Covid-19: 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 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 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 22 December 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 isan 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 B.1.351 variant exhibited markedly more resistance to neutralization by convalescent plasma obtained from individuals previously infected with the ancestral SARS-CoV-2 strains compared to the 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 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 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 25th, the U.S. government stopped 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 non-invasive or invasive mechanical ventilation.
  • Interferon-β-1a (IFN- β-1a): Interferons are cytokines that are essential in mounting an immune response to a viral infection, and SARS-CoV-2 suppresses its release in vitro.[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 FDAapproved 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 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(RA) 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 RA, psoriatic arthritis, and moderate to severe ulcerative colitis. Given its inhibitory effect on the inflammatory cascade, it was hypothesized that its use could ameliorate the viral inflammation-mediated lung injury in patients with severe COVID-19. Results from a small randomized controlled trial that evaluated the efficacy involving 289 patients who were randomized to receive tofacitinib or placebo showed that tofacitinib led to a lower risk of respiratory failure or death(PMID:34133856).
  • Bruton’s tyrosine kinase inhibitors such as acalabrutinib, ibrutinib, 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, non-invasive 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 22 June 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 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]

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There is still a scarcity of sufficient essential data regarding the infection rate to analyze the transmissibility of the new heavily mutated Omicron variant. However, analysis from the early data of South Africa manifested that the Omicron variant can spread way more easily from person to person, though experts could not draw any conclusion within this short period.22 The concern of Omicron variant transmissibility increases as it spreads worldwide within a few days, and cases have been increasing dramatically.23 According to the report of CDC, a 2.5% increasing capacity of Omicron variant has been observed in the US within 2 weeks. However, in New York/New Jersey area, the infection rate is around 13%. On the other hand, in Britain, Omicron variant cases doubled every 2–3 days.22 The infection rate of the Omicron variant in South Africa is increasing faster than any other country’s three previous waves. On November 30, the number of cases was 10.3%, shifting to 16.5% within two days. Surprisingly, on December 2 and 3, cases were 22.4% and 24.3%, respectively.24 When the linear regressions of each pseudovirus were compared to the wild type over the entire range, it was discovered that while the Gamma variant had similar infection rates to the wild type, the Beta variant had less infection, and Delta was nearly two-fold more efficient at infecting target cells. Infection rates were four times higher in the Omicron variant than in the wild type and twice as high in the Delta variant. These findings indicate that spike sequence influences infectivity, with the Omicron variant displaying more effective ACE2-mediated infection than the wild type or other variant strains.13

Numerous factors can influence the high transmissibility of the Omicron variant. Genome sequenced data of the Omicron variant demonstrated more than 30 mutations in the spike protein by which the SARS-CoV-2 protein recognizes host cells.25 Analysis of these mutations data indicates the chance of increased transmission by evading the immune response.26 The N501Y mutation increases the binding affinity with the ACE2 receptor, which is a major influencer of increased transmission, and in combination with Q498R, the binding affinity gets stronger, and the Omicron variant gets easy access into the host.26 Moreover, the risk of reinfection of previously COVID-19 infected patients with the Omicron variant is very evident, indicating higher transmissibility.15 Omicron variant mutations H655Y and N679K are present near the furin cleavage site (FCS) and can increase spike cleavage, making the virus more contagious.2728 On the other hand, P681H can multiply transmissibility by increasing the spike protein cleavage.29

Furthermore, the new variant Omicron gives a false negative result in polymerase chain reaction tests because of the “S gene target failure,” which paves the way of spreading the infection at a higher speed worldwide.4 A previous study suggested a likely relationship between the positive electrostatic potential and affinity in the Delta VOC.30 The increased electrostatic potential is revealed in the case of Delta and Delta-plus variants of SARS-COV-2, including the Omicron variant at the RBD interface with ACE2.31 The titer of several pseudotyped SARS-CoV-2 S/HIV-1 viruses was determined using HEK293T cells stably expressing the ACE2 receptor. Without ACE2, Omicron variant S/HIV-1 pseudotyped viruses cannot enter the HEK293T. The RBD and ACE2 maintain a nanomolar level of binding affinity, which is similar in Beta, Delta, and Omicron. Because ACE2 is required for RBD, it appears that all variants have already reached the nanomolar scale, making it difficult for the virus to progress further.7 Another computational study predicted that the Omicron variant had increased affinity to the ACE2 compared to the other SARS-CoV-2 variant such as Delta. Many mutations in the receptor-binding domain of spike protein of Omicron variants, such as Q493R, N501Y, S371L, S373P, S375F, Q498R, and T478K are responsible for this higher affinity to the ACE2.2132 Therefore, it suggests that omicron VOC is highly transmissible than other variants.31

