Pre-hospital proton pump inhibitor use and clinical outcomes in hospitalized COVID-19 patients: A retrospective case-control study

Abstract

BACKGROUND

Proton pump inhibitors (PPIs) are among the most commonly prescribed medications globally. While concerns exist regarding their association with adverse infection-related outcomes, their impact on coronavirus disease 2019 (COVID-19) severity remains uncertain. Emerging preclinical data suggest immunomodulatory and antiviral properties of PPIs, yet clinical evidence is conflicting.

AIM

To investigate whether chronic pre-hospital PPI use is associated with improved outcomes in patients hospitalized with COVID-19.

METHODS

We conducted a retrospective case-control study of adult inpatients with severe acute respiratory syndrome coronavirus 2 infection admitted to a racially and ethnically diverse community hospital in Massachusetts from July 2021 to March 2022. Patients were stratified by documented pre-hospital PPI use. The primary outcomes were intensive care unit (ICU) admission, need for invasive mechanical ventilation, and in-hospital mortality. Multivariable logistic regression was used to adjust for demographics, comorbidities, and treatment variables. Significance was set at P < 0.05.

RESULTS

Among 248 patients, 83 (33.4%) were on PPIs prior to hospitalization. Compared to non-users, PPI users had significantly lower rates of ICU admission (13.3% vs 24.8%, P = 0.034), mechanical ventilation (13.3% vs 25.5%, P = 0.027), and in-hospital mortality (6.0% vs 17.6%, P = 0.013). Multivariable analysis confirmed these associations: ICU admission [adjusted odds ratios (aOR): 0.462, 95%CI: 0.223–0.955], mechanical ventilation (aOR: 0.447, 95%CI: 0.216–0.923), and mortality (aOR: 0.144, 95%CI: 0.031–0.677). Findings were consistent across demographic and comorbidity strata.

CONCLUSION

In this diverse, real-world United States cohort, chronic pre-hospital PPI use was independently associated with lower odds of intensive care unit admission, mechanical ventilation, and mortality among COVID-19 inpatients. These findings highlight a potentially protective role of PPIs and support continued therapy in eligible patients.

Key Words: Comorbidities; Case-control study; Mortality; Intensive care unit; Proton pump inhibitors; SARS-CoV-2; COVID-19

Core Tip: This retrospective case-control study investigated the association between pre-hospital proton pump inhibitor (PPI) use and outcomes among patients hospitalized with coronavirus disease 2019 (COVID-19). After adjusting for multiple confounders, pre-hospital PPI use was associated with a lower risk of intensive care unit admission and in-hospital mortality. While the underlying mechanisms remain unclear, the findings suggest that chronic PPI use may not be associated with adverse COVID-19 outcomes.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic, driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly strained global healthcare systems. Despite widespread vaccine deployment and therapeutic advancements, substantial morbidity and mortality persist, particularly among hospitalized patients. The United States alone has reported over one million COVID-19-related deaths as of 2024, underscoring the urgency to identify modifiable predictors of disease severity[1-5].

COVID-19 presents with a broad clinical spectrum, ranging from asymptomatic infection to respiratory failure and multiorgan dysfunction. Severe outcomes are often driven by a dysregulated immune response—marked by cytokine storm, endothelial injury, and coagulopathy. Established risk factors such as advanced age, obesity, and chronic comorbidities exacerbate vulnerability to these complications[6-10].

Importantly, the pandemic has magnified longstanding health disparities in the U.S. African American, Hispanic, and Native American communities have experienced disproportionate rates of hospitalization and death. In Massachusetts, Black and Hispanic patients have faced significantly worse outcomes compared to White counterparts, reflecting both structural inequities and comorbidity burden. These observations reinforce the importance of population-specific risk assessment and inclusive research design[11-15].

Proton pump inhibitors (PPIs) are among the most prescribed medications globally, commonly used to manage gastroesophageal reflux disease, peptic ulcer disease, and other acid-related conditions. While generally considered safe, long-term PPI use has been linked to enteric infections, micronutrient deficiencies, and altered gut immunity—raising concerns during the COVID-19 pandemic[16-20].

Contrary to these concerns, preclinical data suggest that PPIs may possess anti-inflammatory and antifibrotic properties relevant to viral pathophysiology. In pulmonary models, PPIs reduce transforming growth factor-β1 signaling, oxidative stress, and epithelial injury. Moreover, in vitro studies show that PPIs inhibit lysosomal acidification—an essential step in viral replication—and enhance the activity of antiviral agents like remdesivir[21-25]. To date, there is limited evidence confirming these effects in human populations.

