Statins in prevention and treatment of severe sepsis and septic shock

European Journal of Internal Medicine 22 (2011) 125–133

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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Review article

Statins in prevention and treatment of severe sepsis and septic shock I. Kouroumichakis a, N. Papanas a,⁎, S. Proikaki a, P. Zarogoulidis b, E. Maltezos a,b a b

Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece Unit of Infectious Diseases, General Hospital of Alexandroupolis, Greece

a r t i c l e

i n f o

Article history: Received 2 June 2010 Received in revised form 28 October 2010 Accepted 7 December 2010 Available online 5 January 2011 Keywords: Infection Inflammation Sepsis Septic shock Statins

a b s t r a c t Severe sepsis is an infection-induced inflammatory syndrome that can lead to multi-organ dysfunction and continues to be a major cause of morbidity and mortality worldwide. Because numerous cascades are triggered during sepsis, selective blocking of inflammatory mediators may be insufficient to arrest this process, and recent therapeutic approaches have proven controversial. Statins are the most commonly prescribed agents for hypercholesterolaemia and dominate the area of cardiovascular risk reduction. Moreover, these drugs have a variety of actions that are independent of their lipid lowering effect. Such antiinflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. By virtue of their pleiotropic effects, statins have also emerged as potentially useful in various critical care areas such as bacteraemia, the early phases of sepsis and septic shock, as well as the management of serious infections. This review outlines current evidence on the use of statins for preventing and treating sepsis. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Severe sepsis and septic shock are infection-induced inflammatory processes that are life-threatening and represent a common reason for admission to intensive care units (ICU). Sepsis affects approximately 751,000 patients every year in USA, with incidence increasing at a rate 1.5% annually [1,2]. Only 50%–70% of patients with severe sepsis survive [1–3]. To date, the most successful therapies are relatively simple clinical interventions, which aim to achieve haemodynamic, respiratory and metabolic support of patients [1,3]. These include administration of intravenous (iv) fluids, appropriate broad spectrum antibiotics, restoration of tissue oxygen delivery, removal of the source of infection (such as iv catheters) and lungprotective ventilation strategies [1,3]. More recently, several therapeutic approaches have shown that it is possible to reduce mortality of severe sepsis and septic shock [4–8]. However, none of new agents has improved survival rates in more than one large, randomised, placebo-controlled clinical trial, except for recombinant human activated protein C (rhAPC). This was the first drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with severe sepsis or septic shock [6,7,20]. Given that mortality of severe sepsis and septic shock remains high, appropriate management represents a great challenge for

⁎ Corresponding author. Democritus University of Thrace, G. Kondyli 22, Alexandroupolis, Greece. Tel.: +30 6977 544337; fax: +30 25510 74723. E-mail address: [email protected] (N. Papanas).

researchers, and many trials have to be developed. The aim of this review is to summarise the evidence of experimental and clinical trials on the role of statins in the abovementioned conditions and examine whether statins, currently, have a role in preventing or treating sepsis. 2. Search strategy We performed an electronic article search through PubMed, Google Scholar, Medscape and Scopus databases, using combinations of the following keywords: infection, inflammation, sepsis, septic shock, and statins. All types of articles (randomised controlled trials, clinical observational cohort studies, review articles, animal and cellbased studies) were included. Selected references from identified articles were searched for further consideration. 3. Pathophysiology of sepsis Sepsis is a complex syndrome caused by an uncontrolled systemic inflammatory response to bacterial infection and characterised by multiple manifestations, which can result in dysfunction or failure of one or more organs and even death [9]. We will outline the main mechanisms that are involved in septic response and relate to statin therapy [3,10–12]. Sepsis (or severe sepsis) is triggered by bacteria or fungi, when the body fails to kill the invaders, despite the extensive inflammatory reaction that, finally, leads to organ damage. Animals have mechanisms for recognising bacterial components such as the lipid A moiety of lipopolysaccharide (LPS or endotoxin) [3,11,12]. LPS is transferred to CD14 from LPS-

0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.12.004

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binding protein on the surfaces of monocytes, macrophages, endothelial cells and neutrophils [3,11,12]. Then, microbial molecules interact with Toll-like receptors (TLRs) and their signal is transduced to the interior of cells (via the nuclear transcription factor-B [NF-B]) [10,11]. TLRs are a family of pattern-recognition receptors (PRRs) [11]. Recognition of microbial molecules by tissue phagocytes triggers the production and release of numerous inflammatory mediators. Systemic responses are activated by neural and/or humoral communication with the hypothalamus and brainstem [3,10–12]. Sepsis originates from the production of abundant host molecules such as cytokines, chemokines, prostanoids, leukotrienes, free radicals, lysosomal enzymes, and others that increase blood flow to the infected tissue, enhance the permeability of local blood vessels and recruit neutrophils to the site of infection [12]. Tumour necrosis factor-alpha (TNF-α) is a central mediator that stimulates leukocytes and vascular endothelial cells to release other cytokines to express cell-surface molecules that enhance neutrophil–endothelial adhesion at sites of infection, and to increase prostaglandin and leukotriene production [3,10–12]. The main pro-inflammatory molecules are TNF-α, interleukin-8 (IL-8), interleukin-1β (IL-1β), interferon γ (INF-γ), interleukin-12 (IL-12), interleukin 6 (IL-6) and platelet activating factor (PAF) [12–15]. Several other factors may be involved in the pathogenesis of sepsis, as recently reviewed elsewhere [11]. Numerous trials on inhibition of these mediators failed to show significant improvements in survival [12,16], but a meta-analysis of all TNF inhibitors demonstrated overall improvement [17]. During inflammatory situations such as sepsis, significant alterations occur at multiple levels, both in the coagulation system and the cells that regulate this system [18]. This cascade initiates clotting, impairs the fibrinolytic system and decreases the activity of natural anticoagulant mechanisms. Septic patients frequently manifest intravascular fibrin deposition, thrombosis, and disseminated intravascular coagulation (DIC) [12,18]. The interaction between the coagulation system, circulating white blood cells and platelets, inflammatory mediators and the endothelium leads to a deregulated activation of both extrinsic and intrinsic clotting pathways [12,18,19]. The latter is characterised by increased generation of fibrin and activity of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF), impaired function of the protein C and protein S inhibitory pathway and depletion of antithrombin and protein C [19]. Protein C deficiency induces additional abnormalities in coagulation. Recombinant activated protein C (rhAPC) is a currently successful FDAapproved therapeutic intervention [6,7,20]. Most researchers propose that widespread vascular endothelial damage, a hallmark of severe sepsis, can lead to multi-organ dysfunction syndrome (MODS) [21]. Many changes occur, when endothelial cells are exposed to inflammatory mediators and endothelial disruption comes about because of increased adhesion molecules and white blood cells [22–25]. According to some studies, numerous vascular endothelial cells are found in the peripheral blood of septic patients, while soluble Fas levels increase in patients with MODS [26,27]. Exposure of endothelial cells to inflammatory mediators stimulates them to produce and release cytokines, procoagulant molecules, platelet-activating factor (PAF) and nitric oxide (NO) [12,18,20,21]. At the same time, neutrophils and phagocytes are attracted to infected sites and this endothelium activation leads to increased vascular permeability, changes of vascular tone, microvascular thrombosis, DIC and, finally, shock [12,18,21]. It is generally accepted that sepsis syndrome reflects the delicate balance between the extensive triggering of defense mechanisms (by invading microorganisms) and both the direct and indirect effects of these microorganisms and their products [3,11,12,21]. In summary, the pathogenesis of sepsis varies according to the invading microorganism, the site of infection,the ability of host immune system and the genetic prediposition of septic patient [28].

