ORIGINAL CONTRIBUTION

Risk of Community-Acquired Pneumonia and

Use of Gastric AcidSuppressive Drugs
Robert J. F. Laheij, PhD
Miriam C. J. M. Sturkenboom, PhD
Robert-Jan Hassing, MSc
Jeanne Dieleman, PhD
Bruno H. C. Stricker, MD, PhD
Jan B. M. J. Jansen, MD, PhD

ASTROINTESTINAL SYMPTOMS

are common: annually, 20%

to 40% of the general population has at least 1 episode
of dyspepsia or gastroesophageal reflux disease, and 5% consult a general
practitioner for these complaints.1,2 The
most effective treatment strategy for
these symptoms in primary care is reduction of gastric acid secretion, which
can be achieved by using H2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs).3 Currently, a common
approach in western countries is to prescribe acid-suppressive drugs for upper gastrointestinal tract symptoms without suspicion of a malignancy and to
refer nonresponders for gastrointestinal endoscopy.4 The consequence of this
policy is that acid-suppressive drugs are
among the most frequently prescribed
drugs, whereas their use is not without
risk.
H2-receptor antagonists and PPIs increase susceptibility to infections by increasing gastric pH.5,6 Intragastric acidity constitutes a major nonspecific
defense mechanism of the stomach to
ingested pathogens. In normal gastric
juice with a pH below 4, most pathogens are promptly killed, whereas they
survive in hypochlorhydric to achlorhydric circumstances. For the effecFor editorial comment see p 2012.

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.

tive management of upper gastrointestinal tract symptoms, the intragastric pH

should, however, be maintained above
4 for at least 18 hours. Treatment with
acid-suppressive drugs may therefore
lead to an insufficient elimination, or

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).

2004 American Medical Association. All rights reserved.

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www.jama.com

JAMA. 2004;292:1955-1960

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ACID-SUPPRESSIVE DRUGS AND PNEUMONIA

tween use of acid-suppressive drugs and

the risk of infections. We examined the
association between the use of gastric
acidsuppressive drugs and community-acquired pneumonia in a population-based cohort study.
METHODS
Setting

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

The study started on January 1, 1995,

and ended on December 31, 2002. The
source population comprised all individuals with at least 1 year of valid database history, which means that the
general practitioner supplied standard
data for at least 1 year and the patient
was registered for 1 year with the general practitioner. We required this preenrollment period to be able to characterize the patient and verify previous use
of drugs and a history of pneumonia. All
1956

individuals were followed up from the

moment they had 1 year of valid history until one of the following events:
pneumonia, death, moving out of the
practice area, or end of the study period, whichever came first. To retain patients without recent occurrence of
pneumonia, we excluded all individuals who had a diagnosis of pneumonia
in the preenrollment period.
From the source population, a study
cohort of incident (no use in the year
before enrollment) acid-suppressive
drug users (those with at least 1 H2RA
or PPI prescription) was identified.
From this exposure cohort, we excluded all individuals who received
acid-suppressive drugs in combination with antibiotics to eradicate Helicobacter pylori infection. The duration
of use of individual acid-suppressive
drugs was calculated from the prescribed quantity and prescribed dosing regimen. Person-time of exposure
was accumulated during follow-up time
for calculation of incidence rates. Individuals who never used acidsuppressive drugs before or during the
study period were considered unexposed; follow-up time was accumulated for calculation of incidence rates.
Identification and Ascertainment
of Pneumonia

The first occurrence of pneumonia for

each individual was identified through
searches on diagnoses and free-text indicators of pneumonia. The medical
records of all potential cases were reviewed manually to classify the pneumonia as certain (proven by thorax radiography or microbiological culture),
probable (clinical symptoms consistent with pneumonia but no objective
evidence), possible, or no pneumonia.
Definitions of pneumonia vary widely.
Some require only the presence of infiltrates on chest radiography, whereas
others require only certain symptoms
or signs. In our analysis, we included
pneumonia proven by chest radiography or sputum culture (certain) or presence of respiratory symptoms (probable). Cases with certain or probable
pneumonia caused by aspiration (n=5),

