Continuing Education Activity

Coronavirus disease 2019 (COVID-19), the highly contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a catastrophic effect on the world’s demographics resulting in more than 6 million deaths worldwide as of March 2022, emerging as the most consequential global health crisis since the era of the influenza pandemic of 1918.

Objectives:

• Identify the etiology and epidemiology of COVID-19.
• Describe the clinical features and radiological findings expected in patients with COVID-19.
• Summarize the latest available treatment in the management of COVID-19, including the different vaccines available to prevent COVID-19.
• Discuss interprofessional team strategies for improving care coordination and communication to care for patients with coronavirus and improve outcomes.

Introduction

Coronavirus disease 2019 (COVID-19), the highly contagious viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a catastrophic effect on the world’s demographics resulting in more than 6 million deaths worldwide as of March 2022, emerging as the most consequential global health crisis since the era of the influenza pandemic of 1918. After the first cases of this predominantly respiratory viral illness were first reported in Wuhan, Hubei Province, China, in late December 2019, SARS-CoV-2  rapidly disseminated across the world in a short span of time, compelling the World Health Organization (WHO) to declare it as a global pandemic on March 11, 2020. Since being declared a global pandemic, COVID-19 has ravaged many countries worldwide and has overwhelmed many healthcare systems. The pandemic has also resulted in the loss of livelihoods due to prolonged shutdowns, which have had a rippling effect on the global economy. Even though substantial progress in clinical research has led to a better understanding of SARS-CoV-2 and the management of COVID-19, limiting the continuing spread of this virus and its variants has become an issue of increasing concern, as SARS-CoV-2 continues to wreak havoc across the world, with many countries enduring a second or third wave of outbreaks of this viral illness attributed mainly due to the emergence of mutant variants of the virus. 

Like other RNA viruses, SARS-CoV-2, while adapting to their new human hosts, is prone to genetic evolution with the development of mutations over time, resulting in mutant variants that may have different characteristics than its 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) by the WHO, given their impact on global public health. Based on the recent epidemiological update by the WHO, as of December 11, 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

Despite the unprecedented speed of vaccine development against the prevention of COVID-19 and robust global mass vaccination efforts including vaccine boosters, the emergence of these new SARS-CoV-2 variants threatens to overturn the significant progress made so far in limiting the spread of this viral illness.

This review article aims to comprehensively describe the etiology, epidemiology, pathophysiology, clinical features, diagnostic methods, and the latest novel therapeutics in the management of COVID-19. This review also briefly provides an overview of the different variants of SARS-CoV-2 and the efficacy of different available vaccines for prevention against COVID-19 and its variants. 

Etiology

Coronaviruses (CoVs) are positive-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. The subfamily Orthocoronavirinae of the Coronaviridae family (order Nidovirales) classifies into four genera of CoVs: 

• Alphacoronavirus (alphaCoV)
• Betacoronavirus (betaCoV)
• Deltacoronavirus (deltaCoV)
• Gammacoronavirus (gammaCoV)

BetaCoV genus is further divided into five sub-genera or lineages.[1] Genomic characterization has shown that bats and rodents are the probable gene sources of alphaCoVs and betaCoVs. On the contrary, avian species seem to represent the gene sources of deltaCoVs and gammaCoVs. CoVs have become the major 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. For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS. To date, seven human CoVs (HCoVs) capable of infecting humans have been identified. Some of the 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 a CoVs and that these viruses are responsible for about 5% to 10% of acute respiratory infections.[2] 

• 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 subjects and the elderly, 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 to be more virulent and capable of causing epidemics manifesting with respiratory and extra-respiratory manifestations of variable clinical severity.

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.[3] It has a round or elliptic and often pleomorphic form and a diameter of approximately 60–140 nm. Like other CoVs, it is sensitive to ultraviolet rays and heat. In this regard, although high temperature decreases the replication of any species of virus. Currently, 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. At 54.5°C, the time for a 90% decrease in infectivity was 35.4 ± 9.0 min and the virus half-life was 10.8 ± 3.0 min.[4] Conversely, it may resist lower temperatures even below 0°C. Also, these viruses can be effectively inactivated by lipid solvents, including ether (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform except for chlorhexidine.

Genomic characterization of the new HCoV, isolated from a cluster-patient with atypical pneumonia after visiting Wuhan, had 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. Hence, it was termed SARS-CoV-2 by experts of the International Committee on Taxonomy of Viruses. The single-stranded RNA genome of SARS-CoV-2 contains 29891 nucleotides, encoding for 9860 amino acids. 

Although the origin of SARS-CoV-2 is currently unknown, it is widely postulated to have originated from an animal implicating zoonotic transmission. 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 indeed revealed high homology (96%) between the SARS-CoV-2 and the betaCoV RaTG13 of bats (Rhinolophus affinis)[5]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.[6][7] A recently released report by the WHO describing the possible origins of SARS-CoV-2 was inconclusive as it did not clearly specify the origin of the virus; however, it did report that the circulation of SARS-CoV-2 occurred as early as December 2019. This report explored several possible hypotheses of the origin of the virus that included the origin of the virus in an animal, the transmission of the virus to an intermediate host, and subsequent passage into humans.

SARS-CoV-2 Variants

As mentioned earlier, SARS-CoV-2 is prone to genetic evolution resulting in multiple variants that may have different characteristics compared to its ancestral strains. Periodic genomic sequencing of viral samples is of fundamental importance, especially in a global pandemic setting, as it helps detect any new genetic variants of SARS-CoV-2. Notably, the genetic evolution was minimal initially with the emergence of the globally dominant D614G variant, which was associated with increased transmissibility but without the ability to cause severe illness.[8] Another variant was identified in humans, attributed to transmission from infected farmed mink in Denmark, which was not associated with increased transmissibility[7]. 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, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in therapeutics or vaccination effectiveness. With the continued 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).

SARS-CoV-2 Variants of Concern (VOCs)

• 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.[9][10]
• 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.[11][12][13]
• 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.[12] 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 since reported that people infected with B.1.1.7 lineage variant had increased severity of disease compared to people infected with other circulating forms of virus variants.[14][10] 
• A large matched cohort study performed in the UK reported that the mortality hazard ratio of patients infected with 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.[15]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).[16] 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.[17]
• The B.1.1.7 variant emerged as one of the most dominant SARS-CoV-2 strains circulating in the US.

