Community-acquired pneumonia is the seventh leading cause of death and the leading cause of infectious death in the United States 1. Although mortality due to community-acquired pneumonia decreased significantly with the introduction of antibiotics in the 1950s since that time mortality has been stable or increasing 2. Despite this, only a few new classes of antibiotics have been added to the armamentarium for treating community-acquired pneumonia in the last 20 years and no new classes of medications beyond antibiotics have been added since the 1950s.

Recent studies have demonstrated that elderly patients taking ACE inhibitors have significantly decreased rates of aspiration pneumonia and may have decreased mortality 345. The hypothesized reason for this protective effect is an increase in substance P which accentuates the cough reflex. Other studies have demonstrated significant changes in systemic cytokine levels for subjects treated with ACE inhibitors 678. These cytokines play an important role in host defense mechanisms for patients with community-acquired pneumonia but under certain conditions may lead to septic shock or acute respiratory distress syndrome (ARDS) 91011.

The study aim was to assess the effects of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia.

This a retrospective cohort study of patients hospitalized with community-acquired pneumonia at 2 academic tertiary care hospitals in San Antonio, Texas. Both hospitals are teaching affiliates of the University of Texas Health Science Center at San Antonio. The Institutional Review Board of the University of Texas Health Science Center at San Antonio approved the research protocol with exempt status.

Data was abstracted on 787 patients at the two hospitals. The mean age was 60 years with a standard deviation of 16 years. The population was 79% male, 84% were admitted through the emergency department, and 20% were admitted to the intensive care unit within the first 24 hours after admission. Mortality was 9.2% at 30-days and 13.6% at 90-days. By pneumonia severity index, 52% were low risk (pneumonia severity index classes I-III), 34% were moderate risk (pneumonia severity index class IV), and 14% were high risk (pneumonia severity index class V). Regarding community-acquired pneumonia-related processes of care, 28% received the initial dose of antibiotics within 4 hours of presentation and an additional 22% received the initial antibiotic dose within 8 hours, 76% of patients had blood cultures obtained within 24 hours and prior to antibiotics, and oxygenation was assessed at presentation in 91%.

Table 1 shows the demographic factors, clinical characteristics, and processes of care data for this population by 30-day mortality. In the univariate analysis numerous individual components of the pneumonia severity index were significantly associated with 30-day mortality including age, nursing home residency, history of congestive heart failure, history of malignancy, altered mental status, systolic blood pressure < 90 mmHg, tachycardia> 125 beats per minute, arterial acidosis, elevated blood urea nitrogen 30 mg/dl, serum sodium < 130 meq/l, and pleural effusion on chest radiograph. The only processes of care that were statistically significant were the assessment of oxygenation within 24 hours or presentation and use of guideline-concordant antibiotics. ACE inhibitor use was significantly associated (p = 0.05) with 30-day mortality.

Table 2 demonstrates clinical and demographic variables and the association with use/non-use of ACE inhibitors at presentation. Co-morbid conditions and demographic variables significantly associated with ACE inhibitor use included coronary artery disease, higher age, diabetes mellitus, chronic obstructive pulmonary disease, not currently smoking, congestive heart failure, prior stroke, no history of liver disease, and chronic renal disease. Physical exam and laboratory findings associated with ACE inhibitor use included decreased numbers of patients with heart rates > 125, higher rates of elevated blood urea nitrogen > 30 mg/dL, lower rates of serum hematocrit < 30%, and higher rates of serum glucose > 250 mg/dL. Of the 787 subjects 194 (25%) were on ACE inhibitors. There was greater ACE inhibitor use in those who were in the moderate (30%, n = 74) and severe (34%, n = 38) risk groups versus those with low severity of illness (19%, n = 77), p < 0.001.

In the multivariable conditional logistic regression analysis after adjusting for potential confounders the use of ACE inhibitors at presentation (odds ratio (OR) 0.44, 95% confidence interval (CI) 0.22–0.89) was associated with 30-day mortality. The other variables in the model included initial antibiotics within 4 hours (OR 1.09, 95% CI 0.64-1.85), obtaining blood cultures prior to antibiotics (OR 1.10, 95% CI 0.6-1.9), oxygenation assessment within 24 hours (OR 1.31, 95% CI 0.5–3.4), and use of guideline-concordant antimicrobial therapy (OR 0.6, 0.35–1.05).

We found that prior outpatient use of ACE inhibitors was associated with decreased 30-day mortality for subjects hospitalized with community-acquired pneumonia. Our findings provide further support to other studies that demonstrate that ACE inhibitor use is associated with decreased mortality for patients with pneumonia.

There are several potential mechanisms for a beneficial effect on mortality for patients on ACE inhibitors. ACE inhibitors have been shown in clinical studies to increased serum levels of substance P, which is hypothesized to lead to a better gag reflex and increased clearance of secretions 345. Our study specifically excluded patients with a discharge diagnosis of aspiration pneumonia; however, this diagnosis can be clinically difficult to distinguish from community-acquired pneumonia. Other studies have demonstrated that ACE inhibitors have significant immunomodulatory effects on circulating cytokines 678. Therefore the beneficial effect may be due to blunting of the cytokine response so that these patients have lower rates of sepsis and/or ARDS.

Although our study was retrospective and subject to the recognized limitations of such studies, we carefully assembled our cohort from complete patient discharge data to avoid ascertainment bias. Additionally, during chart abstraction we encountered a very small amount (<5%) of missing data. Our sample was predominantly men due to the inclusion of a VA hospital and it is possible, but unlikely, that women may have differential responsiveness to ACE inhibitors as compared to men. In addition we are unable to examine whether or not there was significant amounts of non-prescription or non-compliance of ACE inhibitor therapy due to economic considerations. Also we are unable to assess factors such as inpatient continuation of the ACE inhibitor or the dose effect due to the design of this study. Further research is needed to examine these factors. Finally, as in any non-experimental study, we are unable to state conclusively that the prior outpatient use of ACE inhibitors is the cause of decreased mortality in this cohort. However, since patients on ACE inhibitors had significantly higher severity of illness scores at presentation we feel that we have good evidence that these medications may have beneficial effects for patients hospitalized with community-acquired pneumonia.

In conclusion, our study finds that prior outpatient use of ACE inhibitors reduces mortality for patients with community-acquired pneumonia. Our results add further strength to the existent recommendations to use ACE inhibitors in patients with congestive heart failure, diabetes mellitus, and renal disease, since these patients are at higher risk for either contracting pneumonia or dying from pneumonia when they do contract it. Future research, especially randomized clinical trials, are needed to examine whether either ACE inhibitors are protective when used in an inpatient setting for patients lacking traditional indications for the use of these medications.

The author(s) declare that they have no competing interests.

EMM originated and coordinated the study, obtained funding, contributed to the analysis of the data, and preparation of the paper.

MIR contributed to the design of the study, contributed to the analysis of the data, and preparation of the paper.

AA contributed to the design of the study, contributed to the analysis of the data, and preparation of the paper.

JP contributed to the design of the study, contributed to the analysis of the data, and preparation of the paper.