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obstruction (n=6), or nosocomial infection (n=13) were excluded. The date

of first pneumonia was defined as the
index date.
Nested Case-Control Analysis

To reduce confounding by indication,

a nested case-control analysis was conducted within the cohort of persons
who used acid suppressants during the
study period. For each case of pneumonia, we randomly selected up to 10
controls from the cohort, matched on
sex, year of birth, and index date to the
case. Exposure to H2RAs and PPIs was
classified separately by time since last
use. Drug use was defined as current
if the prescription length covered the
index date and as past if the end of the
last prescription was before the index
date. Past use was further categorized
into recent past, past, and distant past
if the end of the last prescription was
less than 30 days ago, between 30 and
180 days ago, and more than 180 days
ago, respectively.
Because all persons had used an acidsuppressive drug during the study period, we had no unexposed subjects. In
analyses of the dose and duration effects of H2RAs and PPIs separately, we
restricted the cases and controls to individuals who never used the other type
of acid suppressant. Among current users of H2RAs or PPIs, we studied the active compound (cimetidine, famotidine, nizatidine, ranitidine, roxatidine,
omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole), the
daily dosage (less than, equal to, and
more than the defined daily dose), and
the duration of use (14 days, 14-28
days, 28-42 days, and 42 days). The
defined daily dose for the PPIs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole is 20, 20, 30,
40, and 20 mg, respectively. The defined daily dose for the H2RAs cimetidine, famotidine, nizatidine, ranitidine, and roxatidine is 800, 40, 300,
300, and 150 mg, respectively.19
Covariates

As covariates in the case-control analysis, we considered age, sex, and calen-

2004 American Medical Association. All rights reserved.

ACID-SUPPRESSIVE DRUGS AND PNEUMONIA

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.

Table 1. Relative Risks for Community-Acquired Pneumonia by Exposure to Gastric

AcidSuppressive Therapy
Exposed to Acid-Suppressive Drugs

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)

54
4.24 (3.18-5.43)

Proton Pump
Inhibitors
12 337
5191
131
4.63 (3.84-5.43)

Abbreviation: CI, confidence interval.

*Some patients used H2-receptor antagonists plus proton pump inhibitors.

Data Analysis

percentage (obtained from adjusted ORs)

was subsequently multiplied with the incidence rate ratio in PPI- and H2RAexposed individuals to obtain the expected incidence rate attributable to
exposure. Because this rate is per 100 person-years and we express number needed
to harm in number of persons, we calculated how many persons were necessary for 100 person-years of exposure by
applying the mean duration of exposure. All analyses were conducted in
SPSS/PC, version 11 (SPSS Inc, Chicago, Ill). The level of significance for all
statistical tests was 2-sided P.05.

Crude incidence rates of pneumonia in

unexposed and exposed individuals
were calculated by dividing the number of pneumonia cases by the corresponding person-years. Relative risks
of pneumonia (plus 95% confidence intervals [CIs]) during current and recent use of H2RAs and PPIs were estimated with odds ratios (ORs) by using
conditional logistic regression analysis adjusted for all covariates that were
univariately associated with pneumonia (P.10). Stratified analyses were
conducted to explore the effect of season and age as effect modifiers. In addition, we stratified for presence of
cancer.
A sensitivity analysis that excluded all
probable cases was conducted to examine the effect of outcome misclassification. We then calculated the population attributable risk percentage. The
attributable risk percentage is the percentage of exposed cases that can be attributed to exposure, which is calculated [(OR1)/OR]. The attributable risk

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-

2004 American Medical Association. All rights reserved.

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H2-Receptor
Antagonists
10 177
2351

years compared with 0.6 for nonusers.

