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Is Statin Use Associated with Reduced Mortality After Pneumonia? A Systematic Review and Meta-analysis
... One possible solution to counter the resistance is drug combinations which may also reduce the rate of recurrence, increase the bactericidal effect, and exert anti-inflammatory effects on leprosy [6]. In various studies, statins have several pleiotropic effects, such as potential bacterial growth inhibitors [7], [8], [9], [10], augmentation of other bactericidal drugs [11], and anti-inflammatory effects [12], [13], [14], [15], [16], [17]. This article aims to provide a comprehensive insight to the link between lipid and leprosy, as well as a more in-depth discussion of statins' role in leprosy treatment, focusing their benefits on enhancing the mycobactericidal effects of rifampicin and its potential as an anti-inflammatory for various leprosy inflammatory pathways. ...
... Various studies revealed that statins can serve as an antibacterial agent [7], [8]. Two meta-analyses have shown that statins can reduce the likelihood of death in patients with infection (OR 0.71; 95% CI; 0.64-0.78) ...
... and pneumonia (OR 0.66; 95% CI; 0.55-0.79) [7], [8]. Various studies have also confirmed the inhibitory effects of Gram-positive and harmful bacteria's growth, both in vitro and in vivo, but the mechanism is still unknown. ...
BACKGROUND: Although leprosy remains as a serious disease of the skin and nervous system, the current treatment is still lacking in its effectiveness.
AIM: This literature review will explore the association of lipid and leprosy, as well as the potential of statin and other lipid-lowering agents as adjunctive drugs to combat leprosy.
MATERIALS AND METHODS: Articles were searched through the PubMed, EBSCOhost, and Google Scholar with the keywords: immunomodulation, lipid-body, lipids, leprosy, Mycobacterium leprae, pathogenesis, rifampin or rifampicin, and statins. A manual searching is also carried out to find an additional relevant information to make this literature review more comprehensive.
RESULTS: The literatures showed that lipids are highly correlated with leprosy through alterations in serum lipid profile, metabolism, pathogenesis, and producing oxidative stress. Statins can diminish lipid utilization in the pathogenesis of leprosy and show a mycobactericidal effect by increasing the effectiveness of rifampicin and recover the function of macrophages. In addition, Statins have anti-inflammatory properties which may aid in preventing type I and II reactions in leprosy. Standard multidrug therapy might reduce the efficacy of statins, but the effect is not clinically significant. The statin dose-response curve also allows therapeutic response to be achieved with minimal dose.
CONCLUSION: The various pleiotropic effects of statins make it a potential adjunct to standard treatment for leprosy in the future.
... Several large retrospective studies have revealed that preexisting cardiovascular disease and diabetes were the most frequent comorbidities of coronavirus disease 2019 (COVID- 19) patients (1-3); these patients even had a higher risk of mortality (4,5) than those with underlying respiratory disease. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely prescribed for these patients. ...
... Patients with cardiovascular disease and diabetes are often taking a combination of medications with statins (19) and oral hypoglycemic agents, especially thiazolidinediones, which have been reported to have an impact on the level of ACE2 by several studies (14,20). To further control for potential confounders, data on the use of statins, thiazolidinediones and other antihypertensive agents (α receptor blocking agents, β receptor blocking agents, calcium channel blockers and diuretics) prior to admission in each group were calculated within 90 days (6). ...
Objectives: To evaluate the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the inflammatory response and viral clearance in coronavirus disease 2019 (COVID-19) patients.
Methods: We included 229 patients with confirmed COVID-19 in a multicenter, retrospective cohort study. Propensity score matching at a ratio of 1:3 was introduced to eliminate potential confounders. Patients were assigned to the ACEI/ARB group ( n = 38) or control group ( n = 114) according to whether they were current users of medication.
Results: Compared to the control group, patients in the ACEI/ARB group had lower levels of plasma IL-1β [(6.20 ± 0.38) vs. (9.30 ± 0.31) pg/ml, P = 0.020], IL-6 [(31.86 ± 4.07) vs. (48.47 ± 3.11) pg/ml, P = 0.041], IL-8 [(34.66 ± 1.90) vs. (47.93 ± 1.21) pg/ml, P = 0.027], and TNF-α [(6.11 ± 0.88) vs. (12.73 ± 0.26) pg/ml, P < 0.01]. Current users of ACEIs/ARBs seemed to have a higher rate of vasoconstrictive agents (20 vs. 6%, P < 0.01) than the control group. Decreased lymphocyte counts [(0.76 ± 0.31) vs. (1.01 ± 0.45) * 10 ⁹ /L, P = 0.027] and elevated plasma levels of IL-10 [(9.91 ± 0.42) vs. (5.26 ± 0.21) pg/ml, P = 0.012] were also important discoveries in the ACEI/ARB group. Patients in the ACEI/ARB group had a prolonged duration of viral shedding [(24 ± 5) vs. (18 ± 5) days, P = 0.034] and increased length of hospitalization [(24 ± 11) vs. (15 ± 7) days, P < 0.01]. These trends were similar in patients with hypertension.
Conclusions: Our findings did not provide evidence for a significant association between ACEI/ARB treatment and COVID-19 mortality. ACEIs/ARBs might decrease proinflammatory cytokines, but antiviral treatment should be enforced, and hemodynamics should be monitored closely. Since the limited influence on the ACEI/ARB treatment, they should not be withdrawn if there was no formal contraindication.
... A total of 315 records were retrieved by the literature search. Among them, the full-text of 46 records was reviewed for eligibility, and 14 articles were considered eligible, corresponding to 25 meta-analyses ( Figure 1) [9][10][11][12][13][14][15][16][17][18][19][20][21][22] . Six articles were meta-analysis of RCTs 10,13,17-19,21 , 4 were of observational studies 9,11,15,20 , and the other 4 were of both RCTs and observational studies 12,14,16,22 . ...
... Among them, the full-text of 46 records was reviewed for eligibility, and 14 articles were considered eligible, corresponding to 25 meta-analyses ( Figure 1) [9][10][11][12][13][14][15][16][17][18][19][20][21][22] . Six articles were meta-analysis of RCTs 10,13,17-19,21 , 4 were of observational studies 9,11,15,20 , and the other 4 were of both RCTs and observational studies 12,14,16,22 . We conducted re-analysis on all included meta-analyses and reported the outcome along with what was reported in each study. ...
OBJECTIVE: Although previous research has reported beneficial effects of statins on infectious diseases, these have yet to be concluded. Therefore, we conducted an umbrella review to provide a comprehensive understanding of the strength of evidence and validity of claimed associations between statins (hydroxymethyl glutaryl-CoA reductase inhibitors) and infectious diseases.
PATIENTS AND METHODS: We conducted an umbrella review and re-analyzed data from meta-analyses of randomized controlled trials and observational studies on associations between statin use and different infectious diseases such as bacteremia/sepsis and pneumonia. We also evaluated the level of evidence for each re-analyzed outcome based on the criteria using p-values of random and fixed-effects, 95% prediction intervals, small-study effects, between-study heterogeneity, and concordance between the effect estimate of the largest study and summary estimates of the meta-analysis. Moreover, publication bias was also examined.
RESULTS: Through a systematic literature search, we obtained 14 eligible articles including 25 meta-analyses. All 4 meta-analyses on overall infection, 3 out of 14 meta-analyses on bacteremia/sepsis, and 5 out of 7 meta-analyses on pneumonia demonstrated that statin use was associated with reduced mortality due to infections (caused by infections). Nonetheless, most significant results only showed a weak level of evidence, and one study with convincing evidence prior to adjustment also showed weak evidence after adjustment.
CONCLUSIONS: The present review identified a protective effect of statins on infection-related mortality, but all available studies had a weak level of evidence. Therefore, further studies with a strong level of evidence are needed, and it is also necessary to investigate the types of statins and to study clinical outcomes other than mortality to gain further insights.
... These are postulated to attenuate pulmonary and systemic inflammatory response by reducing cytokines. [8][9][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 effects 13 and protect against acute lung injury by blocking the classical ACE pathway. ...
... 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. ...
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.
... The clinical potential of statins as antimicrobial agents has been the subject of several studies and reviews. A number of metaanalyses of cohort studies on the impact of overall statin use on different infection outcomes showed positive findings, albeit while highlighting the limitations and heterogeneity of the studies (10)(11)(12)(13). These reviews included studies on infections such as bacteremia, pneumonia, sepsis, and some acute infections, and the patient populations received several different statins. ...
... The latter study also showed that there was an inverse correlation between the duration of statin treatment and the risk of mortality in comparisons of statin use Ն12 and Ͻ12 weeks prior to infection (11% versus 14%, P ϭ 0.04) (15). A meta-analysis of available published data found that the use of statins was specifically associated with a reduced risk of morbidity and mortality resulting from pneumonia (12). A retrospective study of patients in the United Kingdom found that current statin treatment (i.e., treatment administered within the previous 30 days) reduced pneumonia-associated mortality (adjusted odds ratio [OR], 0.47; 95% confidence interval [CI], 0.25 to 0.88) (16), while prior statin treatment also reduced mortality rates in patients in the United States with community-acquired pneumonia (CAP) (adjusted OR, 0.36; 95% CI, 0.14 to 0.92) (17). ...
Statins are a class of pharmaceutical widely used to treat high serum cholesterol. In addition, statins have so-called "pleiotropic effects", which include the reduction of inflammation, immunomodulation, and anti-microbial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and in vitro and in vivo virulence by statin treatment. In this review, we describe the current information available surrounding the effects of statins on bacterial infections, and provide insight regarding the potential use of these compounds as anti-microbial therapeutic agents.
... Although best known for their benefits in cardiovascular disease, statins (3-hydroxy-3-methylgultaryl coenzyme A reductase inhibitors) have antiinflammatory and immunomodulatory effects [5][6][7][8][9], and several large observational studies suggest that statins may improve clinical outcomes in infectious processes [10][11][12][13][14][15][16][17]. Systematic reviews of mainly observational studies that examined the relationship between statins and various infections, including pneumonia mortality, reported significant protective effects [18][19][20]. In contrast, recent randomized controlled trials (RCTs) have not shown any benefit of statins for patients with acute respiratory distress syndrome (ARDS), including sepsis-associated ARDS, and ventilator-associated pneumonia [21][22][23]. ...
... Animal models demonstrate improved survival with statin treatment prior to induction of sepsis [36,37]. Systematic reviews including mostly nonrandomized studies examined the association between statins and infection and reported significant protective effects for various outcomes, including mortality and sepsis [18][19][20]. Multiple retrospective observational studies, most of which used large administrative datasets, have demonstrated a beneficial association of statins with several infectious processes [10][11][12][13][14][15][16][17]. ...
Background:
Prior retrospective studies suggest that statins may benefit patients with community-acquired pneumonia (CAP) due to antiinflammatory and immunomodulatory effects. However, prospective studies of the impact of statins on CAP outcomes are needed. We determined whether statin use was associated with improved outcomes in adults hospitalized with CAP.
Methods:
Adults aged ≥18 years hospitalized with CAP were prospectively enrolled at 3 hospitals in Chicago, Illinois, and 2 hospitals in Nashville, Tennessee, from January 2010-June 2012. Adults receiving statins before and throughout hospitalization (statin users) were compared with those who did not receive statins (nonusers). Proportional subdistribution hazards models were used to examine the association between statin use and hospital length of stay (LOS). In-hospital mortality was a secondary outcome. We also compared groups matched on propensity score.
Results:
Of 2016 adults enrolled, 483 (24%) were statin users; 1533 (76%) were nonusers. Statin users were significantly older, had more comorbidities, had more years of education, and were more likely to have health insurance than nonusers. Multivariable regression demonstrated that statin users and nonusers had similar LOS (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], .88-1.12), as did those in the propensity-matched groups (HR, 1.03; 95% CI, .88-1.21). No significant associations were found between statin use and LOS or in-hospital mortality, even when stratified by pneumonia severity.
Conclusions:
In a large prospective study of adults hospitalized with CAP, we found no evidence to suggest that statin use before and during hospitalization improved LOS or in-hospital mortality.
... Pravastatin and Rosuvastatin have been shown to decrease creatinine levels in patients with normal and abnormal renal function [8,9]. In a meta-analysis study, it is evident that Rosuvastatin decreases the incidence and mortality of pneumonia [10]. Statins upregulate endothelial nitric oxide synthetase (eNOS) that cause increased production of nitric oxide (NO) [11]. ...
Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits’ intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. Materials and Methods: Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit’s aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. Results: The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC50 (7.44 × 10−5 ± 0.16 M) in intact and (4.55 × 10−5 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC50 values for the statins was seen when we added amlodipine in EC50 (Log Ca++ M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10−7 M) produced a right shift in relatively lower EC50 (−2.5 ± 0.10) Log Ca++ M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC50 resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine (p < 0.05). Conclusions: KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.
... Una revisión sistemática que incluyó a 312.309 pacientes, evidenció que la administración de estatinas se asoció con una reducción de la mortalidad después de una neumonía no grave, pero no en una neumonía grave 33 . Otros dos meta-análisis también informaron una disminución de la mortalidad con el uso de estatinas en pacientes con neumonía [34][35] . Sin embargo, los estudios analizados incluyeron pacientes con neumonía de diferentes etiologías. ...
Introducción:
Debido a sus propiedades antiinflamatorias, se ha planteado que el uso de las estatinas podría influir en la evolución de la infección por el virus de influenza.
Objetivo:
Evaluar el efecto de la terapia con estatinas sobre la mortalidad por influenza.
Material y Métodos:
Se realizó un meta-análisis que incluyó estudios que evaluaron el uso de estatinas en pacientes con influenza e informaron los datos sobre mortalidad, después de buscar en las bases de datos PubMed/MEDLINE, Embase y Cochrane Controlled Trials. Se aplicó un modelo de efectos aleatorios. Se analizó el riesgo de sesgos y se desarrolló un análisis de sensibilidad.
Resultados:
Se identificaron y se consideraron elegibles para el análisis ocho estudios (diez cohortes independientes), que incluyeron un total de 2.390.730 de pacientes. Un total de 1.146.995 de sujetos analizados recibieron estatinas mientras que 1.243.735 de sujetos formaron parte del grupo control. La terapia con estatinas se asoció con una menor mortalidad (OR: 0,66; IC 95%: 0,51-0,85). El análisis de sensibilidad mostró que los resultados fueron robustos.
Conclusiones:
Nuestros datos sugieren que, en una población con influenza, el uso de estatinas se asoció con una reducción significativa de la mortalidad. Estos resultados deben confirmarse en futuros ensayos clínicos.
