The Proton Pump Inhibitors Use and COVID-19 from Prior to Vaccination Perspective: A Review Free

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a novel, rapidly spreading infectious pathogen, whereas coronavirus infectious disease 2019 (COVID-19) is a clinical manifestation of a symptomatic SARS-CoV-2 infection. COVID-19 has been declared a pandemic by the WHO on March 11, 2020. As of late February 2021, there have been more than 111 million cases of diagnosed SARS-CoV-2 infection and almost 2.5 million deaths reported worldwide. Since its outbreak, the number of people affected by the pandemic has been increasing.

SARS-CoV-2 utilizes angiotensin-converting enzyme type 2 (ACE2) as an entry receptor to infect mainly alveolar epithelial cells [1]. Typical manifestations of COVID-19 range from mild to a severe systemic disease characterized by an acute respiratory distress syndrome (ARDS), shock, and multiorgan dysfunction. While approximately 80% of symptomatic patients report mild or moderate illness, the rest develop profound hypoxemia, necessitating prompt in-hospital oxygenation. The highest mortality is reported in COVID-19 patients admitted to an intensive care unit (ICU).

Morbidity and mortality increase with age, disproportionately affecting those with preexisting conditions, for example, obesity, chronic kidney disease, diabetes mellitus, cardiovascular disease, and chronic lung disease [2]. Other COVID-19-related risk factors, including commonly used medications, are still being identified.

Proton pump inhibitors (PPIs) suppress gastric acid production by irreversibly binding to the active site of the H⁺/K⁺ ATPase of parietal cells. PPIs have been linked, among others, to gut dysbiosis, increased risk of gastrointestinal (GI) infections [3], community-acquired pneumonia [4, 5], and a higher mortality rate due to cardiovascular or chronic kidney disease [6]. PPIs raise gastric pH, which might facilitate the SARS-CoV-2 infection, whereas bacterial pneumonia or GI-derived infections may complicate the clinical course of COVID-19.

Some early retrospective studies [7‒9] raised concerns about the use of PPIs with respect to SARS-CoV-2 positivity and/or severe clinical course and fatal outcome of COVID-19. However, these preliminary observations have been much criticized [10] and have not been completely confirmed [11, 12].

Moreover, symptomatic SARS-CoV-2 infection increases the demand for nonsteroidal anti-inflammatory drugs (NSAIDs) that can cause GI damage. In addition, prophylactic or therapeutic anticoagulation due to the high prevalence of thromboembolic complications in COVID-19 patients [13, 14] may promote GI bleeding (GIB) from existing mucosal lesions. PPIs used according to the guidelines as gastroprotection decrease the risk of the upper GIB, need for urgent GI endoscopy, GIB-related hospital admissions and surgery, the prevalence of rebleeding, and GIB-related mortality rate in at-risk patients taking antiplatelet therapy, anticoagulants, or NSAIDs, including those admitted to the ICU (stress ulcer prophylaxis), that is a significant proportion of COVID-19 inpatients. Therefore, the beneficial effects of PPIs in selected SARS-CoV-2 positive individuals should not be neglected.

Despite some progress made in the symptomatic management of COVID-19, no drug with proven specific anti-SARS-CoV-2 activity has been discovered until February 2021. In addition, the initial enthusiasm on the first registered anti-COVID-19 vaccines has been soon replaced by the efficacy concerns with respect to the emerging SARS-CoV-2 mutants. Therefore, the need for successful antiviral pharmacotherapy still remains the major goal of research [15].

Interestingly, PPIs have been marked as a potential remedy for COVID-19 within the frame of the idea to use already available drugs with the ascertained mechanism of action, clinical indications, and an acceptable safety profile to prevent/treat SARS-CoV-2 infection in the lack of specific antiviral chemotherapeutics [16]. It has been assumed that PPIs-induced pH change in cells as well as their presumed immunoregulatory, anti-inflammatory, antioxidative, antiproliferative, and antifibrotic effects [17, 18] justify the hypothesis that PPIs may be of value in COVID-19 prophylaxis and/or treatment.

The aim of this review was to summarize early evidence on the questionable impact of PPI use on the SARS-CoV-2 infection and COVID-19 clinical course based on a literature review of studies published in English till the end of February 2021 (key search words and collocations: SARS-CoV-2, COVID-19, proton pump inhibitors, adverse effects, clinical outcome) found in the PubMed database. The results of this search (information available in the selected studies) and evaluation are presented and discussed in a few sections reflecting strong belief in the Janus-faced nature of PPIs found in scientific publications.