• Beta (B.1.351 lineage)
• Another variant of SARS-CoV-2, B.1.351 also referred to as Beta variant or GH501Y.V2 with multiple spike mutations, resulted in the second wave of COVID-19 infections, was first detected in South Africa in October 2020.[18]
• 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.[19][19][11][20] 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.[21]

• Gamma(P.1 lineage)
• The third variant of concern, the P.1 variant also known as Gamma variant or GR/501Y.V3, was identified in December 2020 in Brazil and was first detected in the US in January 2021.[22] 
• The 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.[22]
• Notably, this variant may have reduced neutralization by monoclonal antibody therapies, convalescent sera, and post-vaccination sera.[21]

• 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
  • The Delta variant was initially considered a variant of interest. However, this variant rapidly spread around the world 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
  • Researchers have predicted the B.1.617.2 variant to be the most dominant SARS-CoV-2 strain in the US in the coming weeks

• 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.[23] 
  • 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.[24] 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.[25]
  • Initial modeling suggests that Omicron shows a 13-fold increase in viral infectivity, and is 2.8 times more infectious than the Delta variant.[26] Early reports also suggest that monoclonal antibodies including Bamlanivimab and the Rockefeller University antibody C144 are likely to have reduced efficacy against the Omicron variant, however, REGN-COV2 (Casirivimab and Imdevimab), as well as the Rockefeller University antibody C135 are predicted to still be effective against Omicron based on early modeling studies.[26]
  • 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

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, 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 September 1, 2020, to January 29, 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.[27]

• 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 carry 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 harbor 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 a 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.

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 droplet transmission from presymptomatic, asymptomatic, or symptomatic individuals harboring the virus.  
• Airborne transmission with aerosol-generating procedures has also been implicated in the spread of COVID-19. However, data implicating airborne transmission of SARS-CoV-2 in the absence of aerosol-generating procedures are emerging and being evaluated. 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 noted to be 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.[28] 
• Viable virus was isolated for up to 28 days at 20 degrees C from nonporous surfaces such as glass, stainless steel. Conversely, recovery of SARS-CoV-2 on porous materials was reduced compared with nonporous surfaces.[29]
• A study evaluating the duration of the viability of the virus on objects and surfaces showed that SARS-CoV-2 can be found on plastic and stainless steel for up to 2-3 days, cardboard for up to 1 day, copper for up to 4 hours. Moreover, it seems that contamination was higher in intensive care units (ICUs) than in general wards, and SARS-CoV-2 can be found on floors, computer mice, trash cans, and sickbed handrails as well as in the air up to 4 meters from patients implicating nosocomial transmission as well in addition to fomite transmission.[30] 
• The Centers for Disease Control and Prevention(CDC) recently released an update stating 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 present in feces implying possible fecal-oral transmission.[31] 
• A meta-analysis that included 936 neonates from mothers with COVID-19 showed vertical transmission is possible but occurs in a minority of cases.[32]

Epidemiology

According to the World Health Organization (WHO), the emergence of viral diseases represents a serious public health risk. In the past two decades, several epidemics caused by viruses such as the severe acute respiratory syndrome coronavirus (SARS-CoV) from 2002 to 2003, and H1N1 influenza in 2009, and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 have been described which have had a significant impact on global health. Since being declared a global pandemic by the WHO, SARS-CoV-2, the virus responsible for COVID-19 has spread to 223 countries with more than 472 million cases, and more than 6 million deaths reported globally as of March of 2022. A recent epidemiological update by WHO reported that more than 200 countries around the world have reported SARS-Co-V-2 variants of concern of which the newer VOC, Omicron has been reported by 76 countries so far since first being reported in November 2021. The U.S. has experienced the highest number of SARS-CoV-2 infections and COVID-19 related deaths followed by Brazil and India. In fact, COVID-19 was the third leading cause of death in the U.S. in 2020 after heart disease and cancer, with approximately 375,000 death reported.[33] The WHO’s current estimate of the global case fatality rate for COVID-19 is 2.2%. However, the case fatality rate is affected by factors that include age, underlying preexisting conditions, and severity of illness and significantly varies between countries.

Age, Gender-based Differences And The Impact Of Medical Comorbidities in COVID-19 

Individuals of all ages are at risk of contracting this infection and severe disease. However, patients aged ≥60 years 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. 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 during January 22 to May 30, 2020. Notably, 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 medical conditions (19.5% vs. 1.6%).[34] 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.[35][36] Results from a retrospective cohort study from March 1 to November 21, 2020, evaluating the mortality rate in 209 US acute care hospitals that included 42 604 patients with confirmed SARS-CoV-2 infection, reported a higher mortality rate in male patients (12.5%) compared to female patients (9.6%).[37]

Racial and Ethnic Disparities in COVID-19

The severity of infection and mortality related to COVID-19 also varies between different ethnic groups.[30] Racial and ethnic minority groups were reported to have a higher percentage of COVID-19 related hospitalizations than White patients based on a recent CDC analysis of hospitalizations from a large 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 for exposure to SARS-CoV-2 and an increased risk for developing severe COVID-19 disease.[38] 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.[39] COVID-19 related death rates were the highest among Hispanic persons.[33] 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 both within the general population and within specific racial/ethnic groups.[40]

Pathophysiology

The general description of viral structure and its genome of CoVs is essential for addressing the pathogenesis of SARS-CoV-2. As described earlier, CoVs are enveloped, positive-stranded RNA viruses with a nucleocapsid, and the genomic structure is organized in a +ssRNA of approximately 30 kb in length and with a 5′-cap structure and 3′-poly-A tail making it the largest among RNA viruses. Upon entry into the host, replication of the viral RNA is initiated with the synthesis of polyprotein 1a/1ab (pp1a/pp1ab). The transcription occurs through the replication-transcription complex (RCT) organized in double-membrane vesicles and via the synthesis of subgenomic RNAs (sgRNAs) sequences. Conversely, transcription termination occurs at transcription regulatory sequences, located between the so-called open reading frames (ORFs) that work as templates for the production of subgenomic mRNAs. In an atypical CoV genome, at least six ORFs can be present. Among these, a frameshift between ORF1a and ORF1b guides the production of both pp1a and pp1ab polypeptides that are processed by virally encoded chymotrypsin-like protease (3CLpro) or main protease (Mpro), as well as one or two papain-like proteases for producing 16 with known or predicted RNA synthesis and modification functions non-structural proteins (NSPs 1-16). Besides ORF1a and ORF1b, other ORFs encode structural proteins, including spike, membrane, envelope, and nucleocapsid proteins and accessory proteic chains.[3]. Different CoVs possess unique structural and accessory proteins translated by dedicated sgRNAs.The pathogenesis of CoVs and SARS-CoV-2 is related to the function of the NSPs and structural proteins. For example, researchers have outlined the role of NSPs in blocking the host's innate immune response.[2] Among functions of structural proteins, the envelope has a crucial role in virus pathogenicity as it promotes viral assembly and release. Among the structural elements of CoVs, there are the spike glycoproteins composed of two subunits (S1 and S2). Homotrimers of S proteins compose the spikes on the viral surface, guiding the link to host receptors.[41]

Pathogenesis of SARS-CoV-2

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.[42] 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 containing a fusion peptide, a transmembrane domain, and cytoplasmic domain is responsible for virus-cell membrane fusion.[43][44] The S1 subunit is further divided into a receptor-binding domain (RBD) and 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.[41] The RBD is a fundamental peptide domain 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), as previously hypothesized, does not increase the risk of hospitalization for COVID-19 and severe disease.[45]

SARS-CoV-2 gains entry into the hosts' cells by binding the SARS-CoV-2 spike or S protein (S1) to the 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.[46] 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.[47]

In summary, the spike RBD allows the binding to the ACE2 receptor in the lungs and other tissues. The spike protein of an amino acid site (polybasic site) allows the functional processing of the same by the human enzyme furin (protease). This process enables the exposure of the fusion sequences and, therefore, the fusion of the viral and cell membranes, a necessary passage for the virus to enter the cell.

