Which antihistamine drugs have been found to reduce COVID-19 cases and disease severity?
For context, this is a question I answered on Quora
The most effective one to date is Azelastine administered via nasal spray, but others such as Chlorpheniramine have also been found to inhibit viral action even in already infected persons.
One of the earliest pieces of evidence that antihistamines inhibit SARS-Coronavirus infection and replication came from a cell culture and retrospective analysis study conducted at the University of Florida. They found that drugs like hydroxyzine binds to the angiotensin converting enzyme-2 receptors the spike protein binds to infect cells as well as the sigma-1 receptor that the virus hijacks to replicate itself and the HRH1 receptor that the virus uses as an alternative to the ACE2 receptor. One antihistamine in particular, Azelastine, was found to inhibit the SARS-Coronavirus at doses smaller than what is prescribed in nasal sprays. In a retrospective analysis of medical records from a quarter million California patients they found that those who used certain antihistamines were less likely to test positive for the virus than those who didn’t.
A retrospective observational study conducted in two nursing homes in Spain at the primary care level between March and June 2020 (n = 84) found that early combined use of antihistamines and azithromycin was associated with a lower COVID-19 mortality rate in the two nursing homes than the national average. None of the patients in these two nursing homes died from COVID-19 despite all patients being seropositive for SARS-Coronavirus antibodies in June 2020. In stark contrast, the average COVID-19 mortality rate for elderly nursing home patients in Spain was around 20-30% at this time.
A retrospective cohort trial conducted in the same region of Yepes, Spain between March 2020 and August 2021 among COVID-19 patients confirmed through qPCR or rapid antigen test (n = 468) found that the cohort who received early outpatient treatment with antihistamines and azithromycin had reduced odds of hospitalization (4.3%), ICU admission (1.1%) and COVID-19 mortality (0.6%), compared to the Spanish national average at the time. Compared to official Spanish data for the same period, the odds of hospitalization were reduced by 51% with none of the hospitalized cohort developing Long COVID after discharge.
Placebo controlled double blind RCTs have since verified these preliminary findings.
A phase 2 double blind RCT conducted at a German university hospital between March 2023 and July 2024 among healthy adult participants (n = 450) found that Azelastine 0.1% nasal spray, administered 3x a day, reduced rapid antigen test and PCR confirmed SARS-cornavirus infections nearly 3x compared to the placebo group from a 6.7% infection rate to a 2.2% infection rate over the course of 56 days. That is a 69% relative risk reduction in COVID-19 cases compared to placebo. Azelastine nasal spray also delayed average time to infection from 19.5 days (placebo) to 31.2 days and infected participants given azelastine had fewer COVID-19 symptoms (21) compared to placebo participants (49). Azelastine nasal spray reduced the rapid antigen test rhinovirus (common cold) infection rate 3.5x compared to placebo from 6.3% to 1.8% with a similar rate of adverse events reported across both groups. This is sold under the brand names Astelin, Astepro and Dymista. Another nasally administered antihistamine has also shown promising results against COVID-19.
A review of clinical trial results and in vitro studies found that treating COVID-19 patients with chlorpheniramine maleate (i.e. Chlorpheniramine) nasal spray for 7 days after diagnosis led to faster symptom resolution and lower disease severity scores compared to placebo over the same time frame in the ACCROS I and III phase double blind RCT (n = 45). None of the patients treated with intranasal chlorpheniramine maleate were hospitalized. Long COVID patients treated with intranasal chlorpheniramine maleate in the Phase III clinical trial (n = 180) experienced reduced symptom incidence compared to placebo group in the post intervention analysis. None of the intervention group patients experienced fatigue or mental confusion, compared to 14.2% and 18.3% in the placebo group. About 1% of the intervention group report difficulty performing daily activities compared to 32% of the placebo group and none of the participants in the intervention group reported seeking medical attention for post acute sequela symptoms compared to 40% of the placebo group. This review notes that Chlorpheniramine can inhibit the SARS-Coronavirus by interfering with viral absorption on the ACE2 (angiotensin converting enzyme-2) receptors, reduces viral RNA synthesis by forming hydrogen bonds with RNA-dependent RNA polymerase and the spike protein itself. More importantly, delivering this drug in a nasal spray appears to activate mucosal immunity through the bitter taste receptors in the upper respiratory tract and reduces pro-inflammatory cytokine production through H1 receptor antagonism which explains reduced symptom severity in the aforementioned treatment groups.