Despite these promising mechanisms, clinical data on PPI use in COVID-19 remain inconclusive. Most studies have evaluated inpatient PPI exposure, which is subject to confounding by indication. Few have focused on chronic pre-hospital use—a critical gap in the literature. Furthermore, the impact of PPI therapy in racially and ethnically diverse United States populations remains underexplored[26-28].

To address this gap, we conducted a retrospective case-control study at a community-based teaching hospital in Worcester, Massachusetts. Our institution serves a high-risk population with diverse racial, ethnic, and socioeconomic backgrounds. We examined whether pre-hospital PPI use was associated with clinical outcomes—including intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital mortality—in adults hospitalized with COVID-19. We hypothesized that chronic PPI use would be independently associated with lower odds of severe outcomes, potentially reflecting immunomodulatory or antiviral effects.

MATERIALS AND METHODS

Study design and setting

We performed a retrospective, observational case-control study at Saint Vincent Hospital, a 329-bed community teaching hospital in Worcester, Massachusetts. The institution serves a racially and socioeconomically diverse population, including large proportions of Hispanic, African American, Southeast Asian, and immigrant patients. The hospital’s COVID-19 burden during the study period reflected both regional and national trends in disease severity and healthcare disparities.

Study population

Eligible participants were adults (≥ 18 years) hospitalized with laboratory-confirmed SARS-CoV-2 infection between July 1, 2021 and March 1, 2022. COVID-19 diagnosis was confirmed via reverse transcriptase polymerase chain reaction testing from nasopharyngeal swabs. Patients were excluded if they were pregnant, had incomplete medical records, were discharged directly from the emergency department, or received PPIs only during hospitalization.

Exposure assessment

The primary exposure was documented pre-hospital PPI use within 30 days prior to admission, identified through medication reconciliation at the time of hospitalization. Medications included omeprazole, pantoprazole, esomeprazole, lansoprazole, and dexlansoprazole. Patients were classified as non-users if they had no evidence of PPI use in the preceding 90 days.

Outcomes

Primary outcomes included: ICU admission, defined as transfer to intensive care for respiratory or hemodynamic support; Invasive mechanical ventilation, defined as endotracheal intubation and ventilator support; In-hospital mortality, defined as all-cause death during the index hospitalization.

Covariates and data collection

We extracted demographic and clinical variables using a standardized abstraction tool from the hospital’s Cerner-based electronic medical record. Data included: Age, sex, race/ethnicity; Body mass index (BMI); Vaccination status (≥ 1 dose of any approved vaccine); Comorbidities: Hypertension, diabetes, chronic kidney disease (CKD), chronic liver disease, chronic pulmonary disease, coronary artery disease, congestive heart failure; Use of remdesivir or corticosteroids during admission; Smoking status and home oxygen use.

Missing data

Patients with missing data for key exposure or outcome variables were excluded. For covariates with < 5% missingness, we conducted complete case analysis given high data completeness.

Statistical analysis

Analyses were performed using SPSS v27. Categorical variables were compared using χ² or Fisher’s exact test; continuous variables were assessed with independent t-tests or Mann-Whitney U tests. We used multivariable logistic regression to estimate adjusted odds ratios for each outcome, incorporating covariates significant at P < 0.10 in univariable analysis and those of biological relevance. Model calibration was assessed via Hosmer-Lemeshow test; discrimination was evaluated using area under the receiver operating characteristic curve (AUC).

Sample size and power

Assuming a 20% ICU admission rate and requiring ≥ 10 outcome events per predictor, our final sample (n = 248; 83 exposed) was sufficient to adjust for 8-10 covariates with adequate power.

Ethical considerations

The study was approved by the Saint Vincent-MetroWest Medical Center IRB (Approval No. 2020-035). Informed consent was waived due to the retrospective design and use of de-identified data. The study adhered to the STROBE guidelines and the principles of the Declaration of Helsinki.

RESULTS

Patient characteristics

Out of 320 patients screened, 248 met inclusion criteria (Figure 1). Of these, 83 (33.5%) had documented pre-hospital PPI use. The median age was 64.2 years (IQR: 55–76), and 54.4% were male. Baseline characteristics were largely comparable between PPI users and non-users, although PPI users had slightly higher rates of comorbidities such as hypertension (55.4% vs 43.0%, P = 0.065) and chronic kidney disease (28.9% vs 10.9%, P = 0.012). Racial distribution was diverse—52% White, 22.6% Hispanic, 13.3% Black, and 9.3% Southeast Asian—with no significant differences across groups (P = 0.27). Vaccination rates were low and similar in both groups (17.7%, P = 0.84) (Table 1).

