Cell death and barrier disruption by clinically used iodine concentrations.

Povidone-iodine (PVP-I) inactivates a broad range of pathogens. Despite its widespread use over decades, the safety of PVP-I remains controversial. Its extended use in the current SARS-CoV-2 virus pandemic urges the need to clarify safety features of PVP-I on a cellular level. Our investigation in epithelial, mesothelial, endothelial, and innate immune cells revealed that the toxicity of PVP-I is caused by diatomic iodine (I2), which is rapidly released from PVP-I to fuel organic halogenation with fast first-order kinetics. Eukaryotic toxicity manifests at below clinically used concentrations with a threshold of 0.1% PVP-I (wt/vol), equalling 1 mM of total available I2 Above this threshold, membrane disruption, loss of mitochondrial membrane potential, and abolition of oxidative phosphorylation induce a rapid form of cell death we propose to term iodoptosis. Furthermore, PVP-I attacks lipid rafts, leading to the failure of tight junctions and thereby compromising the barrier functions of surface-lining cells. Thus, the therapeutic window of PVP-I is considerably narrower than commonly believed. Our findings urge the reappraisal of PVP-I in clinical practice to avert unwarranted toxicity whilst safeguarding its benefits.

Effect of the povidone iodine, hypertonic alkaline solution and saline nasal lavage on nasopharyngeal viral load in COVID-19.

OBJECTIVE: The present study aimed to investigate the in vivo activity of nasal irrigation (NI) with saline, NI with povidone-iodine (PVP-I) 1%, NI with a mix of hypertonic alkaline and PVP-I 1% against Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). DESIGN: This study was a prospective randomised clinical trial. SETTING: A multicenter study involving tertiary care centres. PARTICIPANTS: The study included adult outpatients whose qualitative SARS-CoV-2 RT-PCR tests in nasopharyngeal swabs were positive. One hundred twenty patients were divided into four equal groups. Standard COVID-19 treatment was given to Group 1, NI containing saline was added to patients' treatment in Group 2, NI containing 1% PVP-I solution was added to patients' treatment in Group 3, and NI containing 1% PVP-I solution and the hypertonic alkaline solution was added to patients' treatment in Group 4. MAIN OUTCOME MEASURES: On the first day of diagnosis (Day 0), nasopharyngeal swab samples were taken, on the third and fifth days the nasopharyngeal viral load (NVL) reduction in quantitative RT-PCR test was calculated. RESULTS: Between the zeroth to third days and zeroth to fifth days, the NVL reduction was significant in all groups (p < .05). In paired comparisons of groups, the NVL decrease in Group 4 in the first 3 days was significantly lower than all groups (p < .05). The NVL decrease in Groups 3 and 4 in the first 5 days were significantly lower than Group 1 (p < .05). CONCLUSION: This study revealed that the use of NI of 1% PVP-I and the hypertonic alkaline solution mixture was more effective in reducing NVL.

The Effect of Povidone-Iodine Nasal Spray on Nasopharyngeal SARS-CoV-2 Viral Load: A Randomized Control Trial.

OBJECTIVES/HYPOTHESIS: To determine the effect of povidone-iodine (PVP-I) nasal sprays on nasopharyngeal (NP) viral load as assessed by cycle threshold (Ct) on quantitative polymerase chain reaction (qPCR) of SARS-CoV-2 in outpatients. STUDY DESIGN: Three arm, triple blinded, randomized, placebo-controlled clinical trial. METHODS: Participants were randomized within 5 days of testing positive for COVID-19 to receive nasal sprays containing placebo (0.9% saline), 0.5% PVP-I, or 2.0% PVP-I. NP swabs for qPCR analysis were taken at baseline, 1-hour post-PVP-I spray (two sprays/nostril), and 3 days post-PVP-I spray (20 sprays/nostril). Symptom and adverse event questionnaires were completed at baseline, day 3, and day 5. University of Pennsylvania Smell Identification Tests (UPSIT) were completed at baseline and day 30. RESULTS: Mean Ct values increased over time in all groups, indicating declining viral loads, with no statistically significant difference noted in the rate of change between placebo and PVP-I groups. The 2.0% PVP-I group showed statistically significant improvement in all symptom categories; however, it also reported a high rate of nasal burning. Olfaction via UPSIT showed improvement by at least one category in all groups. There were no hospitalizations or mortalities within 30 days of study enrollment. CONCLUSIONS: Saline and low concentration PVP-I nasal sprays are well tolerated. Similar reductions in SARS-CoV-2 NP viral load were seen over time in all groups. All treatment groups showed improvement in olfaction over 30 days. These data suggest that dilute versions of PVP-I nasal spray are safe for topical use in the nasal cavity, but that PVP-I does not demonstrate virucidal activity in COVID-19 positive outpatients. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:2089-2095, 2022.

