Summary of COVID-19 PPI studies

179 patient PPI prophylaxis study: 56% fewer cases (p=0.005).
Retrospective 179 elderly patients in France, showing higher risk of COVID-19 cases with acetaminophen use, without statistical significance.
May 2020, Preprints, https://www.preprints.org/manuscript/202005.0016/v1, https://c19p.org/blanc2ppi

2. Hirsch et al., Proton Pump Inhibitors and Risk of COVID-19 Infection in Children

116,209 patient PPI prophylaxis study: 15% lower hospitalization (p=0.27) and 15% fewer cases (p=0.002).
Retrospective 116,209 pediatric patients showing lower risk of COVID-19 with PPI use. There was no significant difference for hospitalization.
Jun 2024, The J. Pediatrics, https://www.sciencedirect.com/science/article/pii/S0022347624002828, https://c19p.org/hirsch2

3. Cheung et al., Association Between Famotidine Use and COVID-19 Severity in Hong Kong: A Territory-wide Study

952 patient PPI prophylaxis study: 25% lower severe cases (p=0.8).
Retrospective 952 COVID-19 patients in Hong Kong, showing no significant difference in severe disease with famotidine use or PPI use.
Apr 2021, Gastroenterology, https://www.gastrojournal.org/article/S0016-5085(20)34940-4/fulltext, https://c19p.org/cheungppi

4. Morán Blanco et al., Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

84 patient PPI prophylaxis study: 31% fewer symptomatic cases (p=0.34).
Retrospective 84 elderly nursing home residents in Spain showing no mortality, hospitalization, or ICU admission with early treatment with antihistamines alone or in combination with azithromycin.
Apr 2021, Pulmonary Pharmacology & Therapeutics, https://www.sciencedirect.com/science/article/pii/S1094553921000018, https://c19p.org/moranblancoppi

5. Mas Romero et al., COVID-19 outbreak in long-term care facilities from Spain. Many lessons to learn

198 patient PPI prophylaxis study: 26% lower mortality (p=0.44) and 8% more symptomatic cases (p=0.54).
Retrospective 1,084 residents from 6 long-term care facilities in Spain showing no signficant difference in cases and mortality with PPI use in unadjusted results.
Oct 2020, PLOS ONE, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241030, https://c19p.org/masromero

6. Shupp et al., Proton pump inhibitor therapy usage and associated hospitalization rates and critical care outcomes of COVID-19 patients

2,496 patient PPI prophylaxis study: 19% lower mortality (p=0.32) and 10% higher hospitalization (p=0.51).
Retrospective 2,594 COVID-19 patients in the United States showing no significant association between proton pump inhibitor (PPI) use and COVID-19 severity, including need for hospitalization or 30-day mortality. There was increasing mortality with increasing PPI use with 14%, 20%, and 27% mortality for low, standard, and high use, without statistical significance.
May 2022, Scientific Reports, https://www.nature.com/articles/s41598-022-11680-0, https://c19p.org/shupp

7. Elmunzer et al., Association Between Preadmission Acid Suppressive Medication Exposure and Severity of Illness in Patients Hospitalized With COVID-19

1,846 patient PPI prophylaxis study: 13% lower mortality (p=0.31) and 2% higher ventilation (p=0.89).
Retrospective 1,846 hospitalized COVID-19 patients in North America showing no significant association between preadmission proton pump inhibitor (PPI) use and mechanical ventilation or mortality. Results do not account for the risk of hospitalization based on PPI use.
Mar 2021, Gastroenterology, https://www.sciencedirect.com/science/article/pii/S0016508520353956, https://c19p.org/elmunzer

8. Kodvanj et al., People exposed to proton‐pump inhibitors shortly preceding COVID‐19 diagnosis are not at an increased risk of subsequent hospitalizations and mortality: A nationwide matched cohort study

58,529 patient PPI prophylaxis study: 7% lower mortality (p=0.12) and 4% higher hospitalization (p=0.32).
Retrospective 433,609 COVID-19 patients in Croatia showing no significant difference in mortality or hospitalization risk with proton-pump inhibitor (PPI) use before COVID-19 diagnosis compared to matched controls with PPI-requiring morbidities but no PPI prescriptions. There was significantly higher hospitalization for users with 1-3 prescriptions which authors do not comment on. The classification of users and possible users may introduce confounding. Users required a PPI prescription, while possible users includes those with ≥3 NSAID prescriptions. Possible users may be OTC PPI users, and may differ significantly in NSAID use. NSAID use per group is not reported, and was not used in adjustments.
Oct 2022, British J. Clinical Pharmacology, https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15525, https://c19p.org/kodvanj

