The COVID-19 outbreak continues to surge in most parts of India, with health systems being stretched to the limit across the country. Several studies have been carried out in the past few months in the quest for therapeutic options that may have a favorable impact on clinical outcomes. Although there have been no dramatic breakthroughs, outcomes have generally improved with increasing experience in the management of a novel disease. Let us look at some of the newer therapeutic modalities that hold promise in patients who develop severe infection.
Corticosteroids
The use of corticosteroids in viral pneumonias has generated increasing interest over the years, with some studies demonstrating possible harm.1 At the early stage of the pandemic, the World Health Organization had recommended against the use of corticosteroids in COVID-19 based on the evidence available at that time. Since then, four randomized controlled trials (RCT) and a meta-analysis have established the efficacy of modest doses of corticosteroids in improving clinical outcomes in COVID-19 (Table 1).
Table 1. Randomized controlled trials evaluating the efficacy of corticosteroids in COVID-19
| Trial | Location | Type and dose of steroid | Findings |
| RECOVERY2 | UK | Dexamethasone 6 mg once daily IV or orally for a maximum of 10 d | 28-d mortality was significantly less with dexamethasone compared to standard care alone. The greatest benefit was observed in mechanically ventilated patients. The survival benefit was less prominent in patients who received supplemental oxygen alone or non-invasive ventilation. No benefit was observed in patients who did not require respiratory support |
| REMCAP3 | Australia, Canada, France, Ireland, the Netherlands, New Zealand, the United Kingdom, and the United States | Fixed 7-d course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), or a shock-dependent course (50 mg every 6 hours when shock was clinically evident) | A 7-d fixed-dose course or shock-dependent administration of hydrocortisone was associated with 93% and 80% probabilities of superiority regarding improvement in organ support–free days at 21d |
| CODEX4 | Brazil | Dexamethasone 20 mg intravenously daily for 5 d, 10 mg daily for 5 d, or until ICU discharge. | Ventilator-free days were 6 (95% CI, 5.0-8.2) vs 4 d (95% CI, 2.9-5.4) in the dexamethasone vs. standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = 0.04) |
| CAPE COD5 | France | Hydrocortisone 200 mg/d until d 7; decreased to 100 mg/d for 4 d and 50 mg/d for 3 d, for a total of 14 d. If the patient’s respiratory and general status had sufficiently improved by d 4, a short treatment regimen was used (200 mg/d for 4 d, followed by 100 mg/d for 2 d and then 50 mg/d for the next 2 d, for a total of 8 d). | Treatment failure (death or ventilator dependence) on d 21, occurred in 32/76 patients (42.1%) in the hydrocortisone arm vs. 37 of 73 (50.7%) in the placebo arm (difference of proportions, –8.6% [95.48% CI, –24.9% to 7.7%]; P = 0.29) |
The meta-analysis by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group analyzed pooled data from seven randomized controlled trials.6 The study revealed significantly lower mortality with corticosteroid use (222/678 patients) compared to controls (425/1025 patients) (OR: 0.66, 95%; CI: 0.53–0.82, P <0.001). The effect on mortality was seen only with dexamethasone; survival was not significantly different with hydrocortisone or methylprednisolone on fixed-effect analysis. Based on available evidence, modest dose corticosteroids are likely to be of benefit in patients who require supplemental oxygen or higher levels of respiratory support. It is important to remember that higher doses (e.g., high-dose methylprednisolone) may be ineffective, and possibly harmful, as evidenced by previous studies in viral pneumonia.1
Convalescent plasma
Historically, convalescent plasma has been extensively used for more than a century in many viral epidemics beginning with the Spanish flu of 1917–18. There has been increasing interest regarding its use in COVID-19.
