Proton Pump Inhibitors and COVID-19

US Pharm. 2020;12(45):26-2924.

ABSTRACT: COVID-19 is a global respiratory disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2. It is associated with high mortality and morbidity and continues to place a great burden on the worldwide economy. As information regarding the risk factors and potential therapies continues to rapidly emerge, proton pump inhibitors, some of the most widely used drugs in the world, have been reviewed for both their risks and benefits in COVID-19 patients.

COVID-19 is a global respiratory disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹ It was first reported in December 2019 in Wuhan, China, and on March 11, 2020, it was declared a pandemic by the World Health Organization. Coronaviruses are a large family of single-stranded positive-sense RNA viruses that infect both humans and animals. They include the alpha-coronavirus, beta-coronavirus, gamma-coronavirus, and delta-coronavirus.² The SARS-CoV-2 is the seventh human coronavirus to be identified. The total number of reported COVID-19 cases between January 21, 2020, and September 2, 2020, was 6,047,692 in the United States.³

The most common presenting symptoms of COVID-19 are fever, cough, and fatigue. Other symptoms include sputum production, headache, hemoptysis, diarrhea, dyspnea, and lymphopenia.⁴ Clinical features typically include pneumonia, and more severe cases may be aggravated by secondary infections. Patients may develop an acute respiratory distress syndrome (ARDS), which is associated with a high morbidity and mortality.⁵ The incubation period of the virus can range from 2 to 14 days without any symptoms.²

Risks Associated With PPIs in COVID-19 Patients

A number of risk factors have been associated with the disease. These include old age, chronic pulmonary disease, cardiovascular disease, chronic kidney disease, diabetes mellitus, obesity, malignancy, smoking, and the use of certain medications, including proton pump inhibitors (PPIs).¹

PPIs are among the top 10 most widely used drugs in the world, commonly prescribed for the management of gastrointestinal (GI) acid–related disorders (gastroesophageal reflux disease [GERD]). However, in up to 70% of cases they are prescribed without a clear indication.⁶ Furthermore, the long-term use of PPIs exposes patients to potential side effects, including bone fracture, chronic kidney disease, and GI  infections.^7,8 A significant amount of research is conducted on the benefits and risk of PPIs. Most recently, they have been in the limelight for their association with COVID-19 infection. Although there is evidence that the use of PPIs is a risk factor for testing positive with COVID-19, some PPIs have been observed to improve disease outcomes in patients already infected with COVID-19.⁹ This article reviews some of the emerging research in this field, demonstrating the direct and indirect benefits or risk of using PPIs in COVID-19 patients.

PPIs primarily exert their effect by irreversibly inhibiting proton pumps, thereby reducing gastric acid output. Resultant hypochlorhydria has been associated with an increased risk of viral infections, including those caused by rotaviruses, noroviruses, and coronaviruses. Based upon these findings, it has been proposed that the survival of the SARS-CoV-2 may be increased in the stomach of patients taking PPIs.¹⁰ This allows sufficient time for the viral invasion of the GI epithelial cells and, therefore, increases the risk of developing the COVID-19 infection.⁷

Rotaviruses are inactivated at the acidity resembling the normal fasting stomach (pH 2.0); however, inactivation is minimal at pH 4.0.¹¹ Similarly, SARS-CoV-1 seems to be inactivated in acidic conditions (pH <3).¹² Influenza RNA has been found in the gastric mucosa of patients on acid-suppression therapy, indicating that higher pH may predispose individuals to the influenza virus infection of the stomach.¹³ Community-acquired respiratory infections, which generally tend to be of viral origin, seem to be more common in individuals on acid-suppression therapy.¹⁴ Patients treated with PPIs seem to be at a greater risk of norovirus infection than those who are not.¹⁵ The continuous use of PPIs has been associated with an increased risk of enteric viral infections.¹⁶ Specific to coronaviruses, the viral load of MERS-CoV has been found to be higher in in the small intestine of intragastrically injected mice, especially in those pretreated with pantoprazole.¹⁷

The RNA of SARS-CoV-2 has been found in rectal swabs, even in patients who had a negative nasopharyngeal test. This evidence for GI infections with SARS-CoV-2 implies that the fecal-oral route has a part to play in the transmission of SARS-CoV-2 virus.^8,18

A large national health survey conducted in the U.S. found that the use of PPIs is associated with increased odds for reporting a positive COVID-19 test.⁸ The team noticed a high incidence of GI symptoms and discovered that the virus sheds into the saliva and is swallowed into the stomach. Analysis of the data demonstrated a dose-response relationship wherein patients taking a PPI twice daily had significantly higher odds of testing positive for COVID-19 than those using lower dose PPIs up to once daily. Patients taking histamine-2 receptor antagonists were not at an elevated risk. The study was, however, focused on GI symptoms, and the results may be biased towards those with GI symptoms. While the respondents reported a high rate of GERD-related symptoms, few of the respondents using PPIs has a formal diagnosis of GERD by a physician. This might suggest that many patients may be using OTC PPIs for GERD-related symptoms. Furthermore, those who are severely ill or hospitalized with COVID-19 were unlikely to have taken the survey.⁸

