes driving the pathogenesis
of COVID-19 include replication of the virus in the early phase of the illness and dysregulated
immune/inflammatory response to SARS-CoV-2 that leads to systemic tissue damage in the later
phase of the disease.[NIH COVID-19 Treatment Guidelines] The guidelines, therefore, advise
antiviral medications to halt viral replication in the early phase of the illness and
immunomodulators in the later phase.

Remdesivir is the only antiviral drug approved by the USA Food and Drug Administration (FDA) to
treat COVID-19. Ritonavir-boosted nirmatrelvir, molnupiravir, and high-titer COVID-19
convalescent plasma have Emergency Use Authorizations (EUAs) for treating COVID-19.
Tixagevimab 300 mg plus cilgavimab 300 mg monoclonal antibodies have received EUAs that allow
them to be used as SARS-CoV-2 preexposure prophylaxis (PrEP) in certain patients.

Many other monoclonal antibodies had EUAs; however, as Omicron subvariants emerged, their
EUAs were revoked as they were no longer effective.

The most recent NIH treatment guidelines for the management of COVID-19 illness (accessed on
January 3rd, 2023) are outlined below:[NIH COVID-19 Treatment Guidelines]

Nonhospitalized Adults With Mild-to-Moderate COVID-19 Illness Who Do Not Require

Supplemental Oxygen

The NIH recommends against using dexamethasone or any other systemic corticosteroids in
patients who are not hypoxic.[83]

In patients who are at high risk for progression to severe disease, they recommend the following
therapies (in order of preference):

Ritonavir-boosted nirmatrelvir

Ritonavir-boosted nirmatrelvir is a combination of oral protease inhibitors. It has been shown to

reduce hospitalization and death when given to high-risk, unvaccinated, nonhospitalized patients.
It must be given within 5 days of symptoms onset.[84]

It is a strong cytochrome P450 inhibitor with many drug-drug interactions that must be carefully
assessed.

Some interactions can be managed by temporarily holding the medication, some may be managed
with dose adjustment, but some may warrant the use of alternate COVID-19 therapy.

Ritonavir-boosted nirmatrelvir is not recommended in patients with an estimated glomerular

filtration rate (eGFR) of less than 30 mL/min.

The recommended dose is nirmatrelvir 300 mg with ritonavir 100 mg orally twice daily for 5 days.

Remdesivir

This is a nucleotide analog that inhibits the SARS-CoV-2 RNA polymerase

The recommended duration of therapy in this setting is 3 days.

The recommended dose is 200 mg IV on day 1, followed by 100 mg IV for 2 more days.

Molnupiravir

It is a mutagenic ribonucleoside antiviral agent.

Fetal toxicity has been reported in animal studies with this agent. Due to the risk of genotoxicity
with this agent, it is not recommended in pregnant patients.

This agent should only be used if both therapies are unavailable or cannot be given.

The NIH guidelines recommend against using anti-SARS-CoV-2 monoclonal antibodies (mAbs) for
treating COVID-19 in this cohort because the Omicron subvariants are not susceptible to these
agents.

Adequate and close medical follow-up is recommended; however, the frequency and duration of
follow-up depend on individual risk factors and the severity of their symptoms.

Risk factors for progression to severe disease include advanced age and underlying medical
conditions. The CDC maintains an updated list of medical conditions associated with a high risk of
progression.

According to the CDC, conditions with conclusive evidence demonstrating higher risk include:

Asthma

Cancer

Cerebrovascular disease

Chronic kidney disease

Bronchiectasis

COPD (Chronic obstructive pulmonary disease)

Interstitial lung disease

Pulmonary embolism

Pulmonary hypertension

Cirrhosis

Nonalcoholic fatty liver disease

Alcoholic liver disease

Autoimmune hepatitis

Cystic fibrosis

Diabetes, type 1 and 2

Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies)

HIV (Human immunodeficiency virus)

Mental health conditions such as mood disorders and Schizophrenia spectrum disorders
Obesity (defined as body mass index (BMI) of greater than 30 kg/m2 or greater than 95th
percentile in children)

Pregnancy and recent pregnancy

Smoking, current and former

Solid organ or blood stem cell transplantation

Tuberculosis

Use of corticosteroids or other immunosuppressive medications (CDC: Underlying Medical

Conditions Associated with Higher Risk)

Therapeutic Management of Hospitalized Adults With COVID-19 Who Do Not Require Oxygen

If patients are hospitalized for reasons other than COVID-19 illness and are not on oxygen, their
management is similar to nonhospitalized patients.