Ling et al. studied the efficacy of convalescent plasma among patients with severe (tachypnea >30/min, oxygen saturation of ≤93% on room air or PaO2/FiO2 ratio of ≤300 mm Hg) or life-threatening (requirement for mechanical ventilation, shock or extrapulmonary organ failure) COVID-19 infection.7 The transfused plasma units had a S protein–receptor binding domain-specific IgG antibody titers of at least 1:640. Declining enrolment rates led to premature cessation of the trial. Convalescent plasma-treated patients did not reveal greater clinical improvement on a 6-point severity scale, or mortality at 28 days compared to standard treatment. A higher rate of clinical improvement was noted among patients who had severe, but not life-threatening disease. A major drawback of this trial was convalescent plasma administration at a late stage of the disease, with a median time interval between symptom onset and randomization of 30 days.
A large observational study evaluated 35,322 patients who received convalescent plasma in the US and territories.8 This study revealed that transfusion within three days of diagnosis resulted in lower mortality at 7 and 30 days compared to transfusion at a later stage. Furthermore, a mortality gradient was noted with higher IgG antibody levels associated with lower mortality. A dose-response relationship was observed with mortality 7- and 30-day mortality. Although lacking a control arm, the findings of this study suggest that earlier transfusion, using convalescent plasma with higher antibody titers, may reduce mortality.
The PLACID trial was an RCT conducted by the Indian Council of Medical Research (ICMR) to assess the efficacy of convalescent plasma among hospitalized patients with moderate illness, characterized by a PaO2/FiO2 ratio of 200–300 or respiratory rate > 24/min, and SpO2 ≥93% on room air.9 The study included 235 patients randomized to receive convalescent plasma and 229 to standard of care. No significant difference was observed in the composite endpoint of death or progression to severe disease at 28 days. Mortality was 34 (14.5%) vs. 31(13.5%), and progression to severe disease was 17 (7.2%) vs. 17 (7.4%) in the convalescent plasma and control arms, respectively. There was no difference with early administration (within 3 days of symptom onset) compared to later treatment, although only 24 patients received early treatment. Viral clearance at day 7 was significantly higher with plasma therapy. A sobering finding was that only 2/38 patients who underwent invasive mechanical ventilation survived to day 28. The median neutralizing antibody titer was 1:40 (IQR: 1:30–1:80), lower than the >1:160 titer recommended by the FDA. The question remains whether convalescent plasma administration with higher antibody titers may be more efficacious.
Cytokine inhibitors
A retrospective, observational study compared COVID‐19 patients who were treated with the IL-6 blocker, tocilizumab with a control group matched to the requirement for ICU admission and mechanical ventilation.10 There was a significantly higher incidence of infections acquired more than 48 hours after admission in tocilizumab treated patients; bacterial pneumonia was the most common infection. The authors also observed increased mortality (39 vs 23%) in the tocilizumab group. Tocilizumab-related infections and other adverse effects, including impaired liver function and neutropenia occurred in 61% of patients.10 This report raises concern regard the safety of cytokine inhibitor therapy in patients with COVID-19. Although it might seem intuitive, historically, cytokine blocker therapy has revealed a track record of failure in both bacterial and viral infections. A major stumbling block has been to identify the optimal time of administration. Considering the lacunae in our current state of knowledge, it is nearly impossible to identify the point at which the host response spirals out of control to facilitate effective timing of therapy. The host immune response clearly revolves around a complex interplay of several mediators; the response is likely to be neither linear nor uniform. Besides, the prolonged duration of action of cytokine inhibitors commonly used in chronic inflammatory disorders may cause superinfections in critically ill patients. Furthermore, targeting a single cytokine such as IL-6 is unlikely to be beneficial, considering that it may not be the sole driver of the adaptive response.
Prone positioning in non-intubated patients
Prone positioning is being increasingly used in spontaneously breathing patients combined with supplemental oxygen therapy, including high-flow nasal cannula and non-invasive ventilation. The prone position was studied in 24 patients with COVID-19 related acute hypoxemic respiratory failure;11 14 (63%) of patients tolerated the prone position for more than 3 hours. Among patients who maintained the prone position for 3 hours or more, a significant increase in the PaO2level occurred, [73.6 (SD, 15.9) to 94.9 (SD, 28.3)] mm Hg (P = 0.006). No major complications were observed with prone positioning. At 10-day follow-up, five patients received invasive ventilation. Our experience suggests that adopting the prone position in awake, spontaneously breathing patients results in improved PaO2/FiO2 ratios in most patients, with good tolerance for several hours.
