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Immunomodulation Therapy in Severe COVID-19 Infection: Where Do We Stand?


This CHEST series highlights specific studies in the COVID-19 literature that may warrant discourse or reading for members of the chest medicine community. Articles are written by members of CHEST Networks. You can read additional articles in this series.

NOTE: The perspectives shared in this article are those of the author(s) and not those of CHEST.

Immunomodulation Therapy in Severe COVID-19 Infection: Where Do We Stand?

By: Damaris E. Pena Evertz, MD, and Bharat Bajantri, MD
Clinical Research and Quality Improvement Network

Published: June 15, 2021

Immunomodulation in severe COVID-19 plays a pivotal role in the disease process.  As such, immunomodulation therapy has been utilized in several studies to treat patients with COVID-19.


The RECOVERY trial (n = 6000) was a large, randomized controlled trial (RCT) showing that dexamethasone, at a dose of 6 mg for 10 days, reduced 28-day mortality in patients with COVID-19 who were receiving either invasive mechanical ventilation or supplemental oxygen. However, no benefit was seen in patients without hypoxemia, with the results suggesting potential harm with steroids in this group.1

Although data are strongest for the use of dexamethasone, the ideal dose and duration of therapy is still unknown. When adjusting the dose of steroids and duration of treatment, it may be reasonable to follow inflammatory markers like C-reactive protein (CRP) and the acuity of the clinical illness.2

Whether the benefits of glucocorticoids are unique to dexamethasone or are a class effect also is not known. Recently, a small RCT demonstrated decreased length of hospital stay and need for mechanical ventilation in patients receiving methylprednisolone as compared with dexamethasone.3 Methylprednisolone is known to attain high concentrations in the lungs, but the lack of mineralocorticoid action with dexamethasone may help keep the lungs dry. In addition, the longer half-life of dexamethasone makes tapering less cumbersome.3,4

IL-6 Inhibitors

A combination of steroids with interleukin-6 (IL-6) inhibitors, such as tocilizumab, may further enhance immunomodulation, as demonstrated by the REMAP-CAP and RECOVERY trials. This combination has been shown to reduce mortality and improve overall efficacy compared with steroids alone. The most beneficial effect appears to be in patients with a significant inflammatory phase, as evidenced by elevated CRP levels.1,5

The ideal time for tocilizumab dosing is uncertain. In REMAP-CAP, patients had to be enrolled within 24 hours of starting respiratory or cardiovascular organ support in the ICU. In RECOVERY, patients were eligible to receive one to two doses of tocilizumab up to 21 days from hospitalization, with outcomes showing no relationship with the timing of the study drug. We can hypothesize that physiology, rather than timing of the dosing, is the more important feature in deciding whether to administer an IL-6 inhibitor, but further data are needed.

IL-6 inhibitors were not as effective when used as monotherapy in combination with steroids. These findings reflect the anti-inflammatory action of glucocorticoids on many inflammatory pathways, in contrast to IL-6 inhibitors.5

Steroids and JAK Inhibitors

The combination of steroids and Janus kinase (JAK) inhibitors (ie, baricitinib) also has been proposed early in illness based on the suggestion that it might decrease mortality and rate of intubation; however, there is presently limited evidence to support its use. It would be reasonable to assume that this combination may be prudent in moderate or severe COVID-19 infections, as JAK inhibitors intrinsically inhibit cytokines IL-6 along with IFN-γ (JAK1/2), IL-10, and IFN-α (JAK1/TYK2). The ACTT-2 trial showed that combining remdesivir and JAK inhibitors decreased the need for intubation and reduced recovery time. The use of glucocorticoids was explicitly prohibited early in the trial. However, they were administered in 20% of the patients enrolled in the study for other medical reasons (eg, asthma, laryngeal edema).6,7

Convalescent Plasma

Although one randomized trial showed that early administration of high-titer convalescent plasma in older adults with mild COVID-19 reduced disease progression, multiple randomized controlled trials have shown that convalescent plasma has no benefit.8 Inpatients are already in a phase of illness where their viremia is probably dropping, and they have already started to develop antibodies.

