Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Respiratory Infections.

Pneumonia is one of the most common reasons for health care utilization in the United States. It can be caused by many different pathogens, but rarely is it able to be identified in specific cases. This has led most racial disparities research to focus on community acquired pneumonia and microbes of public health concern such as influenza, tuberculosis, and COVID-19. Differences have been shown to exist from prevention with vaccines to management and outcomes. COVID-19 has led to a significant increase in the awareness of this topic.

U.S. Adult Critical Care Beds Per Capita: A 2021 County-Level Cross-Sectional Study.

Per capita geographic distribution of adult critical care beds can be utilized for healthcare resources assessments. OBJECTIVES: Describe the per capita distribution of staffed adult critical care beds across the United States. DESIGN SETTING AND PARTICIPANTS: Cross-sectional epidemiologic assessment of November 2021 hospital data from the Department of Health and Human Services' Protect Public Data Hub. MAIN OUTCOMES AND MEASURES: Staffed adult critical care beds per adult population. RESULTS: The percent of hospitals reporting was high and varied by state/territory (median, 98.6% of states' hospitals reporting; interquartile range [IQR], 97.8-100%). There was a total of 4,846 adult hospitals accounting for 79,876 adult critical care beds in the United States and its territories. Crudely aggregated at the national-level, this calculated to 0.31 adult critical care beds per 1,000 adults. The median crude per capita density of adult critical care beds per 1,000 adults across U.S. counties was 0.00 per 1,000 adults (county, IQR 0.00-0.25; range, 0.00-8.65). Spatially smoothed county-level estimates were obtained using Empirical Bayes and Spatial Empirical Bayes approaches, resulting in an estimated 0.18 adult critical care beds per 1,000 adults (range from both methodological estimates, 0.00-8.20). When compared to counties in the lower quartile of adult critical care bed density, counties in the upper quartile had higher average adult population counts (mean 159,000 vs 32,000 adults per county) and a choropleth map demonstrated high densities of beds in urban centers with low density across rural areas. CONCLUSIONS AND RELEVANCE: Among U.S. counties, the density of critical care beds per capita was not uniformly distributed, with high densities concentrated in highly populated urban centers and relative scarcity in rural areas. As it is unknown what defines deficiency and surplus in terms of outcomes and costs, this descriptive report serves as an additional methodological benchmark for hypothesis-driven research in this area.

Intermediate or Intensive Care Unit Admission across Race and Ethnicity.

OBJECTIVES: The aim of this study was to assess the association between race and ethnicity and admission to intermediate (IMCUs) or intensive care units (ICUs) among hospitalized patients. METHODS: Using Florida hospital discharge data from the Agency for Healthcare Research and Quality-sponsored State Inpatient Database in 2017, we assessed the relationship between race (White, Black, Other) and Hispanic ethnicity and IMCU or ICU admission. Demographic covariates included age, sex, quartile of household income for patient ZIP code, insurance status, and patient residence. An adjusted model assessed the association between race and ethnicity and IMCU or ICU admission using log binomial regression with generalized estimating equations after controlling for demographic characteristics and the Elixhauser Comorbidity Index. RESULTS: After controlling for demographics and comorbidities, the prevalence of IMCU or ICU admission was higher among non-Hispanic Blacks (adjusted prevalence ratio [aPR] 1.04; 95% confidence interval [CI] 1.02-1.05) and non-Hispanic patients of other races (aPR 1.03; 95% CI 1.01-1.04) compared with non-Hispanic Whites. The prevalence of IMCU or ICU use was lower among Hispanic Whites (aPR 0.98; 95% CI 0.86-1.00) and Hispanics of other races (aPR 0.96; 95% CI 0.95-0.98) compared with non-Hispanic Whites after controlling for other demographic characteristics and comorbidities. CONCLUSIONS: Among hospitalized patients, racial minorities are slightly more likely to use higher levels of care, whereas Hispanic patients are generally slightly less likely than non-Hispanic White patients to use higher levels of care. Further evaluation is needed to identify reasons for disparate IMCU or ICU admission.

Early Albumin Infusion Is Associated With Greater Survival to Discharge Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury.

