Continuing Education Activity

COVID-19 is an acute viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 primarily affects the respiratory system; however, it can also affect other major organ systems. Since the onset of the SARS-CoV-2 pandemic, multiple new variants of concern have emerged, such as the Alpha (B.1.1.7); Beta (B.1.351); and Gamma (P.1); Delta (B.1.617.2), and Omicron (B.1.1.529) which are associated with enhanced transmissibility and increased virulence. This activity discusses these new variants and the latest novel therapeutics available to manage COVID-19. It also highlights the role of clinical interprofessional teams, public health agencies, and community participation in improving care for patients with this illness.

Objectives:

• Describe the clinical manifestations, including extrapulmonary manifestations of COVID-19.
• Outline the latest treatments available in the management of COVID-19.
• Summarize the vaccines available to prevent COVID-19 and their efficacy against the new variants.
• Review the importance of having a holistic and interprofessional team approach to enhance the delivery of care for patients with COVID-19 leading to improved patient outcomes.

Introduction

Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a devastating effect on the world's population resulting in more than 6 million deaths worldwide and emerging as the most significant global health crisis since the influenza pandemic of 1918. Since being declared a global pandemic by the World Health Organization (WHO) on 11 March 2020, the virus continues to cause devastation, with many countries continuing to endure multiple waves of outbreaks of this viral illness.

Adaptive mutations in the viral genome can alter the virus's pathogenic potential. Even a single amino acid exchange can drastically affect a virus's ability to evade the immune system and complicate the vaccine development progress against the virus.[1] SARS-CoV-2, like other RNA viruses, is prone to genetic evolution while adapting to their new human hosts with the development of mutations over time, resulting in the emergence of multiple variants that may have different characteristics compared to its ancestral strains. Periodic genomic sequencing of viral samples helps detect new genetic variants of SARS-CoV-2 circulating in communities, especially in a global pandemic. The genetic evolution of SARS-CoV-2 was minimal during the early phase of the pandemic, with the emergence of a globally dominant variant called D614G, which was associated with higher transmissibility but without increased disease severity of its ancestral strain.[2] Another variant was identified in humans, attributed to transmission from infected farmed mink in Denmark, which was not associated with increased transmissibility.[3] 

Since then, multiple variants of SARS-CoV-2 have been described, of which a few are considered variants of concern (VOCs), given their impact on public health. VOCs are associated with enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in therapeutics or vaccination effectiveness. Based on the epidemiological update by the WHO, as of 11 December 2021, five SARS-CoV-2 VOCs have been identified since the beginning of the pandemic:

• Alpha (B.1.1.7): first variant of concern described in the United Kingdom (UK) in late December 2020
• Beta (B.1.351): first reported in South Africa in December 2020
• Gamma(P.1): first reported in Brazil in early January 2021
• Delta (B.1.617.2): first reported in India in December 2020
• Omicron (B.1.1.529): first reported in South Africa in November 2021

All five reported VOCs -Alpha(B.1.1.7); Beta(B.1.351); Gamma (P.1); Delta(B.1.617.2); and Omicron (B.1.1.529) have mutations in the RBD and the NTD, of which N501Y mutation located on the RBD is common to all variants except the Delta variant which results in increased affinity of the spike protein to ACE 2 receptors enhancing the viral attachment and its subsequent entry into the host cells. Along with NBD, RBD serves as the dominant neutralization target and facilitates antibody production in response to antisera or vaccines.[4] Two recent preprints reported that a single mutation of N501Y alone increases the affinity between RBD and ACE2 approximately ten times more than the ancestral strain (N501-RBD). Interestingly the binding affinity of the Beta (B.1.351) variant and Gamma (P.1) variant with mutations N417/K848/Y501-RBD and ACE2 was much lower than that of N501Y-RBD and ACE2.[5][6] The mutations seen in Omicron are described below. 

Despite the extraordinary speed of vaccine development against COVID-19 and continued mass vaccination efforts, including guidelines recommending vaccine boosters, the continued emergence of new variant strains of SARS-CoV-2 threatens to overturn the significant progress made so far in halting the spread of SARS-CoV-2. This review article aims to comprehensively describe these new variants of concern, the latest therapeutics available in managing COVID-19 in adults, and the efficacy of different available vaccines against this virus and its new variants.

SARS-CoV-2 Variants of Concern (VOCs)

With the emergence of multiple variants, the 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).

• Alpha (B.1.1.7 lineage)
  • In late December 2020, a new SARS-CoV-2 variant of concern, B.1.1.7 lineage, also referred to as 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.[7][8]
  • In addition to being detected by genomic sequencing, the B.1.1.7 variant was identified in a frequently used commercial assay characterized by the absence of the S gene (S-gene target failure, SGTF) PCR samples. The B.1.1.7 variant includes 17 mutations in the viral genome. Of these, eight 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.[9][10][11]
  • This variant of concern was circulating in the UK as early as September 2020 and was based on various model projections. It was reported to be 43% to 82% more transmissible, surpassing preexisting variants of SARS-CoV-2 to emerge as the dominant SARS-CoV-2 variant in the UK.[10] The B.1.1.7 variant was reported in the United States (US) at the end of December 2020. 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 virus variants.[12][8] A large matched cohort study performed 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) patients with previously circulating strains.[13] 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).[14] 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 variant of concern compared with individuals with non-1.1.7 SARS-CoV-2.[15]

• Beta (B.1.351 lineage)
  • Tegally et al. reported a new variant of SARS-CoV-2 lineage B.1.351, also referred to as Beta variant or GH501Y.V2, with multiple spike mutations, which resulted in the second wave of COVID-19 infections in Nelson Mandela Bay in South Africa in October 2020.[16]
  • The B.1.351 variant includes nine mutations (L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G, and A701V) in the spike protein, of which three mutations (K417N, E484K, and N501Y) are located in the RBD and increase the binding affinity for the ACE receptors.[17][9][18] SARS-CoV-2 501Y.V2(B.1.351 lineage) was reported in the US at the end of January 2021.
  • This variant is reported to have an increased risk of transmission and reduced neutralization by monoclonal antibody therapy, convalescent sera, and post-vaccination sera.[19]

• Gamma (P.1 lineage)
  • The third variant of concern, the P.1 variant, also known as the Gamma variant or GR/501Y.V3, was identified in December 2020 in Brazil and was first detected in the US in January 2021.[20] 
  • The B.1.1.28 variant harbors 11 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.[20] Based on the WHO epidemiological update on 30 March 2021, this variant has spread to 45 countries. Significantly, this variant may have reduced neutralization by monoclonal antibody therapies, convalescent sera, and post-vaccination sera.[19]

• Delta (B.1.617.2 lineage)
  • The fourth variant of concern, B.1.617.2, also referred to as 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 and is currently the most dominant SARS-CoV-2 strain in the US.
  • The Delta variant was initially considered a variant of interest. However, this variant rapidly spread worldwide, prompting the WHO to classify it as a VOC in May 2021.
  • 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 fifth variant of concern, B.1.1.529, also designated as the Omicron variant by the WHO, was first identified in South Africa on 23 November 2021 after an uptick in the number of cases of COVID-19.[21] 
  • Omicron was quickly recognized as a VOC due to more than 30 changes to the spike protein of the virus, along with the sharp rise in the number of cases observed in South Africa.[22] 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.[23]
  • Initial modeling suggests that Omicron shows a 13-fold increase in viral infectivity and is 2.8 times more infectious than the Delta variant.[24] Previously authorized monoclonal antibodies demonstrated reduced efficacy against the Omicron variant and subsequently revoked their emergency use authorizations. The only authorized monoclonal antibody at this time is sotrovimab because it remains effective against this variant. 
  • The Spike mutation K417N (also seen in the Beta variant) along with E484A is predicted to have an overwhelmingly disruptive effect, making Omicron more likely to have vaccine breakthroughs.[24]
  • The Omicron (B.1.1.529) became the dominant VOC in many countries, and many subvariants, such as BA.1, BA.2, BA.3, BA.4, and BA.5, were identified.
  • The Omicron VOC is currently the dominant SARS-CoV-2 variant in the US, according to the CDC.

