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Joc 41159
Joc 41159
ASTROINTESTINAL SYMPTOMS
Context Reduction of gastric acid secretion by acid-suppressive therapy allows pathogen colonization from the upper gastrointestinal tract. The bacteria and viruses in the
contaminated stomach have been identified as species from the oral cavity.
Objective To examine the association between the use of acid-suppressive drugs
and occurrence of community-acquired pneumonia.
Design, Setting, and Participants Incident acid-suppressive drug users with at
least 1 year of valid database history were identified from the Integrated Primary Care
Information database between January 1, 1995, and December 31, 2002. Incidence
rates for pneumonia were calculated for unexposed and exposed individuals. To reduce confounding by indication, a case-control analysis was conducted nested in a
cohort of incident users of acid-suppressive drugs. Cases were all individuals with
incident pneumonia during or after stopping use of acid-suppressive drugs. Up to
10 controls were matched to each case for practice, year of birth, sex, and index
date. Conditional logistic regression was used to compare the risk of communityacquired pneumonia between use of proton pump inhibitors (PPIs) and H2-receptor
antagonists.
Main Outcome Measure Community-acquired pneumonia defined as certain (proven
by radiography or sputum culture) or probable (clinical symptoms consistent with pneumonia).
Results The study population comprised 364683 individuals who developed 5551
first occurrences of pneumonia during follow-up. The incidence rates of pneumonia
in nonacid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45
per 100 person-years, respectively. The adjusted relative risk for pneumonia among
persons currently using PPIs compared with those who stopped using PPIs was 1.89
(95% confidence interval, 1.36-2.62). Current users of H2-receptor antagonists had a
1.63-fold increased risk of pneumonia (95% confidence interval, 1.07-2.48) compared with those who stopped use. For current PPI users, a significant positive doseresponse relationship was observed. For H2-receptor antagonist users, the variation in
dose was restricted.
Conclusion Current use of gastric acidsuppressive therapy was associated with an
increased risk of community-acquired pneumonia.
www.jama.com
JAMA. 2004;292:1955-1960
even increased colonization, of ingested pathogens.7-12 There is some evidence that acid-suppressive therapy facilitates nosocomial infections.13-15
To our knowledge, there are no largescale studies of the association be-
Author Affiliations: Department of Gastroenterology, University Medical Center St. Radboud, Nijmegen, the Netherlands (Drs Laheij and Jansen); and Department of Medical Informatics (Drs Laheij,
Sturkenboom, Dieleman, and Stricker and Mr Hassing), Pharmacoepidemiology Unit, Department of Epidemiology and Biostatistics (Drs Sturkenboom and
Stricker), and Internal Medicine (Dr Dieleman), Erasmus MC University, Medical Center Rotterdam, Rotterdam, the Netherlands.
Corresponding Author: Robert J. F. Laheij, PhD, University Medical Center St. Radboud, Department of
Gastroenterology, PO Box 9101, 6500 HB, Nijmegen, the Netherlands (R.Laheij@mdl.umcn.nl).
All data were retrieved from the Integrated Primary Care Information (IPCI)
project, a general practice research database containing data from electronic
patient records of a group of about 150
general practitioners in the Netherlands. Details of the database have been
described.16,17 Briefly, the database contains the complete medical records of approximately 500000 patients. The electronic records contain coded and
anonymous data on patient demographics, reasons for visit (in free text), diagnoses (using the International Classification for Primary Care18 and free text)
from general practitioners and specialists, referrals, laboratory findings, hospitalizations, and drug prescriptions, including their indications and dosage
regimen. To maximize completeness of
the data, general practitioners participating in the IPCI project are not allowed to maintain a system of paperbased records aside from the electronic
medical records. The system complies
with European Union guidelines on the
use of medical data for medical research and has been proven valid for
pharmacoepidemiologic research.19 The
Scientific and Ethical Advisory Board of
the IPCI project approved the study.
Source Population
and Exposure Cohorts
dar time (matching factors), the indication for therapy (cancer, peptic ulcer
disease and gastroesophageal reflux disease with or without esophagitis, functional dyspepsia, and endoscopically
uninvestigated), diabetes mellitus, heart
failure, chronic obstructive lung disease (asthma and chronic obstructive
pulmonary disease), lung cancer, stomach cancer, number of physician visits
in the year before, use of antibiotics, and
use of systemic immunosuppressive
agents (glucocorticoids, cyclosporine). In patients empirically treated with
gastric acidsuppressive drugs and endoscopically uninvestigated, the indication for therapy was unknown and
may have varied from relevant organic disease (peptic ulcer disease and
reflux esophagitis) to no organic abnormalities (ie, functional dyspepsia).
The indication for the use of acidsuppressive drugs was obtained from
the prescription records. For patients
with more than 1 indication, the endoscopically verified diagnosis was
used.
No. of patients
Person-years
No. of cases of
pneumonia
Unadjusted relative
risk (95% CI)
Total
Unexposed
Overall
364 683
977 893
345 224
970 331
19 459*
7562*
5551
5366
1.00
185
4.47 (3.82-5.12)
H2-Receptor
Antagonists
10 177
2351
54
4.24 (3.18-5.43)
Proton Pump
Inhibitors
12 337
5191
131
4.63 (3.84-5.43)
Data Analysis
RESULTS
The source population comprised
364683 persons who had on average 2.7
years of follow-up and 5551 first occurrences of pneumonia (TABLE 1).
