Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.

Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) After Surgical Sepsis.

OBJECTIVE: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. BACKGROUND: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. METHODS: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. RESULTS: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). CONCLUSIONS: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study.

BACKGROUND: The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection. STUDY DESIGN: This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection. RESULTS: The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospital-acquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality). CONCLUSION: There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.

Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes.

OBJECTIVE: We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit (SICU) patients with sepsis. SUMMARY OF BACKGROUND DATA: As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. METHODS: We performed a prospective, longitudinal cohort study of SICU patients with sepsis. RESULTS: Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n = 189, 63%) exhibited a rapid recovery (RAP), whereas 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all P < 0.01). At 12 months, overall cohort performance status was persistently worse than presepsis baseline (WHO/Zubrod score 1.4 ±â€Š0.08 vs 2.2 ±â€Š0.23, P > 0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27; 95% confidence interval, 1.14-1.41, P < 0.0001). Among CCI patients, independent risk factors for death by 12 months included severity of comorbidities and persistent organ dysfunction (sequential organ failure assessment ≥6) at day 14 after sepsis onset. CONCLUSIONS: There is discordance between low inpatient mortality and poor long-term outcomes after surgical sepsis, especially among older adults, increasing comorbidity burden and patients that develop CCI. This represents important information when discussing expected outcomes of surgical patients who experience a complicated clinical course owing to sepsis.

The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs.

OBJECTIVES: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. DESIGN: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. SETTING: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. PATIENTS: Adult critically ill patients that survived 14 days or longer after sepsis onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. CONCLUSIONS: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

Prognostic value of NT-proBNP levels in the acute phase of sepsis on lower long-term physical function and muscle strength in sepsis survivors.

BACKGROUND: Sepsis survivors often develop chronic critical illness (CCI) and demonstrate the persistent inflammation, immunosuppression, and catabolism syndrome predisposing them to long-term functional limitations and higher mortality. There is a need to identify biomarkers that can predict long-term worsening of physical function to be able to act early and prevent mobility loss. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-accepted biomarker of cardiac overload, but it has also been shown to be associated with long-term physical function decline. We explored whether NT-proBNP blood levels in the acute phase of sepsis are associated with physical function and muscle strength impairment at 6 and 12 months after sepsis onset. METHODS: This is a retrospective analysis conducted in 196 sepsis patients (aged 18-86 years old) as part of the University of Florida (UF) Sepsis and Critical Illness Research Center (SCIRC) who consented to participate in the 12-month follow-up study. NT-proBNP was measured at 24 h after sepsis onset. Patients were followed to determine physical function by short physical performance battery (SPPB) test score (scale 0 to12-higher score corresponds with better physical function) and upper limb muscle strength by hand grip strength test (kilograms) at 6 and 12 months. We used a multivariate linear regression model to test an association between NT-proBNP levels, SPPB, and hand grip strength scores. Missing follow-up data or absence due to death was accounted for by using inverse probability weighting based on concurrent health performance status scores. Statistical significance was set at p ≤ 0.05. RESULTS: After adjusting for covariates (age, gender, race, Charlson comorbidity index, APACHE II score, and presence of CCI condition), higher levels of NT-proBNP at 24 h after sepsis onset were associated with lower SPPB scores at 12 months (p < 0.05) and lower hand grip strength at 6-month (p < 0.001) and 12-month follow-up (p < 0.05). CONCLUSIONS: NT-proBNP levels during the acute phase of sepsis may be a useful indicator of higher risk of long-term impairments in physical function and muscle strength in sepsis survivors.

Association between air pollution and mammographic breast density in the Breast Cancer Surveilance Consortium.