Although severe infection may be associated with an early phase of hyperinflammation, in most, if not all, patients who survive the acute phase of sepsis, a prolonged state of immune suppression evolves, also referred to as immunoparalysis [11]. Clinical data underline the subsequent high mortality rates associated with patients who are long-term survivors of the acute septic episode [29,30]. The immunosuppression associated with sepsis is, at least in part, a result of the prolonged activities of immunomodulatory chemokines and leads to a secondary infection, thereby increasing risk of death [30,31]. 4. Pharmacology of statins Statins represent a class of lipid-lowering drugs that mainly inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, leading to decreased cholesterol synthesis. HMG-CoA reductase catalyses the conversion of hydroxymethylglutaryl-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis, thereby reducing total cholesterol, low-density lipid cholesterol (LDL), apolipoprotein B and triglyceride levels [32–38]. Statins also have a wide variety of properties that are independent of their lipid-lowering ability [32–37]. These may be described as antiinflammatory, antioxidant, immunomodulatory, antiapoptotic, antiproliferative, antithrombotic, antimicrobial and endothelium-protecting, and are collectively referred to as pleiotropic effects [32–37]. By virtue of their pleiotropic effects, statins have been suggested a useful adjunctive agent in the treatment of sepsis. The most efficacious statins are mevastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rosurvastatin. Their safety profile is excellent [38–41]. The most common untoward effects include elevation of liver aminotransferases and myopathy [38]. Initial post-marketing surveillance studies of these statins revealed an elevation in liver aminotransferases to values greater than three times the upper limit of normal, with a frequency of 1%. Frequency appears to be dose-related [39–41]. Another major side effect of statin use is myopathy. Among active drug recipients, 0.17% had creatine kinase (CK) values exceeding 10 times the upper limit of normal, the value commonly used to define statin-induced severe myositis and rhabdomyolisis [41]. Among placebo-treated subjects, frequency was 0.13% [41]. Interestingly, atherosclerosis and sepsis share several pathophysiologic similarities, including impaired immune system, increased thrombogenesis, and systemic inflammation [12]. Therefore, it is not surprising that statins may exert beneficial effects in patients with sepsis. 5. Cell-based and animal studies In vitro studies have demonstrated that statins are able to decrease the activation of nuclear transcription factor-B (NF-B) by increasing the expression of the NF-B inhibitory protein I-B, resulting in reduced cytokine production. Statins affect the production of many drivers of sepsis, such as IL-1, IL-6, IL-8, TNF-α, monocyte chemotactic protein-1 and C-reactive protein (CRP) [42–51]. They exert beneficial effects by inhibition of leukocyte rolling, adherence, and transmigration. In particular, statins greatly reduce both lipopolysaccharide (LPS)induced and Staphylococcus aureus A-toxin-induced leucocyte migration and recruitment [52–56]. They also reduce the endothelial cell adhesion molecule P-selectin, CD11b and CD18 and have been shown to directly bind to the leucocyte integrin Lymphocyte functionassociated antigen 1 LFA-1 (also known as CD11a/CD18), thereby interfering with its principal ligand ICAM-1 (Intercellular Adhesion Molecule-1) [57–59]. Frey et al. examined the effect of statins on CD14 expression, the major binding site for bacterial lipopolysaccharide (LPS) on the macrophage surface [60]. Treatment of RAW 264.7 macrophages with lovastatin resulted in elevated macrophage CD14 levels and decreased