PPIs – efficient, affordable, and universally available drugs – have been listed among the most commonly used and overused medications, often prescribed and/or taken long-term without a clear indication or any medical supervision [19]. PPIs are generally considered as safe and well-tolerated treatment of gastric acid-related disorders [20]. Nevertheless, they have been associated with several adverse effects [21], including GI infections [3] and pneumonia [4, 5, 22, 23]. However, the association between PPI use and bacterial pneumonia might have been overestimated [24, 25]. An increased susceptibility to bacterial GI infections, gut dysbiosis, and small intestinal bacterial overgrowth as adverse effects of PPIs are supported by randomized trials and meta-analyses [26‒30]. In addition, Vilcu et al. [31] found that continuous use of PPIs is associated with an increased risk for an acute viral enteric infection during periods of high endemic prevalence. It has been documented that increased gastric pH may be a risk factor for rotavirus [32], norovirus [33], and influenza virus [34] infections.

Zhou et al. [35] demonstrated that human intestinal epithelial cells were highly susceptible to the Middle East respiratory syndrome coronavirus infection, and the mice pretreated with pantoprazole in order to increase the Middle East respiratory syndrome coronavirus viability in the stomach preceding intragastric administration of the virus showed more prominent inflammation and epithelial damage in the small intestine than a control group. Of interest, with the progression of the enteric infection, live viruses appeared in the lungs. Previous data revealed that the normal pH of a healthy stomach (pH ≤ 3), unlike less acidic pH achieved with PPIs therapy, inactivates SARS-CoV-1 [36]. Similarly, SARS-CoV-2 may be destroyed in pH levels of 1.5–3, but it can survive in the presence of PPI-induced hypochlorhydria. Thus, iatrogenic hypochlorhydria, which impairs the innate immune system defense mechanisms, may facilitate invasion and replication of SARS-CoV-2 within enterocytes [37].

ACE2 receptors are widely expressed in the GI tract. Once SARS-CoV-2 colonizes the GI tract, it can lead to gastroenterocolitis [38]. There is evidence for the presence of infectious virus in the faeces [39, 40]. Negative nasopharyngeal tests were found in the presence of positive fecal samples collected simultaneously [39], suggesting that fecal-oral transmission cannot be completely excluded [41]. In addition, there is concern that the SARS-CoV-2 could spread beyond the GI tract, seed infection, or promote inflammation in the other organs, including the respiratory tract via a “gut-lung axis” [42].

PPIs may also modulate the immune response of neutrophils, NK cells, and cytotoxic T lymphocytes [5]. PPI use stimulates overgrowth of gut microbiota [26], but diminishes GI microbial diversity, that renders colonization of enteropathogens [43]. The relationship between GI dysbiosis and COVID-19 severity has been raised [42, 44, 45]. PPIs-induced dysbiosis might increase the likelihood of developing enteric infections, facilitate bacterial translocation, and sepsis which could complicate the clinical course of COVID-19. The intestinal lesions may promote the release of endotoxins and microbial metabolites that subsequently trigger inflammation and extreme proinflammatory cytokine release, present in some COVID-19 inpatients, which, in turn, can lead to multiorgan dysfunction and a fatal outcome. In addition, in case of micro-aspiration episodes, the bacteria will colonize the airways. The secondary pulmonary infection increases the probability of a severe clinical course of COVID-19, ARDS, and death.

Furthermore, taking PPIs has been related with a small excess of mortality, including cardiovascular and chronic kidney disease [6]. PPIs can inhibit the activity of dimethylarginine dimethylaminohydrolase and, secondarily, nitric oxide synthase, thus promoting inflammation, thrombosis, and the development of cardiovascular diseases. The idiosyncratic effect of PPIs on the kidneys may also lead to renal injury and dyselectrolytemia [46]. Noteworthy, there is evidence that omeprazole increases the expression of ACE2 in renal tissues [47].

The COVID-19 pandemic has raised safety concerns about the influence of PPI use on the SARS-CoV-2 positivity, disease severity, and clinical outcome of COVID-19. Despite the theoretical background, several respective studies on the association between the PPI use and COVID-19 have produced conflicting results (Table 1).

