PVP-I for COVID-19: real-time analysis of all 34 studies

Povidone-Iodine for COVID-19: real-time meta analysis of 17 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 8 studies from 8 independent teams in 6 different countries show statistically significant improvements in isolation (5 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 49% [36‑60%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.

• Results are robust — in exclusion sensitivity analysis 14 of 17 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.

• Some studies only test short term viral load after a single application. Excessive use of PVP-I could affect thyroid function.

• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 18% of povidone-iodine studies show zero events with treatment.

• All data to reproduce this paper and sources are in the appendix.

[Hasan] present another meta analysis for povidone-iodine, showing significant improvements for viral clearance and viral load.

Covid Analysis et al., 30 Sep 2022, preprint, 1 author.

Effects of Chlorhexidine and Povidone-Iodine on the SARS-CoV-2 Load: A Systematic Review and Meta-analysis

Hasan et al., European Journal of Dentistry, doi:10.1055/s-0042-1753470 (meta analysis)

Systematic review and meta analysis showing significantly improved viral clearance with both povidone-iodine and chlorhexidine.

Hasan et al., 8 Sep 2022, peer-reviewed, 6 authors.

A pilot study of 0.4% povidone-iodine nasal spray to eradicate SARS-CoV-2 in the nasopharynx

Sirijatuphat et al., medRxiv, doi:10.1101/2022.08.18.22278340 (Preprint)

Small single-arm trial testing short-term viral load change after a single administration of three puffs of 0.4% PVP-I, showing lower viral titer at 3 minutes and 4 hours, not reaching statistical significance. Authors note that one reason for the lower change compared to in vitro results is that the spray administration may be less effective.

viral load, 33.3% lower, relative load 0.67, p = 0.58, after median 2560.0 IQR 17790.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 10.0 40.0 2560.0 40960.0 5120.0 1280.0 160.0 2560.0 40960.0 40960.0 10240.0 40.0, relative median viral titer, 3 min, left vs. baseline, Mann-Whitney, Table 3.

viral load, 87.5% lower, relative load 0.12, p = 0.04, after median 480.0 IQR 4340.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 80.0 160.0 10240.0 320.0 320.0 10240.0 40.0 640.0 640.0 40960.0 2560.0 0.0, relative median viral titer, 3 min, right vs. baseline, Mann-Whitney, Table 3.

viral load, 83.3% lower, relative load 0.17, p = 0.11, after median 640.0 IQR 6240.0 n=12, before median 3840.0 IQR 9600.0 n=12, before values 640.0 640.0 40960.0 2560.0 10240.0 10240.0 640.0 2560.0 10240.0 5120.0 40960.0 640.0, after values 160.0 10.0 10240.0 640.0 160.0 1280.0 320.0 640.0 5120.0 40960.0 20480.0 0.0, relative median viral titer, 4 hours, right vs. baseline, Mann-Whitney, Table 3.

Sirijatuphat et al., 22 Aug 2022, prospective, Thailand, preprint, median age 34.0, 4 authors, study period 15 February, 2021 - 15 March, 2021, trial TCTR20210125002.

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

Natto et al., Medicine, doi:10.1097/MD.0000000000028925

60 patient RCT comparing chlorhexidine, PVP-I, and saline in Saudi Arabia with a single mouth rinse treatment and PCR testing 5 minutes later, showing statistically significant improvement in Ct value for PVP-I. PVP-I showed greater improvement than saline, without statistical significance.

risk of viral load, 74.0% lower, RR 0.26, p = 0.27, treatment 12, control 12, relative improvement in Ct value, both genes combined.

risk of viral load, 96.2% lower, RR 0.04, p = 0.12, treatment mean 4.43 (±4.78) n=12, control mean 0.17 (±7.67) n=12, relative improvement in Ct value, E gene.

risk of viral load, 44.4% lower, RR 0.56, p = 0.60, treatment mean 3.33 (±5.6) n=12, control mean 1.85 (±7.68) n=12, relative improvement in Ct value, S gene.

Natto et al., 29 Jul 2022, Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 7 authors, this trial compares with another treatment - results may be better when compared to placebo.

Effect of oral antiseptics on the viral load of SARS-CoV-2: A randomized controlled trial

Sevinç Gül et al., Dental and Medical Problems, doi:10.17219/dmp/150831

RCT with 21 PVP-I and 20 saline patients gargling for 30 seconds and testing PCR Ct after 30 minutes, showing greater improvement with PVP-I, without statistical significance.