Patients using acid-suppressive drugs
developed pneumonia 4.5 (95% CI, 3.85.1) times more often compared with
those who never used acid-suppressive drugs. This association measure
was not adjusted for potential confounders.
For the nested case-control analysis, 475 of the 477 patients who developed pneumonia during or after stopping acid-suppressive drug use could
be matched to a total of 4690 controls
(31% of the pneumonia cases were confirmed by chest radiography or sputum test). Two cases could not be
matched and were therefore excluded
from the analysis. Cases more often had
diabetes mellitus, heart failure, and pulmonary diseases; more frequently used
immunosuppressants; and more frequently had used antibiotics than did
controls in the previous year (TABLE 2).
The indication for acid-suppressive
therapy was not associated with the risk
of pneumonia.
To investigate the association between use of acid-suppressive drugs
overall and pneumonia, we first examined all acid-suppressive drugs together. Current use of acid-suppressive drugs was associated with a small
increase in the risk of pneumonia (adjusted OR, 1.27; 95% CI, 1.06-1.54). To
examine the effects of current use of
H2RAs and PPI separately, we considered current combined use of both compounds in a separate group. Because the
association between pneumonia and
past or distant past use of acidsuppressive drugs was similar, we com-

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ACID-SUPPRESSIVE DRUGS AND PNEUMONIA

Table 2. Characteristics of Cases (With Pneumonia) and Controls

No. (%)
Cases
(n = 475)

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)

Current use of immunosuppressants

Antibiotics used in last year
0
1
2
Indication for acid-suppressant use
Cancer
Peptic ulcer disease
Gastroesophageal reflux disease
Functional dyspepsia
Endoscopically uninvestigated

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

Odds Ratio (95% CI)*

Abbreviation: CI, confidence interval.

*Matched on age, sex, and index date.

bined these 2 categories to have a more

stable reference category. The adjusted relative risk for pneumonia
among persons currently using PPIs
compared with those who stopped using PPIs was 1.89 (95% CI, 1.362.62). Current users of H2RAs had a
1.63-fold increased risk of pneumonia
(95% CI, 1.07-2.48) compared with
those who stopped.
Although there was variation between individual PPIs and H2RAs, numbers were small and the heterogeneity
was not significant. A significant dose
response was observed in current users of PPIs. Persons using more than 1
defined daily dose had a 2.3-fold increased risk of pneumonia compared
with past use of acid suppressants
(TABLE 3). The dose response was not
observed for H2RAs, but the variation
in dose of these drugs was limited.
Among current users of PPIs or H2RAs,
the risk seemed most pronounced
among persons who started drug use
within the last 30 days (Table 3).
1958

Excluding pneumonia without a

laboratory confirmation led to higher
risk estimates for developing pneumonia: 2.2 (95% CI, 1.4-3.5) for PPIs and
1.7 (95% CI, 0.8-2.9) for H2RAs. There
was no significant effect modification
by age, season, or presence of cancer.
The adjusted attributable risk percentage is 42% for PPIs and 37% for
H2RAs. Therefore, 1.05 pneumonia
cases per 100 person-years of PPI exposure can be attributed directly to the
use of PPIs and 0.86 pneumonia cases
during 100 person-years of H2RA exposure. Because the average duration
of use was 0.23 years for H2RAs and
0.42 years for PPIs, this roughly translates to 1 case of pneumonia per 226
patients treated with PPIs and 1 case of
pneumonia per 508 persons treated
with H2RAs.
COMMENT
In this large cohort, current use of acidsuppressive drugs was associated with
an increased risk of community-

