| Background and ObjectivesPneumonia is a common and serious infectious disease associated with high morbidityand mortality. It is the sixth leading cause of death and the most common infectiouscause of death worldwide. Despite effective antibiotic therapy, about12-36%patientsadmitted to the intensive care unit (ICU) with severe pneumonia die within a short time.Previous studies evidenced the importance of individual genetic differences on the risk ofdeveloping or dying from infection. Therefore, host genetic susceptibility may play a keyrole in the pathogenesis of pneumonia. So far, a lot of studies have focused on this field,and angiotensin-converting enzyme (ACE) gene has been studied extensively. Somestudies have investigated the association of this polymorphism with pneumonia.Unfortunately, these epidemiological studies performed in different countries haveyielded conflicting results from strong links to no association.The prevalence of obesity has dramatically increased in the last two decades. Obesityis associated with an increased risk of cardiovascular disease and type2diabetes.However, an inverse relationship between obesity and mortality has been described inpatients with heart failure, coronary heart disease, and diabetes. This phenomenon isknown as the “obesity survival paradox”. Pneumonia is one of the most commoninfectious diseases; however, there is uncertainty about the association between obesityand pneumonia risk or pneumonia mortality. For example, Baik et al. suggested thatobesity was directly associated with the development of community-acquired pneumonia(CAP). However, Phung et al. did not find that obesity was significantly associated withpneumonia risk. Takata et al. indicated that mortality risk was not different betweenobese pneumonia patients and normal weight patients. However, other studies reportedthat obese subjects with pneumonia had lower mortality compared to normal weightsubjects. Thus, whether the “obesity survival paradox” exists in pneumonia is stillunclear.Antibiotics are the most important drugs in the treatment of CAP. However, theoptimal empirical antibiotic therapy is an often debated issue. Chinese guidelinesrecommended dual-therapy consisting of a β-lactam plus a macrolide (BLM) or aβ-lactam (BL) monotherapy for patients hospitalized with CAP in ward. British Thoracic Society (BTS) and Infectious Diseases Society of America/American Thoracic Society(IDSA/ATS) guidelines recommended BLM dual-therapy but not BL monotherapy intreating these patients. All the recommendations were based on the observational studies.These observational studies, however, showed results ranging from beneficial to no effect.To our knowledge, no meta-analysis was designed to determine the effects of twotherapies on mortality in patients with CAP. Thus, the clinical effect of BLMdual-therapy versus BL monotherapy in CAP patients was still unclear.Recently, a multicenter randomized controlled trial (RCT) performed by Confalonieriet al. demonstrated that hydrocortisone treatment in severe CAP was associated with asignificant reduction in mortality. A retrospective study conducted by Garcia-Vidal et al.found that mortality decreased in the patients who received systemic steroids along withantibiotic treatment for severe CAP. Moreover, results from a systematic review showedthat administration of corticosteroids in patients with CAP was associated with a lowermortality. However, these findings were not confirmed in the subsequent larger RCTs.Another recent retrospective study also showed that adjunctive therapy withcorticosteroids did not influence the mortality rate. Furthermore, results from ameta-analysis found that participants receiving corticosteroids displayed no significantdifferences in mortality compared with placebo. Consequently, the benefits ofcorticosteroids treatment in CAP are still uncertain.The aims of this systematic review and meta-analysis were to:1. derive a more preciseestimation of the association between ACE I/D polymorphism and pneumonia risk. Inaddition, we investigated the association between this polymorphism and pneumoniamortality risk.2. investigate the relationships between elevated BMI, pneumonia risk,and mortality.3. summarize all the available evidence and compare the efficacy of BLMdual-therapy with BL monotherapy for CAP patients.4. evaluate the efficacy and safetyof corticosteroids adjunctive therapy in the treatment of CAP in adults.MethodsPubMed, Embase, and the Cochrane Register of Controlled Trials were searched forrelevant studies. No language restrictions were imposed. References from relevantarticles, including review papers, were also reviewed. We used a random-effects modelor fixed-effects model. All statistical analyses were performed with the STATA software(version12.0, Stata Corporation, College Station, Texas) and Review Manager5.1. Results1. ACE I/D polymorphism was significantly with pneumonia risk (OR=1.53,95%CI1.30–1.80, P <0.00001). No significant association between ACE I/D polymorphismand pneumonia-related mortality was found (OR=2.68,95%CI0.80–8.90, P=0.11).2. Overweight and obese individuals were significantly associated with an increasedrisk of pneumonia (RR=1.33,95%CI1.04–1.71, P=0.02). In the dose-response analysis,the estimated summary RR of pneumonia per5kg/m2increase in BMI was1.04(95%CI1.01–1.07, P=0.01). Inversely, overweight and obese subjects were significantlyassociated with reduced risk of pneumonia mortality (RR=0.83,95%CI0.77–0.91,P<0.01). The estimated summary RR of mortality per5kg/m2increase in BMI was0.95(95%CI0.93–0.98, P<0.01).3. Compared with BL monotherapy, BLM dual-therapy was significantly associatedwith reduced mortality (adjusted OR=0.66,95%CI0.61–0.73, P <0.001, I2=3%).Subsequent subgroup analyses confirmed that BLM dual-therapy was statisticallysuperior to BL monotherapy in reduction of mortality.4. Use of corticosteroids did not significantly reduce mortality (Peto odds ratio [OR]0.62,95%confidence interval [CI]0.37-1.04; P=0.07). In the subgroup analysis by theseverity, a survival benefit was found among severe CAP patients (Peto OR0.26,95%CI0.11-0.64; P=0.003). In subgroup analysis by duration of corticosteroids treatment,significant reduced mortality was found among patients with prolonged corticosteroidstreatment (Peto OR0.51,95%CI0.26-0.97; P=0.04; I2=37%). Corticosteroidsincreased the risk of hyperglycemia (Peto OR2.64,95%CI1.68-4.15; P <0.0001), butwithout increasing the risk of gastroduodenal bleeding (Peto OR1.67,95%CI0.41-6.80;P=0.47) and superinfection (Peto OR1.36,95%CI0.65-2.84; P=0.41).Conclusions1. ACE I/D polymorphism was associated with pneumonia risk. However, ACE I/Dpolymorphism was not associated with pneumonia mortality.2. An “obesity survival paradox” exists for pneumonia. Because this meta-analysis isbased on observational studies, more studies are required to confirm the results.3. In comparison with BL monotherapy, BLM dual-therapy might reduce mortality riskin patients with CAP. Because this finding is based on observational studies, randomizedcontrolled trials are required to demonstrate the usefulness of BLM dual-therapy in thetreatment of CAP.4. Results from this meta-analysis did not suggest a benefit for corticosteroids treatment in patients with CAP. However, the use of corticosteroids was associated withimproved mortality in severe CAP. In addition, prolonged corticosteroids therapysuggested a beneficial effect on mortality. These results should be confirmed by futureadequately powered randomized trials. |
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