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Bajwa, Ednan

Background: Elevated levels of biochemical markers of myocardial necrosis have been associated with worsened outcomes in Acute Respiratory Distress Syndrome (ARDS), but there are few prospective data on this relationship. We investigated elevated cardiac troponin T (cTnT) levels and their relationship with outcome in patients with ARDS. Methods A prospective cohort study of patients with ARDS was conducted at a tertiary-care academic medical center. Patients had blood taken within 48 hours of ARDS onset and assayed for cTnT. Patients were followed for the outcomes of 60-day mortality, number of organ failures, and days free of mechanical ventilation. Echocardiographic and electrocardiographic (ECG) data were analyzed for signs of myocardial ischemia, infarction, or other myocardial dysfunction. Results: 177 patients were enrolled, 70 of whom died (40%). 119 patients had detectable cTnT levels (67%). Median cTnT level was 0.03 ng/mL, IQR 0–0.10 ng/mL, and levels were higher among non-survivors (P = .008). Increasing cTnT level was significantly associated with increasing mortality (P = .008). The association between increasing cTnT level and mortality remained significant after adjustment in a multivariate model (HRadj = 1.45, 95% CI 1.17–1.81, P = .001). Elevated cTnT level was also associated with increased number of organ failures (P = .002), decreased number of days free of mechanical ventilation (P = .03), echocardiographic wall motion abnormalities (P = 0.001), and severity of tricuspid regurgitation (P = .04). There was no association between ECG findings of myocardial ischemia or infarction and elevated cTnT. Conclusions: Elevated cTnT levels are common in patients with ARDS, and are associated with worsened clinical outcomes and certain echocardiographic abnormalities. No association was seen between cTnT levels and ECG evidence of coronary ischemia.

Background: Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in septic patients and animals. We hypothesized that the extent of pGSN reduction correlates with outcomes of septic patients and that circulating actin is a manifestation of sepsis. Methodology/Principal Findings: We assayed pGSN in plasma samples from non-surgical septic patients identified from a pre-existing database which prospectively enrolled patients admitted to adult intensive care units at an academic hospital. We identified 21 non-surgical septic patients for the study. Actinemia was detected in 17 of the 21 patients, suggesting actin released into circulation from injured tissues is a manifestation of sepsis. Furthermore, we documented the depletion of pGSN in human clinical sepsis, and that the survivors had significantly higher pGSN levels than the non-survivors (163±47 mg/L vs. 89±48 mg/L, p = 0.01). pGSN levels were more strongly predictive of 28-day mortality than APACHE III scores. For every quartile reduction in pGSN, the odds of death increased 3.4-fold. Conclusion: We conclude that circulating actin and pGSN deficiency are associated with early sepsis. The degree of pGSN deficiency correlates with sepsis mortality. Reversing pGSN deficiency may be an effective treatment for sepsis.

Individual genetic factors have long been suspected of playing a major role in susceptibility to acute lung injury and acute respiratory distress syndrome. Flores and colleagues evaluate the quality of published studies testing the relationships between variation in candidate genes and susceptibility to lung injury syndromes or worsened outcome in patients with these conditions. Their results demonstrate that while important advances have been made in this area, attention should be paid to improving the methodology of future studies in order to minimize the chances of publishing false-positive results.

Among critically ill patients with lower respiratory tract (LRT)-confirmed influenza, we retrospectively observed worse 28-day clinical outcomes in upper respiratory tract (URT)-negative versus URT-positive subjects. This finding may reflect disease progression and highlights the need for influenza testing of both URT and LRT specimens to improve diagnostic yield and possibly inform prognosis.

Background: The Deyo-Charlson Comorbidity Index (DCCI) has low predictive value in the intensive care unit (ICU). Our goal was to determine whether addition of 25-hydroxyvitamin D (25OHD) levels to the DCCI improved 90-day mortality prediction in critically ill patients. Methods: Plasma 25OHD levels, DCCI, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were assessed within 24 h of admission in 310 ICU patients. Receiver operating characteristic curves of the prediction scores, without and with the addition of 25OHD levels, for 90-day mortality were constructed and the areas under the curve (AUC) were compared for equality. Results: Mean (standard deviation) plasma 25OHD levels, DCCI, and APACHE II score were 19 (SD 8) ng/mL, 4 (SD 3), and 17 (SD 9), respectively. Overall 90-day mortality was 19 %. AUC for DCCI vs. DCCI + 25OHD was 0.68 (95 % CI 0.58–0.77) vs. 0.75 (95 % CI 0.67–0.83); p < 0.001. AUC for APACHE II vs. APACHE II + 25OHD was 0.81 (95 % CI 0.73–0.88) vs. 0.82 (95 % CI 0.75–0.89); p < 0.001. There was a significant difference between the AUC for DCCI + 25OHD and APACHE II + 25OHD (p = 0.04) but not between the AUC for DCCI + 25OHD and APACHE II (p = 0.12). Conclusions: In our cohort of ICU patients, the addition of 25OHD levels to the DCCI improved 90-day mortality prediction compared to the DCCI alone. Moreover, the predictive capability of DCCI + 25OHD was comparable to that of APACHE II. Future prospective studies are needed to validate our findings and to determine whether the use of DCCI + 25OHD can influence clinical decision-making.