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serum CD14 levels after LPS stimulation [60]. The increase in macrophage CD14 expression correlated with enhanced response to LPS, at least at the level of TNF-alpha secretion. These results indicated that statin treatment could modulate macrophage function and have beneficial effects on inflammation and sepsis [60]. In another work, simvastatin decreased LPS toxicity by reduction of NF-kappa B activation and subsequent release of TNF by modulating 3-hydroxy-3-methylglutaryl coenzyme A reductase activity [61]. Pre-treatment with simvastatin protected against alphatoxin-induced sepsis associated with reduced p53, TNF-α, apoptosis, and necrosis [62]. Simvastatin also inhibited S. aureus host cell invasion, restricting p85 localization and interrupting the actin dynamics required for bacterial endocytosis [63]. In a further study, simvastatin showed a significant antimicrobial effect against methicillin-susceptible S. aureus (MSSA) [mean MIC (minimal inhibitory concetration) 29.2 mg/L] and to a lesser extent against methicillin resistant S. aureus (MRSA) (mean MIC 74.9 mg/L) [35]. Of note, statins suppress TLR2 and TLR4 expression in inflammatory conditions [64,65]. Protection by simvastatin includes the inhibition of host cell invasion by S. aureus, the most common aetiologic agent of sepsis [66,67]. Inhibition appears to be, at least partly, due to depletion of isoprenoid intermediates within the cholesterol biosynthesis pathway, leading to the cytosolic accumulation of the small GTPases (Guanosine Triphosphatases), CDC42 (cell division cycle 42), Rac (Ribosome-Associated Complex), and RhoB (Rhodamine bright) cells [66,67]. Additionally, statins increase expression of endothelial nitric oxide synthase (eNOS), in conjunction with down-regulation of inducible nitric oxide synthase (iNOS) [68–77]. This action is important in sepsis, given the disequilibrium between the two isoforms of NOS that catalyse nitric oxide (NO) production, namely iNOS and eNOS [68–77]. Several animal models have been used to examine the effects of statins in sepsis. Serum pro-inflammatory cytokines and leukocyte count were determined in an experimental model of abdominal sepsis, using cecal ligation and puncture (CLP) in rats [78]. Serum TNF-α, IL1beta and IL-6 were respectively 364.8 ± 42 pg/mL; 46.3 ± 18 pg/mL and 28.4 ± 13 pg/mL in CLP/Simvastatin rats, significantly lower (p b 0.05) than in group CLP/Saline (778.5± 86 pg/ml; 176.9 ± 46 pg/ ml; and 133.6 ± 21 pg/ml, respectively). The same results were observed in total leukocytes and neutrophil counts. Again, survival in simvastatin-treated mice was increased 4 times in comparison to those receiving placebo, despite similar rates of bacteraemia [79]. Pretreatment with simvastatin preserved cardiac contractility 20 h after ligation and puncture, compared with a 28% decline in cardiac output in control mice [79]. Similarly, leukocytes isolated from treated mice displayed a reduced ability to adhere to cytokine-stimulated murine endothelial cells compared with leukocytes harvested from control mice [79]. Comparable results have been obtained in other animal studies [80–82] that showed significantly improved survival for statin treatment after onset of sepsis in animal models. 6. Clinical studies 6.1. Statins in infections Studies on the use of statins in patients with infectious diseases are either cohort studies (retrospective and prospective observational) or retrospective case–control studies. Table 1 summarises the major clinical studies. 6.1.1. Retrospective studies A retrospective cohort study, which accounted for each individual's likelihood of receiving a statin, included 69,168 patients, of whom 34,584 received a statin and 34,584 did not [83]. This work identified 141,487 patients older than 65 years hospitalised for acute coronary syndrome, ischaemic stroke, or revascularisation, who

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survived for at least 3 months after discharge. Incidence of sepsis was lower in patients receiving statins than in controls (71.2 vs. 88.0 events per 10,000 person-years; HR [Hazard Ratio] = 0.81, CI [95% Confidence Interval]: 0.72–0.91) [83]. Adjustment for demographic variables, risk factors for sepsis, comorbidities, and health-care use yielded similar results (HR = 0.81). Significant reduction was recorded in severe sepsis (HR = 0.83, CI: 0.70–0.97) and fatal sepsis (HR = 0.75, CI: 0.61–0.93) [83]. A retrospective cohort study examined the association between preadmission statin use and mortality among 5353 adult patients hospitalised with bacteraemia [84]. The 30-day mortality among statin recipients did not differ from those not receiving statins (20.0% vs. 21.6%, adjusted mortality HR: 0.93, p = NS, CI: 0.66–1.30) [84]. Among survivors, however, statin therapy was associated with a significant reduction in mortality up to 180 days after onset of bacteraemia (8.4% vs. 17.5%, respectively, adjusted mortality HR: 0.44, CI: 0.24–0.80) [84]. In this study, 75% of the cost of statins was reimbursed by the respective National Health Service and all patients had access to the country's hospitals, suggesting that the favourable outcome was associated with the medication itself. Another retrospective cohort study examined 40 score-defined MODS patients under statin treatment and 80 age- and sex-matched score-defined MODS patients without statin treatment [85]. Inclusion criterion was APACHE II (Acute Physiology and Chronic Health Evaluation) score ≥ 20 on admission to ICU. There were 42/80 deaths in the group without statin treatment and 13/40 deaths in the statin group (28-day mortality 53% vs. 33%, respectively; p = 0.03) [85]. At Cox proportional hazard analysis, HR was 0.53 (CI: 0.29–0.99, p = 0.04). Hospital mortality was 35% in patients receiving statins vs. 72% in those not treated with statins (p b 0.0001) [85]. Similarly, a retrospective cohort study examined 188 ICU patients with a diagnosis of severe sepsis [86]. Of these, 60 (32%) were on statin therapy [86]. The statin group had a 35% relative reduction in mortality compared with the non-statin group (mortality rate 31.7% vs. 48.4%, respectively; p = 0.040) [86]. The greatest benefit was observed in subjects with APACHE II scores higher than 24 (mortality rate 32.3% vs. 57.5%, p = 0.031), while difference was not significant in patients with APACHE II scores of 24 or lower (31% vs. 36.4%, p = 0.810). In the multivariable regression model, statin use had a protective effect (odds ratio [OR] = 0.42, CI: 0.21–0.84; p = 0.014), whereas increasing age (OR = 1.03, CI: 1.01–1.06; p = 0.013) and higher APACHE II score (OR = 1.11, CI: 1.05–1.18; p = 0.001) were associated with increased mortality [86]. A retrospective cohort analysis assessed the association between statin administration and mortality in bacteraemic patients [87]. This work examined 438 patients requiring hospitalisation for bacteraemia. There was a significant reduction in all-cause hospital mortality (10.6% vs. 23.1%, p = 0.022) and death attributable to bacteraemia (6.1% vs. 18.3%, p = 0.014) in patients under statin treatment at the time of bacteraemia (n = 66) [87]. The reduction in all-cause hospital mortality (1.8% vs. 23.1%, p = 0.0002) and death attributable to bacteraemia (1.8% vs. 18.3%, p = 0.0018) was more pronounced in patients who continued to receive statin therapy after diagnosis of bacteraemia (n = 56) [87]. Statin use prior to admission was associated with a reduced adjusted hospital mortality rate (OR = 0.39, CI: 0.17–0.91; p = 0.029), and continuing statin use after bacteraemia increased this effect (OR = 0.06, CI: 0.01–0.44; p = 0.0056) [87]. This work adds strength to the importance of long-term statin therapy for the reduction of immediate sepsisassociated mortality and for the improvement in survival [87]. Another retrospective cohort study provided evidence for a potential clinical role of statins in bacteraemic infection [88]. Among 388 bacteraemic infections due to aerobic gram-negative bacilli and S. aureus, there was a significant reduction in both overall (6% vs. 28%; p = 0.002) and attributable (3% vs. 20%; p = 0.010) mortality among patients taking statins (35) compared with patients not taking statins

