Angiotensin-converting enzyme (ACE) inhibitors and statins may potentially benefit patients with viral infections and pneumonia. Our study aimed to evaluate the impact of ACE inhibitors and statins on the rates of intubation and death in viral pneumonia. We retrospectively studied 1055 adult patients admitted to a tertiary care center in central Texas with a positive respiratory viral polymerase chain reaction test. Of these, 539 had clinical presentation and imaging consistent with pneumonia. We collected information on demographic characteristics, microbiology, comorbid conditions, medication use, and outcomes. ACE inhibitors given prior to admission were associated with an increased risk of death or intubation (odds ratio [OR] = 3.02; 95% confidence interval [CI], 1.30–7.01), whereas statin use prior to admission did not change rates of death or intubation. Lower rates of death and intubation were noted with continued use of ACE inhibitors (OR =0.25; 95% CI, 0.09–0.64) and statins (OR =0.26; 95% CI, 0.08–0.81) throughout the hospital stay. We added further evidence of the beneficial effect of continued use of ACE inhibitors and statins in viral pneumonia.
Keywords: ACE inhibitors, statins, viral pneumonia
Respiratory viruses have been increasingly recognized as important pathogens causing community-acquired pneumonia, with an estimated prevalence in adults of 100 million cases worldwide per year.1 Viral pneumonia represents up to 20% to 40% of all cases of community-acquired pneumonia that require hospitalization2–5 and has been found to be a cause of nosocomial infection.6,7 Despite being so common, viral pneumonia remains poorly characterized and underrecognized in clinical practice. HMG-CoA reductase inhibitors (statins), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) are medications commonly prescribed for chronic medical issues and have been associated with decreased mortality in patients with pneumonia. These are postulated to attenuate pulmonary and systemic inflammatory response by reducing cytokines.8–10 Statins have the ability to inhibit influenza A virus replication in vitro,11 decrease neutrophil influx, and alter the nitric oxide balance to promote hemodynamic stability.12 ACE inhibitors and ARBs also have significant immunomodulatory effects13 and protect against acute lung injury by blocking the classical ACE pathway.14 This study evaluated the impact of statin, ACE inhibitor, and ARB use prior to and during hospitalization on outcomes in viral pneumonia.
MethodsWe performed a retrospective review of consecutive hospitalized patients with an acute respiratory illness and a positive respiratory viral polymerase chain reaction (PCR) test admitted at a tertiary care center in central Texas between January 2011 and February 2014. Inclusion criteria were a positive respiratory viral PCR, admission to hospital for >24 hours, and age >18 years.
A manual review of the electronic medical record was performed to obtain patient demographic characteristics, comorbidities, laboratory and culture results, initial triage location, intensive care unit (ICU) admission, use of mechanical or noninvasive positive pressure ventilation, hospital and ICU length of stay, 90-day hospital readmission, and hospital mortality. Data on the use of statins, ACE inhibitors, and ARBs prior to admission and during admission were collected. The medications were considered to be continued if they were given more than 50% of the days the patient was in the hospital.
Pneumonia was defined by the presence of a pulmonary infiltrate on chest radiograph as interpreted by a board-certified radiologist. Additionally, the diagnosis required a clinical history consistent with pneumonia, with two of the following features: fever, cough, purulent sputum production, dyspnea, and altered mental status.15 Community-acquired pneumonia, hospital-acquired pneumonia, and health care–associated pneumonia were defined based on published guidelines at the time of data collection.16 Patients who had clearly documented aspiration pneumonia and those who did not meet the above definition were excluded.
