1. Medicine

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

  1. Ruijie Zeng
  2. Yuying Ma
  3. Lijun Zhang
  4. Dongling Luo
  5. Rui Jiang
  6. Huihuan Wu
  7. Zewei Zhuo
  8. Qi Yang
  9. Jingwei Li
  10. Felix W Leung
  11. Chongyang Duan  Is a corresponding author
  12. Weihong Sha  Is a corresponding author
  13. Hao Chen  Is a corresponding author
  1. Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China
  2. The Second School of Clinical Medicine, Southern Medical University, China
  3. Shantou University Medical College, China
  4. School of Medicine, South China University of Technology, China
  5. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, China
  6. David Geffen School of Medicine, University of California Los Angeles, United States
  7. Sepulveda Ambulatory Care Center, Veterans Affairs Greater Los Angeles Healthcare System, United States
  8. Department of Biostatistics, School of Public Health, Southern Medical University, China
https://doi.org/10.7554/eLife.94973.3
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Cite this article
  1. Ruijie Zeng
  2. Yuying Ma
  3. Lijun Zhang
  4. Dongling Luo
  5. Rui Jiang
  6. Huihuan Wu
  7. Zewei Zhuo
  8. Qi Yang
  9. Jingwei Li
  10. Felix W Leung
  11. Chongyang Duan
  12. Weihong Sha
  13. Hao Chen
(2024)
Associations of proton pump inhibitors with susceptibility to influenza, pneumonia, and COVID-19: Evidence from a large population-based cohort study
eLife 13:RP94973.
https://doi.org/10.7554/eLife.94973.3
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2 figures, 3 tables and 2 additional files

Figures

Figure 1 with 1 supplement
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Flow diagram of eligible participants selection.
Figure 1—figure supplement 1
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Directed acyclic graph (DAG) for evaluation of covariates in the logistic regression model.
Figure 2 with 3 supplements
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Stratified analysis of regular proton pump inhibitor (PPI) users and the risk of influenza, pneumonia, and COVID-19 infection.

Effect estimates were based on age, sex, deprivation index, alcohol consumption, smoking, body mass index (BMI), indications of PPIs, hypertension, type 2 diabetes, chronic obstructive pulmonary disease (COPD), asthma, aspirin, histamine 2 receptor antagonist (H2RA), and cholesterol-lowering medication, using the fully adjusted model. CI: confidence interval; HR: hazard ratio; Pi: P value for interaction.

Figure 2—figure supplement 1
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Kaplan-Meier curves illustrating the event-free probability for the outcomes among users and non-users of proton pump inhibitors (PPIs).
Figure 2—figure supplement 2
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Stratified analysis of proton pump inhibitor (PPI) users and the risk of COVID-19 severity and mortality.
Figure 2—figure supplement 3
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Directed acyclic graph (DAG) for potential unmeasured confounders.