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Table 1 Major clinical studies. First author [Reference]

Study design

Setting

Study groups

Hackam DG et al. [83]

Population-based cohort analysis

Statin group: 34,584 patients (50%); Use of statins in patients with Non-statin group: 34,584 patients (50%) atherosclerosis is associated with a reduced risk of subsequent sepsis

Thomsen RW et al. [84]

Observational study

Schmidt H et al. [85]

Retrospective cohort study

69,168 patients older than 65 years hospitalised for acute coronary syndrome, ischaemic stroke or revascularisation, who survived for at least 3 months after discharge Association between pre-admission statin use and mortality among patients with bacteraemia in a population-based setting Inclusion criterion: APACHE II score ≥20 at admission to ICU in MODS patients

Statin group: 176/5353 patients (3.3%); Non-statin group: 5177/5353 patients (96.7%)

Almog Y et al. [93]

40 score-defined MODS patients under statin treatment; 80 age- and sexmatched score-defined MODS patients without statin treatment Statin group: 60/188 patients (32%); Retrospective Patients aged 40 years or older with cohort study diagnosis of severe sepsis and admission Non-statin group: 128/188 patients (68%) to ICU Statin group: 66/438 patients (15.1%); Retrospective Association between statin Non-statin group: 372/438 patients cohort analysis administration and mortality in (84.9%) bacteraemic patients Statin group: 35/388 patients (9%); NonRetrospective Bacteraemic infections due to aerobic statin group: 353/388 patients (91%) analysis gram-negative bacilli and Staphylococcus aureus Statin group: 78/311 transplant Retrospective Use of statins in recipients of kidney, recipients (25.1%); Non-statin group: cohort study pancreas, and/or liver transplants with 233/311 transplant recipients (74.9%) bloodstream infections Retrospective national Effect of previous outpatient use of Statin group: 480/3018 patients (15.9%); cohort study statins and/or angiotensin II receptor Non-statin group: 2538/3018 patients blockers (ARBs) on 30-day mortality in (84.1%) patients hospitalised with sepsis Prospective, observational, 11,490 patients with atherosclerotic Statin users: 5698 patients (50.1%); No population-based study disease followed for up to 3 years statin users: 5664 patients

Almog Y et al. [94]

Prospective observational cohort study

Donnino M et al. [95,96]

Prospective, observational cohort study

Novack V et al. [97]

Double-blind placebo controlled randomised clinical trial

Chalmers JD et al. [99]

Prospective observational study

Schlienger RG et al. [100]

Population-based, retrospective, nested case-control analysis

Dobesh PP et al. [86] Kruger P et al. [87] Liappis AP et al. [88] Hsu J et al. [89]

Mortensen EM et al. [90]

Van de Garde EM Case-control study et al. [101] Thomsen RW et al. [102]

Mortensen EM et al. [103]

Investigation whether patients with previous statin treatment develop severe sepsis less frequently Association between statin therapy and mortality in patients with suspected infection in the emergency department Investigation whether statin therapy reduces the incidence of severe sepsis and the levels of inflammatory cytokines in patients with acute bacterial infection Investigation whether statin users had improved outcome following admission with community-acquired pneumonia Investigation of the effect of statin use on pneumonia-related outpatient visits, hospitalisation, survival, and deaths

Effects of statin use on the occurrence of pneumonia in adult diabetic patients

Population-based cohort study

Conclusions

Statin use is associated with a significant decrease in mortality between 31 and 180 days after bacteraemia Patients under statin treatment developing MODS might have a better outcome than those without statin therapy Use of statins is associated with a protective effect in patients with severe sepsis A significant survival benefit is associated with continuing statin therapy in bacteraemic patients There is a potential clinical role of statins in bacteraemic infection

