BACKGROUND:Interferons play a central role in antiviral defense, but their dysregulation contributes to inflammation and immune dysfunction in respiratory viral infections, including COVID-19. While interferon-stimulated genes (ISGs) are essential effectors of this response, their expression patterns in patients are heterogeneous and not always predictive of disease severity. The immunometabolic consequences of this heterogeneity remain poorly understood. METHODS:We analyzed hospitalized COVID-19 patients (n = 37) and uninfected controls (n = 31) using whole-blood transcriptomics, immune cell deconvolution, plasma proteomics, and standardized plasma metabolomics from a previously generated dataset within this cohort. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG score clusters. Plasma innate immune activation markers were measured by ELISA. Interferon-directed antibody reactivity was analyzed by multiplex bead-based assays measuring antigen reactivity. Functional immune responses were assessed via ex vivo stimulation of healthy donor immune cells with patient plasma, and correlations were performed between metabolites and immune activation markers. RESULTS:HIS patients exhibited increased inflammatory mediators and innate immune cell expansion compared with LIS and MIS groups. However, within the HIS group, severe cases displayed distinct metabolic and immune dysregulation. Specifically, severe HIS cases showed reductions in phospholipids, sphingolipids, and tricarboxylic acid cycle intermediates, suggestive of disrupted mitochondrial and lipid metabolism. Plasma from severe HIS patients tended to impair neutrophil and monocyte activation, indicating functional attenuation of innate immune activation within a shared high-ISG background. Correlation analysis revealed that branched-chain lipids, tryptophan-derived metabolites, and a branched-chain dicarboxylic acid were positively associated with immune activation markers. Although type-I interferon neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not fully account for the observed ISG heterogeneity or disease severity. CONCLUSIONS:High ISG expression in COVID-19 defines a transcriptional endotype associated with systemic inflammation and innate immune activation. However, severe cases within this group exhibit metabolic constraints and reduced innate immune responsiveness, supporting an immune-metabolic axis in which inflammatory mediators and altered lipid/energy metabolism intersect with innate immune function. These findings motivate future studies to determine whether interferon-associated immune-metabolic states during acute infection relate to persistent inflammation or post-acute sequelae in selected patient subsets.

The immune response to SARS-CoV-2 is highly heterogeneous, with interferon (IFN)-stimulated gene (ISG) expression playing a dual role in antiviral defense and immune dysregulation. To understand the broader implications of IFN-driven immune responses, we analyzed whole-blood transcriptomics, plasma proteomics, metabolomics, and immune cell profiling in COVID-19 patients and uninfected controls. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG expression clusters, independent of acute disease severity. HIS patients exhibited elevated inflammatory mediators (S100A8/A9, Neopterin) and altered metabolic profiles, yet immune activation patterns varied. Plasma from HIS cases induced differential activation in healthy neutrophils and monocytes, with severe HIS plasma showing reduced activation, suggesting the presence of suppressive soluble factors. Metabolomic analysis revealed widespread lipid metabolism dysregulation, including reductions in phospholipids, sphingolipids, and plasmalogens, which correlated with impaired immune activation. Branched-chain lipids and tryptophan metabolism products correlated strongly with monocyte and neutrophil activation, linking metabolic shifts to immune regulation. Despite IFN autoantibody detection in a subset of patients, no direct association with ISG expression was observed. These findings suggest that IFN-driven immune-metabolic dysregulation may persist beyond acute infection, contributing to post-viral inflammation, immune dysfunction, and susceptibility to long COVID or autoimmune-like sequelae. The interplay between IFN signaling, mitochondrial function, and lipid metabolism highlights novel therapeutic targets for immune modulation in viral infections and chronic inflammatory conditions. Understanding these immune signatures may inform precision medicine approaches in post-viral syndromes and immunometabolic disorders. ### Competing Interest Statement The authors have declared no competing interest.