Eighteen percent of the 5551 pneumonia occurrences were confirmed by radiography or microbiological testing.
During the study period, 19459 individuals received a first prescription for
acid-suppressive drugs, 10177 H2RAs
and 12337 PPIs (some individuals used
both). The mean duration of use for
H2RAs was 2.8 months; for PPIs, 5.0
months. Most persons had not undergone endoscopy and were empirically
treated for upper gastrointestinal tract
symptoms.
In the exposed cohort, 185 persons
developed a first pneumonia occurrence during use of acid-suppressive
drugs and 292 after stopping their use.
The incidence rate during use of PPIs
was 2.5 per 100 person-years and during use of H2RAs, 2.3 per 100 person-
Controls
(n = 4690)
Age, y
20
20-40
41-60
60
Women
1 (0.2)
52 (10.9)
146 (30.7)
276 (58.1)
262 (55.2)
3 (0.1)
544 (11.0)
1530 (30.8)
2883 (58.1)
2770 (55.8)
Diabetes mellitus
Heart failure
Chronic obstructive lung disease
62 (13.1)
95 (20.0)
195 (41.1)
466 (9.4)
449 (9.1)
945 (19.1)
1.47 (1.10-1.97)
2.73 (2.06-3.62)
3.03 (2.48-3.70)
Stomach cancer
Lung cancer
3 (0.6)
13 (2.7)
19 (0.4)
32 (0.6)
1.71 (0.50-5.84)
4.41 (2.29-8.50)
40 (8.4)
126 (2.5)
3.60 (2.47-5.23)
262 (55.2)
111 (23.4)
102 (21.5)
3554 (71.7)
861 (17.4)
545 (11.0)
1.00
1.74 (1.37-2.20)
2.49 (1.95-3.19)
1 (0.2)
27 (5.7)
131 (27.6)
56 (11.8)
260 (54.7)
9 (0.2)
206 (4.2)
1481 (29.9)
661 (13.3)
2603 (52.5)
1.19 (0.15-9.40)
1.34 (0.88-2.05)
0.90 (0.72-1.12)
0.85 (0.63-1.15)
1.00
Characteristics
Table 3. Odds Ratios for Community-Acquired Pneumonia in Patients Using Proton Pump
Inhibitors or H2-Receptor Antagonists
No. (%)
Cases
Controls
Unadjusted
OR
Adjusted OR
(95% CI)*
183 (38.5)
28 (5.9)
34 (7.2)
230 (48.4)
1361 (27.4)
243 (4.9)
346 (7.0)
3010 (60.7)
1.28
1.12
0.96
1.00
1.27 (1.06-1.54)
1.08 (0.78-1.50)
1.00 (0.74-1.36)
99 (20.8)
48 (10.1)
36 (7.6)
28 (5.9)
264 (55.6)
697 (14.1)
417 (8.4)
247 (5.0)
243 (4.9)
3356 (67.7)
1.79
1.43
1.89
1.47
1.00
1.73 (1.33-2.25)
1.59 (1.14-2.23)
1.76 (1.18-2.61)
1.44 (0.94-2.21)
68 (14.3)
25 (5.3)
5 (1.1)
0 (0)
1 (0.2)
470 (9.5)
132 (2.7)
70 (1.4)
20 (0.4)
5 (0.1)
1.80
2.47
0.91
1.74 (1.28-2.35)
2.29 (1.43-3.68)
0.91 (0.35-2.34)
25 (5.3)
59 (12.4)
15 (3.2)
265 (5.3)
358 (7.2)
74 (1.5)
1.21
2.04
2.63
1.23 (0.78-1.93)
1.94 (1.41-2.68)
2.28 (1.26-4.10)
27 (5.7)
40 (8.4)
32 (6.7)
157 (3.2)
291 (5.9)
249 (5.0)
2.07
1.79
1.62
2.24 (1.42-3.54)
1.65 (1.14-2.40)
1.52 (1.01-2.29)
3 (0.6)
39 (8.2)
6 (1.3)
0
0
64 (1.3)
297 (6.0)
50 (1.0)
6 (0.1)
0
0.50
1.67
1.39
NA
NA
0.62 (0.18-2.11)
1.82 (1.26-2.64)
1.58 (0.64-3.93)
41 (8.6)
7 (1.5)
0
341 (6.9)
76 (1.5)
0
1.49
1.14
NA
1.64 (1.14-2.36)
1.36 (0.60-3.07)
21 (4.4)
18 (3.8)
134 (2.7)
165 (3.3)
1.99
1.35
2.12 (1.29-3.48)
1.61 (0.94-2.73)
9 (1.9)
118 (2.4)
0.92
0.99 (0.48-2.03)
Abbreviations: CI, confidence interval; DDD, defined daily dose; H2RAs, H2-receptor antagonists; NA, not applicable;
OR, odds ratio; PPIs, proton pump inhibitors.
*Adjusted for matching factors, respiratory illness, long-term heart failure, diabetes mellitus, use of antibiotics, and use
of immunosuppressants.
Too few cases were available to calculate ORs.
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