COVID-19 treatment: respiratory tract administration

Over 10,000 compounds predicted to reduce risk—SARS-CoV-2 easily disabled SARS-CoV-2 infection and replication involves a complex interplay of over 200 host and viral proteins and other factors1-8, providing many therapeutic targets. Scientists have identified 10,209+ compounds9 potentially beneficial for COVID-19. Hundreds of compounds inhibit SARS-CoV-2 in vitro, including many with known pharmacokinetics and proven safety.

Naso/oropharyngeal treatment is effective Many compounds with existing safety records are expected to be beneficial within the upper respiratory tract. 86 clinical studies show lower risk for early treatment or prophylaxis with povidone-iodine, alkalinization, nitric oxide, iota-carrageenan, phthalocyanine, hydrogen peroxide, chlorhexidine, NaCl, cetylpyridinium chloride, chlorpheniramine, and azelastine10-101, confirmed in multiple additional meta analyses102-105. Targeted administration to the respiratory tract has several advantages:

Naso/oropharyngeal treatments may be effective via many mechanisms, e.g.: inactivating virions, blocking attachment/entry, creating a physical barrier, mechanical clearance, altering the environment to hinder fusion/replication, inhibiting spike-priming proteases, enhancing mucociliary function, and priming local innate immunity(a).

Studies use various administration methods including nasal/oral sprays, rinses, and inhalation. Combined nasal/oral application shows the highest efficacy. Efficacy depends on administration details, e.g., viscosity, mucoadhesion, sprayability, and the angle of administration for sprays106. 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).

Only 4% of studies we cover used direct naso/oropharyngeal treatment, despite the strong potential and advantages. With focused research, safe, inexpensive, and effective naso/oropharyngeal treatments may be rapidly identified for new respiratory pathogens.

Many other treatments may be effective including astodrimer sodium107-110, benzalkonium chloride111, CDCM112,113, dequalinium chloride111, hypochlorous acid112, hexadecyl pyridinium chloride114, ethyl lauroyl arginate115, Sinomarin44, PCANS116, SA58117-120, ColdZyme121, Panthexyl122, HH-120123,124, TriSb92125, IBIO123126, homoharringtonine127, A8G6128,129, STI-9167130, FSY-ACE2-NVs nanoSpray131, and Sentinox132.

Naso/oropharyngeal treatments experience regulatory challenges. For example the US FDA shut down a povidone-iodine treatment133 when 7 RCTs showed efficacy, and the FTC sent warning letters to companies that referenced studies showing benefits of nasal/oral hygiene for COVID-19134-136.

Naso/oropharyngeal treatment reduces transmission Immediate or prophylactic naso/oropharyngeal treatment also logically reduces transmission. A 621-patient RCT showed 92% reduction in transmission with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic acid17. Naso/oropharyngeal treatment shows far greater efficacy against transmission than the commonly recommended masking, where the 4 COVID-19 RCTs to date show no significant efficacy (2.2% [-25‑24%] improvement139).

Protocols 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 actionsThere are many complementary mechanisms of action across treatments, and studies show complementary and synergistic effects with polytherapy143-159. For example, Jitobaom et al.144 shows >10x reduction in IC₅₀ with ivermectin and niclosamide, an RCT by Said et al.151 showed the combination of nigella sativa and vitamin D was more effective than either alone, and an RCT by Wannigama et al.160 showed improved results with fluvoxamine combined with additional treatments, compared to fluvoxamine alone. Treatment efficacy may vary significantly across SARS-CoV-2 variants. For example new variants may gain resistance to targeted treatments161-167, and the role of TMPRSS2 for cell entry differs across variants168. The efficacy of treatments varies depending on cell type169 due to differences in viral receptor expression, drug distribution and metabolism, and cell-specific mechanisms. Efficacy may also vary based on genetic variants170-179. 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 pressure180. Antigenic drift can undermine more variant-specific treatments like monoclonal antibodies and more specific antivirals. Treatment with targeted antivirals may select for escape mutations181. Less variant specific treatments and polytherapy targeting multiple viral and host proteins may be more effective.