... Numerous studies investigating the therapeutic potential of statins in sepsis-induced ALI and ARDS patients have been conducted. A meta-analysis of 13 studies found that treatment with statins in patients with community-acquired pneumonia was associated with improved survival, particularly in those who were treated prior to hospital admission [23]. A randomized clinical study showed that prior statin use was associated with a lower baseline plasma IL-6 in patients with severe sepsis and improved 28-day survival, and the authors hypothesized that pretreatment with statins in critically ill patients at risk of sepsis may be more effective than treating established sepsis [24]. ...
Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-κB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-XL and survivin. Finally, the expression of survivin and its regulator NF-κB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-κB/p65 pathway and Bcl-XL.
... Given that these drugs inhibit the production of infectious virus, they could potentially be given to individuals with an established infection to yield a therapeutic benefit. A number of epidemiological studies have associated statin use with decreased severity of respiratory viral infections and improved clinical outcomes for IAV and SARS-CoV-2 [77][78][79][80][81] . Although in vivo data on statins and RSV are limited, a single study found inhibition of RSV in mice by daily treatment with high doses of lovastatin (50 mg/kg) delivered orally 82 . ...
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of cholesterol and isoprenoid-mediated effects. Notably, RSV infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV infection and highlight geranylgeranyltransferases as an antiviral target for therapeutic development.
... [3,4] The protective effect of statins against cardiac lesion formation during IPD is supported by a meta-analysis that showed that individuals on statin therapy who were hospitalized for pneumonia have significantly better posthospital discharge survival rates than controls. [9] The scenario of reduced LVEF and hemodynamic instability may be precipitated by concurrent purulent pericarditis, which can be overlooked and delayed, especially in complex clinical scenarios. Ultimately, the diagnosis of purulent pericarditis is established by obtaining pericardial fluid for culture and microscopy. ...
This report describes a 61-year-old female with no previous cardiovascular history presented with acute heart failure. Clinical, laboratory, and imaging findings suggested the diagnosis of pneumococcal invasive disease with concomitant purulent pericarditis. Prompt pharmacological and operatory treatment with both pericardiocentesis and further fenestration brought to a complete recovery.
... Statin drugs have also been studied and may reduce ACS due to lipid-lowering and their immunomodulating effects 24 . A meta-analysis of observational studies shows that the use of statins reduces all-cause mortality after pneumonia 25 . Influenza vaccination appears to reduce mortality due to ACS 26 . ...
Acute respiratory infections appear to precipitate vascular events. Acute myocardial infarction (AMI) and stroke are the leading cause of death and disability globally. This study was based on a cohort of patients admitted to Townsville University Hospital between January 2006 and December 2016. Using a self-controlled case series design, we investigated the risk of AMI or ischaemic stroke after an episode of pneumonia. We defined the ‘risk interval’ as the first 14 days after hospitalisation for pneumonia and the ‘control interval’ as one year before and one year after the risk interval. Among a population (N = 4557) with a median age of over 70, a total of 128 AMI and 27 stroke cases were identified within 1 year of an episode of pneumonia in this study. Ten and two admissions occurred during the risk interval, while 118 and 25 admissions occurred during the control period. The relative incidence ratios (RIR) of AMI increased after an episode of pneumonia (RIR=4.85, 95% confidence interval (CI) 2.44–9.67). The risk for stroke after the exposure period of 14 days was 4.94 (95% CI 1.12–21.78) considering only the first stroke incidence. The RIR results for AMI and stroke were not altered by adjusting for age, sex or Indigenous status. The risk of AMI and stroke were significantly higher two weeks after an episode of pneumonia.
... 10 Literature suggests statins may have a beneficial role in some infections, as one study demonstrated decreased mortality after pneumonia and a possible benefit in acute bacterial infections due to decreased level of inflammatory cytokines in patients on statin therapy. 28 Statin exposure has also been associated with decreased risk of new onset ulcerative colitis and Crohn's disease. 29 In general, the immunomodulatory role of statins is currently ill defined, and will require future prospective studies to better understand the role of statin therapy in the setting of active infection and inflammatory disease processes. ...
Background
Patients with inflammatory bowel disease (IBD) are at significantly increased risk for Clostridioides difficile infection (CDI) with an increased risk of adverse outcomes including increased in-hospital mortality, IBD treatment failure, re-hospitalization, and high CDI recurrence rates. The existing literature on predictors of these adverse outcomes is limited. We evaluated four potentially modifiable novel risk factors [body mass index (BMI), statin use, opioid use, and antidepressant use] on CDI risk and adverse outcomes in these patients.
Methods
Using a retrospective design, variables were abstracted from records for patients with IBD and CDI from 2008 to 2013. Statistical analysis comprised descriptive statistics and univariate and multivariate logistic regression analyses.
Results
There were 137 patients with IBD and CDI included in this study. On multivariate analysis controlling for age, 43% of patients in the overweight BMI category had severe or severe, complicated CDI, compared with 22% of patients in the underweight/normal BMI [odds ratio (OR) 2.85, p = 0.02] and 19% in the obese category (OR 3.95, p = 0.04). Statin use was associated with severe or severe, complicated CDI when controlling for age and BMI (OR 5.66, p = 0.01). There was no association between statin use and IBD exacerbations following CDI. Opioid and antidepressant use were not associated with disease severity or frequency of IBD exacerbations following CDI.
Conclusions
An overweight BMI and statin use were associated with severe or severe, complicated CDI in IBD patients. Further studies are needed to better understand how these factors impact management of patients with IBD to improve clinical outcomes and potentially reduce the risk of complications from CDI.
... The observations regarding the association of statin use with the outcomes of types of pneumonia had been reported previously (18,19). Overall, significant decrease in mortality was demonstrated in the hospitalized pneumonia patients taking statins. ...
Background: Statins have multiple protective effects on inflammation, immunity and coagulation, and may help alleviate pneumonia. However, there was no report focusing on the association of statin use with in-hospital outcomes of patients with coronavirus disease 2019 (COVID-19). We investigated the association between the use of statins and in-hospital outcomes of patients with COVID-19.
Methods: In this retrospective case series, consecutive COVID-19 patients admitted at 2 hospitals in Wuhan, China, from March 12, 2020 to April 14, 2020 were analyzed. A 1:1 matched cohort was created by propensity score-matched analysis. Demographic data, laboratory findings, comorbidities, treatments and in-hospital outcomes were collected and compared between COVID-19 patients taking and not taking statins.
Result: A total of 2,147 patients with COVID-19 were enrolled in this study. Of which, 250 patients were on statin therapy. The mortality was 2.4% (6/250) for patients taking statins while 3.7% (70/1,897) for those not taking statins. In the multivariate Cox model, after adjusting for age, gender, admitted hospital, comorbidities, in-hospital medications and blood lipids, the risk was lower for mortality (adjusted HR, 0.428; 95% CI, 0.169–0.907; P = 0.029), acute respiratory distress syndrome (ARDS) (adjusted HR, 0.371; 95% CI, 0.180–0.772; P = 0.008) or intensive care unit (ICU) care (adjusted HR, 0.319; 95% CI, 0.270–0.945; P = 0.032) in the statin group vs. the non-statin group. After propensity score-matched analysis based on 18 potential confounders, a 1:1 matched cohort (206:206) was created. In the matched cohort, the Kaplan-Meier survival curves showed that the use of statins was associated with better survival (P = 0.025). In a Cox regression model, the use of statins was associated with lower risk of mortality (unadjusted HR, 0.254; 95% CI, 0.070–0.926; P = 0.038), development of ARDS (unadjusted HR, 0.240; 95% CI, 0.087–0.657; P = 0.006), and admission of ICU (unadjusted HR, 0.349; 95% CI, 0.150–0.813; P = 0.015). The results remained consistent when being adjusted for age, gender, total cholesterol, triglyceride, low density lipoprotein cholesterol, procalcitonin, and brain natriuretic peptide. The favorable outcomes in statin users remained statistically significant in the first sensitivity analysis with comorbid diabetes being excluded in matching and in the second sensitivity analysis with chronic obstructive pulmonary disease being added in matching.
Conclusion: In this retrospective analysis, the use of statins in COVID-19 patients was associated with better clinical outcomes and is recommended to be continued in patients with COVID-19.
... In older populations at a higher risk of CV events [34], there is a need for an easy-to-use predictive tool for the prevention of CV events. Indeed, there is growing evidence that preventative CV therapies could improve outcomes after AP [35][36][37][38][39]. However, in this frail comorbid population, an individualized assessment of post-AP CV risk is needed to limit the iatrogenic effects of drugs used for CV prevention, including bleeding complications. ...
Cardiovascular (CV) events are particularly frequent after acute pneumonia (AP) in the elderly. We aimed to assess whether cardiac troponin I, a specific biomarker of myocardial injury, independently predicts CV events and death after AP in older inpatients. Among 214 consecutive patients with AP aged ≥75 years admitted to a university hospital, 171 with a cardiac troponin I sample in the 72 h following diagnosis of AP were included, and 71 (42%) were found to have myocardial injury (troponin > 100 ng/L). Patients with and without myocardial injury were similar in terms of age, gender and comorbidities, but those with myocardial injury had more severe clinical presentation (median (interquartile range) Pneumonia Severity Index: 60 (40-95) vs. 45 (30-70), p = 0.003). Myocardial injury was strongly associated with in-hospital myocardial infarction (25% vs. 0%, p < 0.001), CV mortality (11 vs. 1%, p = 0.003) and all-cause mortality (34 vs. 13%, p = 0.002). After adjustment for confounders, myocardial injury remained a strong predictive factor of in-hospital mortality (odds ratio (95% confidence interval): 3.32 (1.42-7.73), p = 0.005) but not one-year mortality (1.61 (0.77-3.35), p = 0.2). Cardiac troponin I elevation, a specific biomarker of myocardial injury, was found in nearly half of an unselected cohort of older inpatients with AP and was associated with a threefold risk of in-hospital death.
... In contrast, however, a multicentre cohort study from the United States found no evidence of protection conferred by statins on clinical outcomes in a similar cohort [40]. A metaanalysis found that although statin treatment was associated with decreased mortality after pneumonia, there was attenuation of this effect in certain subgroups and it was indicated that no robust conclusions could be drawn without a dedicated randomised clinical trial [41]. Data on protectiveness of statins in viral pneumonias are also inconsistent with studies reporting benefit [42][43][44] or no benefit [45]. ...
Background & aims
The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a worldwide pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients, who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations.
Methods
Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrate, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen.
Results & Conclusions
There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.
... Additionally, a meta-analysis by Chopra et al. showed that statin use was associated with lower mortality after pneumonia (OR 0.62, 95% CI: 0.54-0.71) [43]. ...
Current data suggest that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease-19 (COVID-19) seems to follow a more severe clinical course in patients with cardiovascular disease (CVD), hypertension, and overweight/obesity. It appears that lipid-lowering pharmacological interventions, in particular statins, might reduce the risk of cardiovascular complications caused by COVID-19 and might potentially have an additional antiviral activity. It has been shown that high cholesterol levels are associated with more lipid rafts, subdomains of the plasma membrane that can harbour angiotensin-converting enzyme 2 (ACE2) receptors for the S-protein of SARS-CoV-2. Evidence of the importance of cholesterol for viral entry into host cells could suggest a role for cholesterol-lowering therapies in reducing viral infectivity. In addition to their lipid-lowering and plaque-stabilisation effects, statins possess pleiotropic effects including anti-inflammatory, immunomodulatory, and antithrombotic activities. Lower rates of mortality and intubation have been reported in studies investigating statin therapy in influenza infection, and statin therapy was shown to increase viral clearance from the blood during chronic hepatitis C infection. Statins may also serve as potential SARS-CoV-2 main protease inhibitors, thereby contributing to the control of viral infection. In this review, we elaborate on the role of cholesterol level in the process of the coronavirus infection and provide a critical appraisal on the potential of statins in reducing the severity, duration, and complications of COVID-19.
... There have been reports that those patients with bacteremia who had undergone previous statin therapy show a significant reduction in mortality as compared to those who had not [119]. In other studies, it was found that statin treatment was associated with reduced mortality risks in pneumonia patients [120]. ...
The discovery and clinical utilization of antibiotics is one of the most important breakthroughs that has revolutionized medical science and significantly contributed to saving millions of lives. However, due to irrational, rampant misuse of antibiotics along with poor patient compliance has led to current state of almost entering postantibiotic era because of a phenomenon called antimicrobial resistance (AMR). Furthermore, the problem has become compounded due to the dearth of novel and effective antibacterials being discovered and developed owing to a multitude of factors, including ever increasing costs of discovery and development as well as complex and costly clinical trials for regulatory approval. As a result of this, recent reports suggest an estimated death toll of 700,000 deaths each year attributable to AMR along with future projected deaths reaching ∼10 million by 2050. Thus new policies to invigorate antibiotic discovery and development are required to avoid postantibiotic era.
... We collected data on the following parameters from the hospital electronic medical record systems, nursing records, laboratory examination systems, and radiological examinations and obtained standardized data collection forms: demographic characteristics, comorbidities, medication history within one month, symptoms at admission, laboratory finding changes from day 1 to day 14, radiological manifestations, treatment during hospitalization and outcome data that contained the rate of in-hospital death and progression, the duration of viral shedding, the length of hospital stay and the time from onset to death or discharge. Patients with cardiovascular disease and diabetes often combined the medication with statins [19] and oral hypoglycemic agents, especially thiazolidinediones, which have been reported to have an impact on the level of ACE2 by several studies [14,20] . To further control for potential confounders, data on the use of statins, thiazolidinediones and other antihypertensive agents (β receptor blocking agent and diuretics) prior to admission in each group were calculated within 90 days [6] . ...
Objectives: To evaluate the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) patients.
Methods: We included 229 patients with confirmed COVID-19 in a multicenter, retrospective cohort study. Propensity score matching at a ratio of 1:4 was introduced to eliminate the potential confounders. Patients were assigned to the ACEI/ARB group (n=40) or control group (n=160) according to whether they were current users of medication.