Ct values differ across testing platforms, however the reported Ct value difference can represent a large difference in viral load. For example, using the calibration included with the ct2vl converter, the reported difference in mean Ct values corresponds to a reduction in viral load of over 3x for PVP-I.

risk of viral load, 99.5% lower, RR 0.005, p = 0.37, treatment mean 1.85 (±7.06) n=21, control mean 0.01 (±5.89) n=20, relative improvement in Ct value.

Sevinç Gül et al., 29 Jul 2022, Randomized Controlled Trial, Turkey, peer-reviewed, 4 authors, this trial compares with another treatment - results may be better when compared to placebo.

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

Fantozzi et al., American Journal of Otolaryngology, doi:10.1016/j.amjoto.2022.103549

Mouthrinse RCT in Italy comparing short-term viral load after a single 60 second treatment with povidone-iodine, hydrogen peroxide, chlorhexidine, and saline. The greatest efficacy was seen with povidone-iodine, especially for patients with low viral load at baseline.

relative viral load, 57.5% better, RR 0.43, treatment 8, control 11, T2, relative fraction of median baseline viral load remaining.

relative viral load, 100% better, RR <0.001, treatment 8, control 11, T1, relative fraction of median baseline viral load remaining.

risk of no viral clearance, 31.2% lower, RR 0.69, p = 0.26, treatment 5 of 8 (62.5%), control 10 of 11 (90.9%), NNT 3.5, T2.

risk of no viral clearance, 58.7% lower, RR 0.41, p = 0.04, treatment 3 of 8 (37.5%), control 10 of 11 (90.9%), NNT 1.9, T1.

Fantozzi et al., 28 Jul 2022, Randomized Controlled Trial, Italy, peer-reviewed, 14 authors, study period December 2020 - May 2021, this trial compares with another treatment - results may be better when compared to placebo.

Effect of oral antiseptics in reducing SARS-CoV-2 infectivity: evidence from a randomized double-blind clinical trial

Sánchez Barrueco et al., Emerging Microbes & Infections, doi:10.1080/22221751.2022.2098059

RCT hospitalized patients testing viral load shortly after a single mouthwash with PVP-I, hydrogen peroxide, cetylpyridinium chloride, chlorhexidine, and water. For PVP-I, there were only 5 patients with viable virus at baseline. Cross-treatment comparisons are limited due to the very small sample sizes and large difference between baseline viral loads (the baseline viral culture non-log copies/mL was ~10,000 times higher in the water group vs. PVP-I).

The trial registration shows that 160 patients were recruited, with 62 patients added in an October 6, 2021 change, however the paper presents results for only 75 patients.

risk of viral load, 33.9% lower, RR 0.66, treatment 5, control 5, relative viral culture non-log median copies/mL, 60 minutes vs. baseline.

risk of viral load, 49.9% lower, RR 0.50, treatment 5, control 5, relative viral culture non-log median copies/mL, 30 minutes vs. baseline.

Sánchez Barrueco et al., 27 Jul 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, mean age 55.0, 17 authors, trial NCT04707742 (history).

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

Lim et al., Annals of Medicine, doi:10.1080/07853890.2022.2076902 (Review)

Review of in vitro, animal, and clinical studies supporting the use of povidone-iodine for SARS-CoV-2.

Lim et al., 20 May 2022, peer-reviewed, 7 authors.

Combined Nasal, Oropharyngeal Povidone Iodine Plus Glycyrrhizic Acid Sprays, Accelerate Clinical and Laboratory Recovery and Reduces Household Transmission of SARS-CoV-2: A Randomized Placebo-Controlled Clinical Trial

Elsersy et al., Frontiers in Medicine, doi:10.3389/fmed.2022.863917

RCT with 200 patients and 421 contacts in Egypt, with 100 patients and their contacts treated with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic acid, showing significantly faster viral clearance and recovery, and significantly lower transmission.