Mouth rinses efficacy on salivary SARS-CoV-2 viral load: A randomized clinical trial.

Considering the global trend to confine the COVID-19 pandemic by applying various preventive health measures, preprocedural mouth rinsing has been proposed to mitigate the transmission risk of SARS-CoV-2 in dental clinics. The study aimed to investigate the effect of different mouth rinses on salivary viral load in COVID-19 patients. This study was a single-center, randomized, double-blind, six-parallel-group, placebo-controlled clinical trial that investigated the effect of four mouth rinses (1% povidone-iodine, 1.5% hydrogen peroxide, 0.075% cetylpyridinium chloride, and 80 ppm hypochlorous acid) on salivary SARS-CoV-2 viral load relative to the distilled water and no-rinse control groups. The viral load was measured by quantitative reverse transcription PCR (RT-qPCR) at baseline and 5, 30, and 60 min post rinsing. The viral load pattern within each mouth rinse group showed a reduction overtime; however, this reduction was only statistically significant in the hydrogen peroxide group. Further, a significant reduction in the viral load was observed between povidone-iodine, hydrogen peroxide, and cetylpyridinium chloride compared to the no-rinse group at 60 min, indicating their late antiviral potential. Interestingly, a similar statistically significant reduction was also observed in the distilled water control group compared to the no-rinse group at 60 min, proposing mechanical washing of the viral particles through the rinsing procedure. Therefore, results suggest using preprocedural mouth rinses, particularly hydrogen peroxide, as a risk-mitigation step before dental procedures, along with strict adherence to other infection control measures.

A prospective, randomized, open-label trial of early versus late povidone-iodine gargling in patients with COVID-19.

Povidone-iodine (PVP-I) is a broad-spectrum antiseptic reagent that has been used for over 50 years. The purpose of this study is to look into the effect of gargling with PVP-I gargling on virus clearance and saliva infectivity in COVID-19. A prospective, randomized, open-label trial of intervention with PVP-I was conducted at three quarantine facilities in Osaka, Japan, enrolling adolescents and adults with asymptomatic-to-mild COVID-19. Patients were randomly allocated to the early and late intervention group at a 1:1 ratio. The early group gargled with PVP-I from days 2 to day 6; the late group gargled with water first, then with PVP-I from day 5 after sampling till day 6. The primary and secondary endpoints were viral clearance for SARS-CoV-2 using RT-qPCR at days 5 and 6, respectively, and the investigational endpoint was saliva infectivity clearance on day5. We enrolled 430 participants, with 215 assigned to each group, and 139 in the early group and 140 in the late had a positive saliva RT-qPCR test on day 2. On day 5, the early group had a significantly higher RT-qPCR negative rate than that of the late group (p = 0.015), and the early had a significantly higher clearance rate of infectivity (p = 0.025). During the PVP-I intervention, one participant reported oropharyngeal discomfort. Gargling with PVP-I may hasten virus clearance and reduce viral transmission via salivary droplets and aerosols in patients with asymptomatic-to-mild COVID-19. (Clinical trial registration numbers: jRCT1051200078 and dateof registration: 24/11/2020).

The short-term effect of different chlorhexidine forms versus povidone iodine mouth rinse in minimizing the oral SARS-CoV-2 viral load: An open label randomized controlled clinical trial study.

Several investigations evaluated the possibility of different types of mouth wash rinse in minimizing the SARS-CoV-2 load. However, results still controversial. The study aim is to assess the short-term efficiency of several over-the-counter mouth rinses and lozenges in minimizing the salivary viral load for SARS-CoV-2 in patients with confirmed COVID-19 in comparison to saline. This is a randomized controlled clinical trial with 4 arms. The recruited cases were randomized using a simple randomization technique and were assigned to chlorhexidine digluconate mouth rinse (CHX mouth rinse), 2 mg of chlorhexidine digluconate lozenges (CHX lozenges), povidone iodine mouth rinse (PVP-I mouth rinse) or saline as a control group. Saliva were collected from all study subjects by passive drool technique at two time points. First, prior to intervention with mouth rinse or the lozenges, the baseline saliva sample was collected. Second saliva samples were collected immediately after the mouth rinse. Real time PCR was conducted and the value threshold cycle (Ct) for each sample was recorded. Majority of the participants had an education level of high school or less (60%), were married (68.3), males (58.3%), and non-smokers (58.5%). No statistically significant differences between groups at the two times test (P > .05). However, a significant decrease of salivary viral load in all four groups combined (P-value for E genes = .027, and for S genes = .006), and in PVP-I mouth rinse specifically (P = .003 and P = .045, respectively). Povidone iodine mouth rinse showed a potential influence on the reduction of the viral load on a short-term basis. However, longer-term studies of the effect of these products should be conducted.

