COVID-19 treatment: respiratory tract administration

Over 8,000 compounds predicted to reduce COVID-19 risk. SARS-CoV-2 is easily disabled. SARS-CoV-2 infection and replication involves a complex interplay of over 50 host and viral proteins and other factors1-7, providing many therapeutic targets. Scientists have identified 8,859+ compounds8 potentially beneficial for COVID-19. Hundreds of compounds inhibit SARS-CoV-2 in vitro, including many with established pharmacokinetic profiles and proven safety.

Nasopharyngeal/oropharyngeal treatment is effective. Many compounds with existing safety records are expected to be beneficial within the upper respiratory tract. 66 clinical studies show lower risk for early treatment or prophylaxis with povidone-iodine, iota-carrageenan, nitric oxide, alkalinization, phthalocyanine, hydrogen peroxide, chlorhexidine, and chlorpheniramine10-82, confirmed in multiple additional meta analyses83-85. Studies show a degree of efficacy even with delayed treatment. Targeted administration to the respiratory tract has several advantages:

Studies use various administration methods including nasal and oral sprays, nasal irrigation, oral rinses, and inhalation. Nasal application shows higher efficacy than oral application, and the combination of both is most effective in studies to date. Efficacy depends on administration details, e.g. viscosity, mucoadhesion, sprayability, and the angle of administration for sprays86. Some treatments may disrupt beneficial microbial populations, requiring care to avoid side effects and suggesting a preference for more selective treatments, especially with longer-term use(b).

Despite the strong potential and advantages of directing treatment to the primary location of initial infection, only 4% of studies we cover did so. With focused research, safe, inexpensive, and effective nasopharyngeal/oropharyngeal treatments may be rapidly identified after discovery of new respiratory pathogens.

Many other treatments may be effective including cetylpyridinium chloride87, azelastine88,89, astodrimer sodium90-93, benzalkonium chloride94, CDCM87,95, dequalinium chloride94, hypochlorous acid87, hexadecyl pyridinium chloride96, ethyl lauroyl arginate97, Sinomarin59, PCANS98, pHOXWELL99, Panthexyl100, HH-120101,102, TriSb92103, homoharringtonine104, A8G6105,106, STI-9167107, FSY-ACE2-NVs nanoSpray108, and saline109. Several have studies showing lower viral load, but no controlled studies reporting clinical outcomes.

Naso/oropharyngeal treatments experience regulatory challenges. For example the US FDA shut down a povidone-iodine treatment110 at a time when 7 RCTs indicated efficacy. The FTC sent warning letters to companies that referenced studies showing benefits of nasal/oral hygiene for COVID-19111-113. Similarly, the FDA has failed to approve SaNOtize114, although it is available in many other countries115.

Nasopharyngeal/oropharyngeal treatment reduces transmission. Immediate or prophylactic nasopharyngeal/oropharyngeal treatment also logically reduces transmission. An RCT including 200 patients and 421 close contacts showed 92% reduction in transmission with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic acid17.

Protocols typically combine multiple treatments. No single treatment is guaranteed to be effective and safe for a specific individual. Leading evidence-based protocols combine multiple treatments.

Complementary and synergistic actions. There are many complementary mechanisms of action across treatments, and studies show complementary and synergistic effects with polytherapy117-133. For example, Jitobaom et al.118 showed >10x reduction in IC₅₀ with ivermectin and niclosamide, an RCT by Said et al.125 showed the combination of nigella sativa and vitamin D was more effective than either alone, and an RCT by Wannigama et al.134 showed improved results with fluvoxamine combined with bromhexine, cyproheptadine, or niclosamide, compared to fluvoxamine alone. Treatment efficacy may vary significantly across SARS-CoV-2 variants. For example new variants may gain resistance to targeted treatments135-141, and the role of TMPRSS2 for cell entry differs across variants142. The efficacy of specific treatments varies depending on cell type143 due to differences in viral receptor expression, drug distribution and metabolism, cell-specific mechanisms, and the relevance of drug targets to specific cells. Efficacy may also vary based on genetic variants144-147. Variable efficacy across SARS-CoV-2 variants, cell types, different tissues, and host genetics, along with the complementary and synergistic actions of different treatments, all point to greater efficacy with polytherapy. In many studies, the standard of care given to all patients includes other treatments—efficacy seen in these trials may rely in part on synergistic effects. Meta analysis of all early treatment trials shows 68% [57‑77%] lower risk for studies using combined treatments, compared to 33% [30‑36%] for single treatments.

SARS-CoV-2 evolution and the risk of escape mutants suggests treatments with broader mechanisms of action and polytherapy. SARS-CoV-2 can rapidly acquire mutations altering infectivity, disease severity, and drug resistance even without selective pressure148. Antigenic drift can undermine more variant-specific treatments like monoclonal antibodies and more specific antivirals. Treatment with targeted antivirals may select for escape mutations149. Less variant specific treatments and polytherapy targeting multiple viral and host proteins may be more effective.