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Abstract
Objectives:
Approaches to nasal and oral decontamination with povidone-iodine (PVP-I) have been published to reduce nosocomial spread of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2). The safety of PVP-I topically applied to the nasal and oral cavity is addressed by a literature review. The specific efficacy of PVP-I against coronaviruses and its potential efficacy against SARS-CoV-2 is discussed.
Methods:
A review was performed utilizing PubMed and Cochrane Databases. All citations in protocols for nasal and oral PVP-I use regarding COVID-19 were independently reviewed.
Results:
Povidone-iodine has been safely administered for up to 5 months in the nasal cavity and 6 months in the oral cavity. Concentrations less than 2.5% in vitro do not reduce ciliary beat frequency or cause pathological changes in ciliated nasal epithelium, upper respiratory, or mucosal cells. Adverse events with oral use have not been reported in conscious adults or children. Allergy and contact sensitivity is rare. Chronic mucosal use up to 5% has not been shown to result in clinical thyroid disease. PVP-I is rapidly virucidal and inactivates coronaviruses, including SARS-CoV and Middle East Respiratory Syndrome (MERS).
Conclusions:
Povidone-iodine 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. Povidone-iodine rapidly inactivates coronaviruses, including SARS and MERS, when applied for as little as 15 seconds. There is optimism that PVP-I can inactivate SARS-CoV-2, but in vitro efficacy has not yet been demonstrated.
Introduction
Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2), the virus resulting in the disease COVID-19, is a novel coronavirus in the same family as the SARS and Middle East Respiratory Syndrome (MERS) viruses. The World Health Organization (WHO) declared the spread of COVID-19 a global pandemic on March 11, 2020. This has significantly changed the way that we practice medicine. As otolaryngologists, our workflow has been radically altered.
There have been significant concerns noted regarding infection of health care workers and subsequent nosocomial spread within hospitals. Data from the epidemic in Wuhan by the Chinese Center for Disease Control and Prevention noted that 63% of infected patients in Wuhan were health care workers.1 A study of hospitalized patients at a tertiary care center in Wuhan noted that 12% of patients and 29% of health care professionals had acquired COVID-19 from nosocomial spread.2 Particular concern has been expressed regarding the safety of otolaryngologists, patients, and staff during routine and endoscopic examination. Reports have demonstrated high viral loads of SARS-CoV-2 in the nasal cavities, nasopharynx, oral cavities, and oropharynx, with the highest viral loads within the nasopharynx.3-6 In vitro studies have demonstrated that the tissue of the nose and mouth have high expression of ACE2, the main receptor of COVID-19.7,8 Nasal goblet and ciliated cells had the highest expression of ACE2.9 Due to high viral load, these areas are sensitive for diagnosis of the virus.10 The transit of virus via coughing, sneezing, and aerosolizing procedures makes transmission high.11 Aerosols of SARS-CoV-2 have been detected in the air for up to 3 hours.12 There are concerns that many otolaryngology procedures generate aerosols, which was proven for intranasal high-speed drilling in a cadaveric study.13,14
Transmission reduction by the minimization of aerosolized virus is of key importance. Given that the nasopharynx and oropharynx are principal reservoirs of active SARS-CoV-2 virus, there has been immense desire for an approach to nasal and oral decontamination in the era of COVID-19. Povidone-iodine (PVP-I) has been suggested as a topical solution. PVP-I works by releasing free iodine, which disrupts microbial metabolic pathways, destabilizes structural components of cell membranes, and leads to irreversible damage to pathogens.15 It is a potent virucidal via inhibition of N1, N2, and N3 neuraminidase as well as inhibition of hemagglutinin. This inhibition blocks viral attachment to cellular receptors and inhibits viral release and spread from infected cells.16
