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. 2024 Feb 9:69:102472.
doi: 10.1016/j.eclinm.2024.102472. eCollection 2024 Mar.

Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials

Ilias I Siempos  1   2 , Andre C Kalil  3 , Drifa Belhadi  4   5 , Viviane Cordeiro Veiga  6   7 , Alexandre Biasi Cavalcanti  7   8 , Westyn Branch-Elliman  9   10 , Eleni Papoutsi  1 , Konstantinos Gkirgkiris  1 , Nikoleta A Xixi  1 , Anastasia Kotanidou  1 , Olivier Hermine  11 , Raphaël Porcher  12 , Xavier Mariette  13 ; CORIMUNO-19 Collaborative Group; DisCoVeRy Study Group; ACTT-2 Study Group; ACTT-3 Study Group
Collaborators, Affiliations

Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials

Ilias I Siempos et al. EClinicalMedicine. .

Abstract

Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19.

Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care).

Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality.

Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19.

Funding: Hellenic Foundation for Research and Innovation.

Keywords: Acute hypoxemic respiratory failure; Acute respiratory distress syndrome; Cancer; Critically ill; Pneumonia.

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Conflict of interest statement

ACK was investigator for the National Institutes of Health Adaptive COVID-19 Treatment Trial. WBE was the site Principal Investigator for a therapeutics study funded by Gilead Sciences (funds to institution) during the past three years. WBE also reports grant funding support from the VA Health Services Research and Development Service (VA HSRD IIR 20-101, 20-076) and from the VA National Artificial Intelligence Institute. OH reports research funds from Roche. The remaining authors (IIS, DB, VCV, ABC, EP, KG, NAX, AK, RP, XM) report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Study flow diagram.
Fig. 2
Fig. 2
Risk of bias assessment of included randomized controlled trials. Risk of bias for the primary outcome of the meta-analysis (namely, all-cause 28-day mortality) was assessed using the “Cochrane Risk of Bias tool for randomized trials (RoB 2)”. The tool consisted of five domains: 1) the randomization process, 2) the deviations from the intended interventions, 3) the missing outcome data, 4) the measurement of the outcome, and 5) the selection of the reported results. Each domain had up to seven questions. The green circles represent “low risk of bias”, the yellow circles represent “some concerns”, and the red “high risk of bias”.
Fig. 3
Fig. 3
Comparison of immunocompromised patients with COVID-19 randomized to immunomodulators vs control in terms of (A) all-cause 28-day mortality, (B) secondary infections, and (C) change in ordinal scale from baseline to day 15. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random-effects model.
Fig. 4
Fig. 4
All-cause 28-day mortality of immunocompromised patients with COVID-19 randomized to immunomodulators vs control in the subgroup analyses (A) including only immunocompromised patients with hematologic malignancy, (B) including only trials with low risk of bias, (C) including only trials administering IL-6 inhibitors, and (D) including only trials administering immunosuppressants. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random-effects model.
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