Summary of COVID-19 antihistamine H1RA studies

101 patient chlorpheniramine early treatment RCT: 61% improved recovery (p=0.0002) and 74% lower PASC (p=0.001).
RCT and retrospective study of chlorpheniramine nasal spray for COVID-19. The RCT included 101 outpatients showing significantly faster recovery with treatment. The retrospective study results are listed separately [Valerio-Pascua]. Long COVID results are from [Valerio-Pascua].
Oct 2022, Research Square, https://www.researchsquare.com/article/rs-2167465/v1, https://c19p.org/valeriopascua3

2. Sanchez-Gonzalez et al., Intranasal Chlorpheniramine Maleate for the treatment of COVID-19: Translational and Clinical Evidence

45 patient chlorpheniramine early treatment RCT: 87% lower hospitalization (p=0.08).
Small RCT showing significantly improved recovery with intranasal chlorpheniramine maleate. Authors also perform an In Vitro study showing efficacy with a highly differentiated three-dimensional model of normal, human-derived tracheal/bronchial epithelial cells.
Dec 2022, Medical Research Archives, https://esmed.org/MRA/index.php/mra/article/view/2752, https://c19p.org/sanchezgonzalez2

3. Monserrat Villatoro et al., A Case-Control of Patients with COVID-19 to Explore the Association of Previous Hospitalisation Use of Medication on the Mortality of COVID-19 Disease: A Propensity Score Matching Analysis

loratadine prophylaxis PSM study: 80% lower mortality (p=0.05).
PSM retrospective 3,712 hospitalized patients in Spain, showing lower mortality with existing use of loratadine.
Jan 2022, Pharmaceuticals, https://www.mdpi.com/1424-8247/15/1/78, https://c19p.org/monserratvillatoroh1

4. Hunt et al., Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans

26,508 patient antihistamine H1RA prophylaxis study: 43% lower mortality (p<0.0001).
Retrospective 26,508 consecutive COVID+ veterans in the USA, showing lower mortality with multiple treatments including antihistamines. Treatment was defined as drugs administered ≥50% of the time within 2 weeks post-COVID+, and may be a continuation of prophylactic treatment. Further reduction in mortality was seen with combinations of treatments.
Jun 2022, J. General Internal Medicine, https://link.springer.com/10.1007/s11606-022-07701-3, https://c19p.org/hunth1

5. Sánchez-Rico et al., Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study

15,103 patient hydroxyzine prophylaxis study: 46% lower mortality (p=0.02).
Retrospective 15,103 hospitalized COVID-19 patients in France showing lower mortality with hydroxyzine use.
Dec 2021, J. Clinical Medicine, https://www.mdpi.com/2077-0383/10/24/5891, https://c19p.org/sanchezrico2

6. Loucera et al., Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments

15,968 patient antihistamine H1RA prophylaxis study: 40% lower mortality (p=0.003).
Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with antihistamine H1RAs, without statistical significance. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Aug 2022, Virology J., https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02195-9, https://c19p.org/loucera3h1

7. Reznikov et al., Identification of antiviral antihistamines for COVID-19 repurposing

antihistamine H1RA prophylaxis study: 34% fewer cases (p<0.0001).
Retrospective 219,000 patients showing lower risk of COVID-19 with antihistamine H1RA use. In Vitro study showing these drugs exhibit direct antiviral activity against SARS-CoV-2. Molecular docking suggests hydroxyzine and azelastine may exert antiviral effects by binding ACE2 and the sigma-1 receptor.
Jan 2021, Biochemical and Biophysical Research Communications, https://www.sciencedirect.com/science/article/pii/S0006291X20321409, https://c19p.org/reznikov

8. Valerio-Pascua et al., Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials

660 patient chlorpheniramine early treatment study: 54% faster recovery (p<0.0001).
RCT and retrospective study of chlorpheniramine nasal spray for COVID-19. The retrospective study included 660 outpatients showing fewer days with general COVID-19 symptoms, cough, anosmia, and ageusia compared to standard of care alone. The RCT results are listed separately [Valerio-Pascua].
Oct 2022, Research Square, https://www.researchsquare.com/article/rs-2167465/v1, https://c19p.org/valeriopascua3b

9. Hoertel et al., Association between Hydroxyzine Use and Reduced Mortality in Patients Hospitalized for Coronavirus Disease 2019: Results from a multicenter observational study

