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Clinical Context

Some studies have shown that interferon (IFN) treatment in COVID-19 may shorten duration of viral shedding, alleviate symptoms, and reduce cytokine responses, mortality, and intensive care unit (ICU) admission; however, long-term IFN treatment in multiple sclerosis may cause incident thyroid dysfunction and autoimmunity.

Study Synopsis and Perspective

Treatment of COVID-19 with IFN β-1b even for just a few days -- a much shorter period than is commonly used for maintenance in multiple sclerosis (MS), for example -- is associated with potentially important adverse effects on thyroid function, according to research presented at the virtual 90th Annual Meeting of the American Thyroid Association.^[1]

"Our study is the first to report on the impact of [IFN] treatment on the thyroid in the context of COVID-19," first author David T.W. Lui, MBBS, of the department of medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, told Medscape Medical News.

"If short courses of [IFN] treatment become a standard therapy for COVID-19, the modest changes detected thus far may indicate a phenomenon of clinical importance," he noted.

"As for now, our findings suggest that clinicians monitor the thyroid function and antithyroid antibodies [(ATAs)] among [IFN]-treated COVID-19 survivors and call for further follow-up studies regarding the clinical significance of these changes," added Lui.

The study, also published in Frontiers in Endocrinology,^[2] involved 226 patients in Hong Kong who were treated for COVID-19 and had no known prior thyroid disorders.

Among those patients who received treatment with IFN, there were significant increases in ATAs, including anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) at 3 months compared with baseline whereas no similar increases were observed among those patients not receiving IFN treatment.

In a multivariate analysis, treatment with IFN was found to be independently associated with more than 5 times greater odds of having a significant increase in anti-TPO titers at 3 months vs no IFN treatment (adjusted odds ratio [aOR] = 5.73 [95% CI: 1.46, 22.5]; P = .031).

"Interferon treatment for COVID-19, even for a short duration of a few days, could induce significant, though modest, increases in [ATA] titers," Lui reiterated.

Previous studies evaluating the effects of IFN on thyroid function in patients with MS have shown that up to 33% of patients developed thyroid dysfunction and 20% developed thyroid autoimmunity, particularly during the first year of treatment, Lui and coauthors noted in their study.

Although the patients in the current study did not become symptomatic, the changes nevertheless could be indicative of further dysfunction and are important enough to warrant follow-up, Lui noted.

"Despite a modest magnitude of anti-TPO titer elevation among patients who developed incident anti-TPO positivity, further follow-up is warranted for potential subsequent thyroid dysfunction as the occurrence of anti-TPO can precede thyroid dysfunction," he noted.

Interferon, a potent antiviral and anti-inflammatory agent, is well-established in the treatment of MS, often used over months or years as a maintenance therapy, and the drug has been repurposed in the age of COVID-19, where it has shown benefit as a much shorter-term, higher-dose treatment of just a few days, with benefits observed especially when initiated in the initial stages of infection.

With increasing reports of thyroid effects after COVID-19, in general, and known previous reports of incident thyroid dysfunction also associated with the use of interferon in MS, Lui and colleagues sought to evaluate whether IFN treatment for COVID-19 affected thyroid function.

The study's 226 patients were treated at Queen Mary Hospital, in Hong Kong, for COVID-19 between July 2020 and January 2021. They were a median age of 55 years, and about half were men.

A large majority (68.6%) of the COVID-19 cases were mild, 27% were moderate, and 4.4% were severe.

Among the patients, 135 (59.7%) received treatment with IFN for a median duration of 5 (range, 1-15) days at a dose of 16 million IU/d, and 16.4% required dexamethasone.

Of note, patients treated with IFN had a higher SARS-CoV-2 viral load and more lymphopenia upon admission, and as ribavirin was given in combination with IFN, the IFN-treated patients were more likely to also be treated with that drug.

Overall, those patients treated with IFN showed a tendency toward having more abnormal function tests upon reassessment after 3 months (8.1% vs 2.2%; P = .08).

In a further evaluation of 179 patients who had full details on ATAs, persons who were treated with IFN (65.4%) showed significant increases in median anti-TPO levels, from 29.21 U at baseline to 34.3 U (P < .001) at the 3-month reassessment.

Likewise, the IFN-treated patients had median increases in anti-Tg titers, from 8.23 U at baseline to 9.14 U at reassessment (P = .001).

There were meanwhile no similar significant changes in those measures among patients not treated with IFN.

Of the 179 patients, 143 were negative for anti-TPO at baseline, and 22 of these patients had significant interval increases in anti-TPO titers, defined as > 12 U, after 3 months.

Eight of these patients fully switched from being anti-TPO negative to positive, nearly all of whom (n = 7) were IFN-treated, with just one being interferon-naive.

There were no significant differences in disease severity, viral load, or lymphopenia between patients who did and did not have significant increases in anti-TPO titers, Lui noted.

Aside from IFN treatment, other factors found in the multivariate analysis to be independently predictive of higher odds of having a significant increase in anti-TPO titers at 3 months included baseline C-reactive protein (CRP) levels (aOR = 1.59 [95% CI: 1.04, 2.44]; P = .012) and higher baseline anti-TPO titers (aOR = 4.41 [95% CI: 1.85, 10.5]; P = .001).

Of note, the IFN-dosing regimen used in the study of 16 million IU/d contrasts with the usual lower regimen of 8 million IU every other day as a chronic therapy in MS.

"Intriguingly, even with such a short duration of [IFN] therapy, we still observed a 5.6% rate of incident anti-TPO positivity at 3 months, which correlated with a higher chance of abnormal thyroid function tests during convalescence," Lui and coauthors added.

Amid ongoing efforts to disentangle the links between COVID-19 and thyroid dysfunction, the findings suggest importance in also considering COVID treatment, Lui noted.

"The thyroid risk has not been evaluated for other COVID treatments," he said.

The authors have reported no relevant financial relationships.

Clinical Implications

• Interferon for COVID-19, even when used short-term, was associated with modest increases in ATA titers.
• Further follow-up studies are needed regarding the clinical significance of these changes.
• Implications for the Healthcare Team: Clinicians should monitor TFTs and ATAs among IFN-treated COVID-19 survivors.

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