NADPH oxidase limits innate immune responses in the lungs in mice.

BACKGROUND: Chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47(phox-/-) mice and gp91(phox)-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kappaB activation, and elevated downstream pro-inflammatory cytokines (TNF-alpha, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kappaB activation. CONCLUSIONS/SIGNIFICANCE: These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD.

Adult systemic cat scratch disease associated with therapy for hepatitis C.

BACKGROUND: We describe the first case of systemic cat scratch disease in a patient receiving peginterferon alpha-2a and ribavirin for treatment of hepatitis C. Cases of adult systemic CSD are extremely infrequent and immunomodulatory treatment for hepatitis C has been associated with aberrant host responses to common pathogens. CASE PRESENTATION: A 52 year old man being treated for hepatitis C presented with diffuse lymphadenopathy, weight loss, fevers and splenic lesions. Symptoms were initially confused with adverse effects of his regimen, delaying recognition of his infection. Diagnostic investigation, including histopathology, microbiology and serologic parameters, confirmed that his illness was due to disseminated cat scratch disease with Bartonella henselae. CONCLUSION: Disseminated CSD is exceptionally rare in adults. We describe the first case of disseminated cat scratch disease associated with peginterferon alpha and ribavirin to alert clinicians of the need to be aware of unusual manifestations of common infections in this population.

Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients.

Invasive mould infections are a major cause of morbidity and mortality in hematopoietic stem cell transplant recipients (HSCT). Allogeneic HSCT recipients are at substantially higher risk than autologous HSCT recipients. Although neutropenia following the conditioning regimen remains an important risk factor for opportunistic fungal infections, most cases of invasive mould infection in allogeneic HSCT recipients occur after neutrophil recovery in the setting of potent immunosuppressive therapy for graft-versus-host disease. Invasive aspergillosis is the most common mould infection. However, there has been an increased incidence of less common non-Aspergillus moulds that include zygomycetes, Fusarium sp., and Scedosporium sp. Reflecting a key need, important advances have been made in the antifungal armamentarium. Voriconazole has become a new standard of care as primary therapy for invasive aspergillosis based on superiority over amphotericin B. There is significant interest in combination therapy for invasive aspergillosis pairing voriconazole or an amphotericin B formulation with an echinocandin. There have also been advances in novel diagnostic methods that facilitate early detection of invasive fungal infections that include galactomannan and beta-glucan antigen detection and PCR using fungal specific primers. We review the epidemiology, diagnosis, and management of invasive mould infection in HSCT, with a focus on allogeneic recipients. We also discuss options for prevention and early treatment of invasive mould infections.