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

Povidone-iodine (PVP-I) is a time-tested antiseptic agent with excellent virucidal (99.99%) properties. Repurposing it against coronavirus disease-19 (COVID-19) is a relatively newer concept and has been sparsely tested in vivo. The most common route of entry of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the nasopharynx. Averting colonization of the virus could be one of the best options to reduce the incidence of infection. PVP-I gargle and mouthwash were found to be effective in vitro rapid inactivation against SARS-CoV-2 on a smaller scale (Hassandarvish et al. in BDJ 1-4, 2020, Pelletier et al. in ENTJ 1-5, 2020). However, efficacy in humans is lacking. To assess the virucidal effect of PVP-I against SARS-CoV-2 located in the nasopharynx was the objective of this parallel armed randomized clinical trial. We screened all RT-PCR-confirmed COVID-19 cases aged 18 years and above with symptoms. Written informed consent was obtained before randomization. Nasopharyngeal clearance of SARS-CoV-2 was tested after single time application of PVP-I nasal irrigation (NI) at diluted concentrations of .4%, .5% and .6% and PVP-I nasal spray (NS) at diluted concentrations of .5% and .6%. All groups were compared to the corresponding controls (distilled water). The primary outcome was viral clearance in a repeat RT-PCR (qualitative), and the secondary outcome was the number of adverse events. Final data analysis was performed using the statistical software SPSS (Version 20). A total of 189 confirmed COVID-19 cases were randomized into seven groups: 27 patients in each group. Of all, 159 (84.1%) were male, and 30 (15.9%) were female. We observed a statistically significant proportion of nasopharyngeal clearance with all strengths of PVP-I NI and PVP-I NS compared to the corresponding controls. Additionally, 0.5% NI was significantly better than 0.5% NS for viral clearance (p = 0.018) and had the highest nasopharyngeal clearance among all strengths (n = 25, 92.6%). 0.6% NS is better than CNS and 0.5%NS in viral clearance. The only adverse event was nasal irritation recorded in two patients each in the 0.4% and 0.6% PVP-I NI groups (Tables 1 and 2). PVP-I NI and NS are proved as effective virucidal agent against SARS-CoV-2 in human body. Our recommendation is to use PVP-I in naopharynx (as well as oropharynx) to prevent COVID-19. © Association of Otolaryngologists of India 2021.

RCT Entities:   Population Interventions Outcomes

Introduction

Povidone-iodine (PVP-I) is a time-tested antiseptic agent with excellent virucidal (99.99%) properties. Repurposing it against coronavirus disease-19 (COVID-19) is a relatively newer concept and has been sparsely tested in vivo. The most common route of entry of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the nasopharynx. Hence, it was targeted to prevent access and contamination of the nasopharynx by several protective measures, including facemasks. Averting colonization of the virus could be one of the best options to reduce the incidence of infection. PVP-I gargle and mouthwash were found to be effective in vitro rapid inactivation against SARS-CoV-2 on a smaller scale [1, 2]. However, efficacy in humans is lacking. To assess the virucidal effect of PVP-I against SARS-CoV-2 located in the nasopharynx was the objective of this parallel armed randomized clinical trial.

Methods

This single-center, open-label randomized clinical trial with a 7-arm parallel-group design was approved by the ethical review committee of Dhaka Medical College, Bangladesh. (NCT Identifier number: NCT04549376). We screened all reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19 cases aged 18 years and above with symptoms. Written informed consent was obtained before randomization. Nasopharyngeal clearance of SARS-CoV-2 was tested after single time application of PVP-I nasal irrigation (NI) at diluted concentrations of 0.4%, 0.5% and 0.6% and PVP-I nasal spray (NS) at diluted concentrations of 0.5% and 0.6%. All groups were compared to the corresponding controls (distilled water). The primary outcome was viral clearance in a repeat RT-PCR (qualitative), and the secondary outcome was the number of adverse events. Final data analysis was performed using the statistical software SPSS (Version 20). The authors followed the Extension of the Consolidated Standards of Reporting Trials (CONSORT) 2010 guideline [3]. The study protocol was published elsewhere [4].

Results

A total of 189 confirmed COVID-19 cases were randomized into seven groups: 27 patients in each group. All of them completed the study. Of all, 159 (84.1%) were male, and 30 (15.9%) were female. The average age of the participants was 43.98 ± 12.67 years (SD), with the majority ranging from 31 to 40 years (n = 56, 29.60%). The PVP-I NS group had significantly higher proportions of severe patients than the control-NS (C-NS) group (p < 0.001). The 0.6% NS group differed from the C-NS group by sex and the presence of comorbidities (p < 0.05). Adjusting the differences, we observed a statistically significant proportion of nasopharyngeal clearance with all strengths of PVP-I NI and PVP-I NS compared to the corresponding controls. Additionally, 0.5% NI was significantly better than 0.5% NS for viral clearance (p = 0.018) and had the highest nasopharyngeal clearance among all strengths (n = 25, 92.6%) and 0.6% NS is best among 0.5% NS and CNS. The only adverse event was nasal irritation recorded in two patients each in the 0.4% and 0.6% PVP-I NI groups (Tables 1 and 2).