Adults hospitalized with sepsis/septic shock commonly develop acute kidney injury (AKI) which imposes a significant burden on the healthcare system. The administration of early human albumin in this patient population may yield more efficient healthcare resource utilization. Objectives: To examine the association between early use of albumin and time to discharge in adults who develop severe AKI while hospitalized with sepsis/septic shock. Design: Retrospective cohort study using de-identified electronic health records from a national database (Cerner Health Facts; Cerner Corp., Kansas City, MO). Setting and Participants: Patients (n = 2,829) hospitalized between January 2013 and April 2018 with a diagnosis of sepsis/septic shock (identified using International Classification of Diseases, 9th Revision and 10th Revision codes) who developed severe AKI (stage 3 according to Kidney Disease Improving Global Outcomes criteria) during hospitalization (n = 2,845 unique encounters). Main Outcomes and Measures: Patients were grouped according to timing of albumin exposure: within less than or equal to 24 hours of admission ("early albumin") or unexposed/exposed late ("nonearly albumin"). A cause-specific hazard model, censoring for death/discharge to hospice, was used to examine the association between "early albumin" and the rate of hospital discharge with clinical stability. Results: Albumin was administered early in 8.6% of cases. Cases with early albumin administration had a median time to discharge of 13.2 days compared with 17.0 in the nonearly group (Log-rank p < 0.0001). An adjusted analysis showed that the rate of hospital discharge with clinical stability increased by 83% in the early albumin group compared with the nonearly group (hazard ratio, 1.832; 95% CI, 1.564-2.146; p < 0.001 nonearly group. Conclusions and Relevance: The use of albumin within 24 hours of hospital admission was associated with a shorter time to discharge and a higher rate of discharge with clinical stability, suggesting an improvement in healthcare resource utilization among patients with sepsis/septic shock who developed stage 3 AKI during hospitalization.

Pulmonary hypertension mortality trends in United States 1999-2019.

PURPOSE: Pulmonary hypertension (PH) is a heterogenous, often progressive disorder leading to right heart failure and death. Previous analyses show stable PH mortality rates from 1980 to 2001 but increasing from 2001 to 2010 especially among women and non-Hispanic (NH) Black. This study seeks to identify recent trends in PH mortality in the United States from 1999 to 2019. METHODS: Mortality rates among individuals more than or equal to 15 years of age were obtained from the Centers for Disease Control and Prevention's (CDC) Wide-Ranging Online Data for Epidemiology Research (WONDER) database. ICD-10 codes were used to identify individuals with PH. RESULTS: Between 1999 and 2019, PH was included as a cause on 429,105 recorded deaths. The average age-adjusted PH mortality rate was 7.9 per 100,000 individuals and increased by 1.9% per year. Higher age-adjusted mortality rates were experienced by females and NH Black persons. The crude mortality rate was 105.4 per 100,000 among those decedents 85 or older. From 1999 to 2019, mortality in PH and left heart disease co-occurrence increased at nearly double the annual rate of the overall PH group. CONCLUSIONS: Despite therapeutic advances for selected PH subgroups, the overall age-adjusted PH mortality rate increased significantly from 1999 to 2019 and previously reported racial disparities have persisted. These findings emphasize the need for additional study to improve outcomes in PH.

Home-to-hospital distance and outcomes among community-acquired sepsis hospitalizations.

PURPOSE: To examine the hypothesis that longer distance from home-to-hospital is associated with worse outcomes among hospitalizations for community-acquired sepsis. METHODS: A secondary analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) prospective cohort of 30,239 white and Black US adults greater than or equal to 45 years old was conducted. Self-reported hospitalizations for serious infection between 2003 and 2012 fulfilling 2/4 systemic inflammatory response syndrome criteria were included. Estimated driving distance was derived from geocoded data and evaluated continuously and as quartiles of very close, close, far, very far (<3.1, 3.1-5.8, 5.9-11.5, and >11.5 miles respectively). The primary outcome was 30-day mortality while the secondary outcome was sequential organ failure assessment (SOFA) score on arrival. RESULTS: Of the 912 hospitalizations for community-acquired sepsis had adequate data for analysis. The median (interquartile range) estimated driving distance was 5.8 miles (3.1,11.7), and 54 (5.9%) experienced the primary outcome. Compared to living very close, participants living very far had a mortality odds ratio of 1.30 (95% CI 0.64,2.62) and presenting SOFA score difference of 0.33 (95% CI -0.03,0.68). CONCLUSIONS: Among a national sample of community-acquired sepsis hospitalizations, there was no significant association between home-to-hospital distance and either 30-day mortality or SOFA score on hospital presentation.

Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans.

Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition. DESIGN: Observational study. SETTING: Veteran's Health Affairs (VHA) Genealogy/Phenotype resource, a U.S. genealogy database with veterans individually linked to VHA electronic health records. PATIENTS: Sepsis was identified using International Classification of Disease, 9th Edition and 10th Edition codes. There were two comparison groups: one composed of the all veterans with linked data and deep genealogy and the other included 1,000 sets of controls, each set randomly sampled from the entire cohort after matching on sex and 10-year birth year range on a 1:1 ratio with cases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 4,666 cases of sepsis from 2001 to 2018, of which 96% were male and 80% greater than or equal to 65 years old. Utilizing the Genealogical Index of Familiality, there was a significant excess of pairwise relatedness among sepsis cases over that in the control sets sampled from VHA population (p = 0.03). The relative risk (RR) of sepsis among identified relatives compared with the larger linked VHA cohort demonstrated an excess of sepsis cases in the first-degree (RR, 1.39; 95% CI, 1.03-1.92; p = 0.05) and second-degree (RR, 1.50; 95% CI, 1.07-2.17; p = 0.04) relatives that were not demonstrated in higher degree relatives. The sepsis cases clustered into 1,876 pedigrees of which 628 had a significant excess of sepsis cases among the descendants (p < 0.05). CONCLUSIONS: The data from this cohort of nearly all male U.S. veterans demonstrate evidence for contribution of an inherited predisposition to sepsis and the existence of pedigrees with a significant excess of diagnoses that provide a valuable resource for identification of the predisposition genes and variants responsible. This complements studies on individual genetic variants toward estimating the heritability patterns and clinical relevance of genetic sepsis predisposition.

An updated approach to determine minimal clinically important differences in idiopathic pulmonary fibrosis.

INTRODUCTION: Current medications for idiopathic pulmonary fibrosis (IPF) have not been shown to impact patient-reported outcome measures (PROMs), highlighting the need for accurate minimal clinically important difference (MCID) values. Recently published consensus standards for MCID studies support using anchor-based over distribution-based methods. The aim of this study was to estimate MCID values for worsening in IPF using only an anchor-based approach. METHODS: We conducted secondary analyses of three randomised controlled trials with different inclusion criteria and follow-up intervals. The health transition question in the 36-Item Short-Form Health Survey (SF-36) questionnaire was used as the anchor. We used receiver operating curves to assess responsiveness between the anchor and 10 variables (four physiological measures and six PROMs). We used an anchor-based method to determine the MCID values of variables that met the responsiveness criteria (area under the curve ≥0.70). RESULTS: 6-min walk distance (6MWD), the St George's Respiratory Questionnaire (SGRQ), physical component score (PCS) of SF-36 and University of California, San Diego, Shortness of Breath Questionnaire (UCSD SOBQ) met the responsiveness criteria. The MCID value for 6MWD was -75 m; the MCID value for SF-36 PCS was -7 points; the MCID value for SGRQ was 11 points; and the MCID value for the UCSD SOBQ was 11 points. CONCLUSIONS: The MCID estimates of 6MWD, SGRQ, SF-36 and UCSD SOBQ using only anchor-based methods were considerably higher compared to previously proposed values. A single MCID value may not be applicable across all classes of disease severity or durations of follow-up time.

The Epidemiology of Adult Tracheostomy in the United States 2002-2017: A Serial Cross-Sectional Study.