Efficacy of antiseptic mouthrinses against SARS-CoV-2: A prospective randomized placebo-controlled pilot study.

OBJECTIVES: Coronavirus-disease-19 (COVID-19) continues to affect millions of individuals worldwide. Antiviral activity of mouthrinses remains an important research area as the oral cavity is a site of SARS-CoV-2 initial replication. The aim of this study was to assess the effectiveness of three different mouthrinses in reducing the oral/oropharyngeal SARS-CoV-2 viral load. METHODS: Adult patients, hospitalized with confirmed COVID-19 were recruited for the study. Oral/oropharyngeal baseline SARS-CoV-2 samples were collected and analyzed by Real-Time-PCR. Subsequently, patients were instructed to rinse with 1 % hydrogen peroxide (H2O2), 0.12 % chlorhexidine (CHX), 1 % povidone­iodine (PVP-I) or Sodium Chloride 0.9 % (placebo). Viral loads were measured right after (T1), and at 45 min (T2) from the rinse. RESULTS: In the PVP-I 1 % group, 5/8 (62.5 %) patients at T1, and 3/8 (37.5 %) patients at T2, SARS-CoV-2 was not detectable in the swab specimens. In the H2O2 1 % group, 2/11 (18.2 %) patients at T1, and 2/11 (18.2 %) other patients at T2 showed no SARS-CoV-2 loads. One (12.5 %) patient in the CHX 0.12 % group showed SARS-CoV-2 negativity at T2. One (9.1 %) patient at T1, and another (9.1 %) patient at T2 showed no SARS-CoV-2 loads in the placebo group. CONCLUSIONS: Oral SARS-CoV-2 loads were reduced at T1 in the PVP-I 1 % and H2O2 1 % groups. CLINICAL RELEVANCE: PVP-I 1 % was the most effective rinse especially in patients with low viral copy numbers at baseline.

Repurposing povidone-iodine to reduce the risk of SARS-CoV-2 infection and transmission: a narrative review.

BACKGROUND: Accumulating data suggest antiviral effects of povidone-iodine against the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This narrative review aims to examine the antiviral mechanisms of povidone-iodine, efficacy of povidone-iodine against the SARS-CoV-2 virus, and safety of povidone-iodine to human epithelial cells and thyroid function. METHODS: We searched the electronic databases PubMed, Embase, Cochrane Library, ClinicalTrials.gov and World Health Organization's International Clinical Trials Registry Platform for articles containing the keywords "povidone-iodine", "SARS-CoV-2" and "COVID-19" from database inception till 3 June 2021. RESULTS: Despite in vitro data supporting the anti-SARS-CoV-2 effects of povidone-iodine, findings from clinical studies revealed differences in treatment response depending on study settings (healthy vs. hospitalized individuals), treatment target (nasal vs. oral vs. pharynx), method of administration (oral rinse vs. gargle vs. throat spray) and choice of samples used to measure study endpoints (nasopharyngeal vs. saliva). One large-scale clinical trial demonstrated reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak. Povidone-iodine is also used to disinfect the oro-pharyngeal space prior to dental or otolaryngology procedures. Although existing data suggest minimal impact of povidone-iodine on thyroid function, high-quality safety data are presently lacking. CONCLUSIONS: Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.Key messagesAccumulating data suggest antiviral effects of povidone-iodine against the SARS-CoV-2 virus.Findings from clinical studies reveal differences in treatment response depending on study settings, treatment target, method of administration and choice of samples used to measure study endpoints. One large-scale clinical trial observed reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak.Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.

The effect of mouthrinses on severe acute respiratory syndrome coronavirus 2 viral load: A systematic review.