9. Argenziano et al., Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series

1,000 patient PPI prophylaxis study: 1% lower ICU admission (p=1) and 9% higher hospitalization (p=0.01).
Retrospective 1,000 hospitalized COVID-19 patients in New York City showing high rates of acute kidney injury, inpatient dialysis, prolonged intubation times, and length of stay compared to previous cohorts.
May 2020, BMJ, https://www.bmj.com/lookup/doi/10.1136/bmj.m1996, https://c19p.org/argenziano

10. Zhang et al., Analysis of the Effect of Proton-Pump Inhibitors on the Course of COVID-19

154 patient PPI prophylaxis PSM study: 11% longer hospitalization (p=0.29), 6% higher hospital discharge (p=0.82), and 37% improved viral clearance (p=0.05).
Retrospective 154 hospitalized moderate COVID-19 patients in China showing no significant difference in viral clearance time or hospital stay duration with proton pump inhibitor (PPI) use. There was no association between PPI use and viral clearance or hospital stay duration in univariate or multivariate analysis. The same results were obtained after propensity score matching.
Feb 2021, J. Inflammation Research, https://www.dovepress.com/analysis-of-the-effect-of-proton-pump-inhibitors-on-the-course-of-covi-peer-reviewed-article-JIR, https://c19p.org/zhang30

11. Shah et al., Proton-pump inhibitor use is not associated with severe COVID-19-related outcomes: a propensity score-weighted analysis of a national veteran cohort

14,958 patient PPI prophylaxis study: 3% lower mortality (p=0.66), 21% higher ventilation (p=0.06), 13% higher ICU admission (p=0.06), and 5% higher hospitalization (p=0.26).
Retrospective 14,958 US veterans who tested positive for SARS-CoV-2, showing no significant difference in severe COVID-19 outcomes (mechanical ventilation, death, ICU admission, or hospitalization) with proton pump inhibitor (PPI) use compared to non-use in a propensity score weighted analysis.
Oct 2021, Gut, https://gut.bmj.com/lookup/doi/10.1136/gutjnl-2021-325701, https://c19p.org/shah8

12. Shafrir et al., The Association Between Proton Pump Inhibitors and COVID-19 is Confounded by Hyperglycemia in a Population-Based Study

250,655 patient PPI prophylaxis PSM study: 47% higher severe cases (p=0.32) and 8% fewer cases (p=0.06).
Retrospective 255,355 adults in Israel showing no significant association between proton pump inhibitor (PPI) use and SARS-CoV-2 positivity or COVID-19 severity.
Feb 2022, Frontiers in Pharmacology, https://www.frontiersin.org/articles/10.3389/fphar.2022.791074/full, https://c19p.org/shafrir

13. Israelsen et al., Proton Pump Inhibitor Use Is Not Strongly Associated With SARS-CoV-2 Related Outcomes: A Nationwide Study and Meta-analysis

7,910 patient PPI prophylaxis PSM study: 5% lower mortality (p=0.7), 8% higher ventilation (p=0.73), 5% higher ICU admission (p=0.8), and 22% higher hospitalization (p=0.005).
Retrospective 83,224 SARS-CoV-2 cases and 332,799 controls in Denmark showing increased risk of infection and hospital admission with proton pump inhibitor (PPI) use, but no significant association with ICU admission or mortality.
Sep 2021, Clinical Gastroenterology and Hepatology, https://www.sciencedirect.com/science/article/pii/S1542356521005140, https://c19p.org/israelsen

14. Shokri et al., What is the role of proton pump inhibitors consumption on the clinical presentation and severity of COVID-19 infection?

670 patient PPI prophylaxis study: 81% higher severe cases (p=0.05) and 78% higher mortality (p=0.21).
Retrospective 670 COVID-19 patients in Iran showing significantly higher COVID-19 severity scores and more symptomatic presentation in patients with a history of proton pump inhibitor (PPI) use. Adjusted results are only provided for severity. Several values in Table 4 are likely misreported raising concern for the reliability of the main result.
Mar 2023, Annales Pharmaceutiques Françaises, https://www.sciencedirect.com/science/article/pii/S0003450922001122, https://c19p.org/shokri

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

36,160 patient PPI prophylaxis study: 44% higher severe cases (p<0.0001).
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/mckeigue