Effect of SARS-CoV-2 on the Respiratory System/Pathogenesis of SARS-CoV-2-induced Pneumonia

COVID-19 is primarily considered a viral respiratory and vascular illness as its causative agent, SARS-CoV-2, predominantly targets the respiratory and vascular systems. 

The pathogenesis of SARS-CoV-2 induced pneumonia is best explained by two stages, an early and a late phase. The early phase is characterized by viral replication resulting in direct virus-mediated tissue damage, which is 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), ), IL-1β, IL-8, IL-12 and interferon (IFN)-γ. 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.[48][49] The increased vascular permeability and subsequent development of pulmonary edema in patients with severe COVID-19 are explained by multiple mechanisms, which includes a) endotheliitis as a result of direct viral injury and perivascular inflammation leading to microvascular and microthrombi deposition b) dysregulation of the RAAS due to increased binding of the virus to the ACE2 receptors and c)activation of the kallikrein- bradykinin pathway, the activation of which enhances vascular permeability, d)enhanced epithelial cell contraction causing swelling of cells and disturbance of intercellular junctions.[50][51][52] Besides IL-6 and TNF-α, the binding of SARS-CoV-2 to the Toll-Like Receptor (TLR) induces the release of pro-IL-1β, which is cleaved into the active mature IL-1β that mediates lung inflammation, until fibrosis.[53]

Effect of SARS-CoV-2 on Extrapulmonary Organ Systems

Although the respiratory system is the principal 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 system. 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.[54]

• Cardiovascular system (CVS): Although the exact mechanism of cardiac involvement in COVID-19 is unknown, it is likely multifactorial. ACE2 receptors are also exhibited by myocardial cells implicating direct cytotoxicity by the SARS-CoV-2 on the myocardium leading to myocarditis. Proinflammatory cytokines such as IL-6 can also lead to vascular inflammation, myocarditis, and cardiac arrhythmias.[55] Acute coronary syndrome (ACS) is a well-recognized cardiac manifestation of COVID-19 and is likely due to multiple factors that include but are not limited to COVID-19 associated hypercoagulability, the release of proinflammatory cytokines, worsening of preexisting severe coronary artery disease, stress cardiomyopathy, and associated hemodynamic derangement which may reduce coronary blood flow, reduced oxygen supply resulting in the destabilization of coronary plaque microthrombogenesis or worsening of preexisting severe coronary artery disease.[56][57][58][59] 

• Hematological: SARS-CoV-2 has a significant effect on the hematological and hemostatic systems. 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 of the lymphatic organs.[60] Thrombocytopenia is uncommon in COVID-19 and is likely due to multiple factors that include virus-mediated suppression of platelets, formation of autoantibodies, and activation of coagulation cascade that results in platelet consumption.[61] Thrombocytopenia and neutrophilia are considered a hallmark of severe illness.[54] 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 is unknown and likely attributed to the cytokine-induced inflammatory response. The pathogenesis of this associated hypercoagulability is multifactorial and 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, increased expression of tissue factor, von Willebrand factor, and Factor VIII that results in the generation of thrombin and formation of fibrin clot formation.[61][62][61] Other mechanisms that have been proposed include possible mononuclear phagocytes induced prothrombotic sequelae, derangements in the renin-angiotensin system (RAS) pathways, complement-mediated microangiopathy.[61]

• Central Nervous System (CNS): There is emerging evidence of ACE2 receptors in human and mouse brains, implicating the potential infection of the brain by SARS-CoV-2.[63] The possible routes by which SARS-CoV-2 can invade the central nervous system are transsynaptic transfer across infected neurons via the olfactory nerve, vascular endothelial cell infection, or migration of leukocytes across the blood-brain barrier.[64]

• Gastrointestinal (GI) Tract: The pathogenesis of GI manifestations of COVID-19 is unknown and is likely considered to be multifactorial due to several potential mechanisms that include the direct ACE 2-mediated viral cytotoxicity of the intestinal mucosa, cytokine-induced inflammation, gut dysbiosis, and vascular abnormalities.[65]

• Hepatobiliary: Although the pathogenesis of liver injury in COVID-19 patients is unknown, hepatic injury in COVID-19 is likely multifactorial and is explained by many mechanisms alone or in combination that includes ACE-2-mediated viral replication in the liver, direct virus-mediated damage, hypoxic or ischemic injury, immune-mediated inflammatory response, drug-induced liver injury (DILI), or worsening of preexisting liver disease[66].

• Renal: The pathogenesis of COVID-19 associated kidney injury is unknown and 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 such as associated hypovolemia, potential nephrotoxic agents, and nosocomial sepsis can also potentially contribute to kidney injury.[67] During the early phase of the pandemic, a seven-month study by Ziemba et.al reported that the deaths per 1,000 patients among ESRD patients during the pandemic exceeded the expected death rate among ESRD patients based on data from previous years prior to the start of the pandemic.[68]

Implications of New Variants of SARS-CoV-2 on the Pathogenesis of COVID-19

Genetic variation in the viral genes of SARS-CoV-2 can have implications in 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. 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.[69] Two recent preprint studies (not peer-reviewed) 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 B.1.351 variant and P.1 variant with mutations N417/K848/Y501-RBD and ACE2 was much lower than that of N501Y-RBD and ACE2.[70][56]

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.[71]

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.[72]

Heart: Analysis of cardiac tissue from 39 autopsy cases of patients who tested positive for SARS-CoV-2 demonstrated the presence of SARS-CoV-2 viral genome within the myocardium.[73]

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.[74]

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.[75]

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.[76]

History and Physical

Clinical Manifestations of COVID-19

• 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.[77]
• 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.[78][79]
• Conversely, 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% of them experienced fever, cough, shortness of breath, 36% reported myalgia, and 34% reported headache.[34]
• 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%).[58] 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%).[80]
• A meta-analysis of 212 published studies comprising 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 COVID-19.[81]
• The elevated neutrophil-to-lymphocyte ratio (NLR), derived NLR ratio (d-NLR) [neutrophil count divided by the result of WBC count minus neutrophil count], and the platelet-to-lymphocyte ratio is indicative of a cytokine-induced inflammatory storm.[82]

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

• 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 who have clinical symptoms or radiologic evidence of lower respiratory tract disease and who have 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%.
• Critical illness: Individuals who have acute respiratory failure, septic shock, and/or multiple organ dysfunction. Patients with severe COVID-19 illness 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.