Protocols have been recommended regarding nasal and oral use of PVP-I in regard to the COVID-19 pandemic, and there has been much discussion regarding the implementation of these practices. A protocol was developed in the United Kingdom recommending 0.3 mL of 0.5% PVP-I solution via each nostril and 9 mL via the oral cavity in conscious COVID-19 patients and persons under investigation (PUIs) prior to undergoing procedures in and around the mouth, as well as in health care workers performing these procedures.17 In unconscious patients, they recommended applying 2 mL to the mucosal surfaces of the oral cavity. Use was recommended every 2 to 3 hours in health care workers exposed to these patients up to 4 times per day. Another protocol from Pittsburgh recommended 240 mL of 0.4% PVP-I in the nasal cavity via sinus rinse delivery bottle and 10 mL of 0.5% PVP-I oral wash every 2 to 3 hours up to 4 times per day in patients with COVID-19, PUIs, prior to high-risk procedures, and in COVID-19 hotspots.18 They recommended this procedure in health care workers prior to and after care of COVID patients, PUIs, high-risk procedures in COVID hotspots, and in the setting of inadequate PPE. Parhar et al concurred with the use of PVP-I based preparations to reduce viral loads of coronavirus as there was demonstrated efficacy.19 An anesthesia guideline for operative room care in the COVID-19 era recommended 2 doses of nasal PVP-I within 1 hour of incision for all OR cases.20 The American Dental Association guidelines for minimizing risk of COVID-19 transmission recommended preoperative use of 0.2% PVP-I mouthwash for all procedures.21
To minimize toxicity when using PVP-I as a repeated application, most protocols recommend concentrations of PVP-I between 0.2% and 0.5%. Because nasal and oral viral loads are similar in asymptomatic and symptomatic patients3 and can persist in convalescent seroconverted cases, some of these protocols recommend the use of PVP-I in asymptomatic patients. Unaddressed in any report to date is a discussion of the interdependence of PVP-I aqueous concentration, chemical stability, reported toxicity, and known biocidal efficacy.
Most commercial PVP-I preparations suitable for sinonasal or oral application are aqueous concentrations of 10% PVP-I or 5% PVP-I intended for presurgical antisepsis. Although additional scrubs, solutions, swab sticks, and other PVP-I containing products are available in the 5% to 10% range, many contain additional salts, sudsing agents, and cosolvents that should be avoided in the nose and mouth. Most are specifically labeled for external use and carry warnings against exposure to eyes, ears, and mucosal surfaces. The chemical stability of PVP-I in aqueous solutions at room temperature declines with dilution, alkalinization, and contact with common low-density polymer packaging materials.22,23 Naturally acidic aqueous PVP-I solutions reach a critical stability inflection point at about 0.75%.24 Paradoxically, studies have shown that the antibacterial activity of full-strength 10% PVP-I increases with dilution.25 Between 10% and 1%, there is an exponential increase in efficacy which plateaus between 1.0% and 0.1% before decreasing again from 0.1% to 0.001%.
Our objective is to present established uses of PVP-I in the sinonasal and oral cavities and outline the safety profile through the discussion of clinical and in vitro toxicity. In addition, we aim to discuss PVP-I efficacy against coronaviruses and its potential use specifically against SARS-CoV-2 to inform the otolaryngology community regarding its use.
Methods
A review was performed utilizing PubMed and Cochrane Databases. Search terms included “sinonasal povidone-iodine,” “nasal povidone-iodine,” “oral povidone-iodine,” and “povidone-iodine safety.” All citations in published protocols for nasal and oral PVP-I use regarding COVID-19 were independently reviewed. English language studies and studies translated to English were included.
