Oral and nasal application of antiseptics has been proposed as a control measure for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both as prophylaxis to prevent infections and to reduce the risk of transmission by decreasing the viral burden in infected patients. ^{Reference Lim, Teng, Ng, Bao, Tambyah, Quek and Seet1} Povidone iodine is a promising agent for nasal and oral antisepsis because it has potent in vitro activity against SARS-CoV-2¹ and because it has prolonged activity as demonstrated by suppression of methicillin-resistant Staphylococcus aureus (MRSA) in nares for at least 6 hours. ^{Reference Ghaddara, Kumar, Cadnum, Ng-Wong and Donskey2} In a randomized trial, povidone iodine prophylaxis for 42 days significantly reduced SARS-CoV-2 infection. ^{Reference Seet, Quek and Ooi3} Prior to procedures, povidone iodine mouthwashes have been demonstrated to provide effective short-term suppression of SARS-CoV-2 in saliva. ^{Reference Garcia-Sanchez, Peña-Cardelles and Ordonez-Fernandez4–Reference Fantozzi, Pampena and Pierangeli7} For example, a 60-second oral gargle with 0.5% povidone iodine suppressed levels of SARS-CoV-2 RNA in saliva of coronavirus disease 2019 (COVID-19) patients for up to 45 minutes. ^{Reference Chaudhary, Melkonyan and Meethil5} Limited information is available on whether povidone iodine suppresses SARS-CoV-2 for longer durations. Here, we tested the hypothesis that povidone iodine nasal solution and gargle would be effective in reducing nasal and oral SARS-CoV-2 RNA levels 8 hours after dosing in patients with acute COVID-19 infection.

The study protocol was approved by the Cleveland VA Medical Center’s Institutional Review Board. Between November 1, 2020, and April 26, 2021, we conducted a nonblinded, randomized pilot trial to compare the effectiveness of 3 doses of intranasal and oral povidone iodine administered at time 0 (initial dose) and 8 and 16 hours after the initial dose versus a phosphate-buffered saline control in reducing the burden of SARS-CoV-2 RNA in the nares and oropharynx of a convenience sample of patients with COVID-19. The intranasal povidone iodine was a 10% solution (Povidone Iodine SwabSticks, Medline, Northfield, IL) and the oral povidone iodine was a 1% gargle (betadine solution with 10% povidone iodine diluted to 1% solution (Povidone Iodine Prep Solution, U.S.P., Dynarex, Orangeburg, NY)). The initial and 8-hour treatments were observed by research personnel, and the third treatment was administered by the participants themselves. Patients were excluded if they had dementia or delirium, were admitted to the intensive care unit, and if >3 days had passed since their COVID-19 diagnosis. Patients were randomized using block randomization.

Research personnel used premoistened CLASSIQSwabs with universal transport medium (Copan Diagnostics, Murrieta, CA) to collect samples from the anterior nares and from the oropharynx immediately before the initial dose, just prior to the second dose, and 8 hours after the third dose (24 hours after the initial dose). Medical records were reviewed for information on age, sex, and COVID-19 treatments. Reverse-transcription quantitative polymerase-chain reaction (RT-qPCR) was used to assess the burden of viral RNA. ^{Reference Redmond, Li and Haq8,Reference Jones, Chan and Zabarsky9}

To compare characteristics of the 2 groups, the Student t test was used for continuous variables and the Fisher exact test was used for categorical variables. Given repeated measures within subject and some unbalanced data (missing times within subjects), we used mixed-effects linear regression models with random effects for subject, focusing on the interaction of treatment (povidone iodine versus saline) and time. Models were run separately for anterior nares and oropharynx. This analysis was performed using R version 4.1.3 statistical software (R Foundation for Statistical Computing, Vienna, Austria) using functions from the nlme package. Participants were questioned about adverse reactions to treatment including nasal or oral irritation, nasal discharge, and respiratory symptoms.

Of 22 patients enrolled, 12 were randomized to the povidone iodine group and 10 to the control group. Two patients in each group were excluded from the analysis because they did not have 1 or more posttreatment samples available for analysis. For the 18 subjects included in the analysis, the povidone iodine and control groups did not differ in age (mean, 65.1 y and 56.6 y, respectively; P = .2), female sex [3 (30%) of 10 and 1 (12.5%) of 8, respectively (P = .6)], or frequency of requirement for supplemental oxygen and treatment with dexamethasone and/or remdesivir at the time of enrollment [5 (50%) of 10 and 4 (50%) of 8, respectively (P = 1)].

As shown in Figure 1, SARS-CoV-2 cycle thresholds (C_t values) were similar in the povidone iodine and control groups before treatment. After initiation of treatment, there was no significant difference in C_t values of nasal or oropharyngeal swab samples for the povidone iodine versus control subjects (P ≥ .66). No adverse effects of treatment were reported.

Fig. 1. Effect of intranasal and oral application of povidone iodine versus phosphate-buffered saline administered at time 0 (initial dose) and 8 and 16 hours after the initial dose on nasal (A) and oropharyngeal (B) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA. Anterior nares and oropharynx swabs were collected before the initial dose, just prior to the second dose, and 8 hours after the third dose (24 hours after the initial dose). Error bars show standard error. Cycle threshold (C_t) values were measured by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR).

Oral application of povidone iodine has been shown to provide short-term suppression of SARS-CoV-2 RNA in saliva. ^{Reference Garcia-Sanchez, Peña-Cardelles and Ordonez-Fernandez4,Reference Chaudhary, Melkonyan and Meethil5} However, in the current study, oral and nasal application of povidone iodine did not reduce the burden of oral and nasal SARS-CoV-2 RNA in oral and nasal samples collected 8 hours after dosing. These results suggest that nasal and oral application of povidone iodine may not provide prolonged reductions in the burden of SARS-CoV-2. Guenezan et al ^{Reference Guenezan, Garcia, Strasters, Jousselin, Lévêque, Frasca and Mimoz10} similarly reported that povidone iodine treatment 4 times daily for 5 days did not reduce viral RNA measured by RT-qPCR.

Our study had several limitations. We only assessed the impact of treatment 8 hours after dosing. We did not perform viral cultures, and we cannot exclude the possibility that povidone iodine treatment suppressed viable SARS-CoV-2 but not viral RNA. Future studies are needed to assess more frequent dosing intervals and to determine whether povidone iodine reduces the recovery of culturable virus culture. Our study did not address the impact of povidone iodine treatment on acquisition of SARS-CoV-2. Additional studies are needed to determine whether povidone iodine treatment provides sufficient activity to prevent infection with SARS-CoV-2.