Treatment options used in COVID-19 Disease: Steroids, anticoagulants, remdesivir and/or antibiotics – Which worked better or combo was the right choice? Patil S, Narwade G, Gondhali G,

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Treatment options used in COVID-19 Disease: Steroids, anticoagulants, remdesivir and/or antibiotics – Which worked better or combo was the right choice?

Shital Patil¹, Ganesh Narwade¹, Gajanan Gondhali²
¹ Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
² Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India

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Date of Submission	11-May-2022
Date of Decision	04-Jul-2022
Date of Acceptance	07-Jul-2022
Date of Web Publication	27-Oct-2022

Abstract

Coronavirus disease 2019 (COVID-19) is the first coronavirus-related global pandemic caused by a novel severe acute respiratory syndrome coronavirus-2, and rapid evolution of the pandemic has resulted in fast-track developments in antivirals, medical management, and vaccination for use to prevent morbidity and mortality. As of today, different institutional treatment protocols and respective national guidelines have been evolved worldwide with team of medical experts and recommended for combinations of antiviral, antibiotics, steroids, and anticoagulants with variable outcomes. Combination therapy has documented better outcome with a significant reduction in mortality and morbidity and considered frontline protocol during this pandemic.

Keywords: Antibiotics, anticoagulants, COVID-19, remdesivir, steroids

How to cite this URL:
Patil S, Narwade G, Gondhali G. Treatment options used in COVID-19 Disease: Steroids, anticoagulants, remdesivir and/or antibiotics – Which worked better or combo was the right choice?. J Appl Sci Clin Pract [Epub ahead of print] [cited 2023 Mar 29]. Available from: http://www.jascp.org/preprintarticle.asp?id=358987

Introduction

Coronavirus disease 2019 (COVID-19) has evolved over the past 2 years and still evolving with various mutants. There is no precise regimen which will have a significant impact on clinical and radiological outcome with decrease in mortality and morbidity. The current pandemic of COVID-19 caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2), originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally, and 34,752,164 confirmed cases 478,007 deaths in India.^[1] As per available literature, no single group of drugs has full proof protection in currently ongoing pandemic, and combinations of steroids, antivirals, antibiotics, and anticoagulation is the best protocol which is now universally acceptable with minimal mortality and morbidity.

Pathophysiology and Probable Targets in COVID-19 Pneumonia

COVID-19 pneumonia is heterogeneous disease with a variable effect on lung parenchyma, airways, and vasculature leading to long-term effects on lung functions. Although lung is the primary target organ involvement in COVID-19, many patients were shown pulmonary and extrapulmonary manifestations of diseases variably, which has occurred as a resultant pathophysiological effects of immune activation pathway, inflammatory, thrombogenic, and direct viral affection to lungs and extrapulmonary tissues. Potential targets for control of infection and to prevent progression of disease are antivirals, anti-inflammatory drugs, anticoagulants, antifibrotics, and antibiotics in advanced cases with superadded infections. Antivirals available to treat COVID-19 are favipiravir, remdesivir, and recently approved molnupiravir.^[2],[3] The antiviral drugs administered shortly after the onset of symptoms can shorten the course of clinical illness and it can reduce the infectiousness to others by reducing viral shedding.^[4] Coronavirus is an RNA virus with a high mutation rate, and natural trends of interspecies genetic exchange leading to immune escape in previously infected or exposed individuals. Importantly, several currently circulating SARS-CoV-2 variants are associated with loss of efficacy for both vaccines and neutralizing antibodies. In order to optimize the efficacy of antibody treatments, it may be desirable to develop cocktails of neutralizing Abs that can simultaneously bind different sites of the spike protein receptor-binding domain and synergistically neutralize SARS-CoV-2.^[5]

Antibody Cocktail, FAVIPIRAVIR, Remdesivir, and Molnupiravir in COVID-19 Disease

The U.S Food and Drug Administration (FDA) revised emergency use authorization (EUA) for REGEN-COV (casirivimab and imdevimab, administered together) issued a recommendation for emergency use as post-exposure prophylaxis (prevention) for COVID-19 in adults and pediatric individuals (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death, and not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination.^[6]

In the phase 1–2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (COVID-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. REGEN-COV reduced the risk of COVID-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo.^[7] REGEN-COV is not authorized for use in patients hospitalized due to COVID-19, and or requiring oxygen therapy due to COVID-19, and or cases with increase in baseline oxygen flow requirement due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19-related comorbidity. Monoclonal antibodies, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.

