Introduction

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 4.2 million deaths from coronavirus disease 2019 (COVID-19) worldwide until early August 2021, causing a global health crisis [1]. Up to 42% of hospitalized patients with COVID-19 developed acute respiratory distress syndrome (ARDS). In addition, the mortality rate of patients admitted to the ICU reached 39–72% [2].

Acidic gastric juice can deactivate the swallowed source of infection and prevent microorganisms from reaching the intestine. Therefore, gastric juice is considered the first line of defense against infection, and the risk of viral infection could be increased by gastric hypoacidity [3]. SARS-CoV-2 causes an infection in the glandular epithelial cells of the gastrointestinal tract via fecal–oral transmission [4], thereby increasing the possibility of more prevalent COVID-19 as the secretion of gastric acid decreases. Proton pump inhibitors (PPIs), the most potent gastric secretion inhibitors, are among the top 10 most widely used drugs in the world; however, PPIs tended to be overused, and only 30% of users follow the drug label instructions [5]. A meta-analysis of 48 observational articles showed that PPI users had a 43% increased risk of pneumonia compared with non-users [6]. In a retrospective cohort study of hospitalized 152 COVID-19 patients [7], the use of PPIs more than doubled the adverse outcomes, such as secondary infection and ARDS. In contrast to PPIs, ranitidine, a histamine H2 receptor antagonist (H2RA), has been shown to prevent the replication of SARS-CoV-2, alleviating virus pneumonia both in vitro and in vivo [8]. Another retrospective hospitalized cohort study reported that famotidine use decreased the risk of intubation or death from COVID-19 by 58% [9].

A few studies examined the relationship between PPIs/H2RAs and adverse outcomes of [10,11,12], mortality from [11, 13], or incidence of COVID-19 [12, 13] by calculating the meta-estimates. However, all of the aforementioned studies were letters to the editor, not original or review articles. Hence, this study aimed to exhaustively demonstrate the effect of acid suppression treatments on the risk of COVID-19.

Methods

The statement of Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [14] was used to report the results of the present systematic review and meta-analysis.

Literature search

Four electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science) were searched by two authors (H.B.K and J.H.K) using common keywords related to acid-suppressive medication and COVID-19. The last literature search was conducted on July 9, 2021. Supplemental Table 1 describes the comprehensive literature search strategy. A manual review of the bibliographies of appropriate articles was carried out to discover additional studies. No language restriction was indicated to check all plausible articles.

Table 1 Association between PPI use and severe outcomes of COVID-19 in the subgroup meta-analysis by various factors
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Selection criteria

Two authors (H.B.K and J.H.K) independently evaluated the eligibility of all studies. If there were discrepancies in the selection of studies among reviewers, they were settled by consensus. For the current meta-analysis, the following inclusion criteria were used: (a) observational studies with case–control or cohort studies, (b) studies that reported the association between “current use of PPIs or H2RAs” and “COVID-19,” (c) studies in which PPIs and H2RAs had been taken before patients got COVID-19, and (d) studies of human subjects including adults aged ≥ 18 years. Studies including PPI and H2RA concomitant use or not published in peer-reviewed journals, review articles, case reports, and abstracts only presented at academic conferences were excluded. Severe outcomes of COVID-19 include intubation, ventilator support, development of ARDS, admission to ICU, secondary infection, or death due to COVID-19. The protocol was registered in the PROSPERO registry (registration number CRD42021271760).

Data extraction and assessment of methodological quality

A standardized tool was utilized to obtain the following data from the selected studies: name of the first author; study design; location and study period; demographics (mean age or age range, and sex); sample size; ascertainment of exposure and outcome assessment; confounding variables that were adjusted, duration, and dosage of gastric acid suppressants and antacids used; and adjusted OR and 95% CI. Through contact with the corresponding author taken to acquire sufficient data, additional data from a published article were obtained from co-author (B.J.W).

The methodological quality of each selected article was determined using the Newcastle–Ottawa Scale (NOS) to assess the quality of case–control and cohort studies included in the meta-analyses [15]. The NOS uses a star rating system, ranging from 0 to 9, and a maximum of 4, 2, and 3 points are allocated for selection, comparability, and exposure or outcome, respectively. For comparability, if age and sex were adjusted, 1 point was given, and if the medications or comorbidity was described in detail, 2 points were given. Scores 0–3, 4–6, and 7–9 are considered low, moderate, and high methodological qualities.