Table 1

Patient Demographics, baseline clinical characteristics and virucidal activity of PVI-P Nasal spray and mouth wash

	Nasal irrigation (NI)				p-value
	.4% NI	.5% NI	.6% NI	Control-NI (CNI)	.4% NI v CNI	.5% NI v CNI	.6% NI v CNI
Age group
18–30	4 (14.8)	7 (25.9)	3 (11.1)	3 (11.1)	0.787a	0.548a	0.750a
31–40	6 (22.2)	9 (33.3)	5 (18.5)	9 (33.3)
41–50	11 (40.7)	3 (11.1)	7 (25.9)	8 (29.6)
51–60	6 (22.2)	6 (22.2)	8 (29.6)	5 (18.5)
61–70	0	1 (3.7)	3 (11.1)	1 (3.7)
> 70	0	1 (3.7)	1 (3.7)	1 (3.7)
Sex
Male	23 (85.2)	23 (85.2)	20 (74.1)	21 (77.8)	0.484a	0.484b	0.750 b
Female	4 (14.8)	4 (14.8)	7 (25.9)	6 (22.2)
Disease severity
Asymptomatic	1 (3.7)	2 (7.4)	2 (7.4)	0	1.00a	0.075a	0.781a
Mild	12 (44.4)	6 (22.2)	12 (44.4)	12 (44.4)
Moderate	14 (51.9)	19 (70.4)	12 (44.4)	14 (51.9)
Severe	0	0	1 (3.7)	1 (3.7)
Co-morbidities
At least one	16 (59.3)	14 (51.9)	13 (48.1)	11 (40.7)	0.174 b	0.413 b	0.584 b
None	11 (40.7)	13 (48.1)	14 (51.9)	16 (59.3)
Disease duration (days)	2.04 ± 0.72	1.92 ± 0.74	1.65 ± 0.63	1.85 ± 0.61	0.305c	0.686c	0.269c
Outcome
COVID Negative	18 (33.3)	25 (92.6)	23 (85.2)	8 (29.6)	0.006 b	< 0.001b	0.018 b
COVID Positive	9 (33.3)	2 (7.4)	4 (14.8)	19 (70.4)
Adverse event
Present	2 (7.4)	0	0	0	0.493b	NA	NA
Absent	25 (92.6)	27 (100)	27 (100)	23 (100)

Bold indicates significant 'p' value < 0.05%

Comorbidities included Diabetes Mellitus, Hypertension, Bronchial Asthma and Ischemic Heart Disease

Outcome was defined as RT-PCR negativity for COVID after intervention

Only adverse event was ‘Irritation’

p-value was determined by Fisher Exact Test

bChi-square Test

cIndependent Samples t Test

dMultivariate Logistic Regression adjusting for Severity

eSeverity and Comorbidity

Table 2

Level of significance table for pair-wise comparisons of patient demographics, baseline clinical characteristics and virucidal activity of PVI-P Nasal spray and mouth wash

	0.4% NI v CNI	0.5% NI v CNI	0.6%NI v CNI	0.4% NI v 0.5%NI	0.4% NI v 0.6% NI	0.5% NI v 0.6%NI	0.5%NS v CNS
Age*	0.787a	0.548 a	0.75a	0.117a	0.424a	0.349a	0.179a
Sex	0.484a	0.484b	0.75b	1.000a	0.311b	0.311b	0.142a
Severity*	1.000a	0.075a	0.781a	0.242a	0.913a	0.196a	< 0.001a
Comorbidity	0.174b	0.413b	0.584b	0.584b	0.413b	0.785b	0.102b
Duration	0.305c	0.686c	0.269c	0.572c	0.045c	0.165c	0.668c
Outcome	0.006b	< 0.001b	< 0.001b	0.018b	0.111b	0.669*	< 0.001d
Adverse events	0.493	NA	NA	0.493	0.493	NA	NA

Bold indicates significant 'p' value < 0.05%

ap-value was determined by Fisher Exact Test

bChi-square Testb

cIndependent Samples t Test

dMultivariate Logistic Regression adjusting for Severity

eSeverity and Comorbidity

Discussion

Although in vitro testing of PVP-I solution revealed a considerable reduction in SARS-CoV-2 viral titers, its effect on humans was unclear [1]. Our study confirms the presumed effectiveness of PVP-I in nasopharyngeal clearance of SARS-CoV-2 among COVID-19 patients. Compared to controls, we noted viral clearance at two-fifth to three-fifth dilutions of PVP-I nasal irrigation and spray. Our findings agree with the first report of in vivo PVP-I mouthwash application [5]. In contrast, Guenezan et al. [6] observed no effect of PVP-I on nasopharyngeal viral loads. They reported unpleasant nasal tingling and transient elevation of thyroid stimulating hormone after povidone iodine administration. In contrast, we found nasal irritation in only two patients (1.1%). Our study’s strength was testing different strengths of PVP-I nasal solution and comparing those with distilled water controls in a modest number of cases. However, our limitation was the inability to conduct viral quantification before and after intervention.

Conclusion

In this study, a statistically significant proportion of nasopharyngeal clearance with all strengths of PVP-I NI and PVP-I NS (compared to the corresponding controls) is observed, so our recommendation is to use PVP-I prophylactically in nasopharynx as well as oropharynx (through which areas SARS-CoV-2 enters and resides for a while) for prevention of COVID-19.