The Current Standard of Care of COVID-19 Treatment, and the Confusion of the Booster Doses

Internal Medicine Residency Program Director Associate Professor of Infectious Diseases CMU College of Medicine

The management of COVID-19 has evolved over the course of this pandemic. Starting out initially with concerns about the use of steroids, currently, the mainstay of therapy for patients who require supplemental oxygenation is dexamethasone. This was confirmed in the RECOVERY trial in the NEJM on July 17, 2020, and has subsequently been updated a few times. The trial showed a reduction in 28-day mortality among patients treated with dexamethasone who required invasive mechanical ventilation (IMV) or supplemental oxygen but not in those requiring no respiratory support. Subsequently, several trials fine-tuned therapy for COVID-19, especially studied in hospitalized patients who require some form of respiratory support, such that the current standard of care is governed by frequently-updated NIH guidelines, as summarized below.

Currently, the NIH guidelines recommend dexamethasone for hospitalized patients requiring oxygen therapy (level of evidence BI) or invasive respiratory support (ventilation or ECMO, level of evidence AI). The mechanism of action is thought to be related to the anti-inflammatory effect of corticosteroids which diminish lung injury and multiorgan dysfunction from SARS-CoV2-induced systemic inflammation. The dose of dexamethasone is 6 mg IV or PO once per day for up to 10 days. Of note is that equivalent doses of corticosteroids may be administered if dexamethasone is not available, and these are prednisone (40 mg), methylprednisolone (32 mg) or hydrocortisone (160 mg) (BIII for all). Although inhaled corticosteroids have been shown to impair SARS-CoV2 replication, there is currently no firm evidence to support its use in the treatment of COVID-19. Of note is that currently, there is no evidence supporting the use of corticosteroids in patients who do not require supplement oxygen. Corticosteroids may be utilized in IV or oral formulation, as clinically appropriate for the particular patient.

Remdesivir (exists in IV formulation only) is recommended for use with or without dexamethasone in hospitalized patients who require either minimal or high-flow supplemental oxygenation or noninvasive ventilation (NIV) (BII a to BIII), but not in patients requiring IMV or ECMO. Remdesivir is an adenosine nucleotide prodrug that inhibits the SARSCoV2 RNA-dependent RNA polymerase (RdRp), an enzyme essential for viral replication. The ACTT-1 trial, a RCT in 1,062 patients hospitalized with COVID-19 and evidence of lower respiratory tract infection showed that remdesivir shortened the time to recovery from 15 days to 10 days in the placebo vs. treatment arms, which was additionally associated with clinical improvement of symptoms. The current utilization of remdesivir is without corticosteroids in patients who require minimal supplement oxygen who are thought to have an inflammatory response not intense enough to indicate corticosteroids. Its combination with corticosteroids is recommended when there are increasing O2 requirements, although this scenario has not been conclusively evaluated in clinical trials and hence stands at BIII as a level of evidence. The dose is 200 mg IV once daily for 4 to 10 days, and it is not recommended if the eGFR is <30 mg/min.

Baricitinib (exists in oral formulation only) is recommended for hospitalized patients who require supplemental oxygenation via high flow devices or NIV. In this subgroup of patients, it is utilized in addition to either dexamethasone monotherapy or combination therapy of dexamethasone plus remdesivir. It has no documented role in patients who require IMV or ECMO. Baricitinib is a Janus kinase (JAK) inhibitor that reduces the phosphorylation and activation of signal transducers and activator of transcription responsible for cytokine and growth factors involvement in hematopoiesis, inflammation and immune function. Its dose is eGFRdependent, starting at 4 mg/day for normal kidney function, and used daily for up to 14 days. It is not recommended if the eGFR is below 15 ml/min. Barcitinib use was supported by the international randomized controlled COV-BARRIER trial in 1,525 hospitalized COVID-19 patients with pneumonia and elevated inflammatory markers. In the intervention arm, barcitinib was added to standard of care (dexamethasone ± remdesivir). Although the trial demonstrated no difference in frequency of disease progression in the intervention arm, it was associated with reduced 60-day all-cause mortality (10% for baricitinib + SOC vs. 15% for SOC alone), with a similar serious adverse events profile in both arms.

Tofacitinib (oral formulation only), also a JAK inhibitor, is utilized as alternative to baricitinib when this is not available or precluded due to a GFR <15, as Tofacinib may be utilized in CKD patients whose eGFR is <60 mL/min (with renal adjustment to 5 mg PO twice daily from 10 mg twice daily). Duration of use is similar, up to 14 days.

