Efficacy of povidone-iodine nasal rinse and mouth wash in COVID-19 management: a prospective, randomized pilot clinical trial (povidone-iodine in COVID-19 management)

The COVID-19 pandemic has changed the environment in which medicine is practiced. Efforts to minimize the viral spread have concentrated on implementing physical barriers. However, the oropharynx and nasopharynx have a high viral load, and decontamination of these areas could play an important role in improving the disease condition and decreasing transmission of the virus. The value of PVP-I in the inactivation of SARS-CoV-2 was previously proven in vitro. Two different studies indicated that a 0.5% solution was sufficient for virus inactivation [14, 15]. Frank et al. proved that contact for as little as 15 s is effective. No cytotoxic effects were observed at any concentration or duration of contact in either study [16, 17]. However, we selected the lowest effective concentration of PVP-I studied in vitro against SARS-CoV to establish the safest and most tolerable concentration for use in the PVP-I nasal route [18].

In our study, we found a significantly higher rate of SARS-CoV-2 clearance in the PVP-I group, represented by lower detectability duration in nasopharyngeal swab samples, compared to the NS and control groups. To our knowledge, the concentration of PVP-I used in this study (0.23%) is lower than that used in any other published studies against SARS-CoV-2, and our findings are consistent with those of several other clinical trials [19‐25]. In addition, we studied the long-term and continuous effect of PVP-I (up to 18 days) on virus survival. We observed that continuous exposure to PVP-I—even at low concentrations—can decrease the duration of virus detectability and viral load more than exposure to NS and no intervention. These findings align with those of a meta-analysis that studied different types of nasal rinses and mouth washes used against SARS-CoV-2 and included 22 in vitro studies and 11 in vivo studies. Among the in vivo studies, PVP-I was the most studied solution and was found to be the most effective regardless of concentration, with a Log₁₀ reduction value of nearly 3. The results of the in vivo studies were consistent with those of the in vitro studies, with PVP-I displaying the highest mean reduction in viral load (0.86) among all the tested solutions [14].

Ct values determined using RT-PCR represent the number of amplification cycles required for a target gene to exceed a threshold level. Ct values are therefore inversely related to viral load, and measuring Ct values can be an indirect method for quantifying viral RNA copy number in a sample. A systematic review by Rao et al. concluded that a low Ct may be a useful tool for predicting disease severity and prognosis in patients with COVID-19 [26]. In our study, the use of PVP-I resulted in an increase in Ct values, which suggests that it contributed to a decline in the disease severity and an improvement in the prognosis. Also, a minor increase of Ct values was observed in control group. The use of NS resulted in a decrease in Ct values. However, these changes were not statistically significant.

The efficacy of COVID-19 vaccines is continuously under threat because new variants of the causative agent, SARS-CoV-2, are constantly arising. Additionally, the influenza virus exhibits antigenic drift and shift, which means that there is a constant need to update the composition of the inactivated influenza vaccines [27]. Therefore, there is also a need to develop effective and accessible treatments for a range of viruses that threaten human health, such as nasal rinses and mouth washes. PVP-I was tested in an in vitro study against severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), rotavirus strain Wa, and influenza virus A subtype H1N1, and it was found that PVP-I at a concentration of 0.23% rapidly inactivated all the viruses after 15 s of exposure [28]. These data support further study and use of topical PVP-I against different types of upper respiratory tract viruses that share similar pathophysiology with COVID-19.

PVP-I is considered to be safe for use in the nose and on the oral mucosa. Frank et al. concluded in their review that PVP-I can be safely used at concentrations of up to 1.25% and 2.5% for the oral and nasal cavities, respectively [18]. In a study of 12 patients who used mouth washes containing 5% PVP-I, it was found that all the patients had an increase in the level of thyroid stimulating hormone (TSH), with five having levels that exceeded the normal limit. However, no alterations in triiodothyronine or thyroxine were noted [29]. In another study, conducted by Guenezan et al., patients who used solutions containing 0.5% PVP-I reported local side effects described as nasal tingling [30]. In our study, no patient reported any nasal discomfort after PVP-I usage. This might be explained by the low concentration of 0.23%. TSH levels were not measured before and after intervention. However, no patients reported any symptoms of hypothyroidism.

Arakeri et al. suggested that 0.5% PVP-I showed an inhibitory effect on leukotriene B4 and leukocyte extravasation (chemotaxis), which resulted in an anti-edematous effect in a clinical trial conducted after tooth extraction [31]. In contrast, two other clinical trials found no significant differences in the SNOT-22 scores of patients with chronic rhinosinusitis after endoscopic nasal surgery who used or did not use 0.1% PVP-I [32, 33]. Additionally, Zarabanda et al. found a more favorable course of improvement in UPSIT scores and olfaction among COVID-19 patients who used PVP-I nasal rinses (0.5% and 2%) compared to the placebo group. However, their findings did not result in statistical significance between the groups [25]. These findings are similar to ours, as we did not find a significant difference between the PVP-I and control groups in terms of symptom severity and quality of life. This might be due to the lower dose of PVP-I used in our study compared to that used by Arakeri et al. Another factor that could explain this is that participants included in this study had received at least one vaccine dose. As has been proven in multiple trials, different types of vaccines significantly decrease the severity of COVID-19 symptoms [34].

Although the findings of this study are encouraging, several limitations should be noted. First, RT-PCR and Ct values were used as markers for viral survival and viral load, and these have limitations in their capacity to detect virus viability compared to viral culture [35]. Second, we faced recruitment difficulties. These included but were not limited to the emergence of COVID-19 home tests, which decrease the detectability of infected people. Also, recently, people have lost interest in being diagnosed and receiving any intervention for COVID-19 [36]. Third, as the pattern of COVID-19 infection occurs as waves, the availability of laboratory facilities for research is compromised when cases are high. Therefore, more studies with larger sample sizes are warranted, as is the use of viral culture methods and standardization of the timing and the sample population.