Tables

Table 1
Baseline characteristics of the included participants.
CharacteristicsRegular PPI useOverall
YesNo
Number of participants, n (%)9 997 (6.2)150 926 (93.8)160 923 (100.0)
Age, years, mean (SD)59.4 (7.4)56.3 (8.2)56.5 (8.1)
Sex, female, n (%)5 533 (55.4)79 709 (52.8)85 242 (53.0)
Ethnicity, white, n (%)9 571 (95.7)144 295 (95.6)153 866 (95.6)
Deprivation index, mean (SD)–0.9 (3.3)–1.4 (3.0)–1.4 (3.0)
Alcohol consumption, n (%)
Daily or almost daily1 805 (18.1)28 846 (20.5)32 874 (20.4)
3 or 4 times a week1 923 (19.2)33 533 (23.8)37 570 (23.4)
1 or 2 times a week2 396 (24.0)37 443 (26.6)42 228 (26.2)
1–3 times a month1 179 (11.8)15 669 (11.1)17 988 (11.2)
Special occasions only1 522 (15.2)14 965 (10.6)17 616 (11.0)
Never1 161 (11.6)10 414 (7.4)12 570 (7.8)
Smoking, n (%)
Never smoker4 572 (45.7)82 998 (55.0)87 570 (54.4)
Previous smoker4 289 (42.9)52 013 (34.5)56 302 (35.0)
Current smoker1 136 (11.4)15 915 (10.6)17 051 (10.6)
Physical activity, MET minutes/week, median (IQR)1 525.5 (2 722.0)1 815.0 (2 848.5)1 794.0 (2 838.5)
Fresh fruit intake, pieces, mean (SD)2.0 (2.6)1.9 (2.6)1.9 (2.6)
BMI, kg/m2, mean (SD)29.2 (5.1)27.4 (4.7)27.5 (4.8)
Indication of PPIs, n (%)
GERD3 235 (32.4)4 015 (2.7)7 250 (4.5)
Peptic ulcer561 (5.6)1 303 (0.9)1 864 (1.2)
Upper gastrointestinal bleeding18 (0.2)38 (0.03)56 (0.03)
Comorbidities, n (%)
Hypertension4 116 (41.2)38 162 (25.3)42 278 (26.3)
Type 2 diabetes124 (1.2)890 (0.6)1 014 (0.6)
Renal failure60 (0.6)243 (0.2)303 (0.2)
Myocardial infarction331 (3.3)1 632 (1.1)1 963 (1.2)
Stoke140 (1.4)943 (0.6)1 083 (0.7)
COPD46 (0.5)200 (0.1)246 (0.2)
Asthma841 (8.4)8 471 (5.6)9 312 (5.8)
Medication use, n (%)
Aspirin2 457 (24.6)21 108 (14.0)23 565 (14.6)
Non-aspirin NSAIDS1 224 (12.2)22 568 (15.0)23 792 (14.8)
H2RA297 (3.0)2 956 (2.0)3 253 (2.02)
Cholesterol lowering medications1 537 (15.4)9 241 (6.1)10 778 (6.70)
Multivitamin use, n (%)2 227 (22.3)33 201 (22.0)35 428 (22.0)

  1. BMI: body mass index; COPD: chronic obstructive pulmonary disease; GERD: gastroesophageal reflux disease; H2RA: histamine 2 receptor antagonist; IQR: interquartile range; MET: metabolic equivalent of task; PPI: proton pump inhibitor; NSAIDS: non-steroidal anti-inflammatory drugs; SD: standard deviation.

Table 2
Associations of PPI use with the susceptibility to pneumonia, influenza, COVID-19 positivity, and other respiratory infections.
Case/person-yearsNon-adjusted modelAge/sex-adjusted modelFully adjusted model*
HR (95% CI)pHR (95% CI)pHR (95% CI)p
Influenza
Non-regular PPI use2 009/6 0111.00 (reference) 1.00 (reference) 1.00 (reference) 
Regular PPI use183/5391.38 (1.19–1.62)<0.0011.49 (1.28–1.74)<0.0011.32 (1,12–1.56)0.001
Pneumonia
Non-regular PPI use2 904/12 8671.00 (reference) 1.00 (reference) 1.00 (reference) 
Regular PPI use378/1 7022.04 (1.83–2.27)<0.0011.74 (1.56–1.94)<0.0011.42 (1.26–1.59)<0.001
COVID-19 positivity
Non-regular PPI use23 989/29 0801.00 (reference) 1.00 (reference) 1.00 (reference) 
Regular PPI use1 440/1 7021.18 (1.09–1.26)<0.0011.07 (0.99–1.15)0.0581.08 (0.99–1.17)0.101
Other upper respiratory infections
Non-regular PPI use14 449/52 4991.00 (reference) 1.00 (reference) 1.00 (reference) 
Regular PPI use1 118/3 9881.30 (1.22–1.38)<0.0011.31 (1.23–1.39)<0.0011.19 (1.11–1.27)<0.001
Other lower respiratory infections
Non-regular PPI use14 494/55 3841.00 (reference) 1.00 (reference) 1.00 (reference) 
Regular PPI use1 486/5 5981.78 (1.67–1.88)<0.0011.65 (1.56–1.74)<0.0011.37 (1.29–1.46)<0.001

  1. CI: confidence interval; COVID-19: coronavirus disease 2019; HR: hazard ratio; PPI: proton pump inhibitor.

  2. *

    Adjusted for age, sex, ethnicity, deprivation index, smoking, alcohol consumption, physical activity, fresh fruit intake, body mass index, any indication of PPIs (gastroesophageal reflux disease [GERD], peptic ulcer, upper gastrointestinal bleeding), comorbidities (hypertension, type 2 diabetes, renal failure, myocardial infarction, stroke, chronic obstructive pulmonary disease [COPD], asthma), medications (aspirin, non-aspirin non-steroidal anti-inflammatory drugs [NSAIDs, ibuprofen], histamine 2 receptor antagonists (H2RAs), cholesterol lowering medications), multivitamin use, and influenza vaccination (for influenza) or COVID-19 vaccination (for COVID-19-related outcomes).