Favipiravir is a purine nucleic acid analog, is an RNA-dependent RNA polymerase inhibitor, discovered by Japanese company Toyama in 2002 and approved in Japan for resistant Influenza infection in 2014, and has shown potent in vitro activity against severe acute respiratory syndrome coronavirus-2. It is activated in its phosphoribosylated form in cells, inhibiting viral RNA polymerase activity.^[8] It is recommended in mild cases of COVID-19 to prevent progression and risk of hospitalization in outdoor setting. It is a weak antiviral in vivo and showing least potency against SARS-CoV-2 which will have a lesser impact on progression and further complications. Although it is included in treatment guidelines, many medical experts restricted its use in outdoor setting with mild involvement on imaging and normal inflammatory markers, and normal oxygen saturation.

Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir has been approved by the U.S. FDA on May 1, 2020, and Central Drugs Standard Control Organization (CDSCO) India on June 20, 2020, for its emergency use in COVID-19 in adults and children's above 12 years of age exclusively in indoor care facility. As per the Ministry of Health and Family Welfare (MOHFW) and Indian Council of Medical Research (ICMR) India on April 23, 2021, remdesivir should be used only in select moderate/severe hospitalized COVID-19 patients on supplemental oxygen as it is a reserve drug approved under Emergency Use Authorization only based on limited scientific evidence globally; and should not use in mild COVID-19 patients who are in-home care/COVID care centers.^[9] Remdesivir use in COVID-19 has been evolved over the last 1 year and research data from trials are available suggesting its use and also of no benefit; clinching overall clinicians' decision to use in indoor setting. “Adaptive COVID-19 Treatment [GM1] Trial” found that remdesivir is useful in cases of COVID-19 with SpO2 <94% on room air (moderate-to-severe cases) if it is administered within 7–10 days of illness. Remdesivir led to a shorter median time from randomization to recovery (10 days vs. 15 days with placebo) and may have reduced the time to hospital discharge (12 days vs. 17 days) but did not show a mortality benefit.^[10] The “Solidarity Trial” conducted by WHO in 30 countries from March 2020 at 405 hospitals; 11330 adults underwent randomization; 2750 were assigned to receive Remdesivir. The interim results of the “WHO Solidarity trial” published on December 2020 showed that remdesivir had little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.^[11] Remdesivir was the first FDA-approved drug for the treatment of patients with COVID-19 but its effectiveness is disputed, emphasizing the need to develop new antiviral drugs.

Molnupiravir is an isopropylester prodrug of the nucleoside analog β-D-N4-hydroxycytidine. Molnupiravir interferes with the replication of various viruses, including SARS-CoV-2. It inhibits SARS-CoV-2 replication in human lung tissue, blocks SARS-CoV-2 transmission in ferrets, and reduces SARS-CoV-2 RNA in patients. In a phase 2a, double-blind, placebo-controlled, randomized, multicenter clinical trial molnupiravir has shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile.^[12],[13] Molnupiravir should be provided only to non-severe COVID-19 patients with the highest risk of hospitalization. These are typically people who have not received a COVID-19 vaccination, older people, people with immunodeficiencies, and people living with chronic diseases.^[14]

Steroids in COVID-19 Disease

Medical experts worldwide involved in the treatment of COVID-19 pneumonia cases have been documented crucial and outcome-defining role of inflammatory pathway in these cases, and disproportionately in few cases hyperactive immune stimulation syndrome called cytokine storm is observed and having a poor outcome. Cytokine-induced pulmonary or extrapulmonary injury was an important pathophysiological mechanism involved in COVID-19 pneumonia which has been evaluated and completely analyzed with the measurement of inflammatory markers C-reactive protein (CRP), lactate dehydrogenase, ferritin, and interleukin-6 (IL-6). Glucocorticoids exert anti-inflammatory by stimulating the synthesis and release of anti-inflammatory proteins and by inhibiting that of pro-inflammatory proteins. Glucocorticoids suppress the production of acute-phase reactants and chemokines, thereby preventing leukocyte recruitment.^[15]

