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DOI: 10.1542/peds.2005-16552006;117;e817-e820Pediatrics

Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP)Morelli, Alfredo Guarino and for the Working Group on Intestinal Infections of theMalamisura, Gianluca Terrin, Annalisa Passariello, Francesco Manguso, Lorenzo

Roberto Berni Canani, Pia Cirillo, Paola Roggero, Claudio Romano, Basilio Gastroenteritis and Community-Acquired Pneumonia in Children

Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute

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ARTICLE

Therapy With Gastric Acidity Inhibitors Increases theRisk of Acute Gastroenteritis and Community-Acquired Pneumonia in ChildrenRoberto Berni Canani, MD, PhD a , Pia Cirillo, MD a , Paola Roggero, MD b , Claudio Romano, MD c , Basilio Malamisura, MD d , Gianluca Terrin, MD a ,Annalisa Passariello, MD a , Francesco Manguso, MD, PhD e , Lorenzo Morelli, MD f , Alfredo Guarino, MD a , for theWorking Group on IntestinalInfections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP)

Departments of aPediatrics ande Clinical Experimental Medicine, University Federico II of Naples, Naples, Italy;b Department of Pediatrics, University of Milan, Milan, Italy;cDepartment of Pediatrics, University of Messina, Messina, Italy;d Pediatric Unit, Cava dei Tirreni Hospital, Cava dei Tirreni, Italy;f Institute of Microbiology, UniversityCattolica 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

(H 2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesoph-ageal reux disease (GERD) treatment. A prolonged GA inhibitorinduced hypo-chlorhydria has been suggested as a risk factor for severe gastrointestinal infec-tions. In addition, a number of papers and a meta-analysis have shown anincreased risk of pneumonia in H 2 -blockertreated intensive care patients. Morerecently, an increased risk of community-acquired pneumonia associated with GAinhibitor treatment has been reported in a large cohort of adult patients. Thesendings are particularly relevant to pediatricians today because so many childrenreceive some sort of GA-blocking agent to treat GERD. To test the hypothesis thatGA suppression could be associated with an increased risk of acute gastroenteritisand pneumonia in children treated with GA inhibitors, we conducted a multi-center, prospective study.

METHODS.The study was performed by expert pediatric gastroenterologists from 4pediatric gastroenterology centers. Children (aged 4 36 months) consecutivelyreferred for common GERD-related symptoms (for example, regurgitation andvomiting, feeding problems, effortless vomiting, choking), from December 2003 toMarch 2004, were considered eligible for the study. Exclusion criteria were ahistory of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic brosis, immunode-ciency, food allergy, congenital motility gastrointestinal disorders, neuromusculardiseases, or malnutrition. Control subjects were recruited from healthy childrenvisiting the centers for routine examinations. The diagnosis of GERD was con-rmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine perday in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed

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

doi:10.1542/peds.2005-1655

Key Wordshistamine-2 receptor antagonists, protonpump inhibitors, diarrhea, infections,pneumonia

AbbreviationsGAgastric acidityH2 blockerhistamine-2 receptorantagonistPPIproton pump inhibitorGERDgastroesophageal reux diseaseCIcondence intervalORodds ratio

Accepted for publication Nov 18, 2005

Address correspondence to Roberto BerniCanani, MD, PhD, Department of Pediatrics,University Federico II of Naples, Via SergioPansini, 5, 80131 Naples, Italy. E-mail: [email protected]

PEDIATRICS(ISSNNumbers:Print, 0031-4005;Online, 1098-4275). Copyright 2006by theAmericanAcademy of Pediatrics

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by the physicians for 2 months. All enrolled childrenwere evaluated during a 4-month follow-up. The endpoint was the number of patients presenting with acutegastroenteritis or community-acquired pneumonia dur-ing a 4-month follow-up study period.