Figure 1 Cohort flow diagram: Flowchart illustrating the selection of patients for inclusion in the study. Out of 320 patients screened, 248 were eligible based on confirmed severe acute respiratory syndrome coronavirus 2 infection and availability of complete clinical data. Patients were stratified into pre-hospital proton pump inhibitor users (n = 83) and non-users (n = 165) for outcome comparison.

Table 1 Baseline characteristics of proton pump inhibitors users and non-users, n (%).

Variable	PPI users (n = 83)	Non-users (n = 165)	P value
Age (mean ± SD)	66.1 ± 13.9	63.1 ± 15.1	0.12
Male	56 (67.5)	79 (47.9)	0.006
BMI > 30	35 (42.2)	57 (34.5)	0.24
Hypertension	46 (55.4)	71 (43.0)	0.065
Diabetes mellitus	29 (34.9)	53 (32.1)	0.72
CKD	24 (28.9)	18 (10.9)	0.012
COPD	10 (12.0)	21 (12.7)	0.91
Vaccinated	14 (16.9)	30 (18.2)	0.84

Comparison of demographic and clinical characteristics between hospitalized coronavirus disease 2019 patients with and without pre-hospital proton pump inhibitors (PPIs) use. No statistically significant differences were observed in baseline vaccination status or body mass index. Chronic kidney disease was more prevalent among PPIs users. PPI: Proton pump inhibitors; BMI: Body mass index; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease.

Primary clinical outcomes

PPI users had significantly better outcomes: ICU admission: 13.3% vs 24.8% in non-users (P = 0.034); Invasive mechanical ventilation: 13.3% vs 25.5% (P = 0.027); In-hospital mortality: 6.0% vs 17.6% (P = 0.013); Kaplan-Meier survival analysis demonstrated superior overall survival in PPI users (log-rank P = 0.02).

Multivariable regression

After adjusting for age, sex, BMI, race/ethnicity, vaccination status, and relevant comorbidities, pre-hospital PPI use remained independently associated with improved outcomes as shown in Figure 2: ICU admission: AOR 0.462 (95%CI: 0.223–0.955), P = 0.036; Mechanical ventilation: AOR 0.447 (95%CI: 0.216–0.923), P = 0.028; Mortality: AOR 0.144 (95%CI: 0.031–0.677), P = 0.014; Model performance metrics showed strong calibration (Hosmer-Lemeshow P > 0.1) and discrimination (AUC = 0.78 for ICU model) (Table 2).

Figure 2 Forest plot of adjusted odds ratios for coronavirus disease 2019 outcomes: Forest plot depicting adjusted odds ratios and 95% confidence intervals for intensive care unit admission, mechanical ventilation, and in-hospital mortality among proton pump inhibitors users compared to non-users. Proton pump inhibitors use was independently associated with a significant reduction in severe outcomes. COVID-19: Coronavirus disease 2019; PPI: Proton pump inhibitor.

Table 2 Clinical outcomes by proton pump inhibitors use, n (%).

Outcome	PPI users (n = 83)	Non-users (n = 165)	P value
ICU admission	11 (13.3)	41 (24.8)	0.034
Mechanical ventilation	11 (13.3)	42 (25.5)	0.027
In-Hospital mortality	5 (6.0)	29 (17.6)	0.013
Length of stay (median, IQR)	6.2 (4.5-8.3)	6.8 (5.0-9.2)	0.52
Remdesivir use	38 (45.8)	82 (49.7)	0.56
Systemic steroid use	70 (84.3)	143 (86.7)	0.61

Primary and secondary clinical outcomes in hospitalized coronavirus disease 2019 patients stratified by pre-hospital proton pump inhibitors (PPIs) use. PPI users demonstrated significantly lower rates of intensive care unit admission, mechanical ventilation, and in-hospital mortality compared to non-users. No significant differences were observed in length of stay or antiviral treatment administration. ICU: Intensive care unit.

Subgroup findings

Subgroup analyses indicated that the protective effect of PPI use was especially prominent in: Patients aged > 65: 65% lower odds of ICU admission (aOR: 0.35, 95%CI: 0.15–0.85); Patients with CKD: Significantly reduced mortality (4.1% vs 22.2%, P = 0.04) There was no significant interaction with race or vaccination status) (Table 1).