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Tocilizumab (IV formulation only) has a role in combination therapy with standard of care for hospitalized patients who require supplemental O2 via high flow, noninvasive ventilation, IMV or ECMO. In the latter two subgroups of hospitalized patients, it is added to dexamethasone therapy alone (where remdesivir is not indicated). Hence, its use is substitutive of Baricitinib in the subgroup of hospitalized patients requiring high flow O2 or NIV, whereas in the IMV/ECMO requiring patients, it is utilized in conjunction with dexamethasone (Barcitinib not being indicated in this subgroup). It is an interleukin-6 (IL-6) inhibitor that binds specifically to both the soluble and membrane-bound IL-6 receptors and has been shown to inhibit IL-6 mediated signaling via these receptors. It is administered as a single IV dose of 8 mg/kg, and a second dose at least 8 hours later may be considered if clinical signs or symptoms worsen or do not improve. Data on outcomes in patients who received one vs. two doses are not available (REMAP-CAP). The RECOVERY trial showed mortality benefit but did not delineate a particular subgroup of hospitalized patients to benefit most from it, hence there are no clear recommendations on its preferential use over baricitinib, and hence its utilization should be based on local factors such as local guidelines, availability and other patient related factors. Of note is that baricitinib and tocilizumab are utilized in combination with corticosteroid therapy and so far have not documented role as monotherapies, with no preference of one over the other as there are no studies that directly compare one to the other. Additionally, there are no studies to support the combination of those two agents together, as they are both potent immune suppressants and consequently may have deleterious consequences when combined.

Sarilumab (subcutaneous formulation only) is utilized as alternative to tocilizumab when this latter is not available. It is similarly an IL-6 inhibitor. The dose is 400 mg once. Its indication was supported by the REMAP-CAP trial in the treatment of hospitalized patients with COVID-19, in combination with dexamethasone alone or combination dexamethasone/remdesivir in patients requiring high flow O2 or NIV, or in combination with dexamethasone alone in patients who require IMV or ECMO. The bottom line in management of severe COVID-19 is dexamethasone, in combination with remdesivir when supplemental O2 is required. Addition of baricitinib OR tocilizumab to dexamethasone is indicated when there is a need for high flow or NIV. For hospitalized patients requiring IMV or ECMO, the current standard of care is dexamethasone plus tocilizumab. Alternatives to barcitinib is tofacinib, and for tocilizumab is sarilumab, with less data to support use of alternatives at this time.

In patients who do not require hospitalization or supplemental O2, with mild to moderate COVID-19 at high risk of progression to severe disease, there are three monoclonal antibody (mAbs) regimens currently recommended based on local circulation of variants, availability and local guidelines: • Bamlanivimab plus etesevimab; or • Casirivimab plus imdevimab; or • Sotrovimab Delta (B.1.617.2) is the predominant circulating variant in the U.S. and is susceptible to the above three mAbs. Treatment should be started soon after a positive test, within 10 days of symptom onset, to those who are at highest risk (immune suppression, age >50, malignancy, cardiovascular disease, diabetes, chronic lung disease, obesity BMI >30, pregnancy and sickle cell disease). CDC recommends deferring COVID-19 vaccination for at least 90 days in those who have received anti-SARS-CoV-2 mAbs. This approach is more of a precautionary measure since the prior receipt of mAbs treatment may interfere with vaccine-induced immune responses. Notably, individuals who develop breakthrough COVID-19 infection (i.e. who are fully vaccinated and get COVID-19) would be eligible for treatment with mAbs using the same standard of eligibility for unvaccinated individuals. The mechanism of action of mAbs is binding to one more epitopes in the spike protein. Recently, the FDA has expanded the EUA for bamlanivimab plus etesevimab and casirivimab plus imdevimab as postexposure prophylaxis for exposed individuals who are at high risk for progressing to serious illness. So far, although studied in hospitalized patients with severe COVID-19, mAbs have not demonstrated benefit neither in reduction of disease severity nor in mortality, and hence their use in this setting should occur in the context of a clinical trial.