Remdesivir
The efficacy of remdesivir in COVID-19 has been evaluated in three RCTs. In the first RCT from Hubei in China, remdesivir was compared to placebo within 12 days of symptom onset in patients with oxygen saturation ≤ 94% while breathing room air or a PaO2/FiO2 ratio of ≤ 300 mm Hg, with radiological evidence of consolidation.12 In this RCT, the time to clinical improvement at 28 days was not different between groups. However, the study did not attain the projected sample size as enrolment ceased with the containment of the outbreak.
Subsequently, the ACTT-1 trial compared remdesivir with placebo in hospitalized patients with lower respiratory tract involvement.13 Remdesivir administration resulted in earlier hospital discharge, or continued hospitalization was required only for infection control purposes alone. The 14-day mortality was not significantly different between groups in this study. A subsequent study compared a 5 or 10-day course of remdesivir with standard care alone.14 Patients who received a 5-day course of treatment had a more favorable clinical status on day 11 compared to patients who received standard care. Furthermore, no significant difference in clinical status was observed with a more prolonged, 10-day course of treatment.
These studies do not offer unequivocal evidence regarding the clinical benefits of remdesivir in COVID-19. Several important questions remain unanswered. First, what is the most appropriate time to commence treatment? Second, does it improve outcomes in severely ill patients who require mechanical ventilation? Importantly, the question remains, whether it reduces the time to recovery alone, with no impact on mortality among severely ill patients.
Summary
- Four RCTs and a meta-analysis offer robust evidence that supports corticosteroid administration in COVID-19 patients with acute hypoxemic respiratory failure
- Studies with the use of convalescent plasma have yielded mixed results. Earlier administration using convalescent plasma with high antibody titers need further investigation regarding possible beneficial effect
- Evidence is lacking regarding the benefit of cytokine inhibitors; the likelihood of adverse outcomes related to nosocomial infections need to be considered
- Remdesivir administration may shorten the duration of illness; however, its impact on mortality and efficacy in severely ill patients remain unclear
- Prone positioning in unintubated patients, combined with high-flow nasal cannula or non-invasive ventilation results in improved oxygenation and needs further investigation regarding the impact on clinical outcomes
References
1. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. doi:10.1164/rccm.201706-1172OC
2. Horby P, Lim WS, Emberson J, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. Published online June 22, 2020:2020.06.22.20137273. doi:10.1101/2020.06.22.20137273
3. The Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17022
4. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17021
5. Dequin P-F, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16761
6. Group TWREA for C-19 T (REACT) W, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17023
7. Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044
8. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. Infectious Diseases (except HIV/AIDS); 2020. doi:10.1101/2020.08.12.20169359
9. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent Plasma in the Management of Moderate COVID-19 in India: An Open-Label Parallel-Arm Phase II Multicentre Randomized Controlled Trial (PLACID Trial). Infectious Diseases (except HIV/AIDS); 2020. doi:10.1101/2020.09.03.20187252
10. Pettit NN, Nguyen CT, Mutlu GM, et al. Late onset infectious complications and safety of tocilizumab in the management of COVID‐19. J Med Virol. Published online August 21, 2020:jmv.26429. doi:10.1002/jmv.26429
11. Elharrar X, Trigui Y, Dols A-M, et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA. 2020;323(22):2336. doi:10.1001/jama.2020.8255
12. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020;395(10236):1569-1578. doi:10.1016/S0140-6736(20)31022-9
13. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N Engl J Med. Published online May 22, 2020:NEJMoa2007764. doi:10.1056/NEJMoa2007764
14. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. Published online August 21, 2020. doi:10.1001/jama.2020.16349