16. 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 PPI prophylaxis study: 9% more cases (p=0.58).
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/vilacorcoles2

17. Freedberg et al., Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study

1,620 patient PPI prophylaxis PSM study: 34% higher combined mortality/intubation (p=0.01).
PSM retrospective 1,620 hospitalized patients in the USA, showing higher risk of combined death/intubation with PPI treatment.
May 2020, Gastroenterology, https://www.gastrojournal.org/article/S0016-5085(20)34706-5/fulltext, https://c19p.org/freedbergppi

18. Fan et al., Effect of Acid Suppressants on the Risk of COVID-19: A Propensity Score-Matched Study Using UK Biobank

PPI prophylaxis PSM study: 17% higher mortality (p=0.69) and 22% more cases (p=0.15).
PSM retrospective 9,469 UK Biobank participants tested for COVID-19, showing no significant association between proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) use and risk of SARS-CoV-2 infection or COVID-19 mortality. Omeprazole was associated with higher risk of cases in patients with upper gastrointestinal diseases. The results for patients with upper gastrointestinal diseases should be more accurate due to reduced confounding and more accurate ascertainment of current use.
Jan 2021, Gastroenterology, https://www.sciencedirect.com/science/article/pii/S0016508520352094, https://c19p.org/fan4

19. Yan et al., Clinical Characteristics of Coronavirus Disease 2019 in Hainan, China

168 patient PPI prophylaxis study: 240% higher severe cases (p<0.0001).
Retrospective 168 hospitalized COVID-19 patients in China showing higher risk of severe cases with acid suppression drugs.
Mar 2020, medRxiv, https://www.medrxiv.org/content/10.1101/2020.03.19.20038539, https://c19p.org/yan6

20. Zeng et al., Associations of proton pump inhibitors with susceptibility to influenza, pneumonia, and COVID-19: Evidence from a large population-based cohort study

160,923 patient PPI prophylaxis study: 46% higher mortality (p=0.02), 33% higher severe cases (p=0.004), and 8% more cases (p=0.1).
UK Biobank retrospective with 160,923 patients showing increased risks of influenza, pneumonia, COVID-19 severity, and COVID-19 mortality with proton pump inhibitor (PPI) use.
Jul 2024, eLife, https://elifesciences.org/articles/94973, https://c19p.org/zeng2

21. Lee et al., Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching

27,746 patient PPI prophylaxis PSM study: 79% higher severe cases (p=0.009) and 10% fewer cases (p=0.11).
PSM retrospective 132,316 patients in South Korea, showing significantly higher risk of severe COVID-19 with PPI use, but no significant difference in cases.
Jul 2020, Gut, https://gut.bmj.com/lookup/doi/10.1136/gutjnl-2020-322248, https://c19p.org/lee15

22. Cheung et al., Proton pump inhibitors associated with severe COVID‐19 among two‐dose but not three‐dose vaccine recipients

439,154 patient PPI prophylaxis study: 49% higher mortality (p=0.005), 36% higher severe cases (p=0.27), 20% higher hospitalization (p=0.0003), and 9% more cases (p<0.0001).
Retrospective 627,514 patients in Hong Kong showing slightly higher risk of COVID-19 with pre-vaccination proton pump inhibitor (PPI) use in two-dose or three-dose vaccine recipients, and higher risk of hospitalization and severe outcomes only in two-dose recipients.
May 2024, J. Gastroenterology and Hepatology, https://onlinelibrary.wiley.com/doi/10.1111/jgh.16601, https://c19p.org/cheung2

23. Elkanzi et al., Effect of Preadmission Proton Pump Inhibitor (PPI) on the clinical outcome of Covid-19 Hospitalised Patients during the Pandemic

309 patient PPI prophylaxis study: 17% higher mortality (p=0.49), 25% higher ICU admission (p=0.05), 126% higher progression (p=0.14), and 19% shorter hospitalization (p=0.18).
Retrospective 309 hospitalized patients showing higher risk of severe cases (ASA≥3) with PPI use.
Nov 2023, Academic J. Gastroenterology & Hepatology, https://www.researchgate.net/publication/375801185_Effect_of_Preadmission_Proton_Pump_Inhibitor_PPI_on_the_clinical_outcome_of_Covid-19_Hospitalised_Patients_during_the_Pandemic_Academic_Journal_of, https://c19p.org/elkanzi

