Monika Sarkar, MD; Sean Hennessy, PharmD, PhD; Yu-Xiao Yang, MD, MSCE
Grant Support: By an Academic Development Fund by the Department of Medicine, University of Pennsylvania (Dr. Yang).
Potential Financial Conflicts of Interest:Consultancies: S. Hennessy (Wyeth), Y.X. Yang (AstraZeneca). Grants received: Y.X. Yang (AstraZeneca, GlaxoSmithKline).
Reproducible Research Statement:Study protocol: Available from Dr. Yang (e-mail, email@example.com). Statistical code and data set: Not available.
Requests for Single Reprints: Yu-Xiao Yang, MD, MSCE, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 722 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Sarkar: Hospital of the University of Pennsylvania, 3400 Spruce Street, 100 Centrex, Philadelphia, PA 19104.
Dr. Hennessy: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 803 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021.
Dr. Yang: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 722 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021.
Author Contributions: Conception and design: M. Sarkar, S. Hennessy, Y.-X. Yang.
Analysis and interpretation of the data: M. Sarkar, S. Hennessy, Y.-X. Yang.
Drafting of the article: M. Sarkar, Y.-X. Yang.
Critical revision of the article for important intellectual content: M. Sarkar, S. Hennessy, Y.-X. Yang.
Final approval of the article: M. Sarkar, S. Hennessy, Y.-X. Yang.
Provision of study materials or patients: Y.-X. Yang.
Statistical expertise: Y.-X. Yang.
Obtaining of funding: Y.-X. Yang.
Administrative, technical, or logistic support: Y.-X. Yang.
Collection and assembly of data: Y.-X. Yang.
Sarkar M., Hennessy S., Yang Y.; Proton-Pump Inhibitor Use and the Risk for Community-Acquired Pneumonia. Ann Intern Med. 2008;149:391-398. doi: 10.7326/0003-4819-149-6-200809160-00005
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Published: Ann Intern Med. 2008;149(6):391-398.
Proton-pump inhibitors (PPIs) are potent gastric acid suppressants. With its excellent efficacy for acid-related diseases and increasing availability of both over-the-counter and generic formulations, PPI use continues to escalate (1). Antiulcer drugs, primarily PPIs, ranked second in overall U.S. retail sales at $10.8 billion in 2001 (2).
Two studies recently suggested that PPI use may increase the risk for community-acquired pneumonia (CAP) (3, 4). A proposed mechanism is increased bacterial colonization in the upper gastrointestinal tract due to gastric acid suppression (3, 4). However, other noncausal mechanisms may also be responsible for the association between PPIs and CAP. Residual confounding may have contributed to the relatively modest increased risk seen in these studies. Furthermore, both studies found that the association was weakest among current recipients who had been taking PPIs for the longest duration, which is contrary to what one would expect if PPIs increase the risk for CAP.
Department of Surgery,
October 15, 2008
Relation of Gastric Acid Suppression to Community-Acquired Pneumonia
TO THE EDITOR: In contrast to 2 previous population-based studies concluding that current use of gastric acid suppression therapy with proton-pump inhibitors (PPIs) or histamine-2-receptor antagonists was weakly but significantly associated with increased risk of community- acquired pneumonia (CAP)(1,2), in their larger nested case-control analysis, Dr Sarkar and colleagues(3)revealed that current PPI use was not independently associated with an increased risk for CAP. Consistent with a recent report that new treatment with PPIs within 7days before index date resulted in a strong association with CAP (odds ratio [OR] 5.9, 95 % confidence interval [CI] 2.1-11.7) (2), current use of PPIs started within the previous 7days was strongly associated with an increased risk for CAP (OR 3.79, 95 % CI 2.66-5.42). The authors mention that the risk for CAP among patients with antibiotic treatment that was started within 7 days of index date was 10-fold higher than for those without antibiotic exposure during the same period. These findings suggest that antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) might be newly prescribed for patients with early manifestations of pneumonia such as low -grade fever and throat pain, and PPIs might be concurrently used to reduce the risk of NSAIDs-related upper gastrointestinal adverse events. I would like to ask the authors whether a group of new PPI recipients within 7 days before the diagnosis of CAP is to be excluded from analysis as an outlier.