Severe COVID-19 is characterized by immune-coagulation dysregulation, yet the contribution of related autoantibodies remains poorly understood. We investigated relationships between plasma autoantibody reactivities, whole-blood transcriptomics, plasma proteomics, and clinical laboratory parameters in a cohort of hospitalized COVID-19 patients. Transcriptomic analysis revealed that 42 curated coagulation and complement cascade genes were upregulated in severe cases compared to healthy controls, with 15 genes, including CR1L, ELANE, ITGA2B, ITGB3, VWF, TFPI, PROS1, MMRN1, and SELP (> 1.2 log2 fold-change), also significantly different from mild cases. Autoantibody profiling against eight coagulation-related proteins (ADAMTS13, Factor V, Protein S, SERPINC1, Apo-H, PROC1, Prothrombin, and PF4) showed reactivities below positivity thresholds across all groups. Using an exploratory approach, in severe cases, subthreshold autoantibody candidates (FDR < 0.25) showed negative correlation trends with select gene expressions and inflammatory markers (Factor V with IL-6 and CXCL10), suggesting potential disease-specific immunomodulatory associations. In contrast, while mild cases exhibited stronger gene-protein correlations, they showed limited associations with antigen reactivities or clinical laboratory parameters. Additionally, no correlations were observed between autoantibodies and platelet-counts or Fibrin-D-dimer levels. Age-associated increases in antigen reactivities were noted in severe disease, implying a role for immunosenescence. These findings support further investigation into the role of subthreshold autoantibody candidates in thromboinflammatory COVID-19 pathogenesis.

BACKGROUND:Residual immune activation is common in people living with HIV (PWH) despite antiretroviral therapy (ART) and may be associated with HIV-specific, as well as lifestyle-related factors. OBJECTIVE:We aimed to investigate markers of immune activation and neuronal injury in PWH on ART compared with controls with similar lifestyle. METHODS:Cerebrospinal fluid (CSF) and blood were collected from 50 men who have sex with men (MSM) with HIV on ART, 50 HIV-negative MSM on preexposure prophylaxis (PrEP), and 25 HIV-negative controls without PrEP. β2-microglobulin, neopterin, and neurofilament light protein (NfL) were analyzed. Cytomegalovirus and herpes simplex virus-2 serostatus, as well as sexually transmitted bacterial infections were registered. RESULTS:Serum and CSF β2-microglobulin and neopterin did not differ significantly between MSM with HIV and MSM on PrEP. However, both groups had significantly higher serum levels of β2-microglobulin and neopterin compared with HIV-negative controls without PrEP. Age-adjusted CSF NfL levels were also similar in MSM with HIV and MSM on PrEP, but higher than in controls without PrEP. A recent syphilis infection was associated with increased immune activation in CSF and blood. CONCLUSION:Increased levels of immune activation and neuronal injury markers were found in virologically suppressed MSM with HIV and MSM on PrEP compared with controls. These findings imply that other factors than HIV contribute to the residual immune activation and impact on neurons observed in MSM with HIV on ART, and emphasize the importance of appropriate controls with similar lifestyle in studies of biomarkers in PWH.

Severe COVID-19 is characterized by immune dysregulation and coagulation abnormalities, leading to complications such as thromboembolism and multi-organ failure. This study explores the relationship between autoantibodies targeting coagulation-related factors and gene expression in severe COVID-19. Whole-blood transcriptomics revealed upregulation of coagulation-related genes, including VWF and Factor V, in severe patients compared to mild cases and healthy controls. Autoantibody profiling against seven coagulation-related proteins (ADAMTS13, Factor V, Protein S, SERPINC1, Apo-H, PROC1, and Prothrombin) showed reactivities below established positivity thresholds, but mean-fluorescent intensities were elevated numerically in severe (Protein S) and convalescent (SERPINC1) patients. Correlation analysis revealed trends of negative associations between autoantibody reactivities and coagulation gene expression in severe cases, suggesting a potential role for autoantibodies in modulating immune-coagulation interactions warranting further orthogonal validation. Furthermore, age-dependent increases in subthreshold autoantibody reactivities were observed in severe cases, highlighting the potential impact of immunosenescence on disease severity. These findings do not exclude the possibility that subthreshold autoantibodies may contribute indirectly to immune-coagulation dynamics in severe COVID-19 through mechanisms beyond direct transcriptional regulation. This study highlights the complexity of immune-coagulation interactions and provides foundation for future research into their biological and clinical relevance, particularly for identifying biomarkers and therapeutic targets in thromboinflammatory diseases. ### Competing Interest Statement The authors have declared no competing interest.