RESULTS.We obtained data in 186 subjects: 95 healthycontrols and 91 GA-inhibitor users (47 on ranitidineand 44 on omeprazole). The 2 groups were comparablefor age, gender, weight, length, and incidence of acutegastroenteritis and pneumonia in the 4 months beforeenrollment. Rate of subjects presenting with acute gas-troenteritis and community-acquired pneumonia wassignicantly increased in patients treated with GA in-hibitors compared with healthy controls during the4-month follow-up period. In the GA inhibitor-treatedgroup, the rate of subjects presenting with acute gastro-enteritis and community-acquired pneumonia was in-creased when comparing the 4 months before and afterenrollment. No differences were observed between H 2 blocker and PPI users in acute gastroenteritis and pneu-monia incidence in the previous 4 months and duringthe follow-up period. On the contrary, in healthy con-trols, the incidence of acute gastroenteritis and pneumo-nia remained stable.

CONCLUSIONS.This is the rst prospective study performedin pediatric patients showing that the use of GA inhibi-tors was associated with an increased risk of acute gas-troenteritis and community-acquired pneumonia inGERD-affected children. It could be interesting to under-line that we observed an increased incidence of intesti-

nal and respiratory infection in otherwise healthy chil-dren taking GA inhibitors for GERD treatment. On thecontrary, the majority of the previous data showed thatthe patients most at risk for pneumonia were those withsignicant comorbid illnesses such as diabetes or immu-nodeciency, and this points to the importance of GAsuppression as a major risk factor for infections. In ad-dition, this effect seems to be sustained even after theend of therapy. The results of our study are attributableto many factors, including direct inhibitory effect of GAinhibitors on leukocyte functions and qualitative andquantitative gastrointestinal microora modication.Additional studies are necessary to investigate the mech-anisms of the increased risk of infections in childrentreated with GA inhibitors, and prophylactic measurescould be considered in preventing them.

G ASTRIC ACIDITY (GA) inhibitors, including hista-mine-2 receptor antagonists (H 2 blockers) andproton pump inhibitors (PPIs), are the mainstay of gas-troesophageal reux disease (GERD) treatment. A pro-longed GA inhibitorinduced hypochlorhydria has beensuggested as a risk factor for severe gastrointestinal in-fections. 13 In addition, a number of papers and a meta-

analysis have showed an increased risk of pneumonia inH2 -blockertreated intensive care patients. 46 More re-cently, an increased risk of community-acquired pneu-monia associated with GA inhibitor treatment has beenreported in a large retrospective study. 7

Although it is not at all certain that information col-lected in adults should be directly applied to pediatric

patients, these data are particularly relevant to pediatri-cians today because so many children receive some sortof GA-blocking agent to treat GERD. To test the hypoth-esis that GA suppression could be associated with anincreased risk of acute gastroenteritis and pneumonia inchildren treated with GA inhibitors, we conducted amulticenter, prospective study.

METHODS

This study was performed by expert pediatric gastroenter-ologists from 4 pediatric gastroenterology centers. Children(aged 436 months) consecutively referred for common

GERD-related symptoms (for example, regurgitation andvomiting, feeding problems, effortless vomiting, choking),from December 2003 to March 2004, were consideredeligible for the study. Exclusion criteria were: history of GAinhibitor therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases,cystic brosis, immunodeciency, food allergy, congenitalmotility gastrointestinal disorders, neuromuscular diseases,or malnutrition. The diagnosis of GERD was made in allpatients by esophageal pH monitoring and endoscopy with biopsies according to previously validated standard crite-ria. 8 GA inhibitors (10 mg/kg ranitidine per day divided

twice daily or 1 mg/kg omeprazole once a day) were pre-scribed for 8 weeks. Because of ethical reasons associatedwith performing a long-term follow-up in GERD-affectedpatients in the absence of a specic treatment, controlsubjects were recruited from healthy children visiting thecenters for routine examination and not treated with GAinhibitors 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 rotavirusand respiratory syncytial virus infections in Italy.

The end point was the number of patients presentingwith acute gastroenteritis or community-acquired pneu-monia during a 4-month follow-up study period.

