Iodine increases pulmonary type I interferon responses and decreases COVID-19 disease severity: results from an open-label randomized clinical trial

Objective To investigate whether oral treatment with 12.5 mg iodine additional to standard of care is effective in reducing mortality and clinical deterioration of patients hospitalized with COVID-19.

We performed a single center, randomized clinical trial (EudraCT 2020-001852-16) in which patients with severe covid-19 in need of hospitalization were randomized in two groups. The first group received 12.5 mg oral iodine for 8 days, the second group did not receive iodine next to the standard of care. Primary endpoints were deterioration of disease defined as transfer from the ward to the intensive care unit (ICU) or death. Next to these parameters we collected parameters in line with the recommendations made by the WHO in the early days of the pandemic. On these additional datasets we performed an exploratory analysis and investigated possible confounders and trends. The inclusion phase of the study was between October 2020 and April 2022. Finally, in vitro validations were performed.

Outcomes from 141 participants were analyzed, revealing no significant differences in mortality or transfers to intensive care between the iodine-treated group (67 patients) and the control group (74 patients). In an exploratory analysis we found that patients randomized to receive oral iodine had a significantly shorter stay at the ICU (p=0.016). In vitro validations proved increased virus-induced type I interferon responses upon iodine administration in pulmonary cells.

These findings suggest that while iodine does not reduce mortality or ICU admissions, it may enhance antiviral immunity through increased type I interferon responses, contributing to shorter ICU stays in COVID-19 patients. The role of iodine in enhancing IFN-I mediated antiviral immunity warrants future research. Competing Interest Statement The authors have declared no competing interest. Clinical Trial EudraCT no. 2020-001852-16 Funding Statement This study has been performed with financial aid of the Maxima Medical Center Innovation Fund (date of registration: April 1st 2020), for which we are grateful. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the Declaration of Helsinki (EudraCT no. 2020-001852-16, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001852-16), and approved by the local ethical committee (METC Brabant, Netherlands no. NL73784.028.20). All participants provided written informed consent prior to inclusion. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Full anonymized data and analyses are available upon request from the corresponding author.