SARS-CoV-2 Variants of Interest (VOIs)

VOIs are defined as variants with specific genetic markers that have been associated with changes that may cause enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in the effectiveness of therapeutics or vaccination. So far, since the beginning of the pandemic, the WHO has described eight variants of interest (VOIs), namely Epsilon (B.1.427 and B.1.429); Zeta (P.2); Eta( B.1.525); Theta (P.3); Iota (B.1.526); Kappa(B.1.617.1); Lambda(C.37)and Mu (B.1.621).

• Epsilon (B.1.427 and B.1.429) variants, also called CAL.20C/L452R, emerged in the US around June 2020 and increased from 0% to >50% of sequenced cases from 1 September 2020 to 29 January 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. These variants harbor specific mutations (B.1.427: L452R, D614G; B.1.429: S13I, W152C, L452R, D614G). Due to its increased transmissibility, the CDC classified this strain as a variant of concern in the US.[25]

• Zeta (P.2) has key spike mutations (L18F; T20N; P26S; F157L; E484K; D614G; S929I; and V1176F) and was first detected in Brazil in April 2020. This variant is classified as a VOI by the WHO and the CDC due to its potential reduction in neutralization by antibody treatments and vaccine sera.

• Eta (B.1.525) and Iota (B.1.526) variants harbor key spike mutations (B.1.525: A67V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L; B.1.526: (L5F*), T95I, D253G, (S477N*), (E484K*), D614G, (A701V*)) and were first detected in New York in November 2020 and classified as a variant of interest by CDC and the WHO due to their potential reduction in neutralization by antibody treatments and vaccine sera.

• Theta (P.3) variant, also called GR/1092K.V1, carries key spike mutations (141-143 deletion E484K; N501Y; and P681H) and was first detected in the Philippines and Japan in February 2021 and is classified as a variant of interest by the WHO.

• Kappa(B.1.617.1) variant harbors key mutations ((T95I), G142D, E154K, L452R, E484Q, D614G, P681R, and Q1071H) and was first detected in India in December 2021 and is classified as a variant of interest by the WHO and the CDC.

• Lambda(C.37) variant was first detected in Peru and has been designated as a VOI by the WHO in June 2021 due to a heightened presence of this variant in the South American region.

• Mu(B.1.621) variant was identified in Columbia and was designated as a VOI by the WHO in August 2021.

The CDC has designated the Epsilon (B.1.427 and B.1.429) variants as VOC and Eta(B.1.525); Iota (B.1.526); Kappa(B.1.617.1); Zeta (P.2); Mu(B.1.621, B.1.621.1) and B.1.617.3 as VOIs.

In comparison to the current circulating SARS-CoV-2 variants, previously designated VOCs and VOIs that are circulating in at negligible levels or are undetectable and do not pose a significant risk to global public health are designated as previously circulating VOCs or VOIs by the WHO and Variants Being Monitored (VBM) by the CDC.

Etiology

Coronaviruses (CoVs) are large, enveloped, positive-sense single-stranded RNA (+ssRNA) viruses that belong to the Nidovirales order within the subfamily Coronaviridae. The genome encodes four or five proteins, including the spike (S) protein which projects through the viral envelope and forms the characteristic "crown" appearance of the virus, deriving its name from the Latin word corona, meaning crown. Based on their genomic structure, these viruses are classified into four different genera:[26]

• Alphacoronavirus (αCoV)
• Betacoronavirus (βCoV)
• Gammacoronavirus (γCoV)
• Deltacoronavirus (δCoV)

Coronaviruses are widespread among birds and mammals, but only alpha and beta coronaviruses have been associated with human disease. The alpha coronaviruses include two human virus species, HCoV-229E and HCoV-NL63, and the beta coronaviruses include five human virus species, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV, and now SARS-CoV-2. Most of these viruses involve the respiratory system, typically causing common cold symptoms.[27] Genomic characterization of the 2019 novel coronavirus demonstrated 89% nucleotide identity with bat SARS-like CoV and 82% with human SARS-CoV. Hence, it was termed SARS-CoV-2 by experts of the International Committee on Taxonomy of Viruses.[28] 

SARS-CoV-2 is a novel beta coronavirus 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 epidemics with mortality rates up to 10% and 35%, respectively.[29]

Epidemiology

Since the first cases of COVID-19 were reported in Wuhan, Hubei Province, China, in December 2019 and the subsequent declaration of COVID-19 as a global pandemic by the WHO in March 2020, this highly contagious infectious disease has spread to 223 countries with more than 643 million cases, and more than 6 million deaths reported globally. A recent epidemiological update by WHO reported that more than 200 countries worldwide had reported SARS-CoV-2 variants of concern, of which the Omicron VOC has been reported as the most dominant current circulating VOC since first being reported in November 2021. The US has experienced the highest number of SARS-CoV-2 infections and COVID-19-related deaths, followed by India and Brazil.

Persons of all ages are at risk for infection and severe disease. However, patients aged ≥60 and with underlying medical comorbidities (obesity, cardiovascular disease, chronic kidney disease, diabetes, chronic lung disease, smoking, cancer, solid organ or hematopoietic stem cell transplant patients) are at an increased risk of developing severe COVID-19 infection. The percentage of COVID-19 patients requiring hospitalization was six 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. Notably, the study also showed that the percentage of patients who succumbed to this viral illness was 12 times higher in those with preexisting medical conditions than in those without medical conditions (19.5% vs. 1.6%).[30]

Data regarding the gender-based differences in COVID-19 suggests that male patients are at risk of developing severe illness and increased mortality due to COVID-19 compared to female patients.[31][32] Similarly, the severity of infection and mortality related to COVID-19 differs between different ethnic groups.[33] Based on the results of a meta-analysis of 50 studies from the US 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.[34]

Pathophysiology

Structurally and phylogenetically, SARS-CoV-2 is similar to SARS-CoV and MERS-CoV and is composed of four main structural proteins: spike (S), envelope (E) glycoprotein, nucleocapsid (N), membrane (M) protein, along with 16 nonstructural proteins, and 5-8 accessory proteins.[35] The surface spike (S) glycoprotein, which resembles a crown, is located on the outer surface of the virion and undergoes cleavage into an amino (N)-terminal S1 subunit, which facilitates the incorporation of the virus into the host cell and a carboxyl (C)-terminal S2 subunit which is responsible for virus-cell membrane fusion.[36][37] The S1 subunit is further divided into a receptor-binding domain (RBD) and an N-terminal domain (NTD), which is implicated in facilitating viral entry into the host cell and serves as a potential target for neutralization in response to antisera or vaccines.[38] 

SARS-CoV-2 gains entry into the hosts' cells by binding the SARS-CoV-2 spike or S protein (S1) to the angiotensin-converting enzyme 2 (ACE2) receptors abundantly on respiratory epithelium such as type II alveolar epithelial cells. Besides 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.[39] 