24. Gramont et al., Proton pump inhibitors and risk of severe COVID-19 in older people

834 patient PPI prophylaxis study: 59% higher severe cases (p=0.002).
Retrospective 834 elderly patients in France showing higher risk of severe COVID-19 with PPI use, and increasing risk with increasing dosage.
Apr 2024, Age and Ageing, https://academic.oup.com/ageing/article/doi/10.1093/ageing/afae082/7645558, https://c19p.org/gramont

25. Liwang et al., High vs Low Dose Proton Pump Inhibitor (PPI) related Mortality in Hospitalized Coronavirus Disease-19 (COVID-19): A Retrospective Cohort Study

365 patient PPI late treatment study: 204% higher mortality (p=0.02).
Retrospective hospitalized COVID-19 patients in Indonesia showing higher mortality with high dose proton pump inhibitor (PPI) use compared to low dose.
Aug 2022, J. Of The Indonesian Medical Association, https://mki-ojs.idionline.org/jurnal/article/view/802, https://c19p.org/liwang

26. Yao et al., Impact of proton pump inhibitors on the in-hospital outcome of COVID-19 patients: a retrospective study

3,024 patient PPI late treatment study: 600% higher severe cases (p<0.0001).
Retrospective 3,024 hospitalized COVID-19 patients in China showing increased risk of the composite outcome of ICU admission, mechanical ventilation, or death with proton pump inhibitor (PPI) use. Intravenous administration was significantly worse than oral. Authors hypothesize that PPIs may lead to worse COVID-19 outcomes by increasing the risk of secondary infections, cardiac damage, renal damage, and liver complications.
Jan 2022, Therapeutic Advances in Gastroenterology, http://journals.sagepub.com/doi/10.1177/17562848221104365, https://c19p.org/yao3

27. Jimenez et al., Acid pH Increases SARS-CoV-2 Infection and the Risk of Death by COVID-19

1,357 patient PPI prophylaxis study: 124% higher mortality (p<0.0001).
In Vitro study showing lower pH increased ACE2 expression and viral load on SARS-CoV-2 infection, and retrospective study showing proton pump inhibitor use, which is correlated with low gastric pH-related diseases, was associated with higher mortality.
Aug 2021, Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2021.637885/full, https://c19p.org/jimenez2ppi

28. Liu et al., Increased ACE2 Levels and Mortality Risk of Patients With COVID-19 on Proton Pump Inhibitor Therapy

686 patient PPI prophylaxis study: 127% higher mortality (p=0.001).
Prospective study showing COVID- PPI users had higher salivary ACE2 expression, and retrospective analysis of 694 hospitalized COVID-19 patients, showing higher mortality with PPI use.
May 2021, American J. Gastroenterology, https://journals.lww.com/10.14309/ajg.0000000000001311, https://c19p.org/liu22

29. Zhou et al., Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study

3,144 patient PPI late treatment PSM study: 165% higher severe cases (p=0.0001).
Retrospective 4,445 COVID+ patients in China, showing higher risk of combined death/intubation/ICU with famotidine and with PPIs.
Dec 2020, Gut, https://gut.bmj.com/content/70/10/2012.full, https://c19p.org/zhou3ppi

30. Almario et al., Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors

51,973 patient PPI prophylaxis study: 179% more cases (p=0.0001).
Survey of 53,130 individuals with a history of GI symptoms showing increased risk of COVID-19 positivity with proton pump inhibitor (PPI) use, especially twice-daily PPI use. There was a dose-response relationship between PPI use and COVID-19 risk. Those taking PPIs twice daily had 3.67 times higher odds of testing positive compared to those not taking PPIs. The authors hypothesize that PPI-induced hypochlorhydria may impair the body's defense against ingested pathogens like SARS-CoV-2.
Aug 2020, American J. Gastroenterology, https://journals.lww.com/10.14309/ajg.0000000000000798, https://c19p.org/almario

31. Kim et al., Histamine-2 Receptor Antagonists and Proton Pump Inhibitors Are Associated With Reduced Risk of SARS-CoV-2 Infection Without Comorbidities Including Diabetes, Hypertension, and Dyslipidemia: A Propensity Score-Matched Nationwide Cohort Study

874 patient PPI prophylaxis PSM study: 28% higher mortality (p=0.63), 75% higher ventilation (p=0.37), 150% higher ICU admission (p=0.11), and 21% higher progression (p=0.6).
PSM retrospective in South Korea, showing lower risk of COVID-19 cases with H2RA (including famotidine) and PPI use, but no significant difference in severe outcomes (results provided for the combined groups only).
Mar 2023, J. Korean Medical Science, https://jkms.org/DOIx.php?id=10.3346/jkms.2023.38.e99, https://c19p.org/kim11ppi

