Povidone-Iodine Safety, Efficacy, and Lugol’s

In the last issue, I covered the potential of nasal irrigation, rinsing, and gargling with 0.5% povidone-iodine to kill SARS-CoV-2, the coronavirus that causes COVID-19.

Several issues then came up as responses that I consider worth addressing:

  • How well can we generalize from the in vitro (test tube) study to the likely in vivo (live human) efficacy of this approach?
  • How safe is it?
  • Can Lugol's be substituted?

Efficacy

We obviously cannot know how effective this is without randomized controlled trials, but we can reason through how likely it is to be effective.

Nasal irrigation and gargling has been shown to be very effective against bacteria.

This trial tested inhalation of a 1% solution by jet nebulizer and gargling twice a day in 16 people, 9 of whom had chronic respiratory problems. This protocol was effective in 44% of the subjects at eliminating MRSA and/or aerobic GNB i.e. Pseudomonas aeruginosa, and Enterobacteriaceae from the throat, and was effective in 86% of the subjects without chronic respiratory problems.

This paper found that 30 seconds of gargling eliminated 60-90% of the bacteria tested, and that recommending it to middle school students appeared to lower the rate of cold and flu when comparing one middle school that used it to others that did not.

This paper cites five papers in support of oral use of povidone-iodine in reducing the risk of ventilator-associated pneumonia, which is typically caused by bacterial infection.

This brochure from 3M supports safety and efficacy against the bacterium S. aureus when applied nasally using a swab and a “virgorous stirring motion” for at least ten seconds.

Despite the evidence supporting its efficacy against bacteria in the human respiratory tract, it isn't obvious that it would be just as effective against viruses, since most bacteria live outside human cells while viruses spend a lot of their lifecycle inside human cells. Presumably topical application of povidone-iodine in the nose, mouth, and throat reaches extracellular bacteria much better than intracellular viruses.

Nevertheless, viruses still spend part of their lifecycle outside of human cells, and this is an essential part of how they first start an infection as they are transmitted to us, and is an essential part of how they replicate and spread, as they exit one human cell to infect another. So, if it can totally inactivate SARS-CoV-2 within 60 seconds in vitro, it seems to me that it must at least be effective in reducing peak viral load when used with the right frequency and timing. It also seems to me that if it is used immediately before and after specific high-risk exposure events, it is likely to significantly reduce the risk of acquiring an infection. After all, the initial exposure is when incoming viruses would all start their journey on the surface of the respiratory tract without yet having entered any human cells.

This paper estimated that the povidone-iodine would likely remain for approximately ten minutes after application, which supports the concept of using it immediately before and after high-risk exposure events and suggests that using it randomly or at a consistent time unrelated to specific exposure events would probably not be effective.

Safety

In the previously cited trial of inhalation of 1% with a jet nebulizer, no adverse effects were noted in 16 subjects.

The brochure from 3M reports their internal studies suggesting that using a sterile swab to apply a 0.5% solution into the nose with ten seconds of “vigorous stirring” had no adverse effects, and that 96% of 76 subjects rated the product as acceptable or very acceptable. These studies don't appear to be published in peer-reviewed literature.

Povidone-iodine has been used extensively in routine medicine for many decades and is overwhelmingly considered safe.

There is a risk that one could be allergic to it, or could develop an allergy by using it, but this appears to be very small. This paper reported the rate of allergic contact sensitivity to povidone-iodine in 500 consecutive patients seeking a skin patch test for suspected skin allergy. The rate was 0.4%. Just under 41% of the patients reported using povidone-iodine topically, often repeatedly, though no information was provided about what concentration or how it was applied. Given that they all had a suspected skin allergy, it seems that the rate of allergy to povidone-iodine must be far less than 0.4% in the general population, and that the risk of developing an allergy while using it would be much less than this when using a low concentration like 0.5% in a targeted manner. Even more to the point, one of the most common uses of povidone-iodine is as an antiseptic on wounds, and open wounds contain “damage-associated molecular patterns” (DAMPs) that could train the immune system to develop an inflammatory response to anything put in the wound. So the rate of developing an allergy while using povidone-iodine is probably even less when using it to sanitize healthy tissue, as would be the case for COVID-19 prevention.

As noted in this paper, there are a number of contraindications for povidone-iodine:

A history of allergy to PVP-I or its relevant excipients (alkyl phenol ether sulphate (ammonium salt), disodium hydrogen phosphate dodecahydrate), all forms of thyroid disease or current radioactive iodine treatment, lithium therapy, known pregnancy, renal failure and dermatitis herpetiformis. The protocol should not be used in a sustained manner in children, but can be used as a single episode, e.g. for dental treatment.