Systemic glucocorticoids have been demonstrated to improve survival when administered to patients who are moderately or severely ill. Systemic steroids are recommended in both the World Health Organization (WHO) guidance for the clinical management of COVID-19 and the National Institutes of Health COVID-19 treatment guidelines. The prospective meta-analysis of systemic glucocorticoids from the WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group found that administration of systemic glucocorticoids was associated with lower 28-day all-cause mortality.^[16] Randomized controlled trials with subsequent high-quality meta-analyses have provided moderate-to-strong certainty for an increased chance of survival and relief from life-supportive therapy with corticosteroids given at a dose of 6 mg/day dexamethasone or equivalent doses of hydrocortisone or methylprednisolone.^[15] The included trials, which enrolled patients who were severely ill and reported a broadly consistent treatment effect, evaluated daily glucocorticoid equivalent doses that ranged from 6 mg to 20 mg of dexamethasone. The treatment effects were similar to low-dose versus high-dose regimens.^[16] Various observational studies have evaluated the beneficial effects of corticosteroids in the treatment of COVID-19 as these agents are widely available, inexpensive, and easy to use.^[17]

Methylprednisolone and dexamethasone were used globally in the management of COVID-19 pneumonia with different dosages, durations, and treatment outcomes. Methylprednisolone has higher lung penetration; thus, it can act as a better immunosuppressive agent in the treatment of COVID-19 and improvement of respiratory complications in comparison to dexamethasone. In one study, authors documented lower mortality rates in patients who received methylprednisolone as compared to dexamethasone (8 vs. 15) with statistical insignificance.^[17] In a retrospective cohort study done by Wang et al., evaluating the treatment of patients suffering from COVID-19 with low-dose methylprednisolone with short-term duration, patients who received 1–2 mg/kg/day methylprednisolone for 5–7 days had shorter hospital course duration, less need for mechanical ventilation.^[18] In a randomized clinical trial done by Edalatifard et al. documented pulse methylprednisolone 250 mg/day for 3 days had a lower mortality rate and higher survival time than the control group, observed an increase in O2 saturation, lesser clinical findings such as myalgia, chest pain, cough, and gastrointestinal symptoms and reduction in the (CRP) level and an increase in the platelet count in those who were treated with methylprednisolone compared to those who received standard care.^[19] In the current trial by the COVID STEROID 2 Trial Group, patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days.^[20]

Interleukin-6 Antagonists in COVID-19

Monocytes and macrophages produce IL-6 after stimulated by Toll-like receptors and its upregulation in COVID-19 has documented poor outcome. The primary consideration of IL-6 inhibitors in the treatment of COVID-19 may be based on the ability to inhibit IL-6, which plays a central role in acute inflammation and cytokine release syndrome. Other immune modulators, including IL-6 receptor antagonists, such as tocilizumab and sarilumab, and the Janus kinase inhibitor (JK-1) baricitinib, have been demonstrated to improve outcomes when administered to patients with COVID-19 who are moderately or severely ill. There is evidence that the beneficial effects of IL-6 receptor antagonists are additive to glucocorticoids, at least for lower doses of glucocorticoids (i.e., 6–7.5 mg/d of dexamethasone).^[21] The reported improvement in outcomes for patients treated with baricitinib was in a study in which a high proportion of patients received glucocorticoids.^[22] IL-6 inhibitors agents have shown potential benefit in reducing the risk of mortality in COVID-19 patients, especially in severe disease. Issue of concern is that IL-6 promotes immune processes associated with resistance to infection, and IL-6 neutralization could interfere with anti-viral responses or increase susceptibility to secondary respiratory infections in hospitalized patients with COVID-19.^[23] However, the appropriate dosage and drug administration remain unclear.

Anticoagulants in COVID-19 Disease

In COVID-19 pneumonia, thromboembolic events documented in increased proportion to other pneumonias due to prothrombotic pathway activation as a result of exaggerated inflammatory response, endotheliitis, stasis of blood due to deconditioning, and activation of the coagulation cascade in critical care setting as mentioned in Virchow's triad, i.e., endothelial injury, stasis of blood flow, and hypercoagulable state resulting into thrombosis and embolism.^[24] Other mechanisms responsible for hypercoagulable state in COVID-19 pneumonia are platelet dysfunction, compliment activation, inhibition of plasminogen activation, and development of antiphospholipid antibodies. The use of anticoagulation during management in indoor setting has been documented since the beginning of pandemic, although timing, dosage and duration, drug of choice are variable and depend on trends of practice in these geographical setting. The American Society of Hematology and The American College of Cardiology suggest using prophylactic-intensity over intermediate intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed venous thromboembolism (VTE) and there is no specific contraindication such as active bleeding exists.^[25]

