Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute Gastroenteritis and Community-Acquired Pneumonia in Children Roberto

Berni Canani, Pia Cirillo, Paola Roggero, Claudio Romano, Basilio Malamisura, Gianluca Terrin, Annalisa Passariello, Francesco Manguso, Lorenzo Morelli, Alfredo Guarino and for the Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) Pediatrics 2006;117;e817-e820 DOI: 10.1542/peds.2005-1655

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute Gastroenteritis and CommunityAcquired Pneumonia in Children
Roberto Berni Canani, MD, PhDa, Pia Cirillo, MDa, Paola Roggero, MDb, Claudio Romano, MDc, Basilio Malamisura, MDd, Gianluca Terrin, MDa, Annalisa Passariello, MDa, Francesco Manguso, MD, PhDe, Lorenzo Morelli, MDf, Alfredo Guarino, MDa, for the Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) Departments of aPediatrics and eClinical Experimental Medicine, University Federico II of Naples, Naples, Italy; bDepartment of Pediatrics, University of Milan, Milan, Italy; Department of Pediatrics, University of Messina, Messina, Italy; dPediatric Unit, Cava dei Tirreni Hospital, Cava dei Tirreni, Italy; fInstitute of Microbiology, University Cattolica del Sacro Cuore, Piacenza, Italy

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists

(H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reux disease (GERD) treatment. A prolonged GA inhibitorinduced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections. In addition, a number of papers and a meta-analysis have shown an increased risk of pneumonia in H2-blockertreated intensive care patients. More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large cohort of adult patients. These ndings are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study.
METHODS. The study was performed by expert pediatric gastroenterologists from 4

www.pediatrics.org/cgi/doi/10.1542/ peds.2005-1655 doi:10.1542/peds.2005-1655

Key Words histamine-2 receptor antagonists, proton pump inhibitors, diarrhea, infections, pneumonia Abbreviations GA gastric acidity H2 blocker histamine-2 receptor antagonist PPIproton pump inhibitor GERD gastroesophageal reux disease CI condence interval OR odds ratio
Accepted for publication Nov 18, 2005 Address correspondence to Roberto Berni Canani, MD, PhD, Department of Pediatrics, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: berni@ unina.it PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2006 by the American Academy of Pediatrics

pediatric gastroenterology centers. Children (aged 4 36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic brosis, immunodeciency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. Control subjects were recruited from healthy children visiting the centers for routine examinations. The diagnosis of GERD was conrmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine per day in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed

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by the physicians for 2 months. All enrolled children were evaluated during a 4-month follow-up. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period.
RESULTS. We obtained data in 186 subjects: 95 healthy

controls and 91 GA-inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. Rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was signicantly increased in patients treated with GA inhibitors compared with healthy controls during the 4-month follow-up period. In the GA inhibitor-treated group, the rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was increased when comparing the 4 months before and after enrollment. No differences were observed between H2 blocker and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period. On the contrary, in healthy controls, the incidence of acute gastroenteritis and pneumonia remained stable.
CONCLUSIONS. This is the rst prospective study performed

analysis have showed an increased risk of pneumonia in H2-blockertreated intensive care patients.46 More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large retrospective study.7 Although it is not at all certain that information collected in adults should be directly applied to pediatric patients, these data are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study. METHODS This study was performed by expert pediatric gastroenterologists from 4 pediatric gastroenterology centers. Children (aged 4 36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were: history of GA inhibitor therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic brosis, immunodeciency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. The diagnosis of GERD was made in all patients by esophageal pH monitoring and endoscopy with biopsies according to previously validated standard criteria.8 GA inhibitors (10 mg/kg ranitidine per day divided twice daily or 1 mg/kg omeprazole once a day) were prescribed for 8 weeks. Because of ethical reasons associated with performing a long-term follow-up in GERD-affected patients in the absence of a specic treatment, control subjects were recruited from healthy children visiting the centers for routine examination and not treated with GA inhibitors during the 4 months before enrollment. All subjects were enrolled during the same 4-month time period. This period corresponds to the peak season for rotavirus and respiratory syncytial virus infections in Italy. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period. The parents of all children were told to contact the centers in the event of any gastrointestinal or respiratory symptoms. In this case, the child was evaluated to assess the occurrence of acute gastroenteritis or pneumonia. The family pediatrician of each enrolled subject was also contacted to collect data on acute gastroenteritis or pneumonia incidence in the 4 months before enrollment and on a monthly basis during follow-up. Acute gastroenteritis was dened by a decrease in consistency (loose or liquid) and increase in frequency in bowel movements 3 per day for at least 2 and no more than 7 days in the presence or in the absence of other symptoms

in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and community-acquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data showed that the patients most at risk for pneumonia were those with signicant comorbid illnesses such as diabetes or immunodeciency, and this points to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. The results of our study are attributable to many factors, including direct inhibitory effect of GA inhibitors on leukocyte functions and qualitative and quantitative gastrointestinal microora modication. Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them.