An internet survey study of a voluntary subject self-reporting of COVID-19 test results, demographics, GI symptoms, and PPIs and histamine type 2 receptor antagonists (H2RAs) use disclosed that PPIs used up to once daily or twice daily increased odds (aOR) (2.15 and 3.67, respectively) for self-reporting a positive COVID-19 test when compared with PPIs nonusers [7]. These alarming results soon gained the general public interest but have been later either questioned, mainly due to a selection bias [4, 10, 48, 49, 50], or not confirmed by other researchers [8, 11, 51, 52].

It is worth to emphasize that OR >3 falls into “zone of interest,” whereas 0.33 < OR < 3 falls within the “zone of potential bias.” In addition, it is recommended to use the Bradford Hill criteria [53] to assess presumed associations between PPI use and an outcome.

In Almario et al. [7] study, information on the number of participants tested for COVID-19 is missing. It is unclear whether the control group consists of participants who were tested and were COVID-19 negative or were a mixture of tested and untested subjects. If PPI nonusers received fewer tests, it could result in fewer positive tests. Moreover, subjects taking more potent gastric acid suppressants by prescription may be more involved into the healthcare system and, therefore, more likely to get tested and hence, could report more positive results. The question is, if the study demonstrates an association between PPI use and the risk of SARS-CoV-2 infection or the likelihood of being interested in SARS-CoV-2 testing or being tested for COVID-19.

Hadi et al. [50] claimed that Almario et al. [7] included participants who were not currently using PPIs as their reference group, so they were unable to determine the association between past PPI use and the odds of reporting a positive COVID-19 test. In addition, data regarding relevant comorbidities (cardiovascular disease, diabetes mellitus, chronic respiratory, or kidney disease) are absent.

Hajifathalian and Katz [10] noted that the COVID-19 positive respondents have a substantially different demographics than the overall study participants. Almario et al. [7] explain anomalies in data by suggesting that participants might be dishonest about their education or income or might not remember their correct diagnosis, but, on the contrary, postulate that it is unlikely for respondents to be wrong about COVID-19 diagnosis or PPI use. In addition, the reason for PPI use, dose, or compliance is unknown. It is not clear why once daily PPI use for more than 6 months should have a significantly smaller effect than once daily PPI use of less than 6 months. PPIs twice daily for less than 6 months was no different than once daily PPIs, whereas the same dose for more than 6 months had a significantly larger effect than once daily dosing.

Contrarily to the Almario et al. study, Tarlow et al. [52] found OR of SARS-CoV-2 positivity with PPI use of 0.48 compared with PPIs nonusers. Interestingly, in a retrospective case-control study on 179 elderly patients, PPI users were 2.3 times less likely to be infected by SARS-CoV-2 and develop COVID-19 than PPIs nonusers [11].

Some studies showed the improved clinical outcome (a low risk of mechanical ventilation or death over a 30-day period) in hospitalized COVID-19 patients who use famotidine but not PPIs [54]. However, these initial observations were later criticized (retrospective analysis, inpatient cohort, small number of patients, inclusion of the individuals without a proven COVID-19 diagnosis, lack of a control group, any difference in the outcome between oral vs. IV administration of famotidine not addressed in the study, concomitant drugs not considered, laboratory parameters, serving as surrogate markers for disease severity not adjusted for in the analysis).

In a more complex study of 952 COVID-19 patients (5.4% with severe disease) including 26 covariates (age, sex, comorbidities, other medications, laboratory parameters), no significant association between severe COVID-19 disease and the use of famotidine or PPIs with laboratory parameters (leukocyte count >11 × 10⁹/L and LDH >280 U/L as independent markers associated with severe COVID-19) was disclosed [12].

In the study including 9,469 participants, neither PPI nor H2RA use was associated with the risk of SARS-CoV-2 infection or death in-patients with COVID-19 [51]. The pooled OR of testing positive for SARS-CoV-2 associated with PPI use (previous and current) and current PPI use only was 1.06 and 1.03, respectively.

These results are consistent with a study from South Korea with reference to SARS-CoV-2 positivity, however, Korean patients taking PPIs (mainly short-term use of PPIs for less than a month starting within the previous 30 days) were at increased risk for severe clinical outcomes of COVID-19 (admission to the ICU, the need for invasive ventilation, or death) [8]. The relationship with past PPI use remained insignificant. The researcher admitted that: (a) PPIs prescriptions do not reflect actual drug exposure (probable noncompliance); (b) the results of SARS-CoV-2 test may be false negative/positive; (c) genetic polymorphisms of CYP2C19 and gastric H⁺ K⁺-ATPase may be a potential confounder; (d) smoking and BMI have not been included in the final analysis.