ARDS is characterized by a severe new-onset respiratory failure or worsening of an already identified respiratory picture. The diagnosis requires a set of clinical and ventilatory criteria such as chest imaging utilized including chest radiograph, CT scan, or lung ultrasound demonstrating bilateral opacities (lung infiltrates > 50%), not fully explained by effusions, lobar, or lung collapse. If there are clinical and radiologic findings of pulmonary edema, heart failure, or other causes such as fluid overload, they should be excluded before assessing it to be ARDS. The Berlin definition classifies ARDS into three types based on the degree of hypoxia, with the reference parameter being PaO2/FiO2 or P/F ratio[83]:

• Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg in patients not receiving mechanical ventilation or in those managed through non-invasive ventilation (NIV) by using positive end-expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) ≥ 5 cmH2O.
• Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg
• Severe ARDS: PaO2/FiO2 ≤ 100 mmHg. 

When PaO2 is not available, a ratio of SpO2/FiO2 ≤ 315 is suggestive of ARDS. 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.[84]

Extrapulmonary Manifestations 

Although COVID-19, the illness caused by SARS-CoV-2, predominantly affects the respiratory system, COVID-19 can be considered a systemic viral illness given the multiple organ dysfunction associated with this 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 an increased risk of mortality.[85] 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% patients required renal replacement therapy(RRT).[86] Other clinical and laboratory manifestations include proteinuria, hematuria, electrolyte abnormalities such as hyperkalemia, hyponatremia, acid-base balance disturbance such as metabolic acidosis.[87][54][36]

• 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 ACS, 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 than patients with normal troponin levels.[87] A meta-analysis study of 198 published studies involving 159, 698 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.[88]

• Hematologic manifestations: Lymphopenia is a common laboratory abnormality 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. As previously discussed, COVID-19 is also associated with a hypercoagulable, 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) in patients at risk of developing arterial and venous thrombosis.[54][87][54] Clinical trials are required to determine the benefit of therapeutic anticoagulation in patients with COVID-19, especially at what stage of the illness.

• Gastrointestinal manifestations: GI symptoms such as diarrhea, nausea and/or vomiting, anorexia, and abdominal pain are seen in up to 1 in 5 patients with COVID-19 infection based on the results of a meta-analysis study by Tariq et al. that analyzed 78 studies involving 12, 797 patients. The weighted pool prevalence of diarrhea was 12.4% (95% CI, 8.2% to 17.1%), nausea and/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.[89] Cases of acute mesenteric ischemia and portal vein thrombosis have also been described.[90]

• Hepatobiliary manifestations: Elevation in liver function tests manifesting as an acute increase in aspartate transaminase(AST) and alanine transaminase(ALT) are frequently noted in 14% to 53% of patients with COVID-19 infection.[91] Hepatic dysfunction occurs more frequently in patients with severe COVID-19 illness.

• Endocrinologic manifestations: Patients with underlying endocrinologic disorders such as diabetes mellitus who contract this virus 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.[87]

• 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.[92][64]

• Cutaneous manifestations: Acral lesions resembling pseudo chilblains (40.4%) were the most common cutaneous manifestations noted in patients with COVID-19 based on the results of a meta-analysis study which included 34 published studies describing 996 patients with COVID-19. Other cutaneous manifestations described erythematous maculopapular rash (21.3%), vesicular rashes (13%), and urticarial rashes (10.9%). Notably, the appearance of a specific type was rash appeared to be dependent on the patient's age. Other uncommon rashes described were vascular rashes (4%) resembling livedo or purpura, especially in elderly patients, and erythema multiforme-like eruptions (3.7%), mostly in children.[93]

Evaluation

A detailed clinical history regarding the onset and duration of symptoms, travel history, exposure to people with COVID-19 infection, underlying preexisting medical conditions, and drug history should be elicited 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, patients with atypical symptoms of COVID-19 or anyone with known high-risk exposure to SARS-CoV-2 should be tested for SARS-CoV-2 infection even in the absence of symptoms.

Diagnostic Testing In COVID-19

Molecular Testing

• 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 collection of BAL samples should only be performed in mechanically ventilated patients as lower respiratory tract samples seem to remain positive for a more extended period.
• 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.[94] However, the specificity of most commercial FDA-approved SARS-CoV-2 PCR assays is nearly 100%, provided that there is no cross-contamination during specimen processing.
• SARS-CoV-2 antigen tests are less sensitive but have a faster turnaround time compared to molecular PCR testing.[95] Comprehensive testing for other respiratory viral pathogens should be considered for appropriate patients as well.

Serology Testing

• An antibody test can evaluate for the presence of antibodies that occurs as a result of infection. Antibody tests play an important role in broad-based surveillance of COVID-19, and many commercial manufactured antibody testing kits are available to evaluate the presence of antibodies against SARS-CoV-2 are available.
• Despite the numerous antibody tests designed to date, serologic testing has limitations in specificity and sensitivity, and results from different tests vary. However, an antibody test with a specificity higher than 99% and a sensitivity of 96% has been developed by the CDC, which can identify past SARS-CoV-2 infection.
• Antibody testing may be instrumental in broad-based surveillance of COVID-19 and evaluate the immunity conferred from infection or vaccination. There is currently ongoing research to determine quantitative and qualitative aspects of antibodies regarding protection from future SARS-CoV-2 infection and the duration of the protection.

Other Laboratory Assessment

• 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.
• 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 Modalities

Considering this viral illness commonly manifests itself as pneumonia, radiological imaging has a fundamental role in the diagnostic process, management, and follow-up. Imaging studies may include chest x-ray, lung ultrasound, or chest computed tomography (CT). 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.

Chest X-ray 

• Standard radiographic examination (X-ray) of the chest has a low sensitivity in identifying early lung changes; it can be completely normal in the initial stages of the disease.
• In the more advanced stages of infection, the chest X-ray examination commonly shows bilateral multifocal alveolar opacities, which tend to confluence up to the complete opacity of the lung. Pleural effusion can also be demonstrated.