The parents of all children were told to contact thecenters in the event of any gastrointestinal or respiratorysymptoms. In this case, the child was evaluated to assessthe occurrence of acute gastroenteritis or pneumonia.The family pediatrician of each enrolled subject was alsocontacted to collect data on acute gastroenteritis orpneumonia incidence in the 4 months before enrollmentand on a monthly basis during follow-up. Acute gastro-enteritis was dened by a decrease in consistency (looseor liquid) and increase in frequency in bowel move-ments 3 per day for at least 2 and no more than 7 daysin the presence or in the absence of other symptoms

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associated as fever, abdominal pain, and vomiting. Pneu-monia was dened by the presence of pathologic chestexamination and chest radiograph in the presence of thefollowing symptoms: cough or difcult breathing, fever,or tachypnea. A senior radiologist in each center, un-aware of clinical ndings, reviewed all chest radio-graphs. In the case of acute gastroenteritis or pneumonia

symptom occurrence, the child was examined and thenal diagnosis was performed by at least 2 cliniciansunaware to the study aim and group assignment. Whendiagnosis of pneumonia was made, 24-hour esophagealpH monitoring was performed to assess the efcacy ofanti-GERD treatment. The pediatric gastroenterologist incharge of treatment prescription monitored the GERDtherapy clinical efcacy and compliance, and only pa-tients presenting with clear and stable GERD-relatedsymptom resolution were included in the nal studyoutcomes evaluation. Written informed consent was ob-tained by the parents before enrollment. The study pro-

tocol was approved by the medical ethics committee ofall the participating centers.We estimated a minimum sample size of 55 children

in each group with a 5% level of signicance and apower of 80% to yield a smallest statistically signicantdifference of 25% (specically, 0.45 vs 0.20) in the in-cidence of acute gastroenteritis. Ninety patients for eachgroup were required to obtain a power of the study of80% (type 1 error .05 with a 2-tailed test) consideringthe smallest difference in proportion of pneumonia of10% (specically, .02 vs .12). Finally, assuming a studywithdrawal rate of 20%, we planned to enroll 110 pa-tients in each group.

For continuous variables, groups were compared us-ing the Mann-Whitney test. For categorical variables,the 2 test and Fishers exact test were used. For 2related dichotomous variables, the McNemar test wasused for detecting differences before and after the use ofGA inhibitors. Relative risks of acute gastroenteritis,pneumonia, and antibiotic use (plus 95% condenceintervals [CI]) in patients treated with GA inhibitorsduring 4-month follow-up period were estimated with

odds ratios (ORs) by logistic regression analysis. Thelevel of signicance for all statistical tests was 2-sided ( P

.05). Statistical analysis was performed by a statisticianwho was blinded to patients group assignment withSPSS 13.0 for Windows (SPSS Inc, Chicago, IL).

RESULTS

During the study period, we enrolled 220 subjects. Nine-teen GA inhibitor-treated patients were excluded fromthe analysis because of limited compliance ( 80% of thetotal daily dose intake for at least 2 consecutive days)(n 3), incomplete follow-up ( n 2), or ineffectivetreatment ( n 14). Fifteen subjects in the control groupwere excluded because of incomplete follow-up. There-fore, we obtained data in 186 subjects: 95 healthy con-trols and 91 GA inhibitor users (47 on ranitidine and 44on omeprazole). The 2 groups were comparable for age,gender, weight, length, and incidence of acute gastroen-teritis and pneumonia in the 4 months before enroll-

ment (Table 1). There were no differences between ra-nitidine- and omeprazole-treated children for age,gender, weight, length, and incidence of acute gastroen-teritis and pneumonia in the 4 months before enroll-ment. GA inhibitortreated patients showed a signicantincrease of acute gastroenteritis ( P .001) and commu-nity-acquired pneumonia ( P .03) compared withhealthy controls during the 4-month follow-up period(Table 1). In addition, logistic regression analysis showedthat subjects using acid-suppressive drugs were morelikely to have acute gastroenteritis (OR: 3.58; 95% CI:1.876.86) and pneumonia (OR: 6.39; 95% CI: 1.3829.70) than controls. Furthermore, in the GA inhibitor-treated group, the number of subjects with acute gastro-enteritis ( P .0001) and pneumonia ( P .02) increasedwhen comparing the 4 months before and after enroll-ment (Table 1). On the contrary, in healthy controls,incidence of acute gastroenteritis and pneumonia re-mained stable (Table 1). No differences were observed between H 2 blockers and PPI users in acute gastroenter-itis and pneumonia incidence in the previous 4 monthsand during the follow-up period (Table 1). In the ex-