Background: MicroRNAs (miRNAs) can play important roles in inflammation and infection, which are common manifestations of acute respiratory distress syndrome (ARDS). We assessed if whole blood miRNAs were potential diagnostic biomarkers for human ARDS. Methods: This nested case-control study (N = 530) examined a cohort of ARDS patients and critically ill at-risk controls. Whole blood miRNA profiles and logistic regression analyses identified miRNAs correlated with ARDS. Stratification analysis also assessed selected miRNA markers for their role in sepsis and pneumonia associated with ARDS. Receiver operating characteristic (ROC) analysis evaluated miRNA diagnostic performance, along with Lung Injury Prediction Score (LIPS). Results: Statistical analyses were performed on 294 miRNAs, selected from 754 miRNAs after quality control screening. Logistic regression identified 22 miRNAs from a 156-patient discovery cohort as potential risk or protective markers of ARDS. Three miRNAs—miR-181a, miR-92a, and miR-424—from the discovery cohort remained significantly associated with ARDS in a 373-patient independent validation cohort (FDR q < 0.05) and meta-analysis (p < 0.001). ROC analyses demonstrated a LIPS baseline area-under-the-curve (AUC) value of ARDS of 0.708 (95% CI 0.651–0.766). Addition of miR-181a, miR-92a, and miR-424 to LIPS increased baseline AUC to 0.723 (95% CI 0.667–0.778), with a relative integrated discrimination improvement of 2.40 (p = 0.005) and a category-free net reclassification index of 27.21% (p = 0.01). Conclusions: miR-181a and miR-92a are risk biomarkers for ARDS, whereas miR-424 is a protective biomarker. Addition of these miRNAs to LIPS can improve the risk estimate for ARDS. Electronic supplementary material The online version of this article (10.1186/s40635-017-0155-0) contains supplementary material, which is available to authorized users.

Summary Background: Influenza causes significant morbidity and mortality despite currently available treatments. Anecdotal reports suggest plasma with high antibody titers towards influenza may be of benefit in the treatment of severe influenza. Methods: We conducted a randomized, open-label, multicenter phase 2 trial at 29 academic medical centers in the United States to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition (HAI) antibody titers of ≥ 1:80 to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as hypoxia or tachypnea) were randomly assigned to receive either 2 units (or pediatric equivalent) of anti-influenza plasma plus standard care (P+S), versus standard care alone (S), and were followed for 28 days. The primary endpoint was time to normalization of patients’ respiratory status (respiratory rate of ≤ 20 for adults or age defined thresholds of 20–38 for children), and a room air saturation of oxygen ≥ 93%. ClinicalTrials.gov Identifier: NCT01052480 Findings: Between January 13, 2011 and March 2, 2015, 113 participants were screened, and 98 were randomized. Of the participants with confirmed influenza, 28 of 42 (67%) of P+S participants normalized their respiratory status by Day 28, as compared to 24 of 45 (53%) of S participants (p=0·069). The estimated hazard ratio comparing P+S to S was 1·71 (95% CI: 0·96 to 3·06). Six participants died, 1 (2%) and 5 (10%) from the P+S and S arms respectively (p=0·093). P+S participants had non-significant reductions in days in hospital (median 6 vs. 11 days, p=0·13) and days on mechanical ventilation (median 0 vs. 3 days, p=0·14), and significantly improved clinical status at Day 7 (p=0·020). Fewer P+S participants experienced SAEs compared to S recipients (20% vs. 38%, p= 0·041), the most frequent of which were acute respiratory distress syndrome (1 [2%] vs 2 [4%]) and stroke (1 [2%] vs 2 [4%]). Interpretation Results from this Phase II randomized trial of immune plasma for the treatment of severe influenza provides support for a possible benefit of immunotherapy across the primary and secondary endpoints. A Phase III randomized trial is now underway to further evaluate this intervention.