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 endocytosis with the assembly of virions.[40] Two phases explain the pathogenesis, an early phase characterized by viral replication followed by a late phase when the infected host cells trigger an immune response with the recruitment of T lymphocytes, monocytes, and neutrophil recruitment which releases cytokines such as tumor necrosis factor-α (TNF α), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon (IFN)-γ. As seen in severe COVID-19, the immune system's overactivation results in a cytokine storm characterized by the release of high levels of cytokines, especially IL-6 and TNF-α, into the circulation, causing a local and systemic inflammatory response.[41][42] 

Genetic variation in the viral genes of SARS-CoV-2 can have implications for its pathogenesis, especially if it involves the RBD, which mediates viral entry into the host cells and is an essential target of vaccine sera monoclonal antibodies. As described previously, the three reported VOCs (B.1.1.7; B.1.351; and P.1) have mutations in the RBD and the NTD, of which N501Y mutation located on the RBD is common to all variants and results in increased affinity of the spike protein to ACE 2 receptors enhancing the viral attachment and its subsequent entry into the host cells. Although the respiratory system is the predominant target for SARS-CoV-2, as described above, it can affect other major organ systems such as the gastrointestinal tract (GI), hepatobiliary, cardiovascular, renal, and central nervous systems. SARS-CoV-2–induced organ dysfunction, in general, is possibly explained by either one or a combination of the proposed mechanisms, such as direct viral toxicity, ischemic injury caused by vasculitis, thrombosis, or thrombo-inflammation, immune dysregulation, and renin-angiotensin-aldosterone system (RAAS) dysregulation.[43]

• Effect of SARS-CoV-2 on the Central Nervous System (CNS)
  • There is emerging evidence of ACE2 receptors in human and mouse brains, indicating the potential brain infection by SARS-CoV-2. Zubair et al. outlined that neuroinvasion by SARS-CoV-2 can occur with various possible routes, such as transsynaptic transfer across infected neurons via the olfactory nerve, vascular endothelial cell infection, or migration of leukocytes across the blood-brain barrier.[44]

• Effect of SARS-CoV-2 on the Cardiovascular system
  • The pathogenesis of CVS involvement in COVID-19 is unknown and is likely multifactorial, and several theories have been postulated. ACE2 receptors are also exhibited by myocardial cells implicating direct cytotoxicity by the SARS-CoV-2 on the myocardium leading to myocarditis. Conversely, the release of proinflammatory cytokines such as IL-6 can lead to vascular inflammation, myocarditis, and cardiac arrhythmias.[45]
  • Acute coronary syndrome (ACS) is also a well-recognized cardiac manifestation of COVID-19. It is likely multifactorial due to the associated thrombogenicity associated with this virus and possibly due to the release of inflammatory cytokines, which may reduce coronary blood flow, reduce oxygen supply resulting in the destabilization of coronary plaque microthrombogenesis.[46][47]

• Effect of SARS-CoV-2 on the Gastrointestinal (GI) Tract
  • The pathogenesis of GI manifestations of COVID-19 is unknown and is likely multifactorial. Several mechanisms have been proposed, including the direct ACE 2-mediated viral cytotoxicity of the intestinal mucosa, cytokine-induced inflammation, gut dysbiosis, and vascular abnormalities.[48]

• Effect of SARS-CoV-2 on the Hepatobiliary System
  • The pathogenesis of liver injury in COVID-19 patients is unknown. Liver injury is likely multifactorial and is explained by various hypotheses, including ACE-2-mediated viral replication in the liver and its resulting cytotoxicity, hypoxic or ischemic damage, immune-mediated inflammatory response, and drug-induced liver injury (DILI), or worsening of pre-existing liver disease.

• Effect of SARS-CoV-2 on the Renal System
  • The pathogenesis of COVID-19-associated kidney injury is unknown. It is likely multifactorial, explained by a single or a combination of many factors such as direct cytotoxic injury from the virus, imbalance in the RAAS, associated cytokine-induced hyperinflammatory state, microvascular injury, and the prothrombotic state associated with COVID-19. Other factors can contribute to kidney injury, such as associated hypovolemia, potential nephrotoxic agents, and nosocomial sepsis.[49]

Histopathology

Lungs: A multicenter analysis of lung tissue obtained during autopsies of patients who tested positive for COVID-19 demonstrated typical diffuse alveolar damage features in 87% of cases. Additionally, there was a frequent presence of type II pneumocyte hyperplasia, airway inflammation, and hyaline membranes in alveolar zones. Forty-two percent of patients were noted to have large vessel thrombi, platelet (CD61 positive), and/or fibrin microthrombi were present in 84% of cases.[50]

GI Tract: Endoscopic specimens demonstrated positive staining of the viral nucleocapsid protein in the gastric, duodenal, and rectal epithelium cytoplasm. Numerous infiltrating plasma cells and lymphocytes with interstitial edema were seen in the lamina propria of the stomach, duodenum, and rectum.[51] 

Liver: A prospective single-center clinicopathologic case series study involving the postmortem histopathological exam of major organs of 11 deceased patients with COVID-19 reported hepatic steatosis findings in all patients. The liver specimens of 73% of patients demonstrated chronic congestion. Different forms of hepatocyte necrosis were noted in 4 patients, and 70% showed nodular proliferation.[52]

Heart: Analysis of cardiac tissue from 39 autopsy cases of patients who tested positive for SARS-CoV-2 demonstrated the presence of the SARS-CoV-2 viral genome within the myocardium.[53]

Brain: A single-center histopathological study of brain specimens obtained from 18 patients who succumbed to COVID-19 demonstrated acute hypoxic injury in all patients' cerebrum and cerebellum. Notably, no features of encephalitis or other specific brain changes were seen. Additionally, immunohistochemical analysis of brain tissue did not show cytoplasmic viral staining.[54]

Kidney: Histopathology analysis of kidney specimens obtained from autopsies of 26 patients with confirmed COVID-19 demonstrated signs of diffuse proximal tubular injury with loss of brush border, non-isometric vacuolar degeneration, and necrosis. Additionally, electron microscopy showed clusters of coronavirus-like particles with spikes in the tubular epithelium and podocytes.[55]

History and Physical

COVID-19, the illness caused by SARS-CoV-2, primarily affects the respiratory system and is spread mainly from person to person through respiratory particles from activities such as coughing and sneezing. Most transmission occurs from close contact with presymptomatic, asymptomatic, or symptomatic carriers. Transmission with aerosol-generating procedures and contamination of inanimate surfaces with SARS-CoV-2 has also been implicated in the spread of COVID-19. Epidemiologic data from several case studies have reported that patients with SARS-CoV-2 infection have the live virus present in feces implying possible fecal-oral transmission.[56] A meta-analysis that included 936 neonates from mothers with COVID-19 showed vertical transmission is possible but occurs in a minority of cases.[57] 

The median incubation period for SARS-CoV-2 is estimated to be 5.1 days, and the majority of patients will develop symptoms within 11.5 days of infection.[58] Estimates are that 17.9% to 33.3% of infected patients will remain asymptomatic.[59][60] Patients with SARS-CoV-2 infection can experience a range of clinical manifestations ranging from no symptoms to critical illness associated with respiratory failure, septic shock, and multiorgan failure. The vast majority of symptomatic patients commonly present with fever, cough, and shortness of breath and less commonly with a 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 US, 70% experienced fever, cough, and shortness of breath, 36% reported myalgia, and 34% reported headache.[30] 

Another large meta-analysis that aimed to summarize 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%).[61] 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%).[61] The common radiographic findings in patients with COVID-19 include bilateral multifocal opacities on chest X-rays and bilateral, peripheral ground-glass opacities, with or without areas of consolidation on chest CT.