Moreover, once within the cells, the Omicron variant was less effective than Delta at causing cell fusion, linked to the poor cell-to-cell transmission. Fused cells are frequently found in respiratory tissues collected after a serious illness. Indeed, in a spreading infection experiment utilizing lung cells, a live Omicron variant virus was compared to Delta variant and found that the Omicron variant was considerably worse at replication, corroborating the findings of the decreased entrance.33


The Omicron variant of SARS-CoV-2 was identified from the COVID-19 vaccinated patients, suggesting the new variant’s immune invasion and demanded updated vaccines.34 Saxena et al. analyzed the mutations reported in the RBD of the spike of Omicron variant of SARS-CoV-2 and hypothesized that currently, available entry inhibitors might not be effective for emerging variants.35 

The heavy mutation in the spike protein of the Omicron variant is related to increased infectivity and antibody evasion.36 In SARS-CoV-2 convalescent or vaccinated people, the amount of neutralizing epitopes targeted by polyclonal antibodies is a significant predictor of the genetic barrier to viral escape. Single monoclonal antibodies are susceptible to escape mutations, but combinations targeting nonoverlapping epitopes are more resistant.37 Surprisingly, Omicron variant neutralization was undetectable in the majority of vaccines.14 

The computational approach also demonstrated that antigenic properties of the Omicron variant are ominous and correlated with its mutations.38 Although various investigations have been performed to create effective vaccines, the emergence of new VOCs has raised concern over the efficacy of neutralizing antibodies induced by COVID-19 vaccines as the Omicron variant has already infected vaccinated individuals in South Africa, Hong Kong, and many other countries.36, 39, 40 The potential impact of the COVID-19 vaccine is still being analyzed against this new variant.

Two BNT vaccinations, which can provide more than 90% protection against serious disease when infected with the Delta variant, maybe significantly less effective against the Omicron type of SARS-CoV-2.14 However, the effect of COVID-19 vaccines against the previous VOC, such as Delta, manifested the vaccine’s potential in reducing severe disease and death.41 Moreover, multiple Delta transmissions from and between completely vaccinated persons were confirmed using genomic and epidemiological data.42 

As vaccine-induced immunity is targeted through the spike proteins of the virus, heavily mutated Omicron variant spike protein is capable of reducing the neutralization activity of sera of vaccinated individuals that indicated less protection from Omicron variant.26 Only 20% and 24% of BNT162b2 recipients had detectable neutralizing antibodies against the Omicron variants HKU691 and HKU344-R346K, respectively, but none of the Coronavac recipients did.

The geometric mean neutralization antibody titers (GMT) of the Omicron variant isolates were 35.7–39.9-fold lower than the ancestral virus for BNT162b2 recipients, and the GMT of both Omicron isolates were significantly lower than the Beta and Delta variants. Between HKU691 and HKU344-R346K, there was no discernible difference in GMT.43 Pfizer/BioNTech and Moderna’s mRNA vaccines have been essential in launching mass vaccination campaigns in the United States and worldwide.

Both vaccines produce high-titer anti-SARS-CoV-2 Spike (S) protein-specific antibodies that can neutralize the original circulating SARS-CoV-2 strains and subsequent variations developed after the vaccine design phase. In animal models and humans, neutralizing antibodies generated by mRNA vaccinations appear to be the primary correlate of COVID-19 protection.44 

Laboratory investigations on Pfizer-BioNTech vaccines show a high level of protection from the Omicron variant with three doses.45 Only the booster dose can increase the neutralizing antibody titers by 25-fold compared with the other two doses. Anti-spike antibody levels can predict the neutralization of SARS-CoV-2 variants. CD4 + T cell responses are strong in SARS-CoV-2 mRNA vaccines. TFH cell responses are critical in the formation of long-term immunity by this successful human vaccination, according to recent findings.44

Individuals given mRNA vaccinations had robust neutralization of the Omicron variant that was only 4–6 times lower than the wild type, implying increased cross-reactivity of neutralizing antibody responses.14 Therefore, it is hypothesized that current COVID-19 vaccines will protect in reducing disease severity to the vaccinated individuals as a majority of the epitopes targeted by vaccine-induced T cells are not mutated in the Omicron variant.

However, the various institutions have already started the development of Omicron variant-specific COVID-19 vaccines and are confident enough to supply the vaccine within March 2022 in the market.45 Because of worries about diminishing immunity and the likelihood of a new wave of illnesses throughout the winter, booster doses of the COVID-19 vaccine have been rolled out in many nations since summer.46 

On the other hand, 75% of Omicron variant-positive patients in a South African hospital (NetCare’s Hospital) are unvaccinated and have critical outcomes compared to the vaccinated individuals, which indicates the possible protection of the existing vaccines from the variant Omicron.47 Omicron variant, a novel and potentially more transmissible strain of the SARS-CoV-2, is suspected of having emerged in a location where vaccination rates are low, with only 7.5% of people in South Africa vaccinated. Scientists have discovered that the virus is more likely to mutate in low vaccination rates and high transmission rates.48

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