BACKGROUND: Considering that the oral cavity is a major entryway and reservoir for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aim of the authors was to perform a systematic review of in vivo and in vitro studies to assess the effectiveness of mouthrinses on SARS-CoV-2 viral load. TYPES OF STUDIES REVIEWED: The authors searched PubMed, Web of Science, Scopus, MedRxiv, and bioRxiv databases, including in vitro and in vivo studies assessing the virucidal effect of mouthrinses on SARS-CoV-2 or surrogates. From a total of 1,622 articles retrieved, the authors included 39 in this systematic review. RESULTS: Povidone-iodine was the most studied mouthrinse (14 in vitro and 9 in vivo studies), frequently showing significant reductions in viral load in in vitro assays. Similarly, cetylpyridinium chloride also showed good results, although it was evaluated in fewer studies. Chlorhexidine gluconate and hydrogen peroxide showed conflicting results on SARS-CoV-2 load reduction in both in vitro and in vivo studies. PRACTICAL IMPLICATIONS: Povidone-iodine-based mouthrinses appear to be the best option as an oral prerinse in the dental context for SARS-CoV-2 viral load reduction. Although the results of primary studies are relevant, there is a need for more in vivo studies on mouthrinses, in particular, randomized controlled clinical trials, to better understand their effect on SARS-CoV-2 viral load and infection prevention.

Povidone-Iodine as a Pre-Procedural Mouthwash to Reduce the Salivary Viral Load of SARS-CoV-2: A Systematic Review of Randomized Controlled Trials.

The use of pre-procedural rinses has been investigated to reduce the number of viral particles and bacteria in aerosols, potentially decreasing the risk of cross-infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during medical and dental procedures. This review aims to confirm whether there is evidence in the literature describing a reduction in salivary load of SARS-CoV-2 when povidone-iodine (PVP-I) is used as a pre-intervention mouthwash. An search of the MEDLINE, Embase, SCOPUS, and the Cochrane library databases was conducted. The criteria used followed the PRISMA® Statement guidelines. Randomized controlled trials investigating the reduction of salivary load of SARS-CoV-2 using PVP-I were included. Ultimately, four articles were included that met the established criteria. According to the current evidence, PVP-I is effective against SARS-CoV-2 in saliva and could be implemented as a rinse before interventions to decrease the risk of cross-infection in healthcare settings.

The effectiveness of mouthwash against SARS-CoV-2 infection: A review of scientific and clinical evidence.

The COVID-19 pandemic, caused by the spread of SARS-CoV-2 infection that is mainly through the airborne transmission, is a worldwide health concern. This review seeks to assess the potential effectiveness of mouthwash in reducing the oropharyngeal load of SARS-CoV-2 based on the available evidence. Articles related to mouthwash and COVID-19 in PubMed were electronically searched in July, 2021. After manually excluding articles lacking sufficient scientific evidence or validation processes, those with inaccessible online full text, those that did not test the effectiveness of mouthwash against SARS-CoV-2, and those not written in English, 17 original and 13 review articles were chosen for this review. The eligible articles revealed that the main virucidal mechanism of mouthwash was via interactions with the viral envelope. Povidone-iodine (PVP-I), cetylpyridinium chloride (CPC), and essential oils with ethanol showed virucidal effects on SARS-CoV-2 in vitro, potentially by interfering with the viral envelope. A few clinical studies demonstrated that PVP-I, CPC, hydrogen peroxide, and chlorhexidine reduced the oropharyngeal load of SARS-CoV-2. Although the available evidence is limited, mouthwash containing PVP-I or CPC shows potential for reducing the oropharyngeal load of SARS-CoV-2 and thus may present a risk-mitigation strategy for COVID-19 patients.

Review of the use of nasal and oral antiseptics during a global pandemic.

A review of nasal sprays and gargles with antiviral properties suggests that a number of commonly used antiseptics including povidone-iodine, Listerine®, iota-carrageenan and chlorhexidine should be studied in clinical trials to mitigate both the progression and transmission of SARS-CoV-2. Several of these antiseptics have demonstrated the ability to cut the viral load of SARS-CoV-2 by 3-4 log10 in 15-30 s in vitro. In addition, hypertonic saline targets viral replication by increasing hypochlorous acid inside the cell. A number of clinical trials are in process to study these interventions both for prevention of transmission, prophylaxis after exposure, and to diminish progression by reduction of viral load in the early stages of infection.

Topical Ocular Povidone-Iodine as an Adjunctive Preventative Practice in the Era of COVID-19.

ABSTRACT: Ophthalmologists and patients have an inherent increased risk for transmission of SARS-CoV-2. The human ocular surface expresses receptors and enzymes facilitating transmission of SARS-CoV-2. Personal protective equipment alone provides incomplete protection. Adjunctive topical ocular, nasal, and oral antisepsis with povidone iodine bolsters personal protective equipment in prevention of provider-patient transmission of SARS-CoV-2 in ophthalmology.

Could antiseptic gargling prevent COVID-19?