Based on the severity of presenting illness, the National Institutes of Health (NIH) has issued guidelines that classify COVID-19 into five distinct types into which adults with SARS-CoV-2 infection can be grouped. It considers the severity of clinical symptoms, laboratory and radiographic abnormalities, hemodynamics, and organ function.

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

• Mild illness: Individuals who have any 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 with oxygen saturation (SpO2) ≥ 94% on room air.

• Severe illness: Individuals who have (SpO2) ≤ 94% on room air; a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, (PaO2/FiO2) <300 with marked tachypnea with respiratory frequency >30 breaths/min or lung infiltrates >50%.Neutrophilia is also considered an essential hallmark of severe illness.[43]

• Critical illness: Individuals with acute respiratory failure, septic shock, and/or multiple organ dysfunction. Patients with severe disease may become critically ill with the development of acute respiratory distress syndrome (ARDS), which tends to occur approximately one week after the onset of symptoms. A multicenter prospective observational study that analyzed 28-day mortality in mechanically ventilated patients with ARDS concluded that COVID-19 ARDS patients had similar ARDS features from other causes. The risk of 28-day mortality increased with ARDS severity.[62]

The frequency of the spectrum of disease was described in a report from the Chinese Center for Disease Control and Prevention that reported mild disease in 81% of patients, severe disease (with shortness of breath, hypoxia, or abnormal imaging) in 14%, critical disease (respiratory failure, shock, multiorgan dysfunction in 5%, and an overall case fatality rate of 2.3%.[63] A comprehensive systematic review and meta-analysis involving 212 studies comprised of 281,461 individuals from 11 countries/regions reported that severe disease course was noted in about 23% with a mortality rate of about 6% in patients infected with COVID-19.[64]

Extrapulmonary Manifestations of COVID-19

• Neurologic manifestations: Besides anosmia and ageusia, other neurological findings include headache, stroke, impairment of consciousness, seizure disorder, and toxic metabolic encephalopathy. Five patients with COVID-19 developed Guillain-Barré syndrome (GBS) based on a case series report from Northern Italy.[65][66]

• Cardiac manifestations: Myocardial injury manifesting as myocardial ischemia/infarction (MI) and myocarditis are well-recognized cardiac manifestations in patients with COVID-19. Other common cardiac manifestations include arrhythmias, cardiomyopathy, and cardiogenic shock. A 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 high mechanical ventilation rate compared with patients with normal troponin levels. Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19.[67]

• Hematologic manifestations: Lymphopenia is a common laboratory finding in the vast majority of 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 state of coagulopathy as evidenced by the high prevalence of venous and thromboembolic events such as PE, DVT, MI, ischemic strokes, and arterial thromboses that also occurred in patients despite being maintained on prophylactic or even therapeutic systemic anticoagulation. Notably, COVID-19 is associated with markedly elevated D-dimer, fibrinogen levels, prolonged prothrombin time (PT), and partial thromboplastin time(aPTT) patients at risk of developing arterial and venous thrombosis.[43][67] Clinical trials are required to determine the benefit of therapeutic anticoagulation in patients with COVID-19, especially at what stage of the illness.

• Renal manifestations: Patients hospitalized with severe COVID-19 are at risk for developing kidney injury, most commonly manifesting as acute kidney injury (AKI), which is likely multifactorial in the setting of hypervolemia, drug injury, vascular injury, and drug-related injury, and possibly direct cytotoxicity of the virus itself. AKI is the most frequently encountered extrapulmonary manifestation of COVID-19 and is associated with increased mortality risk.[68] 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).[69] Other clinical and laboratory manifestations include proteinuria, hematuria, electrolyte abnormalities such as hyperkalemia, hyponatremia, and acid-base balance disturbance such as metabolic acidosis.[67][43]

• Gastrointestinal manifestations: Based on a meta-analysis by Elmunzer et al.; that involved 1992 patients across 36 centers,1052 patients (53%) experienced GI symptoms, with the most common reported symptoms being diarrhea (34%), nausea (27%), vomiting (16%), abdominal pain (11%).[70] Cases of acute mesenteric ischemia and portal vein thrombosis have also been described.[71]

• Hepatobiliary manifestations: Elevations in liver function tests are frequently noted in 14% to 53% of patients with COVID-19 infection.[72] Hepatic dysfunction occurs more frequently in patients with severe COVID-19 illness.

• Endocrinologic manifestations: Patients with pre-existing endocrinologic disorders such as diabetes mellitus are at increased risk of developing severe illness. Clinical manifestations such as abnormal blood glucose levels, euglycemic ketosis, and diabetic ketoacidosis have been noted in patients hospitalized with COVID-19.[67]

Evaluation

A detailed clinical history regarding the onset and duration of symptoms, travel history, exposure to people with COVID-19 infection, underlying medical comorbidities, and medication history should be obtained by treating providers. Patients with typical clinical signs suspicious of COVID-19, such as fever, cough, sore throat, loss of taste or smell, malaise, and myalgias, should be promptly tested for SARS-CoV-2. Besides symptomatic patients, anyone with known high-risk exposure to SARS-CoV-2 should be tested for SARS-CoV-2 infection even in the absence of symptoms.

The standard diagnostic mode of testing is testing a nasopharyngeal swab for SARS-CoV-2 nucleic acid using a real-time PCR assay. Commercial PCR assays have been validated by the US Food and Drug Administration (FDA) with emergency use authorizations (EUAs) for the qualitative detection of nucleic acid from SARS-CoV-2 from 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 is dependent on multiple factors that include the adequacy of the specimen, technical specimen collection, time from exposure, and specimen source.[73] However, the specificity of most commercial FDA-approved 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.[74] Comprehensive testing for other respiratory viral pathogens should also be considered for appropriate patients.

Routine laboratory assessment with complete blood count (CBC), a comprehensive metabolic panel (CMP) that includes testing for renal and liver function, and a coagulation panel should be performed in all hospitalized patients. Troponin levels and a baseline EKG to rule out cardiac injury should be performed if clinically indicated, especially in patients presenting with chest tightness or shortness of breath.

Additional tests, such as testing for inflammatory markers such as ESR, C-reactive protein (CRP), ferritin, lactate dehydrogenase, D-dimer, and procalcitonin, can be considered in hospitalized patients. However, their prognostic significance in COVID-19 is not clear. Imaging studies may include chest x-ray, lung ultrasound, or chest computed tomography (CT). The American College of Radiology recommends against computed tomography's routine use as an initial imaging study or screening. There are no guidelines available regarding the timing and choice of pulmonary imaging studies in patients with COVID-19, and the type of imaging should be considered based on clinical evaluation.