Monoclonal Antibodies

This may also explain why monoclonal antibodies are unlikely to be useful in the later or more severe phases of illness. When administered in patients with milder disease early in the disease process, REGN-COV2, an antibody cocktail that neutralizes human IgG1 antibodies targeting the receptor binding domain of SARS-COV-2 spike protein, and LY-CoV555, an anti-spike neutralizing monoclonal antibody, showed a rapid, significant decrease in viral load. These findings potentially can improve clinical outcomes in patients with early COVID-19 infection since higher viral loads have been associated with poor outcomes and an increased risk of death in hospitalized patients.1,9

The SOLIDARITY trial, with more than 11,000 patients, showed that remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had no effect on hospitalized patients with COVID-19 infection, as indicated by overall mortality, initiation of mechanical ventilation, and duration of hospital stay.10 This study was limited by a lack of blinding, however, in addition to wide variations in the standards of care in its participating sites, limiting the generalizability of the trial despite its size.

It is imperative for future studies to focus on the appropriate timing of these and other immunomodulatory interventions to ensure maximum therapeutic effects.


  1. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704. Preprint. Posted online July 17, 2020. PMID: 32678530; PMCID: PMC7383595. doi:10.1056/NEJMoa2021436
  2. Tomazini BM, Maia IS, Cavalcanti AB, et al; COALITION COVID-19 Brazil III Investigators. 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. 2020;324(13):1307-1316. PMID: 32876695; PMCID: PMC7489411. doi:10.1001/jama.2020.17021
  3. Ranjbar K, Moghadami M, Mirahmadizadeh A, et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis. 2021;21(1):337. doi:10.1186/s12879-021-06045-3
  4. Vichyanond P, Irvin CG, Larsen GL, et al. Penetration of corticosteroids into the lung: evidence for a difference between methylprednisolone and prednisolone. J Allergy Clin Immunol. 1989;84(6 pt 1):867-873. PMID: 2600321. doi:10.1016/0091-6749(89)90381-3
  5. Gordon AC, Mouncey PR, Al-Beidh F, et al; REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491-1502. Preprint. Posted online February 25, 2021. PMID: 33631065; PMCID: PMC7953461. doi:10.1056/NEJMoa2100433
  6. Horby PW, Pessoa-Amorim G, Peto L, et al; RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;397(10285):1637-1645. doi:10.1101/2021.02.11.21249258
  7. Kalil AC, Patterson TF, Mehta AK, et al; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795-807. Preprint. Posted online December 11, 2020. PMID: 33306283; PMCID: PMC7745180. doi:10.1056/NEJMoa2031994
  8. Libster R, Pérez Marc G, Wappner D, et al; Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610-618. Preprint. Posted online January 6, 2021. PMID: 33406353; PMCID: PMC7793608. doi:10.1056/NEJMoa2033700
  9. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-251.
  10. Pan H, Peto R, Henao-Restrepo AM, et al; WHO Solidarity Trial Consortium. Repurposed antiviral drugs for Covid-19 - interim WHO Solidarity trial results. N Engl J Med. 2021;384(6):497-511. Preprint. Posted online December 2, 2020. PMID: 33264556; PMCID: PMC7727327. doi:10.1056/NEJMoa2023184

Damaris Pena Evertz, MD

Damaris E. Pena Evertz, MD

Dr. Pena Evertz is is a Pulmonary and Critical Care Physician at AdventHealth Sebring.

Bharat Bajantri, MD

Bharat Bajantri, MD

Dr. Bajantri is a Pulmonary and Critical Care Physician at Parkview Regional Medical Center.

Read more COVID in Focus: Perspectives on the Literature:

Safety of Bronchoscopy During the COVID-19 Pandemic: An Update

Proning in COVID-19 Patients

Pulmonary Vasculopathy and Thrombosis in Patients With COVID-19