Coronavirus Disease 2019 (COVID-19) has infected more than 8 million people globally since its discovery in December 2019. For COVID-19 prevention, the World Health Organization recommended regular handwashing with soap, cough etiquette, mask wearing and social distancing. However, COVID-19 is rather difficult to contain because of its high transmissibility property. Gargling is effective for reducing infection in the respiratory tract. Most antiseptic gargles have antimicrobial properties against common respiratory pathogens. No published study on the effectiveness of antiseptic gargling among COVID-19 patients has been available to date. This article reviewed available literature on methods and solutions available for gargling and their effect on respiratory tract infections.

Efficacy of commercial mouth-rinses on SARS-CoV-2 viral load in saliva: randomized control trial in Singapore.

PURPOSE: One of the key approaches to minimize the risk of COVID-19 transmission would be to reduce the titres of SARS-CoV-2 in the saliva of infected COVID-19 patients. This is particularly important in high-risk procedures like dental treatment. The present randomized control trial evaluated the efficacy of three commercial mouth-rinse viz. povidone-iodine (PI), chlorhexidine gluconate (CHX) and cetylpyridinium chloride (CPC), in reducing the salivary SARS-CoV-2 viral load in COVID-19 patients compared with water. METHODS: A total of 36 SARS-CoV-2-positive patients were recruited, of which 16 patients were randomly assigned to four groups-PI group (n = 4), CHX group (n = 6), CPC group (n = 4) and water as control group (n = 2). Saliva samples were collected from all patients at baseline and at 5 min, 3 h and 6 h post-application of mouth-rinses/water. The samples were subjected to SARS-CoV-2 RT-PCR analysis. RESULTS: Comparison of salivary Ct values of patients within each group of PI, CHX, CPC and water at 5 min, 3 h and 6 h time points did not show any significant differences. However, when the Ct value fold change of each of the mouth-rinse group patients were compared with the fold change of water group patients at the respective time points, a significant increase was observed in the CPC group patients at 5 min and 6 h and in the PI group patients at 6 h. CONCLUSION: The effect of decreasing salivary load with CPC and PI mouth-rinsing was observed to be sustained at 6 h time point. Within the limitation of the current study, as number of the samples analyzed, the use of CPC and PI formulated that commercial mouth-rinses may be useful as a pre-procedural rinse to help reduce the transmission of COVID-19. ISRCTN (ISRCTN95933274), 09/09/20, retrospectively registered.

Tolerability and effectiveness of povidone-iodine or mupirocin versus saline sinus irrigations for chronic rhinosinusitis.

OBJECTIVES: The role of topical anti-infectives in acute exacerbations of chronic rhinosinusitis is controversial. Povidone-iodine is an anti-bacterial and anti-viral that is affordable and available over-the-counter and may demonstrate advantages over mupirocin as a sinus irrigation therapy. The objective was to compare povidone-iodine or mupirocin versus saline sinus irrigations for sinusitis exacerbations in post-surgery subjects as well as to assess tolerability of povidone-iodine sinus irrigations. MATERIALS AND METHODS: This was a prospective single-blinded (clinician only) randomized controlled trial. Subjects were post-surgery with acute exacerbations of chronic rhinosinusitis and gram-positive bacteria on culture. They received povidone-iodine, mupirocin, or saline sinus irrigations, twice daily for 30 days. Outcomes were post-treatment culture negativity (primary) and Sinonasal Outcome Test-20 and Lund-Kennedy endoscopic score change (secondary). RESULTS: Of the 62 subjects analyzed, post-treatment culture negativity rate was higher in the MUP (14/20, 70%) group compared to the PI (9/21, 43%) and SAL (9/19, 47%) groups, although this was not significant (p = 0.29). Povidone-iodine sinus irrigations at the 1% concentration were very well-tolerated, similar to saline irrigations. There were no significant differences in Sinonasal Outcome Test-20 score (povidone-iodine -0.3 [-0.6, 0.05] vs. mupirocin -0.3 [-0.7, 0.05] vs. saline -0.4 [-0.8, 0.05]; p = 0.86) or Lund-Kennedy endoscopic score (povidone-iodine -3.5 [-7, -0.5] vs. mupirocin -2 [-4, 2] vs. saline -3 [-5, 0]; p = 0.45) change. No serious adverse effects were reported. CONCLUSIONS: In patients who have had prior sinus surgery with acute exacerbations of CRS and gram-positive bacteria on culture, mupirocin sinus irrigations achieved a better post-treatment culture "control" rate compared to saline and povidone-iodine. In addition, 1% povidone-iodine solution was well-tolerated as a sinus irrigation and may represent a feasible method for temporarily disinfecting the sinonasal cavity of bacteria and viruses such as COVID-19.