Chest Computed Tomography (CT)

• The American College of Radiology recommends against Chest CT's routine use as an initial imaging study or screening.
• Given its high sensitivity, chest computed tomography (CT), particularly high-resolution CT (HRCT), is the diagnostic method of choice in evaluating COVID-19 pneumonia, particularly when associated with disease progression.
• Several non-specific findings and radiologic patterns can be found on Chest CT. Most of these findings may also be observed in other lung infections, such as Influenza A (H1N1), CMV, SARS, MERS, streptococcus, and Chlamydia, Mycoplasma.
• The most common CT findings in COVID-19 are multifocal bilateral "ground or ground glass" (GG) areas associated with consolidation areas with patchy distribution, mainly peripheral/subpleural, and greater involvement of the posterior region's lower lobes. The "crazy paving" pattern can also be observed.
• This latter finding is characterized by GG areas with superimposed interlobular septal thickening and intralobular septal thickening. It is a non-specific finding that can be detected in different conditions.
• Other notable findings include the "reversed halo sign," a focal area of GG delimited by a peripheral ring with consolidation, and the findings of cavitations, calcifications, lymphadenopathies, and pleural effusion. 

Lung Ultrasound

Ultrasonographic examination of the lung allows evaluating the progression of the disease, from a focal interstitial pattern up to a "white lung" with evidence of subpleural consolidations. Considering its noninvasive nature and zero risks of radiation, it is a useful diagnostic modality for patient follow-up and assists in determining the setting of mechanical ventilation and prone positioning. The main sonographic features are:

• Pleural lines: appear often thickened, irregular, and discontinuous until it almost seems erratic; subpleural lesions can be seen as small patchy consolidations or nodules.
• B lines: They are often motionless, coalescent, and cascade and can flow up to the square of "white lung."
• Thickenings: They are most evident in the posterior and bilateral fields, especially in the lower fields; the dynamic air bronchogram within the consolidation is a manifestation of disease evolution.
• Perilesional pleural effusion

In summary, during the course of the illness, it is possible to identify the first phase with focal areas of fixed B lines followed by a phase of numerical increase of the lines B up to the white lung with small subpleural thickening, which progresses further until there is evidence of posterior consolidations.

Treatment / Management

Initially, early in the pandemic, the understanding of COVID-19 and its therapeutic management was limited, creating an urgency to mitigate this new viral illness with experimental therapies and drug repurposing. Since then, due to the intense efforts of clinical researchers globally, significant progress has been made, which has led to a better understanding of not only COVID-19 and its management but also has resulted in the development of novel therapeutics and vaccine development at an unprecedented speed.

Pharmacologic Therapies In The Management Of Adults With COVID-19

Currently, a variety of therapeutic options are available that include antiviral drugs (e.g., molnupiravir, paxlovid, remdesivir), anti-SARS-CoV-2 monoclonal antibodies (e.g., bamlanivimab/etesevimab, casirivimab/imdevimab), anti-inflammatory drugs (e.g., dexamethasone), immunomodulators agents (e.g., baricitinib, tocilizumab) are available under FDA issued Emergency Use Authorization( EUA) or being evaluated in the management of COVID-19.[54]

The clinical utility of these treatments is specific and is based on the severity of 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 causes 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 therapies.[95] Below is a summary of the latest potential therapeutic options proposed, authorized, or approved for clinical use in the management of COVID-19.

Antiviral Therapies 

• 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 was noted to demonstrate a significant reduction in hospitalization and death in mild COVID-19 disease[96] 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.[97]  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.[97] 

• Paxlovid (ritonavir in combination with 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 paxlovid group when compared to placebo when started within three days of symptom onset. Further studies are ongoing to establish the efficacy reported.[98] On December 22, 2021, the FDA issued a EUA authorizing the use of Paxlovid 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.[99] 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 U.S. 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.[100][101][102] However, results from the WHO SOLIDARITY Trial conducted at 405 hospitals spanning across 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.[103] 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.[104] 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 initially during 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.[105][103] Data from randomized control trials of hydroxychloroquine used as postexposure prophylaxis did not prevent SARS-CoV-2 infection or symptomatic COVID-19 illness.[106][107][107]

• Lopinavir/ritonavir is an FDA-approved combo therapy for the treatment of 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 standard of care in patients hospitalized with severe COVID-19.[108] Lopinavir/Ritonavir is currently not indicated for the treatment of COVID-19 in hospitalized and nonhospitalized patients.

• Ivermectin is an FDA-approved anti-parasitic drug used worldwide in the treatment of COVID-19 based on an in vitro study that showed inhibition of SARS-CoV-2 replication.[109] 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.[110] Ivermectin is currently not indicated for the treatment of COVID-19 in hospitalized and nonhospitalized patients.

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 the management of COVID-19 is extensively being pursued in ongoing 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 a EUA for patients with severe life-threatening COVID-19.[111][112] 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 U.S. 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.[113][114][115] An in vitro analysis of convalescent plasma obtained from individuals previously infected with the ancestral SARS-CoV-2 strains demonstrated significantly reduced neutralization against SARS-CoV-2 variant B.1.351/ 501Y.V2.[116] Another in vitro study reported that the 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 than the B.1.1.7 variant, which was not more resistant to neutralization.[117]

• REGN-COV2 (Casirivimab and Imdevimab): REGN-COV2 is an antibody cocktail containing two noncompeting IgG1 antibodies (casirivimab and imdevimab) that target the RBD on the SARS-CoV-2 spike protein that has been shown to decrease the viral load in vivo, preventing virus-induced pathological sequelae when administered prophylactically or therapeutically in non-human primates.[118] Results from an interim analysis of 275 patients from an ongoing double-blinded trial involving non hospitalized patients with COVID-19 who were randomized to receive placebo, 2.4 g of REGN-COV2 (casirivimab 1,200 mg and imdevimab 1,200 mg) or 8 g of REGN-COV2 COV2 (casirivimab 2,400 mg and imdevimab 2,400 mg) reported that the REGN-COV2 antibody cocktail reduced viral load compared to placebo. This interim analysis also established the safety profile of this cocktail antibody, similar to that of the placebo group.[119] Preliminary data from a Phase 3 trial of REGN-COV (casirivimab/imdevimab) revealed a 70% reduction in hospitalization or death in nonhospitalized patients with COVID-19. In vitro data is available regarding the effect of REGN-COV2 on the two new SARS-CoV-2 variants of concern (B.1.1.7; B.1.351 variants) that reveal retained activity. A recent preprint study by Wilhelm et al. reported that the SARS-CoV-2 Omicron variant was resistant to casirivimab and imdevimab in their in-vitro study.