Appropriate antibiotic therapy and statin use are associated with lower risk of mortality from bloodstream infections Use of statins and/or ARBs before admission is associated with decreased mortality in patients hospitalised with sepsis Therapy with statins may be associated with a reduced risk of infection-related mortality Prior therapy with statins may be Previous statin treatment: 82/361 patients (22.7%) No treatment: 279/361 associated with a reduced rate of severe sepsis and ICU admission patients (77.3%) Statin group: 474/2132 patients (22.2%); Ongoing statin therapy in patients hospitalised with infection results in Non-statin group: 1458/2132 patients significantly lower in-hospital mortality (77.8%) compared to no statin treatment Statin therapy may be associated with a 42/83 patients (50.6%): 40 mg reduction in the levels of inflammatory simvastatin followed by 20 mg cytokines in patients with acute bacterial simvastatin; 41/83 patients (49.4%): infections placebo Statin group: 257/1007 patients (25.5%); Statin use is associated with reduced markers of systemic inflammation and Non-statin group: 750/1007 patients improved outcomes in patients admitted (74.5%) with community-acquired pneumonia Use of statins is associated with reduced Statins and/or fibrates: 55,118/134,262 patients (41%); hyperlipidaemia without risk of pneumonia. Risk reduction is particularly strong in the subgroup of lipid-lowering agents: 29,144/134,262 patients with fatal pneumonia patients (21.7%); Randomly selected without hyperlipidaemia and without lipid-lowering treatment: 50,000/ 134,262 patients (37.3%) Use of statins is associated with a Statin use: 52/4719 (1.1%) among considerable reduction in risk of patients and 322/15,322 (2.1%) among matched controls pneumonia in diabetic patients Use of statins is associated with Statin group: 1371/29,900 (4.6%) decreased mortality after hospitalisation patients; Non-statin group: 28,529/ with pneumonia 29,900 patients (95.4%)

Investigation whether pre-admission statin use decreased risk of death, bacteraemia, and pulmonary complications after pneumonia Retrospective cohort study Effect of prior use of statins on mortality Statin group: 110/787 patients (14%); Non-statin group: 677/787 patients in patients hospitalised with (86%) community-acquired pneumonia

Prior outpatient statin use is associated with decreased mortality in patients hospitalised with community-acquired pneumonia

ICU: intensive care unit; MODS: multi-organ dysfunction syndrome; APACHE: Acute Physiology and Chronic Health Evaluation.

(353) [88]. Reduction in mortality was confirmed in multivariate analysis (OR = 7.6; CI: 1.01–57.5) [88]. A retrospective cohort study of kidney, pancreas, and/or liver transplant recipients with bloodstream infections showed that statin

use was associated with lower mortality rates [89]. Statin use was protective (OR = 0.18, CI: 0.04–0.78) [89]. A retrospective national cohort study showed that use of statins and/or angiotensin II receptor blockers (ARBs) before admission was

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associated with decreased mortality in 3018 patients hospitalised with sepsis [90]. After adjusting for potential confounders, statin use (OR = 0.48, CI: 0.36–0.64) and ARB use (OR = 0.42, CI: 0.24–0.76) were significantly associated with decreased 30-day mortality. A retrospective cohort study showed that statins prevented deterioration of sepsis, predominantly through prevention of hypotension [92]. Of 53 patients admitted with sepsis, 16 were initially receiving statins and 37 were not. Pre-admission statin therapy was associated with a 30% lower rate of severe sepsis (56% vs. 86%, respectively; p b 0.02) [91]. In-hospital mortality was not significantly different between the two groups (38% vs. 49%, p = 0.33). However, the rate of cardiovascular dysfunction was significantly lower in the statin group (38% vs. 73%, p b 0.02) [91]. The number of patients in this study is very small and no safe conclusions can be drawn. By contrast, a retrospective Taiwanese study on patients with sepsis showed that statin treatment was not associated with decreased mortality at 30 days (p = 0.853) [92]. Nonetheless, caution is needed in the interpretation of this study. Indeed, only 22.9% of patients were treated with statins, which possibly did not allow the magnitude of their protective effect to become manifest [92]. Moreover, follow-up was short [92]. Finally, as the authors themselves suggest, results may not be generalisable outside oriental, particularly Taiwanese population [92]. In summary, there is circumstantial evidence from retrospective cohort studies that statins may be helpful in sepsis. However, these works do not explain why the incidence of sepsis is increasing, despite increasing use of statins in the population, and they also have methodological flaws. Nine retrospective studies [83–91] showed statistical significance in favour of statin use in patients with sepsis, bacteraemia or MODS in terms of rate of sepsis, rate of hospitalacquired bacteraemia and mortality and overall hospital mortality. By contrast, no such significance was observed by Yang et al. [92]. 6.1.2. Prospective studies A prospective, observational, population-based study including 11,490 patients with atherosclerotic disease, of whom 5698 were on statins examined whether these agents reduced mortality [93]. The risk of infection-related mortality was significantly lower in the statin-, as compared with the non-statin group (0.9% vs. 4.1%, respectively; RR [Relative Risk]: 0.22, CI: 0.17-0.28) [93]. Stepwise Cox proportional hazard survival analysis revealed that the protective effect of statins, adjusted for all potential confounders, remained highly significant (HR = 0.37, CI: 0.27–0.52) [93]. A prospective observational cohort study in patients admitted with presumed or documented acute bacterial infection evaluated the rate of severe sepsis and admission to ICU [94]. Of the 361 patients enrolled, 82 (22.7%) were treated with statins before admission. Both groups had similar severity of illness. Severe sepsis developed in 19% of patients in the non-statin group and 2.4% in the statin group (p b 0.001). Statin treatment reduced the relative risk of developing severe sepsis (RR = 0.13, CI: 0.03–0.52). Among patients not receiving statins, admission rates to ICU were higher than among statin-treated patients (12.2% vs. 3.7%, respectively; p = 0.025, OR= 0.30, CI: 0.1–0.95; p b 0.05) [94]. A prospective observational study of 2036 patients with suspected infection reported that continuation of statin therapy was linked to significantly lower in-hospital mortality [95]. Patients who received statins (n = 474) had a lower unadjusted crude mortality (compared to those who did not (1.9% vs. 4.5%, respectively; p b 0.01)) [95]. Adjusting for gender, MEDS (Matson Evaluation of Drug Side Effects) score, Charlson Comorbidity Index, and duration of statin therapy, statin use was associated with OR = 0.27 (CI: 0.1–0.72, p ≤ 0.01) for death. A secondary analysis of this study led to the same conclusion [96]. A double-blind placebo-controlled randomised trial examined whether statin therapy reduced the incidence of severe sepsis and the