SOC included vitamin C and zinc. The spray active ingredients included a compound of glycyrrhizic acid in the form of ammonium glycyrrhizate 2.5 mg/ml plus PVI 0.5% for oropharyngeal and dipotassium glycyrrhizinate 2.5 mg/ml plus PVI 0.5% for nasal spray. Patients were advised to concomitantly use oropharyngeal and nasal sprays 6 times per day. They were instructed to abstain from food, drink, and smoke for 20min, particularly after oropharyngeal spray. The oropharyngeal spray bottle contains an atomizer that ends with a long arm applicator to insert inside the mouth cavity and can be directed up, down, right, or left to cover the entire pharyngeal area.

risk of hospitalization, 90.9% lower, RR 0.09, p = 0.06, treatment 0 of 100 (0.0%), control 5 of 100 (5.0%), NNT 20, relative risk is not 0 because of continuity correction due to zero events.

recovery time, 14.6% lower, relative time 0.85, p = 0.008, treatment mean 7.6 (±2.0) n=100, control mean 8.9 (±2.0) n=100.

recovery time, 49.1% lower, relative time 0.51, p < 0.001, treatment mean 5.6 (±1.3) n=100, control mean 11.0 (±3.4) n=100, smell.

recovery time, 48.2% lower, relative time 0.52, p < 0.001, treatment mean 5.7 (±1.0) n=100, control mean 11.0 (±4.0) n=100, taste.

risk of no viral clearance, 67.7% lower, RR 0.32, p < 0.001, treatment 21 of 100 (21.0%), control 65 of 100 (65.0%), NNT 2.3, mid-recovery, day 7.

risk of no viral clearance, 90.0% lower, RR 0.10, p = 0.010, treatment 1 of 100 (1.0%), control 10 of 100 (10.0%), NNT 11, day 10.

risk of no viral clearance, 29.3% lower, RR 0.71, p < 0.001, treatment 70 of 100 (70.0%), control 99 of 100 (99.0%), NNT 3.4, day 4.

risk of transmission, 91.9% lower, RR 0.08, p < 0.001, treatment 12 of 194 (6.2%), control 173 of 227 (76.2%), NNT 1.4, symptomatic.

risk of transmission, 94.0% lower, RR 0.06, p < 0.001, treatment 8 of 194 (4.1%), control 157 of 227 (69.2%), NNT 1.5, PCR+.

Elsersy et al., 19 Apr 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Egypt, peer-reviewed, 8 authors, study period March 2021 - July 2021, this trial uses multiple treatments in the treatment arm (combined with glycyrrhizic acid) - results of individual treatments may vary, trial PACTR202101875903773.

In vivo (human) and in vitro inactivation of SARS-CoV-2 with 0.5% povidone-iodine nasal spray

Friedland et al., Australian Journal of Otolaryngology, doi:10.21037/ajo-21-40

Small study of povidone-iodine nasal spray with 14 patients, showing rapid reduction in viral load for the 6 patients that had culturable virus at baseline. All patients remained PCR+ despite no culturable virus detected for 3 of 6 patients. This study also contains In Vitro results showing rapid reduction in viable virus with povidone-iodine.

Friedland et al., 9 Feb 2022, Australia, peer-reviewed, 12 authors.

Gargling with povidone iodine has a short-term inhibitory effect on SARS-Cov-2 in COVID-19 patients

Seikai et al., Journal of Hospital Infection, doi:10.1016/j.jhin.2022.01.001

Small study of 11 patients showing a rapid short-term decrease of viral load in saliva samples with povidone-iodine.

Seikai et al., 15 Jan 2022, peer-reviewed, 9 authors.

Clinical evaluation of antiseptic mouth rinses to reduce salivary load of SARS-CoV-2

Ferrer et al., Scientific Reports, doi:10.1038/s41598-021-03461-y

Small very late (>50% 7+ days from symptom onset, 9 PVP-I patients) RCT testing mouthwashing with cetylpyridinium chloride, chlorhexidine, povidone-iodine, hydrogen peroxide, and distilled water, showing no significant differences. Over 30% of patients show >90% decrease in viral load @2 hrs with all 5. Authors note that a trend was observed for viral load decrease with PVP-I @2h for patients <6 days from onset (p=0.06, Wilcox test).

relative decrease in log viral load, 34.0% better, RR 0.66, p = 0.82, treatment 9, control 12, calculated from Supplementary Table 1.

Ferrer et al., 22 Dec 2021, Randomized Controlled Trial, Spain, peer-reviewed, 19 authors.

