A correction has been published 1

Review ArticleCritical Care Medicine

Severe Sepsis and Septic Stupor

List of authors.
  • Derek C. Angus, 1000.D., 1000.P.H.,
  • and Tom van der Poll, One thousand.D., Ph.D.

Introduction

Sepsis is 1 of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis (σήψις) was the process by which flesh rots, swamps generate foul airs, and wounds fester.1 Galen afterwards considered sepsis a laudable outcome, necessary for wound healing.2 With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was recast every bit a systemic infection, often described as "blood poisoning," and assumed to be the effect of the host'due south invasion past pathogenic organisms that then spread in the bloodstream. However, with the advent of mod antibiotics, germ theory did not fully explicate the pathogenesis of sepsis: many patients with sepsis died despite successful eradication of the inciting pathogen. Thus, researchers suggested that it was the host, non the germ, that collection the pathogenesis of sepsis.3

In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes and that septicemia was neither a necessary condition nor a helpful term.4 Instead, the panel proposed the term "severe sepsis" to describe instances in which sepsis is complicated by acute organ dysfunction, and they codified "septic shock" as sepsis complicated by either hypotension that is refractory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus panel endorsed most of these concepts, with the caveat that signs of a systemic inflammatory response, such as tachycardia or an elevated white-cell count, occur in many infectious and noninfectious conditions and therefore are not helpful in distinguishing sepsis from other conditions.5 Thus, "severe sepsis" and "sepsis" are sometimes used interchangeably to describe the syndrome of infection complicated past astute organ dysfunction.

Incidence and Causes

The incidence of severe sepsis depends on how astute organ dysfunction is divers and on whether that dysfunction is attributed to an underlying infection. Organ dysfunction is often defined past the provision of supportive therapy (e.g., mechanical ventilation), and epidemiologic studies thus count the "treated incidence" rather than the actual incidence. In the United States, astringent sepsis is recorded in two% of patients admitted to the hospital. Of these patients, one-half are treated in the intensive intendance unit (ICU), representing ten% of all ICU admissions.6,vii The number of cases in the United states of america exceeds 750,000 per year7 and was recently reported to be ascent.8 Nevertheless, several factors — new International Classification of Diseases, 9th Revision (ICD-ix) coding rules, defoliation over the distinction betwixt septicemia and severe sepsis, the increasing capacity to provide intensive care, and increased awareness and surveillance — confound the interpretation of temporal trends.

Studies from other high-income countries show similar rates of sepsis in the ICU.ix The incidence of severe sepsis outside modern ICUs, particularly in parts of the globe in which ICU care is deficient, is largely unknown. Extrapolating from treated incidence rates in the Us, Adhikari et al. estimated up to 19 1000000 cases worldwide per year.10 The true incidence is presumably far college.

Astringent sepsis occurs as a result of both customs-acquired and wellness intendance–associated infections. Pneumonia is the most mutual cause, accounting for almost half of all cases, followed by intraabdominal and urinary tract infections. vii,8,11,12 Blood cultures are typically positive in only ane tertiary of cases, and in up to a third of cases, cultures from all sites are negative. seven,11,13,14 Staphylococcus aureus and Streptococcus pneumoniae are the most common gram-positive isolates, whereas Escherichia coli, klebsiella species, and Pseudomonas aeruginosa predominate among gram-negative isolates.eleven,14 An epidemiologic study of sepsis showed that during the menstruation from 1979 to 2000, gram-positive infections overtook gram-negative infections.xv All the same, in a more contempo study involving 14,000 ICU patients in 75 countries, gram-negative bacteria were isolated in 62% of patients with severe sepsis who had positive cultures, gram-positive leaner in 47%, and fungi in 19%.12

Take a chance factors for astringent sepsis are related both to a patient's predisposition for infection and to the likelihood of acute organ dysfunction if infection develops. There are many well-known risk factors for the infections that most commonly precipitate astringent sepsis and septic shock, including chronic diseases (e.1000., the caused immunodeficiency syndrome, chronic obstructive pulmonary illness, and many cancers) and the use of immunosuppressive agents.7 Among patients with such infections, however, the chance factors for organ dysfunction are less well studied but probably include the causative organism and the patient's genetic composition, underlying health condition, and preexisting organ function, along with the timeliness of therapeutic intervention.16 Age, sex, and race or indigenous grouping all influence the incidence of severe sepsis, which is college in infants and elderly persons than in other age groups, higher in males than in females, and higher in blacks than in whites.7,17