BACKGROUND: Mammographic breast density is a well-established strong risk factor for breast cancer. The environmental contributors to geographic variation in breast density in urban and rural areas are poorly understood. We examined the association between breast density and exposure to ambient air pollutants (particulate matter <2.5 µm in diameter (PM2.5) and ozone (O3)) in a large population-based screening registry. METHODS: Participants included women undergoing mammography screening at imaging facilities within the Breast Cancer Surveillance Consortium (2001-2009). We included women aged ≥40 years with known residential zip codes before the index mammogram (n = 279,967). Breast density was assessed using the American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS) four-category breast density classification. PM2.5 and O3 estimates for grids across the USA (2001-2008) were obtained from the US Environmental Protection Agency Hierarchical Bayesian Model (HBM). For the majority of women (94%), these estimates were available for the year preceding the mammogram date. Association between exposure to air pollutants and density was estimated using polytomous logistic regression, adjusting for potential confounders. RESULTS: Women with extremely dense breasts had higher mean PM2.5 and lower O3 exposures than women with fatty breasts (8.97 vs. 8.66 ug/m3 and 33.70 vs. 35.82 parts per billion (ppb), respectively). In regression analysis, women with heterogeneously dense vs. scattered fibroglandular breasts were more likely to have higher exposure to PM2.5 (fourth vs. first quartile odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.16 - 1.23). Women with extremely dense vs. scattered fibroglandular breasts were less likely to have higher levels of ozone exposure (fourth vs. first quartile OR = 0.80, 95% CI 0.73-0.87). CONCLUSION: Exposure to PM2.5 and O3 may in part explain geographical variation in mammographic density. Further studies are warranted to determine the causal nature of these associations.

The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers.

OBJECTIVE: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. DESIGN: Prospective observational cohort study (NCT01810328). SETTING: Two level-one trauma centers in the United States. PATIENTS: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long-term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95). CONCLUSIONS: Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.

Adolescent fiber intake and mammographic breast density in premenopausal women.

BACKGROUND: To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women. METHODS: This study included 743 cancer-free premenopausal women (mean age, 44.9 years) within the Nurses' Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts). RESULTS: In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake (fruits, vegetables, or nuts) during adolescence were associated with any of the mammographic density phenotypes. CONCLUSIONS: Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density.

Associations of individual characteristics and lifestyle factors with metabolism of di-2-ethylhexyl phthalate in NHANES 2001-2012.

BACKGROUND: Previous studies suggest that a higher ratio of primary to secondary metabolites of di-2-ethylhexyl phthalate (DEHP), reflective of a slower DEHP conversion rate, is associated with a greater physiologic effect. We examined associations of several individual characteristics and lifestyle factors with the ratio of mono-2-ethylhexyl phthalate to mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHP:MEHHP) and %MEHP (the ratio of MEHP to the sum of the secondary metabolites). METHODS: We used the data from the National Health and Nutrition Examination Survey, 2001-2012. The study included adults with BMI<30 and no diabetes. Pregnant women were excluded. We examined associations of age, race, gender, Body Mass Index, smoking, alcohol and caffeine consumption, medication use, cancer history, and menopausal status and postmenopausal hormone use (in women) with MEHP:MEHHP and %MEHP using multivariable linear regression. The values for %MEHP were log-transformed in the analysis. RESULTS: In multivariable analysis, non-Caucasian individuals had higher %MEHP (non-Hispanic Blacks: ß=0.114, 95% Confidence interval [CI]: 0.050, 0.177; Hispanic: ß=0.089, 95% CI: 0.024, 0.154; other race: ß=0.126, 95% CI: 0.033, 0.219). Age was inversely associated with MEHP:MEHHP (ß=-0.001, 95% CI: -0.002, -0.001) and %MEHP (ß=-0.006, 95% CI: -0.008, -0.004). Overweight individuals had lower MEHP: MEHHP and lower %MEHP (ß=-0.035, 95% CI: 0.062, -0.008 and ß=-0.104, 95% CI: -0.162, -0.046, respectively). Alcohol consumption was inversely associated with %MEHP among men (p-trend=0.03). CONCLUSIONS: Individual and lifestyle characteristics are associated with differences in DEHP metabolism. Understanding underlying biological mechanisms could help to identify individuals at a greater risk of adverse effects from DEHP exposure.

Different distribution of NOTCH1 mutations in chronic lymphocytic leukemia with isolated trisomy 12 or associated with other chromosomal alterations.