Results: Compared to the control group, patients in the ACEI/ARB group had lower levels of plasma IL-1β [(6.27±0.50) vs. (8.23±0.39) pg/ml, P=0.028], IL-8 [(35.74±4.00) vs. (45.88±2.06) pg/ml, P=0.037] and TNF-α [(8.79±0.40) vs. (10.91±0.21) pg/ml, P<0.01]. Patients with the current use of ACEIs/ARBs had a higher risk of shock (23% vs. 8%, P<0.01). Decreased lymphocyte counts [(0.85±0.45) vs. (1.02±0.52)*10^9/L, P=0.041] and elevated plasma levels of IL-10 [(7.39±0.51) vs. (6.18±0.16) pg/ml, P<0.01] were also important discoveries in the ACEI/ARB group. Patients in the ACEI/ARB group had a prolonged duration of viral shedding [(25±7) vs. (20±6) days, P=0.031] and increased length of hospitalization [(23±12) vs. (16±8) days, P<0.01]. These trends were similar in patients with hypertension.
Conclusions: For patients with excessive inflammatory responses and stable hemodynamics, ACEIs or ARBs might be tried to relieve the inflammatory storm, but the antiviral treatment should be enforced and the hemodynamics should be monitored closely; for patients with low levels of proinflammatory factors or instability hemodynamics, the agents might not be used to avoid a delay in viral clearance or increase the risk of shock.
... By inhibiting the mevalonate pathway and production of isoprenoid, it reduces inflammatory cell influx into the lung and pro-inflammatory cytokine release in innate and adaptive immune pathways. A multitude of observational studies have shown variable results with the use of adjunctive oral therapy [95][96][97] , overall suggesting that it improves mortality in severe cases of CAP. Others have studied its positive effect in reducing the risk of severe progression of respiratory failure to the point of requiring mechanical ventilation and some have gone on to study its effects on mortality after pneumonia infection. ...
Community acquired pneumonia is a leading cause of mortality in the United States. Along with predisposing comorbid health status, age is an independent risk factor for determining the outcome of pneumonia. Research over the last few decades has contributed to better understanding the underlying immunodysregulation and imbalanced redox homeostasis tied to this aged population group that increases susceptibility to a wide range of pathologies. Major approaches include targeting oxidative stress by reducing ROS generation at its main sources of production which includes the mitochondrion. Mitochondria-targeted antioxidants have a number of molecular strategies that include targeting the biophysical properties of mitochondria, mitochondrial localization of catalytic enzymes, and mitigating mitochondrial membrane potential. Results of several antioxidant studies both in vitro and in vivo have demonstrated promising potential as a therapeutic in the treatment of pneumonia in the elderly. More human studies will need to be conducted to evaluate its efficacy in this clinical setting.
... An undefined number of patients in the trial by Sapey and colleagues (1) were taking maintenance, lower-dose statins, and statin "reloading" has been associated with beneficial outcomes after percutaneous coronary intervention (8). However, whether prior use of statins has a beneficial effect on outcomes after CAP remains contentious (9,10), and acute use of statins for acute coronary syndrome (analogous to application in the trial considered here) does not improve outcomes (11). ...
... 23 Experimental and clinical studies suggest that statins exhibit anti-inflammatory activity that reduces the risk of pneumonia and related outcomes. [24][25][26] This activity may help us to explain why patients with RYR prescription had a significant reduction in post-operative pneumonia risk in this study. Third, RYR extract inhibits high-glucose-induced b-galactosidase activation and reduces high-glucose-induced oxidative stress in proangiogenic cells in a dose-dependent manner. ...
Background:
The influence of red yeast rice (RYR) on perioperative outcome remains unknown.
Aim:
We aimed to compare the complications and mortality after surgery between patients treated with and without RYR prescription.
Design:
In this surgical cohort study of 3.6 million surgical patients who underwent major inpatient surgeries, 2581 patients who used RYR prescription preoperatively were compared with 25,810 non-RYR patients selected by matching for age and sex.
Methods:
Patients' demographics and medical conditions were collected from the claims data of the National Health Insurance in Taiwan. Complications and mortality after major surgeries in association with RYR prescription were investigated by calculating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) by multiple logistic regression.
Results:
Compared with patients without RYR prescription, patients prescribed RYR had lower risks of postoperative bleeding (OR 0.36, 95% CI 0.15-0.89), pneumonia (OR 0.54, 95% CI 0.36-0.83), stroke (OR 0.66, 95% CI 0.47-0.92), and 30-day in-hospital mortality (OR 0.37, 95% CI 0.15-0.92). Decreased risk of intensive care (OR 0.64, 95% CI 0.54-0.77), shorter length of hospital stay (p < 0.001), and lower medical expenditures (p = 0.0008) during the index surgical admission were also noted for patients with RYR prescription compared to those for patients without RYR prescription.
Conclusions:
This study showed a potentially positive effect of RYR on outcomes after major surgeries. However, patient noncompliance for taking medication should be noted. Our findings require future prospective studies to validate RYR prescription for improving perioperative outcomes.
... Substantial efforts have been invested in understanding the role of statins during human infections caused by bacteria, fungi and viruses. Statins have been strongly associated with improved clinical outcomes despite study limitations such as the use of different types of statins and the heterogeneity of the studies 90 . ...
Statins were first identified over 40 years ago as lipid-lowering drugs and have been remarkably effective in treating cardiovascular diseases. As research advanced, the protective effects of statins were additionally attributed to their anti-inflammatory, antioxidative, anti-thrombotic and immunomodulatory functions rather than lipid-lowering abilities alone. By promoting host defence mechanisms and inhibiting pathological inflammation, statins increase survival in human infectious diseases. At the cellular level, statins inhibit the intermediates of the host mevalonate pathway, thus compromising the immune evasion strategies of pathogens and their survival. Here, we discuss the potential use of statins as an inexpensive and practical alternative or adjunctive host-directed therapy for infectious diseases caused by intracellular pathogens, such as viruses, protozoa, fungi and bacteria.
... In their meta-analysis, Chopra et al. revealed that two prospective studies (Majumdar and Yende et al.) found that statins did not reduce pneumonia-related mortality, but another prospective study (Chalmers et al.) found that they did [52]. Thus, Chopra et al. concluded that although statin use is associated with decreased pneumonia-related mortality, this effect weakens in important subgroups. ...
We investigated the effects of statins on tuberculosis (TB) and pneumonia risks in asthma–chronic pulmonary disease overlap syndrome (ACOS) patients. We extracted data of patients diagnosed as having ACOS during 2000–2010 from the Taiwan National Health Insurance Research Database and divided them into statin users and nonusers. All study participants were followed up from the index date until death, withdrawal from insurance, or TB and pneumonia occurred (31 December 2011). The cumulative TB and pneumonia incidence was analyzed using Cox proportional regression analysis with time-dependent variables. After adjustments for multiple confounding factors including age, sex, comorbidities, and use of medications [statins, inhaled corticosteroids (ICSs), or oral steroids (OSs)], statin use was associated with significantly lower TB [adjusted hazard ratio (aHR) 0.49, 95% confidence interval (CI) 0.34–0.70] and pneumonia (aHR 0.52, 95% CI 0.41–0.65) risks. Moreover, aHRs (95% CIs) for statins combined with ICSs and OSs were respectively 0.60 (0.31–1.16) and 0.58 (0.40–0.85) for TB and 0.61 (0.39–0.95) and 0.57 (0.45–0.74) for pneumonia. Thus, statin users had lower TB and pneumonia risks than did nonusers, regardless of age, sex, comorbidities, and ICS or OS use. Pneumonia risk was lower among users of statins combined with ICSs or Oss and TB risk was lower among the users of statins combined with OSs.
... Among these, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) had been shown to attenuate inflammation in murine lung injury models [3]. Pretreatment with statins was also found to attenuate pulmonary inflammation in lipopolysaccharide-induced inflammation in healthy human volunteers, and prior statin therapy was associated with a survival benefit in patients with community-acquired pneumonia [4,5]. Two multicenter RCTs, hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction-2 study (HARP-2) [6] and rosuvastatin in sepsis-associated acute respiratory distress syndrome (SAILS) study [7], were recently conducted to test the hypothesis that statin treatment may be beneficial in treating ARDS. ...
Purpose
Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes.
Methods
LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n = 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin.
Results
The two-class LCA model best fit the population. Forty percent of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo.
Conclusions
LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.
... The effect of statins in CAP prevention has been evaluated by several studies. A recent meta-analysis (254,950 patients, 13 studies) concluded that the overall mortality rate following CAP in statin users was significantly lower (OR = 0.62, 95% CI: 0.54 to 0.71) than in non-statin users [104]. ...
Introduction: Despite advances in modern medicine, severe community-acquired pneumonia (CAP) continues to be a potentially deadly disease. Mortality rate reaches up to the 50% in patients requiring admission to the Intensive Care Unit (ICU) when developing septic shock.
Areas covered: We aim to describe the optimal management of severe CAP including antibiotic therapy, future antimicrobial options, and non-antibiotic (so-called adjunctive) therapies. A literature search was performed to identify all clinical trials, observational studies, meta-analysis, and reviews about this topic from PubMed.
Expert commentary: Antibiotic therapy, the cornerstone of the management of CAP, must be started prompt because the delay in the administration of antimicrobials is associated with mortality. Diverse observational studies have reported a lower adjusted mortality in patients with severe CAP treated with combined antibiotic therapy, especially those in septic shock or with pneumococcal bacteremia. We summarize the available information about new antibiotics in the pipeline for severe CAP. Finally, we review the available evidence about the role of corticosteroids, immunoglobulins, and statins as adjunctive for CAP.
... The postulated mechanisms of protectiveness of statins were lowering the proinflammatory responses of macrophages and neutrophils via various intracellular signaling pathways and cytokines, limiting endothelial cell activation, and inhibiting expression of major histocompatibility complex (MHC)-II genes [22,23]. However, findings concerning the protectiveness of statins in these diseases have been conflicting, probably due to the complexity of the immunomodulatory actions of statins which do not target individual mediators, the diversity of the causative agents of the infectious diseases examined, and the heterogeneous study design [24][25][26]. Optimism regarding the protective effects of statins in infectious diseases should not be directly extended to the link between HZ and statins: HZ is a well-documented disease entity caused by a single viral pathogen (VZV) and the increased risk of HZ associated with statin use has been consistently observed in several epidemiologic studies [4][5][6][7]. Statins inhibit interferon-γ-induced MHC-II expression and prevent antigen presentation to CD4 + T cells [27]. ...
Objectives
Statins, which are lipid-lowering agents, have anti-inflammatory and immunomodulatory properties that may affect the occurrence of various infectious diseases. We assessed whether statins increase the risk of herpes zoster (HZ) with propensity score-matching.
Methods
The study was based on the National Health Insurance database and its subset database of the “medical check-up” population of South Korea. These cohorts consist of about one million and 570,000 people, respectively, representative of the entire population of South Korea. We identified 103,930 statin users and 430,685 non-statin users. After propensity score-matching, 25,726 statin users and the same number of non-statin users were finally analyzed. The development of HZ was monitored in these matched pairs over the 11 years from 2003 to 2013.
Results
Statin users had a significantly higher risk of HZ than non-statin users: hazard ratio (HR) 1.25 (95% CI, 1.15 to 1.37) (p < .0001). The risk of HZ associated with statins was especially high in the elderly: HR 1.39 (95% CI, 1.12 to 1.73) in the over 70-year-olds (p = 0.003) and HR 1.18 (95% CI, 1.00 to 1.39) in the 60-to-69-year-olds (p = 0.056). Furthermore, there was a significant p for trend in terms of cumulative dose effect between the risk of HZ and the duration of statin use (p < .0001).
Conclusions
These epidemiologic findings provide strong evidence for an association between HZ and statin use, and suggest that unnecessary statins should be avoided.
... However, such an effect has not been observed in our study. Although the degree of its effect remains controversial, statins are also known to modify the risk of pneumonia and pneumonia-related outcomes [39][40][41]. The impact of statin use on the IVE may be different according to influenza outcomes. ...
Background:
The effectiveness of inactivated influenza vaccine (IIV) against laboratory-confirmed influenza pneumonia in older adults remains to be established.
Methods:
Pneumonia patients aged ≥65 years who visited a study hospital in Chiba, Japan, were prospectively enrolled from February 2012 to January 2014. Sputum samples were collected from participants and tested for influenza virus by polymerase chain reaction assays. Influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza pneumonia was estimated by a test-negative design.
Results:
Among a total of 814 pneumonia patients, 42 (5.2%) tested positive for influenza: 40 were positive for influenza A virus, and two were positive for influenza B virus. The IVE against laboratory-confirmed influenza pneumonia was 58.3% (95% confidence interval, 28.8-75.6%). The IVE against influenza pneumonia hospital admission, severe pneumonia, and death was 60.2% (95% CI, 22.8-79.4%), 65.5% (95% CI, 44.3-78.7%), and 71% (95% CI, -62.9% to 94.8%), respectively. In the subgroup analyses, the IVE against influenza pneumonia was higher for patients with immunosuppressive conditions (85.9%; 95% CI, 67.4-93.9%) than for those without (48.7%; 95% CI, 2.7-73%) but did not differ by patients' statin use status.
Conclusion:
IIV effectively reduces the risk of laboratory-confirmed influenza pneumonia in older adults.
... 6 Although the approved indications to use statins are largely cardiovascular, they have been shown to improve outcomes in infections such as pneumonia, pulmonary hypertension, new-onset inflammatory bowel disease, venous thromboembolism, autoimmune conditions such as systemic lupus erythematosus, and certain cancers such as hepatocellular carcinoma and gastric cancer. [7][8][9][10][11][12][13] Statin use has been found to prevent infections in patients with cirrhosis and to be associated with decreased risks of severe sepsis and decompensation and all-cause mortality in compensated liver disease secondary to hepatitis C. [14][15][16] By inhibiting the production of isoprenoid intermediates, which are required for the activation of intracellular messengers, statins have pleiotropic effects on inflammatory and immunomodulatory pathways. 17 Conceivably, statins may modify the risk of CDI. ...
Purpose
Statins have pleiotropic effects beyond cholesterol lowering by immune modulation. The association of statins with primary Clostridium difficile infection (CDI) is unclear as studies have reported conflicting findings. We performed a systematic review and meta-analysis to evaluate the association between statin use and CDI.
Patients and methods
We searched MEDLINE, Embase, and Web of Science from January 1978 to December 2016 for studies assessing the association between statin use and CDI. The Newcastle–Ottawa Scale was used to assess the methodologic quality of included studies. Weighted summary estimates were calculated using generalized inverse variance with random-effects model.
