Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

T helper (Th) 17 cells have been recently discovered in both mouse and human. Here we show that interleukin-1 (IL-1) signaling on T cells is critically required for the early programming of Th17 cell lineage and Th17 cell-mediated autoimmunity. IL-1 receptor1 expression in T cells, which was induced by IL-6, was necessary for the induction of experimental autoimmune encephalomyelitis and for early Th17 cell differentiation in vivo. Moreover, IL-1 signaling in T cells was required in dendritic cell-mediated Th17 cell differentiation from naive or regulatory precursors and IL-1 synergized with IL-6 and IL-23 to regulate Th17 cell differentiation and maintain cytokine expression in effector Th17 cells. Importantly, IL-1 regulated the expression of the transcription factors IRF4 and RORgammat during Th17 cell differentiation; overexpression of these two factors resulted in IL-1-independent Th17 cell polarization. Our data thus indicate a critical role of IL-1 in Th17 cell differentiation and this pathway may serve as a unique target for Th17 cell-mediated immunopathology.

The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.