ASTRIC ACIDITY (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reux disease (GERD) treatment. A prolonged GA inhibitorinduced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections.13 In addition, a number of papers and a meta-

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associated as fever, abdominal pain, and vomiting. Pneumonia was dened by the presence of pathologic chest examination and chest radiograph in the presence of the following symptoms: cough or difcult breathing, fever, or tachypnea. A senior radiologist in each center, unaware of clinical ndings, reviewed all chest radiographs. In the case of acute gastroenteritis or pneumonia symptom occurrence, the child was examined and the nal diagnosis was performed by at least 2 clinicians unaware to the study aim and group assignment. When diagnosis of pneumonia was made, 24-hour esophageal pH monitoring was performed to assess the efcacy of anti-GERD treatment. The pediatric gastroenterologist in charge of treatment prescription monitored the GERD therapy clinical efcacy and compliance, and only patients presenting with clear and stable GERD-related symptom resolution were included in the nal study outcomes evaluation. Written informed consent was obtained by the parents before enrollment. The study protocol was approved by the medical ethics committee of all the participating centers. We estimated a minimum sample size of 55 children in each group with a 5% level of signicance and a power of 80% to yield a smallest statistically signicant difference of 25% (specically, 0.45 vs 0.20) in the incidence of acute gastroenteritis. Ninety patients for each group were required to obtain a power of the study of 80% (type 1 error .05 with a 2-tailed test) considering the smallest difference in proportion of pneumonia of 10% (specically, .02 vs .12). Finally, assuming a study withdrawal rate of 20%, we planned to enroll 110 patients in each group. For continuous variables, groups were compared using the Mann-Whitney test. For categorical variables, the 2 test and Fishers exact test were used. For 2 related dichotomous variables, the McNemar test was used for detecting differences before and after the use of GA inhibitors. Relative risks of acute gastroenteritis, pneumonia, and antibiotic use (plus 95% condence intervals [CI]) in patients treated with GA inhibitors during 4-month follow-up period were estimated with

odds ratios (ORs) by logistic regression analysis. The level of signicance for all statistical tests was 2-sided (P .05). Statistical analysis was performed by a statistician who was blinded to patients group assignment with SPSS 13.0 for Windows (SPSS Inc, Chicago, IL). RESULTS During the study period, we enrolled 220 subjects. Nineteen GA inhibitor-treated patients were excluded from the analysis because of limited compliance (80% of the total daily dose intake for at least 2 consecutive days) (n 3), incomplete follow-up (n 2), or ineffective treatment (n 14). Fifteen subjects in the control group were excluded because of incomplete follow-up. Therefore, we obtained data in 186 subjects: 95 healthy controls and 91 GA inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment (Table 1). There were no differences between ranitidine- and omeprazole-treated children for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. GA inhibitortreated patients showed a signicant increase of acute gastroenteritis (P .001) and community-acquired pneumonia (P .03) compared with healthy controls during the 4-month follow-up period (Table 1). In addition, logistic regression analysis showed that subjects using acid-suppressive drugs were more likely to have acute gastroenteritis (OR: 3.58; 95% CI: 1.87 6.86) and pneumonia (OR: 6.39; 95% CI: 1.38 29.70) than controls. Furthermore, in the GA inhibitortreated group, the number of subjects with acute gastroenteritis (P .0001) and pneumonia (P .02) increased when comparing the 4 months before and after enrollment (Table 1). On the contrary, in healthy controls, incidence of acute gastroenteritis and pneumonia remained stable (Table 1). No differences were observed between H2 blockers and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period (Table 1). In the ex-

TABLE 1 Baseline Clinical Data and Outcome Measures

Characteristics Age, median, mo (IQR) Male, n (%) Weight, median, kg (IQR) Length, median, cm (IQR) Patients presenting with Acute gastroenteritis in the previous 4 mo, n (%) Acute gastroenteritis in the follow-up period, n (%) Pneumonia in the previous 4 mo, n (%) Pneumonia in the follow-up period, n (%)
aP bP

Controls (n 95) 10 (815) 50 (53) 9.3 (810) 74 (7078) 17 (18) 19 (20) 1 (1) 2 (2)

GA Inhibitors (n 91) 10 (816) 48 (53) 9.1 (815) 74 (7080) 18 (20) 43 (47)a,b 3 (3) 11 (12)a,b

.05, GA inhibitor users versus control children. .05, 4 months before versus 4 months after the enrollment. IQR indicates interquartile range.