At that place is considerable interest in the contribution of host genetic characteristics to the incidence and issue of sepsis, in office because of strong bear witness of inherited risk factors.xviii Many studies have focused on polymorphisms in genes encoding proteins implicated in the pathogenesis of sepsis, including cytokines and other mediators involved in innate amnesty, coagulation, and fibrinolysis. Notwithstanding, findings are oft inconsistent, owing at to the lowest degree in role to the heterogeneity of the patient populations studied.19,twenty Although a recent genomewide clan study21 explored drug responsiveness in sepsis, no such large-scale studies of susceptibility to or outcome of sepsis take been performed.

Clinical Features

Tabular array 1. Table 1. Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.

The clinical manifestations of sepsis are highly variable, depending on the initial site of infection, the causative organism, the design of acute organ dysfunction, the underlying wellness status of the patient, and the interval earlier initiation of treatment. The signs of both infection and organ dysfunction may be subtle, and thus the most recent international consensus guidelines provide a long list of warning signs of incipient sepsis (Table ane).5 Acute organ dysfunction most unremarkably affects the respiratory and cardiovascular systems. Respiratory compromise is classically manifested every bit the acute respiratory distress syndrome (ARDS), which is defined as hypoxemia with bilateral infiltrates of noncardiac origin.22 Cardiovascular compromise is manifested primarily as hypotension or an elevated serum lactate level. After adequate volume expansion, hypotension frequently persists, requiring the use of vasopressors, and myocardial dysfunction may occur.23

The encephalon and kidneys are likewise often affected. Primal nervous system dysfunction is typically manifested as obtundation or delirium. Imaging studies generally evidence no focal lesions, and findings on electroencephalography are unremarkably consequent with nonfocal encephalopathy. Critical illness polyneuropathy and myopathy are also common, especially in patients with a prolonged ICU stay.24 Acute kidney injury is manifested equally decreasing urine output and an increasing serum creatinine level and oftentimes requires treatment with renal-replacement therapy. Paralytic ileus, elevated aminotransferase levels, altered glycemic command, thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and the euthyroid sick syndrome are all mutual in patients with severe sepsis.5

Outcome

Before the introduction of modern intensive care with the power to provide vital-organ support, severe sepsis and septic daze were typically lethal. Even with intensive care, rates of in-hospital death from septic stupor were ofttimes in excess of lxxx% equally recently as thirty years ago.25 However, with advances in training, improve surveillance and monitoring, and prompt initiation of therapy to care for the underlying infection and back up failing organs, mortality is now closer to 20 to 30% in many series.7,26 With decreasing death rates, attention has focused on the trajectory of recovery among survivors. Numerous studies have suggested that patients who survive to hospital discharge afterward sepsis remain at increased risk for death in the following months and years. Those who survive oft accept impaired physical or neurocognitive operation, mood disorders, and a depression quality of life.27 In most studies, determining the causal part of sepsis in such subsequent disorders has been difficult. However, a recent analysis of the Health and Retirement Study, involving a large, longitudinal cohort of crumbling Americans, suggested that severe sepsis significantly accelerated concrete and neurocognitive decline.28

Pathophysiology

Host Response

Figure i. Figure 1. The Host Response in Astringent Sepsis.

The host response to sepsis is characterized by both proinflammatory responses (superlative of panel, in ruby) and antiinflammatory immunosuppressive responses (bottom of panel, in blue). The management, extent, and duration of these reactions are determined by both host factors (east.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (eastward.m., microbial load and virulence). Inflammatory responses are initiated past interaction between pathogen-associated molecular patterns expressed by pathogens and pattern-recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible cistron 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–similar receptors [NLRs]). The upshot of exaggerated inflammation is collateral tissue harm and necrotic cell death, which results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in role by acting on the same pattern-recognition receptors that are triggered by pathogens.