TABLE 1 Baseline Clinical Data and Outcome MeasuresCharacteristics Controls

(n 95)GA Inhibitors

(n 91)

Age, median, mo (IQR) 10 (815) 10 (816)Male,n (%) 50 (53) 48 (53)Weight, median, kg (IQR) 9.3 (810) 9.1 (815)Length, median, cm (IQR) 74 (7078) 74 (7080)Patients presenting with

Acute gastroenteritis in the previous 4 mo,n (%) 17 (18) 18 (20)Acute gastroenteritis in the follow-up period,n (%) 19 (20) 43 (47)a,b

Pneumonia in the previous 4 mo,n (%) 1 (1) 3 (3)Pneumonia in the follow-up period,n (%) 2 (2) 11 (12)a,b

a P .05, GA inhibitor users versus control children.b P .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 ( n21) and pneumonia ( n 5) episodes remained stableduring the use of GA inhibitor drugs and after stoppingtherapy ( n 22 and 6, respectively). In all GA inhibitor-treated subjects with community-acquired pneumonia,the 24-hour esophageal pH study results were negative.

DISCUSSIONSeveral nonimmune or immune defense factors are re-sponsible for infection resistance in children. Gastric acidis directly involved in this network by limiting the sur-vival of microorganisms accidentally ingested and, indi-rectly, by regulating gastrointestinal microora compo-sition. 9,10 The gastric bactericidal barrier is thought toreect mainly the low pH, because other constituents ofthe gastric juice seem to contribute little to the barrierfunction. 11 At the best of our knowledge, this is the rstprospective study performed in pediatric patients show-ing 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 in-creased incidence of intestinal and respiratory infectionin otherwise healthy children taking GA inhibitors forGERD treatment. On the contrary, the majority of theprevious data, including the large study by Laheij et al, 7

showed that the patients most at risk for pneumoniawere those with signicant comorbid illnesses such asdiabetes or immunodeciency, and this point outs to theimportance of GA suppression as a major risk factor forinfections. In addition, this effect seems to be sustained

even after the end of therapy. We observed a similarincidence of acute gastroenteritis and pneumonia duringthe use of GA inhibitor drugs and in the 2 months afterstopping their use, resembling that previous observed byLaheij et al. 7 How much this effect can last remains to bedened in future studies.

The results of our study are attributable to manyfactors, including a direct inhibitory effect of GA inhib-itors on several leukocyte functions. 12,13 Another expla-nation could be found in the qualitative and quantitativegastrointestinal microora modication induced bythese drugs. 14,15 A study of the numbers and types of bacteria in nasogastric tubes of patients receiving GAinhibitors demonstrated increased numbers of bacteria,including hemolytic Streptococcus, a known cause ofcommunity-acquired pneumonia. 16 Additional studiesare necessary to investigate the mechanisms of the in-creased risk of infections in children treated with GAinhibitors, and prophylactic measures could be consid-ered in preventing them.

GERD is commonly clinically diagnosed in childrenwith many nonspecic symptoms and frequently thetreatment is empiric. The results of our study could leavepediatricians with some unanswered questions abouthow to handle GA blocker treatment in selected patients

with severe neurologic impairment or chronic lung dis-eases. These subjects seem to be at increased risk forreux and aspiration. Protecting these selected patientsfrom aspiration pneumonia secondary to untreated re-ux is probably more convenient than the risk of infec-tion associated with GA inhibitor therapy. At the sametime, we believe that in other children who are not high

risk, the pediatrician needs to consider the increased riskof infection before prescribing an acid blocker.

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DOI: 10.1542/peds.2005-16552006;117;e817-e820PediatricsItalian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP)

Morelli, Alfredo Guarino and for the Working Group on Intestinal Infections of theMalamisura, Gianluca Terrin, Annalisa Passariello, Francesco Manguso, Lorenzo

Roberto Berni Canani, Pia Cirillo, Paola Roggero, Claudio Romano, Basilio Gastroenteritis and Community-Acquired Pneumonia in Children

Therapy With Gastric Acidity Inhibitors Increases the Risk of Acute

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