Background: Angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recognizing that angiotensin receptor blockers upregulate the expression of ACE2, it has been proposed that these drugs may have a beneficial effect in Covid-19. Methods: We did an open-label randomized controlled trial to test whether addition of losartan to standard of care lowers the risk of death or intensive care unit (ICU) admission in patients with confirmed SARS-CoV-2 infection. The trial was run in a secondary hospital in Stockholm, Sweden between October 5th 2020 and June 21st 2021. Included patients were randomized using a 1:1 allocation ratio, to receive standard care or losartan in addition to standard care, using an electronic tool. The study was not blinded. The primary outcome was a composite of ICU admission or death within 28 days of admission. Findings: The study was terminated for futility after a planned interim analysis. A total of 302 patients were included of whom 151 were assigned to each group. The primary outcome occurred in 12 (7·9%) in the intervention group and 17 (11·4%) in the standard-of-care group (risk difference, 3·5 percentage points;95% confidence interval, −3·5-11). Among secondary outcomes, there were no differences between the groups in the occurrence of death (p=1·00), ICU admission (p=0·24), or the National Early Warning Scale 2 (NEWS2) score levels (p=0·15), but patients randomized to losartan treatment had a 6·7 percentage points lower risk of mechanical ventilation (95% confidence interval, 1·6-12·7) and 12·5 mg/L lower c-reactive protein concentration (95% confidence interval, 2·8-22 mg/L;p=0·01). Interpretation: Addition of losartan to standard care treatment did not result in a lower occurrence of the primary outcome of death or ICU admission.

OBJECTIVE:Low-level viraemia (LLV) occurs in some people with HIV (PWH) receiving antiretroviral therapy (ART) and has been linked to inferior treatment outcomes. We investigated factors associated with LLV in a nationwide cohort of Swedish PWH starting ART.METHODS:Participants were identified from the InfCareHIV register, with the following inclusion criteria: ART initiation 2006-2017, age >15 years, ≥4 viral load (VL) results available and no documented treatment interruptions or virologic failure (≥2 consecutive VL ≥200 copies/ml) during follow-up. Starting from 6 months after ART initiation, participants were followed for 24 months and categorised as viral suppression (VS; VL <50 copies/ml) or LLV (≥2 consecutive VL 50-199 copies/ml). We analysed the association between the following factors and LLV using multivariable logistic regression: sex, age, pre-ART VL and CD4 count, ART regimen, country of birth, HIV-1 subtype and transmission category.RESULTS:Among 3383 participants, 3132 (92.6%) had VS and 251 (7.4%) had LLV. In univariable analyses, factors associated with LLV were male sex, higher age, lower pre-ART CD4 count, higher pre-ART VL and ART regimen. After adjustment, the following factors were associated with LLV (adjusted odds ratio; 95% confidence interval): male sex (1.6; 1.1-2.3), higher pre-ART VL (2.7; 2.2-3.3), pre-ART CD4 count <200 cells/μl (1.6; 1.2-2.2), protease inhibitor (PI)-based regimen (1.5; 1.1-2.1), non-standard ART (2.4; 1.0-5.5) and injecting drug use (2.0; 1.1-3.7).CONCLUSION:Among Swedish PWH, LLV during ART was associated with markers of HIV disease severity before starting ART, male sex, injecting drug use and use of PI-based or non-standard ART regimens.