Data synthesis and statistical analysis

The primary outcome was severe outcomes of COVID-19. We also conducted a series of subgroup analyses according to study design, mean age of participants, research location (hospital or community), administration time of PPIs or H2RAs, active use of PPI (active or inactive), geographical region, number of participants, and confounding factors such as body mass index (BMI), smoking status, and comorbidity. Among the studies in which comorbidity was adjusted for, only those using propensity score matching were selected [16]. The relationship between acid suppressants and the incidence of COVID-19 was also estimated as a secondary outcome.

The HRs (hazard ratios) and 95% CIs of each selected article demonstrating the relationship between PPIs/H2RAs use and risk of COVID-19 were used to calculate the pooled HRs with the corresponding 95% CI. The Higgins I2 test was employed to identify the percentage of total variation to rate the heterogeneity among the articles [17]. The I2 results obtained were between 0% (no observed heterogeneity) and 100% (maximal heterogeneity). An I2 of 0–25% indicated an insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity, and 76–100% high heterogeneity [17]. A random-effect model based on the DerSimonian and Laird method was used to present the overall HR and 95% CI values, given that the participant characteristics and research methods of each included paper were dissimilar [18]. When the HR was obtained using multiple adjustment models, the model with the greatest number of confounding variables was selected. Meta-regression analysis was utilized to verify whether covariates at study level might account for heterogeneity.

Lastly, publication bias, which suggests that articles describing statistically significant results are more likely to be published than those describing null results, was estimated using Begg’s funnel plot and Egger’s test. An asymmetric Begg’s funnel plot or a P-value of < 0.05 in the Egger’s test indicated the presence of a publication bias. All statistical analyses were performed using Stata SE version 13.1 (StataCorp, College Station, TX, USA).

Results

Identification of relevant articles

The procedure for selecting suitable articles is shown in Supplemental Fig. 1. In total, our search strategy initially identified 1345 articles after searching the four databases. After eliminating duplicated articles and additional ones that did not meet the predetermined selection criteria, the remaining 26 articles were assessed. And additional 13 articles that did not meet the inclusion criteria were excluded. In addition, a further two studies were identified and included after screening the references, which were extracted after reviewing the full texts. Finally, 15 cohort studies [7, 9, 13, 19,20,21,22,23,24,25,26,27,28,29,30] were selected in the current meta-analysis.

Fig. 1
figure 1

Forest plot estimating association between acid suppressant use and severe outcomes of COVID-19

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Characteristics of studies and methodological quality assessment

Characteristics of the included 15 observational studies are described in Supplemental Table 2. The number of participants in the selected articles ranged from 152 to 132,316 and 18,109 people were diagnosed with COVID-19. The mean age of participants ranged from 44.8 to 73.8 years, and the mean proportion of female participants was 48.9%. The included studies were conducted in the following geographical regions: North America (n = 7) [9, 19, 21,22,23,24, 26], Europe (n = 5) [7, 13, 28,29,30], and Asia (n = 3) [20, 25, 27].

Table 2 Association between H2RA use and adverse outcomes of COVID-19 in the subgroup meta-analysis by various factors
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Eleven of the studies provided data on adverse outcomes [7, 9, 19, 22,23,24,25,26,27, 29, 30], two studies reported the incidence of COVID-19 [21, 28], and two studies presented the results of adverse outcomes as well as the COVID-19 incidence [13, 20]. With regard to exposure assessment, seven studies [7, 19, 20, 23, 28,29,30] investigated PPI use, two [9, 22] used famotidine as H2RAs, and six [13, 21, 24,25,26,27] used both PPIs and H2RAs. The variables adjusted in each article are explained in Supplemental Table 3.

The NOS scores of selected studies ranged from 6 to 9 stars (Supplemental Table 4) and the mean scores of the selected cohort studies were 7.7. All included studies except Almario et al. [21] were considered to be of high quality.