Results
Sinonasal PVP-I Uses and Safety
Nasal decontamination is a routine step to reduce postoperative infectious contamination.26 Efficacy of PVP-I for intranasal antisepsis has been proven. Patients undergoing orthopedic surgery who had tested positive for methicillin-sensitive staphylococcus aureus (MSSA) or methicillin-resistant staphyloccocus aureus (MRSA) nasal colonization were treated with 5% PVP-I in both nostrils twice daily for 5 days prior to surgery.27 This completely eradicated MRSA in all patients and reduced rate of MSSA infection by 94%. Another study used 5% PVP-I solution the night before and morning of surgery for hardware implantation and noted a significantly lower rate of surgical site infection (SSI) in the treatment group.28 A randomized controlled trial treated patients with 5% PVP-I 2 hours prior to surgery and noted a significant decrease in the number of patients colonized with MRSA 4 hours after treatment.29 Although safety was not specifically evaluated in these studies, there were no reports of toxicity or adverse events.
The repeated administration of PVP-I to the sinonasal mucosa has been described as a safe and effective treatment for chronic sinus disease (Table 1). Panchmatia et al and Mullings et al reported the use of a 0.08% PVP-I solution for recalcitrant chronic rhinosinusitis (CRS) for up to 7 weeks.30,31 Patients showed clinical improvement and decreased bacterial growth. Over the 7 weeks of treatment, there was no detrimental effect on thyroid function or mucociliary clearance. Nasal mucociliary time remained within normal ranges. Thyroid dysfunction was not noted. Panchmatia et al additionally studied olfaction utilizing the Sniffin’ 16 smell identification test and did not detect a significant difference after 7 weeks. Safety was evaluated in an in vivo study utilizing 2.2% and 4.4% liposomal dispersions of PVP-I.32 In healthy patients, results did not demonstrate a significant change in mucosal appearance, ciliary activity, or olfactory function based on 11 odors at 10 time points over 80 days.
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Table 1. Overview of Safety Data for Mucociliary Clearance, Olfaction, Thyroid Function, and Mucosal Appearance for in Vivo Sinonasal Use of PVP-I.
In vitro safety of nasal PVP-I appears highly concentration dependent with a clear distinction in toxicity that occurs at 2.5% in vitro. A 0.5% PVP-I solution was applied to air liquid interface cultures of human nasal epithelial cells from patients with CRS.33 PVP-I did not cause pathological effects on paracellular permeability or cilia beat frequency; 10% and 5% PVP-I solutions were applied to human ciliated respiratory cells, which resulted in a drop in ciliary beat frequency34; 5% and 2.5% PVP-I solutions tested in vitro completely inhibited activity of the cilia, whereas there was no inhibitory effect at 1.25%.35
Oral PVP-I Uses and Safety
Diluted concentrations of PVP-I gargle have been shown to be bactericidal.36 Povidone-iodine gargle has been utilized throughout the world for decades. In addition to antisepsis for oral surgical procedures,37 PVP-I gargles have been utilized to prevent respiratory infections in patients with variable results.38-40 The Committee for the Japanese Respiratory Society guidelines recommend that inpatients and health care workers gargle with PVP-I 4 times daily to prevent hospital acquired pneumonia.41
In vitro safety data regarding PVP-I use in the rat oral mucosa demonstrated apoptosis of cells when exposed to a concentration of 1 × 10−2 µM for 1 day, but did not demonstrate this apoptosis at a concentration of 1 × 10−3 µM.42 Although the concentrations tested were lower than available PVP-I products, they saturated the mucosal cells for 24 hours, as compared to a few minutes, so the cytotoxicity is likely not comparable. In vivo, prolonged use of 1% to 1.25% PVP-I gargle did not cause irritation or damage, and no adverse safety effects were noted in patients for up to 28 months (Table 2).36,38,43,44 Povidone-iodine gargle was not shown to stain teeth or cause a change in gustatory function.49
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Table 2. Overview of Safety and Tolerance Data for in Vivo Oral Use of PVP-I.