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levels of inflammatory cytokines in patients with acute bacterial infection [97]. Enrolled were 83 patients with suspected or documented bacterial infection, of whom 42 received simvastatin and 41 received placebo. Four patients developed severe sepsis, two in each group. No difference was observed in other clinical variables [97]. Comparing cytokine levels measured at baseline reveals higher cytokine levels in the statin group, even though this difference was not significant: median level of IL-6 15.5 pg/ml vs. 0.0 pg/ml, p = 0.15; median level of TNF-a 16.0 pg/ml vs. 2.0 pg/ml, p = 0.20 [97]. Patients treated with simvastatin had a significant reduction in IL-6 and TNF-α level after 72 h of therapy [97]. Despite the significant decrease in both cytokine levels in the statin group (no significant changes in the placebo group), comparing the 72-h levels between two groups revealed no significant difference: median IL-6 level of 0.0 pg/ml vs. 19.0 pg/ml, p = 0.17 and TNF-a level of 0.0 pg/ml vs. 0.0 pg/ml, p = 0.97, respectively [97]. In summary, all prospective cohort studies, which probably provide stronger evidence for the effect of statins than retrospective cohort studies, demonstrated decreased mortality or decreased risk of infection in statin users [93–97]. 6.2. Statins in pneumonia, ICU infections and other bacterial infections 6.2.1. Prospective studies A prospective national study for the epidemiology and management of acute lung injury and acute respiratory distress syndrome (ARDS) in Ireland showed that patients under treatment with a statin during admission had a 73% lower risk of death (OR = 0.27, CI: 0.06-1.21; p = 0.09) [98]. The prevalent predisposing risk factors were pneumonia (50%) and non-pulmonary sepsis (26%) [98]. A prospective observational study of patients hospitalised with community-acquired pneumonia showed that statin use was associated with reduced markers of inflammation and improved outcomes [99]. Statin use was associated with significantly lower 30-day mortality (adjusted OR = 0.46, CI: 0.25–0.85; p = 0.01) and development of complicated pneumonia (adjusted OR = 0.44, p = 0.006). In multivariate logistic regression, statin use was independently protective against a C-reactive protein that failed to fall by 50% or more at day 4 (adjusted OR = 0.50, CI: 0.25–0.79; p = 0.02) [99]. These studies [98,99] established that the use of statins improves outcome in patients with acute lung injury, acute respiratory distress syndrome and community-acquired pneumonia. 6.2.2. Retrospective and other studies 6.2.2.1. Positive studies. A population-based, retrospective, nested case–control analysis examined 55,118 patients who took statins and/ or fibrates, 29,144 patients with hyperlipidaemia not taking lipidlowering agents, and 50,000 randomly selected patients without hyperlipidaemia and without lipid-lowering treatment [100]. This study identified 1253 patients with pneumonia and matched them with 4838 control subjects. After adjusting for comorbidity and frequency of visits to general practitioners, the authors found that current statin users had a significantly reduced risk of fatal pneumonia (adjusted OR = 0.47, CI: 0.25–0.88) [100]. However, it is important to note that statin users were more likely to have been vaccinated against influenza virus or Streptococcus pneumoniae [100]. Thus, they had a priori higher likelihood of favourable outcome in case of infection. In general, it is plausible that patients receiving statins may belong to higher socioeconomic class, have better education and more immediate access to healthcare facilities. In a retrospective case-control study, van de Garde and colleagues found that use of statins was associated with a significant reduction in the risk of pneumonia among diabetic patients [101]. They detected 4719 diabetic patients who developed pneumonia after starting statin therapy, and matched them with controls on a 1:3 ratio. Statins were

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used in 1.1% of 4719 cases and in 2.1% of 15 322 matched controls (crude OR= 0.51, CI: 0.37–0.68). After adjusting for potential confounders, treatment with statins was associated with a significant reduction in the risk of pneumonia (adjusted OR = 0.49, CI: 0.35–0.69) [101]. This study is important, because it evaluates the protective effect of statins specifically in diabetic subjects [101]. A population-based cohort study of 29,900 adults hospitalised with pneumonia examined whether pre-admission statin use decreased risk of death, bacteraemia, and pulmonary complications [102]. Mortality among statin users (4.6%) was lower than among non-users: 10.3% vs. 15.7% after 30 days and 16.8% vs. 22.4% after 90 days [102]. Adjusted OR for death at 30 days was 0.69 (CI: 0.58–0.82) and adjusted OR for death at 90 days was 0.75 (CI: 0.65–0.86) [102]. In statin users, adjusted RR for bacteraemia was 1.07 (CI; 0.69–1.67) and adjusted RR for pulmonary complications was 0.69 (CI: 0.42–1.14) [102]. A retrospective cohort study of 787 patients hospitalised for community-acquired pneumonia found that prior outpatient statin use was associated with decreased mortality [103]. In multivariate regression analysis, after adjusting for potential confounders including a propensity score, use of statins at presentation was associated with a 64% reduction in 30-day mortality (OR = 0.36, CI: 0.14–0.92) [103]. 6.2.2.2. Neutral or negative studies. However, two retrospective cohort studies found that statins were not associated with reduced mortality or admission rates to ICU in patients with community acquired pneumonia and reports of benefit in the setting of sepsis may be a result of confounding [104,105]. In the first work, a population-based prospective cohort study of 3415 patients with pneumonia admitted to hospital, overall 624 patients (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%) vs. 574/3090 (19%), p = 0.15) [104]. Surprisingly, after more complete adjustment for confounding, however, the odds ratios changed from potential benefit (OR = 0.78, CI: 0.57–1.07, adjusted for age and sex, p = 0.12) to potential harm (OR = 1.10, fully adjusted including propensity scores, CI: 0.76–1.60, p = 0.55) [104]. The second report, a cohort study of 438 patients, showed that statin therapy is associated with worse outcome in patients with ICU-acquired infections [105]. Statin-treated patients were older (71.7±8.3 vs. 61.5± 18.3 years), but differences in predicted mortality risk by APACHE II (39.5 ± 24.7% vs. 35.8 ± 24.3%) did not reach significance [105]. The ICU-acquired infection rate in statin-treated patients was non-significantly lower (29% vs. 38%) and delayed (median 12 vs.10 days), without differences regarding the source of infections [105]. Nevertheless, hospital mortality was significantly higher in statin-treated patients (61% vs. 42%), even after adjustment for APACHE II [105]. We indentified five studies where the role of statins was examined in patients with pneumonia [100–104]. Four of these [100–103] reported beneficial effects from the use of statins in terms of reduction of mortality and the risk of developing pneumonia. However, in the study by Majumdar et al. [104], there was no difference between the two groups regarding the outcome of pneumonia or the need for admission to an ICU. In the study of Fernandez et al. [105], the ICUacquired infection rate in statin-treated patients was non-significantly lower and delayed, while hospital mortality was significantly higher in statin-treated patients. In summary, beneficial effects of statins at the onset of sepsis cannot be ignored. However, no definitive conclusions can be drawn and the included studies employed different methods and are heterogeneous in aspects such as patient number, dosage and duration of statin administration and type of infection. 6.3. Statins in viral infection A matched cohort study (n = 76,232) and two separate casecontrol studies (397 influenza and 207 COPD deaths) found a