Results
Eight studies (6 case–control and 2 cohort) were included in the meta-analysis, which comprised 156,722 patients exposed to statins and 356,185 controls, with 34,849 total cases of CDI available in 7 studies. The rate of CDI in patients with statin use was 4.3%, compared with 7.8% in patients without statin use. An overall meta-analysis of 8 studies using the random-effects model demonstrated that statins may be associated with a decreased risk of CDI (maximally adjusted odds ratio [OR], 0.80; 95% CI, 0.66–0.97; P=0.02). There was significant heterogeneity among the studies, with an I² of 79%. No publication bias was seen. Meta-analysis of studies that adjusted for confounders revealed no protective effect of statins (adjusted OR, 0.84; 95% CI, 0.70–1.01; P=0.06, I²=75%). However, a meta-analysis of only full-text studies using the random-effects model demonstrated a decreased risk of CDI with the use of statins (OR 0.77; 95% CI, 0.61–0.99; P=0.04, I²=85%).
Conclusion
Meta-analyses of existing studies suggest that patients prescribed a statin may be at decreased risk for CDI. The results must be interpreted with caution given the significant heterogeneity and lack of benefit on analysis of studies that adjusted for confounders.
... Multiple SRMA based mainly on observational studies have shown that chronic therapy with statins is associated with lower incidence of pneumonia and/or lower CAP-related mortality. [81][82][83][84][85][86] However, these results are conflictive by heterogeneity, healthy user bias and methodological limitations that preclude drawing a consistent conclusion. It is unclear if this suggested effect is driven by preventing CC due to the immunomodulatory properties observed with statins or the limitations mentioned above. ...
Community-acquired pneumonia (CAP) is an important cause of death around the globe. Up to 30% of patients admitted to hospital for CAP develop cardiovascular complications (i.e. new/worsening heart failure, new/worsening arrhythmias, myocardial infarctions and/or strokes), acutely and up to 10 years thereafter. Cardiac complications result from complex interactions between preexisting conditions, relative ischaemia, upregulation of the sympathetic system, systemic inflammation and direct pathogen-mediated damage to the cardiovascular system. The exact mechanisms underlying the direct host–pathogen interactions are of great interest to identify potential therapeutic and preventative targets for CAP. In this review, we summarize the epidemiological data, risk factors and the pathogen-driven cardiovascular damage affecting patients with CAP.
... Regarding patients who are already on statins at admission, a meta-analysis showed a reduced 30-day mortality rate among all pneumonia patients, but no protective effect was seen when comparing the effect in important subgroups [247]. A nested case-control study (approximately 25,000 patients) showed that patients treated with statins due to a previous myocardial infarction had a 15% reduced risk of developing pneumonia [248]. ...
Based on expert group work, Swedish recommendations for the management of community-acquired pneumonia in adults are here updated. The management of sepsis-induced hypotension is addressed in detail, including monitoring and parenteral therapy. The importance of respiratory support in cases of acute respiratory failure is emphasized. Treatment with high-flow oxygen and non-invasive ventilation is recommended. The use of statins or steroids in general therapy is not found to be fully supported by evidence. In the management of pleural infection, new data show favourable effects of tissue plasminogen activator and deoxyribonuclease installation. Detailed recommendations for the vaccination of risk groups are afforded.
... On the other hand, statin therapy has been associated to important beneficial outcomes in other organs including the brain, ranging from anti-inflammatory activity to reduction of brain atrophy and disability in multiple sclerosis. Depending on the physiopathological circumstances, it is uncertain whether these events are related to hepatic effects and/or whether they are independent of MVA pathway inhibition [20][21][22][23][24][25][26][27][28]. In this review we will summarize and discuss, providing up-todate information, the current knowledge about the pleiotropic effects of statins in the brain. ...
Background:
Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquired increased interest as potential and novel modulators in brain processes, especially during pathological conditions.
Objective:
The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, statin effect on brain diseases are discussed providing the most up-to-date information.
Methods:
Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke.
Results:
315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect.
Conclusion:
Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.
... While prior statin use has been shown in systematic reviews and meta-analyses to be associated with a decreased risk and/or mortality of CAP (127)(128)(129)(130), there is not enough evidence from randomised controlled trials to recommend their routine use to either prevent CAP or to improve its mortality. The only randomised, double-blind, placebocontrolled, intervention study investigating the impact of statin use on admission of patients with CAP to hospital was not associated with a reduction in cytokine levels, nor was it associated with a reduction in time to clinical stability among the patients (131). ...
... The metaanalysis demonstrated that the presence of the unknown confounder has to be severely imbalanced between the statin users and non-users to explain the reported associations. Moreover, other meta-analyses have reported on the topic and came to a similar conclusion [42,43]. However, these meta-analyses are hypothesis generating and do not conclusively prove or disprove the association of the use of statins with the development of CAP. ...
Purpose of the review:
Community-acquired pneumonia (CAP) is still associated with a large burden and causes significant morbidity and mortality. Besides universal vaccination and antibiotic treatment, statins as adjunctive therapy may also have a beneficial role in the prevention and treatment of CAP. Our goal from this review is to discuss the epidemiology of CAP, and role of statins as adjunctive therapy in the development of CAP.
Recent findings:
Statins are lipid-lowering medications characterized by their ability to control hypercholesterolemia in addition to other pleiotropic effects that could explain their role in the pathogenesis of CAP. While most observational studies have shown that statins reduce risk of pneumonia in the general population, patients with diabetes, and recently in patients with myocardial infarction, no randomized controlled trial (RCT) to date has been conducted to assess the efficacy of statins to prevent development of CAP. Given the paucity of robust randomized evidence to assess statin use and the development of CAP, and considering conflicting results of the observational studies, we are not in favor of initiation of statins for either the prevention or treatment of CAP.
... Owing to their oral availability, favorable pharmacokinetic properties, and relatively low level of associated side effects, these drugs have become a mainstay of low-density lipoprotein (LDL) cholesterol-lowering therapy that is now used to treat tens of millions of individuals with hyperlipidemia worldwide. Interestingly, recent meta-analyses have compiled a heterogeneous collection of retrospective and prospective cohort studies and randomized trials to conclude that statin use may provide a beneficial effect in reducing morbidity and mortality associated with different infectious disease conditions, including pneumonia, bacteremia, and sepsis [87,88]. Thus it has been hypothesized that statins may have pharmacological effects, either through cholesterol reduction itself or via an independent 'off-target' mechanism, to aid in pathogen resistance. ...
The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms.
... In addition, there is new evidence to support that statins possess other properties beyond the ability to lower lipid levels, referred to as pleiotropic effects, such as stabilizing atherosclerotic plaques, improving vascular endothelial function, reducing vascular inflammation, and inhibiting thromboses, as well as antioxidant effects [2] . Some recent studies found that statin use is associated with reduced mortality after pneumonia [3,4] . Statins also possess potential preventive effects and antimetastatic effects against many kinds of cancer [5,6] . ...
Erkeklerde yaşam kalitesini bozduğu çok iyi bilinen alt üriner sistem semptomları (AÜSS) prevalansı %18–40 arasında değişmektedir (1–4). Alt üriner sistem semptomlarına yol açan ve ileri yaş hastalığı olarak kabul edilen benign prostatik hiperplazinin (BPH) 40 yaş öncesi oldukça nadir olduğu, görülme oranının 50–79 yaş arasında %56 ve 80-
89 yaş arasında ise %80 civarında olduğu bildirilmiştir (1). BPH, Üroloji pratiğinde uzun yıllardır bilinmesine rağmen etyopatogenezi ve tedavisi hakkında yoğun araştırmalar ve tartışmalar halen devam etmektedir. Son yıllarda tüm dünyada önemli bir sağlık sorunu olan obezite ve bununla ilişkili metabolik sendromun BPH etyopatogenezinde yer alabileceği bildirilmiştir. Dünya Sağlık Örgütü (DSÖ) verilerine göre toplumun %25’i obez, %25’i fazla kilolu ve %25’i de normal kilolu ancak genetik olarak obeziteye eğilimli olup, dünyada 400 milyonun üzerinde obez ve yaklaşık 1.6 milyardan fazla, kilolu birey bulunmaktadır (5). Gelişmiş ülkeler başta olmak üzere tüm dünyada obezite prevalansının
1980’den beri yaklaşık iki katına çıktığı anlaşılmaktadır (6). Dünya Sağlık Örgütü (DSÖ) 1998 yılında metabolik sendromu, diyabet, bozulmuş açlık glikozu, bozulmuş glikoz toleransı veya insülin direnci ile birlikte, hipertansiyon (>160/90 mmHg), hiperlipidemi, santral obezite ve mikroalbuminüriden en az ikisinin olması olarak tanımlamıştır (7). Bu durum artmış kardiyovasküler risk, tip 2 diabetes
mellitus (DM) ve kardiyak spesifik mortaliteye ile ilişkilidir. Metabolik sendromun dünyadaki prevalansı %20–25 olup, 60–69 yaşlarında %43.5’e kadar çıkabilmektedir (8). Son dönemlerde yapılan klinik ve epidemiyolojik çalışmalar metabolik sendrom ve anormal lipid seviyelerinin BPH ile ilişkili olabileceğini göstermektedir (8–11). BPH’ı olan metabolik sendromlu erkek olguların metabolik sendromu olmayanlara göre istatistiksel olarak anlamlı olacak şekilde daha yüksek total prostat ve prostatik transizyonel zon volümlerine sahip oldukları gösterilmiştir (12,13). Buna göre prostat volümü, 1895 olgunun incelendiği Zou Prof. Dr. Fikret Erdemir, Prof. Dr. Mete Kilciler, Uzm. Dr. Mustafa Suat Bolat Gaziosmanpaşa Üniversitesi Tıp Fakültesi, Üroloji AD ve arkadaşlarının çalışmalarında metabolik sendromu olan BPH’lı olgularda metabolik sendromu olmayanlara göre 10.5 ml daha fazla saptanmıştır. Ayrıca, yıllık PSA artışıda metabolik sendromu olan grupta daha yüksek saptanmıştır (11). Karşıt sonuçlar bildiren çalışmalar bulunsa da (14–18) yüksek LDL seviyesi, obezite, hipertansiyon ve DM gibi metabolik sendromla ilişkili risk faktörlerinin BPH ya da AÜSS olasılığını ve şiddetini arttırdığı gösterilmiştir (19–24). Bundan başka epitelyal değişikliklerle artan fibroblast büyüme faktörü (FGF-2) prostat hiperplazisinden sorumlu tutulmuştur (25). Yine benzer deneysel çalışmalarda kontrollere kıyasla yüksek yağlı diyet ile beslenen ratların anlamlı prostat büyüklüğüne sahip oldukları, hücre proliferasyon belirteçlerinin arttığı anlaşılmıştır (26). İnflamatuar bir durum olarak kabul edilen metabolik sendromun prostat inflamasyonuna neden olduğu (27–30) prostatektomi materyallerinde inflamatuar infiltratif skorların metabolik sendrom, trigliserid (TG) ve azalmış HDL ile ilişkili olduğu gösterilmiştir (31). Yukarıda belirtildiği üzere proinflamatuar bir patoloji olarak kabul edilen metabolik sendromun IL-6, IL-8 ve hs-CRP gibi inflamatuar sitokinleri arttırdığı prostat stromasında da sekrete edilebilen yüksek serum IL-6 seviyelerinin prostatta inflamasyona neden olarak BPH riski ile ilişkili olabileceği bildirilmiştir (32–35). Gerçektende BPH’ı olan metabolik sendromlu olgulardan alınan örneklerde kontrollere göre artmış IL-6 seviye ve ekspresyonları görülmüştür (36,37). Bir çalışma serum CPR seviyelerinin BPH’lı olgularda AÜSS şiddeti, işeme volümü düşüklüğü, depolama semptomları bozukluğu ile ilişkili olduğunu göstermiştir. Çoklu değişkenli analizlerde ise IPSS depolama derecesinin bağımsız olarak artmış CRP ile ilişkili olduğu ortaya konulmuştur (33). Bundan başka biyoyararlı kolesterol seviyesindeki azalmanın membran sinyal yapılarını değiştirdiği ve prostatta apoptozisi indüklediği ileri sürülmektedir. Metabolik sendrom ve bununla ilişkili olan inflamasyon modifiye edilebilir risk faktörleridir.
... P=0.15). 64 in a prospective observational study conducted in icU prior statin users were found to have higher survival than non-statin users in the setting of ventilator associated pneumonia (VaP) after adjusting major confounders. 65 on the other hand, Dublin et al. 66 75 although there is some evidence of the beneficial outcome of statin following tBi, large rcts are needed to support the use of statin in patients with tBi. the dose (low or high) and type (either lipophilic or hydrophilic) of statins should be considered in the future comparative study. ...
Owing to statin's immune modulatory, anti-inflammatory, antioxidant, antithrombotic and endothelial function actions, they are widely used in the critical care settings in diverse disease scenarios. We aim to explore the evidence to globalize the utilization of statins in the intensive care practice for different indications. We carried out a search of the PubMed, Cochrane and EMBASE databases up to January 2016. We included review articles, meta-analyses, and original trials on the effects of statin therapy in the intensive care unit (ICU) combining the following MESH terms: 'satins', 'intensive care, 'cardiac surgery', 'sepsis', 'acute respiratory distress syndrome' 'pneumonia', subarachnoid hemorrhage', traumatic brain injury and 'critical illness'. Case reports were excluded. Language restrictions were not applied. References were looked at for other potentially useful articles. In conclusions, beneficial effects of statins utilization perceived in cardiac surgery; however, no robust proof supports its profit in diverse critical care settings. The decision of discontinuing statins in native users should be related to the clinical circumstances.
... This supports the hypothesis that pretreatment with statins may be more effective [5]. A metaanalysis of 13 studies involving 254,950 patients found that treatment with statins in community-acquired pneumonia was associated with improved survival but that the effect was more pronounced if treatment was initiated in the community prior to hospital admission [15]. This is supported by data that pretreatment with simvastatin attenuated the systemic and pulmonary inflammatory response to lipopolysaccharide (LPS) in healthy human subjects [10]. ...
... Taken together, compelling evidence to support statins in sepsis treatment is lacking, as is confident guidance on whether to continue statins during critical illness. found that statins were associated with a significant reduction in mortality, but also determined that no significant effect was found in prospective studies, and that the pooled Gabor effect was attenuated when studies were analyzed according to the inclusion of important confounders in their models [187]. Another meta-analysis of 18 studies found that statins were associated with a lower risk of developing CAP and with reduced short-term mortality in patients with CAP, but that publication bias was evident in the treatment group and that there was substantial heterogeneity among the included trials [188]. ...