There is concern that gargling a PVP-I solution could lead to inadvertent aspiration. When used as oral antisepsis in the operating room, there have been 6 case reports of aspiration pneumonia, in concentrations from 0.25% to 10%. In 2 of these cases, there was overt concern of lack of integrity of the endotracheal tube balloon.50,51 One author reports using this solution for antisepsis for over 20 years without any prior complications.52 The effect of PVP-I on lung tissue was studied in rats, demonstrating atelectasis, edema, alveolar rupture, and leukocyte infiltration, followed by lung parenchyma loss and pulmonary fibrosis at 1% and 5% concentrations with less severe findings in rats exposed to 0.1% concentrations.53 There were no case reports of aspiration pneumonia in awake patients.
Povidone-Iodine General Safety
Urinary iodine excretion in patients undergoing thyroid surgery with routine application of 10% PVP-I to large surface areas was studied revealing an increase of 7 times the preoperative value compared to patients disinfected with chlorhexidine54; 10% PVP-I was used prior to cataract surgery, and urinary iodide excretion at a time point 24 hours after surgery was elevated when the solution was applied to the conjunctiva and periorbital skin.55 These studies failed to demonstrate significance for these findings. The recommended daily intake of iodine by the WHO is 0.15 mg.56 The majority of iodine is cleared by the kidneys in urine, 35% is excreted in sweat, and a negligible amount is excreted fecally.57 When healthy patients were given more than 100 times the recommended intake of iodine daily for 38 days, there were no deleterious effects. The renal iodine clearance has been shown to be stable and not saturatable.58
The limited number of in vitro membrane penetration studies has been conducted in experimental models highly dissimilar to typical clinical conditions. In the only quantitative in vitro study to specifically measure iodine flux across a human epithelial membrane, the protocol included an infinite dose regime, saturation of the complete surface area of the experimental membrane, and exposure time of 24 hours.59 They concluded that 10% PVP-I applied to human skin demonstrated a maximum “iodine” medium flux of 0.73 µg/cm2 per hour. However, based on the limitations of the study, this conclusion cannot be utilized as evidence based.
Elevated levels of iodine intake have been associated with autoimmune thyroiditis, goiter, and hypothyroidism.60 A study was conducted on healthy patients in areas of Japan with high iodine intake from kelp. Patients had a urinary iodide excretion of 1.5 mg/d in these areas. However, there were no increases in thyroglobulin antibodies or thyroid peroxidase antibodies, and no reported negative health effects61; 5% PVP-I mouthwash effects on thyroid function were studied in patients 4 times per day for 2 weeks and 6 months daily without effect on thyroid function (Table 2).45,46
There is a single report of possible iodine toxicity after irrigation with 300 mL of 10% PVP-I during a 3 hour functional endoscopic sinus surgery in one patient.62 Topical application of 1% PVP-I on denuded skin in rats was shown to compete with I125 thyroid uptake.63 Allergy, contact sensitivity, and skin reactions are rare.64-67 Although safety of cutaneous use of PVP-I in pregnant patients has been demonstrated,68-70 the safety of nasal and/or oral use is unclear. Safety regarding oral use of PVP-I gargle in the pediatric population has been demonstrated with single use and intermittent use for 6 months (Table 2).47,48
Virucidal Capabilities and Efficacy Against Coronaviruses
Evaluation against human coronaviruses HCoV 229E, HCV0OC43, SARS, and MERS has demonstrated concentration-dependent virucidal activity in contact times as little as 15 seconds.71-73 The lowest concentration effective against MERS was 1% with reduction of viral activity of more than 99.99%74; 0.23% was the lowest effective concentration against SARS-CoV demonstrated in 2 in vitro studies after 15 seconds and 2 minutes of contact.73,75 Recent studies have shown up to 82% homology of SARS-CoV-2 with SARS-CoV.76 Given the high homology with these viruses proven to be inactivated by PVP-I, there is optimism that PVP-I is effective against novel SARS-CoV-2. However, in vitro inactivation of SARS-CoV-2 by PVP-I has not yet been proven, and studies are needed to determine the factors that will optimize efficacy.