Determinants of Outcome Among Critically Ill Police Personnel With COVID-19: A Retrospective Observational Study From Andhra Pradesh, India

Jamir et al., Cureus, doi:10.7759/cureus.20394

Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir.

risk of death, 57.0% lower, RR 0.43, p < 0.001, treatment 39 of 163 (23.9%), control 62 of 103 (60.2%), NNT 2.8, adjusted, multivariable Cox regression.

Jamir et al., 13 Dec 2021, retrospective, India, peer-reviewed, 6 authors, study period June 2020 - October 2020.

In Vivo Efficacy of Povidone-iodine Mouth Gargles in Reducing Salivary Viral Load in COVID-19 Patients: A Systematic Review

Sudhakar et al., World Journal of Dentistry, doi:10.5005/jp-journals-10015-1868 (meta analysis)

Systematic review of the use of povidone-iodine gargles for COVID-19, concluding that PVP-I effectively reduces SARS-CoV-2 viral load.

Sudhakar et al., 24 Nov 2021, peer-reviewed, 5 authors.

The Effect of Povidone-Iodine Nasal Spray on COVID-19 Nasopharyngeal Viral Load in Patients: A Randomized Control Trial

Zarabanda et al., Laryngoscope, doi:10.1002/lary.29935

Very late treatment (7 days from onset) RCT comparing 11 & 13 PVP-I (0.5% and 2%), and 11 saline spray patients in the USA, showing no significant differences. There was no control group (saline is likely not a placebo, showing efficacy in other trials). There are large unadjusted differences between groups, e.g. 7.1 days from onset for PVP-I versus 4.8 for saline. Baseline Ct was higher for PVP-I, providing less room for improvement. Authors note that they cannot determine if earlier use is more beneficial.

risk of no recovery, 26.9% higher, RR 1.27, p = 1.00, treatment 3 of 13 (23.1%), control 2 of 11 (18.2%), 2%.

risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 11 (27.3%), control 2 of 11 (18.2%), 0.5%.

risk of no viral clearance, no change, RR 1.00, p = 1.00, treatment 2 of 7 (28.6%), control 2 of 7 (28.6%), day 5, minus strand PCR.

Zarabanda et al., 1 Nov 2021, Randomized Controlled Trial, USA, peer-reviewed, 13 authors, average treatment delay 7.0 days, this trial compares with another treatment - results may be better when compared to placebo.

Utility of mouth rinses with povidone-iodine and hydrogen peroxide in patients with COVID-19

Pablo-Marcos et al., Enfermedades Infecciosas y Microbiología Clínica, doi:10.1016/j.eimc.2021.10.005

Small prospective study with 31 patients gargling povidone-iodine, 17 hydrogen peroxide, and 40 control patients, showing lower viral load mid-recovery with povidone-iodine, without reaching statistical significance. Oropharyngeal only, and only every 8 hours for two days. Results may be better with the addition of nasopharyngeal use, more frequent use, and without the two day limit.

Authors are not familiar with the literature, having found only one of the 7 previous trials for PVP-I and COVID-19. Non-randomized study with no adjustments or group details. Some results in Figure 1 appear to be switched compared to the text and the labels in the figure. The viral clearance figures do not match the group sizes - for example authors report 62% PCR- for PVP-I at the 3rd test, however there is no number of 31 patients that rounds to 62%.

relative viral load, 29.2% better, RR 0.71, p = 0.40, treatment 31, control 40, 3rd PCR (mid-recovery).

relative viral load, 9.1% better, RR 0.91, p = 0.91, treatment 31, control 40, 4th PCR (most patients recovered).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Pablo-Marcos et al., 25 Oct 2021, prospective, Spain, peer-reviewed, mean age 43.0, 6 authors, study period May 2020 - November 2020.

Tolerance of nasal and oral povidone-iodine antisepsis amid COVID-19 pandemic

Frank et al., Otolaryngology - Head and Neck Surgery, 165:89 (Preprint)

Prospective study of 42 otolaryngology and dental patients, showing low-dose nasal and oral PVP-I solutions to be well-tolerated.

Frank et al., 3 Oct 2021, preprint, 6 authors.

