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Community acquired pneumonia (CAP) is one of the most common infectious diseases in the Western World. Over the years, it remains a major reason for hospitalization and a common cause of mortality. Aging, cigarette smoking and co-morbidity such as chronic obstructive pulmonary disease (COPD) are well known causes for the development of CAP.
Proton pump inhibitors (PPI's) are the major treatment for many gastroesophageal diseases. Since the first introduction in the late 1980s PPI's usage is widespread worldwide. We have previously shown that gastric acid suppressive therapy, such as PPI's or histamine-2 receptor antagonists (H2RA's) also predispose to CAP. The reduction of gastric acid secretion seem to have an important effect on the risk of developing CAP, with the lowest relative risk among patients using a lower defined daily dose and the highest relative risk among patients using a higher defined daily dose.
This observation was subsequently confirmed in several other observational studies and summarized in a recent meta-analysis. In this meta-analysis, the results of six studies including approximately 1 million subjects showed that patients using PPI therapy have an estimated 36% higher risk to develop CAP compared to subjects not using PPI's. However, significant heterogeneity between the studies limited the interpretation of the estimated risk ratio. Furthermore, a retrospective analysis of the original safety data from several randomized clinical trials has shown that patients using esomeprazole did not have an increased risk for developing CAP compared to patients using placebo.
Community acquired pneumonia is an infection of the pulmonary parenchyma that can be caused by various pathogens including bacteria, viruses, fungi and parasites. Thus CAP is not a single disease entity but covers a group of specific infections, each with its own specific clinical features. The pathophysiological mechanisms, which contribute to an increased risk of CAP during PPI therapy, are not well established. There are several supposed mechanisms like anti-infective, anti-inflammatory and immunomodulatory effects that could potentially affect the susceptibility to bacterial infections in patients using PPI including CAP but also enteric infections.[7-9] In a previous study we hypothesized that PPI therapy impairs the immune system leading to an increased susceptibility to infections. The low pH of the intra-gastric environment constitutes a major non-specific defense mechanism of the body against pathogen invasion of the gastrointestinal tract. Decreasing the gastric acidity may result in insufficient eradication of ingested pathogens through several mechanisms like alteration of the gut microflora, enhanced bacterial translocation altering various immunomodulatory and anti-inflammatory effects.[10, 11]
The result of this may well be that patients on acid suppressive therapy often have pathogen colonization in the stomach. Reduction of gastric acid secretion by PPI therapy led in almost 60% of patients to bacterial overgrowth in the stomach with predominantly gram-positive potential pathogenic microorganisms, and in particular pathogens normally found in the oropharyngeal cavity. If our pathophysiological hypothesis is indeed true, then one would expect that patients using PPI's more often are being or becoming infected with microorganisms originating from the oropharyngeal cavity. Although the aforementioned mechanisms (backflow and overgrowth) are suggested in several reports this remains speculative in CAP patients.[14-16] A recent study did not confirm an increased presence of gastrointestinal nor oropharyngeal bacteria in CAP patients using PPI. In the present study, we examined the difference in microbial etiology of CAP between patients with and without PPI's in a population based prospective cohort study.
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Despite overwhelming epidemiological evidence, the mechanism of the association between PPI therapy and CAP is still being debated. We and several others have previously demonstrated that current use of acid suppressive therapy, in particular PPI's is associated with an increased risk of CAP as well as hospital-acquired pneumonia.[3, 4, 20, 21] There are several mechanisms that potentially could attribute to the increased risk of CAP in PPI users. Besides possible overgrowth of oropharyngeal bacteria other mechanisms are altered like host susceptibility due hypoclorhydria and direct immunomodulatory effects of PPI's through several pathways.[22-25]
In this study we observed that more than 40% of patients using PPI's had a previous CAP before being included in this study. Moreover, the results from this prospective study demonstrate that PPI usage was indeed associated with developing CAP by pathogens originating from the endogenous oropharyngeal flora, i.e. S. pneumoniae. This association was stronger in high dose PPI users. We also observed that patients using PPI do not develop CAP due to pathogens spread by airborne transmission or non-oropharyngeal endogenous flora.
PPI's have been used in clinical practice for almost 25 years, and are generally believed to have an excellent safety profile. Several recent publications have demonstrated that PPI use is however associated with significant side effects that were not detected in the original safety trials. None of these original randomized clinical trials investigating efficacy and safety demonstrated an increased incidence of CAP while using PPI's. This is explained by the fact that randomized trials (RCTs) are generally not designed to detect low-incidence adverse events. While demonstrating an increased risk of a low-incidence event in RCTs often leads to the conclusion that this is of negligible clinical significance, this is not the case with our findings. First, the use of PPI's is widespread; with population studies showing that more than 10% of the population has used PPI's at least once in their lives, and many even for an extended period. The large number of PPI users means that even a small increase in the risk of an adverse event may affect large numbers of people. Furthermore, there is considerable evidence that a substantial proportion of PPI use is inappropriate, leading to significant overuse. From this, one can conclude that there is a potential for a significant health benefit, especially when patients with an increased risk for CAP can be identified and their use of PPIs can be curtailed.
