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Other Immunomodulators

Last Updated: May 12, 2020

Interferons (Alfa, Beta)

Recommendation:

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of interferons for the treatment of COVID-19, except in the context of a clinical trial (AIII).

Rationale for Recommendation

Studies have shown that there was no benefit when interferons were used in patients with other coronavirus infections (i.e., severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]), and the significant toxicities of interferons outweigh the potential for benefit. In addition, there is a lack of clinical trial results for patients with COVID-19.

Rationale for Use in Patients with COVID-19

Interferons, a family of cytokines with antiviral properties, have been suggested as a potential treatment for COVID-19 because of their in vitro and in vivo antiviral properties.

Clinical Data for COVID-19

Interferon-beta used alone and in combination with ribavirin in patients with SARS and MERS has failed to show a significant positive effect on clinical outcomes.1-5

In a retrospective observational analysis of 350 critically ill patients with MERS2 from 14 hospitals in Saudi Arabia, mortality rates were higher among patients who received ribavirin and interferon (beta-1a, alfa-2a, or alfa-2b) than among those who did not receive either drug.

A randomized clinical trial that included 301 patients with acute respiratory distress syndrome6 found that, compared to placebo, intravenous interferon beta-1a had no benefit as measured by ventilator-free days over a 28-day period (median of 10.0 days vs. 8.5 days) or mortality (26.4% vs. 23.0%).

Interferon-alfa-1b, which is not available in the United States, has been used in patients with COVID-19 in China, but it has been primarily used by atomization inhalation, and the clinical data have not yet been presented.

Adverse Effects

The most frequent adverse effects of interferon-alfa include flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities (cytopenias), elevated transaminases, and psychiatric problems (depression and suicidal ideation). Interferon-beta is better tolerated than interferon-alfa.

Drug-Drug Interactions

The most serious interactions with interferons are the potential for added toxicity with other immunomodulators and chemotherapeutic agents.

Considerations in Pregnancy

Data from several large pregnancy registries did not demonstrate an association between exposure to interferon-beta-1b preconception or during pregnancy and an increased risk of adverse birth outcomes (e.g., spontaneous abortion, congenital anomaly), and exposure did not influence birth weight, height, or head circumference.

Considerations in Children

There are limited data on the use of interferons for the treatment of respiratory viral infections in children.

Janus Kinase Inhibitors (e.g., Baricitinib)

Recommendation:

  • The Panel recommends against the use of Janus kinase (JAK) inhibitors (e.g., baricitinib) for the treatment of COVID-19, except in the context of a clinical trial (AIII).

Rationale for Recommendation

At present, the broad immunosuppressive effect of JAK inhibitors outweighs the potential for benefit.

Baricitinib is an oral JAK inhibitor that works by inhibiting the JAK signal transducer and activator of transcription pathway. Baricitinib is approved by the Food and Drug Administration to treat rheumatoid arthritis and can ameliorate the chronic inflammation seen in interferonopathies.7-9

Rationale for Use in Patients with COVID-19

Baricitinib is a potent anti-inflammatory with activity against interferon-associated inflammation. It has also been postulated to have an antiviral effect. A related drug, ibrutinib, has been shown to decrease lung inflammation in a mouse model of influenza.10,11

Clinical Data for COVID-19

No clinical data has been reported to date.

Adverse Effects

Side effects have been observed with prolonged use, including upper respiratory infections (>10% of patients), increased levels of low-density lipoproteins, herpesvirus infections, increased liver function test levels, and thrombocytosis.

Considerations in Pregnancy

In animal studies of embryo-fetal development, there was increased embryo lethality in some species that were given baricitinib at very high doses, well above the recommended dose for humans.12 The limited human data on the use of baricitinib are insufficient to evaluate the drug-associated risk for major birth defects or miscarriage.12

Corticosteroids

The role of corticosteroids as concomitant therapy in persons with COVID-19 is discussed in Considerations for Certain Concomitant Medications in Patients with COVID-19.

References

  1. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis. 2014;20:42-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24406736.
  2. Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and interferon therapy for critically ill patients with Middle East Respiratory Syndrome: a multicenter observational study. Clin Infect Dis. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31925415.
  3. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14985565.
  4. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25278221.
  5. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN- alfa2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother. 2015;70(7):2129-2132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25900158.
  6. Ranieri VM, Pettila V, Karvonen MK, et al. Effect of Intravenous Interferon beta-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32065831.
  7. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13):1243-1252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27028914.
  8. Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol. 2019;46(1):7-18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30219772.
  9. Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(1):88-95. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27689735.
  10. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32032529.
  11. Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400-402. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32113509.
  12. Baricitinib (OLUMIANT) [prescribing information]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207924s001lbl.pdf. Accessed: April 8, 2020.