7,345 patient hydroxyzine prophylaxis study: 58% lower mortality (p=0.001).
Retrospective 7,345 hospitalized COVID-19 patients in France showing lower mortality with hydroxyzine use, with a significant dose-response relationship. Hydroxyzine was also associated with a faster decrease in inflammatory markers.
Oct 2020, medRxiv, https://www.medrxiv.org/content/10.1101/2020.10.23.20154302, https://c19p.org/hoertel6

10. Meiser et al., Azelastine Nasal Spray in Non-Hospitalised Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial

251 patient azelastine late treatment RCT: 13% improved recovery (p=0.42) and 6% improved viral clearance (p<0.0001).
RCT 294 low-risk subjects with mild COVID-19 showing significantly greater reduction in viral load with azelastine 0.1% nasal spray vs. placebo. There was no COVID-19 related hospitalization in either group. The reduction in viral load was significantly higher in the azelastine group at day 3, 6 and 11. Authors report that treatment was associated with significant improvement in fever (p=0.0046), weakness (p=0.0012) and hypoxia (p<0.0001) compared to placebo, however detailed results are not provided for these and other symptoms. Treatment delay from symptom onset is not specified, however the baseline viral load, lack of progression, and recovery profile are consistent with relatively late treatment among low-risk patients. Time to recovery results are not clear, with an inconsistent HR and 95% CI reported 0.32 [0.83-2.32].
Oct 2024, MDPI AG, https://www.preprints.org/manuscript/202410.2532/v1, https://c19p.org/meiser

11. Vila‐Corcoles et al., Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

34,936 patient antihistamine H1RA prophylaxis study: 61% fewer cases (p=0.1).
Retrospective 34,936 hypertensive outpatients in Spain showing no significant difference in COVID-19 cases with PPIs and antihistamine H1RAs.
Jul 2020, The J. Clinical Hypertension, https://onlinelibrary.wiley.com/doi/10.1111/jch.13948, https://c19p.org/vilacorcoles2h1

12. Vila-Córcoles et al., Influence of prior comorbidities and chronic medications use on the risk of COVID-19 in adults: a population-based cohort study in Tarragona, Spain

79,083 patient antihistamine H1RA prophylaxis study: 53% fewer cases (p=0.05).
Retrospective 79,083 adults aged ≥50 years in Spain showing lower with of PCR-confirmed COVID-19 with antihistamine use, close to statistical significance.
Dec 2020, BMJ Open, https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2020-041577, https://c19p.org/vilacorcoles

13. Salvucci et al., Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation

27 patient antihistamine H1RA long COVID study: 29% lower PASC (p=0.1).
Retrospective 14 patients with long-COVID symptoms attributed to mast cell activation treated with H1 and H2 antihistamines compared to 13 control patients, showing significant improvements in several symptoms in the treatment group compared to controls after 20 days. 29% of treated patients had complete resolution of long-COVID symptoms, compared with none in the control group.
Jul 2023, Frontiers in Cardiovascular Medicine, https://www.frontiersin.org/articles/10.3389/fcvm.2023.1202696/full, https://c19p.org/salvucci

14. Mura et al., Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients

176 patient antihistamine H1RA late treatment PSM study: 25% lower mortality (p=0.4).
PSM retrospective TriNetX database analysis of 1,379 severe COVID-19 patients requiring respiratory support, showing lower mortality with H1RAs+H2RAs versus famotidine alone, without statistical significance.
Mar 2021, Signal Transduction and Targeted Therapy, https://www.nature.com/articles/s41392-021-00689-y, https://c19p.org/murah1

15. Hoertel et al., Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study

5,772 patient antihistamine H1RA prophylaxis study: 7% higher mortality (p=0.5).
Retrospective 72,105 COVID+ hospitalized patients in France, showing no significant difference in mortality with antihistamine H1RAs desloratadine and hydroxyzine.
Aug 2023, Pharmaceuticals, https://www.mdpi.com/1424-8247/16/8/1107, https://c19p.org/hoertel5h1

16. McKeigue et al., Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study

36,160 patient antihistamine H1RA prophylaxis study: 30% higher severe cases (p=0.0004).
Retrospective 4,251 severe COVID-19 cases and 36,738 matched controls in Scotland showing increased risk of severe COVID-19 with PPI use and antihistamine H1RA use. Adjusted results are only provided for the patients not in care homes (2,357 cases and 33,803 controls).
Feb 2021, BMC Medicine, https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-01907-8, https://c19p.org/mckeigueh1

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