Equally the concept of the host theory emerged, information technology was first assumed that the clinical features of sepsis were the result of overly exuberant inflammation. Afterward, Bone et al.29 advanced the idea that the initial inflammatory response gave way to a subsequent "compensatory antiinflammatory response syndrome." Still, information technology has become credible that infection triggers a much more complex, variable, and prolonged host response, in which both proinflammatory and antiinflammatory mechanisms can contribute to clearance of infection and tissue recovery on the one paw and organ injury and secondary infections on the other.30 The specific response in any patient depends on the causative pathogen (load and virulence) and the host (genetic characteristics and coexisting illnesses), with differential responses at local, regional, and systemic levels (Figure 1). The limerick and direction of the host response probably change over time in parallel with the clinical course. In general, proinflammatory reactions (directed at eliminating invading pathogens) are thought to be responsible for collateral tissue harm in severe sepsis, whereas antiinflammatory responses (important for limiting local and systemic tissue injury) are implicated in the enhanced susceptibility to secondary infections.

Innate Immunity

Knowledge of pathogen recognition has increased tremendously in the past decade. Pathogens activate immune cells through an interaction with pattern-recognition receptors, of which four main classes — toll-like receptors, C-blazon lectin receptors, retinoic acid inducible gene 1–like receptors, and nucleotide-binding oligomerization domain–like receptors — have been identified, with the last grouping partially acting in poly peptide complexes chosen inflammasomes (Figure i).31 These receptors recognize structures that are conserved among microbial species, so-called pathogen-associated molecular patterns, resulting in the upward-regulation of inflammatory gene transcription and initiation of innate immunity. The same receptors also sense endogenous molecules released from injured cells, so-chosen damage-associated molecular patterns, or alarmins, such equally high-mobility group protein B1, S100 proteins, and extracellular RNA, Dna, and histones.32 Alarmins are besides released during sterile injury such every bit trauma, giving rise to the concept that the pathogenesis of multiple organ failure in sepsis is not fundamentally unlike from that in noninfectious critical illness.32

Coagulation Abnormalities

Figure ii. Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.

Sepsis is associated with microvascular thrombosis caused past concurrent activation of coagulation (mediated by tissue cistron) and harm of anticoagulant mechanisms as a effect of reduced activity of endogenous anticoagulant pathways (mediated by activated poly peptide C, antithrombin, and tissue cistron pathway inhibitor), plus dumb fibrinolysis owing to enhanced release of plasminogen activator inhibitor type 1 (PAI-1). The chapters to generate activated protein C is dumb at least in part by reduced expression of two endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated past neutrophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion, which is aggravated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired by the loss of barrier function of the endothelium attributable to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial jail cell-to-cell tight junctions, loftier levels of angiopoietin 2, and a disturbed balance between sphingosine-i phosphate receptor 1 (S1P1) and S1P3 within the vascular wall, which is at least in role due to preferential induction of S1P3 through protease activated receptor i (PAR1) as a result of a reduced ratio of activated protein C to thrombin. Oxygen apply is impaired at the subcellular level because of impairment to mitochondria from oxidative stress.

Astringent sepsis is almost invariably associated with altered coagulation, frequently leading to disseminated intravascular coagulation.33 Excess fibrin degradation is driven past coagulation through the action of tissue factor, a transmembrane glycoprotein expressed past various prison cell types; by impaired anticoagulant mechanisms, including the protein C system and antithrombin; and by compromised fibrin removal owing to low of the fibrinolytic system (Figure 2).33 Protease-activated receptors (PARs) class the molecular link betwixt coagulation and inflammation. Among the four subtypes that have been identified, PAR1 in particular is implicated in sepsis.33 PAR1 exerts cytoprotective furnishings when stimulated by activated protein C or depression-dose thrombin but exerts disruptive effects on endothelial-cell barrier part when activated by high-dose thrombin.34 The protective issue of activated protein C in animal models of sepsis is dependent on its capacity to actuate PAR1 and not on its anticoagulant backdrop.34

