Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Identification of a Novel EIF2AK Variant and Genetics-Assisted Approach to Diagnosis of Pulmonary Capillary Hemangiomatosis.

Pulmonary capillary hemangiomatosis (PCH) is an uncommon type of pulmonary vascular disease characterized by capillary proliferation and very poor prognosis owing to misdiagnosis and lack of effective therapeutic options. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have been reported in pulmonary veno-occlusive disease and PCH. In this report, we present a patient whose diagnosis of PCH was delayed by 2 ½ years despite prior surgical lung biopsy and clinical and laboratory findings suggestive of pulmonary hypertension. Genotyping revealed a novel likely pathogenic variant in the EIF2AK4 gene. Review of surgical lung biopsy performed 2 ½ years prior confirmed PCH histology along with constrictive bronchiolitis.

Bedside estimates of dead space using end-tidal CO2 are independently associated with mortality in ARDS.

PURPOSE: In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. METHODS: We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. RESULTS: The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2-PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. CONCLUSION: Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection.

Metabolites produced by the intestinal microbiome modulate mucosal immune defenses and optimize epithelial barrier function. Intestinal dysbiosis, including loss of intestinal microbiome diversity and expansion of antibiotic-resistant pathobionts, is accompanied by changes in fecal metabolite concentrations and increased incidence of systemic infection. Laboratory tests that quantify intestinal dysbiosis, however, have yet to be incorporated into clinical practice. We quantified fecal metabolites in 107 patients undergoing liver transplantation (LT) and correlated these with fecal microbiome compositions, pathobiont expansion, and postoperative infections. Consistent with experimental studies implicating microbiome-derived metabolites with host-mediated antimicrobial defenses, reduced fecal concentrations of short- and branched-chain fatty acids, secondary bile acids, and tryptophan metabolites correlate with compositional microbiome dysbiosis in LT patients and the relative risk of postoperative infection. Our findings demonstrate that fecal metabolite profiling can identify LT patients at increased risk of postoperative infection and may provide guideposts for microbiome-targeted therapies.

Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Immediate Effect of Mechanical Ventilation Mode and Sedative Infusion on Measured Diaphragm Thickness.

Rationale: In patients who are mechanically ventilated, diaphragm thinning on ultrasound is thought to correlate with diaphragm atrophy and has been associated with prolonged intubation. Factors other than atrophy, however, may cause changes in diaphragm thickness, which may confound studies examining changes in diaphragm thickness over time. Objectives: To determine if changes in the mode of mechanical ventilation or an interruption of sedatives have immediate effects on diaphragm thickness measurements in adult patients in the intensive care unit who are mechanically ventilated. Methods: Adult patients receiving invasive mechanical ventilation for less than 48 hours were included. Diaphragm thickness was measured at end-expiration and peak inspiration using ultrasound while patients were receiving both volume assist-control and pressure-support modes in a randomized crossover fashion. In patients receiving sedatives, additional measurements were taken after an interruption of sedatives. Measurements were compared between modes and on assist-control before and after an interruption of sedatives. Results: Of 85 patients enrolled, 66 had measurements on assist-control and spontaneous modes, and 40 had measurements before and after an interruption of sedatives. End-expiratory diaphragm thickness increased by a median of 0.08 mm after an interruption of sedatives (95% confidence interval [CI], 0.002 mm to 0.164 mm; P = 0.017), corresponding to a median increase of 6.5%. No difference was seen when comparing measurements taken on volume assist-control and pressure support (median difference, 0 mm; 95% CI, -0.07 mm to 0.08 mm; P = 0.98). Conclusions: End-expiratory diaphragm thickness increased by 6.5% after an interruption of sedatives. The effect of sedatives on measured diaphragm thickness should be considered in future studies examining changes in diaphragm thickness over time. Clinical trial registered with Clinicaltrials.gov (NCT04319939).

Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure.

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

Using photovoice to promote diabetes self-management in Latino patients.

Innovative, patient-centered interventions that employ novel educational methods are needed to address the burden of diabetes in the growing Latino population. Objective of this study was to assess the acceptability, feasibility, and perceived utility of photovoice in a diabetes self-management intervention for Latinos. Thirty-seven adults with diabetes attended a church-based self-management education program that included a photovoice exercise where participants were asked to take photographs to illustrate their successes and challenges in diabetes management. Participants discussed their photographs in the group classes and evaluated the exercise in an exit survey. Photographs and discussion notes were analyzed for prevalent themes. We measured participant participation in the photovoice activity, content of photographs, themes of the discussions that were prompted by the photographs in class, and participants' satisfaction with the photovoice exercise. Of the 37 participants, 70% took photos and 65% shared them in class. Photos depicted family, social gatherings, diet, exercise, the neighborhood, diabetes supplies and medications, and home life. Almost all the group discussions involved aspects of social support, including giving advice, empathizing, or providing motivation for self-care to one another. Eighty-six percent reported learning how to better manage their diabetes from others' photos; 93% noted sharing photos made them feel connected to the group. In a diabetes self-management education program, photovoice was well received by Latino adults and provided a vehicle to receive and provide social support in self-care. This trial was registered at clinicaltrials.gov with identifier NCT01288300.