It has become increasingly recognized that cholesterol and lipoproteins play significant roles in both lung physiology and the innate immune response. It is now known that the innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate their own replication. Given that over 50% of adults in the U.S. have cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance. This review addresses the emerging link between the innate immune response and sterol homeostasis, with a focus upon implications for respiratory infection. Clinical translations, including in the area of potential therapeutic development for infectious lung disease, are also discussed.
Background
There have been ongoing efforts to understand when and how data from observational studies can be applied to clinical and regulatory decision making. The objective of this review was to assess the comparability of relative treatment effects of pharmaceuticals from observational studies and randomized controlled trials (RCTs).
Methods
We searched PubMed and Embase for systematic literature reviews published between January 1, 1990, and January 31, 2020, that reported relative treatment effects of pharmaceuticals from both observational studies and RCTs. We extracted pooled relative effect estimates from observational studies and RCTs for each outcome, intervention-comparator, or indication assessed in the reviews. We calculated the ratio of the relative effect estimate from observational studies over that from RCTs, along with the corresponding 95% confidence interval (CI) for each pair of pooled RCT and observational study estimates, and we evaluated the consistency in relative treatment effects.
Results
Thirty systematic reviews across 7 therapeutic areas were identified from the literature. We analyzed 74 pairs of pooled relative effect estimates from RCTs and observational studies from 29 reviews. There was no statistically significant difference (based on the 95% CI) in relative effect estimates between RCTs and observational studies in 79.7% of pairs. There was an extreme difference (ratio < 0.7 or > 1.43) in 43.2% of pairs, and, in 17.6% of pairs, there was a significant difference and the estimates pointed in opposite directions.
Conclusions
Overall, our review shows that while there is no significant difference in the relative risk ratios between the majority of RCTs and observational studies compared, there is significant variation in about 20% of comparisons. The source of this variation should be the subject of further inquiry to elucidate how much of the variation is due to differences in patient populations versus biased estimates arising from issues with study design or analytical/statistical methods.
Objectives: We examined the role of statins in influenza and pneumonia associated 26 mortality and morbidity to inform policy for mitigating COVID-19. 27 Methods: Systematic search of electronic databases and hand searching of full text references 28 published up to 14 April 2021 were undertaken. Studies that explored the effectiveness of 29 statins (HMG-CoA reductase inhibitors) on influenza and/or pneumonia were included in this 30 systematic review. Quality of the included studies was assessed by an appropriate tool like 'risk 31 of bias's assessment tool of the Cochrane Handbook for randomised controlled trials (RCTs) 32 and Newcastle-Ottawa Scale (NOS) for observational studies. Protocol was registered with 33 Cochrane: https://www.cochranelibrary.com/cdsr/ Results: We included 37 papers with 38 studies with a total of 56,64,917 participants, of those 35 23 publications with a pooled sample of 521,511 were included in meta-analysis. Of the 37 36 included articles, there were 27 cohort studies, six case control studies, three RCTs and one 37 having both cohort and case control components. Our aggregated data suggest that the use of 38 statins had favorable effects on pneumonia 30-day mortality (RR 0.72, 95% CI 0.59 to 0.88), 39 pneumonia in-hospital mortality (RR 0.68, 95% CI 0.63 to 0.72) and pneumonia long-term all-40 cause mortality (RR 0.65, 95% CI 0.57to 0.73) but no benefit was detected for 41 hospitalisation (OR 1.29, 95% CI 0.88 to 1.90) intensive care unit (ICU) admission (RR 42 0.89, 95% CI 0.70 to 1.12) for pneumonia. 43 Conclusions: Statin use appears to reduce pneumonia mortality via their anti-inflammatory 44 and immunomodulatory capability but their effectiveness on influenza remains uncertain. The 45 use of statins in COVID-19 warrants further in-depth investigation including RCTs. 46
Purpose of review:
Coronavirus Disease 2019 (COVID19) has caused significant global morbidity and mortality, especially in persons with underlying cardiovascular disease. There have been concerns that lipid-lowering therapy (LLT) increases angiotensin-converting enzyme 2 levels. Conversely, pleiotropic effects of statins can theoretically protect against severe COVID19 infection, supporting evidence from other respiratory illnesses in which statin use probably confers benefit.
Recent findings:
There is an abundance of studies that show that statins are safe and potentially protect against severe COVID19 infection (critical illness and death), even when adjustment for potential confounders is undertaken. However, the evidence is limited to retrospective cohorts. The benefit for patients with diabetes is less clear. There is a paucity of evidence for other LLT agents. Available clinical guidelines recommend the ongoing use of LLT in patients with COVID19 (unless specifically contra-indicated) and the data from available studies support these.
Summary:
In patients with COVID19 infection, LLT should be continued. However, the current findings need substantiating in larger prospective clinical studies with specific examination of the possible mechanisms by which LLT confers benefit from COVID19.
Novel therapeutic options are needed to halt the unabated spread of multiple-drug resistance. Phage-derived proteins, especially enzymes that can degrade the bacterial cell wall and cause cell-lysis, offer an attractive new paradigm for treating serious drug-resistant infections. Recent research and clinical data on this class of anti-infective agents have revealed their novel properties. This chapter describes the development path for phage-derived lysins, starting with discovery and leading to the strategy into the clinic, with P128, a novel chimeric antistaphylococcal lysin, as example. Standard regulatory pathways that apply to chemical antibiotics need to be modified to accommodate and accelerate the development of this class. The similarities and differences between these macromolecular bactericidal agents, and the traditional small molecule antibiotics are highlighted throughout this chapter. The data-intensive exemplification of research and development of lysin P128 in this write-up is aimed at influencing all the stakeholders, research community, clinicians, patients, biopharma industry, and regulators, into capitalizing the benefits that lysins offer.
Current data suggests that infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) causing CoronaVIrus Disease-19 (COVID-19) seems to follow a more severe clinical course in patients with cardiovascular disease (CVD), hypertension and overweight/obesity. It appears that lipid-lowering pharmacological interventions, in particular statins, might reduce the risk of cardiovascular complications caused by COVID-19 and might potentially have an additional antiviral activity. It has been shown that high cholesterol levels are associated with more lipid rafts, subdomains of the plasma membrane that can harbour angiotensin-converting enzyme 2 (ACE-2) receptor for the S protein of SARS-CoV-2. Evidence of the importance of cholesterol for viral entry into host cells could suggest a role for cholesterol-lowering therapies in reducing viral infectivity. In addition to its lipid lowering and plaque stabilisation effects, statins possess pleiotropic effects including anti-inflammatory, immunomodulatory and anti-thrombotic activities. Lower rates of mortality and intubation have been reported in studies investigating statin therapy in influenza infection, and statin therapy was shown to increase viral clearance from the blood during chronic hepatitis C infection. Statin may also serve as potential SARS-CoV-2 main protease inhibitors, thereby contributing to the control of viral infection. In this review, we elaborate on the role of cholesterol level in the process of the coronavirus infection, and provide a critical appraisal on the potential of statin in reducing severity, duration and complications of COVID-19.
Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking.These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections.
Recommendations for the management of low-density lipoprotein cholesterol (LDL-C) and the strategy of statin therapy differ between current guidelines. We performed a prospective cohort study using data from the National Health and Nutrition Examination Survey from 1999 to 2010. For all-cause, cardiovascular, and noncardiovascular mortalities, we used Cox proportional hazards models to analyze unadjusted and multivariable-adjusted hazard ratios (HRs). We included age, gender, race and ethnicity, educational attainment, smoking status, body mass index, previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, high-density lipoprotein cholesterol levels, log-transferred triglyceride levels, estimated glomerular filtration rate levels, and the presence or absence of macroalbuminuria for the adjustment. The present study included 1,500 patients with LDL-C levels of <120 mg/dl (mean LDL-C level 88.7 mg/dl) who were at high risk of cardiovascular disease. A total of 99% patients completed the follow-up. Using multivariable Cox proportional hazards models, all-cause mortality was significantly lower in patients receiving statins than in those not on statins (HR 0.62, 95% confidence interval 0.45 to 0.85, p = 0.004). Analyses limited to propensity score-matched patients and patients with LDL-C levels of <100 mg/dl (mean LDL-C level 78.6 mg/dl) showed similar results. All-cause mortality in patients receiving statins was not significantly lower in those with LDL-C levels of <70 mg/dl than in those with LDL-C levels of 70 to 120 mg/dl (HR 1.27, 95% confidence interval 0.76 to 2.10, p = 0.35). In conclusion, statin therapy was effective in reducing all-cause death in high-risk patients, even with low levels of LDL-C. All-cause mortality did not differ between patients receiving statins with lower levels of LDL-C.
The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.
Purpose of review:
Here, we review the incidence, prognosis, potential mechanisms and therapeutic implications of cardiovascular disease in community-acquired pneumonia (CAP).
Recent findings:
Recent evidence suggests that a large proportion of deaths from CAP are attributable to cardiovascular disease, including sudden cardiac death, acute myocardial infarction (MI), arrhythmias and cardiac failure. Up to one-third of patients with CAP may experience cardiovascular complications within 30 days of hospital admission, while data also suggest that CAP managed in the community is associated with increased risk of acute MI. The risk is maximal within a few days of hospitalization with CAP and reduces over time. Most studies suggest that risk is still increased at 1 year, and some suggest risk continues to be increased at 10 years post-CAP. This clearly contributes to the well-recognized increased long-term mortality associated with CAP. The mechanism is not entirely clear, but recent published data have better defined the impact of the host response, including systemic inflammation and platelet activation. The contribution of Streptococcus pneumoniae has also been recently investigated, with animal studies suggesting a direct effect of S. pneumoniae on the myocardium, forming microlesions that heal with resulting myocardial fibrosis. Several studies suggest a key role for the pore-forming toxin pneumolysin in S. pneumoniae-induced cardiac toxicity.
Summary:
Several therapies have been shown to improve the outcomes in cardiovascular disease, but whether these would be effective in improving outcomes in CAP is unknown. In this review, we argue that cardioprotective treatments may hold the greatest promise in terms of reducing long-term mortality in patients with CAP.
Angiotensin converting enzyme inhibitors (ACEIs) and statins have been identified to have possible beneficial effects in the management of pneumonia. ACEIs have been shown to increase cough and reduce dysphagia-two mechanisms that could reduce susceptibility to pneumonia. Studies have found a reduction in pneumonia incidence in those taking ACEIs however overall benefit remains unproven. The reason for this is that studies have only been conducted in those with risk factors requiring ACEI treatment. Statins have multiple cellular effects that could be beneficial in pneumonia. Benefit in animal studies has been shown. While associations between statin use and both reduced pneumonia incidence and better outcomes have been found the results are not consistent between studies and a causal effect has not been proven. Randomised controlled trials in the general population, with pneumonia as an endpoint, are required for both ACEIs and statins to determine whether beneficial effects from such treatments in pneumonia occur.
Background
To our knowledge, no previous study has systematically examined pneumonia-related and pneumonia-unrelated mortality. This study was performed to identify the cause(s) of death and to compare the timing and risk factors associated with pneumonia-related and pneumonia-unrelated mortality.
Methods
For all deaths within 90 days of presentation, a synopsis of all events preceding death was independently reviewed by 2 members of a 5-member review panel (C.M.C., D.E.S., T.J.M., W.N.K., and M.J.F.). The underlying and immediate causes of death and whether pneumonia had a major, a minor, or no apparent role in the death were determined using consensus. Death was defined as pneumonia related if pneumonia was the underlying or immediate cause of death or played a major role in the cause of death. Competing-risk Cox proportional hazards regression models were used to identify baseline characteristics associated with mortality.
Results
Patients (944 outpatients and 1343 inpatients) with clinical and radiographic evidence of pneumonia were enrolled, and 208 (9%) died by 90 days. The most frequent immediate causes of death were respiratory failure (38%), cardiac conditions (13%), and infectious conditions (11%); the most frequent underlying causes of death were neurological conditions (29%), malignancies (24%), and cardiac conditions (14%). Mortality was pneumonia related in 110 (53%) of the 208 deaths. Pneumonia-related deaths were 7.7 times more likely to occur within 30 days of presentation compared with pneumonia-unrelated deaths. Factors independently associated with pneumonia-related mortality were hypothermia, altered mental status, elevated serum urea nitrogen level, chronic liver disease, leukopenia, and hypoxemia. Factors independently associated with pneumonia-unrelated mortality were dementia, immunosuppression, active cancer, systolic hypotension, male sex, and multilobar pulmonary infiltrates. Increasing age and evidence of aspiration were independent predictors of both types of mortality.
Conclusions
For patients with community-acquired pneumonia, only half of all deaths are attributable to their acute illness. Differences in the timing of death and risk factors for mortality suggest that future studies of community-acquired pneumonia should differentiate all-cause and pneumonia-related mortality.
Because of the pressure for timely, informed decisions in public health and clinical practice and the explosion of information in the scientific literature, research results must be synthesized. Meta-analyses are increasingly used to address this problem, and they often evaluate observational studies. A workshop was held in Atlanta, Ga, in April 1997, to examine the reporting of meta-analyses of observational studies and to make recommendations to aid authors, reviewers, editors, and readers.
Twenty-seven participants were selected by a steering committee, based on expertise in clinical practice, trials, statistics, epidemiology, social sciences, and biomedical editing. Deliberations of the workshop were open to other interested scientists. Funding for this activity was provided by the Centers for Disease Control and Prevention.
We conducted a systematic review of the published literature on the conduct and reporting of meta-analyses in observational studies using MEDLINE, Educational Research Information Center (ERIC), PsycLIT, and the Current Index to Statistics. We also examined reference lists of the 32 studies retrieved and contacted experts in the field. Participants were assigned to small-group discussions on the subjects of bias, searching and abstracting, heterogeneity, study categorization, and statistical methods.
From the material presented at the workshop, the authors developed a checklist summarizing recommendations for reporting meta-analyses of observational studies. The checklist and supporting evidence were circulated to all conference attendees and additional experts. All suggestions for revisions were addressed.
The proposed checklist contains specifications for reporting of meta-analyses of observational studies in epidemiology, including background, search strategy, methods, results, discussion, and conclusion. Use of the checklist should improve the usefulness of meta-analyses for authors, reviewers, editors, readers, and decision makers. An evaluation plan is suggested and research areas are explored.
Community-acquired pneumonia is one of the most common causes of hospitalisation and death in older people. Recent research suggests that statins might improve the outcome of infectious diseases because of their anti-oxidative and anti-inflammatory properties.
To estimate the association between current statin use and the risk of community-acquired pneumonia.