Treatment / Management

At the onset of this pandemic, there was an urgency to mitigate this new viral illness with experimental therapies and drug repurposing. Since then, significant progress has been made in the management of COVID-19 due to the intense clinical research efforts globally that have resulted in novel therapeutics and vaccine development at an unprecedented speed. Currently, a variety of therapeutic options are available that include antiviral medications (e.g., molnupiravir, ritonavir in combination with nirmatrelvir, remdesivir), anti-SARS-CoV-2 monoclonal antibodies (e.g., bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, bebtelovimab), anti-inflammatory drugs (e.g., dexamethasone), immunomodulators agents (e.g., baricitinib, tocilizumab) are available under EUA for the management of COVID-19.[43] 

However, not every patient with COVID-19 qualifies for treatment with any of these medications. The utility of these treatments is specific and based on the severity of the illness or certain risk factors. The clinical course of the COVID-19 illness occurs in 2 phases, an early phase when SARS-CoV-2 replication is greatest before or soon after the onset of symptoms. Antiviral medications and antibody-based treatments are likely to be more effective during this stage of viral replication. The later phase of the illness is driven by a hyperinflammatory state induced by the release of cytokines and the coagulation system's activation that induces a prothrombotic state. Anti-inflammatory drugs such as corticosteroids, immunomodulating therapies, or a combination of these therapies may help combat this hyperinflammatory state more than antiviral therapy.[74] Below is a summary of the latest potential therapeutic options proposed, authorized, or approved for clinical use in the management of COVID-19.

Antiviral Agents 

• Molnupiravir (named after the Norse god Thor's hammer Mjölnir) is a directly acting broad-spectrum oral antiviral agent acting on the RdRp enzyme was initially developed as a possible antiviral treatment for influenza, alphaviruses including Eastern, Western, and Venezuelan equine encephalitic viruses. Based on a meta-analysis of available phase 1-3 studies, molnupiravir demonstrated a significant reduction in hospitalization and death in mild COVID-19 disease.[75] Results from a phase 3 double-blind, randomized, placebo-controlled trial reported that early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19.[76]

• Ritonavir-boosted nirmatrelvir is an oral combination pill of two antiviral agents which, on an interim analysis of phase 2-3 data (reported via press release), which included 1219 patients, found that the risk of COVID-19-related hospital admission or all-cause mortality was 89% lower in the ritonavir-boosted nirmatrelvir group when compared to placebo when started within three days of symptom onset. Further studies are ongoing to establish the efficacy reported.[77] On 22 December 2021, the FDA issued a EUA authorizing the use of ritonavir-boosted nirmatrelvir for patients with mild to moderate COVID-19.

• Remdesivir is a broad-spectrum antiviral agent that previously demonstrated antiviral activity against SARS-CoV-2 in vitro.[78] Based on results from three randomized, controlled clinical trials that showed that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with mild-to-severe COVID-19, the US Food and Drug Administration(FDA) approved remdesivir for clinical use in adults and pediatric patients (over age 12 years and weighing at least 40 kilograms or more) to treat hospitalized patients with COVID-19.[79][80][81] However, results from the WHO SOLIDARITY Trial conducted at 405 hospitals spanning 40 countries involving 11,330 inpatients with COVID-19 who were randomized to receive remdesivir (2750) or no drug (4088) found that remdesivir had little or no effect on overall mortality, initiation of mechanical ventilation, and length of hospital stay.[82] A recently published randomized double-blind placebo-controlled trial reported an 87% lower risk of hospitalization or death than placebo when at-risk non-hospitalized patients with COVID-19 were treated with a 3-day course of remdesivir.[83] There is no data available regarding the efficacy of remdesivir against the new SARS-CoV-2 variants; however, acquired resistance against mutant viruses is a potential concern and should be monitored.

• Hydroxychloroquine and chloroquine were proposed as antiviral treatments for COVID-19 during the early onset of the pandemic. However, data from randomized control trials evaluating the use of hydroxychloroquine with or without azithromycin in hospitalized patients did not improve the clinical status or overall mortality compared to placebo.[84][85][86][87] Data from randomized control trials of hydroxychloroquine used as postexposure prophylaxis did not prevent SARS-CoV-2 infection or symptomatic COVID-19 illness. Hydroxychloroquine and chloroquine are currently not indicated for the treatment of COVID-19 in hospitalized and non-hospitalized patients.

• Lopinavir/ritonavir is FDA approved combo therapy for treating HIV and was proposed as antiviral therapy against COVID-19 during the early onset of the pandemic. Data from a randomized control trial that reported no benefit was observed with lopinavir-ritonavir treatment compared to the standard of care in patients hospitalized with severe COVID-19.[88] Lopinavir/ritonavir is currently not indicated for the treatment of COVID-19 in hospitalized and non-hospitalized patients.

• Ivermectin is an FDA-approved anti-parasitic drug used worldwide to treat COVID-19 based on an in vitro study that showed inhibition of SARS-CoV-2 replication.[89] A single-center double-blind, randomized control trial involving 476 adult patients with mild COVID-19 illness was randomized to receive ivermectin 300 mcg/kg body weight for five days or placebo did not achieve significant improvement or resolution of symptoms.[90] Ivermectin is currently not indicated for the treatment of COVID-19 in hospitalized and non-hospitalized patients.

A recent study evaluating the effect of remdesivir, nirmatrelvir, and molnupiravir reported that these three antiviral drugs might have therapeutic value against the Omicron subvariants BA.2.12.1, BA.4, and BA.5.[91]

Anti-SARS-CoV-2 Neutralizing Antibody Products 

Individuals recovering from COVID-19 develop neutralizing antibodies against SARS-CoV-2, and the duration of how long this immunity lasts is unclear. Nevertheless, their role as therapeutic agents in managing COVID-19 is extensively being pursued in clinical trials.

• Convalescent plasma therapy was evaluated during the SARS, MERS, and Ebola epidemics; however, it lacked randomized control trials to back its actual efficacy. The FDA approved convalescent plasma therapy under EUA for patients with severe life-threatening COVID-19.[92][93] Although it appeared promising, data from multiple studies evaluating the use of convalescent plasma in life-threatening COVID-19 has generated mixed results. One retrospective study based on a US national registry reported that among patients hospitalized with COVID-19, not on mechanical ventilation, there was a lower risk of death in patients who received a transfusion of convalescent plasma with higher anti-SARS-CoV-2 IgG antibody than patients who received a transfusion of convalescent plasma with low antibody levels. Data from three small randomized control trials showed no significant differences in clinical improvement or overall mortality in patients treated with convalescent plasma versus standard therapy.[94][95][96] An in vitro analysis of convalescent plasma obtained from individuals previously infected with the ancestral SARS-CoV-2 strains demonstrated significantly reduced neutralization against the beta (B.1.351).[97] Another in vitro study reported that the beta (B.1.351) variant exhibited markedly more resistance to neutralization by convalescent plasma obtained from individuals previously infected with the ancestral SARS-CoV-2 strains compared to the alpha( B.1.1.7) variant, which was not more resistant to neutralization.[98]

• Previously, multiple monoclonal antibodies suggest Bamlanivimab/Etesevimab, Sotrovimab, Casirivimab/Imdevimab and Beptelovimab had received FDA authorization for in the clinical management of COVID-19.  However, due to the emergence and dominance of Omicron subvariants, there are currently no monoclonal antibodies authorized to treat COVID-19.

• Tixagevimab and Cilgavimab(AZD7442) are potent anti-spike neutralizing monoclonal antibodies obtained from antibodies isolated from B cells of patients infected with SARS-CoV-2 that have demonstrated neutralizing activity against SARS-CoV-2 virus by binding to nonoverlapping epitopes of the viral spike-protein RBD.[99][100][101].Results of an ongoing multicenter, double-blind, randomized placebo-controlled trial evaluating the safety and efficacy of single-dose combining these two monoclonal antibodies for preexposure prophylaxis against COVID-19 in high-risk patients, patients who had an inadequate response to COVID-19 vaccination or were unable to receive vaccines demonstrated the efficacy of this monoclonal antibody combination for the prevention of COVID-19 with no safety concerns.[99] In December 2021, the US Food and drug administration showed a EUA for the emergency use of this monoclonal antibody combination for use in preexposure prophylaxis of COVID-19 in adults and pediatric population (12 years of age and older being at least 40 kg in weight) with no current evidence of SARS-CoV-2  infection and no recent exposure to SARS-CoV-2 positive individuals AND who have moderate or severe immunocompromised due to several types of conditions and treatments OR are on immunosuppressive medications and may not mount an adequate immune response to COVID-19 vaccination OR in individuals in whom COVID-19 vaccination is contraindicated due to history of severe adverse reaction to the vaccine or vaccine components.