Association between acid suppressant use and the incidence and severe outcomes of COVID-19

The present meta-analysis revealed a significant relationship between PPI use and severe outcomes of COVID-19, albeit with high heterogeneity (HR = 1.53, 95% CI, 1.20–1.95, I2 = 74.6%; Fig. 1). In contrast, treatment with H2RAs was not associated with increased severe outcomes. Unlike severe outcomes, no significant relationship was observed between PPI use and incidence of COVID-19 (Fig. 2). H2RAs use was associated with decreased incidence of COVID-19 (HR = 0.86, 95% CI: 0.76–0.97, I2 = 0.0%; Fig. 2). With regard to the types of adverse outcomes, the association with PPI remained significant for mortality and ARDS incidence from COVID-19 (Supplemental Fig. 2). Mortality from COVID-19 was not associated with H2RAs (Supplemental Fig. 3).

Fig. 2
figure 2

Forest plot estimating association between acid suppressant use and incidence of COVID-19

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Subgroup analysis of association between acid suppressants use and adverse outcomes of COVID-19

Table 1 presents the association between PPI use and severe outcomes of COVID-19 in a series of subgroup analyses of diverse factors. The significant association was consistently observed in the subgroup analyses by mean age, research location, administration time of PPIs, number of participants, and studies adjusted for comorbidity using propensity score matching also showed consistent associations. The association was stronger in the subgroup of people aged under 60 years, active use of PPIs, and in-hospital administration of PPIs. In addition, a harmful association was observed in studies conducted in Asia and Europe, but not in those conducted in North America. However, when studies that adjusted for BMI or smoking status were separately analyzed, no significant association was observed.

The association between H2RA use and severe outcomes of COVID-19 in a series of subgroup analyses is shown in Table 2. In cases of mean age > 60 years, the use of H2RA was associated with decreased odds of the serious outcome of COVID-19 (HR = 0.57, 95% CI: 0.33–0.98, I2 = 36.7%). Contrary to at-home use of H2RAs, in-hospital use was significantly linked to an increased risk of adverse outcomes (HR = 1.73, 95% CI: 1.29–2.30, I2 = 0.0%). In addition, a harmful association was observed in studies conducted in Asia. According to meta-regression analysis, the overall effect of each subgroup was not statistically significant. A subgroup analysis of active H2RA use was not considered as all studies presented only active use.

Publication bias

No publication bias was found in this meta-analysis of the effect of PPI use on adverse outcomes; the Begg’s funnel plots were all symmetrical, and the Egger’s test yield a P-value of 0.57 (Supplemental Fig. 4).

Discussion

Based on the results from the current meta-analysis, PPI use was weakly associated with increased odds of severe outcomes of COVID-19, especially in patients aged under 60 years, in-hospital use, and in those living in Asia. Unlike PPIs, the use of H2RAs was weakly associated with the decreased incidence of COVID-19, although in-hospital use was moderately linked to increased severe outcomes.

Recently, four meta-analyses [31,32,33,34] were published regarding the association between the use of acid suppressants and COVID-19. Three meta-analyses [31,32,33] identified the relationship for PPIs and one by Kow et al. [34] for famotidine. Supplemental Table 5 describes the differences in study characteristics and the main results among the past meta-analysis and the present study. Most meta-analyses showed similar findings to our results, except for Zippi et al. [32], which found that PPIs use was not significantly associated with an increased risk of severe COVID-19 outcomes. The differences between our study and previous meta-analyses are that the most recent articles were searched, the search formulas were detailed, and subgroup analyses for a variety of factors were performed. Moreover, the exclusion of studies that only looked at the past use of acid suppressant is thought to be attributable to different selection criteria. Above all, the inclusion of only published cohort studies has strength compared to previous meta-analyses. All of the aforementioned meta-analyses were partly based on unpublished data. Thus, their accuracy cannot be guaranteed because unpublished data did not go through peer-review process. In addition, unpublished studies are susceptible to bias and may have lower methodological quality than published studies [35].