Nested case-control study of 443 general practices in the UK within the QResearch® database.
Individuals with newly recorded pneumonia, diagnosed between 1996 and 2006 and aged 45 years and older, were matched with up to five controls by age, sex, general practice, and calendaryear Odds ratios for pneumonia associated with statin use were adjusted for smoking status, deprivation, comorbidities, use of acid-lowering drugs, influenza, and pneumococcal vaccines.
The analysis found a decreased risk of pneumonia in patients prescribed statins in the year prior to diagnosis (adjusted odds ratio = 0.78, 95% confidence interval [CI] = 0.74 to 0.83), particularly in patients with prescriptions in the last 28 days (adjusted odds ratio = 0.68, 95% CI = 0.63 to 0.73). Atorvastatin and simvastatin had similar associations with pneumonia risk. Analysis repeated on lobar and pneumococcal pneumonia cases showed comparable results.
In this large population-based case-control study, current exposure to statins was associated with a reduced risk of pneumonia. The findings were similar to other observational population-based studies, but further randomised controlled trials are necessary before recommending statins to patients at high risk of pneumonia.
Statins are prescribed to lower cholesterol, but also have anti-inflammatory properties. Some observational studies suggest that statins may reduce mortality from sepsis.
Using a highly detailed administrative database, we conducted an observational cohort study of all patients aged ≥18 years who received a discharge diagnosis of pneumonia from 2003-2005 at 376 hospitals. Patients with contraindications to statins, and those unable to take oral medications or discharged within 2 days were excluded. We used multivariable logistic regression and propensity matching to compare mortality among patients who did and did not receive statins on hospital day 1 or 2.
Of the 121,254 patients who met the inclusion criteria, median age was 74; 56% were female and 70% were white; 19% received a statin on day 1 or 2. Compared to patients who did not receive statins, statin-treated patients were less likely to be admitted to intensive care (15.7% vs 18.1%, p < 0.001), require mechanical ventilation (6.9% vs. 9.3%, p < 0.001), or die in hospital (3.9% vs 5.7%, p < 0.001). After multivariable adjustment, including the propensity for statin treatment and severity at presentation, mortality was lower in statin-treated patients [OR for propensity-adjusted 0.86 (95% CI 0.79 to 0.93) OR for propensity-matched 0.90, (0.82 to 0.99)]. For patients admitted to intensive care the adjusted odds ratio for mortality with statins was 0.93 (95% CI 0.81 to 1.06), whereas outside intensive care it was 0.79 (95% CI 0.71 to 0.87).
Inpatient treatment with statins is associated with a modest reduction in pneumonia mortality outside of intensive care.
Pneumonia, along with influenza, is currently the eighth leading overall cause of death in the USA, and is the leading cause of infectious death [1]. However, this only considers the immediate impact of an episode of pneumonia on mortality. Almost all research on pneumonia has focused on mortality in the first 30–90 days after presentation [2]. However, there is growing interest in the effects of pneumonia after this immediate period. Sir William Osler famously remarked in his Principals and Practices of Medicine , “Pneumonia may well be called the friend of the aged. Taken off by it in an acute, short, not often painful illness, the old male escapes those cold gradations of decay so distressing to himself and to his friends” [3]. Although this may have been the case prior to the advent of antimicrobial therapy in the 1940s, recent studies have cast this assertion into serious doubt.
In 1998, Brancati et al. [4] published a study examining 141 patients hospitalised for pneumonia. They found that 16% died during the initial hospitalisation and that an additional 32% of the cohort, who survived until discharge, died within the next 24 months. Although this increased mortality was associated with …
David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
Better evidence than can be provided by observational studies is needed to determine the association
To determine whether statins protect against all cause mortality after a diagnosis of pneumonia.
Cohort study using propensity score based method to control for differences between people prescribed and not prescribed statins.
United Kingdom Health Improvement Network database, which contains electronic primary care medical records of more than six million patients.
Every patient starting a statin between 1995 and 2006 (129,288) matched with up to five non-statin users (n = 600,241); 9073 patients had a recorded diagnosis of pneumonia, of whom 1398 were using a statin.
All cause mortality within six months of diagnosis of pneumonia.
Among users and non-users of statins with comparable propensity scores, 95/942 users and 686/3615 non-users died on the day that pneumonia was diagnosed. In the following six month period, 109/847 statin users died compared with 578/2927 non-users, giving an adjusted hazard ratio of 0.67 (0.49 to 0.91). If these observed benefits translated into clinical practice, 15 patients would need to be treated with a statin for six months after pneumonia to prevent one death.
Compared with people who were not taking statins, the risk of dying in the six month period after pneumonia was substantially lower among people who were already established on long term statin treatment when the pneumonia occurred. Whether some or all of this protective effect would be obtained if statin treatment begins when a patient first develops pneumonia is not known. However, given that statins are cheap, safe, and well tolerated, a clinical trial in which people with pneumonia are randomised to a short period of statin treatment is warranted.
David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
Limited data are available on the impact of time to ICU admission and outcomes for patients with severe community acquired pneumonia (CAP). Our objective was to examine the association of time to ICU admission and 30-day mortality in patients with severe CAP.
A retrospective cohort study of 161 ICU subjects with CAP (by International Classification of Diseases, 9th edition, codes) was conducted over a 3-year period at two tertiary teaching hospitals. Timing of the ICU admission was dichotomized into early ICU admission (EICUA, direct admission or within 24 h) and late ICU admission (LICUA, >or= day 2). A multivariable analysis using Cox proportional hazard model was created with the primary outcome of 30-day mortality (dependent measure) and the American Thoracic Society (ATS) severity adjustment criteria and time to ICU admission as the independent measures.
Eighty-eight percent (n = 142) were EICUA patients compared with 12% (n = 19) LICUA patients. Groups were similar with respect to age, gender, comorbidities, clinical parameters, CAP-related process of care measures, and need for mechanical ventilation. LICUA patients had lower rates of ATS severity criteria at presentation (26.3% vs 53.5%; P = .03). LICUA patients (47.4%) had a higher 30-day mortality compared with EICUA (23.2%) patients (P = .02), which remained after adjusting in the multivariable analysis (hazard ratio 2.6; 95% CI, 1.2-5.5; P = .02).
Patients with severe CAP with a late ICU admission have increased 30-day mortality after adjustment for illness severity. Further research should evaluate the risk factors associated and their impact on clinical outcomes in patients admitted late to the ICU.
Emerging epidemiological evidence suggests that statin use may reduce the risk of infections and infection-related complications. Our objective was to examine the association between statin use and the risk of infections and related outcomes.
We searched several electronic databases from inception through December 2007 for randomized trials and cohort studies that examined the association between statin use and the risk or outcome of infections. Data on study characteristics, measurement of statin use, outcomes (adjusted for potential confounders), and quality assessment were extracted.
Sixteen cohorts were eligible and differed in representativeness, outcome assessment, and comparability of exposed (statin) and unexposed (nonstatin) groups. Nine cohorts addressed the role of statins in treating infections: bacteremia (n = 3), pneumonia (n = 3), sepsis (n = 2), and bacterial infection (n = 1). The pooled adjusted effect estimate was 0.55 (95% confidence interval, 0.36-0.83; I(2) = 76.5%) in favor of statins. Seven cohorts addressed infection prevention in patients with vascular diseases (n = 3), chronic kidney disease (n = 1), diabetes (n = 1), intensive care unit-acquired infections (n = 1), and in general practice (n = 1). The pooled effect estimate was 0.57 (95% confidence interval, 0.43-0.75; I(2) = 82%) in favor of statin use; there was some evidence of publication bias for this analysis (Egger test; P = .07). Meta-regression did not identify potential effect modifiers that explain the between-study heterogeneity.
Results for our meta-analysis suggest that statin use may be associated with a beneficial effect in treating and preventing different infections. Given the presence of heterogeneity and publication bias, there is a need for randomized trials to confirm the benefit of statin use in this context.
To test the hypothesis that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) may decrease the risk of community acquired pneumonia.
Population based case-control study.
Group Health, a large integrated healthcare delivery system. Population Immunocompetent, community dwelling Group Health members aged 65 to 94; two matched controls for each case with pneumonia. Information on comorbid illnesses and functional and cognitive status, potential confounders of the association between statin use and risk of pneumonia, came from medical record review and computerised pharmacy data.
Adjusted estimates of risk of pneumonia in relation to current statin use.
1125 validated cases of pneumonia and 2235 matched controls were identified. Compared with controls, cases were more likely to have chronic lung and heart disease, especially severe disease, and functional or cognitive impairment. Current statin use was present in 16.1% (181/1125) of cases and 14.6% (327/2235) of controls (adjusted odds ratio 1.26, 95% confidence interval 1.01 to 1.56). Among cases admitted to hospital and matched controls, current statin use was present in 17.2% (68/395) of cases and 14.2% (112/788) of controls (adjusted odds ratio 1.61, 1.08 to 2.39, compared with non-use). In people in whom statins were indicated for secondary prevention, the adjusted odds ratio for risk of pneumonia in relation to current statin use was 1.25 (0.94 to 1.67); in those with no such indication, it was 0.81 (0.46 to 1.42).
Statin use was not associated with decreased risk of pneumonia among immunocompetent, community dwelling older people. Findings of previous studies may reflect "healthy user" bias.
To our knowledge, no previous study has systematically examined pneumonia-related and pneumonia-unrelated mortality. This study was performed to identify the cause(s) of death and to compare the timing and risk factors associated with pneumonia-related and pneumonia-unrelated mortality.
For all deaths within 90 days of presentation, a synopsis of all events preceding death was independently reviewed by 2 members of a 5-member review panel (C.M.C., D.E.S., T.J.M., W.N.K., and M.J.F.). The underlying and immediate causes of death and whether pneumonia had a major, a minor, or no apparent role in the death were determined using consensus. Death was defined as pneumonia related if pneumonia was the underlying or immediate cause of death or played a major role in the cause of death. Competing-risk Cox proportional hazards regression models were used to identify baseline characteristics associated with mortality.
Patients (944 outpatients and 1343 inpatients) with clinical and radiographic evidence of pneumonia were enrolled, and 208 (9%) died by 90 days. The most frequent immediate causes of death were respiratory failure (38%), cardiac conditions (13%), and infectious conditions (11%); the most frequent underlying causes of death were neurological conditions (29%), malignancies (24%), and cardiac conditions (14%). Mortality was pneumonia related in 110 (53%) of the 208 deaths. Pneumonia-related deaths were 7.7 times more likely to occur within 30 days of presentation compared with pneumonia-unrelated deaths. Factors independently associated with pneumonia-related mortality were hypothermia, altered mental status, elevated serum urea nitrogen level, chronic liver disease, leukopenia, and hypoxemia. Factors independently associated with pneumonia-unrelated mortality were dementia, immunosuppression, active cancer, systolic hypotension, male sex, and multilobar pulmonary infiltrates. Increasing age and evidence of aspiration were independent predictors of both types of mortality.
For patients with community-acquired pneumonia, only half of all deaths are attributable to their acute illness. Differences in the timing of death and risk factors for mortality suggest that future studies of community-acquired pneumonia should differentiate all-cause and pneumonia-related mortality.
Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
Statins have anti-inflammatory properties that are independent of their lipid-lowering abilities. We hypothesized that statin therapy before the onset of an acute bacterial infection may have a protective effect against severe sepsis. The aim of this study was to determine whether patients treated with statins develop severe sepsis less frequently.
In this prospective observational cohort study, consecutive patients admitted with presumed or documented acute bacterial infection were enrolled. The primary outcomes were the rate of severe sepsis and intensive care unit (ICU) admission. Of the 361 patients enrolled, 82 (22.7%) were treated with statins before their admission. Both groups had a similar severity of illness on admission. Severe sepsis developed in 19% of patients in the no-statin group and in only 2.4% of the statin group (P<0.001). Statin treatment was associated with a relative risk of developing severe sepsis of 0.13 (95% CI, 0.03 to 0.52) and an absolute risk reduction of 16.6%. The overall ICU admission rate was 10.2% (37/361): 12.2% of the no-statin group required ICU admission, whereas in the statin group only 3.7% were admitted to the ICU (P=0.025), reflecting a relative risk of ICU admission of 0.30 (95% CI, 0.1 to 0.95).
Prior therapy with statins may be associated with a reduced rate of severe sepsis and ICU admission. If supported by prospective controlled trials, statins may have a role in the primary prevention of sepsis.
Recent studies suggest that HMG-CoA reductase inhibitors ("statins") may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of statins on mortality for patients hospitalized with community-acquired pneumonia.
A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation.
Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk based on the pneumonia severity index. In the multivariable regression analysis, after adjusting for potential confounders including a propensity score, the use of statins at presentation (odds ratio 0.36, 95% confidence interval 0.14-0.92) was associated with decreased 30-day mortality.
Prior outpatient statin use was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect.
Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of ACE inhibitors on mortality for patients hospitalized with community-acquired pneumonia.
A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation.
Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk. In the multivariable conditional logistic regression analysis, after adjusting for potential confounders, the use of ACE inhibitors at presentation (odds ratio 0.44, 95% confidence interval 0.22-0.89) was significantly associated with 30-day mortality.
Prior outpatient use of an ACE inhibitor was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect.
Pneumonia causes significant mortality and morbidity among persons aged 65 years or older. However, few studies have explored trends according to age groups, which may affect intervention strategies.
To examine trends in hospitalizations for pneumonia among persons aged 65 years or older and to compare characteristics, outcomes, and comorbid diagnoses.Design, Setting, and
Data from 1988 through 2002 on pneumonia and comorbid diagnoses among patients aged 65 to 74 years, 75 to 84 years, and 85 years or older from the National Hospital Discharge Survey.
Hospitalization rates by first-listed and any-listed discharge codes for pneumonia; proportions of hospitalizations reporting comorbid diagnoses for the 3 age groups (65-74 years, 75-84 years, > or =85 years).
Hospitalization rates by both first-listed and any-listed discharge codes for pneumonia increased by 20% from 1988-1990 to 2000-2002 for patients aged 65 to 74 years (P = .01) and for patients aged 75 to 84 years (P<.001). Rates of hospitalization for pneumonia were 2-fold higher for patients aged 85 years or older (51 per 1000 population for first-listed discharge code of pneumonia; 95% confidence interval [CI], 46-55 per 1000 population) than among patients aged 75 to 84 years (26 per 1000 population; 95% CI, 24-28 per 1000 population), but did not significantly increase from 1988-1990 to 2000-2002. The proportion of patients aged 65 years or older diagnosed with pneumonia and a chronic cardiac disease, chronic pulmonary disease, or diabetes mellitus increased from 66% (SE, 1.0%) in 1988-1990 to 77% (SE, 0.8%) in 2000-2002. The risk of death during a hospitalization for pneumonia compared with the risk of death during a hospital stay for the 10 other most frequent causes of hospitalization was 1.5 (95% CI, 1.4-1.7) and remained constant from 1988-1990 to 2000-2002.
