Surviving sepsis guidelines: management of critically ill adults with COVID-19[19]

Investigational therapies

Remdesivir

Remdesivir, a nucleotide analog prodrug that inhibits viral RNA polymerases and has shown in vitro activity against severe acute respiratory syndrome coronavirus 2.[4]

In a study of 53 patients with severe COVID-19 (oxygen saturation of <94 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_192_20#JR_5" xss=removed>5]

Lopinavir-Ritonavir

Lopinavir/ritonavir combination showed in vitro activity against other novel coronaviruses through inhibition of 3-chymotrypsin-like protease.[4] It is Food and Drug Administration (FDA) approved for the treatment for HIV.

A randomized controlled, open-label trial was done in adult hospitalized Chinese patients with severe COVID-19 (oxygen saturation of <94 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_192_20#JR_6" xss=removed>6] Currently, this is the only published phase 3 randomized controlled trial (RCT) for the management of COVID-19 infection.

Hydroxychloroquine/chloroquine and azithromycin

Chloroquine and hydroxychloroquine are used in the treatment of malaria, discoid/systemic lupus erythematosus, and rheumatoid arthritis. These drugs have immunomodulatory effects and block the viral entry into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification.[4]

A French study included twenty patients with COVID-19 infection who were treated with oral hydroxychloroquine sulfate 200 mg, 3 times/day with or without azithromycin for 10 days and were compared to controls. There was a reduction in viral loads on day 6 as compared to the controls. The limitations of this study are small sample size, nonrandomized design, and mortality not being the endpoint.[7] Another French study with 11 patients with severe COVID-19 infection treated with hydroxychloroquine (600 mg/day for 10 days) and azithromycin (500 mg on day 1 and 250 mg from day 2 to day 5) showed no evidence of rapid antiviral clearance or clinical benefit.[8] Moreover, severe side effects of chloroquine can include psychiatric manifestations, arrhythmias, and sudden death.[9]

Inhalational plasminogen therapy

Plasminogen is a key regulator in fibrin degradation, wound healing, and infection.[10]

A study from China with 13 patients who had moderate-to- severe COVID-19 infection were treated with atomization inhalation of free-dried plasminogen (10 mg OD for moderate and 10 mg BD for severe infection). Six patients with severe infection had improvement in oxygen saturation, five patients with moderate infection had radiological improvement of pneumonia, and two critical patients with hypoxemia had improvement in saturation within an hour.[10] The limitations of this study are the small sample size, nonrandomized design, and mortality not being evaluated as an endpoint.

Convalescent plasma therapy

Passive immunization for the treatment of human infectious diseases can be traced back to the 20th century when antibodies were used from the serum of stimulated animals, especially rabbits and horses.[11]

A study has been reported from China, in which ten patients who had severe COVID-19 infection received one dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 in addition to supportive care, antiviral agents, and steroids. The clinical symptoms were significantly improved along with an increase in oxygen saturation within 3 days. Radiological examinations showed varying degrees of resolution of lung lesions within 7 days. The viral load was undetectable after transfusion in seven patients who had previous viremia. The limitations of this study are a small number, nonrandomized design, confounding use of antiviral therapy and steroids, and nonassessment of cytokine changes. This study also does not answer the question of an optimal concentration of neutralizing antibodies and treatment schedule.[12] In another uncontrolled case series of five critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS) from China, the administration of CP containing neutralizing antibody was followed by an improvement in clinical status.[13]

The Indian Council of Medical Research (ICMR) is planning to do a randomized controlled, open-label trial of CP therapy versus conventional therapy in COVID-19-infected patients.[14]

Tocilizumab

Tocilizumab is a novel monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its receptor. It is FDA approved for the treatment of rheumatoid arthritis and cytokine release syndrome.[4]

A study from China reported 15 moderate-to-seriously ill COVID-19-infected patients treated with injection tocilizumab (80–600 mg) with or without methylprednisolone. This study showed a reduction of C-reactive protein and IL-6 in patients who received tocilizumab. The limitations of this study are small sample size, nonrandomized design, and again, mortality was not an endpoint.[15]

Methylprednisolone

A retrospective cohort study from China evaluated 201 COVID-19-infected patients with ARDS who were treated with methylprednisolone and reported a lower risk of death (hazard ratio: 0.38; 95%-CI: 0.20–0.72).[16] The Chinese thoracic society recommends methylprednisolone 0.5–1 mg/kg for <7 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_192_20#JR_17" xss=removed>17] The limitations include the retrospective study design and the potential adverse effects of steroids.