If they are hospitalized for COVID-19 illness but do not require oxygen, the NIH advises against the
use of dexamethasone or any other systemic corticosteroid.

A prophylactic dose of anticoagulation should be given if there is no contraindication.

If they are hospitalized for COVID-19 illness, do not require oxygen, but are at high risk of
progression to severe disease, they should be treated with remdesivir.

The benefit of remdesivir is greatest when given early, ideally within ten days of symptom onset.

Remdesivir should be given for 5 days or until hospital discharge.

Therapeutic Management of Hospitalized Adults With COVID-19 Who Require Conventional

Oxygen

Conventional oxygen is defined as oxygen that is NOT high-flow nasal cannula, noninvasive
mechanical ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)

For most patients in this cohort, the recommended treatment is dexamethasone plus remdesivir.

Dexamethasone dose is 6 mg IV or oral (PO) once daily for up to 10 days or until hospital discharge
(dexamethasone should not be continued at discharge).[83]

If the patient is on minimal oxygen, remdesivir monotherapy (without dexamethasone) should be

used.

If remdesivir cannot be obtained or given, dexamethasone monotherapy is recommended.

If dexamethasone is unavailable, corticosteroids such as prednisone, methylprednisolone, or

hydrocortisone may be used.
If the patient is already receiving dexamethasone but has rapidly increasing oxygen needs and/or
signs of systemic inflammation, oral baricitinib or intravenous (IV) tocilizumab should be added to
the treatment regimen as these agents have been shown to improve outcomes in rapidly
decompensating patients.[85]

Alternate immunomodulatory agents for this cohort include oral tofacitinib and IV sarilumab.
These agents should only be used if baricitinib and tocilizumab are not available.

If the D-dimer level is above normal in this cohort of patients, they recommend therapeutic
anticoagulation if the patient is not pregnant and has no increased risk of bleeding.
Contraindications for therapeutic anticoagulation in these patients include a platelet count of less
than 50 x10^9 /L, hemoglobin less than 8 g/dL, use of dual antiplatelet therapy, any significant
bleeding within the past 30 days, a history of a bleeding disorder or an inherited or active acquired
bleeding disorder.

For pregnant patients, a prophylactic dose of anticoagulation is recommended.

Therapeutic Management of Hospitalized Adults With COVID-19 who Require High-flow Nasal
Cannula (HFNC) or Noninvasive Mechanical Ventilation (NIV)

A meta-analysis study evaluating the effectiveness of HFNC compared to conventional oxygen

therapy and NIV before mechanical ventilation reported that HFNC, when used before mechanical
ventilation, could improve the prognosis of patients compared to conventional oxygen therapy
and NIV.[86] HFNC or NIV is associated with decreased dispersion of exhaled air, especially when
used with good interface fitting, thus creating a low risk of nosocomial transmission of the
infection.[87] However, these treatment modalities are associated with a greater risk of
aerosolization and should be used in negative-pressure rooms.[88]

According to the NIH, dexamethasone plus oral baricitinib or dexamethasone plus IV tocilizumab
are the preferred treatment regimens in these patients.

Alternate immunomodulatory agents for this cohort include oral tofacitinib and IV sarilumab.

Dexamethasone monotherapy is recommended if baricitinib, tocilizumab, or sarilumab cannot be

obtained/given.

Clinicians may consider adding remdesivir to corticosteroid and immunomodulator combination

regimens in immunocompromised patients who require HFNC or NIV ventilation; however, using
remdesivir without immunomodulators is not recommended.

A prophylactic dose of anticoagulation is recommended in these patients.

If patients were started on a therapeutic dose of heparin while on conventional oxygen therapy,
they should be switched to prophylactic dosing at this time unless they have another indication for
full anticoagulation.

Therapeutic Management of Hospitalized Adults With COVID-19 who Require Mechanical

Ventilation (MV)
The management of this cohort is the same as those requiring HFNC or NIV, except that remdesivir
is not recommended.

Remdesivir is most effective earlier in the course of the disease and in patients not on mechanical
ventilation or ECMO.