Antiinflammatory Mechanisms and Immunosuppression

The immune system harbors humoral, cellular, and neural mechanisms that attenuate the potentially harmful effects of the proinflammatory response (Effigy 1).30 Phagocytes can switch to an antiinflammatory phenotype that promotes tissue repair, and regulatory T cells and myeloid-derived suppressor cells further reduce inflammation. In add-on, neural mechanisms can inhibit inflammation.35 In the and so-chosen neuroinflammatory reflex, sensory input is relayed through the afferent vagus nerve to the brain stem, from which the efferent vagus nerve activates the splenic nerve in the celiac plexus, resulting in norepinephrine release in the spleen and acetylcholine secretion by a subset of CD4+ T cells. The acetylcholine release targets α7 cholinergic receptors on macrophages, suppressing the release of proinflammatory cytokines.36 In animal models of sepsis,35 disruption of this neural-based organisation by vagotomy increases susceptibility to endotoxin daze, whereas stimulation of the efferent vagus nervus or α7 cholinergic receptors attenuates systemic inflammation.

Patients who survive early sepsis but remain dependent on intensive care take bear witness of immunosuppression, in part reflected by reduced expression of HLA-DR on myeloid cells.37 These patients ofttimes have ongoing infectious foci, despite antimicrobial therapy, or reactivation of latent viral infection.38,39 Multiple studies accept documented reduced responsiveness of blood leukocytes to pathogens in patients with sepsis,30 findings that were recently corroborated by postmortem studies revealing strong functional impairments of splenocytes obtained from patients who had died of sepsis in the ICU.37 Too the spleen, the lungs besides showed bear witness of immunosuppression; both organs had enhanced expression of ligands for T-cell inhibitory receptors on parenchymal cells.37 Enhanced apoptosis, especially of B cells, CD4+ T cells, and follicular dendritic cells, has been implicated in sepsis-associated immunosuppression and death.xl,41 Epigenetic regulation of gene expression may also contribute to sepsis-associated immunosuppression.42

Organ Dysfunction

Although the mechanisms that underlie organ failure in sepsis have been merely partially elucidated, dumb tissue oxygenation plays a key role (Figure two). Several factors — including hypotension, reduced carmine-cell deformability, and microvascular thrombosis — contribute to macerated oxygen commitment in septic stupor. Inflammation tin crusade dysfunction of the vascular endothelium, accompanied by cell death and loss of barrier integrity, giving rise to subcutaneous and trunk-cavity edema.43 In addition, mitochondrial damage caused past oxidative stress and other mechanisms impairs cellular oxygen use.44 Moreover, injured mitochondria release alarmins into the extracellular environment, including mitochondrial Dna and formyl peptides, which can actuate neutrophils and cause further tissue injury.45

Handling

Table 2. Tabular array 2. Guidelines for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Entrada.

The Surviving Sepsis Campaign, an international consortium of professional societies involved in critical care, treatment of infectious diseases, and emergency medicine, recently issued the third iteration of clinical guidelines for the management of severe sepsis and septic stupor (Table 2).23 The most of import elements of the guidelines are organized into two "bundles" of care: an initial management package to be accomplished within vi hours after the patient's presentation and a management bundle to be accomplished in the ICU.23 Implementation of the bundles is associated with an improved outcome.46,47

The principles of the initial management bundle are to provide cardiorespiratory resuscitation and mitigate the firsthand threats of uncontrolled infection. Resuscitation requires the use of intravenous fluids and vasopressors, with oxygen therapy and mechanical ventilation provided as necessary. The exact components required to optimize resuscitation, such as the selection and amount of fluids, appropriate type and intensity of hemodynamic monitoring, and role of adjunctive vasoactive agents, all remain the field of study of ongoing argue and clinical trials; many of these problems will be covered in this series.23 Withal, some form of resuscitation is considered essential, and a standardized approach has been advocated to ensure prompt, effective management.23 The initial direction of infection requires forming a likely diagnosis, obtaining cultures, and initiating advisable and timely empirical antimicrobial therapy and source control (i.e., draining pus, if appropriate).