Hospitalization rates for pneumonia have increased among US adults aged 64 to 74 years and aged 75 to 84 years during the past 15 years. Among those aged 85 years or older, at least 1 in 20 patients were hospitalized each year due to pneumonia. Concomitantly, the proportion of comorbid chronic diseases has increased. Efforts to prevent pneumonia should include reducing preventable comorbid conditions and improving vaccine effectiveness and vaccination programs in elderly persons.
Recent prognostic studies have shown that previous treatment with statins is associated with a better outcome in patients admitted to hospital with pneumonia. Because of an increased risk of pneumonia in patients with diabetes, we assessed the effects of statin use on the occurrence of pneumonia in adult diabetic patients.
All patients with a diagnosis of diabetes (types 1 and 2) enlisted in the UK General Practice Research Database between 1 June 1987 and 21 January 2001 were included. A case-control study was performed with cases defined as patients with a first recorded diagnosis of pneumonia. For each case up to four controls were matched by age, sex, practice, and index date. Patients were classified as current users when the index date was between the start and end date of statin treatment. Conditional multiple logistic regression analysis was used to estimate the strength of the association between statin treatment and the occurrence of pneumonia.
Statins were used in 1.1% of 4719 cases and in 2.1% of 15 322 matched controls (crude odds ratio (OR) 0.51, 95% CI 0.37 to 0.68). After adjusting for potential confounders, treatment with statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.49, 95% CI 0.35 to 0.69). The association was consistent among relevant subgroups (cardiovascular diseases, pulmonary diseases) and independent of the use of other prescription drugs.
The use of statins is associated with a considerable reduction in the risk of pneumonia in diabetic patients. In addition to lowering the risk of cardiovascular disease, statins may be useful in preventing respiratory infections.
To determine whether statins reduce mortality or need for admission to intensive care in patients admitted to hospital with community acquired pneumonia; and to assess whether previously reported improvements in sepsis related outcomes were a result of the healthy user effect.
Population based prospective cohort study.
Six hospitals in Capital Health, Edmonton, Alberta, Canada.
Adults admitted to hospital with pneumonia and categorised according to use of statins for at least one week before admission and during hospital stay.
Composite of in-hospital mortality or admission to an intensive care unit.
Of 3415 patients with pneumonia admitted to hospital, 624 (18%) died or were admitted to an intensive care unit. Statin users were less likely to die or be admitted to an intensive care unit than non-users (50/325 (15%) v 574/3090 (19%), odds ratio 0.80, P=0.15). After more complete adjustment for confounding, however, the odds ratios changed from potential benefit (0.78, adjusted for age and sex) to potential harm (1.10, fully adjusted including propensity scores, 95% confidence interval 0.76 to 1.60).
Statins are not associated with reduced mortality or need for admission to an intensive care unit in patients with pneumonia; reports of benefit in the setting of sepsis may be a result of confounding.
To determine if the use of statins affects pneumonia-related outpatient visits, hospitalizations with survival, and deaths.
Population-based, retrospective, nested case-control analysis.
United Kingdom-based General Practice Research Database.
The study population (134,262 patients aged > or = 30 yrs) consisted of 55,118 patients who took statins and/or fibrates, 29,144 patients with hyperlipidemia not taking lipid-lowering agents, and 50,000 randomly selected patients without hyperlipidemia and without lipid-lowering treatment.
We identified 1253 patients with pneumonia and matched them with 4838 control subjects based on age, sex, general practice, and index date. After adjusting for comorbidity and frequency of visits to general practitioners, we calculated the risks (odds ratios with 95% confidence intervals) of uncomplicated pneumonia, hospitalization for pneumonia with survival, and fatal pneumonia in participants who used statins compared with those who did not. Current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25-0.88) and slightly but not significantly reduced risks of uncomplicated pneumonia and pneumonia hospitalization with survival. Recent or past statin use and fibrate use at any time were not associated with a reduced risk of pneumonia.
Current use of statins was associated with a reduced risk of pneumonia. The risk reduction was particularly strong in the subgroup of patients with fatal pneumonias.
Error in Figure Legends. In the article titled “Statins for the Prevention and Treatment of Infections: A Systematic Review and Meta-analysis” by Tleyjeh et al, published in the October 12, 2009, issue of the Archives (2009;169[18]:1658-1667), the figure legends for Figures 3 and 4 were mistakenly switched. The legend for Figure 3 on page 1664 should read as follows: “Contoured funnel plot for treatment cohorts. Ln indicates natural logarithm.” The legend for Figure 4 on page 1665 should read as follows: “Contoured funnel plot for prevention cohorts. Ln indicates natural logarithm.”
The Cochrane Handbook for Systematic Reviews of Interventions (the Handbook) has undergone a substantial update, and Version 5 of the Handbook is now available online at www.cochrane-handbook.org and in RevMan 5. In addition, for the first time, the Handbook will soon be available as a printed volume, published by Wiley-Blackwell. We are anticipating release of this at the Colloquium in Freiburg. Version 5 of the Handbook describes the new methods available in RevMan 5, as well as containing extensive guidance on all aspects of Cochrane review methodology. It has a new structure, with 22 chapters divided into three parts. Part 1, relevant to all reviews, introduces Cochrane reviews, covering their planning and preparation, and their maintenance and updating, and ends with a guide to the contents of a Cochrane protocol and review. Part 2, relevant to all reviews, provides general methodological guidance on preparing reviews, covering question development, eligibility criteria, searching, collecting data, within-study bias (including completion of the Risk of Bias table), analysing data, reporting bias, presenting and interpreting results (including Summary of Findings tables). Part 3 addresses special topics that will be relevant to some, but not all, reviews, including particular considerations in addressing adverse effects, meta-analysis with non-standard study designs and using individual participant data. This part has new chapters on incorporating economic evaluations, non-randomized studies, qualitative research, patient-reported outcomes in reviews, prospective meta-analysis, reviews in health promotion and public health, and the new review type of overviews of reviews.
To investigate whether the use of pravastatin reduces the frequency of ventilator-associated pneumonia and whether it is related to favorable outcomes in critical care patients.
Two-center, two-arm, randomized, open-label, controlled trial.
University Hospital and General Hospital of Larissa, Greece.
Consecutive patients were recruited from the intensive care units of the two hospitals. Patient inclusion criteria included mechanical ventilation and intensive care unit stay of >48 hrs.
The two arms consisted of treatment plus oral pravastatin sodium (40 mg) (n = 71 patients, pravastatin group) and treatment without pravastatin (n = 81 patients, control group). Treatment was started after randomization and ended 30 days later.
Ventilator-associated pneumonia frequency and intensive care unit mortality at 30 days and at the end of intensive care unit stay were measured. Adverse events related to statin treatment in the intensive care unit were documented. Sixteen patients (22.5%) in the pravastatin group and 28 (34.5%) in the control group (p = .11) presented pneumonia during the 30-day treatment period in the intensive care unit. There was an indication for increased probability of being free from ventilator-associated pneumonia during the 30-day treatment period in the pravastatin group compared to the control group (p = .06) and significantly increased probability during the whole intensive care unit period of stay (p = .04) in the pravastatin group compared to the control group in the subgroup of patients with Acute Physiology and Chronic Health Evaluation scores of ≥ 15. Six patients (8.45%) in the pravastatin group and 16 (19.85%) in the control group died during the 30-day treatment period (p = .06), whereas 10 (14.1%) patients in the pravastatin group and 24 (29.1%) patients in the control group died during the whole period of intensive care unit stay (p = .03). Pravastatin group patients with Acute Physiology and Chronic Health Evaluation scores of ≥ 15 had significantly increased probability of survival compared to controls during the 30-day treatment period (p = .04). Creatine kinase and hepatic function enzyme levels during the whole study period were not significantly different between the pravastatin group and control group.
This study provides evidence that pravastatin may favorably affect the outcome of critical care patients.
Published data on antiinflammatory and immunomodulatory effects of statins suggest they may reduce mortality risks associated with an unchecked immune response to selected infections, including influenza and COPD. We assessed whether statin users had reduced mortality risks from these conditions.
We conducted a matched cohort study (n = 76,232) and two separate case-control studies (397 influenza and 207 COPD deaths) to evaluate whether statin therapy is associated with increased or decreased mortality risk and survival time using health-care encounter data for members of health maintenance organizations. For the cohort study, baseline illness risks from all causes prior to initiation of statin therapy were used to statistically adjust for the occurrence of outcomes after initiation of treatment.
For moderate-dose (>/= 4 mg/d) statin users, this cohort study found statistically significant reduced odds ratios (ORs) of influenza/pneumonia death (OR, 0.60; 95% confidence interval [CI], 0.44 to 0.81) and COPD death (OR, 0.17; 95% CI, 0.07 to 0.42) and similarly reduced survival hazard ratios. Findings were confirmed with the case-control studies. Confounding factors not considered may explain some of the effects observed.
This study found a dramatically reduced risk of COPD death and a significantly reduced risks of influenza death among moderate-dose statin users.
National practice guidelines have recommended specific initial empiric antimicrobial regimens for patients with community-acquired pneumonia. Our aim was to determine the association between the use of guideline-concordant antimicrobial therapy and 30-day mortality in patients with pneumonia.
We conducted a retrospective cohort study at two tertiary teaching hospitals. Eligible patients were admitted with a diagnosis of community-acquired pneumonia, had a chest radiograph consistent with pneumonia, and had a discharge diagnosis of pneumonia. All eligible patients were identified and a random sample was abstracted. We determined whether the use of guideline-concordant antibiotics was associated with 30-day mortality in an analysis that adjusted for potential confounders using propensity scores.
Information was obtained on 420 patients with pneumonia. The mean (+/- SD) age was 63 +/- 16 years, 355 were men, and 82 patients were initially admitted to the intensive care unit. At 30 days after presentation, 41 patients (9.8%) had died: 21 of 97 (21.7%) in the non-guideline-concordant group and 20 of 323 (6.2%) in the guideline-concordant group. Antibiotics were concordant with national guidelines in 323 patients. In the regression analysis, after adjustment for the propensity score, failure to comply with antimicrobial therapy guidelines was associated with increased 30-day mortality (odds ratio = 5.7; 95% confidence interval: 2.0 to 16.0).
Receipt of antimicrobial regimens concordant with national published guidelines may reduce 30-day mortality among patients hospitalized with pneumonia.
To examine the association of statin use with clinical outcomes and circulating biomarkers in community-acquired pneumonia and sepsis.
Multicenter inception cohort study.
Emergency departments of 28 U.S. hospitals.
A total of 1895 subjects hospitalized with community-acquired pneumonia.
None.
Our approach consisted of two different comparison cohorts, each reflecting methods used in prior publications in this area. We first compared subjects with prior statin use (prior use cohort), defined as a history of statin use in the week before admission, with those with no prior use. We then compared prior statin users whose statins were continued inhospital (continued use cohort) with those with either no prior use or no inhospital use. We adjusted for patient characteristics, including demographics, comorbid conditions, and illness severity, and accounted for healthy user effect and indication bias using propensity analysis. We determined risk of severe sepsis and 90-day mortality. We measured markers inflammation (tumor necrosis factor, interleukin-6, interleukin-10), coagulation (antithrombin, factor IX, plasminogen activator inhibitor, d-dimer, thrombin antithrombin complex), and lymphocyte cell surface protein expression during the first week of hospitalization. There were no differences in severe sepsis risk between statin users and nonusers for prior (30.8% vs. 30.7%, p = .98) or continued statin use (30.2% vs. 30.8%, p = .85) in univariate analyses and after adjusting for patient characteristics and propensity for statin use. Ninety-day mortality was similar in prior statin users (9.2% vs. 12.0%, p = .11) and lower in continued statin users (7.9% vs. 12.1%, p = .02). After adjusting for patient characteristics and propensity for statin use, there was no mortality benefit for prior (odds ratio, 0.90 [0.63-1.29]; p = .57) or continued statin use (odds ratio, 0.73 [0.47-1.13]; p = .15). Only antithrombin activity over time was higher in statin subjects, yet the magnitude of the difference was modest. There were no differences in other coagulation, inflammatory, or lymphocyte cell surface markers.
We found no evidence of a protective effect for statin use on clinical outcomes and only modest differences in circulating biomarkers in community-acquired pneumonia, perhaps as a result of healthy user effects and indication bias.
Healthcare-associated pneumonia (HCAP) guidelines were first proposed in 2005 but have not yet been validated. The objective of this study was to compare 30-day mortality in HCAP patients treated with either guideline-concordant (GC)-HCAP therapy or GC community-acquired pneumonia (CAP) therapy. We performed a population-based cohort study of >150 hospitals in the US Veterans Health Administration. Patients were included if they had one or more HCAP risk factors and received antibiotic therapy within 48 h of admission. Critically ill patients were excluded. Independent risk factors for 30-day mortality were determined in a generalised linear mixed-effect model, with admitting hospital as a random effect. Propensity scores for the probability of receiving GC-HCAP therapy were calculated and incorporated into a second logistic regression model. A total of 15,071 patients met study criteria and received GC-HCAP therapy (8.0%), GC-CAP therapy (75.7%) or non-GC therapy (16.3%). The strongest predictors of 30-day mortality were recent hospital admission (OR 2.49, 95% CI 2.12-2.94) and GC-HCAP therapy (OR 2.18, 95% CI 1.86-2.55). GC-HCAP therapy remained an independent risk factor for 30-day mortality (OR 2.12, 95% CI 1.82-2.48) in the propensity score analysis. In nonsevere HCAP patients, GC-HCAP therapy is not associated with improved survival compared with GC-CAP therapy.
Several studies have suggested an increased risk of cardiovascular events, primarily acute myocardial infarction, around the time of hospital admission for pneumonia. Therefore, we examined cardiovascular events, including myocardial infarction, congestive heart failure, unstable angina, stroke, and serious cardiac arrhythmias, within 90 days after hospitalization for pneumonia.