Table 3
Comparisons of the risks of influenza, pneumonia, and COVID-19 between proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) users.
Cases / Person-yearsHR (95% Cl)*p
Influenza
Regular H2RA use32/1021.00 (Reference)
Regular PPI use175/5241.74 (1.19–2.54)0.004
Pneumonia
Regular H2RA use86/3851.00 (Reference)
Regular PPI use368/16531.22 (0.96–1.54)0.104
COVID-19 positivity
Regular H2RA use425/5061.00 (Reference)
Regular PPI use1 409/1 6651.06 (0.90–1.24)0.509
Other upper respiratory infection
Regular H2RA use146/5221.00 (Reference)
Regular PPI use602/20991.28 (1.07–1.54)0.008
Other lower respiratory infection
Regular H2RA use339/13501.00 (Reference)
Regular PPI use1438/53981.33 (1.18–1.50)<0.001

  1. CI: confidence interval; COVID-19: coronavirus disease 2019; H2RA: histamine-2 receptor antagonist; HR: hazard ratio; PPI:585 proton pump inhibitor.

  2. *

    Adjusted for age, sex, ethnicity, deprivation index, smoking, alcohol consumption, physical activity, fresh fruit intake, body mass index, any indication of PPIs (gastroesophageal reflux disease [GERD], peptic ulcer, upper gastrointestinal bleeding), comorbidities (hypertension, type 2 diabetes, renal failure, myocardial infarction, stroke, chronic obstructive pulmonary disease [COPD], asthma), medications (aspirin, non-aspirin non-steroidal anti-inflammatory drugs [NSAIDs, ibuprofen], cholesterol lowering medications), multivitamin use, and influenza vaccination (for influenza) or COVID-19 vaccination (for COVID-19-related outcomes).

Additional files

Supplementary file 1

Supplementary information for the analyses.

(a) Generic name and examples of trade name of proton pump inhibitors. (b) Definitions of outcomes in the UK Biobank cohort. (c) The proportional hazards assumption tested by Schoenfeld residuals tests. (d) Associations of PPI use with the risk of influenza, pneumonia, and other respiratory infections (with inclusion of self-reported cases). (e). Associations of PPI use with COVID-19 severity and mortality. (f) Associations of PPI use with the risk of influenza, pneumonia, COVID-19, and other respiratory infections by different types of PPIs. (g) Associations of PPI use with the risk of influenza, pneumonia, COVID-19, and other respiratory infections by CYP2C19 phenotypes (h) Associations of PPI use with COVID-19 severity and mortality by CYP2C19 phenotypes. (i) Associations of PPI use with the risk of influenza, pneumonia, COVID-19, and other respiratory infections with multiple imputation. (j) Analysis of associations of PPI use with COVID-19 severity and mortality with multiple imputation. (k) Clinical characteristics of included participants after propensity score-matching. (l) Propensity score-matched analysis of associations of PPI use with the risk of influenza, pneumonia, COVID-19, and other respiratory infections. (m) Propensity score-matched analysis of associations of PPI use with COVID-19 severity and mortality. (n) Comparisons between proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) users for COVID-19 severity and mortality.

https://cdn.elifesciences.org/articles/94973/elife-94973-supp1-v1.docx
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  1. Ruijie Zeng
  2. Yuying Ma
  3. Lijun Zhang
  4. Dongling Luo
  5. Rui Jiang
  6. Huihuan Wu
  7. Zewei Zhuo
  8. Qi Yang
  9. Jingwei Li
  10. Felix W Leung
  11. Chongyang Duan
  12. Weihong Sha
  13. Hao Chen
(2024)
Associations of proton pump inhibitors with susceptibility to influenza, pneumonia, and COVID-19: Evidence from a large population-based cohort study
eLife 13:RP94973.
https://doi.org/10.7554/eLife.94973.3