The selection of empirical therapy depends on the suspected site of infection, the setting in which the infection developed (i.eastward., habitation, nursing home, or hospital), medical history, and local microbial-susceptibility patterns. Inappropriate or delayed antibiotic treatment is associated with increased mortality.48,49 Thus, intravenous antibiotic therapy should exist started as early as possible and should embrace all likely pathogens. It has not been adamant whether combination antimicrobial therapy produces improve outcomes than acceptable single-amanuensis antibiotic therapy in patients with astringent sepsis.50-53 Current guidelines recommend combination antimicrobial therapy but for neutropenic sepsis and sepsis caused by pseudomonas species. Empirical antifungal therapy should be used merely in patients at high gamble for invasive candidiasis.50

The patient should also exist moved to an appropriate setting, such equally an ICU, for ongoing care. After the first 6 hours, attention focuses on monitoring and support of organ function, avoidance of complications, and de-escalation of care when possible. De-escalation of initial broad-spectrum therapy may prevent the emergence of resistant organisms, minimize the risk of drug toxicity, and reduce costs, and evidence from observational studies indicates that such an approach is safe.54 The only immunomodulatory therapy that is currently advocated is a short form of hydrocortisone (200 to 300 mg per twenty-four hour period for upwards to 7 days or until vasopressor support is no longer required) for patients with refractory septic shock.23 This recommendation is supported by a meta-assay,55 but the two largest studies had alien results,56,57 and other clinical trials are ongoing. 58,59

Search for New Therapies

Recent Failures

Ane of the great disappointments during the past 30 years has been the failure to convert advances in our understanding of the underlying biologic features of sepsis into effective new therapies.60 Researchers have tested both highly specific agents and agents exerting more than pleiotropic effects. The specific agents can be divided into those designed to interrupt the initial cytokine pour (e.chiliad., antilipopolysaccharide or anti–proinflammatory cytokine strategies) and those designed to interfere with dysregulated coagulation (e.g., antithrombin or activated protein C).61 The only new agent that gained regulatory blessing was activated protein C.62 However, postapproval business organisation most the safety and efficacy of activated protein C prompted a repeat study, which did not show a do good and led the manufacturer, Eli Lilly, to withdraw the drug from the market.11 All other strategies thus far have non shown efficacy. With the recent decision to stop further clinical development of CytoFab, a polyclonal anti–tumor necrosis cistron antibody (ClinicalTrials.gov number, NCT01145560), there are no current large-calibration trials of anticytokine strategies in the handling of sepsis.

Amid the agents with broader immunomodulatory effects, glucocorticoids accept received the nigh attention. Intravenous immune globulin is also associated with a potential do good,63 but of import questions remain, and its utilize is non part of routine practice.23 Despite a large number of observational studies suggesting that the use of statins reduces the incidence or improves the consequence of sepsis and severe infection,64 such findings accept non been confirmed in randomized, controlled trials, and so the utilise of statins is not part of routine sepsis care. 23

Problems with Therapeutic Evolution

Faced with these disappointing results, many observers question the current approach to the development of sepsis drugs. Preclinical studies commonly examination drugs in young, healthy mice or rats exposed to a septic claiming (e.g., bacteria or bacterial toxins) with express or no ancillary handling. In dissimilarity, patients with sepsis are frequently elderly or have serious coexisting illnesses, which may affect the host response and increment the risk of acute organ dysfunction. Furthermore, death in the clinical setting often occurs despite the use of antibiotics, resuscitation, and intensive life support, and the disease mechanisms in such cases are probably very dissimilar from those underlying the early deterioration that typically occurs in animal models in the absence of supportive care. There are as well large between-species genetic differences in the inflammatory host response.65

In clinical studies, the enrollment criteria are typically very broad, the agent is administered on the basis of a standard formula for only a short period, there is petty information on how the agent changes the host response and host–pathogen interactions, and the master terminate point is death from whatsoever crusade. Such a inquiry strategy is probably overly simplistic in that it does not select patients who are most likely to benefit, cannot adjust therapy on the footing of the evolving host response and clinical course, and does non capture potentially important effects on nonfatal outcomes.