32. Wu et al., Use of proton pump inhibitors are associated with higher mortality in hospitalized patients with COVID-19

4,634 patient PPI prophylaxis study: 197% higher mortality (p=0.0004) and 10% worse viral clearance (p=0.02).
Retrospective 4,634 hospitalized COVID-19 patients in China, showing higher mortality and slower viral clearance with proton pump inhibitor (PPI) use. Authors hypothesize that PPIs may increase susceptibility to COVID-19 by increasing ACE2 expression.
Feb 2022, J. Global Health, http://jogh.org/documents/2022/jogh-12-05005.pdf, https://c19p.org/wu12

33. Al-Momani et al., Proton pump inhibitors and gastrointestinal symptoms among patients with COVID-19 infection

253 patient PPI prophylaxis study: 100% higher mortality (p=0.39), 48% higher ventilation (p=0.54), and 25% higher ICU admission (p=0.64).
Retrospective 254 hospitalized COVID-19 patients in Jordan showing higher rates of gastrointestinal symptoms such as abdominal pain and diarrhea with proton pump inhibitor (PPI) use. There were no significant differences for mortality, ventilation, and ICU admission. Authors hypothesize that PPIs may facilitate SARS-CoV-2 survival and invasion in the gastrointestinal tract.
Jun 2024, Annals of Medicine, https://www.tandfonline.com/doi/full/10.1080/07853890.2024.2355581, https://c19p.org/almomani

34. Patil et al., Factors Associated With Poor Outcomes Among Patients With SARS-CoV-2 Coronavirus Infection and Gastrointestinal Symptoms

19,915 patient PPI prophylaxis study: 48% higher mortality (p<0.0001), 119% higher ARDS (p<0.0001), 88% worse results (p<0.0001), and 73% higher need for oxygen therapy (p<0.0001).
Retrospective 19,915 hospitalized COVID-19 patients with gastrointestinal symptoms, showing that use of proton pump inhibitors or H2 receptor antagonists was associated with higher mortality, ARDS, sepsis, and ventilator or oxygen requirement among patients
Dec 2023, Gastro Hep Advances, https://www.sciencedirect.com/science/article/pii/S277257232200142X, https://c19p.org/patil3

35. Ramachandran et al., Pre-hospitalization proton pump inhibitor use and clinical outcomes in COVID-19

295 patient PPI prophylaxis study: 92% higher mortality (p=0.02) and 80% higher progression (p=0.02).
Retrospective 295 hospitalized COVID-19 patients showing higher mortality and acute respiratory distress syndrome (ARDS) with pre-hospitalization proton pump inhibitor (PPI) use. Authors hypothesize that hypochlorhydria caused by PPIs may allow SARS-CoV-2 to more easily infect the gastrointestinal tract.
Nov 2021, European J. Gastroenterology & Hepatology, https://journals.lww.com/10.1097/MEG.0000000000002013, https://c19p.org/ramachandran

36. García-Menaya et al., Outcomes and Laboratory and Clinical Findings of Asthma and Allergic Patients Admitted With Covid-19 in a Spanish University Hospital

113 patient PPI prophylaxis study: 228% higher mortality (p=0.008) and 392% higher ICU admission (p=0.02).
Retrospective 113 hospitalized COVID-19 patients in Spain showing higher mortality and ICU admission with PPI use.
Sep 2020, Frontiers in Pharmacology, https://www.frontiersin.org/article/10.3389/fphar.2020.570721/full, https://c19p.org/garciamenaya

37. Luxenburger et al., Treatment with proton pump inhibitors increases the risk of secondary infections and ARDS in hospitalized patients with COVID‐19: coincidence or underestimated risk factor?

152 patient PPI prophylaxis study: 248% higher mortality (p=0.02), 124% higher ARDS (p=0.02), and 86% worse results (p=0.03).
Retrospective 152 hospitalized COVID-19 patients showing increased risk of secondary infections, ARDS, and mortality with proton pump inhibitor (PPI) use. Authors hypothesize that reduced gastric acid production from PPIs leads to bacterial overgrowth and microaspiration, increasing the risk of secondary lung infections. PPIs may also have immunomodulatory effects.
Jul 2020, J. Internal Medicine, https://onlinelibrary.wiley.com/doi/10.1111/joim.13121, https://c19p.org/luxenburger

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