In the other study, exposure to PPIs prior to hospitalization was associated with worse clinical outcomes, including mortality in COVID-19 patients, regardless of the presence of cardiovascular diseases [9]. Despite some heterogeneity of the adverse clinical outcomes utilized in clinical trials, the meta-analysis of five studies with a total of 37,372 patients [55] disclosed increased odds for a severe or fatal course of COVID-19 (3 studies) and secondary infections (2 other studies) with the use of PPIs in COVID-19 patients compared with PPIs nonusers (pooled OR of 1.46 and 2.91, respectively). However, the increased risk for severe or fatal course of COVID-19 was small.

In the Cunye et al. [56] analysis (online publication without a peer-review) of eight studies with more than 268,683 subjects, PPI use did not influence the risk of SARS-CoV-2 infection or mortality risk of COVID-19 patients, but the risk of severe disease (OR 1.54) and secondary infection (OR 4.33) was increased. However, the authors stress the need of more high-quality studies to further clarify the relationship.

In Hariyanto et al. [57] meta-analysis, a total of 5884 COVID-19 patients (six studies) showed that PPI use was associated with an increased risk of severe COVID-19 (RR 1.35) and mortality from COVID-19 (RR 1.72), but (a) confounders such as patients’ age and comorbidities (not included in the analysis) may affect the relationship; (b) the information about the type, dose, duration, frequency, and compliance for PPI use is missing in the majority of analyzed studies; and (c) the RR values lower than 2.0 decrease the clinical meaning of the association; (d) most studies are of limited scientific value.

Meta-analysis by Li et al. [58] showed that PPI users were more likely to have severe outcomes of COVID-19 than PPI nonusers, with a pooled OR of 1.67. Past use of PPIs was not associated with increased susceptibility to SARS-CoV-2 infection (OR 0.85) or severe outcomes of COVID-19 (OR 1.03).

With reference to potential confounders, obesity, especially with BMI >40 kg/m² is an established risk factor for severe COVID-19 and death. GERD is more prevalent in obese patients, and it is a risk factor for micro-aspiration that might worsen the clinical outcome of COVID-19, just like the majority of obesity-related comorbitities, rather than PPI use itself.

Noteworthy, according to the Spain predictors of ICU admission study, COVID-19 patients suffering from asthma or allergic diseases were often the previous PPI users [59]. On the contrary, Savarino et al. [60] addressed the issue of the risk of COVID-19 in eosinophilic GI diseases treated with PPIs, glucocorticosteroides, or biologics depending on the location and initial response to pharmacotherapy. Despite the remarkable intake of acid suppressants (67.7%), no case of COVID-19 was diagnosed.

GI symptoms are common in COVID-19 [38] and may be the first clinical manifestation of SARS-CoV-2 infection [60, 61]. GIB has been reported in 4–13.7% of COVID-19 patients with GI symptoms in association with mucosal lesions in the esophagus, peptic ulcers, and SARS-CoV-2 detection in the cytoplasm of gastric, duodenal, and rectal epithelial cells [62, 63]. Of note, the first documented emergency surgery in a SARS-CoV-2-positive patient was performed due to perforated duodenal ulcer [64]. In addition, SARS-CoV-2 may affect the liver and negatively impact coagulation [65].

The following factors are considered in the pathophysiology of GIB in COVID-19 patients: (a) direct damage to the GI epithelium by SARS-CoV-2; (b) COVID-19-associated coagulopathy; and (c) pharmacotherapy including NSAIDs, glucocorticosteroids, IL-6 inhibitors [66], antiplatelet drugs, and prophylactic/therapeutic anticoagulation in COVID-19 patients that promotes GIB from existing mucosal lesions.

GIB can be a life-threatening complication to a severely ill COVID-19 patient, especially the elderly with comorbidities. Overt GIB in a COVID-19 patient necessitating endoscopy is also challenging to the endoscopic unit staff (the risk of airborne transmission of SARS-CoV-2), especially with reference to the upper GI tract examinations [67, 68].