All the guidelines recommend heparin in therapeutic doses only in diagnosed or highly suspected macrothrombi (pulmonary embolism/deep vein thrombosis), while ignoring the issue of undiagnosable microthrombi. Although significantly elevated levels of d-dimer are more likely to be associated with VTE, it is difficult at this point to identify the threshold that can only be used to diagnose thrombus non-invasively.^[26] Low-molecular-weight heparin, i.e., enoxaparin or fondaparinux is preferred due to easy to use, lesser side effects, wheel tolerability, lesser risk of bleeding, and no need to activated partial thromboplastin time (aPTT) monitoring. Decisions regarding post-discharge prophylactic anticoagulation should be individualized, routine administration of oral anticoagulants in all patients with COVID-19 at the time of discharge is not recommended. The American College of Chest Physicians guidelines published in CHEST as well as the American College of Cardiology guidelines published in the Journal of the American College of Cardiology do not elucidate post-discharge thromboprophylaxis.^[27]

Antibiotics in COVID-19 Disease

Although antibiotics play a crucial role in bacterial pneumonia, antibiotics were prescribed in majority of cases of COVID-19 pneumonia across the globe. Two types of pneumonia have been documented in COVID-19 cases, primary viral pneumonia, and secondary bacterial pneumonia. Proportionately, a large number of COVID-19 cases were having secondary bacterial pneumonia due to cytokine-induced immune suppression, concurrent use of steroids during treatment of these cases resulting in immune suppression or/and COVID-19 or steroid-associated hyperglycemia leading to immunosuppression resulting in secondary bacterial infection. Secondary bacterial infection also documented in ICU setting due to contamination of nebulization kits and chambers, oxygen humidifiers ports, ventilator masks, and circuits and other accessories used during the handling of these cases. A systematic review on bacterial and fungal coinfections in coronaviruses reported an overall percentage of 8% coinfections in COVID-19 patients at any time during hospitalization.^[28] Two studies from Wuhan in China reported on secondary infections in hospitalized COVID-19 patients.^[29] Sieswerda et al.,^[30] in their review on recommendations on the use of antibiotics in COVID-19 pneumonia mentioned that eight studies reported information on bacterial pathogens, and three studies reported no bacterial pathogens, and pathogens reported in COVID-19 patients with possible bacterial coinfection were mainly Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae. In one study,^[31] authors have documented 19% of patients with COVID-19 have coinfections and 24% have superinfections. The presence of either coinfection or superinfection was associated with poor outcomes, including increased mortality. Antibiotics used during treatment should target common and atypical organisms associated with co-infection and appropriate duration and de-escalation can be done with procalcitonin assessment. As per available data of published literature, no single antibiotic is offering full proof protection and combination of beta-lactamase inhibitors with macrolides will be sufficient if underlying bacterial pathology is the coexistent etiology along with COVID-19 pneumonia. Antibiotic stewardship is equally important to prevent the development of and emergence of “superbugs” and protocolized antibiotic as per recommendations by local expertise or institutional infection control board is a key step while managing critical cases with long hospital stay requirement in intensive care units.

Additional Role of Combo in COVID-19 Disease

COVID-19-related pathophysiology linked to pulmonary and extrapulmonary effects with inflammatory surge, direct virus-induced lung damage, altered coagulation cascade leading localized pulmonary, and systemic thrombotic insults, and this is the rational for “combination therapy” is the best treatment approach with combinations of available group of drugs which will improve outcome in the majority of cases.

Conclusions

COVID-19 pandemic is not ended up till today due to various mutants and genetic structural recombinations, and the main hurdle is no effective treatment is available in spite of fast-track developments. Medical evidence suggests that the beneficial role of combo therapy as combination of antiviral, anticoagulants, and steroids has shown mortality and morbidity benefit across the globe. Even after 2½ years of pandemic, and with updated vaccination available and incorporated worldwide, still we believe “COVID appropriate behavior” as key step in this pandemic. Finally, in this pandemic, important step is to follow the basics of epidemiology as early diagnosis, isolation of infected cases, treatment of cases with available resources and preventive methods.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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