Rapid initiation of nasal saline irrigation: hospitalizations in COVID-19 patients randomized to alkalinization or povidone-iodine compared to a national dataset

Baxter et al., medRxiv, doi:10.1101/2021.08.16.21262044 (Preprint)

Small RCT 79 PCR+ patients 55+ comparing pressure-based nasal irrigation with povidone-iodine and sodium bicarbonate, showing improved recovery with povidone-iodine, and 0/37 COVID-19 related hospitalizations for povidone-iodine compared to 1/42 for sodium bicarbonate.

risk of hospitalization, 65.3% lower, RR 0.35, p = 1.00, treatment 0 of 37 (0.0%), control 1 of 42 (2.4%), NNT 42, relative risk is not 0 because of continuity correction due to zero events.

risk of no recovery, 56.8% lower, RR 0.43, p = 0.03, treatment 6 of 27 (22.2%), control 18 of 35 (51.4%), NNT 3.4.

risk of transmission, 36.9% lower, RR 0.63, p = 0.51, treatment 4 of 37 (10.8%), control 6 of 35 (17.1%), NNT 16.

risk of hospitalization, 94.1% lower, RR 0.06, p = 0.004, nasal irrigation vs. CDC data.

Baxter et al., 17 Aug 2021, Randomized Controlled Trial, USA, preprint, 9 authors, average treatment delay 4.0 days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04559035 (history).

Estimating salivary carriage of severe acute respiratory syndrome coronavirus 2 in nonsymptomatic people and efficacy of mouthrinse in reducing viral load

Chaudhary et al., The Journal of the American Dental Association, doi:10.1016/j.adaj.2021.05.021

Small RCT comparing mouthrinsing with saline, 1% hydrogen peroxide, 0.12% chlorhexidine, and 0.5% povidone-iodine, showing significant reductions in salivary viral load for all 4 mouthrinses at 15 and 45 minutes after rinsing. NCT04603794.

Chaudhary et al., 11 Jun 2021, Randomized Controlled Trial, USA, peer-reviewed, 17 authors, trial NCT04603794 (history).

Virucidal effect of povidone iodine on COVID-19 in the nasopharynx: an open-label randomized clinical trial

Arefin et al., Indian Journal of Otolaryngology and Head & Neck Surgery, doi:10.1007/s12070-021-02616-7

RCT with 189 patients showing significantly greater viral clearance with a single application of PVP-I. Authors recommend using PVP-I prophylactically in the nasopharynx and oropharynx. NCT04549376 [trialsjournal.biomedcentral.com].

1. trialsjournal.biomedcentral.com, https://trialsjournal.biomedcentra..rticles/10.1186/s13063-020-04963-2.

risk of no viral clearance, 78.9% lower, RR 0.21, p = 0.02, treatment 4 of 27 (14.8%), control 19 of 27 (70.4%), NNT 1.8, 0.6% nasal irrigation.

risk of no viral clearance, 89.5% lower, RR 0.11, p < 0.001, treatment 2 of 27 (7.4%), control 19 of 27 (70.4%), NNT 1.6, 0.5% nasal irrigation.

risk of no viral clearance, 52.6% lower, RR 0.47, p = 0.006, treatment 9 of 27 (33.3%), control 19 of 27 (70.4%), NNT 2.7, 0.4% nasal irrigation.

risk of no viral clearance, 80.0% lower, RR 0.20, p < 0.001, treatment 5 of 27 (18.5%), control 25 of 27 (92.6%), NNT 1.4, 0.6% nasal spray.

risk of no viral clearance, 64.0% lower, RR 0.36, p < 0.001, treatment 9 of 27 (33.3%), control 25 of 27 (92.6%), NNT 1.7, 0.5% nasal spray.

risk of no viral clearance, 73.6% lower, RR 0.26, p < 0.001, treatment 29 of 135 (21.5%), control 44 of 54 (81.5%), NNT 1.7, all treatment vs. all control.

Arefin et al., 18 May 2021, Randomized Controlled Trial, Bangladesh, peer-reviewed, 9 authors, trial NCT04549376 (history).

Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial

Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035

Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C.

Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters.

There were no hospitalizations and no deaths. NCT04446104.

risk of symptomatic case, 44.7% lower, RR 0.55, p = 0.002, treatment 42 of 735 (5.7%), control 64 of 619 (10.3%), NNT 22.

risk of case, 31.1% lower, RR 0.69, p = 0.01, treatment 338 of 735 (46.0%), control 433 of 619 (70.0%), NNT 4.2, adjusted, OR converted to RR, model 6.