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acquired pneumonia. The increase in

risk was most pronounced for PPIs and
showed a clear dose-response relationship, which supports a real biological
effect. The results are in agreement with
a previous small study that was conducted ad hoc in a clinical setting. This
study showed that subjects using acidsuppressive drugs more often reported
clinical manifestations of respiratory
tract infections and complications compared with those who did not use acidsuppressive drugs.15
Gastric acid is an important barrier
against pathogen invasion through the
gastrointestinal tract. Although it is well
known that a raised pH increases bacterial and virus colonization, the clinical consequences of gastrointestinal
pathogen overgrowth have not been
convincingly demonstrated. 5,6 Reports on the clinical consequences have
been only anecdotal or nonclinical. Already in 1934, Hurst20 suggested that
bacillary and amoebic dysentery occurred much more frequently in subjects with achlorhydria or hypochlorhydria. More recent studies suggested
that acid-suppressive drugs might be responsible for the development of esophageal candidiasis and enteric infections, although this was not solidly
supported by clinical evidence.10,13,14,20-22
Furthermore, experimental evidence
suggests that acid-suppressive drugs inhibit polymorphonuclear neutrophil
functions and cytotoxic T lymphocyte
and natural killer cell activity,23-26 which
might add to the increased susceptibility to infection because of these drugs.
Studies in mechanically ventilated
patients support the results from our
study that the use of acid-suppressive
drugs modifies the risk of pneumonia.
These studies showed that during mechanical ventilation, intestinal pathogens colonize the oral space via the
stomach.13,14 The colonized secretions
may gain access to the lower airways
and cause lower respiratory infections. Aspiration of gastric acid itself
carries a risk of developing chemical
pneumonia.27 Backflow of gastric acid
and content into the esophagus because of incompetent barriers at the gas-

2004 American Medical Association. All rights reserved.

ACID-SUPPRESSIVE DRUGS AND PNEUMONIA

troesophageal junction is a prevalent

gastrointestinal disorder. Reflux of gastric contents into the lower esophagus
even occurs in the majority of healthy
individuals but usually does not result
in clinical sequelae.
In this study, we were able to take
advantage of the fact that in the Dutch
health care system, all medical information is prospectively collected at general practices that cover the total population instead of subjects presenting in
a clinical setting. As a consequence, the
data are generalizable to the general
population and are not prone to selection bias. Nevertheless, given its observational nature, this study should be
interpreted in the light of its limitations. First, we cannot exclude that
some misclassification of outcome occurred. Such misclassification might be
false negative or false positive. Falsenegative misclassification by underestimation of pneumonia may have occurred because of the exclusion of the
possible cases (ie, cases for which we
had insufficient diagnostic information). False-positive misclassification
was possible in the group of probable
pneumonia; most of the mild pneumonia is dealt with in primary care and
therefore is not confirmed by chest radiograph or microbiological testing. Although we classified as probable pneumonia only infections with all clinical
symptoms of pneumonia, we may have
included some patients with bronchitis. When we excluded all probable
cases from the analysis, the detected associations became stronger. Diagnostic bias could have occurred if patients who were taking acid-suppressive
drugs had better diagnostic evaluation than distant-past users; however,
the percentage of certain cases confirmed by radiograph or sputum was
similar for current users (32%) and distant-past users.
Second, misclassification of exposure may have occurred because we
used outpatient prescription data and
had no information about whether the
prescription was actually dispensed and
taken. It is likely, however, that such
exposure misclassification was ran-

dom and evenly distributed among

cases and controls.
Third, one could suspect that pneumonia would be diagnosed especially
when the patient was treated by the general practitioner, the so-called diagnostic classification bias. However, the re-

Table 3. Odds Ratios for Community-Acquired Pneumonia in Patients Using Proton Pump
Inhibitors or H2-Receptor Antagonists
No. (%)

Use of acid-suppressive drugs

Current
Recent (30 days ago)
Past (30-180 days ago)
Distant past (180 days ago)
Drug classes
Current PPIs
Current H2RAs
Current use of H2RAs and PPIs
Recent use of H2RAs or PPIs
Past plus distant past use
of H2RAs or PPIs
Among current users of PPIs alone
Drug
Omeprazole
Pantoprazole
Lansoprazole
Rabeprazole
Esomeprazole
Daily dose
1 DDD
1 DDD
1 DDD
Duration of use in last year, days
30
30-180
180
Among current users of H2RAs alone
Drug
Cimetidine
Ranitidine
Famotidine
Nizatidine
Roxatidine
Daily dose
1 DDD
1 DDD
1 DDD
Duration of use in last year, days
30
30-180
180

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.