The team applied the Hill criteria to establish causality between the use of PPIs and the risk of COVID-19.⁸ The Hill criteria is a group of nine principles (strength of the association, consistency, specificity, temporal sequence, biological gradient, biological rationale, coherence, experimental evidence, and analogous evidence) that are used to establish causation between a presumed cause and an observed effect. The outcomes showed preliminary evidence of an association between the use of PPIs (particularly twice-daily dosing) and COVID-19. The authors note, however, that since this is not a placebo-controlled, randomized trial, further studies exploring this association are required.⁸

A single-center, retrospective small cohort study based in the U.S. found that 15.6% of hospitalized COVID-19 patients were using PPIs at home.¹⁰ Patients taking PPIs demonstrated a significantly higher mortality than patients without PPIs (34.8% vs. 16.2%, P = .007). The study was conducted on patients older than age 18 years admitted to a tertiary-care academic medical center in Brooklyn, New York, between March 1 and April 25, 2020. At the time of writing this article, the paper had not been peer-reviewed. The authors point out that their findings should be interpreted with caution as there may be potential unrecognizable confounders.¹⁰ Furthermore, they were not able to obtain accurate information on the type, dose, duration, and frequency of the PPIs that the patients were using.¹⁰

A large retrospective cohort study noted that current PPI usage was associated with an increased risk for severe clinical outcomes of COVID-19 but not susceptibility to SARS-CoV-2 infection.¹ The data for that analysis were obtained from the Korean national health insurance claims–based database. Data of 132,316 individuals older than  age 18 years who tested positive for SARS-CoV-2 between January 1 and May 15, 2020, were analyzed. The study found that the use of PPIs (current and past) did not increase a patient’s risk of COVID-19 infection. However, the team noted that current users of PPIs were at a risk of worse outcomes of COVID-19.¹

Similarly, a small, single-centered retrospective study was conducted on patients confirmed with SARS-CoV-2 infection to determine whether PPIs were a risk factor for the development of secondary infections and ARDS in hospitalized patients with COVID-19.⁵ PPIs reduce gastric-acid production, leading to bacterial overgrowth in the upper GI tract. Micro-aspiration results in bacterial colonization of the lung, triggering the development of pneumonia. The study showed that 48.4% of patients taking PPIs presented with secondary infections, whereas only 20.0% of patients not taking PPIs developed secondary infections. After adjusting for other risk factors, including predisposing comorbidities, the difference was found to be statistically significant. The study also found that a significantly higher number of PPI-treated patients developed ARDS compared with non-PPI patients and that the development of ARDS was strongly associated with the presence of a secondary infection.⁵

The authors conclude that PPIs indirectly lead to the development of ARDS by triggering secondary infections. These patients showed a significantly higher index mortality.⁵

Potential Benefits of PPIs in COVID-19 Patients

Lysosomotropic agents seem to have an antiviral action through a pH modulation–mediated effect on endolysosomal trafficking.¹⁹ They can passively diffuse through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vessels. These agents could provide therapeutic benefits in the management of COVID-19 patients.¹⁹

Some of these agents include azithromycin, indomethacin, some nonsteroidal anti-inflammatory drugs, PPIs, and fluoxetine. As these agents are already available on the market, they may be considered for management of COVID-19 patients until newer molecules are developed and there are completed clinical trials.²⁰

Hydroxychloroquine, a weak base, has been used in the management of COVID-19.²¹ Hydroxychloroquine accumulates in organelles of acidic content, golgi vesicles, endosomes, and lysosomes, raising their pH.²⁰ In an acidic environment, viral particles spread through the endosome junction. It is thought that one of the ways in which hydroxychloroquine exerts its effect is by neutralizing this acid. The net effect is an inhibition of viral spread and replication. 

It has been proposed that PPIs may in fact be beneficial in the treatment and prophylaxis of COVID-19.²⁰ Looking at the positive effects of PPIs, a trial to evaluate the effect of the pantoprazole on the absorption of hydroxychloroquine was conducted. The data from this trial were not available at the time of writing this article.²¹

A team in Germany found that omeprazole interferes with the viral formation of SARS-CoV-2 at plasma concentrations of about 8 μM.²² However, they also noted that at therapeutic concentrations, omeprazole enhanced the anti–SARS-CoV-2 effects of aprotinin (an approved protease inhibitor) and remdesivir (a SARS-CoV nucleotide analog RNA polymerase inhibitor) by 2.7-fold and 10-fold, respectively. It is therefore suggested that omeprazole combination therapy with aprotinin or remdesivir may be possible candidates for therapy for the treatment of COVID-19 and should be explored further.^22,23

COVID-19 is associated with a number of clinical manifestations, including a disproportionally high rate of thromboembolic complications.²³ In an attempt to decrease thromboembolic complications, many facilities are using empiric intermediate or therapeutic doses of anticoagulants in high-risk patients. GI bleeding is a common complication of anticoagulation, and clinicians may find that they are presented with COVID-19 patients requiring endoscopic intervention. Since the risks of endoscopy might outweigh the benefits, some patients might be managed more conservatively using PPIs.^24,25

A small, single-centered retrospective study conducted on patients admitted to the Shanghai Public Health Clinical Center found no effect of PPI use in prolonging or shortening the course of disease in adults hospitalized with COVID-19.²⁶ The authors note, however, that the study does not include severe and critical cases of COVID-19.