• Bamlanivimab and Etesevimab (LY-CoV555 or LY3819253 and LY-CoV016 or LY3832479) are potent anti-spike neutralizing monoclonal antibodies. Bamlanivimab is a neutralizing monoclonal antibody derived from convalescent plasma obtained from a patient with COVID-19. Like REGN-COV2, it also targets the RBD of the spike protein of SARS-CoV-2 and has been shown to neutralize SARS-CoV-2 and reduce viral replication in non-human primates.[102] In vitro experiments revealed that etesevimab binds to a different epitope than bamlanivimab and neutralizes resistant variants with mutations in the epitope bound by bamlanivimab. In Phase 2 of the BLAZE-1 trial, bamlanivimab/etesevimab was associated with a significant reduction in SARS-CoV-2 viral load compared to placebo.[120] Data from the Phase 3 portion of BLAZE-1 is pending release, but preliminary information indicates that therapy reduced the risk of hospitalization and death by 87%. In vitro data is available regarding the effect of bamlanivimab/etesevimab on the new SARS-CoV-2 variants of concern (B.1.1.7; B.1.351) reveals retained activity.[121]

• Sotrovimab (VIR-7831) is a potent anti-spike neutralizing monoclonal antibody that demonstrated in vitro activity against all the four VOCs Alpha (B.1.1.7), Beta (B.1.351), Gamma(P1), and Delta (B.1.617.2). Results from a preplanned interim analysis(not yet peer-reviewed) of the multicenter, double-blind placebo-controlled Phase 3, COMET-ICE trial by Gupta et al. that evaluated the clinical efficacy and safety of sotrovimab demonstrated that one dose of sotrovimab (500 mg) reduced the risk of hospitalization or death by 85% in high-risk non hospitalized patients with mild to moderate COVID-19 compared with placebo.

• REGN-COV2 (casirivimab and imdevimab) and sotrovimab were approved for clinical use by the FDA under two separate EUAs issued in November 2020 and May 2021, respectively, that allowed the use of these drugs only in nonhospitalized patients (aged ≥12 years and weighing ≥40 kg) with laboratory-confirmed SARS-CoV-2 infection and mild to moderate COVID-19 who are at high risk for progressing to severe disease and/or hospitalization. On March 25, the U.S. government stopped the recent treatment study distribution of bamlanivimab alone, citing that the increasing emergence of coronavirus variants makes the treatment ineffective. Ongoing local vigilance regarding the prevalence of emerging variants will be necessary to determine which antibody treatments retain efficacy.

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. The Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which included hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 who were randomly assigned to received 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.[122] Based on the results of this landmark trial, 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 noninvasive 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.[123] However, previous experience with IFN- β-1a in acute respiratory distress syndrome (ARDS) has not benefited.[124] 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.[125] 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 the interpretation of these results difficult.[126] Currently, there is no data available regarding the efficacy of interferon β-1a on the four SARS-CoV-2 VOCs Alpha (B.1.1.7), Beta (B.1.351), Gamma(P1), and Delta (B.1.617.2). Given the insufficient and small amount of data regarding this agent's use and the relative potential for toxicity, this therapy is 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 the severe COVID-19 is driven by cytokine production, including interleukin (I.L.)-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.[127] 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 that is 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.[53][128][129] 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 that has been 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.[130] 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 not effective in preventing intubation or death rate.[131] The REMAP-CAP and RECOVERY trials (not yet published), two large randomized controlled trials, showed a mortality benefit in patients exhibiting rapid respiratory decompensation.[132]

• 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, there are no known published clinical trials supporting 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 did not show any significant improvement in clinical status or mortality rate.[133] Another randomized, double-blind placebo-controlled study on sarilumab's clinical efficacy and safety in adult patients hospitalized with COVID-19 is currently 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(R.A.) 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.[134][135][134] 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 noninvasive ventilation.[136] 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 that is 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 than the standard of care. However, most of the patients demonstrated significant chest C.T. improvement and faster recovery from lymphopenia.[137] 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 R.A., 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, 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.[138] Clinical trials are in progress to validate the actual efficacy of these drugs in severe COVID-19 illness.

Oxygenation And Ventilation Management In COVID-19

Conventional Oxygen Therapy

COVID-19 patients with associated respiratory insufficiency should be monitored closely with continuous pulse oximetry. Supplemental oxygen supplementation via nasal cannula or Venturi mask must be administered to maintain oxygen saturation (SpO2) between 92 to 96% (< 88-90% if COPD). If there is improvement in clinical and oxygen saturation, supplemental oxygen should be continued with periodic reassessment. If there is no clinical improvement or worsening of symptoms and/or oxygen saturation, noninvasive treatments such as High-Flow Nasal Cannula (HFNC) or Noninvasive Positive Pressure Ventilation(NIPPV) are recommended.

Management of Acute Hypoxemic Respiratory Failure in COVID-19

Acute hypoxemic respiratory failure is the most common complication in adult patients with COVID-19, and conventional oxygen therapy is not helpful to address the oxygen demand in these patients. These patients should be managed with enhanced respiratory support modalities such as high-flow nasal cannula (HFNC), noninvasive positive pressure ventilation (NIPPV), endotracheal intubation, and invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)

High-Flow Nasal Cannula (HFNC) and Noninvasive Positive Pressure Ventilation (NIPPV) 

HFNC and NIPPV are noninvasive enhanced respiratory support modalities available in managing COVID-19-associated acute hypoxemic respiratory failure and are instrumental in avoiding invasive mechanical ventilation in carefully selected patients. A meta-analysis study evaluating the effectiveness of HFNC compared to conventional oxygen therapy and NIPPV before mechanical ventilation reported that HFNC, when used before mechanical ventilation, could improve the prognosis of patients compared to conventional oxygen therapy and NIPPV.[139] The use of HFNC or NIPPV is associated with decreased dispersion of exhaled air, especially when used with a good interface fitting, thus creating a low risk of nosocomial transmission of the infection.[140] However, these treatment modalities are associated with a greater risk of aerosolization and should be used in negative pressure rooms.[141]

Noninvasive Positive-pressure Ventilation (NIPPV) 

• NIPPV (bilevel positive airway pressure [BiPAP]/continuous positive airway pressure [CPAP]) is instrumental in the management of COVID-19-associated acute hypoxemic respiratory failure and may help avoid invasive mechanical ventilation in carefully selected patients. 
• NIPPV should be restricted to hospitalized patients with COVID-19 who develop respiratory insufficiency due to COPD, cardiogenic pulmonary edema, or have underlying obstructive sleep apnea (OSA) rather than ARDS.[142] 
• A helmet is preferred for minimizing the risk of aerosolization. In NIPPV with face masks (full-face or oronasal), the use of masks integrated with an expiratory valve fitted with an antimicrobial filter is recommended. 
• Results from the HENIVOT trial, an Italian open-label multicenter randomized clinical trial, reported that there was no significant difference in the number of days free of respiratory support with the utilization of helmet noninvasive ventilation treatment compared to high flow nasal oxygen in COVID-19 patients hospitalized with moderate to severe degree of hypoxemia.