A COVID-19 vaccine booster is recommended for certain individuals. These are persons 65 years of age and older, those 18 and older who live in long-term care, have underlying medical conditions or work or live in high-risk settings. For those who received the single-shot Johnson & Johnson (J&J) vaccine, individuals 18 and older who were vaccinated at least two months previously are eligible. The nuance between the nomenclatures of a booster versus a third dose is related to

the indication. A third dose is indicated in individuals who do not achieve an adequate response after the first series primarily due to immune suppression, whereas a booster is indicated for other individuals without immune suppression. Emergent data suggest that immunity from SARS-CoV-2 vaccination may wane over time, and that vaccines may be less effective at protecting vaccinees against the Delta variant. A recent NEJM study showed that six months after completion of the Pfizer COVID-19 vaccine series, the level of neutralizing antibodies decreased across all recipient subpopulations, particularly men, individuals older than 65, and immune suppressed individuals. Additionally, the Israeli ministry of health has observed the waning immunity in their population and the effectiveness of an additional booster dose. Recently, the FDA has granted additional booster recommendations for the three existing vaccines. FDA decisions were based on several types of data for each of the three licensed vaccines. The first set of data are from the manufacturers, which ranged in number of participants. Antibody responses were measured after the additional doses and compared with those after the initial series. We do not know at this stage of the pandemic and from studies to date, the absolute antibody level that would correlate with an adequate level of protection. However, higher neutralizing antibody levels do appear to impart better immunity. Importantly, no additional safety concerns were noted after a third dose, except for additional cases of myocarditis. However, for meaningful interpretation of immunologic observations, we need to see them pegged to clinical outcomes. And the reason for this observation is that immunity is not solely a function of neutralizing antibody levels, and innate T-cell responses do play a role in the immunologic parameters. We do know antibodies work, but we also know they are not the only immune parameter preventing disease. This leads us to believe that a booster dose will likely boost the cellular immune response as it does the humoral one (antibody levels). In a study by the largest Israeli PHO (Calit) during a time when all disease was caused by the Delta variant, protection was shown to dramatically increase after the second dose. This is one of the first studies that was relied upon to recommend a booster dose. Regarding J&J, the company demonstrated data on boosting. A single dose has shown protection, which in most published studies was not as robust as that from two doses of mRNA vaccines. Hence, a second dose may likely provide more protection. One difference with that J&J vaccine as compared to mRNA vaccines is that the antibody levels decline less over time, (data not published nor peer reviewed yet). One concern with the J&J vaccine remains, and some trial of boosting were paused after reports of Thrombosis with Thrombocytopenia (TTS).

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It is still rather early to have clear recommendations regarding the absolute indication of boosters, as well as, regarding mixing of vaccine. The safest approach is now to get the ‘booster’ in persons in whom it is indicated. Yet, recently, the CDC gave a green light to the ‘mix-and-match’ strategy, so individuals who are eligible for boosters can decide to get a dose of a different brand than the one they first received. How would one decide on such a strategy? Let me help with this. Early results of the “Mix and Match” study looked at receipt of a different booster than the primary vaccines received. There were nine small groups since the permutation of three different vaccines would result in nine possible combinations. Several immunologic outcomes were measured, mostly antibody levels. In all those trials, an additional dose of any vaccine increased antibody levels. The additional mRNA vaccines, however, increased levels more robustly than did the J&J vaccine, and all combinations appeared to be safe. It is likely that individuals who initially received the J&J vaccine will be recommended to receive a mRNA vaccine booster. Hence, the current approach to ‘mixing and matching’ is based on encouraging safety and immunogenicity data that support boosting and possibly using a different vaccine, particularly in J&J followed by mRNA vaccines. There remain multitudes of challenges - especially when we factor in the broader options of vaccines utilized globally, the time interval between vaccines, vaccine doses, and other factors, all of which are parameters that need to be analyzed. What is next? Children between 5 and 11 years old are up next on the FDA’s regulators’ list to approve for vaccination. Early data from Pfizer have highlighted the benefits for this subgroup of the population, with essentially no added risk, and hence Emergency authorization could come very soon. Moderna’s data are being finalized now and will follow suit. The big question remains: Will there be another wave? The U.S. has already had four waves of COVID-19 surges, and a fifth major one could be speculated. Although we certainly hope it won’t be as severe if it occurs, and most importantly we do know based on robust information that it will be so in vaccinated individuals. As for those who are not vaccinated, it is prime time they do. The data demonstrate robust protective effects and a very high safety profile. Hence, we hereby send a sincere plea to them to reconsider their decision, if not for society at large, for themselves and their families.

Transmission of the SARS-CoV2 virus is primarily via the respiratory route. Both droplet and airborne transmissions have been well documented, and account for the vast majority of infections. This is why infections occur more commonly in indoor settings, when individuals are unmasked and susceptible to it (e.g. due to lack of vaccine-induced immunity or those

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