Cytokine Augmentation Reverses Transplant Recipient Neutrophil Dysfunction Against the Human Fungal Pathogen Candida albicans.

BACKGROUND: Solid organ transplant (SOT) and stem cell transplant (SCT) recipients are at increased risk of invasive fungal disease despite normal neutrophil counts. Here, we measure neutrophil anti-Candida activity. METHODS: Twenty-one SOT and 19 SCT recipients were enrolled 2-4 months posttransplant and compared to 23 healthy control patients (HC). Neutrophils were coincubated with Candida albicans, and percentage killing and swarming responses were measured. RESULTS: Neutrophils from transplant patients had decreased fungicidal capacity compared to HC (42%, 43%, and 72% for SCT, SOT, and HC, respectively; SCT vs HC: P < .0001; SOT vs HC: P < .0001; SOT vs SCT: P = .8), including diminished ability to control hyphal growth (HC vs SOT: 0.1455 vs 0.3894, P ≤ .001; HC vs SCT: 0.1455 vs 0.6295, P ≤ .0001, respectively). Serum from SCT, but not SOT, recipients, inhibited the ability of HC neutrophils to control C. albicans (37%, 45%, and 55% for SCT, SOT, and HC, respectively). Neutrophils' control of hyphal growth was partially restored with granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor. CONCLUSIONS: Despite normal circulating numbers, our data suggest that neutrophils from SOT and SCT recipients mount dysfunctional responses against C. albicans. Intrinsic neutrophil changes and extrinsic serum factors may be responsible for the dysfunction, which is partially reversed with cytokine augmentation.

Computed Tomography Findings as a Novel Predictor of Alcohol-Associated Hepatitis Outcomes.

BACKGROUND: Accurate prediction of outcomes for alcohol-associated hepatitis (AH) is critical, as prognosis determines treatment eligibility. Computed tomography (CT) features may provide prognostic information beyond traditional models. AIMS: Our aim was to identify CT features that predict outcomes in AH. METHODS: We studied 108 patients retrospectively with definite or probable AH, who underwent admission abdominal CT. A radiologist blinded to outcome evaluated eight CT features. The primary outcome was 90-day mortality. RESULTS: Twenty-five (23.2%) patients died within 90 days. While traditional prognostic tools, including Maddrey discriminant function (DF), predicted 90-day mortality (OR 1.01 [1.00, 1.03], P = 0.02), abdominal CT findings were also accurate predictors. On abdominal CT, patients with severe AH had larger volume of ascites (moderate/large volume: 34.0 vs. 8.2%, P < 0.0001), longer liver length (17.1 vs. 15.1 cm, P = 0.001), greater liver heterogeneity (moderate/severe: 21.3 vs. 8.2%, P = 0.007), and more likely to have splenomegaly (42.6 vs. 18.0%, P = 0.009) than those with mild AH. Univariate analysis revealed that ascites volume (OR 2.59 [1.35, 4.96], P = 0.004) predicted 90-day mortality. In multivariate analysis, degree of ascites predicted 90-day mortality when controlling for Maddrey DF (OR 2.36 [1.19, 4.69], P = 0.01) and trended toward significance when controlling for MELD score (OR 2.02 [0.95, 4.30], P = 0.07). CONCLUSION: CT findings in AH differentiate disease severity and predict 90-day mortality; therefore, the role of CT warrants further investigation as a tool in AH management.

Loss of Coordinated Neutrophil Responses to the Human Fungal Pathogen, Candida albicans, in Patients With Cirrhosis.

Neutrophils are the most abundant white blood cell in the body and are key participants in the defense against fungal infections. Fungal infections occur often in patients with cirrhosis and are associated with increased 30-day and 90-day mortality. Previous studies have shown that specific neutrophil functions are abnormal in patients with cirrhosis, although the extent of neutrophil dysfunction is not well understood. We tested the ability of neutrophils from 21 hospitalized patients with cirrhosis and 23 healthy control patients to kill Candida albicans, a common fungal pathogen in patients with cirrhosis. Using an assay, we also measured the ability of neutrophils to coordinate multicellular, synchronized control of C. albicans hyphae through a process known as swarming. We found that neutrophils from patients with cirrhosis have significantly decreased fungicidal capacity compared with healthy control neutrophils (53% vs. 74%, P < 0.0001) and diminished ability to control hyphal growth normalized as a ratio to healthy control (0.22 vs. 0.65, P < 0.0001). Moreover, serum from patients with cirrhosis decreases the ability of healthy control neutrophils to kill C. albicans (from 60% to 41%, P < 0.003). Circulating concentration of the inflammatory cytokines tumor necrosis factor α, interleukin-6, and interleukin-8 were found to be significantly elevated in patients with cirrhosis compared to healthy controls. Following pretreatment with granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor, neutrophil function was restored to almost that of healthy controls. Conclusion: Our data establish profound neutrophil dysfunction against, and altered swarming to, C. albicans in patients with cirrhosis. This dysfunction can be partially reversed with cytokine augmentation ex vivo.