dramatically reduced risk of COPD (Chronic Obstructive Pulmonary Disease) death and a significantly reduced risks of influenza death among moderate-dose statin users [106]. Moderate-dose (≥4 mg/ day) statin use succeeded in reducing mortality due to both influenza/ pneumonia (OR = 0.6, CI: 0.44–0.81) and COPD (OR = 0.17, CI: 0.07– 0.42) [106]. A prospective observational work found that the survival benefit conferred by statins interacted with Cytomegalovirus (CMV) seropositivity and high CRP to significantly reduce mortality rates among patients with coronary artery disease (CAD) [107]. Horne and colleagues monitored 2315 patients with CAD. Mortality rate was higher for CMV seropositivity (+) with high CRP (HR = 2.0, CI: 1.1–3.7; p = 0.03) and lower for statins (HR = 0.50, CI: 0.32–0.78; p = 0.002). Compared with CMV(−)/low CRP (mortality rate, 5% with statin versus 4% without statin), the protective effect of statin therapy was more pronounced for CMV(+)/low CRP (mortality rate, 2% vs. 7%; HR= 0.44, CI: 0.16–1.3; p = 0.065), CMV (−)/high CRP (mortality rate, 1% vs. 8%; HR= 0.16, CI: 0.02–1.2; p = 0.051), and CMV(+)/high CRP (mortality rate, 6% vs. 17%; HR, = 0.42, CI: 0.25–0.70; p = 0.024) [107]. Finally, Mihăilă and colleagues studied the effect of statins on the level of viraemia and of the pro-and anti-inflammatory cytokines in patients with chronic hepatitis C [108]. Patients were treated with fluvastatin 40 mg/day or lovastatin 20 mg/day for 28 days. Both in the lovastatin- and in the fluvastatin-group, viraemia was significantly reduced (p = 0.032 and p = 0.00092, respectively) [108]. In summary, three studies demonstrated beneficial effects of statins in viral infections in terms of mortality due to influenza/ pneumonia and COPD, level of viraemia of HCV (hepatitis C virus) and mortality of CMV infection in patients with CAD [106–108]. 6.4. Clinical studies: overall summary There is evidence from most retrospective cohort studies [83–91] and from all prospective cohort studies [93–97] that statin therapy in patients with sepsis, bacteraemia or MODS is associated with reduced rate of hospital-acquired bacteraemia and hospital mortality. Specifically, there is some evidence of a beneficial effect of statins in pneumonia, ICU infections and other bacterial infections [98–103], but other works have been negative [104,105], and it is difficult to draw definitive conclusions, given the heterogeneity of studies. Finally, three studies in viral infections demonstrated beneficial effects of statins in terms of mortality and level of viraemia in patient with comorbidities [106–108]. All in all, results are encouraging, but more clinical experience is needed. 7. Clinical implications: randomised placebo controlled clinical trials (RCTs) are needed Basic science studies and observational cohort studies, as outlined previously, show that there is a rationale for the clinical use of statins in sepsis and their beneficial effects. However, several methodological limitations are inherent in such works. Thus, we need to wait for the results of ongoing RCTs. Several clinical trials are now underway examining the potential clinical benefit of statins in sepsis. Only major trials will be herein briefly presented. NCT00528580 trial is testing the hypothesis that treatment with once-daily statins has a beneficial effect on inflammatory cytokines and clinical outcomes in adults hospitalised with sepsis [109]. In Israel, NCT00676897 trial is investigating if simvastatin will attenuate IL-6 levels and lead to a more rapid shock reversal than placebo [110]. In Porto Alegre, trial NCT00452608 is designed to investigate whether atorvastatin can improve inflammatory response in septic patients [111]. Similarly, NCT00979121 trial is trying to assess the efficacy and safety of oral rosuvastatin in patients with sepsis-induced acute lung injury [112]. In Vienna, NCT00450840 trial is testing the hypothesis that short-term treatment with simvastatin