Objective: To investigate the association between HIV viremia exposure during antiretroviral therapy (ART) and cardiovascular disease (CVD) risk. Design: Nationwide observational cohort. Methods: Participants (age >15 years) from the Swedish nationwide InfCareHIV register initiating ART 1996-2017 were categorized in a time-updated manner into four viremia categories, starting from 12 months after ART initiation: suppression (<50 copies/ml), low-level viremia (50-199 copies/ml and 200-999 copies/ml, respectively), and high-level viremia (>= 1000 copies/ml). In addition, cumulative viremia was estimated as the area under the log viral load (VL) curve. Proportional subhazard models adjusted for sex, age, pre-ART CD4 and VL, injection drug use, and country of birth were used to analyze the association between viremia exposure and CVD risk (ischemic heart disease, stroke, and heart failure; data obtained by linkage to national registers), accounting for the competing risk of non-CVD death. Results: In all, 337 cases of CVD were observed during 44 937 person-years of follow-up (n = 6562). Higher viremia exposure was associated with CVD, both when parameterized as cumulative viremia (adjusted subhazard ratio [aSHR] per 1 log(10) copy x year/ml, 1.03; 95% confidence interval [CI], 1.01-1.05) and as viremia category (aSHR for high-level viremia versus suppression, 1.45; 95% CI, 1.03-2.05). We observed no association between CVD and low-level viremia compared with those with suppression. Conclusions: Higher exposure to HIV viremia was linked to CVD in ART recipients, whereas no increased risk was detected for people with low-level viremia compared with viral suppression. Causal inference is limited by the observational nature of this study.

Background: The impact of pre-antiretroviral treatment (ART) HIV-RNA on time to successful virological suppression and subsequent failure in HIV patients remains poorly investigated. Methods: We used the Swedish InfCareHIV database and the Danish HIV Cohort Study to evaluate impact of pre-ART HIV-RNA on primary virological suppression (HIV-RNA < 50 copies/ml) and risk of secondary virological failure (two consecutive HIV-RNA > 200 copies/ml or one >1000 copies/ml). The study included 3366 Swedish and 2050 Danish ART naïve individuals who initiated ART in the period 2000–2018. We used Kaplan–Meier estimates and Cox regression analyses to estimate absolute risks and hazard ratios. Results: In both cohorts, more than 95% of patients with a pre-ART HIV-RNA <100 000 copies/ml obtained virological suppression within the first year after ART initiation contrasting 74% (Sweden) and 86% (Denmark) in those with HIV-RNA >1 000 000 copies/ml. Almost all patients obtained virological suppression after four years irrespective of pre-ART HIV-RNA. In contrast, we observed no substantial impact of pre-ART HIV-RNA on risk of virological failure once virological suppression was obtained. Conclusion: High pre-ART HIV-RNA is strongly associated with increased time to successful virological suppression, but pre-ART HIV-RNA has no impact on risk of subsequent virological failure.

Abstract Background Human immunodeficiency virus (HIV) viremia could be involved in the increased risk of cancer in people with HIV (PWH) receiving combination antiretroviral therapy (cART). We analyzed the association between plasma HIV ribonucleic acid levels in PWH starting cART and incident invasive cancer using the Swedish cohort InfCare HIV linked with national registers. Methods Adults starting cART in 1996–2017 were included if they had ≥1 viral load (VL) measurement before receiving any antiretroviral agent (pre-ART VL) and ≥2 VLs ≥6 months after start of cART. Viremia during cART was analyzed both as viremia-copy-years and categorized as suppression (<50 copies/mL), low-level viremia ([LLV] 50–999 copies/mL), and nonsuppression (≥1000 copies/mL). The main outcome was a composite of invasive malignancies with increased incidence among PWH. We fitted proportional subhazard models (including sex, age, pre-ART CD4 count, and injection drug use) for both pre-ART VL and viremia during cART. Results After 32 105 person-years, 3254 of 4931 participants (66%) were classified as suppressed, 438 (9%) were classified as LLV, and 1221 (25%) were classified as nonsuppressed. Neither viremia category nor cumulative viremia during cART had a statistically significant association with cancer. Higher pre-ART VL was associated with cancer (adjusted subhazard ratio, 1.4; 95% confidence interval, 1.0–1.8); this remained statistically significant with viremia during cART in the model. In subanalysis, the association with pre-ART VL was statistically significant for acquired immune deficiency syndrome (AIDS)-defining and infection-related non-AIDS-defining cancer, but not for other malignancies. Conclusions In this nationwide cohort, pre-ART VL was an independent predictor of invasive cancer, whereas viremia profile during cART was not associated with cancer incidence.