Seet et al., 14 Apr 2021, Cluster Randomized Controlled Trial, Singapore, peer-reviewed, 15 authors, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04446104 (history).

Povidone Iodine (PVP-I) Oro-Nasal Spray: An Effective Shield for COVID-19 Protection for Health Care Worker (HCW), for all

Arefin, M., Indian Journal of Otolaryngology and Head & Neck Surgery, doi:10.1007/s12070-021-02525-9

Report on clinical experience with prophylactic use of PVP-I for COVID-19 in a very high risk environment with no infections, review of the use of PVP-I for the prevention of respiratory infections, and recommendations for use with COVID-19.

Arefin et al., 8 Apr 2021, peer-reviewed, 1 author.

In vivo evaluation of the virucidal efficacy of chlorhexidine and povidone-iodine mouthwashes against salivary SARS-CoV-2. A randomized-controlled clinical trial

Elzein et al., Journal of Evidence Based Dental Practice, doi:10.1016/j.jebdp.2021.101584 (date from earlier preprint)

Small RCT comparing mouthwashing with PVP-I, Chlorhexidine, and water, showing significant efficacy for both PVP-I and Chlorhexidine, with PVP-I increasing Ct by a mean of 4.45 (p < 0.0001) and Chlorhexidine by a mean of 5.69 (p < 0.0001), compared to no significant difference for water.

relative improvement in Ct value, 88.8% better, RR 0.11, p < 0.05, treatment 25, control 9.

Elzein et al., 17 Mar 2021, Double Blind Randomized Controlled Trial, Lebanon, peer-reviewed, 7 authors.

Can povidone Iodine gargle/mouthrinse inactivate SARS-CoV-2 and decrease the risk of nosocomial and community transmission during the COVID-19 pandemic? An evidence-based update

Chopra et al., Japanese Dental Science Review, doi:10.1016/j.jdsr.2021.03.001 (Review)

Review discussing the rationale, safety, recommendations, and dosage of PVP-I gargle/mouthwash as an effective method to decrease the viral load of SARS-CoV-2.

Chopra et al., 15 Mar 2021, peer-reviewed, 5 authors.

Differential Effects of Antiseptic Mouth Rinses on SARS-CoV-2 Infectivity In Vitro

Xu et al., Pathogens, doi:10.3390/pathogens10030272 (In Vitro)

In Vitro study showing that PVP-I and other mouthwashes inactivated replication-competent SARS-CoV-2.

Xu et al., 1 Mar 2021, peer-reviewed, 7 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Povidone iodine, hydrogen peroxide and chlorhexidine mouthwashes reduce SARS-CoV2 burden in whole mouth fluid and respiratory droplets

Jayaraman et al., medRxiv, doi:10.1101/2021.02.25.21252488 (Preprint)

Study of SARS-CoV2 burden in whole mouth fluid and respiratory droplets with povidone iodine, hydrogen peroxide, and chlorhexidine mouthwashes in 36 hospitalized COVID-19 patients using PCR and rapid antigen testing. There were significant reductions in SARS-CoV2 burden with all treatments in both respiratory droplets and whole mouth fluid.

Jayaraman et al., 1 Mar 2021, prospective, India, preprint, 12 authors.

Povidone Iodine Mouthwash, Gargle, and Nasal Spray to Reduce Nasopharyngeal Viral Load in Patients With COVID-19: A Randomized Clinical Trial

Guenezan et al., JAMA Otolaryngol Head Neck Surg., doi:10.1001/jamaoto.2020.5490

RCT of PCR+ patients with Ct<=20 with 12 treatment and 12 control patients, concluding that nasopharyngeal decolonization may reduce the carriage of infectious SARS-CoV-2 in adults with mild to moderate COVID-19. All patients but 1 had negative viral titer by day 3 (group not specified). There was no significant difference in viral RNA quantification over time. The mean relative difference in viral titers between baseline and day 1 was 75% [43%-95%] in the intervention group and 32% [10%-65%] in the control group. Thyroid dysfunction occurred in 42% of treated patients, with spontaneous resolution after the end of treatment. Patients in the treatment group were younger.

relative improvement in viral titer reduction between baseline and day 1, 63.2% better, RR 0.37, p = 0.25, treatment 12, control 12.

Guenezan et al., 4 Feb 2021, Randomized Controlled Trial, France, peer-reviewed, 7 authors.