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may mitigate the detrimental vascular effects of acute inflammation in ICU patients with septic shock [113]. In Vienna, again, NCT00309374 trial is about to determine the effects of HMG-CoA reductase inhibitor pre-treatment on the activation of inflammation and coagulation in human endotoxaemia [114]. Also, NCT00357123 trial [115] is attempting to assess the anti-inflammatory efficacy of rosuvastatin in abdominal sepsis. In addition, NCT00367458 trial is examining the effects of atorvastatin on the human immunodeficiency virus (HIV) [116]. The researchers are about to evaluate HIV genotype, immune response to the virus, and how genes may determine the way in which the drug may or may not work against the strain of virus [116]. Finally, NCT00446940 is designed to examine if different doses of rosuvastatin and atorvastatin may help towards reduction of HCV viral load changes and improvement of liver function tests [117]. Simvastatin and severe sepsis trial (SIMSEPT), will be the first doubleblind, randomised, controlled trial of simvastatin (40 mg) versus placebo in the treatment of severe sepsis in humans. It will investigate the effect of simvastatin on important inflammatory markers and monitor the safety and feasibility of administering simvastatin to patients with severe sepsis [118]. A prospective randomised double blind placebo controlled trial of Atorvastatin (20 mg) or matched placebo in 150 patients does not support a beneficial role of continuing pre-existing statin therapy on sepsis and inflammatory parameters. Cessation of established statin therapy was not associated with an inflammatory rebound [119]. The STATInS trial (ACTRN 12607000028404) is a phase II, randomised, placebo-controlled study of the safety, pharmacokinetics, and effect on inflammatory marker levels of atorvastatin in intensive care patients with severe sepsis. This trial is currently underway in more than 14 intensive care units in Australia and New Zealand, and researchers hope the results will provide a platform to plan future trials examining mortality as an endpoint [120]. Several other trials are still in progress or nearing completion. 8. Discussion The aim of this review was to outline current evidence on the use of statins for preventing and treating sepsis. The majority, but not all studies established benefits of statin use in septic patients, as shown by decreased mortality or decreased risk of infections [121,122]. However, several reasons preclude drawing definitive conclusions based on the literature. First, there is considerable heterogeneity of studies in terms of patient number, dosage and duration of statin administration, type of infection, number of statin users and population setting. Secondly, many works are retrospective. While there are several valid statistical tests to handle retrospective data, such works, generally, provide less strong evidence than welldesigned prospective studies. Another question is whether statins have to be prescribed continuously as prophylaxis against infections and sepsis (as in case of prevention of cardiovascular diseases) or whether they should be administered in the beginning of sepsis. Of note, various changes occur in the liver during sepsis, and this increases the likelihood of the most common side effect of statin use, i.e. elevation of liver aminotransferases, contributing to further deterioration of liver function. 9. Conclusions Current evidence from both observational studies and basic research suggests that statin therapy might be associated with a lower incidence of sepsis and a reduction in sepsis-related mortality [121,122]. There is growing interest among clinicians in the role that statins may play in preventing and treating serious infections [8,11]. Given their pleiotropic effects related to many cascades of sepsis, these agents may represent a useful therapeutic adjunct in the management of sepsis [8,11,12]. Nonetheless, our knowledge is based on either cohort studies (retrospective and prospective observational) or retrospective casecontrol studies. Therefore, the results of ongoing large randomised

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controlled trials are eagerly awaited [109–120] to draw safe conclusions on the potential beneficial effects of statin therapy in sepsis. Learning points • Statin therapy might be associated with a lower incidence of sepsis and a reduction in sepsis-related mortality. • There is growing interest among clinicians in the role that statins may play in preventing and treating serious infections. • Given their pleiotropic effects related to many cascades of sepsis, these agents may prove to be a useful therapeutic adjunct in the management of sepsis. Conflicts of interest Nothing to declare. References [1] Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546–54. [2] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303–10. [3] Balk RA. Severe sepsis and septic shock: definitions, epidemiology, and clinical manifestations. Crit Care Clin 2000;16:179–92. [4] Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–71. [5] Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Eng J Med 2001;345:1359–67. [6] Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709. [7] Angus DC, Laterre PF, Helterbrand J, Ely EW, Ball DE, Garg R, et al. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med 2004;32:2199–206. [8] Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med 2003;9:517–24. [9] Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003;29:530–8. [10] Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol 1995;13:437–57. [11] Anas AA, Wiersinga WJ, de Vos AF, van der Poll T. Recent insights into the pathogenesis of bacterial sepsis. Neth J Med 2010;68:147–52. [12] Remick DG. Pathophysiology of sepsis. Am J Pathol 2007;170:1435–44. [13] Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, De Backer D, et al. Year in review in intensive care medicine, 2006. II. Infections and sepsis, haemodynamics, elderly, invasive, and noninvasive mechanical ventilation, weaning, ARDS. Intensive Care Med 2007;33:214–29. [14] Gao F, Linhartova L, Johnston AM, Thickett DR. Statins and sepsis. Br J Anaesth 2008;100:288–98. [15] Van der Poll T, Opal SM. Host–pathogen interactions in sepsis. Lancet Infect Dis 2008;8:32–43. [16] Glauser MP. Pathophysiologic basis of sepsis: considerations for future strategies of intervention. Crit Care Med 2000;28:S4–8. [17] Marshall JC. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2003;2:391–405. [18] Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005;131:417–30. [19] Cohen J. The immunopathogenesis of sepsis. Nature 2002;420:885–91. [20] Abraham E, Laterre PF, Garg R, Levy H, Levy H, Talwar D, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332–41. [21] Hack CE, Zeerleder S. The endothelium in sepsis: source of and a target for inflammation. Crit Care Med 2001;29:S21–7. [22] Abraham E. Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol 2000;22:4014. [23] Curzen NP, Griffiths MJ, Evans TW. Role of the endothelium in modulating the vascular response to sepsis. Clin Sci Lond 1994;86:359–74. [24] Baker CH. Vascular endothelium in sepsis and endotoxemia. J Fla Med Assoc 1994;81:119–22. [25] Karima R, Matsumoto S, Higashi H, Matsushima K. The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 1999;5:123–32. [26] Mutunga M, Fulton B, Bullock R, Batchelor A, Gascoigne A, Gillespie JI, et al. Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001;163:195–200. [27] Matute-Bello G, Liles WC, Steinberg KP, Kiener PA, Mongovin S, Chi EY. Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J Immunol 1999;163:2217–25.

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