Secondary outcomes

There were no significant differences in length of stay (median 6.2 vs 6.8 days, P = 0.52), use of remdesivir (45.8% vs 49.7%, P = 0.56), or systemic corticosteroids (84.3% vs 86.7%, P = 0.61), suggesting that outcome differences were unlikely due to treatment disparities.

DISCUSSION

This study provides novel evidence that chronic pre-hospital PPI use is associated with significantly improved clinical outcomes among patients hospitalized with COVID-19. Specifically, PPI users demonstrated lower rates of ICU admission, mechanical ventilation, and in-hospital mortality. These associations remained robust after adjustment for demographic, clinical, and therapeutic covariates. Our findings are consistent with emerging hypotheses about the immunomodulatory potential of PPIs and offer reassurance regarding their safety in COVID-19.

Contextualizing with prior studies

Previous literature has painted a mixed picture of PPIs in viral illness. While some observational studies have linked PPI use to adverse outcomes due to possible microbiome disruption or impaired barrier function, others suggest benefits through anti-inflammatory effects. Our results align more closely with the latter and support the notion that PPIs may modulate host responses in a way that tempers COVID-19 progression[21,29,30].

Biologic plausibility

PPIs have been shown to reduce oxidative stress, inhibit cytokine release, and attenuate pulmonary inflammation in animal models (Figure 3). Their ability to alter lysosomal pH may also interfere with SARS-CoV-2 replication, potentially enhancing the activity of antiviral agents like remdesivir. These mechanisms may underlie the improved outcomes observed in this study, particularly among older adults and patients with CKD—groups prone to exaggerated immune responses[31].

Figure 3 Proposed mechanistic pathways of proton pump inhibitors in coronavirus disease 2019: Illustration hypothesizing the potential biological effects of chronic proton pump inhibitor use in coronavirus disease 2019. Mechanisms include reduction of lysosomal acidification, attenuation of inflammatory cytokine release, mitigation of pulmonary oxidative stress, and enhancement of antiviral drug activity, ultimately leading to decreased disease severity. PPI: Proton pump inhibitors; COVID-19: Coronavirus disease 2019.

Clinical implications

Our findings challenge the prevailing caution against PPI use during respiratory infections and support continued therapy in patients with clinical indications. For hospitalized COVID-19 patients already on PPI therapy, withholding treatment may not only be unnecessary but potentially harmful. These results are particularly relevant in real-world, diverse patient populations where baseline risk is elevated.

Strengths and limitations

This study has several strengths, including a well-defined exposure, comprehensive multivariable adjustment for clinical and demographic factors, and use of a large, racially and ethnically diverse urban cohort. However, several limitations must be acknowledged. The retrospective design precludes causal inference, and the absence of viral genotype data and long-term follow-up limits broader applicability. Medication exposure was based on documentation at admission, without pharmacy refill data for validation. Although sex was adjusted for in the analysis, the higher proportion of male patients in the PPI group may have introduced residual confounding given known sex-based differences in COVID-19 outcomes. Additionally, detailed data on PPI dose, treatment duration, and clinical indication (e.g., prior gastrointestinal bleeding or reflux) were unavailable, limiting the ability to explore dose-response relationships. While vaccination status was included as a covariate, information on vaccination timing, dosage completeness, or vaccine type was lacking and may have affected outcomes. Finally, as this was a single-center study conducted at a tertiary hospital in Massachusetts, generalizability to other geographic regions and healthcare systems may be limited, underscoring the need for external validation.

Future directions

Further studies are needed to replicate these findings in multicenter cohorts and assess potential interactions with viral variants or antiviral therapies. Mechanistic research into PPI-mediated modulation of host immunity could identify new therapeutic pathways relevant to respiratory viruses beyond SARS-CoV-2.

CONCLUSION

This study provides compelling evidence that chronic pre-hospital PPI use is independently associated with improved clinical outcomes in hospitalized COVID-19 patients. Rather than posing risk, PPIs may confer protective effects through modulation of inflammation or interference with viral replication. These findings challenge earlier assumptions and point to a nuanced interaction between common medications and viral pathophysiology. Future prospective and mechanistic studies are essential to validate this signal and explore its implications in broader infectious disease management. Until then, clinicians can be reassured that continuation of PPI therapy in COVID-19 patients is not only safe—it may be beneficial.