Risk factors for the upper GIB in patients initiated on anticoagulants include older age, a prior history of GIB, chronic renal failure, H. pylori infection, concomitant use of antiplatelet drugs, and preexisting GI tract lesions [69]. The risk of GIB increases with the number of risk factors [70]. COVID-19 and anti-IL-6 therapy might be regarded as adjunctive risk factors influencing risk stratification of GIB in hospitalized patients [71].

The incidence of hospitalization for upper GIB is lower among patients who receive PPIs [72]. PPIs promote ulcer healing, prevent ulcer recurrence, and diminish the risk of GIB in high-risk populations. Several studies have demonstrated an overall benefit with the use of prophylactic PPIs, particularly in patients taking dual antiplatelet therapy and/or anticoagulation [73]. The meta-analysis of Mo et al. [74] confirmed that PPIs are also effective in prevention of low-dose aspirin-associated upper GI ulcers and bleeding. Moayyedi et al. [75] demonstrated that pantoprazole reduced overt GIB in patients receiving low anticoagulation and/or aspirin by approximately 50%, confirming the protective effect of PPIs.

NSAIDs, often used in COVID-19, have long been associated with an increased risk of GIB, particularly in older patients (>65 years), in-patients with previous complicated ulcers, and in those receiving high-dose NSAIDs or concomitant anticoagulation, aspirin, or glucocorticosteroids [76]. If NSAIDs cannot be stopped while receiving anticoagulation, PPIs may decrease the risk of the upper GIB in this population [77, 78].

For higher-risk critically ill patients, PPIs reduce the prevalence of GIB compared with no prophylaxis [79]. For patients at low risk, the reduction in bleeding may be unimportant. Therefore, the use of PPIs for the prevention of stress ulcers in non-critically ill patients admitted to the hospital is currently not recommended [80]. On the contrary, the use of PPIs for the prevention of stress ulcers in critical care patients has been supported by evidence and is recommended for high-risk patients [81]. Meta-analysis of 19 clinical trials showed that PPIs were more effective than H2RAs in reducing the risk of clinically important and overt GIB without an increased risk of pneumonia, ICU, length of stay, or death [82]. No effect of continuous daily treatment with PPIs versus H2RAs on risk of ventilator-associated events in critically ill patients who underwent mechanical ventilation for at least 5 days has been found [83].

Undoubtedly, careful risk stratification of the upper GIB, including medications and past medical history, should be performed in COVID-19 patients. If necessary, concomitant treatment with PPIs is strongly recommended [84‒87].

The COVID-19 pandemic raised, yet again, controversy about PPIs safety but also hope for their prophylactic and therapeutic potential against SARS-CoV-2. With the respect to the risk and severity of SARS-CoV-2 infection, there is no consensus regarding whether the use of PPIs might be beneficial, harmful, or indifferent. Although an increased pH in the stomach may, theoretically, be advantageous to the SARS-CoV-2 virus, the clinical significance of this hypothesis still remains unclear.

The results of clinical studies (often of an inferior scientific quality, including no precise data as to the PPIs dose and/or duration of treatment) on the risk of SARS-CoV-2 infection, disease severity, and mortality rate in COVID-19 patients exposed to PPIs are highly inconclusive. Numerous confounding factors could bias the interpretation of available data regarding the correlation between PPI use and SARS-CoV-2 infection and disease severity.

In fact, precipitous entering “negative public relations” of PPIs into general public may result in unnecessary anxiety and needless, potentially harmful PPI withdrawal in patients who definitely should continue the treatment. It ought to be stressed that both outpatient and in-hospital PPI use may prevent the upper GIB and the need for challenging endoscopic procedures at the time of airborne pandemic. The unproven potential of PPIs’ harmful effects and safety concerns referring to SARS-CoV-2 infection should not prevent proper prophylactic or therapeutic PPI use.

Any physician prescribing PPIs should always assess the individual benefit-risk ratio. Patients with a proven indication for PPI use should continue pharmacotherapy in the lowest effective dose. Whenever possible, prophylaxis of severe clinical course of COVID-19, for example, vaccinations or weight loss in obese patients, should be recommended.

The authors have no conflicts of interest to declare.

No funding in the preparation of data or the manuscript applies to the manuscript.

Dorota Ksiądzyna contributed to the manuscript as follows: conception and design of the work, acquisition, analysis, and interpretation of the data, drafting of the manuscript, and final approval of the preliminary manuscript to be submitted. Adam Szeląg contributed to the manuscript as follows: acquisition, analysis, interpretation and critical revision of the data, and final approval of the submitted version.