Describe the longitudinal national epidemiology of tracheostomies performed in acute care hospitals and describe the annual rate of tracheostomy performed for patients with respiratory failure with invasive mechanical ventilation. DESIGN: Serial cross-sectional study. SETTING: The 2002-2014 and 2016-2017 Healthcare Utilization Project's National Inpatient Sample datasets. PATIENTS: Discharges greater than or equal to 18 years old, excluding those with head and neck cancer or transferred from another hospital. We used diagnostic and procedure codes from the International Classification of Diseases, 9th and 10th revisions to define cases of respiratory failure, invasive mechanical ventilation, and tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were an estimated 80,612 tracheostomies performed in 2002, a peak of 89,545 tracheostomies in 2008, and a nadir of 58,840 tracheostomies in 2017. The annual occurrence rate was 37.5 (95% CI, 34.7-40.4) tracheostomies per 100,000 U.S. adults in 2002, with a peak of 39.7 (95% CI, 36.5-42.9) in 2003, and with a nadir of 28.4 (95% CI, 27.2-29.6) in 2017. Specifically, among the subgroup of hospital discharges with respiratory failure with invasive mechanical ventilation, an annual average of 9.6% received tracheostomy in the hospital. This changed over the study period from 10.4% in 2002, with a peak of 10.9% in 2004, and with a nadir of 7.4% in 2017. Among respiratory failure with invasive mechanical ventilation discharges with tracheostomy, the annual proportion of patients 50-59 and 60-69 years old increased, whereas patients from 70 to 79 and greater than or equal to 80 years old decreased. The mean hospital length of stay decreased, and in-hospital mortality decreased, whereas discharge to intermediate care facilities increased. CONCLUSIONS: Over the study period, there were decreases in the annual total case volume and adult occurrence rate of tracheostomy as well as decreases in the rate of tracheostomy among the subgroup with respiratory failure with invasive mechanical ventilation. There is some evidence of changing patterns of patient selection for in-hospital tracheostomy among those with respiratory failure with invasive mechanical ventilation with decreasing proportions of patients with advanced age.

Minimal clinically important difference in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with an estimated median survival of 2-5 years and a significant impact on quality of life (QoL). Current approved medications, pirfenidone and nintedanib, have shown a reduction in annual decline of forced vital capacity but no impact on QoL. The minimal clinically important difference (MCID) is a threshold value for a change in a parameter that is considered meaningful by the patient rather than solely relying on statistically significant change in the parameter. This review provides a brief overview of the MCID methodology along with detailed discussion of reported MCID values for commonly used physiological measures and patient-reported outcome measures in IPF. While there is no gold standard methodology for determining MCID, there are certain limitations in the MCID literature in IPF, mainly the choice of death, hospitalisation and pulmonary function tests as sole anchors, and pervasive use of distribution-based methods which do not take into account the patient's input. There is a critical need to identify accurate thresholds of outcome measures that reflect patient's QoL over time in order to more precisely design and evaluate future clinical trials and to develop algorithms for patient-oriented management of IPF in outpatient clinics. EDUCATIONAL AIMS: To understand the concept of MCID and the methods used to determine these values.To understand the indications and limitations of MCID values in IPF.

Loss of Smell and Taste Among Healthcare Personnel Screened for Coronavirus 2019.

Among 283 symptomatic healthcare personnel (HCP) tested for SARS-CoV-2, 51 (18%) were positive. Among those 51 HCP, self reported loss of smell and taste were present in 51% and 52.9%, respectively, with either present in 60.8%. These symptoms had high specificity (93% each, 96% for either) for a positive SARS-CoV-2 test.

The Epidemiology of Respiratory Failure in the United States 2002-2017: A Serial Cross-Sectional Study.