In vitro inactivation of SARS-CoV-2 with 0.5% povidone iodine nasal spray (Nasodine) at clinically relevant concentrations and timeframes using tissue culture and PCR based assays

Tucker et al., bioRxiv, doi:10.1101/2021.01.31.426979 (Preprint) (In Vitro)

In Vitro study showing that PVP-I eliminated the viability of SARS-CoV-2 with short exposure times. Authors find that PCR alone may not be adequate for viral quantification and recommend incorporating cell culture to assess viral viability.

Tucker et al., 1 Feb 2021, preprint, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Tolerability and usability of 0.5% PVP-I gargles and nasal drops in 6692 patients: Observational study

Khan et al., American Journal of Otolaryngology, doi:10.1016/j.amjoto.2020.102880

Study of the use of PVP-I gargles and nasal drops before and after ENT examinations with a total of 6,692 patients, finding high usability and good tolerance for use.

21 patients (0.76%) reported an itching sensation in the nose on the first day of use of 0.5% PVP-I nasal drops and discontinued its further use. However, none of the patients reported any serious side effects or allergic reaction to 0.5% PVP-I nasal drops and gargles.

The 0.5% PVP-I gargles and nasal drops were used by healthcare workers about three to four times in a day for 5 months. None of them developed any COVID-19 symptoms.

Khan et al., 3 Jan 2021, peer-reviewed, 2 authors.

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

Seneviratne et al., Infection, doi:10.1007/s15010-020-01563-9

Small mouthwash RCT with 4 PVP-I patients and 2 water patients concluding that PVP-I may have a sustained effect on reducing the salivary SARS-CoV-2 level in COVID-19 patients. ISRCTN95933274.

relative fold change, 32.9% better, RR 0.67, p < 0.01, treatment 4, control 2, PVP-I vs. water, 6 hours.

Seneviratne et al., 14 Dec 2020, Randomized Controlled Trial, Singapore, peer-reviewed, 12 authors.

Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient

Choudhury et al., Bioresearch Communications, Volume 7, Issue 1, January 2021

RCT 606 patients in Bangladesh for povidone iodine mouthwash/gargle, nasal drops and eye drops showing significantly lower death, hospitalization, and PCR+ at day 7.

risk of death, 88.2% lower, RR 0.12, p < 0.001, treatment 2 of 303 (0.7%), control 17 of 303 (5.6%), NNT 20.

risk of hospitalization, 84.4% lower, RR 0.16, p < 0.001, treatment 12 of 303 (4.0%), control 77 of 303 (25.4%), NNT 4.7.

risk of no viral clearance, 96.2% lower, RR 0.04, p < 0.001, treatment 8 of 303 (2.6%), control 213 of 303 (70.3%), NNT 1.5, day 7.

Choudhury et al., 3 Dec 2020, Randomized Controlled Trial, Bangladesh, peer-reviewed, 6 authors.

Efficacy of Povidone-Iodine Nasal and Oral Antiseptic Preparations Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2)

Pelletier et al., Ear, Nose & Throat Journal, doi:10.1177/0145561320957237 (In Vitro)

In Vitro study testing nasal and oral PVP-I formulations with 60 second exposure time, showing complete inactivation of SARS-CoV-2 with all concentrations (1% to 5% PVP-I).

Pelletier et al., 21 Sep 2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

In Vitro Efficacy of a Povidone-Iodine Nasal Antiseptic for Rapid Inactivation of SARS-CoV-2

Frank et al., JAMA Otolaryngol Head Neck Surg, doi:10.1001/jamaoto.2020.3053 (In Vitro)

In Vitro study showing povidone-iodine nasal antiseptics at concentrations (0.5%, 1.25%, and 2.5%) completely inactivated SARS-CoV-2 within 15 seconds of contact. No cytotoxic effects on cells were observed after contact with each of the nasal antiseptics tested.

Frank et al., 17 Sep 2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Early viral clearance among COVID-19 patients when gargling with povidone-iodine and essential oils: a pilot clinical trial

Mohamed et al., medRxiv, doi:10.1101/2020.09.07.20180448 (Preprint)

Tiny RCT with 5 PVP-I patients, gargling 30 seconds, 3x per day, and 5 control patients (essential oils and tap water were also tested), showing improved viral clearance with PVP-I.

risk of no viral clearance, 85.7% lower, RR 0.14, p = 0.17, treatment 0 of 5 (0.0%), control 3 of 5 (60.0%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events, day 12.