Immunomodulatory Agents

• Corticosteroids: Severe COVID-19 is associated with inflammation-related lung injury driven by the release of cytokines characterized by an elevation in inflammatory markers. During the pandemic's early course, glucocorticoids' efficacy in patients with COVID-19 was not well described. It was a debate and uncertainty topic purely due to the lack of scientific data from large-scale randomized clinical trials. The Randomized Evaluation of the Covid-19 Therapy (RECOVERY) trial, which included hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 who were randomly assigned to receive dexamethasone (n=2104) or usual care (n=4321), showed that the use of dexamethasone resulted in lower 28-day mortality in patients who were on invasive mechanical ventilation or oxygen support but not in patients who were not receiving any respiratory support.[102] Based on these landmark trial results, dexamethasone is currently considered the standard of care, either alone or in combination with remdesivir, based on the severity of illness in hospitalized patients who require supplemental oxygen or non-invasive or invasive mechanical ventilation.

• Interferon-β-1a (IFN- β-1a): Interferons are cytokines that are essential in mounting an immune response to a viral infection, and SARS-CoV-2 suppresses its release in vitro.[103] However, previous experience with IFN- β-1a in acute respiratory distress syndrome (ARDS) has not benefited.[104] Results from a small randomized, double-blind, placebo-controlled trial showed the use of inhaled IFN- β-1a had greater odds of clinical improvement and recovery compared to placebo.[105] Another small randomized clinical trial showed that the clinical response using inhaled IFN- β-1a was not significantly different from the control group. The authors reported when used early, this agent resulted in a shorter length of hospitalization stay and decreased 28-day mortality rate. However, four patients who died in the treatment group before completing therapy were excluded, thus making interpreting these results difficult.[106] Currently, there is no data available regarding the efficacy of interferon β-1a on the three new SARS-CoV-2 variants (B.1.1.7; B.1.351 and P.1). Given the insufficient and small amount of data regarding this agent's use and the relative potential for toxicity, this therapy is currently not recommended to treat COVID-19 infection.

• Interleukin (IL)-1 Antagonists: Anakinra is an interleukin-1 receptor antagonist that is FDA-approved to treat rheumatoid arthritis. Its off-label use in severe COVID-19 was assessed in a small case-control study trial based on the rationale that severe COVID-19 is driven by cytokine production, including interleukin (IL)-1β. This trial revealed that of the 52 patients who received anakinra and 44 patients who received standard of care, anakinra reduced the need for invasive mechanical ventilation and mortality in patients with severe COVID-19.[107] There is no data available regarding the efficacy of interleukin-1 receptor antagonists on the three new SARS-CoV-2 variants (B.1.1.7; B.1.351, and P.1). Given the insufficient data regarding this treatment based on case series only, this is not currently recommended to treat COVID-19 infection.

• Anti-IL-6 receptor monoclonal antibodies: Interleukin-6 (IL-6) is a proinflammatory cytokine considered the key driver of the hyperinflammatory state associated with COVID-19. Targeting this cytokine with an IL-6 receptor inhibitor could slow down the process of inflammation based on case reports that showed favorable outcomes in patients with severe COVID-19.[108][109][110] The FDA approved three different types of IL-6 receptor inhibitors for various rheumatological conditions (Tocilizumab, Sarilumab) and a rare disorder called Castleman's syndrome (siltuximab).
  • Tocilizumab is an anti-interleukin-6 receptor alpha receptor monoclonal antibody indicated for various rheumatological diseases. The data regarding the use of this agent is mixed. A randomized control trial involving 438 hospitalized patients with severe COVID-19 pneumonia, among which 294 were randomized to receive tocilizumab and 144 to placebo, showed that tocilizumab did not translate into a significant improvement in clinical status or lower the 28-day mortality compared to placebo.[111] Results from another randomized, double-blind, placebo-controlled trial involving patients with confirmed severe COVID-19 that involved 243 patients randomized to receive tocilizumab or placebo showed that the use of tocilizumab was ineffective in preventing intubation or death rate.[112] The REMAP-CAP and RECOVERY trials (not yet published), two large randomized controlled trials, showed evidence of a mortality benefit in patients exhibiting rapid respiratory decompensation.[113]
  • Sarilumab and Siltuximab are IL-6 receptor antagonists that may potentially have a similar effect on the hyperinflammatory state associated with COVID-19 as tocilizumab. Currently, no known published clinical trials support the use of siltuximab in severe COVID-19. Conversely, a 60-day randomized, double-blind placebo control multinational phase 3 trial that evaluated the clinical efficacy, mortality, and safety of sarilumab in 431 patients showed no significant improvement in clinical status or mortality rate.[114] Another randomized, double-blind, placebo-controlled study on sarilumab's clinical efficacy and safety in adult patients hospitalized with COVID-19 is ongoing (NCT04315298).

• Janus kinase (JAK) inhibitors 
  • Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2 currently indicated for moderate to severely active rheumatoid arthritis patients. Baricitinib was considered a potential treatment for COVID-19 based on its inhibitory effect on SARS-CoV-2 endocytosis in vitro and on the intracellular signaling pathway of cytokines that cause the late-onset hyperinflammatory state that results in severe illness.[115][116] This dual inhibitory effect makes it a promising therapeutic drug against all stages of COVID-19. A multicenter observational, retrospective study of 113 hospitalized patients with COVID-19 pneumonia who received baricitinib combined with lopinavir/ritonavir (baricitinib arm, n=113) or hydroxychloroquine and lopinavir/ritonavir (control arm, n=78) reported significant improvement in clinical symptoms and 2-week mortality rate in the baricitinib arm compared with the control arm. Results from the ACTT-2 trial, a double-blind, randomized placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adult patients with COVID-19, reported that the combination therapy of baricitinib plus remdesivir was superior to remdesivir therapy alone in not only reducing recovery time but also accelerating clinical improvement in hospitalized patients with COVID-19, particularly who were receiving high flow oxygen supplementation or non-invasive ventilation.[117] Baricitinib, in combination with remdesivir, has been approved for clinical use in hospitalized patients with COVID-19 under a EUA issued by the FDA. The efficacy of baricitinib alone or in combination with remdesivir has not been evaluated in the SARS-CoV-2 variants, and there is limited data on the use of baricitinib with dexamethasone.  
  • Ruxolitinib is another oral selective inhibitor of JAK 1 and 2 indicated for myeloproliferative disorders, polycythemia vera, and steroid-resistant GVHD. Similar to baricitinib, it has been hypothesized to have an inhibitory effect on cytokines' intracellular signaling pathway, making it a potential treatment against COVID-19. Results from a small prospective multicenter randomized controlled phase 2 trial evaluating the efficacy and safety of ruxolitinib reported no statistical difference from the standard of care. However, most patients demonstrated significant chest CT improvement and faster recovery from lymphopenia.[118] A large randomized, double-blind, placebo-controlled multicenter trial (NCT04362137) is ongoing to assess ruxolitinib's efficacy and safety in patients with severe COVID-19.
  • Tofacitinib is another oral selective inhibitor of JAK 1 and JAK3 that is indicated for moderate to severe RA, psoriatic arthritis, and moderate to severe ulcerative colitis. Given its inhibitory effect on the inflammatory cascade, it was hypothesized that its use could ameliorate the viral inflammation-mediated lung injury in patients with severe COVID-19. Results from a small randomized controlled trial that evaluated the efficacy involving 289 patients who were randomized to receive tofacitinib or placebo showed that tofacitinib led to a lower risk of respiratory failure or death (PMID:34133856).