OBJECTIVES: Respiratory failure with mechanical ventilation is a limited labor-intensive resource that is associated with high mortality. Understanding the longitudinal national epidemiology is essential for the organization of healthcare resources. DESIGN: Serial cross-sectional study. SETTING: The 2002-2017 Healthcare Utilization Project's National Inpatient Sample datasets. INTERVENTIONS: None. MEASUREMENTS: We use six diagnosis codes and five procedural codes from International Classification of Diseases, 9th Revision, Clinical Modification, and 19 diagnosis codes and 15 procedures codes from International Classification of Diseases, 10th Revision, Clinical Modification to examine national epidemiology of different case definitions for respiratory failure. RESULTS: In the United States in 2017, there were an estimated 1,146,195 discharges with a diagnosis of respiratory failure and procedural code for mechanical ventilation, with an average length of stay of 10.5 days and hospital charge of $158,443. Over the study period, there was an 83% increase in incidence from 249 to 455 cases per 100,000 adults with a 48% decrease in hospital mortality from 34% to 23%. Exploring a case definition that captures only diagnosis codes for respiratory failure, there was a 197% increase in annual incidence, from 429 to 1,275 cases per 100,000 adults with a 57% decrease in hospital mortality from 28% to 12%. For invasive mechanical ventilation without a requisite diagnosis code, there was no change in incidence over the study period, with the 2017 incidence at 359 cases per 100,000 adults, but a 19% decrease in hospital mortality from 37% to 30%. For the noninvasive mechanical ventilation procedural codes, there was a 437% increase in incidence from 41 to 220 cases per 100,000 adults, with a 38% decrease in hospital mortality from 16% to 10%. CONCLUSIONS: Examining different case definitions for respiratory failure, there was a large increase in the population incidence and decrease in the hospital mortality for respiratory failure diagnosis codes with more modest changes procedural codes for invasive mechanical ventilation. There was a large increase in incidence of noninvasive mechanical ventilation.

The gut microbiome's role in the development, maintenance, and outcomes of sepsis.

The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.

Higher serum vitamin D levels are associated with decreased odds of obstructive lung disease in the general population: an NHANES analysis (2007-2008 to 2009-2010).

BACKGROUND: Obstructive lung disease is a significant cause of morbidity and healthcare burden within the USA. A growing body of evidence has suggested that vitamin D levels can influence the course or incidence of obstructive lung disease. However, there is an insufficient previous investigation of this association. STUDY DESIGN AND METHODS: We used the National Health and Nutrition Examination Survey (NHANES) cycles 2007-2008 and 2009-2010 spirometry results of individuals aged 40 years and older to assess the association between serum 25-hydroxyvitamin D levels and obstructive lung disease, as defined by the American Thoracic Society using the lower limit of normal. We used stage multivariate survey-logistic regression. RESULTS: The final model included age, gender, body mass index, pack-years smoking history, season, income-to-poverty ratio and race/ethnicity. In the primary analysis using vitamin D as a continuous variable, there was no association between vitamin D levels and obstructive lung disease. We noted a trend between 'other Hispanic' self-identified race and serum vitamin D levels wherein higher levels were associated with higher odds of obstructive lung disease in this ethnicity, but not among other racial or ethnic groups (OR (95% CI)=1.40 (0.98 to 1.99), p=0.06). In a secondary analysis, when vitamin D was measured as a categorical variable, there was a significant association between the highest levels of serum vitamin D levels and lesser odds of obstructive lung disease (OR (95% CI)=0.77 [0.61 to 0.98], p=0.04). CONCLUSIONS: Higher serum vitamin D levels among adults are associated with decreased odds of obstructive lung disease in the general population. Results among non-Mexican Hispanic participants highlight the need for further research in minority populations. More work is needed to address the course and incidence of lung disease in the USA.

Definitions, Epidemiology, Clinical Risk Factors, and Health Disparities in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a syndrome of inflammatory lung injury currently defined as the rapid onset of hypoxemia and radiographic opacities from a recent direct or indirect insult that is not explained by other causes. While the diagnostic criteria used to define ARDS are helpful in the clinical setting, they are not entirely specific for the characteristic pathophysiology of diffuse alveolar lung damage. This case definition introduces challenges to the reliable and accurate epidemiologic study of the condition. Within these limitations, ARDS appears to be a condition that is relatively rare within the general population but common within the context of the intensive care unit. Furthermore, the frequency and outcomes of ARDS seem to vary between populations, with no clearly discernible temporal trends in incidence or case fatality that are uniform across studies.

Physician agreement on the diagnosis of sepsis in the intensive care unit: estimation of concordance and analysis of underlying factors in a multicenter cohort.

BACKGROUND: Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. METHODS: We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κ free) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. RESULTS: Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κ free 0.68), (2) the consensus discharge diagnosis of the site investigators (κ free 0.62), and (3) the consensus diagnosis of the external expert panel (κ free 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κ free 0.79). When stratified by infection site, κ free for agreement between initial and later diagnoses had a mean value + 0.24 (range - 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. CONCLUSIONS: Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.