Mohamed et al., 9 Sep 2020, Randomized Controlled Trial, Malaysia, preprint, 16 authors.

Povidone-Iodine Demonstrates Rapid In Vitro Virucidal Activity Against SARS-CoV-2, The Virus Causing COVID-19 Disease

Anderson et al., Infectious Diseases and Therapy, doi:10.1007/s40121-020-00316-3 (In Vitro)

In Vitro study showing rapid and effective virucidal activity of PVP-I
against SARS-CoV-2. All four products tested [antiseptic solution (PVP-I 10%), skin cleanser (PVP-I 7.5%), gargle and mouth wash (PVP-I 1%) and throat spray (PVP-I 0.45%)] achieved C 99.99% virucidal activity against SARS-CoV-2, corresponding to C 4 log10 reduction of virus titre, within 30s of contact.

Anderson et al., 8 Jul 2020, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Is povidone iodine mouthwash effective against SARS‐CoV‐2? First in vivo tests

Martínez Lamas et al., Oral Diseases, doi:doi.org/10.1111/odi.13526

Small study analyzing the impact of PVP-I mouthwash on the salivary viral load of SARS-CoV-2 in 4 patients with COVID-19. In 2 of the 4 patients (those with a higher initial viral load), PVP-I resulted in a significant drop in viral load, which remained after 3 hours.

Martínez Lamas et al., 2 Jul 2020, peer-reviewed, 9 authors.

Povidone iodine gargle and mouthwash

Hassandarvish et al., British Dental Journal volume, doi:10.1038/s41415-020-1794-1 (In Vitro)

In Vitro study showing undiluted PVP-I (1% w/v) achieved >5 log10 reduction in SARS-CoV-2 virus titres at 15, 30 and 60 seconds treatment exposure under both clean and dirty conditions. In contrast, when PVP-I was tested at 1:2 dilution a >4 log10 kill at 15 seconds and >5 log10 kill at 30 and 60 seconds in comparison to control was seen in both clean and dirty conditions.

Hassandarvish et al., 26 Jun 2020, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Repurposing 0.5% povidone iodine solution in otorhinolaryngology practice in Covid 19 pandemic

Khan et al., Am J Otolaryngol, doi:10.1016/j.amjoto.2020.102618

Study of the use of PVP-I gargles and nasal drops before ENT appointments finding good tolerability.

Khan et al., 18 Jun 2020, peer-reviewed, 3 authors.

Povidone-Iodine Use in Sinonasal and Oral Cavities: A Review of Safety in the COVID-19 Era

Frank et al., Ear, Nose & Throat Journal, doi:10.1177/0145561320932318

Review of povidone-iodine finding that it can safely be used in the nose at concentrations up to 1.25% and in the mouth at concentrations up to 2.5% for up to 5 months.

Frank et al., 10 Jun 2020, peer-reviewed, 4 authors.

Rapid In-Vitro Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Using Povidone-Iodine Oral Antiseptic Rinse

Bidra et al., Journal of Prosthodontics, doi:10.1111/jopr.13209 (In Vitro)

In Vitro study showing PVP-I rapidly inactivated SARS-CoV-2. Viricidal activity was present at the lowest concentration and contact time tested (0.5% PVP-I and 15 seconds).

Bidra et al., 8 Jun 2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Potential Role of Oral Rinses Targeting the Viral Lipid Envelope in SARS-CoV-2 Infection

O’Donnell et al., Function, doi:10.1093/function/zqaa002 (Review)

Review of the mechanisms of action and studies supporting oral rinsing for the prevention of transmission of SARS-CoV-2, including chlorhexidine, cetylpyridinium chloride, hydrogen peroxide, and povidone-iodine.

O’Donnell et al., 5 Jun 2020, peer-reviewed, 12 authors.

Prevention of COVID-19 Infection with Povidone-Iodine

Mendoza et al., SSRN, doi:10.2139/ssrn.3589404 (Preprint)

Review of the antiviral efficacy of PVP-I and its potential use as a prophylactic on the oropharyngeal and nasopharyngeal mucosa for COVID-19.

Mendoza et al., 7 May 2020, preprint, 1 author.