New Strategies

Consequently, hope is pinned on newer so-called precision-medicine strategies with better preclinical models, more targeted drug development, and clinical trials that incorporate ameliorate patient selection, drug commitment, and outcome measurement. For case, options to enrich the preclinical portfolio include the study of animals that are more genetically various, are older, or have preexisting disease. Longer experiments with more avant-garde supportive care would permit better mimicry of the later stages of sepsis and multiorgan failure, permitting the testing of drugs in a more than realistic setting and perhaps facilitating the measurement of outcomes such as cognitive and physical functioning. In addition, preclinical studies could be used to screen for potential biomarkers of a therapeutic response for which there are human homologues.

Activated poly peptide C mutants that lack anticoagulant properties are examples of more than targeted drug development and were shown to provide protection from sepsis-induced death in animals, without an increased risk of bleeding.66 Biomarkers such equally whole-genome expression patterns in peripheral-blood leukocytes may aid in stratifying patients into more homogeneous subgroups or in developing more targeted therapeutic interventions.67 The insight that severe sepsis can cause immunosuppression raises the possibility of using immune-stimulatory therapy (e.g., interleukin-7, granulocyte–macrophage colony-stimulating factor,68 or interferon-γ69), but ideally, such therapy would be used only in patients in whom immunosuppression is identified or predicted. Thus, such therapies could be deployed on the basis of laboratory measures, such as monocyte HLA-DR expression. In addition, business organization about accelerated neurocognitive decline in survivors of sepsis opens up avenues to explore agents currently being tested in patients with dementia and related conditions.

The designs of trials could be modified to more easily incorporate these ideas. For example, the considerable uncertainty at the beginning of a trial with regard to the appropriate selection of patients and drug-administration strategy and the possibility of handling interactions may be better handled with the apply of a Bayesian design. A trial could commence with multiple study groups that reflect the various uncertainties to be tested but then automatically narrow assignments to the all-time-performing groups on the ground of predefined-response adaptive randomization rules. Such designs could be peculiarly helpful when testing combination therapy or incorporating potential biomarkers of drug responsiveness.

Conclusions

Severe sepsis and septic stupor represent i of the oldest and most pressing problems in medicine. With advances in intensive intendance, increased awareness, and dissemination of evidence-based guidelines, clinicians have taken large strides in reducing the chance of imminent death associated with sepsis. However, equally more than patients survive sepsis, concern mounts over the lingering sequelae of what was previously a lethal event. Strategies are also needed to reach the many millions of patients with sepsis who are far from mod intensive intendance. At the aforementioned time, advances in molecular biology have provided not bad insight into the complexity of pathogen and alarm recognition past the homo host and of import clues to a host response that has gone awry. However, harnessing that information to provide effective new therapies has proved to be difficult. To further improve the consequence of patients with sepsis through the development of new therapeutic agents, newer, smarter approaches to clinical-trial blueprint and execution are essential.

Funding and Disclosures

Dr. Angus reports receiving grant support through his institution from Eisai, consulting fees from Idaho Technology, Pfizer, Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli Lilly for serving as a fellow member of a clinical-trial data and safe monitoring board. Dr. van der Poll reports receiving grant support through his establishment from Sirtris Pharmaceuticals and consulting fees from Eisai. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was updated on November 21, 2013, at NEJM.org.

Author Affiliations

From the CRISMA (Clinical Inquiry, Investigation, and Systems Modeling of Astute Disease) Heart, Department of Critical Care Medicine, University of Pittsburgh Schoolhouse of Medicine, Pittsburgh (D.C.A.); and the Center for Experimental and Molecular Medicine, Partitioning of Infectious Diseases, and Eye for Infection and Amnesty Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam (T.P.).

Address reprint requests to Dr. Angus at the Department of Critical Care Medicine, University of Pittsburgh, 614 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261, or at [email protected]; or to Dr. van der Poll at the Sectionalisation of Infectious Diseases, Academic Medical Eye, Meibergdreef 9, Rm. G2-130, 1105 AZ Amsterdam, the Netherlands, or at [email protected].

Supplementary Material

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