Means and frequencies were calculated for patient characteristics and clinical measures, collectively and by pneumonia group status (pneumonia-positive vs. pneumonia-negative/other). Bivariate analyses assessed underlying differences by group status. Chi-square analyses compared categorical characteristics across groups (with Fisher’s exact test used for small expected cell counts). The nonparametric Wilcoxon rank-sum test assessed differences for continuous measures between patient groups. Multivariable logistic regression analysis was used to further assess the association between patient characteristics and pneumonia clinical outcomes. A type I error of α = 0.05 was used for all tests. All analyses were performed using SAS Version 9.2 (SAS Institute, Cary, NC). Research was approved by the local institutional review board and the need for consent was waived due to the retrospective nature of the study.
The primary outcome was a combined in-hospital mortality and intubation for the patients with viral pneumonia on ACE inhibitors, ARBs, or statins. Secondary outcomes that were assessed included hospital length of stay, intubation, ICU admission, hospital readmission, and use of noninvasive positive pressure ventilation.
ResultsThere were 1055 patients with a positive respiratory viral PCR. Five hundred thirty-nine patients (51%) had radiographic and clinical signs of pneumonia. Demographic information and comorbid conditions for the pneumonia-positive and pneumonia-negative groups are listed in Table 1. Use of a statin, ACE inhibitor, or ARB prior to hospitalization or continued use during hospitalization did not affect the risk of being diagnosed with pneumonia.
Table 1.Cohort characteristics
Variable Pneumonia positive (N = 539) Pneumonia negative (N = 516) P value Age (years) 63.8 (±19.1) 60.5 (±18.0) <0.01 Women 286 (53.1%) 319 (61.8%) <0.01 Body mass index 29.3 (±9.9) 31.0 (±9.3) <0.01 Smoker (ever) 289 (53.6%) 291 (56.4%) 0.36 Acute exacerbation of COPD 89 (16.5%) 113 (21.9%) 0.03 Acute decompensation of CHF 46 (8.5%) 51 (9.9%) 0.45 Diabetes mellitus 126 (23.4%) 151 (29.3%) 0.03 Chronic kidney disease 98 (18.2%) 77 (14.9%) 0.15 HIV infection 12 (2.2%) 6 (1.2%) 0.18 Cirrhosis 6 (1.1%) 6 (1.2%) 0.94 Hepatitis 14 (2.6%) 10 (1.9%) 0.47 Immunocompromised 59 (11.0%) 47 (9.1%) 0.32 Heart disease 201 (37.3%) 204 (39.5%) 0.45 COPD 138 (25.6%) 150 (29.1%) 0.21 Asthma 37 (6.9%) 94 (18.2%) <0.01 Interstitial lung disease 13 (2.4%) 7 (1.4%) 0.21 Drug abuse 14 (2.6%) 19 (3.7%) 0.31 Alcoholic 17 (3.2%) 18 (3.5%) 0.76 Coinfection 103 (19.1%) 28 (5.4%) <0.01 ACE prior to hospitalization 145 (26.9%) 144 (27.9%) 0.71 ACE continued in hospital 108 (20.0%) 122 (23.6%) 0.16 ARB prior to hospital 52 (9.7%) 53 (10.3%) 0.74 ARB continued in hospital 35 (6.5%) 45 (8.7%) 0.17 Statin prior to hospital 197 (36.6%) 199 (38.6%) 0.50 Statin continued in hospital 175 (32.5%) 188 (36.4%) 0.18The types of viruses for the total population, the pneumonia-positive group, and the pneumonia-negative group are shown in Figure 1. Of patients with pneumonia, the most common viral pathogens recovered were rhinovirus/enterovirus (37.5%), influenza A (33%), and respiratory syncytial virus (10%). The rate of bacterial coinfection was 19.1% in the pneumonia-positive group, with Staphylococcus aureus (combined methicillin-resistant and methicillin-sensitive) being the most common (6.2%), followed by Pseudomonas aeruginosa (5.4%) and Streptococcus pneumoniae (4.5%). Sputum bacterial cultures in the pneumonia-positive group were negative in 42.1% of the patients, and no culture was performed in 39.2%. Outcomes for patients with pneumonia versus those without pneumonia are listed in Table 2.
Figure 1.Distribution of viruses.