Low-molecular-weight heparin

A study from China evaluated the use of low-molecular-weight heparin in patients with severe COVID-19. This study enrolled 449 patients, and among them, 99 patients received heparin for 7 or more days. There was no difference in mortality between patients who used heparin and those who did not (30.3%-vs. 29.7%, P = 0.910). However, the mortality was reduced in patients who used heparin with sepsis-induced coagulopathy score >4 (40.0%-vs. 64.2%, P = 0.029) or D-dimer >6-fold of upper limit of normal (32.8%-vs. 52.4%, P = 0.017).[18] The limitations of this study are retrospective design and the influence of confounding variables (other therapies).

Infectious Disease Society of America Guidelines

The Infectious Disease Society of America does not recommend the use of hydroxychloroquine/chloroquine ± azithromycin, lopinavir/ritonavir, corticosteroids, tocilizumab, and CP as a treatment for COVID-19 infection outside the context of a clinical trial.

Prophylaxis (Indian Council of Medical Research National Taskforce Recommendation)

1. Asymptomatic health-care workers involved in the care of suspected or confirmed cases of COVID-19:

   tablet hydroxychloroquine 400 mg twice a day on day 1, followed by 400 mg once weekly for the next 7 weeks

2. Asymptomatic household contacts of laboratory-confirmed cases:

   tablet hydroxychloroquine 400 mg twice a day on day 1, followed by 400 mg once weekly for the next 3 weeks[20]

Contraindications

Hydroxychloroquine is contraindicated in children below 6 years and patients with preexisting retinopathy.

Monitoring

A baseline electrocardiogram should be done to rule out congenital/acquired long QT syndrome and second- or third-degree atrioventricular blocks. Electrolyte imbalances (hypokalemia/hypomagnesemia/hypocalcemia) must be corrected before starting hydroxychloroquine.

Side effects

Hydroxychloroquine can cause hypoglycemia,[21] QTc prolongation, and torsades de pointes that can lead to fatal ventricular arrhythmia[22] or cardiomyopathy.[23]

Is there evidence to support hydroxychloroquine prophylaxis?

Anin vitro study showed hydroxychloroquine to be more potent than chloroquine in inhibiting COVID-19 infection.[24] A phase 3 RCT from Columbia University comparing hydroxychloroquine prophylaxis with placebo for household contacts of index cases with an estimated sample size of 1600 is planned.[25] The hydroxychloroquine prophylaxis is debatable given the inadequate evidence to support, potentially fatal side effects due to QTc prolongation, risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, and a possible shortage of hydroxychloroquine for patients with malaria, rheumatoid arthritis, and systemic lupus erythematosus.[26]

Prevention

Vaccine

Vaccines are a crucial component for COVID-19 prevention as there is rapid clinical deterioration and no effective treatment. Currently, m-RNA and nucleic acid-based vaccine clinical trials against COVID-19 infection are ongoing.[27]

World Health Organization – Solidarity trial

This trial randomizes patients with COVID-19 infection to either local standard of care or local standard of care plus one of the four experimental therapies (remdesivir, chloroquine or hydroxychloroquine, lopinavir + ritonavir, lopinavir + ritonavir + interferon beta-1a). Currently, the Canadian arm is recruiting patients for the treatment with lopinavir + ritonavir, and Norwegian arm is recruiting patients for the treatment with remdesivir or hydroxychloroquine.

Conclusion

Currently, the appropriate prevention, prophylaxis, and treatment of COVID-19 infection are largely unknown. Symptomatic supportive care with active participation in clinical trials is encouraged. We await the results of many ongoing RCTs to guide us in the prevention and management of COVID-19 infection [Table 2] and [Table 3].

Ongoing phase 3 clinical trials

Anticancer clinical trials for COVID-19 infection

References

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Address for correspondence

Publication History

Received: 25 April 2020

Accepted: 01 May 2020

Article published online:
17 May 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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