According to the NIH, one study showed a slight trend toward an increase in mortality in patients
who received remdesivir while on mechanical ventilation or ECMO.[89]

With this data in mind, the NIH recommends against using remdesivir in patients receiving MV or
ECMO; however, if the patient was started on remdesivir and progressed to requiring mechanical
ventilation or ECMO, they recommended continuing remdesivir to complete the treatment course.

High-Titer COVID-19 Convalescent Plasma (CCP)

The United States Food and Drug Administration (FDA) approved convalescent plasma therapy
under a EUA for patients with severe life-threatening COVID-19.[90][91] Data from multiple
studies evaluating the use of convalescent plasma in life-threatening COVID-19 has generated
mixed results. Data from 3 small randomized control trials showed no significant differences in
clinical improvement or overall mortality in patients treated with convalescent plasma versus
standard therapy.[92][93][94]

According to the NIH, high-titer CCP is not recommended in immunocompetent individuals.

However, the NIH states that some experts consider it appropriate for use in
immunocompromised individuals. Therefore, the current NIH guidelines state that there is
insufficient evidence for or against the use of high-titer CCP for treating COVID-19 in hospitalized
or nonhospitalized patients who are immunocompromised.

Medications/Treatments That Should NOT Be Used for the Treatment of COVID-19 According to
the Latest NIH Guidelines [NIH COVID-19 Treatment Guidelines]

Chloroquine or hydroxychloroquine with or without azithromycin

Lopinavir/ritonavir

Azithromycin

Doxycycline

Colchicine

Fluvoxamine

Ivermectin

Inhaled corticosteroids
Metformin

Excess supplementation of vitamin C, vitamin D, and zinc

Interferons alfa, beta, or lambda

Nitazoxanide

Bamlanivimab plus etesevimab

Bebtelovimab

Go to:

Complications

COVID-19 is a systemic viral illness based on its involvement in multiple major organ systems.

Patients with advanced age and comorbid conditions such as obesity, diabetes mellitus, chronic
lung disease, cardiovascular disease, chronic kidney disease, chronic liver disease, and neoplastic
conditions are at risk of developing severe COVID-19 and its associated complications. The most
common complication of severe COVID-19 illness is progressive or sudden clinical deterioration
leading to acute respiratory failure and ARDS or multiorgan failure leading to death.

Patients with COVID-19 illness are also at increased risk of developing prothrombotic
complications such as pulmonary embolisms, myocardial infarctions, ischemic strokes, and arterial
thrombosis.[55]

Cardiovascular system involvement results in malignant arrhythmias, cardiomyopathy, and

cardiogenic shock.

GI complications such as bowel ischemia, transaminitis, gastrointestinal bleeding, pancreatitis,

Ogilvie syndrome, mesenteric ischemia, and severe ileus are often noted in critically ill patients
with COVID-19.[99]

Acute renal failure is the most common extrapulmonary manifestation of COVID-19 and is
associated with an increased mortality risk.[69]

A meta-analysis study of 14 studies evaluating the prevalence of disseminated intravascular

coagulation (DIC) in hospitalized patients with COVID-19 reported that DIC was observed in 3%
(95%: 1%-5%, P <0.001) of the included patients. Additionally, DIC was noted to be associated with
severe illness and was a poor prognostic indicator.[100]

More recent data have emerged regarding prolonged symptoms in patients who have recovered
from COVID-19 infection, termed "post-acute COVID-19 syndrome." A large cohort study of 1773
patients performed 6 months after hospitalization with COVID-19 revealed that most exhibited at
least one persistent symptom: fatigue, muscle weakness, sleep difficulties, or anxiety. Patients
with severe illness also had an increased risk of chronic lung issues.[101]
A retrospective cohort study that included 236,379 patients reported substantial neurological
(intracranial hemorrhage, ischemic stroke) and psychiatric morbidity (anxiety disorder, psychotic
disorder) 6 months after being diagnosed with COVID-19.[102]

Secondary invasive fungal infections such as COVID-19-associated pulmonary aspergillosis and

rhino-cerebro-orbital mucormycosis have increasingly been reported as complications in patients
recovering from COVID-19. Risk factors for developing secondary fungal infection include
comorbid conditions such as uncontrolled diabetes, associated lymphopenia, and excessive use of
corticosteroids.