Table 2.Outcomes
Variable Pneumonia positive (N = 539) Pneumonia negative (N = 516) P value Median hospital length of stay (days) 6.0 (4–9 IQR) 4.0 (3–6 IQR) <0.01 In-hospital death 43 (8.0%) 17 (3.3%) <0.01 Noninvasive ventilation 69 (12.8%) 53 (10.3%) 0.20 Intubation 96 (17.8%) 19 (3.7%) <0.01 ICU admission 101 (18.7%) 29 (5.6%) <0.01 Median ICU length of stay (days) 5.0 (3–12 IQR) 3.0 (1–5 IQR) <0.01 Readmission rate 128 (23.8%) 114 (22.1%) 0.52 In-hospital death and/or intubation 112 (20.8%) 33 (6.4%) <0.01In the patients with viral pneumonia, the risk of death increased with use of ACE inhibitors prior to admission (odds ratio [OR] = 3.02; 95% confidence interval [CI], 1.30–7.01; P = 0.01), though continued use of ACE inhibitors or continued use of statins was associated with decreased mortality and/or intubation (ACE inhibitors: OR = 0.25; 95% CI, 0.09–0.64; P < 0.01; statins: OR = 0.26; 95% CI, 0.08–0.81; P = 0.02).
Hospital length of stay for patients with pneumonia increased with use of statins on admission (OR = 2.18; 95% CI, 1.61–2.95; P < 0.01). Length of stay in the hospital was lower for patients with continued use of ACE inhibitors during hospital stay (OR = 0.70; 95% CI, 0.53–0.91; P < 0.01). Table 3 lists other results from the multivariate regression analysis, several of which were statistically significant but beyond the scope of this article.
Table 3.Multivariate analysis
Risk of pneumonia In-hospital death and/or intubation Hospital length of stay OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value Age (decade effect) 1.12 (1.04–1.22) <0.01 0.82 (0.72–0.94) <0.01 0.94 (0.91–0.97) <0.01 Women 0.77 (0.59–1.00) <0.05 0.98 (0.62–1.56) 0.94 1.06 (0.94–1.20) 0.31 ACE prior to hospital 1.34 (0.74–2.44) 0.33 3.02 (1.30–7.01) 0.01 1.22 (0.96–1.56) 0.10 ACE continued in hospital 0.64 (0.34–1.19) 0.16 0.25 (0.09–0.64) <0.01 0.70 (0.53–0.91) 0.01 ARB prior to hospital 1.65 (0.63–4.29) 0.30 1.12 (0.30–4.10) 0.87 0.97 (0.68–1.39) 0.88 ARB continued in hospital 0.48 (0.17–1.37) 0.17 0.75 (0.16–3.44) 0.71 0.80 (0.53–1.21) 0.30 Statin prior to hospital 1.15 (0.5–2.67) 0.74 2.66 (0.90–7.81) 0.08 2.18 (1.61–2.95) <0.01 Statin continued in hospital 0.78 (0.33–1.81) 0.56 0.26 (0.08–0.81) 0.02 0.39 (0.28–0.53) <0.01 Smoker (ever) 1.04 (0.78–1.39) 0.81 0.83 (0.50–1.38) 0.47 0.84 (0.74–0.96) 0.01 Coinfection 4.25 (2.70–6.69) <0.01 2.90 (1.75–4.82) <0.01 1.29 (1.11–1.49) <0.01 Chronic kidney disease 1.30 (0.90–1.89) 0.16 1.78 (0.96–3.31) 0.07 1.33 (1.13–1.56) <0.01 Asthma 0.35 (0.23–0.54) <0.01 0.56 (0.20–1.56) 0.27 0.78 (0.61–0.99) 0.04 DiscussionIn our cohort of patients hospitalized with acute respiratory illness who tested positive for respiratory virus by PCR, over half developed pneumonia; among those with pneumonia, continued use of statins and continued use of ACE inhibitors correlated with a decreased risk of mortality or intubation.