Despite the fact that CAP is a common major health problem, relatively few studies have examined the etiology of infection in outpatients.[28-31] In this study we identified pathogens as causing factor of CAP in almost 70% of the patients, despite ongoing antibiotic therapy in a significant proportion of patients. This is similar to other studies, in which a pathogen was identified in between 50% and 80% of patients. As in most other studies, we found that S. pneumoniae was the most common pathogen in CAP. S. pneumoniae colonizes the oropharynx in up to 10% of the healthy adults and may persist for a period up to 6 months. Apart from its etiological role in CAP, this pathogen is also able to infect the middle ear, sinuses, meninges, joints, etc., possible by direct spread from the oropharynx or by hematogenous spread. An interesting hypothesis in line with our results is that S. pneumoniae may also spread from the gastrointestinal tract. This is in contrast with a recent study that did not show a shift in oropharyngeal pathogens in patients with CAP using PPI.
Our study has several limitations. First, it is well known that patients with CAP often have underlying diseases that predispose them to infection. One of the most important predisposing conditions is age, with CAP being common in the elderly. Besides age, several comorbidities have repeatedly been associated with CAP, such as COPD, diabetes mellitus, cerebrovascular disease, etc. COPD patients are well known to have an increased prevalence of reflux and smoking related COPD has been known for many years to have an increased prevalence of peptic ulcer. It is difficult to correct statistically for this sort of confounding in cohort studies, as we know from previous observational studies associating PPI reduced efficacy of Clopidogrel.[33-35] Although we studied many patient characteristics, comorbidity and co-current therapy, certain other conditions predisposing to CAP were not evaluated, including splenectomy, malnutrition and the current use of specific medications reported to influence the risk of CAP (statins and angiotensin II receptor antagonists). As the difference between the unadjusted and adjusted odds ratios were relatively small, it is unlikely that these factors contributed to a major extent to our findings. Nevertheless, it remains difficult to correct for this type of confounding and the apparent effect of PPI's in our study cohort could still reflect the possibility of factors attributed to co-morbidity that predispose to S. pneumoniae CAP rather then the use of PPI.
Second, confounding by indication and protopathic bias cannot be ruled out as the indication for PPI treatment was not included.
Third, patients with esomeprazole had a higher incidence of CAP due to S. pneumoniae st pneumonia. This could be related to the difference in DDD, being higher in patients using esomeprazole. However due to local hospital prescription therapy regulations (not related to the study) in patients previously admitted to the hospital esomeprazole (and not omeprazole) was prescribed. Consequently this may have introduced bias as patients on esomeprazole might sustain more severe comorbidity than patients using omeprazole. Although no difference was found in comorbidity between those patients (esomeprazole versus omeprazole) we did not study the severity of illness attributed to the patients comorbidity. Patients in our study cohort using esomeprazole could have been potentially sicker compared to patients using omeprazole. Unfortunately it was not possible to correct for this confounder.
Fourth, the epidemiology of CAP is changing over time. During our study period, we were confronted with epidemics of two different pathogens being, a regional Q fever epidemic and the influenza A (H1N1) pandemic. These two outbreaks make it more difficult to compare the etiology of CAP in our study with those of previous studies. Q fever is acquired by exposure to C. burnetii contaminated dust particles originating from excreta from infected animals, in our case particularly goats.[36, 37] However, as in most other studies, S. pneumoniae was still the most frequent pathogen observed followed by C. burnetti. C. burnetti, has not been a significant pathogen in most other etiology studies. Furthermore, several younger patients presented to our hospital with CAP due to influenza A H1N1 virus, probably as a result of the publicity about the outbreak and a nationwide vaccination campaign. Both these two pathogens are spread by airborne transmission, which we found not to be associated with PPI therapy.
In conclusion, our results suggest that PPI therapy is associated with an approximately 2-fold increased risk of develop CAP possibly as a result of the endogenous oropharyngeal flora. In particular we found a significantly increased association between PPI use and S. pneumoniae pneumonia. It should be reminded that, in line with previous observational studies, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of CAP due to S. pneumoniae. Therefore further studies are required to delineate the exact pathophysiologic mechanisms relating PPI usage to respiratory infection.