The authors mention that the risk for CAP in PPI recipients younger than age 60 years moderately increased before excluding new recipients of PPI therapy. Also in subgroup analysis of another study, increased OR for PPI users younger than 40 years has been shown (2). In a prospective comparative study in children, gastric acid suppression therapy with PPIs or histamine-2-receptor antagonists for gastroesophageal reflux disease was independently associated with increased risk of CAP and gastroenteritis (4). Furthermore, in a group of children treated with gastric acidity inhibitors, the incidence of pneumonia and gastroenteritis significantly increased after the initiation of gastric acid suppression. Among the case patients with a mean age of 73.5 years in the current study, about 22 % had chronic obstructive pulmonary disease or asthma, 19 % had a history of stroke, and 14 % suffered from dementia, implying that these patients with CAP collected for the study were frail and have been at high risk for CAP. I think subgroup analysis of younger patients with less co-morbidity would be helpful, because strong confounders such as chronic illness and frequent hospital visits in frailer aged patients are likely to weaken the impact of PPI use in multivariate analysis. Besides its possible relation to CAP, there are data to support an association between PPI use and an increased risk of Clostridium infections in the community (5,6). The assumption that PPIs and histamine-2-receptor antagonists could break a gastric acid defense against upward and downward infections is to be kept in mind.
1. Laheij RJ, 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: 1955-60.
2. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community acquired pneumonia. Arch Intern Med 2007; 167: 950-5.
3. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149: 391-8.
4. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, et al. Therapy with gastric acidity inhibitors increases risk of acute gastroenteritis and community-acquired pneumonia. Pediatrics 2006; 117: e817-20.
5. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294: 2389-95.
6. Dial S, Kezouh A, Dascal A, Barkun A, Suissa S. Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection. CMAJ 2008; 179: 767-72.
Department of Pulmonary Medicine, National Hospital Organization, Tokyo National Hospital, Kiyose, T
November 6, 2008
PPI inhibitor use and the risk of pneumonia
Sarkar and colleagues have suggested that chronic use of PPI inhibitor is not associated with the increased use risk of community-acquired pneumonia (CAP).However, their analysis was not accepted in clinical settings. Because those that received PPI were older patients, their age-adjusted results were not compared with the control results from middle-aged subjects. In the elderly, aspiration pneumonia is very dominant in CAP diagnosis (1). Stroke, dysphasia, and gastro-esophageal reflux disease(GERD) are very strong risk factors for the development of aspiration pneumonia (2). Aspiration of or pharyngeal secretions as well as aspiration of gastric contents are very important for the pathogenesis of aspiration pnuemonia. The PPI use impairs gastric eradication of bacteria, resulting in the increased risk of regurgitation and aspiration of the contents in the elderly during the night at supine position. Because the age-dependent retraction of the larynx, age-dependent muscle weakness, and decreased volume of salivary secretion with age dependently or independently affect the impaired swallowing function, the impaired gastric eradication of common bacteria may exaggerated the aspiration itself and aspirated materials.
It has recently reported that tracheal acidification, which could represent aspiration, has been observed in 9 of 32 stroke patients assessed as safe to take diet and fluids orally by bedside assessment and videofluoroscopy (3). Thus the conventional methods are not efficient to detect the aspiration in older patients. That is why the PEG, which is believed to prevent aspiration, did not show good results of prognosis. The patient with PEG feeding may have oropharengeal and gastric content aspiration during night time at supine position (4). In fact, it has reported that PEG-fed stroke patients indicates that lower esophageal sphincter (LES) dysfunction and GERD are common and that GERD is influenced by patient position (5). Thus, the study should be separated the two categories of the patients, i.e., non-aspirated risk and aspirated risk groups.
In the end, the correlation between beneficial effects of PPI inhibitors for gastric symptoms and the possible increased risk of aspiration pneumonia should be seriously considered in older patients in clinical settings.
1) Teramoto S, Fukuchi Y, Sasaki H, Sato K, Sekizawa K, Matsuse T; Japanese Study Group on Aspiration Pulmonary Disease. High incidence of aspiration pneumonia in community- and hospital-acquired pneumonia in hospitalized patients: a multicenter, prospective study in Japan. J Am Geriatr Soc. 2008;56: 577-9.
2) Teramoto S, Matsuse T, Ouchi Y. Clinical significance of cough as a defence mechanism or a symptom in elderly patients with aspiration and diffuse aspiration bronchiolitis.. Chest 1999; 115: 602ï¿½E03
3) Clayton J, Jack CI, Ryall C, Tran J, Hilal E, Gosney M. Tracheal pH monitoring and aspiration in acute stroke. Age Ageing. 2006; 35: 47-53.
4) Teramoto S, Ishii T, Yamamoto H, Yamaguchi Y, Ouchi Y. Nasogastric tube feeding is a cause of aspiration pneumonia in ventilated patients Eur Respir J. 2006; 27: 436-437.
5) Elphick DA, Elphick HL, Smith L, Da Costa D, Riley SA. Does gastro-esophageal reflux following PEG placement in stroke patients predict a poorer outcome? Age Ageing. 2006; 35 :545-546.
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Infectious Disease, Pulmonary/Critical Care, Pneumonia.
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