Endotracheal Intubation and Lung Protective Invasive Mechanical Ventilation

• Impending respiratory failure should be recognized as early as possible, and a skilled operator must promptly perform endotracheal intubation to maximize first-pass success.[143] 
• Clinicians and other healthcare staff must wear appropriate PPE that includes gowns, gloves, N95 masks, and eye protection when performing endotracheal intubation and manual ventilation before intubation, physical proning of the patient, or providing critical patient care such as upper airway suctioning, disconnecting the patient from the ventilator.[143]
• Preoxygenation (100% O2 for 5 minutes) should be performed via HFNC. 
• Invasive mechanical ventilation in COVID-19 associated acute hypoxemic respiratory failure and ARDS should be with lower tidal volumes (V.T.) (4 to 8 ml/kg predicted body weight, PBW) and lower inspiratory pressures reaching a plateau pressure (Pplat) < 30 cm of H2O. 
• Positive end-expiratory pressure (PEEP) must be as high as possible to maintain the driving pressure (Pplat-PEEP) as low as possible (< 14 cmH2O).
• Use of neuromuscular blocking agents (NMBA) should be used as needed to facilitate lung-protective ventilation.
• In patients with refractory hypoxemia (PaO2:FiO2 of <150 mm Hg), prone ventilation for > 12 to 16 hours per day and the use of a conservative fluid management strategy for ARDS patients without tissue hypoperfusion are strongly emphasized.
• The National Institutes of Health (NIH) Covid-19 Treatment Guidelines Panel recommends against inhaled pulmonary vasodilators such as nitric oxide.
• Lung-protective ventilation can also reduce the risk of new or worsening AKI by preventing ventilator-induced hemodynamic effects.
• ECMO should be considered in carefully selected patients with refractory hypoxemia despite lung-protective ventilation and patients who fail to respond to prone position ventilation.

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 is manageable 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.  
• SARS-CoV-2 neutralizing antibodies such as REGN-COV2 (casirivimab and imdevimab) or bamlanivimab/etesevimab or sotrovimab can be considered for outpatients who are at risk of disease progression with a low threshold to consider hospitalization for closer monitoring. 
• 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 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%.[144]
• 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 and should be maintained on thromboembolic prophylaxis with appropriate anticoagulation.
• Remdesivir and dexamethasone can be considered for patients who are hospitalized and 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 but are not receiving HFNC or NIPPV or IMV or ECMO.

• Severe/Critical Illness [143][144][54] 
• 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 include 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 noninvasive positive pressure ventilation that may potentially lead to the aerosol generation.[144]
• Renal replacement therapy should be considered in renal failure when indicated.
• HFNC or NIPPV can be considered in patients who do not require intubation.
• Having awake patients self-prone while receiving HFNC 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 noninvasive or invasive ventilation. Combination therapy with dexamethasone plus remdesivir or baricitinib or tocilizumab in combination with dexamethasone alone is also recommended in hospitalized patients on HFNC or NIPPV with evidence of disease progression. If corticosteroids cannot be used, baricitinib plus remdesivir may be used in non intubated patients.
• The National Institutes of Health (NIH) Covid-19 Treatment Guidelines Panel also recommends tocilizumab (as a single intravenous dose) in recently hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19.
• Impending respiratory failure should be recognized as early as possible, and endotracheal intubation with IMV must be initiated as described earlier.
• Vasopressors should be started to maintain mean arterial pressure (MAP) 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 requires evaluation for appropriateness based on the diagnosis.
• Management of COVID-19 patients with ARDS should be similar to classical ARDS management from other causes, including prone positioning as per The Surviving Sepsis Campaign guidelines for managing COVID-19.[144]
• ECMO should be considered in patients with refractory respiratory failure as previously described

Prevention of COVID-19

Besides the importance of imposing public health and infection control measures to prevent or decrease the transmission of SARS-CoV-2, the most crucial step to contain this global pandemic is by vaccination to prevent SARS-CoV-2 infection in communities across the world. Extraordinary efforts by clinical researchers worldwide 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. 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 June 22, 2021, with approximately 22% of the world's population receiving at least one dose of the vaccine. 

BNT162b2 vaccine: Results of an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial reported that individuals 16 years of age or older receiving two-dose regimen 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.[145] Based on the results of this vaccine efficacy trial, the FDA issued a EUA on December 11, 2020, granting the use of the BNT162b2 vaccine to prevent COVID-19.

mRNA-1273 vaccine: 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.[146] Based on the results of this vaccine efficacy trial, the FDA issued a EUA on December 18, 2020, granting the use of the mRNA-1273 vaccine to prevent COVID-19.

Ad26.COV2.S vaccine: A third vaccine Ad26.COV2.S vaccine for the prevention of COVID-19 received EUA by the FDA on February 27, 2021, based on the results of an international multicenter, randomized,placebo-controlled multicenter, phase 3 trial showed that a single dose of Ad26.COV2.S vaccine conferred 73.1% efficacy in preventing COVID-19 in adult participants who were randomized to receive the vaccine. [147]

ChAdOx1 nCoV-19 vaccine: Interim analysis of an ongoing multicenter randomized control trial demonstrated an acceptable safety profile and clinical efficacy of 70.4% against symptomatic COVID-19 after two doses and 64 % protection against COVID-19 after at least one standard dose.[148] The ChAdOx1 nCoV-19 vaccine has been approved or granted emergency use authorization to prevent COVID-19 in many countries across the world but has not yet received a EUA or approval from the FDA for use in the U.S.

NVX-CoV2373 vaccine: Preliminary results from a randomized, observer-blinded, placebo-controlled, phase 2 trial in South Africa evaluating the efficacy and safety of NVX-CoV2373(Novavax), a recombinant SARS-CoV-2 nanoparticle genetically engineered vaccine, reported that NVX-CoV2373 vaccine was efficacious in preventing COVID-19.[149] This trial was conducted when the country was experiencing a second wave of infection due to the Beta(B.1.351)variant implying efficacy against this virus. 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.[150]

In addition to the vaccines mentioned above, as many as seven other vaccines, including protein-based and inactivated vaccines, have been developed indigenously in India(Covaxin), Russia(Sputnik V), and China(CoronaVac) and have been approved or granted emergency use authorization to prevent COVID-19 in many countries around the world.

In early 2021, a new clinical syndrome characterized by thrombosis at atypical sites (cerebral venous sinus thrombosis/splanchnic venous thrombosis) combined with thrombocytopenia was observed in multiple patients days after vaccination with the ChAdOx1 nCoV-19 vaccine and Ad26.COV2. S vaccine. This novel clinical syndrome demonstrated striking similarities to heparin-induced thrombocytopenia(HIT); however, in the absence of prior heparin exposure was named vaccine-induced immune thrombotic thrombocytopenia (VITT). Conversely, the management of VITT is similar to HIT[151] 

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 2 doses and a third dose offering higher protection levels.[152][153] A phase 2 randomized controlled trial from the United Kingdom which compared various combinations of boosting regimens concluded that mixing vaccine types boosted antibody as well as neutralizing responses for all seven vaccines studied, which included most major commercially available vaccines.[154]

Differential Diagnosis

The symptoms of the early stages of the disease are nonspecific. Differential diagnosis should include the possibility of a wide range of infectious and non-infectious (e.g., vasculitis, dermatomyositis) respiratory disorders.