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries. Chromosomal abnormalities commonly found using conventional cytogenetics and FISH are del(11)(q22-23), trisomy 12, del(13)(q14), and del(17)(p13). Trisomy 12 is the most frequent numerical abnormality in CLL. It can appear isolated or associated with other chromosomal aberrations, including t(14;18)(q32;q21) and trisomy 18. The aim of this study was to determine whether CLL patients with isolated trisomy 12 or associated with other chromosomal alterations have different clinico-pathological features, including a different distribution NOTCH1 mutation. Patients were classified into four groups: Group 1, isolated trisomy 12 (n=14); Group 2, trisomy 12 plus trisomy 18 (n=4); Group 3, trisomy 12 plus t(14;18) (n=8); and Group 4: patients with trisomy 12 plus other abnormalities not involving BCL2 (n=28). The Binet stage and expression of ZAP70 were significantly different among cytogenetic groups. NOTCH1 mutations were detected in 6/12 (50%) patients from Group 1, 4/25 (16%) patients from Group 4, and in no patient from groups 2 and 3 (P=0.020). Patients in Group 2 had a more rapid disease progression (median Treatment-free Survival 2 months) as against patients from Groups 1 (50 months), 3 (69 months), or 4 (68 months; P=0.001). These findings indicate that the distribution of NOTCH1 mutations in CLL with trisomy 12 is heterogeneous and that the presence of additional chromosomal abnormalities such as trisomy 18 could change the prognosis of these patients.

Older Adults Demonstrate Biomarker Evidence of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) After Sepsis.

BACKGROUND: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. METHOD: Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. RESULTS: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis. CONCLUSION: Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

Estimated vs measured energy expenditure in ventilated surgical-trauma critically ill patients.

BACKGROUND: The American and European guidelines recommend measuring resting energy expenditure (REE) using indirect calorimetry (IC). Predictive equations (PEs) are used to estimate REE, but there is limited evidence for their use in critically ill patients. The aim of this study is to evaluate the degree of agreement and accuracy between IC-measured REE (REE-IC) and 10 different PEs in mechanically ventilated critically ill patients with surgical trauma who met their estimated energy requirement. METHODS: REE-IC was retrospectively compared with REE-PE by 10 PEs. The degree of agreement between REE-PE and REE-IC was analyzed by the Bland-Altman test (BAt) and the concordance correlation coefficient (CCC). The accuracy was calculated by the percentage of patients whose REE-PE values differ by up to ±10% in relation to REE-IC. All analyses were stratified by gender and body mass index (BMI; <25 vs ≥25). RESULTS: We analyzed 104 patients and the closest estimate to REE-IC was the modified Harris-Benedict equation (mHB) by the BAt with a mean difference of 49.2 overall (61.6 for males, 28.5 for females, 67.5 for BMI <25, and 42.5 for BMI ≥25). The overall CCC between the REE-IC and mHB was 0.652 (0.560 for males, 0.496 for females, 0.570 for BMI <25, and 0.598 for BMI ≥25). The mHB equation was the most accurate with an overall accuracy of 44.2%. CONCLUSION: The effectiveness of PEs for estimating the REE of mechanically ventilated surgical-trauma critically ill patients is limited. [Correction added on 17 February 2022, after first online publication: The word "with" was deleted before "is limited" in the preceding sentence.] Nonetheless, of the 10 equations examined, the closest to REE-IC was the mHB equation.

Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma.

Follicular lymphoma (FL), a typically nodal disease, can arise in extranodal sites in about 10% of cases. The present study aimed to analyse the main differential features of patients with primary extranodal FL. Thirty-nine patients with primary extranodal FL were identified from a series of 354 patients with FL diagnosed at a single institution and their main clinicobiological features were analysed. Twenty patients (5·6%) had a primary extranodal non-cutaneous FL, and 19 (5·4%) a cutaneous FL. BCL2(+) and CD10(+) expression and BCL2/IGHJ@ rearrangement were less frequently observed in cutaneous FL. Absence of 'B'-symptoms, early stage, absence of bone marrow involvement and low-risk Follicular Lymphoma International Prognostic Index (FLIPI) were more frequent in extranodal FL. Five-year overall survival (OS) was 100%, 83% and 78% for cutaneous, non-cutaneous and nodal FL, respectively. When stage I patients were analysed separately, no differences were seen in terms of OS. In multivariate analysis, FLIPI was the most important variable to predict outcome. In conclusion, extranodal FLs, particularly cutaneous, have particular clinico-biological features, which differentiate them from nodal cases. Nevertheless, primary site of the disease is not the main issue to predict outcome.

