By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: Proton pump inhibitor use in infants is associated with a 34% increase in the risk of subsequent infection-related hospitalization. These medications should be used only when the benefits clearly outweigh the risks.
SOURCE: Lassalle M, Zureik M, Dray-Spira R. Proton pump inhibitor use and risk of serious infections in young children. JAMA Pediatr 2023; Aug 14:e232900. doi: 10.1001/jamapediatrics.2023. [Online ahead of print].
Proton pump inhibitors (PPIs) are effective in blocking gastric acid secretion and are believed to relieve symptoms of gastroesophageal reflux disease in infants. Interestingly, however, there is not conclusive data-based evidence that infantile fussiness, vomiting, and feeding problems with gastroesophageal reflux are reduced by acid suppression. Uncomplicated gastroesophageal reflux (without disease that is provable by identifying esophageal pathology or altered growth) is very common during infancy but does not require acid suppression. However, use of PPIs is common (more than 5% of children in some countries) and increasing (three- to five-fold increase over the past two decades).
A breadth of medical literature suggests that there are adverse side effects of PPI use in children. PPI use is associated with pediatric fractures, allergy and asthma, and inflammatory bowel disease. It has been suspected that PPI use might increase the risk of infection, either by altering stomach acidity and allowing survival and spread of ingested pathogens or by directly suppressing immune function. However, there have not been many data proving an association between PPI use and serious childhood infections.
Thus, investigators in France used a national database to compare hospitalization rates for serious infection in children who were treated with PPIs to the hospitalization rates of children treated with other acid-blocking treatments. From 2010 through 2018, 24% of the 6,349,003 babies born in France received some sort of antacid treatment. A total of 606,645 infants who received a PPI were compared to 655,779 infants who received a different treatment (a histamine-2 receptor blocker or a topical agent such as calcium carbonate or alginate). Thus, all studied children were treated with some sort of acid suppression (although we do not know whether those treated with PPIs were sicker than the children treated with other agents). Treatment was initiated at a median age of 84 days; follow-up extended for a median of 3.8 years.
Overall, children with ongoing PPI use were 34% more likely to be hospitalized for a serious infection than were children treated with a non-PPI antacid therapy. The incidence of serious infection requiring hospitalization was 9.27 per 100 child-years with PPI treatment and 2.64 per 100 child-years among children with no PPI treatment (whether treated with a different acid blocker or no acid-related medication).
The risks of infection-related hospitalization were similarly elevated whether considering gastrointestinal, respiratory, ear-nose-throat, urinary, or central nervous system infections. The rates of musculoskeletal infections were increased with PPI use, but less so than were the other sorts of infection. Skin infection rates were not significantly different between infants whose acid secretion was treated with PPIs and those treated with other medications. The risk of PPI-associated bacterial infections requiring hospitalization was a bit higher than the still-significant increased risk of viral infections requiring hospitalization. The increased risk of infection-related hospitalizations with PPI use was not related to whether the child had been born prematurely or had other chronic diseases.
The authors acknowledged that their data did not allow them to determine if the treated infants truly had gastroesophageal reflux disease (for which PPIs could be indicated) or simply had some fussiness with uncomplicated gastroesophageal reflux (for which PPIs are not indicated). Nonetheless, with both subtlety and profundity, the authors advised that “proton pump inhibitors should not be used without a clear indication” in infants.
COMMENTARY
PPIs are said to be among the most commonly prescribed medications worldwide.1 Beyond the current study, other literature indicates that the use of PPIs is increasing.1
Infectious disease experts deal daily with patient care issues related to antimicrobial stewardship. These new data remind us that we might also frequently be dealing with infections that are associated with or even caused by inadequate stewardship of other medications. Following the numerical facts of this study, 24% of infants in France (and the situation is presumably similar elsewhere in Europe and North America) receive treatment for gastric acid problems, and 4% of infants treated with a PPI go on to require hospitalization for a serious infection.
A recent review of antacid use for infants revealed that both histamine-2 receptor blocking agents and PPIs are effective in reducing gastric pH and in reducing the number of acid reflux events.2 But there is no demonstrated effectiveness of these medications in altering clinically relevant outcomes such as irritability, feeding tolerance, and weight gain.2 Despite evidence of clinical efficacy, these medications are used widely with, particularly for PPIs, increased risk of subsequent infections.
Of course, the risks of PPI use are not limited to children. Data from adults suggest that PPI use is related to the development of community-acquired pneumonia and Clostridioides difficile infection as well as renal disease, osteoporosis-associated fractures, and dementia.3
It is certainly plausible that PPIs act as potent inhibitors of gastric acid secretion, which leaves more living organisms in the stomach either to be regurgitated to cause respiratory infections or to be transmitted down the intestinal tract to cause diarrheal disease. Indeed, the continuous use of antacids in children and adults raises the risk of seasonal gastroenteritis by about 81%.4 The mechanism by which PPI use increases the risk of more distant infections (of the urinary tract and the central nervous system, for instance) is less clear. Altered stomach acid can change the microbiome, and varied population balances within the microbiome can alter short-chain fatty acid production and, thus perhaps, neutrophil function.3
REFERENCES
- Dipasquale V, Cicala G, Spina E, Romano C. A narrative review on efficacy and safety of proton pump inhibitors in children. Front Pharmacol 2022;13:839972.
- Tan J, Jeffries S, Carr R. A review of histamine-2 receptor antagonist and proton pump inhibitor therapy for gastroesophageal reflux disease in neonates and infants. Paediatr Drugs 2023;25:557-576.
- Berry JG, Mansbach JM. Questionable safety of proton pump inhibitor use in children. JAMA Pediatr 2023; Aug 14. doi: 10.1001/jamapediatrics.2023.2906. [Online ahead of print].
- Vilcu AM, 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:e1916205.