The major goal of our study was to assess the effect of ACE inhibitors, ARBs, and statins in patients with viral pneumonia. Mortensen et al found a significant decrease in mortality, length of stay, and mechanical ventilation in patients taking statins, ACE inhibitors, or ARBs who were hospitalized with pneumonia compared to a matched cohort.17 A meta-analysis by Chopra et al noted a decrease in pneumonia-related mortality for those taking statins.9 Similarly, we found a decrease in intubation or mortality in patients with continued use of ACE inhibitors or statins during their hospital admission for viral pneumonia, though not for continued ARB use. Furthermore, those who were on ACE inhibitors prior to admission and subsequently discontinued the medication had a higher mortality than those not on an ACE inhibitor prior to admission. We speculate that the ACE inhibitors were discontinued in patients with shock or acute renal failure, thus representing more severe viral pneumonia than those in whom it was continued throughout their hospital stay. Alternatively, this difference could be due to the attenuating effects of ACE inhibitors on the innate immune system through deactivation of the classical ACE pathway.14 In the aforementioned study by Mortensen et al, patients were included only if the medication was started as an outpatient, with a sufficient supply to last through the hospitalization, and was subsequently administered within the first 48 hours of admission.8 A similar effect was not seen for ARBs, though a trend was noted that did not reach statistical significance. This could be due to the relatively small sample of patients on an ARB in our study.
Similar to previous studies, rhinovirus/enterovirus and influenza A made up the majority of the infections, both with and without pneumonia.2,4,18,19 Our viral findings are in concordance with the meta-analysis by Burk et al.18 Our study also included the 2013–2014 H1N1 influenza virus, which may explain the severity of illness seen as well as the worse outcomes with younger patients. This particular influenza season was noted to have a high mortality rate in adults <65 years.20,21 Bacterial coinfection was seen in one-fifth of the patients, much higher than the 3% reported by Jain et al.4 Not surprisingly, those with bacterial coinfection had a threefold higher risk of death or intubation compared to those without a bacterial coinfection. Viral infection has a synergistic effect on bacterial infection, allowing for a more severe infection.1,3,22,23 Staphylococcus aureus and Streptococcus pneumoniae were the most common bacterial pathogens, thought to be due to the high number of H1N1 influenza infections.24
Several studies have evaluated the risk of developing pneumonia when on ACE inhibitors or ARBs, with mixed results. ACE inhibitor use in stroke patients has been found to decrease the risk of pneumonia in several studies from Asia.25 These results have not been consistently replicated in other populations.26–28 A meta-analysis by Caldeira et al reported a significant decrease in the risk of developing pneumonia and decrease in mortality among those taking ACE inhibitors or ARBs.29 We found no difference in rates of use of these medications prior to hospitalization between those with a viral infection who developed pneumonia and those who did not develop pneumonia.
Our study has several limitations. First, as with all retrospective observational studies, our study can only present associations and not causality pertaining to improved outcomes with continued use of ACE inhibitors and statins. Secondly, this study only represents the experience of a single center. Thirdly, nearly 20% of patients had a bacterial coinfection by sputum culture. It is possible that we could have underestimated the true bacterial burden because this depended on adequate and timely sputum sampling prior to antibiotic administration. Previous studies have revealed that cultures are negative in up to 68% of bacterial pneumonia4 and that coinfection is present in up to 10% of patients with viral pneumonia.18 Fourthly, being a pragmatic study, this study did not account for the code status of the patients, which could have affected the primary outcome. The number of viral PCRs obtained via bronchoalveolar lavage was not available. There is an increased rate of positive viral PCR results in studies where lower respiratory tract samples were obtained.2,30
Our study supports the continued use of statins and ACE inhibitors in patients admitted with viral pneumonia and encourages further prospective studies on the beneficial effects of ACE inhibitors and statins in pneumonia.
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