By using data from the administrative databases of the Department of Veterans Affairs, we examined a cohort of subjects hospitalized with pneumonia between October 2001 and September 2007. Subjects were at least 65 years of age. We examined the incidence of myocardial infarction, congestive heart failure, cardiac arrhythmias, unstable angina, and stroke by International Classification of Diseases, Ninth Revision codes, excluding those with a diagnosis before the admission for pneumonia.
The cohort comprised 50,119 subjects with a mean age of 77.5 years (standard deviation 6.7 years), 98% of whom were male. The 90-day incidence of cardiovascular events was 1.5% for myocardial infarction, 10.2% for congestive heart failure, 9.5% for arrhythmia, 0.8% for unstable angina, and 0.2% for stroke. The majority of events occurred during the hospitalization for pneumonia.
A clinically important number of subjects in this cohort had a cardiovascular event within 90 days of hospital admission, suggesting that such events may have an important role in post-pneumonia mortality. Additional research is needed to determine whether interventions may reduce the number of cardiovascular events after pneumonia.
Community-acquired pneumonia is the most common infectious cause of death in the US. Over the last 2 decades, patient characteristics and clinical care have changed. To understand the impact of these changes, we quantified incidence and mortality trends among elderly adults.
We used Medicare claims to identify episodes of pneumonia, based on a validated combination of diagnosis codes. Comorbidities were ascertained using the diagnosis codes located on a 1-year look back. Trends in patient characteristics and site of care were compared. The association between year of pneumonia episode and 30-day mortality was then evaluated by logistic regression, with adjustment for age, sex, and comorbidities.
We identified 2,654,955 cases of pneumonia from 1987-2005. During this period, the proportion treated as inpatients decreased, the proportion aged ≥80 years increased, and the frequency of many comorbidities rose. Adjusted incidence increased to 3096 episodes per 100,000 population in 1999, with some decrease thereafter. Age/sex-adjusted mortality decreased from 13.5% to 9.7%, a relative reduction of 28.1%. Compared with 1987, the risk of mortality decreased through 2005 (adjusted odds ratio, 0.46; 95% confidence interval, 0.44-0.47). This result was robust to a restriction on comorbid diagnoses assessing for the results' sensitivity to increased coding.
These findings show a marked mortality reduction over time in community-acquired pneumonia patients. We hypothesize that increased pneumococcal and influenza vaccination rates as well as wider use of guideline-concordant antibiotics explain a large portion of this trend.
Purpose The aim of these study was to systematically review the literature on the effect of stains Materials and Methods MI DI INI I MBASI Piperslarsi and the Cochrane collaboration and the Cochrane Register of controlled trials were searched and were current as of December 2009 Randomized double blind placebo controlled studies observational cohort studies (retrospective and prospective) and case controlled studies were included Types of Participants included adult and pediatric subjects with sepsis or various other types of infection Exposure was defined as the use of a statin for any indication The primary outcome chosen was mortality from any cause and secondary outcomes included 30 day mortality from mixed infection Results A total of 20 studies were included in the analysis 18 being cohort studies (12 retrospective 6 prospective) 1 matched cohort study with 2 case control studies and 1 randomized control trial Men analysis for various infection related outcomes revealed the following pooled odds ratios all in favor of statin users not 0 61 (95% confidence interval [Cl] 0 48 0 73) for 30 day meitility (n = 7) 0 38 (95% CE 0 1, 0 4) for in hospital mortality (n = 7) 0 63 (95% CI 0 55 0 71) for pneumoni related mortality (n = 4) and 0 50 (95% CI 0 18 0 83) for mixed infection related mortality (n = 4) Conclusions This meti analysis demonstrated protective effect for statins in patients with sepsis and/or other infections compared to placebo for various infection related outcomes However out results are limited by the cohort design of the selected studies and the degree of heterogencity among them and result further randomized trials are needed to valid the use of stains for sepsis and/or other infections (C) 2010 Elsevier Inc All rights reserved
Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity, dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk.
In spite of the many advances in the diagnosis and management of community-acquired pneumonia (CAP), the mortality associated with this infection remains high. In recent years scientific evidence has emerged that shows that an excessive inflammatory response is a major cause of unfavorable outcome in patients with CAP, especially in the first few days. The use of immunomodulation appears to be an appealing option for improving prognosis in CAP. It has recently been demonstrated that statins have immunomodulatory, antioxidative and anticoagulant effects, and the beneficial effects of these drugs in sepsis have been discussed. Experimental studies have shown their effect in the modulation of the cytokine cascade and in the organization of the immunological response to respiratory infection. Most observational studies published to date support the idea that the use of statins may improve the prognosis of CAP. Randomized controlled trials are needed to validate these findings.
Pneumonia is a common diagnosis in general practice in the United Kingdom. Previous studies suggest that commonly prescribed drugs in general practice may influence pneumonia mortality.
We investigated whether statins, angiotensin converting enzyme inhibitors (ACEIs), proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H(2)RAs) have an impact on short-term and long-term mortality in pneumonia cases.
Population-based cohort study SETTTING: United Kingdom
Data on 3681 pneumonia cases above the age of 40 years were obtained from a comprehensive database called the health improvement network (THIN) which has computerised medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses.
Current statin use was associated with a 67% decrease in 30-day mortality (adj. HR: 0.33, 95% CI: 0.19-0.58) and a 55% decrease in long-term mortality (adj. HR: 0.45, 95% CI: 0.32-0.62) over a median follow-up of 2.8 years as compared to no-use. Current ACEI use decreased the 30-day mortality risk by nearly 38% as compared to no-use (adj. HR: 0.62, 95% CI: 0.47-0.82) but was not associated with long-term mortality. No significant impact on mortality was observed for either gastric acid suppressant.
The use of statins is associated with a lower risk of short- and long-term mortality following pneumonia whereas the use of ACEIs is associated with a decreased mortality risk only in the short-term.
Little is known about the long-term sequelae of community-acquired pneumonia (CAP). Therefore, we describe the long-term morbidity and mortality of patients after pneumonia requiring hospitalization. We specifically hypothesized that the Pneumonia Severity Index (PSI), designed to predict 30-day pneumonia-related mortality, would also be associated with longer-term all-cause mortality. Between 2000 and 2002, 3415 adults with CAP admitted to 6 hospitals in Edmonton, Alberta, Canada, were prospectively enrolled in a population-based cohort. At the time of hospital admission, demographic, clinical, and laboratory data were collected and the PSI was calculated for each patient. Postdischarge outcomes through to 2006 were ascertained using multiple linked administrative databases. Outcomes included all-cause mortality, hospital admissions, and re-hospitalization for pneumonia over a maximum of 5.4 years of follow-up. Follow-up data were available for 3284 (96%) patients; 66%were > or =65 years of age, 53% were male, and according to the PSI fully 63% were predicted to have greater than 18% 30-day pneumonia-related mortality (that is, PSI class IV-V). Median follow-up was 3.8 years. The 30-day, 1-year, and end of study mortality rates were 12%, 28%, and 53%, respectively. Overall, 82(19%) patients aged <45 years died compared with 1456 (67%) patients aged > or =65 years (hazard ratio [HR], 5.07; 95% confidence interval [CI], 4.06-6.34). Male patients were more likely to die than female patients during follow-up (971 [56%] vs. 767 [49%], respectively; HR, 1.20; 95% CI, 1.13-1.37). Initial PSI classification predicted not only 30-day mortality, but also long-term postdischarge mortality, with 92 (15%) of PSI class I-II patients dying compared with 616 (82%) PSI class V patients (HR, 11.80; 95% CI, 4.70-14.70). Of 2950 patients who survived the initial CAP hospitalization, 72% were hospitalized again (median, 2 admissions over follow-up) and 16% were re-hospitalized with pneumonia. In conclusion, long-term morbidity and mortality are high following hospitalization for pneumonia and are strongly correlated with initial PSI class. This suggests that patients with pneumonia, especially those with PSI class IV and V at admission, might need better attention paid to preventive strategies and much closer follow-up due to their elevated risk of subsequent adverse events and increased health resource utilization.
While some experimental and clinical research suggests that statins improve outcomes after severe infections, the evidence for pneumonia is conflicting. We examined whether preadmission statin use decreased risk of death, bacteremia, and pulmonary complications after pneumonia.
We conducted a population-based cohort study of 29,900 adults hospitalized with pneumonia for the first time between January 1, 1997, and December 31, 2004 in northern Denmark. Data on statin and other medication use, comorbidities, socioeconomic markers, laboratory findings, bacteremia, pulmonary complications, and death were obtained from medical databases. We used regression analyses to compute adjusted mortality rate ratios within 90 days and relative risks of bacteremia and pulmonary complications after hospitalization in both statin users and nonusers.
Of patients with pneumonia, 1371 (4.6%) were current statin users. Mortality among statin users was lower than among nonusers: 10.3% vs 15.7% after 30 days and 16.8% vs 22.4% after 90 days, corresponding to adjusted 30- and 90-day mortality rate ratios of 0.69 (95% confidence interval, 0.58-0.82) and 0.75 (0.65-0.86). Decreased mortality associated with statin use remained robust in various subanalyses and in a supplementary analysis using propensity score matching. In contrast, former use of statins and current use of other prophylactic cardiovascular drugs were not associated with decreased mortality from pneumonia. In statin users, adjusted relative risk for bacteremia was 1.07 (95% confidence interval, 0.69-1.67) and for pulmonary complications was 0.69 (0.42-1.14).
The use of statins is associated with decreased mortality after hospitalization with pneumonia.
Statins have potent anti-inflammatory effects in laboratory studies of pulmonary inflammation. We investigated whether statin users had improved outcome when admitted with community-acquired pneumonia.
We carried out a prospective observational study of patients admitted to the hospital with community-acquired pneumonia between January 2005 and November 2007. The use of statins, angiotensin-converting enzyme inhibitors, beta-blockers, and aspirin were recorded. The outcomes of interest were 30-day mortality, need for mechanical ventilation or inotropic support, and the development of complicated pneumonia.
On multivariate logistic regression, statin use was associated with significantly lower 30-day mortality (adjusted odds ratio [AOR] 0.46, 95% confidence interval [CI], 0.25-0.85, P=.01) and development of complicated pneumonia (AOR 0.44, 95% CI, 0.25-0.79, P=.006). There was no effect on requirement of mechanical ventilation or inotropic support (AOR 0.93, 95% CI, 0.49-1.76, P=.8). Patients prescribed statins had more severe pneumonia (median Pneumonia Severity Index 4, interquartile range [IQR] 3-4) compared with patients not prescribed cardiovascular drugs (median Pneumonia Severity Index 3, IQR 2-4, P < .0001). Despite this, C-reactive protein levels on admission were significantly lower in patients prescribed statins (median 119 mg/L, IQR 46-215) compared with patients prescribed no cardiovascular drugs (182 mg/L, IQR 66-326, P < .0001). On multivariate logistic regression, statin use was independently protective against a C-reactive protein that failed to fall by 50% or more at day 4 (AOR 0.50, 95% CI 0.27-0.92, P=.02).
Statin use is associated with reduced markers of systemic inflammation and improved outcomes in patients admitted with community-acquired pneumonia.
This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
To test the feasibility of creating a valid and reliable checklist with the following features: appropriate for assessing both randomised and non-randomised studies; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting, internal validity (bias and confounding) and power, but also for external validity.
A pilot version was first developed, based on epidemiological principles, reviews, and existing checklists for randomised studies. Face and content validity were assessed by three experienced reviewers and reliability was determined using two raters assessing 10 randomised and 10 non-randomised studies. Using different raters, the checklist was revised and tested for internal consistency (Kuder-Richardson 20), test-retest and inter-rater reliability (Spearman correlation coefficient and sign rank test; kappa statistics), criterion validity, and respondent burden.
The performance of the checklist improved considerably after revision of a pilot version. The Quality Index had high internal consistency (KR-20: 0.89) as did the subscales apart from external validity (KR-20: 0.54). Test-retest (r 0.88) and inter-rater (r 0.75) reliability of the Quality Index were good. Reliability of the subscales varied from good (bias) to poor (external validity). The Quality Index correlated highly with an existing, established instrument for assessing randomised studies (r 0.90). There was little difference between its performance with non-randomised and with randomised studies. Raters took about 20 minutes to assess each paper (range 10 to 45 minutes).
This study has shown that it is feasible to develop a checklist that can be used to assess the methodological quality not only of randomised controlled trials but also non-randomised studies. It has also shown that it is possible to produce a checklist that provides a profile of the paper, alerting reviewers to its particular methodological strengths and weaknesses. Further work is required to improve the checklist and the training of raters in the assessment of external validity.
Divergent results on the same scientific question generate controversy. We hypothesized that controversial data are attractive to investigators and editors, and thus the most extreme, opposite results would appear very early rather than late, as data accumulate, provided data can be generated rapidly.
We used data from MEDLINE-indexed meta-analyses of case-control studies on genetic associations (retrospective, hypothesis-generating research with usually rapid turnaround) and meta-analyses of randomized trials of health care interventions (prospective, targeted research that usually takes longer) sampled from the Cochrane Library. Using cumulative meta-analysis, we evaluated how the between-study variance for studies on the same question changed over time and at what point the studies with the most extreme results ever observed had been published.
The maximal between-study variance was more likely to be recorded early in the 44 eligible meta-analyses of genetic associations than in the 37 meta-analyses of health care interventions (P = .013). At the time of the first heterogeneity assessment, the most favorable-ever result in support of a specific association was more likely to appear than the least favorable-ever result (22 vs. 10, P = .017); the opposite was seen at the second heterogeneity assessment (15 vs. 5, P = .031). Such a sequence of extreme opposite results was not seen in the clinical trials meta-analyses. The estimated between-study variance decreased over time in genetic association studies (P = .010), but not in clinical trials (P = .30).
In contrast to prospective trials, a rapid early sequence of extreme, opposite results is frequent in retrospective hypothesis-generating molecular research.
HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins.
Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27+/-2.3 hours), survival time was extended from 23+/-1.2 hours for placebo-treated mice to 37+/-3.6 hours for simvastatin-treated, to 40+/-4.2 hours for atorvastatin-treated, and to 39+/-3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment.
Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.
Chronic inflammation is a key feature of vascular disease states such as atherosclerosis. Multiple clinical studies have shown that a class of medications termed statins lower cardiovascular morbidity and mortality. Originally developed to lower serum cholesterol, increasing evidence suggests that these medications have potent anti-inflammatory effects that contribute to their beneficial effects in patients. Here, we discuss the clinical and experimental evidence underlying the anti-inflammatory effects of these agents.