• Bruton's tyrosine kinase inhibitors, such as acalabrutinib, ibrutinib, and rilzabrutinib, are tyrosine kinase inhibitors that regulate macrophage signaling and activation currently FDA-approved for some hematologic malignancies. It is proposed that macrophage activation occurs during the hyperinflammatory immune response seen in severe COVID-19. Results from a small off-label study of 19 hospitalized patients with severe COVID-19 who received acalabrutinib highlighted the potential clinical benefit of BTK inhibition.[119] Clinical trials are in progress to validate the efficacy in severe COVID-19 illness.

Management of COVID-19 Based on the Severity of Illness 

• Asymptomatic or Presymptomatic Infection

• Individuals with a positive SARS-CoV-2 test without any clinical symptoms consistent with COVID-19 should be advised to isolate themselves and monitor clinical symptoms.

• Mild Illness

• Based on the NIH guidelines, individuals with mild illness can be managed in the ambulatory setting with supportive care and isolation. 
• Laboratory and radiographic evaluations are routinely not indicated.
• Elderly patients and those with pre-existing conditions should be monitored closely until clinical recovery is achieved.  
• The National Institutes of Health (NIH) Covid-19 treatment guidelines panel recommends the use of Paxlovid or Remdesivir in order of preference as preferred therapies for outpatients at high risk of disease progression with a low threshold to consider hospitalization for closer monitoring. The panel recommends clinical use of alternative therapies such as Molnupiravir ONLY if there is non-availability of preferred therapies, not feasible to use, or clinically inappropriate. 
• The National Institutes of Health (NIH) Covid-19 Treatment Guidelines Panel recommends against dexamethasone in mild illness.

• Moderate Illness

• Patients with moderate COVID-19 illness should be hospitalized for close monitoring.
• Clinicians and healthcare staff should don appropriate personal protective equipment (PPE) while interacting with or taking care of the patient. 
• All hospitalized patients should receive supportive care with isotonic fluid resuscitation if volume-depleted, and supplemental oxygen therapy must be initiated if SpO2 and be maintained no higher than 96%. Patients should be monitored by continuous pulse oximetry.[120]
• Empirical antibacterial therapy should be started only if there is a suspicion of bacterial infection and should be discontinued as early as possible if not indicated.
• Patients with COVID-19 are at risk of developing venous and thromboembolic events. Thus all hospitalized patients with COVID-19 should receive thromboembolic prophylaxis with appropriate anticoagulation.
• Remdesivir and dexamethasone can be considered for hospitalized patients who require supplemental oxygen.
• The National Institutes of Health (NIH) Covid-19 treatment guidelines panel recommends the use of either remdesivir alone or dexamethasone plus remdesivir or dexamethasone alone if combination therapy (remdesivir and dexamethasone) is not available in hospitalized patients who require supplemental oxygen provided they are not on high flow oxygen delivery or require non-invasive ventilation or receive invasive mechanical ventilation or ECMO

• Severe/Critical Illness[121][120][43] 

• Patients with severe/critical COVID-19 illness require hospitalization.
• Considering that patients with severe COVID-19 are at increased risk of prolonged critical illness and death, discussions regarding care goals, reviewing advanced directives, and identifying surrogate medical decision-makers must be made.
• All patients should be maintained on prophylactic anticoagulation, considering COVID-19 is associated with a prothrombotic state.
• Clinicians and other healthcare staff must wear appropriate PPE that includes gowns, gloves, N95 masks, and eye protection when performing aerosol-generating procedures on patients with COVID-19 in the ICU, such as endotracheal intubation, bronchoscopy, tracheostomy, manual ventilation before intubation, physical proning of the patient or providing critical patient care such as nebulization, upper airway suctioning, disconnecting the patient from the ventilator, and non-invasive positive pressure ventilation that may potentially lead to the aerosol generation.[122]
• Renal replacement therapy should be considered in renal failure when indicated.
• High-flow nasal cannula oxygen or non-invasive ventilation can be considered in patients who do not require intubation.
• Having awake patients self-prone while receiving high-flow nasal cannula oxygen can improve oxygenation if endotracheal intubation is not indicated. However, the efficacy of performing this maneuver on awake patients is not clear and more data from clinical trials is needed.
• The National Institutes of Health (NIH) Covid-19 Treatment Guidelines Panel strongly recommends using dexamethasone in hospitalized patients who require oxygen via non-invasive or invasive ventilation. Combination therapy with dexamethasone plus baricitinib or tocilizumab in combination with dexamethasone alone can also be considered.
• Impending respiratory failure should be recognized as early as possible, and a skilled operator must promptly perform endotracheal intubation to maximize first-pass success.
• Vasopressors should be started to maintain mean arterial pressure between 60 mmHg and 65 mmHg. Norepinephrine is the preferred initial vasopressor. 
• Empiric antibacterial therapy should be considered if there is a concern for a secondary bacterial infection. Antibiotic use must be reassessed daily for de-escalation, and the duration of the treatment must be evaluated for appropriateness based on the diagnosis.
• Management of COVID-19 patients with ARDS should be similar to classical ARDS management from other causes that include prone positioning as per The Surviving Sepsis Campaign guidelines for managing COVID-19.[120]
• ECMO should be considered in patients with refractory respiratory failure.

Prevention of COVID-19

• Vaccination to prevent SARS-CoV-2 infection

Besides the importance of imposing public health and infection control measures to prevent or decrease the transmission of SARS-CoV-2, the key to containing this global pandemic is vaccination to prevent SARS-CoV-2 infection in communities across the world. Extraordinary efforts in global research during this pandemic have resulted in the development of novel vaccines against SARS-CoV-2 at an unprecedented speed to contain this viral illness that has devastated communities worldwide and has had a downward spiraling effect on the global economy. Vaccination triggers the immune system leading to the production of neutralizing antibodies against SARS-CoV-2. As per the WHO Coronavirus (COVID-19) Dashboard, more than 2.4 billion doses of vaccine doses have been administered as of 22 June 2021, with approximately 22% of the world's population receiving at least one dose of the vaccine.

Vaccination triggers the immune system leading to the production of neutralizing antibodies against SARS-CoV-2. Results of an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial reported that individuals 16 years of age or older receiving a two-dose regimen of the trial vaccine BNT162b2 (mRNA-based, BioNTech/Pfizer), when given 21 days apart, conferred 95% protection against COVID-19 with a safety profile similar to other viral vaccines.[123] Results from another multicenter, Phase 3, randomized, observer-blinded, placebo-controlled trial demonstrated that individuals who were randomized to receive two doses of mRNA-1273 (mRNA-based, Moderna) vaccine given 28 days apart showed 94.1% efficacy at preventing COVID-19 illness and no safety concerns were noted besides transient local and systemic reactions.[124]

After granting an initial EUA, FDA approved the clinical use of the BNT162b2 vaccine to prevent COVID-19 in August 2021 and subsequently approved the mRNA-1273  vaccine to prevent COVID-19 in January 2022. A third vaccine, Ad26.COV2.S for the prevention of COVID-19 received EUA by the FDA on 27 February 2021, based on a multicenter, placebo control phase trial that showed a single dose of Ad26.COV2.S vaccine conferred 66.3% efficacy in the US in preventing COVID-19.[125]A single dose of NVX-CoV2373, which is an adjuvanted, recombinant spike protein nanoparticle vaccine, demonstrated 92.6% (95% CI, 83.6 to 96.7) vaccine efficacy against any variant of concern based on results from a randomized observer-blinded placebo-controlled trial in the United States and Mexico involving more than 29,000 participants.[126] IN July 2022, the NVX-CoV2373 received a EUA to prevent COVID-19 in individuals 12 years of age and older.