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posed cohort, the number of acute gastroenteritis (n 21) and pneumonia (n 5) episodes remained stable during the use of GA inhibitor drugs and after stopping therapy (n 22 and 6, respectively). In all GA inhibitortreated subjects with community-acquired pneumonia, the 24-hour esophageal pH study results were negative. DISCUSSION Several nonimmune or immune defense factors are responsible for infection resistance in children. Gastric acid is directly involved in this network by limiting the survival of microorganisms accidentally ingested and, indirectly, by regulating gastrointestinal microora composition.9,10 The gastric bactericidal barrier is thought to reect mainly the low pH, because other constituents of the gastric juice seem to contribute little to the barrier function.11 At the best of our knowledge, this is the rst prospective study performed in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and communityacquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data, including the large study by Laheij et al,7 showed that the patients most at risk for pneumonia were those with signicant comorbid illnesses such as diabetes or immunodeciency, and this point outs to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. We observed a similar incidence of acute gastroenteritis and pneumonia during the use of GA inhibitor drugs and in the 2 months after stopping their use, resembling that previous observed by Laheij et al.7 How much this effect can last remains to be dened in future studies. The results of our study are attributable to many factors, including a direct inhibitory effect of GA inhibitors on several leukocyte functions.12,13 Another explanation could be found in the qualitative and quantitative gastrointestinal microora modication induced by these drugs.14,15 A study of the numbers and types of bacteria in nasogastric tubes of patients receiving GA inhibitors demonstrated increased numbers of bacteria, including hemolytic Streptococcus, a known cause of community-acquired pneumonia.16 Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them. GERD is commonly clinically diagnosed in children with many nonspecic symptoms and frequently the treatment is empiric. The results of our study could leave pediatricians with some unanswered questions about how to handle GA blocker treatment in selected patients
e820 CANANI et al

with severe neurologic impairment or chronic lung diseases. These subjects seem to be at increased risk for reux and aspiration. Protecting these selected patients from aspiration pneumonia secondary to untreated reux is probably more convenient than the risk of infection associated with GA inhibitor therapy. At the same time, we believe that in other children who are not high risk, the pediatrician needs to consider the increased risk of infection before prescribing an acid blocker. REFERENCES
1. Khatami SS, Mukunda B, Ravakhah K. Coinfection with Giardia lamblia and Clostridium difcile after use of ranitidine. Am J Med Sci. 2004;327:9193 2. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difcile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:3338 3. Neal KR, Scott HM, Slack RCB, Logan RFA. Omeprazole as risk factor for Campylobacter gastroenteritis: case-control study. BMJ. 1996;312:414 415 4. OKeefe GE, Gentiello LM, Maier RV. Incidence of infectious complications associated with the use of histamine 2-receptor antagonists in critically ill trauma patients. Ann Surg. 1998;227: 120 125 5. Prodhom G, Leuenberger P, Koerfer J, et al. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer: a randomized controlled trial. Ann Intern Med. 1994;120:653 662 6. Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ. 2000;321:17 7. Laheij RJF, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:19551960 8. Hillemeier AC. Gastroesophageal reux. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ontario, Canada: BC Decker Inc; 2000:289 296 9. Bourlioux P, Koletzko B, Guarner F, Braesco V. The intestine and its microora are partners for the protection of the host. Am J Clin Nutr. 2003;78:675 683 10. Guarner F, Malagelada JR. Gut ora in health and disease. Lancet. 2003;361:512519 11. Martinsen TC, Bergh K, Waldum HL. Gastric juice: a barrier against infectious diseases. Basic Clin Pharmacol Toxicol. 2005; 96:94 102 12. Vannier E, Dinarello CA. Histamine enhances interleukin (IL)-1 induced IL-6 gene expression and protein synthesis via H2-receptors in peripheral blood mononuclear cells. J Biol Chem. 1994;269:99529956 13. Holt TL, Coombes ID, Pillans PI, Scott IA. Neutropenia associated with omeprazole. Med J Aust. 1999;170:141142 14. Thorens J, Froehlic F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996;39: 54 59 15. Cothran DS, Borowitz SM, Sutphen JL, Dudley SM, Donowitz LG. Alteration of normal gastric ora in neonates receiving ranitidine. J Perinatol. 1997;17:383388 16. Simms HH, De Maria E, Mc Donald L, Peterson D, Robinson A, Buchard KW. Role of gastric colonization in the development of pneumonia in critically ill trauma patients: results of a prospective randomised trial. J Trauma. 1991;31:531536

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Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute Gastroenteritis and Community-Acquired Pneumonia in Children Roberto Berni Canani, Pia Cirillo, Paola Roggero, Claudio Romano, Basilio Malamisura, Gianluca Terrin, Annalisa Passariello, Francesco Manguso, Lorenzo Morelli, Alfredo Guarino and for the Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) Pediatrics 2006;117;e817-e820 DOI: 10.1542/peds.2005-1655
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/117/5/e817 This article cites 15 articles, 8 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/117/5/e817#BIBL This article has been cited by 4 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/117/5/e817#otherarticl es This article, along with others on similar topics, appears in the following collection(s): Premature & Newborn http://www.pediatrics.org/cgi/collection/premature_and_newbor n Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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