The impact of sarcopenia and acute muscle mass loss on long-term outcomes in critically ill patients with intra-abdominal sepsis.

BACKGROUND: Sarcopenia is a known risk factor for poor outcomes across many chronic diseases. The impact on outcomes of both pre-existing sarcopenia and acute muscle wasting (AMW) in acute critical illness caused by sepsis remain unclear. METHODS: We conducted a prospective longitudinal cohort study of critically ill patients with intra-abdominal sepsis utilizing abdominal computed tomography at sepsis onset to determine baseline skeletal muscle index (SMI). Biomarkers of inflammation and catabolism were measured through 28 days while hospitalized. We performed follow-up evaluations of strength and physical function at 3, 6, and 12 months, with interval CT analyses at 3 and 12 months to evaluate changes in muscle mass. Measured clinical outcomes included development of chronic critical illness (≥14 days in intensive care with persistent organ dysfunction), long-term functional status, and 1 year mortality. RESULTS: Among 47 sepsis patients enrolled (mean age 53 ± 14 years), half (n = 23; 49%) were sarcopenic at baseline. Overall, sepsis patients exhibited acute and persistent muscle wasting with an average 8% decrease in SMI from baseline at 3 months (P = 0.0008). Sarcopenic (SAR) and non-sarcopenic (NSAR) groups were similar in regards to age and comorbidity burden. SAR patients had greater acute physiologic derangement (APACHE II, 18 vs. 12.5), higher incidence of multiple organ failure (57% vs. 17%), longer hospital (21 vs. 12 days) and intensive care unit length of stays (13 vs. 4 days), and higher inpatient mortality (17% vs. 0%; all P < 0.05). Pre-existing SAR was a strong independent predictor of early death or developing chronic critical illness (odds ratio 11.87, 95% confidence interval CI 1.88-74.9; P = 0.009, area under the curve 0.880) and was associated with significantly higher risk of 1-year mortality (34.9% vs. 4.2%, p = 0.007). Lower baseline SMI was also predictive of poor functional status at 12 months (OR 0.89, 95% confidence interval 0.80-0.99; p = 0.039, area under the curve 0.867). Additionally, SAR patients had AMW with persistent muscle mass loss at 3 months that was associated with decreased health-related quality of life and SF-36 physical function domains (P < 0.05). Persistent AMW at 3 months was not predictive of mortality or poor functional status, with return to near-baseline muscle mass among sepsis survivors by 6 months. CONCLUSIONS: Critically ill patients have an acute and persistent loss of muscle mass after intra-abdominal sepsis, which is associated with decreased health-related quality of life and physical function at 3 months. However, pre-existing sarcopenia, rather than persistent acute muscle mass loss at 3 months after sepsis, is independently associated with poor long-term functional status and increased 1 year mortality.

Lipid and lipoprotein predictors of functional outcomes and long-term mortality after surgical sepsis.

RATIONALE: Sepsis is a life-threatening, dysregulated response to infection. Lipid biomarkers including cholesterol are dynamically regulated during sepsis and predict short-term outcomes. In this study, we investigated the predictive ability of lipid biomarkers for physical function and long-term mortality after sepsis. METHODS: Prospective cohort study of sepsis patients admitted to a surgical intensive-care unit (ICU) within 24 h of sepsis bundle initiation. Samples were obtained at enrollment for lipid biomarkers. Multivariate regression models determined independent risk factors predictive of poor performance status (Zubrod score of 3/4/5) or survival at 1-year follow-up. MEASUREMENTS AND MAIN RESULTS: The study included 104 patients with surgical sepsis. Enrollment total cholesterol and high-density lipoprotein (HDL-C) levels were lower, and myeloperoxidase (MPO) levels were higher for patients with poor performance status at 1 year. A similar trend was seen in comparisons based on 1-year mortality, with HDL-C and ApoA-I levels being lower and MPO levels being higher in non-survivors. However, multivariable logistic regression only identified baseline Zubrod and initial SOFA score as significant independent predictors of poor performance status at 1 year. Multivariable Cox regression modeling for 1-year survival identified high Charlson comorbidity score, low ApoA-I levels, and longer vasopressor duration as predictors of mortality over 1-year post-sepsis. CONCLUSIONS: In this surgical sepsis study, lipoproteins were not found to predict poor performance status at 1 year. ApoA-I levels, Charlson comorbidity scores, and duration of vasopressor use predicted 1 year survival. These data implicate cholesterol and lipoproteins as contributors to the underlying pathobiology of sepsis.

