 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
a Departments of Pediatrics
e Clinical Experimental Medicine, University "Federico II" of Naples, Naples, Italy
b Department of Pediatrics, University of Milan, Milan, Italy
c Department of Pediatrics, University of Messina, Messina, Italy
d Pediatric Unit, Cava dei Tirreni Hospital, Cava dei Tirreni, Italy
f Institute of Microbiology, University Cattolica del Sacro Cuore, Piacenza, Italy
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS. The 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 a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic fibrosis, immunodeficiency, 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 confirmed 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 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 significantly 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 first prospective study performed 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 significant comorbid illnesses such as diabetes or immunodeficiency, 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 microflora modification. 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.
Key Words: histamine-2 receptor antagonists • proton pump inhibitors • diarrhea • infections • pneumonia
Abbreviations: GA—gastric acidity • H2 blocker—histamine-2 receptor antagonist • PPI—proton pump inhibitor • GERD—gastroesophageal reflux disease • CI—confidence interval • OR—odds ratio
Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reflux disease (GERD) treatment. A prolonged GA inhibitor–induced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections.1–3 In addition, a number of papers and a meta-analysis have showed an increased risk of pneumonia in H2-blocker–treated intensive care patients.4–6 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 |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
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 defined 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 associated as fever, abdominal pain, and vomiting. Pneumonia was defined by the presence of pathologic chest examination and chest radiograph in the presence of the following symptoms: cough or difficult breathing, fever, or tachypnea. A senior radiologist in each center, unaware of clinical findings, reviewed all chest radiographs. In the case of acute gastroenteritis or pneumonia symptom occurrence, the child was examined and the final 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 efficacy of anti-GERD treatment. The pediatric gastroenterologist in charge of treatment prescription monitored the GERD therapy clinical efficacy and compliance, and only patients presenting with clear and stable GERD-related symptom resolution were included in the final 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 significance and a power of 80% to yield a smallest statistically significant difference of 25% (specifically, 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% (specifically, .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 Fisher's 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% confidence 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 significance 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 |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
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 inhibitor–treated patients showed a significant 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 inhibitor-treated 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 exposed 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 inhibitor-treated subjects with community-acquired pneumonia, the 24-hour esophageal pH study results were negative.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
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 microflora modification 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 ß 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 nonspecific 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 with severe neurologic impairment or chronic lung diseases. These subjects seem to be at increased risk for reflux and aspiration. Protecting these selected patients from aspiration pneumonia secondary to untreated reflux 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.
|
FOOTNOTES |
|---|
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{at}unina.it
The authors have indicated they have no financial relationships relevant to this article to disclose.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. H. Wang, R. S. Finkel, E. S. Bertini, M. Schroth, A. Simonds, B. Wong, A. Aloysius, L. Morrison, M. Main, T. O. Crawford, et al. Consensus Statement for Standard of Care in Spinal Muscular Atrophy J Child Neurol, August 1, 2007; 22(8): 1027 - 1049. [Abstract] [PDF]
|
|
|
|
 |
|
 S. E. Gulmez, A. Holm, H. Frederiksen, T. G. Jensen, C. Pedersen, and J. Hallas Use of Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: A Population-Based Case-Control Study Arch Intern Med, May 14, 2007; 167(9): 950 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Hoffman and S. I. Miller The systems biology of infection in animal models bears fruit PNAS, June 20, 2006; 103(25): 9377 - 9378. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved. |
||
|
||