• Adenovirus
• Influenza
• Human metapneumovirus (HmPV)
• Parainfluenza
• Respiratory syncytial virus (RSV)
• Rhinovirus (common cold)

For suspected cases, rapid antigen detection and other investigations should be adopted for evaluating common respiratory pathogens and non-infectious conditions. 

Pertinent Studies and Ongoing Trials

Efficacy Of Available COVID-19 Vaccines In Prevention Against SARS-CoV-2 Variants Of Concern

The four novel vaccines, BNT162b2 vaccine, mRNA-1273 vaccine, Ad26.COV2.S vaccine and ChAdOx1 nCoV-19 were developed to target the SARS-CoV-2 spike protein main site where these variants have developed mutations, raising concerns regarding the efficacy of these vaccines against the new variants.

• BNT162b2 vaccine: The efficacy of the BNT162b2 vaccine against the Alpha (B.1.1.7) variant was 87%(95% CI 81.8 to 90.7) and 75.0% (95% CI, 70.5 to 78.9) against the Beta (B.1.351) variant based on an observational cohort study design in the population of Qatar.[155] In vitro analysis of 20 serum samples obtained from 15 participants from the BNT162b2 clinical efficacy trial efficiently neutralized all SARS-CoV-2 variants. Neutralization of B.1.1.7 variant and P.1 was roughly equivalent. The neutralization of B.1.351 was vigorous but lower than the ancestral SARS-CoV-2 strain.[156][145][156] In terms of symptomatic disease, real-world data from the United Kingdom showed that the BNT162b2 had a vaccine efficacy of 93.7% against Alpha and 88% against Delta infections.[157] Lu et.al in their in vitro study reported that the SARS-CoV-2 Omicron variant escapes neutralization efficacy of the BNT162b2 vaccine-elicited sera.[158] Another retrospective data analysis comparing the effectiveness of the BNT162b2 vaccine against hospitalization for COVID-19 during the SARS-CoV-2 Delta variant period and SARS-CoV-2 Omicron variant period in South Africa demonstrated that BNT162b2 vaccine was 70% effective in preventing COVID-19 during the dominant Omicron period compared to the 93% efficacy noted during the dominant Delta variant period.[159]

• mRNA-1273 vaccine: Results from a matched test-negative case-control study at a large health organization reported that two doses of mRNA-1273 vaccine were highly effective against all SARS-CoV-2 variants (Omicron not included), especially against hospitalizations with COVID-19. The study also reported progressive waning of vaccine effectiveness against the Delta variant with increasing time since vaccination.[160] The efficacy of the mRNA-1273 vaccine against the SARS-CoV-2 Omicron variant is unknown at this time.

• Ad26.COV2.S vaccine: A single dose of this vaccine offers protection against COVID-19 consistently across many countries, including Brazil with a predominant percentage of strains from the P.2 lineage and across South Africa with a predominant percentage of strains from the B.1.135 lineage (data not yet reported). It is important to note that the vaccine's efficacy in the US was higher by a factor of 1.3 compared to South Africa (72% versus 57%).[161] The efficacy of the Ad26.COV2.S vaccine against the SARS-CoV-2 Omicron variant is unknown at this time.

• ChAdOx1 nCoV-19 vaccine: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not confer protection against mild to moderate COVID-19 SARS-CoV-2 B.1.351 variant based on results from a multicenter, double-blind, randomized control trial 33725432. Results of another randomized control trial regarding the ChAdOx1 nCoV-19 vaccine showed that in vitro neutralization activity against the B.1.1.7 variant was reduced compared with a non-B.1.1.7 variant and the clinical efficacy of the vaccine was 70.4 % for B.1.1.7 showed compared to 81.5 % efficacy noted in non-B.1.1.7 variants.[162] Two doses of ChaAdOx1 nCoV-19 were found to have a vaccine efficacy of 74.5% against symptomatic disease by Alpha and 67% against symptomatic disease by Delta by Public Health England in real-world conditions.[157] The efficacy of the ChAdOx1 nCoV-19 vaccine against the SARS-CoV-2 Omicron variant is unknown at this time.

Prognosis

The prognosis of COVID-19 is largely dependent on various factors that include 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 WHO’s current estimate of the global case fatality rate for COVID-19 is 2.2%. However, the case fatality rate is affected by factors such as age, underlying pre-existing conditions, and severity of illness. Results from a European multicenter prospective cohort study that included 4000 critically ill patients with COVID-19 reported a 90-day mortality of 31%, with higher mortality noted in elderly, diabetic, obese, and severe ARDS patients.[163]

Complications

COVID-19 can be regarded as 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 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.[54]
• 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 [164]
• Acute renal failure is the most common extrapulmonary manifestation of COVID-19 and is associated with an increased risk of mortality.[85]
• 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. [165]
• 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.[166]
• 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.[167]
• Secondary invasive fungal infections such as COVID-19 associated pulmonary aspergillosis and rhino-cerebro-orbital mucormycosis have increasingly been reported as a complication in patients recovering from COVID-19. Risk factors for the development of secondary fungal infection include comorbid conditions such as uncontrolled diabetes, associated lymphopenia, excessive use of corticosteroids.

Deterrence and Patient Education

• Patients and families must be educated and encouraged to adhere to social distancing guidelines, use of facemasks and travel guidelines as per CDC guidelines, and social distancing state and local authorities' 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.
• High-risk patients should be encouraged to seek treatment early and be educated on new treatment options such as monoclonal antibodies.
• Patients require education regarding the efficacy of the available vaccines and the benefits of the vaccination.

Enhancing Healthcare Team Outcomes

• SARS-CoV-2 and its variants continue to cause havoc across the world and have overwhelmed many healthcare systems and economies of many countries. Three vaccines have been authorized for use in the US by the FDA under an Emergency Use Authorization (EUA), and other approvals have been issued worldwide.
• Until most of the world’s population gets completely vaccinated (including booster shots), 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 the management of COVID-19 especially considering the emergence of new SARS-CoV-2 variants, which could have a huge impact on morbidity and mortality.
• Clinicians should maintain a high index of suspicion in patients from a high risk of 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 in the management of COVID-19.
• There must be a strong focus to educate the public about the importance of receiving the vaccination against COVID-19, and consideration must be made to establish mass vaccination sites.
• Continued viral surveillance of new variants is crucial 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 potentially lead to the exhaustion of healthcare resources.
• 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.
• Such interprofessional team 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.

The interprofessional healthcare team will include all public health authorities, clinicians, specialists, mid-level practitioners, nursing staff, pharmacists, and even the patients and potential patients of this illness, all working collaboratively and openly sharing information bring about positive outcomes both for individual patients as well as society as a whole. [Level 5]