Abstract Background The impact of low levels of human immunodeficiency virus (HIV) RNA (low-level viremia [LLV]) during combination antiretroviral therapy (cART) on clinical outcomes is unclear. We explored the associations between LLV and all-cause mortality, AIDS, and serious non-AIDS events (SNAEs). Methods We grouped individuals starting cART 1996–2017 (identified from the Swedish InfCare HIV register) as virologic suppression (VS; <50 copies/mL), LLV (repeated viral load, 50–999 copies/mL), and nonsuppressed viremia (NSV; ≥1000 copies/mL). Separately, LLV was subdivided into 50–199 and 200–999 copies/mL (reflecting different definitions of virologic failure). Proportional-hazard models (including sex, age, pre-ART CD4 count and viral load, country of birth, injection drug use, treatment experience and interruptions, and an interaction term between viremia and time) were fitted for the study outcomes. Results A total of 6956 participants were followed for a median of 5.7 years. At the end of follow-up, 60% were categorized as VS, 9% as LLV, and 31% as NSV. Compared with VS, LLV was associated with increased mortality (adjusted hazard ratio [aHR], 2.2; 95% confidence interval [CI], 1.3–3.6). This association was also observed for LLV 50–199 copies/mL (aHR, 2.2; 95% CI, 1.3–3.8), but was not statistically significant for LLV 200–999 copies/mL (aHR, 2.1; 95% CI, .96–4.7). LLV 50–999 copies/mL was not linked to increased risk of AIDS or SNAEs, but in subanalysis, LLV 200–999 copies/mL was associated with SNAEs (aHR, 2.0; 95% CI, 1.2–3.6). Conclusions In this population-based cohort, LLV during cART was associated with adverse clinical outcomes.

Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untar-geted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral -induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of car-bohydrate transporter, glucose transporter 1, in CD8(+) T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolomics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a substantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and personalized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as α-ketoglutarate, succinate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

BACKGROUND:There is little epidemiologic data on sepsis, particularly in areas of low antibiotic resistance. Here we report a prospective observational study of severe sepsis and septic shock in patients admitted to the Intensive Care Unit (ICU) at Karolinska University Hospital, Sweden. We aimed to evaluate short- and long-term mortality, and risk factors for sepsis-related death. A second aim was to investigate patient care in relation to gender.METHODS:One hundred and one patients with severe sepsis and septic shock, admitted to the ICU between 2005 and 2009, were prospectively enrolled in the study. Defined primary endpoints were day 28, hospital, and 1-year mortality. Risk factors for sepsis-related death was evaluated with a multivariate analysis in a pooled analysis with two previous sepsis cohorts. In the subset of patient admitted to the ICU through the emergency department (ED), time to clinician evaluation and time to antibiotics were assessed in relation to gender.RESULTS:In the septic cohort, the day 28, hospital, and 1-year mortality rates were 19, 29, and 34%, respectively. Ninety-three percent of the patients received adequate antibiotics from the beginning. Multi-resistant bacteria were only found in three cases. Among the 43 patients admitted to the ICU through the ED, the median time to antibiotics was 86 min (interquartile range 52-165), and overall 77% received appropriate antibiotics within 2 h. Female patients received antibiotics significantly later compared to male patients (p = 0.047).CONCLUSION:The results demonstrate relatively low mortality rates among ICU patients with severe sepsis/septic shock, as compared to reports from outside Scandinavia. Early adequate antibiotic treatment and the low incidence of resistant isolates may partly explain these findings. Importantly, a gender difference in time to antibiotic therapy was seen.

INTRODUCTION:Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.METHODS:A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden.RESULTS:Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥ 17 and suPAR ≥ 12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥ 12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥ 17 and suPAR ≥ 12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort.CONCLUSIONS:A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections.