Interim analysis of an ongoing multicenter randomized control trial demonstrated that ChAdOx1 nCoV-19 demonstrated clinical efficacy against symptomatic COVID-19 and had an acceptable safety profile.[127] The ChAdOx1 nCoV-19 vaccine has been approved or granted emergency use authorization to prevent COVID-19 in many countries worldwide but has not yet received a EUA or approval from the FDA for use in the US. Besides the vaccines mentioned above, as many as seven other vaccines that include protein-based and inactivated vaccines have been developed indigenously in India, Russia, and China and have been approved or granted emergency use authorization to prevent COVID-19 in many countries around the world.

A third dose (booster dose) has been included in the vaccination schedule of various nations, with studies showing some amount of waning of immunity after two doses and a third dose offering higher protection levels.[128][129] A phase 2 randomized controlled trial from the United Kingdom, which compared various combinations of boosting regimens, concluded that mixing vaccine types boosted antibodies and neutralizing responses for all seven vaccines studied, including most major commercially available vaccines.[130]

• Preexposure Prophylaxis(PrEP) to prevent SARS-CoV-2 infection

Although vaccination is considered the most effective and crucial step to prevent this viral infection, some individuals may not develop an adequate immune response to COVID-19 vaccination OR in individuals in whom COVID-19 vaccination is contraindicated due to a history of severe adverse reaction to the vaccine or vaccine component. In such individuals, the US Food and drug administration showed a EUA for the emergency use of this tixagevimab in combination with cilgavimab for use in preexposure prophylaxis of COVID-19 in adults and pediatric population (12 years of age and older being at least 40 kg in weight) with no current evidence of SARS-CoV-2  infection and no recent exposure to SARS-CoV-2 positive individuals AND who have moderate or severe immunocompromised due to several types of conditions and treatments OR are on immunosuppressive medications and may not mount an adequate immune response to COVID-19 vaccination OR in individuals in whom COVID-19 vaccination is contraindicated due to history of severe adverse reaction to the vaccine or vaccine components.

Differential Diagnosis

• Influenza A and B
• Parainfluenza virus
• Respiratory syncytial virus
• Adenovirus
• Cytomegalovirus
• Rhinovirus

Prognosis

The prognosis of COVID-19 largely depends on various factors, including the patient's age, the severity of illness at presentation, pre-existing conditions, how quickly treatment can be implemented, and response to treatment. As previously described, the frequency of the spectrum of disease was described in a report from the Chinese Center for Disease Control and Prevention that reported mild disease in 81% of patients, severe disease (with shortness of breath, hypoxia, or abnormal imaging) in 14%, critical disease (respiratory failure, shock, multiorgan dysfunction in 5%, and an overall case fatality rate of 2.3%.[63] 

A comprehensive systematic review and meta-analysis involving 212 studies comprised of 281,461 individuals from 11 countries/regions reported that severe disease course was noted in about 23% with a mortality rate of about 6% in patients infected with COVID-19.[64] 

Complications

• COVID-19 can be regarded as a systemic viral illness based on the involvement of 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 disorders 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 and/or multiorgan failure leading to death.
• Patients with COVID-19 illness are also at increased risk of developing prothrombotic complications such as PE, DVT, MI, ischemic strokes, and arterial thrombosis.[43]
• Cardiovascular system involvement results in malignant arrhythmias, cardiomyopathy, and cardiogenic shock.
• Acute renal failure is the most frequently encountered extrapulmonary manifestation of COVID-19 and is associated with increased mortality risk.[68]
• 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 six 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.[131]

Deterrence and Patient Education

• Patients must be educated and encouraged to adhere to social distancing guidelines and the use of facemasks and travel guidelines as per CDC guidelines and social distancing state and local authority's social distancing protocols.
• Patients must be educated about frequent handwashing for a minimum of 20 seconds with soap and water when they come in contact with contaminated surfaces.
• Patients should be educated and encouraged to seek emergency care when necessary.
• Patients should be educated and given an option for telehealth services in place of office visits if applicable.
• Patients must be educated about the efficacy of the available vaccines and the benefits of the vaccination.
• Patients should be encouraged to seek treatment early and be educated on new treatment options, such as monoclonal antibodies.

Enhancing Healthcare Team Outcomes

SARS-CoV-2 and its variants continue to wreak havoc worldwide and, in the process, have overwhelmed many healthcare systems and economies of many countries. Four vaccines have been authorized for use in the US by the FDA, two (BNT162b2 and mRNA-1273) of which have been approved, and two( Ad26.COV2.S and NVX-CoV2373)have been authorized for use under an Emergency Use Authorization (EUA).

Until most of the world's population gets completely vaccinated (including booster shots) against this illness, COVID-19 will continue to remain a threat to global public health with the emergence of potentially treatment-resistant variants.

Prevention and management of this highly transmissible respiratory viral illness require a holistic and interprofessional approach that includes physicians' expertise across specialties, nurses, pharmacists, public health experts, and governmental authorities. There should be closed-loop communication between the clinical providers, pharmacists, and nursing staff while managing patients with COVID-19.

Clinical providers managing COVID-19 patients on the frontlines should keep themselves periodically updated with the latest clinical guidelines about diagnostic and therapeutic options available in managing COVID-19, especially considering the emergence of new SARS-CoV-2 variants has a significant impact on morbidity and mortality.

Clinicians should maintain a high index of suspicion in patients from a high-risk exposure area or recent travel to a high-exposure area who present with extrapulmonary manifestations in the absence of pulmonary symptoms. These patients should be appropriately triaged and tested for SARS-CoV-2.

Resources for contact tracing and testing must be enhanced to limit the spread of this virus. Patients must be educated and encouraged to adhere to social distancing guidelines, travel guidelines, and the use of facemasks as per CDC guidelines and COVID-19 protocols of state and local authorities.

Clinical pharmacists must also keep themselves updated about the emergence of novel therapeutics that have been approved or granted emergency use authorization to manage COVID-19.

Hospitals and communities should have in place a plan to triage moderate and high-risk patients for additional therapy, such as monoclonal antibodies, on an outpatient basis.

A strong focus must be made to educate the public about the importance of receiving the vaccination, including the recommended booster dose against COVID-19, and consideration must be made to establish mass vaccination sites.

Continued viral surveillance of new variants must be performed at regular intervals with viral genomic sequencing given the possibility that more highly transmissible, more virulent variants and treatment-resistant variants could emerge that can have a more catastrophic effect on global health in addition to the current scenario.

Such a multi-pronged approach enhances improved patient care and outcomes. It also reduces the burden of hospitalizations that could lead to the exhaustion of healthcare resources.

Such measures could immensely change the dynamic of healthcare infrastructure and go a long way in eradicating or eliminating this virus and limiting its devastating effect on socioeconomic and healthcare situations across the entire world.