Conclusion

Given the lack of a universal consensus on the effects of PPIs in the COVID-19 patients, the importance of individualized, evidence-based therapy is emphasized. Healthcare practitioners need to weigh the benefits against the risks of using PPIs in patients with COVID-19. Further studies, particularly prospective cohort and controlled trials, are required for better quality data. Pharmacists and other healthcare professionals are encouraged to stay abreast of all the changes within this field for maximal patient benefit. In the meantime, PPIs should be utilized judiciously, with a periodic review of appropriateness conducted, and they should be deprescribed or therapy decreased to the lowest effective dose, when possible.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

REFERENCES

1. Lee SW, Ha EK, Yeniova AÖ, et al. Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching [published online ahead of print, 2020 Jul 30]. Gut. 2020;65:1932-1939.
2. Kopel J, Perisetti A, Gajendran M, et al. Clinical insight into the gastrointestinal manifestations of COVID-19. Dig Dis Sci. 2020.
3. CDC. United States COVID-19 cases and deaths by state. https://covid.cdc.gov/covid-data-tracker/#cases. Accessed September 3, 2020.
4. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433.
5. Luxenburger H, Sturm L, Biever P, 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? J Intern Med. July 1, 2020 [published online ahead of print].
6. Marks D. Time to halt the overprescribing of proton pump inhibitors. Clin Pharm. 2016. www.pharmaceutical-journal.com/20201548.fullarticle. Accessed August 29, 2020.
7. Charpiat B, Bleyzac N, Tod M. Proton pump inhibitors are risk factors for viral infections: even for COVID-19? Clin Drug Investig. 2020;40:897-899.
8. Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol. 2020;65:1707-1715.
9. Dibner JJ. Direct COVID-19 infection of enterocytes: the role of hypochlorhydria. Am J Infect Control. August 10, 2020 [published online ahead of print].
10. Ramachandran P, Perisetti A, Gajendran M, et al. Prehospitalization proton pump inhibitor (PPI) use and clinical outcomes in COVID-19. www.medrxiv.org/content/10.1101/2020.07.12.20151084v1.full.pdf+html. Accessed September 2, 2020.
11. Weiss C, Clark HF. Rapid inactivation of rotaviruses by exposure to acid buffer and acidic gastric juice. J Gen Virol. 1985;66:2725-2730.
12. Darnell ME, Subbarao K, Feinstone SM, Taylor DR. Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV. J Virol Methods. 2004;121(1):85-91.
13. Hayase Y, Tobita K, Sato H. Detection of type B influenza virus genes from biopsied gastric mucosa. J Gastroenterol. 2002;37:101-105.
14. Fisher L, Fisher A. Acid-suppressive therapy and risk of infec- tions: pros and cons. Clin Drug Investig. 2017;37:587-624.
15. Prag C, Prag M, Fredlund H. Proton pump inhibitors as a risk factor for norovirus infection. Epidemiol Infect. 2017;145:1617-1623.
16. Vilcu A, Sabatte L, Blanchon T, et al. Association between acute gastroenteritis and continuous use of proton pump inhibitors during winter periods of highest circulation of enteric viruses. JAMA Netw Open. 2019;2(11):e1916205.
17. Zhou J, Li C, Zhao G, et al. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci Adv. 2017;3(11).
18. Xiao F, Tang M, Zheng X, et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158:1831-1833.
19. Homolak J, Kodvanj I. Widely available lysosome targeting agents should be considered as potential therapy for COVID-19. Int J Antimicrob Agents. 2020;56(2):106044.
20. Tastemur S, Ataseven H. Is it possible to use proton pump inhibitors in COVID-19 treatment and prophylaxis? Med Hypotheses. 2020;143:110018.
21. Stoll F, Blank A, Mikus G, et al. Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):584.
22. Bojkova D, McGreig E, McLaughlin KM, et al. SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles. BioRxiv. 2020. www.biorxiv.org/content/10.1101/2020.04.03.024257v1.
23. Aguila EJT, Cua IHY. Repurposed GI drugs in the treatment of COVID-19. Dig Dis Sci. 2020;65(8):2452-2453.
24. Patel P, Sengupta N. PPIs and beyond: a framework for managing anticoagulation-related gastrointestinal bleeding in the era of COVID-19. Dig Dis Sci. 2020;65(8):2181-2186.
25. Cavaliere K, Levine C, Wander P, et al. Management of upper GI bleeding in patients with COVID-19 pneumonia. Gastrointest Endosc. 2020;92(2):454-455.
26. Xiao-Yu Zhang, Hai-Bing Wu, Ling Y, et al. Analysis of the effect of proton pump inhibitors on the course of common COVID-19.
www.medrxiv.org/content/10.1101/2020.06.07.20124776v2. Accessed September 3, 2020.

To comment on this article, contact rdavidson@uspharmacist.com.