Objective:Resistin induces insulin resistance in mice. In humans, recent data suggest that resistin functions as a proinflammatory cytokine. Here, we studied resistin up to 2 wks after admission in patients with septic shock and/or severe sepsis. Design:Two prospective studies of patients with sepsis and in vitro studies of resistin interaction with monocytes. Setting:Intensive care unit at Karolinska University Hospital and Center for Infectious Medicine, Karolinska Institute, Huddinge, Sweden. Patients:Twenty-nine patients with severe sepsis and 66 with septic shock. Interventions:None. Measurements and Main Results:Ninety-five patients were studied, 25 of whom died within 28 days. Resistin and cytokine levels and routine biochemistry were measured at three to six defined time points during the first 2 wks after admission and were correlated to other cytokines, glucose levels, body mass index, Acute Physiology and Chronic Health Evaluation II, and Sepsis-related Organ Failure Assessment scores.Serum resistin was significantly elevated compared with healthy controls (p < .000001) and correlated with severity of disease as measured by Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores, with an increasingly strong degree of correlation over time. Median levels were four- to eight-fold higher than controls and remained high up to 2 wks after admission to the intensive care unit. Levels correlated with interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-&agr;, creatinine, D-dimer, and lactate, but not with p-glucose or body mass index. In vitro, resistin was released from monocytes after stimulation with either lipopolysaccharide or high mobility group box 1 protein. Recombinant resistin itself up-regulated intercellular adhesion molecule-1 on monocytes. Conclusions:This is the first study assessing systemic levels of resistin in patients with septic shock/severe sepsis. We show that resistin is a marker of severity of disease and possibly a mediator of the prolonged inflammatory state seen in infected critically ill patients. Further exploration of resistin as a therapeutic target and marker of disease is merited.

BackgroundThe pathogenesis of endotoxemic tubular dysfunction with failure in urine concentration is poorly understood.Urea plays an important role in the urinary concentrating mechanism and expression of the urea transporters UT-A1, UT-A2, UT-A3, UT-A4 and UT-B is essential for tubular urea reabsorption.The present study attempts to assess the regulation of renal urea transporters during severe inflammation in vivo.Materials and methods By agreement of the animal protection committee C57BL/6J, mice were injected with lipopolysaccharides (LPS, 10 mg/kg) or proinflammatory cytokines.Hemodynamic, renal parameters and the expression of renal urea transporters were investigated.To clarify the role of cytokines and renal ischemia in the regulation of renal urea transporters, experiments were performed with cytokine knockout mice, mice treated with low-dose LPS (1, 5 mg/kg) as a sepsis model without induction of hypotension, glucocorticoid-treated mice, and mice with renal artery clipping serving as a model for renal ischemia.Results and discussion LPS-injected mice (10 mg/kg) presented with reduced glomerular filtration rate, fractional urea excretion and inner medulla osmolality associated with a marked decrease in expression of UT-A1, UT-A2, UT-A3, UT-A4 and UT-B (Figure 1).Similar alterations were observed after application of TNFα, IL-1β, IFNγ or IL-6.LPS-induced downregulation of urea transporters was not affected in knockout mice with deficient TNFα, IL-receptor-1, IFNγ or IL-6.Glucocorticoid treatment inhibited LPS-induced increases of tissue TNFα, IL-1β, IFNγ or IL-6 concentration, diminished LPS-induced renal dysfunction and attenuated the downregulation of renal urea transporters.Injection of low-dose LPS (1, 5 mg/kg) also led to renal dysfunction paralleled by a downregulation of renal urea transporters without alterations in blood pressure.Renal ischemia induced by renal artery clipping did not influence the expression of urea transporters.Conclusion Our findings demonstrate downregulation of renal urea transporters that probably accounts for tubular dysfunction during sepsis.Furthermore, they suggest that downregulation of Figure 1 (abstract P1) Effect of lipopolysaccharide (LPS) (10 mg/kg), dexamethasone (10 mg/kg) and the combination of both on UT-A1, UT-A2, UT-A3, UT-A4 and UT-B mRNA in the kidney 6, 12 and 24 hours after intraperitoneal injection.Values are related to signals obtained for β-actin mRNA and presented as the percentage of vehicle control.Mean ± SEM of six animals per group.*P < 0.05 versus control, # P < 0.05 versus LPS treatment.S2