The povidone, because it can bind iodine, can interfere with the effectiveness of radioactive iodine treatment. Lithium and povidone-iodine can both have hypothyroid effects and when combined they can be additive. Excess iodine has the potential to disrupt thyroid hormone metabolism, and that could be harmful to fetal development during pregnancy or early life. Excess iodine is excreted in the urine, and that is impaired during renal failure. Excess iodine has been linked to flareups of dermatitis herpetiformis, the skin manifestation of celiac disease.

Outside of these contraindications and the rare allergy, most adverse effects are associated with high concentrations, high volumes, long durations, and/or general anesthesia. One patient developed hypothyroidism after 3-5 gargles per day for 10 years with a 5% solution, and it fully reversed after stopping the practice. Four patients have developed pneumonitis after pre-surgical use in the oral cavity, but they were all under general anesthesia and appear to have inhaled the povidone-iodine-containing fluid while unconscious. One patient developed cardiovascular collapse, metabolic acidosis, renal failure, and seizures after a 3-hour-long sinus irrigation with 300 mL of a 10% solution. The patient fully recovered with medical treatment.

In vitro evidence also suggests some harm to the respiratory tract when using concentrations above 1%.  As noted in this paper, 1.25% can alter ciliary beat frequency, suggesting functional impairment of respiratory tissue, and 2.5% is toxic to the nasal mucosa.

In sum:

  • There is no documented harm of using 0.5-1.0% solutions in the nose, mouth, or throat, in conscious humans who don't have the contraindications listed above.
  • Allergy is rare, and likely much rarer than 0.4%.
  • Hypothyroidism can occur from frequent use of much higher concentrations over a much longer period of time, and more serious but fully treatable consequences can rarely occur during more extreme procedures or during use in unconscious patients.

Can Lugol's Be Substituted?

Lugol's solution contais a mix of potassium iodide and molecular iodine, freely dissolved in water without any binders. Povidone acts as a binder, and allows a small amount of iodine to be free at any given moment. It was invented to achieve the well established antimicrobial effects of iodine with less of a risk of skin irritation.

In the original patent, it was observed that Lugol's was only effective against S. aureus when diluted down to 4%, while povidone-iodine was effective down to 0.33%. Because povidone binds iodine, it also leads to a lower proportion of the iodine entering the circulation.

It's possible that Lugol's would lead to greater systemic iodine exposure (which could be desirable for some people and undesirable for others) both because it is more freely available and because higher concentrations might be needed.

However, it doesn't follow that the relative efficacy of the two products would be the same for SARS-CoV-2 as observed for S. aureus. There is no way to know the concentration of Lugol's required without it being directly tested.

Would it be effective? Probably. It's just unclear how much would be required compared to povidone-iodine.

The Bottom Line

Outside of the listed contraindications, apart from very rare allergies, there is no evidence that use of 0.5% povidone-iodine in the nose, mouth, or throat causes adverse effects.

It is not clear how effective it would be, but the recent in vitro study showing that 0.5% can completely inactivate SARS-CoV-2 within 60 seconds is promising.

Prior to that study, a number of professional organizations or physicians within them had released protocols to use povidone-iodine for COVID-19 prevention. The American Dental Association currently recommends a 0.2% mouth rinse pre-procedure for COVID-19 prevention in dental patients. This protocol proposed by physicians from the otolaryngology departments of Johns Hopkins and University of Pittsburgh School of Medicine involves nasal irrigation with 240 mL 0.4% and oropharyngeal wash with 10 mL 0.5% every 2-3 hours up to four times per day. This protocol proposed by physicians from the Royal Surrey County Hospital and King’s College London recommended two sprays of 0.5% into each nostril, in each case sniffing while holding the opposite nostril blocked, then swishing with 9 mL for 30 seconds, gargling for 30 seconds, and spitting the solution out, repeating every 2-6 hours up to four times per day. This was recommended for all patients having procedures in and around the nose and mouth, all patients with presumed or confirmed COVID-19, and all health care workers with COVID-19 exposure. The latest in vitro study showing its activity against SARS-CoV-2 adds support to the rationale for these protocols.

It is unlikely to be effective when used randomly, or at a consistent time of day independent of potential exposures, but it is probably useful when used strategically immediately before and after high-risk exposure events.

I have now just released Version 4.1 of The Food and Supplement Guide to the Coronavirus, which contains more extensive coverage of the safety concerns of povidone-iodine and uses copper spray as a backup when povidone-iodine is contraindicated.

Stay safe and healthy,
Chris

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Disclaimer

I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.

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*Footnotes

*  The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.