Discussion
The SARS-CoV-2 pandemic has altered the environment in which we practice medicine. Attempts to minimize spread have mainly concentrated on strict adherence to the use of physical barriers, spatial separation, and personal protective equipment. The nasal cavities, nasopharynx, oral cavity, and oropharynx have high viral loads of SARS-CoV-2. There is a growing interest for decontamination of these areas in patients and health care workers to prevent virus transmission. PVP-I is of primary interest due to its ability to inactivate coronaviruses, the lack of microbial resistance, and the long history of clinical use. Protocols have been published describing regimens for use. We performed a review regarding the use and safety of PVP-I in the nasal and oral cavities to inform protocols based on known in vitro toxicity, clinical safety, in vitro efficacy, and solution chemistry.
PVP-I has been utilized for years in the nasal cavity for preoperative decontamination to prevent SSIs with proven efficacy. Chronic use has been implemented in CRS with efficacy and without effects on thyroid function, mucociliary clearance, or olfaction. Ciliotoxic effects have been demonstrated at concentrations of 2.5% and above, with safety demonstrated at 1.25% and lower.
Oral cavity use of PVP-I has been used acutely for surgical disinfection and chronically to treat plaque and dental caries. Chronic use in patients has not resulted in toxicity, irritation, staining of teeth, or change in taste. There is concern for aspiration of oral PVP-I in unconscious patients leading to aspiration pneumonia, with 6 case reports published in the surgical setting. However, there have been no case reports of aspiration pneumonia following PVP-I use in awake patients. Therefore, it is prudent to take care when instilling PVP-I in unconscious patients.
Chronic mucosal applications of PVP-I in doses up to 5% have been shown to increase urinary excretion of iodine without suggestion of clinical risk or thyroid disease associated with this transient increase in patients with normal renal function when used for up to 6 months. Iodine is primarily metabolized via urinary clearance in a linear, nonsaturable fashion. Povidone-iodine should not be used in patients undergoing radioactive iodine treatment as it was found to compete with thyroid radioactive iodine uptake in rats. Povidone-iodine has been used safely on the skin of pregnant patients but has not been evaluated on nasal or oral mucosa. Chronic oral use of 10% PVP-I intermittently for months has been safely reported in pediatric patients. Allergy and contact sensitivity are rare.
Povidone-iodine is safe in the nose up to 1.25% and mouth up to 5% for up to 5 and 6 months, respectively. Absorption of iodine is poorly described, inconsistently analyzed, and without clear conclusions. Regardless, PVP-I has been demonstrated to be systemically risk free at concentrations up to 5% daily for 5 months. The nose and mouth contain high viral loads of SARS-CoV-2, and aerosolization via these surfaces is of significant concern for virus transmission. Protocols have been put forth regarding PVP-I in the nasal and oral cavities to reduce transmission of SARS-CoV-2. Following our review, based on available data, we recommend nasal mucosal decontamination with 0.5 to 2 mL of 1.25% PVP-I and oral rinse with up to 10 mL at 2.5% as frequently as needed for decontamination without risk of adverse effects. Povidone-iodine nasal and oral use should be avoided in patients with thyroid disease, pregnant patients, and patients receiving radioactive iodine therapy. If PVP-I is to be used in unconscious patients, care must be taken by using small amounts via direct application to mucosal surfaces to avoid the risk of aspiration.
Povidone-iodine is effective against SARS-CoV and MERS at 0.23% after 15 seconds of exposure in vitro. Based on homology demonstrated between SARS-CoV and SARS-CoV-2, it is likely that PVP-I is effective in safely eradicating SARS-CoV-2 in the nasal cavity, nasopharynx, oral cavity, and oropharynx. However, there are no existing data evaluating the efficacy of PVP-I on SARS-CoV-2. Studies are needed to characterize the utility of PVP-I against this new pathogen.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Samantha Frank 
https://orcid.org/0000-0002-5068-1065
Belachew Tessema https://orcid.org/0000-0002-7418-6034
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