Several plausible biological mechanisms can account for the relationship between PPI use and increased severe outcomes of COVID-19. First, PPIs can strongly inhibit the secretion of gastric acid, thereby increasing the likelihood of SARS-CoV-2 infiltrating the digestive tract [36]. This state can increase the spread of the virus, consequently raising the likelihood of a cytokine storm, further exacerbating the severe consequences of the COVID-19 [37]. Second, the substantial hypochlorhydria can lead to dysbiosis of the gut microbiota, which can increase enteric infections or sepsis. Hypochlorhydria can also increase the overgrowth of bacteria in the small intestine, which amplifies the severity of COVID-19 [38]. Finally, by inhibiting the anti-inflammatory activity of neutrophils, PPIs can reduce defense against infectious agents, thereby increasing the severity of COVID-19 [39].

Apart from plausible biological mechanisms, the relationship between PPI use and adverse outcomes of COVID-19 can be caused by protopathic bias. Protopathic bias, or reverse causality, is a source of systematic bias that takes place when exposure conditions change in response to the demonstration of potential consequences. For example, people using PPIs tend to have more severe gastroesophageal reflux disease (GERD) than those not taking these medications [40]. Tobacco use, non-steroidal anti-inflammatory drugs (NSAIDs) use, and obesity are associated with the risk of gastroesophageal reflux symptoms [41]. Since GERD is associated with the risk of developing pneumonia [42], an increase of severe outcomes from COVID-19 might have occurred due to obesity and tobacco or NSAIDs use rather than PPIs use. As can be seen in Table 2, when only the studies that adjusted for obesity, smoking status, and use of NSAIDs analyzed separately, the significant association disappeared.

It remains uncertain why H2RA intake, especially pre-admission administration, can reduce the incidence of COVID-19. Mast cells in the nasal cavity and respiratory tract secrete histamine [43] and can increase the inflammatory response by secreting inflammatory cytokines [44]. Moreover, it has an angiotensin-converting enzyme 2 receptor, which SARS-CoV-2 utilizes to enter the body and proliferate [45]. Therefore, H2RAs may play a role in reducing the secretion of histamine and inflammatory reactions, which are at least partially involved in the development of COVID-19 [46].

Contrary to at-home use, increased severe outcomes were observed with in-hospital use of H2RAs. This result might be due to the occurrence of gastrointestinal symptoms of COVID-19 or other medical conditions (e.g., for the purpose of preventing digestive side effects that may occur during COVID-19 treatment) rather than the medication per se. SARS-CoV-2 can also spread to the digestive system aside from the respiratory system and can cause gastrointestinal symptoms [47]. Another reason might be a decreased gastric acid inhibition as a result of tolerance to H2RAs [48]. Among population who used acid suppressants such as H2RAs, those more vulnerable to COVID-19 get prone to this disease early after beginning to take acid-suppressive medications, while those who can tolerate such medications due to a longer dosing period can lessen the adverse outcomes [49].

The association between PPIs use and severe outcomes from COVID-19 was most prominent in Asia. The first possible mechanism to explain this is that the use of PPI may suppress gastric acid secretion to a greater extent in Asians due to a lower mass of parietal cell [50]. Second, the incidence of genetic polymorphism for cytochrome P450 2C19 is higher in Asians compared to other regions, which makes it easier to slow down the metabolism of PPIs, and thus the degree of gastric acid inhibition may be stronger [51, 52]. Finally, the prevalence of Helicobacter pylori infection in Asia is higher than in Europe or North America [53] and PPIs may inhibit gastric acid secretion greater in the presence of Helicobacter pylori infection.

The current study has several important limitations. First, all of the selected articles had an observational design, and many studies were conducted in a single hospital; hence, the results of these studies can be difficult to generalize. Second, several essential factors associated with antacid use and COVID-19 may not have been adjusted for in the selected articles. For example, the use of concomitant medications such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), or statins has been linked to decreased disease severity [54, 55]. When three studies [19, 23, 27] that were adjusted for these factors were collected, a significant relationship between PPI use and severity was not observed (HR = 1.24, 95% CI: 0.76–2.00, I2 = 68.7%). Third, most included studies did not specify the dosage, duration, and particular type of acid suppressant used.

Conclusion

Our meta-analysis presents evidence that the use of PPIs but not H2RAs was associated with increased adverse outcomes from COVID-19. Despite the fact that our study showed a lower quality of evidence due to a lack of prospective cohort studies and RCTs, close observation is recommended for COVID-19 patients who use PPIs to prevent serious consequences. More evidence is required to verify our results, and prospective cohort studies and RCTs must be utilized.