2004 American Medical Association. All rights reserved.

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sults from our study showed that the

risk for pneumonia was increased in
current drug users (pneumonia was reported during prescription length) but
also in patients for whom the last prescription was at least 30 days old (recent past). These patients were prob-

(Reprinted) JAMA, October 27, 2004Vol 292, No. 16 1959

ACID-SUPPRESSIVE DRUGS AND PNEUMONIA

ably no longer being treated by the

general practitioner, making classification bias less likely.
Finally, protopathic bias (ie, pneumonia symptoms) may have resulted in
an acid-suppressive-drug prescription
if patients received acid-suppressive
drugs for symptoms related to pneumonia. However, on exclusion of all
persons who began receiving acidsuppressive drugs within 1 week before the index date, the relative risk estimates did not change, and therefore
protopathic bias can be excluded.
We observed a large difference between the unadjusted incidence rate ratios and the adjusted ORs in the nested
case-control study. The incidence rate
ratio should be interpreted with caution because it compares users of acidsuppressive drugs (with more comorbidity) with nonusers, which may result
in substantial confounding by indication. In fact, we designed the nested
case-control study to control for this
confounding effect. As confounding factors, we included other respiratory illnesses, comorbidities, and drug use that
are strongly associated with pneumonia. Inclusion of these confounders in
the model did not change the estimates to a large extent, which implies
that confounding was minimal. Despite this outcome, we cannot exclude
the presence of uncontrolled confounders, which is a limitation inherent in all
unrandomized studies.
The effectiveness of acid-suppressive drugs in the treatment of upper
gastrointestinal tract symptoms is excellent. Acid-suppressive drugs nevertheless seem to have some significant
drawbacks. Persons using acidsuppressive drugs more often develop
a community-acquired pneumonia compared with those who do not use acidsuppressive drugs, which is in general
not a problem because the risk for developing pneumonia is low. The increased risk for pneumonia is a problem for patients who are at increased risk
for infection, especially because community-acquired pneumonia is potentially dangerous.28 Groups of persons
1960

who are at increased risk for infection

and for whom pneumonia is a major
source of mortality have been identified.29 Pneumonia is more pronounced
in persons with asthma or chronic obstructive lung disease, immunocompromised persons, children, and elderly persons. Elderly patients are likely to incur
severe infection, which is partly due to
a decreased immune response, including the natural reduction of gastric acid
secretion after age 60 years. To avoid the
calculated excess pneumonia, patients
with asthma or chronic obstructive lung
disease, immunocompromised persons, children, and elderly persons
should be treated with acid-suppressive drugs only when necessary and with
the lowest possible dose.
In conclusion, our results suggest
that acid-suppressive drugs such as
H2RAs and PPIs are associated with an
increased risk of community-acquired
pneumonia, probably because of reduction of gastric acid secretion, facilitating oral infections.
Author Contributions: Dr Laheij had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Laheij, Sturkenboom.
Acquisition of data: Laheij, Sturkenboom, Hassing.
Analysis and interpretation of data: Laheij, Sturkenboom,
Dieleman, Stricker, Jansen.
Drafting of the manuscript: Laheij, Sturkenboom,
Stricker, Jansen.
Critical revision of the manuscript for important intellectual content: Hassing, Dieleman.
Statistical analysis: Laheij, Sturkenboom, Stricker.
Administrative, technical, or material support: Hassing.
Study supervision: Jansen.
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