EDITORIAL

Immunomodulation and COVID-19: Is There a Winning

A b s t r ac t​
COVID-19 has been testing the boundaries of science on several fronts. Pharmacotherapy has seen the highs of several drugs being tried as the
best option as well as the lows of no drug proven to be effective. In this edition of the IJCCM, Mahale and colleagues retrospectively evaluated
a combination of drugs targeted at immunomodulation.
Keywords: COVID-19, Immunomodulation, SARS-CoV-2, Tocilizumab.
Indian Journal of Critical Care Medicine (2020): 10.5005/jp-journals-10071-23691

Ever since the COVID-19 pandemic broke out in December last year,
several strategies to improve the patient outcome have been tried Department of Critical Care, Virinchi Hospital, Hyderabad, Telangana,
with varied results. The exact mechanism of pathogenesis and India
the consequences thereof associated with SARS-CoV-2 infection Corresponding Author: Srinivas Samavedam, Department of Critical
are yet to be completely and correctly understood. A four-stage Care, Virinchi Hospital, Hyderabad, Telangana, India, Phone: +91
classification system starting with early infection (stage I) through 8885543632, e-mail: [email protected]
to multiorgan failure (stage IV) has been proposed as a reasonable How to cite this article: Samavedam S. Immunomodulation and
method to understand the disease.1,2 Stage II seems to characterize COVID-19: Is There a Winning Combination? Indian J Crit Care Med
the hyperresponsiveness of the immune system. This is the stage in 2020;24(11):1015–1017.
which hypoxia and systemic inflammation appear to be dominant. Source of support: Nil
Intervention at this stage could help in limiting progression to more Conflict of interest: None
advanced stages. Elevated levels of pro-inflammatory cytokines
seem to be the feature of this stage. The so-called cytokine storm
or cytokine release syndrome (CRS) is a consequence of the release for the use of HCQ as a therapeutic agent for SARS-CoV-2 has
of these pro-inflammatory cytokines. 3–5 Neutralizing the effect emerged.16
of cytokines by blocking the receptors or the signal transduction Glucocorticoids have been used for managing many acute
appears to be an option. inflammatory and autoimmune disorders.17 This effect of
Non-specific immunomodulation with corticosteroids, glucocorticoids seems to be mediated by direct and indirect
interferons, macrolides, or hydroxychloroquine (HCQ) has been effects on gene expression as well as receptor-mediated effects.
attempted. The combination that is likely to confer the greatest Moderate doses of corticosteroids in hypoxemic patients seem to
benefit is yet to be identified (except for a benefit with the use be of some benefit.
of steroids6–8). In this edition of the IJCCM, Mahale et al. have The potent anti-inflammatory medication, colchicine, inhibits
attempted to correlate retrospectively, the effect of a combination the polymerization of microtubes and acts through cellular
of immunomodulatory agents on COVID-19 severity and outcome. adhesion molecules and inflammatory chemokines.18 It is therefore
Interleukin-1 receptor antagonists like Anakinra were proven a potential agent to counter the CRS. The evidence for colchicine
to be effective in macrophage activation syndrome.9 This raises the has been negative so far.19
possibility of a role for Anakinra in the severe COVID-19 infection. Mahale and colleagues evaluated several combinations of
Several observational studies10–12 have established a benefit in therapies targeted at COVID-19. The combinations studied included
terms of improved clinical and biological markers with the use HCQ, steroids, colchicine, and TCZ in various permutations.
of Anakinra. No major controlled trial has been published yet to Methylprednisolone was the common steroid used in this cohort.
substantiate these observations. Among the various steroids used and evaluated for COVID-19,
Interleukin-6 receptor antagonists like tocilizumab (TCZ) dexamethasone seemed to have the highest benefit, especially
have also been hypothesized to be of benefit in the management among hypoxic patients. 6 –8 The inclusion criteria for this
of severe COVID-19. Although initial data emerging from China retrospective study included oxygen requirements. This would
seemed to indicate a benefit with the use of TCZ,13,14 subsequent suggest that the patients included would be in stage II as discussed
large randomized trials have failed to establish benefit.15 earlier. In this predominantly male cohort, nearly half the patients
Coincidental immunomodulators like HCQ, corticosteroids, were either diabetic or hypertensive. This group had lower PaO2/
macrolides, and colchicine have also be en evaluate d. FiO2 values and consequently needed more oxygen than those
Hydroxychloroquine is thought to act by altering the cell without the twin comorbidities. A notable observation from the
membrane pH needed for viral fusion. Despite a large number data is that a small proportion of patients were actually tested for
of trials evaluating this intervention, no conclusive support the markers of inflammation—IL-6, ferritin, and D-dimer. Since the

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.
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Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
 Immunomodulation and COVID-19: Is There a Winning Combination?

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TCZ and etoricoxib is too small to draw any inference. Rabbani et al.20 4. Wong CK, Lam CWK, Wu AKL, Ip WK, Lee NLS, Chan IHS, et al. Plasma
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