Distinct immunologic endotypes are associated with clinical trajectory after severe blunt trauma and hemorrhagic shock.

BACKGROUND: The genomic/cytokine "storm" after severe trauma is well described. However, the differing composition, magnitude and resolution of this response, and its relationship to clinical outcomes remain unclear. METHODS: This is a secondary analysis of a prospective longitudinal cohort study of severely injured trauma patients in hemorrhagic shock. Peripheral blood sampling was performed at 0.5, 1, 4, 7, 14, and 28 days after injury for measurement of circulating immune biomarkers. K-means clustering using overall mean and trajectory slope of selected immunologic biomarkers were used to identify distinct temporal immunologic endotypes. Endotypes were compared with known clinical trajectories defined as early death (<14 days), chronic critical illness (CCI) (ICU length of stay of ≥14 days with persistent organ dysfunction), and rapid recovery (RAP) (ICU length of stay of <14 days with organ recovery). RESULTS: The cohort included 102 subjects enrolled across 2 level 1 trauma centers. We identified three distinct immunologic endotypes (iA, iB, and iC), each with unique associations to clinical trajectory. Endotype iA (n = 47) exhibited a moderate initial proinflammatory response followed by a return to immunologic homeostasis, with a primary clinical trajectory of RAP (n = 44, 93.6%). Endotype iB (n = 44) exhibited an early hyperinflammatory response with persistent inflammation and immunosuppression, with the highest incidence of CCI (n = 10, 22.7%). Endotype iC (n = 11) exhibited a similar hyperinflammatory response, but with rapid return to immunologic homeostasis and a predominant trajectory of RAP (n = 9, 81.8%). Patients with endotype iB had the highest severity/duration of organ dysfunction and highest incidence of nosocomial infections (50%, p = 0.001), and endotype iB was the predominant endotype of patients who developed CCI (10 of 13 patients, 76.9%; p = 0.002). CONCLUSION: We identified three distinct immunologic endotypes after severe injury differing the magnitude and duration of the early response. The clinical trajectory of CCI is characterized by an endotype (iB) defined by persistent alteration in inflammation/immunosuppression and is associated with poor clinical outcomes. LEVEL OF EVIDENCE: Prognostic, level III.

Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

Endothelial dysfunction after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation.

There is endothelial activation and damage in hematopoietic stem cell transplantation (HSCT). The impact of the conditioning and type of HSCT on endothelial dysfunction in the early phases of HSCT has been evaluated. Plasma samples were obtained before and at different times after autologous and allogeneic HSCT with and without early complications. Changes in soluble markers of endothelial damage (VWF, ADAMTS-13, sVCAM-1, sICAM-1, and sTNFRI) were measured. There were changes in all markers evaluated that followed different patterns in auto and allo settings. For VWF and sTNRI, progressive increases from day Pre to day 14 and to day 21 were observed in the auto and the allo group, respectively. ADAMTS-13 activity correlated inversely with VWF levels. Levels of sVCAM-1 decreased until day 7, and raised significantly to day 14 and to day 21 in the auto and the allo HSCT, respectively. No significant changes were detected for sICAM-1. Our results confirm that there is endothelial damage at the early phases of HSCT, apparently induced by the consecutive effects of the conditioning, the proinflammatory agents used during transplantation, the translocation of endotoxins across the damaged gastrointestinal tract, and the engraftment. However, the comparative analysis between patients with and without complications suggests that none of these markers has diagnostic or prognostic value.

Abdominal sepsis patients have a high incidence of chronic critical illness with dismal long-term outcomes.

BACKGROUND: As hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes. METHODS: Review of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis. RESULTS: Of the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p < 0.05). CONCLUSION: Over 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.