Invasive fungal infections in congenital immunodeficiencies

Abstract

Both acquired and congenital immunodeficiencies may be associated with increased susceptibility to invasive fungal infections (IFIs), depending on the type of immune deficit. IFIs frequently occur in patients with phagocytic and cellular immune defects, but are rarely observed in those with humoral or complement deficits. Among congenital immune disorders, chronic granulomatous disease and hyper-IgE syndrome are most frequently associated with IFIs; variable susceptibility to fungal pathogens is also seen in patients with severe combined immunodeficiency, X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome, DiGeorge syndrome, common variable immunodeficiency, defects in the interferon-γ-interleukin-12 axis, and myeloperoxidase deficiency. Aspergillus, Candida, Cryptococcus, Histoplasma and other fungal genera are variably implicated in causing invasive infections in these patients. Prompt diagnosis of IFIs in this patient population requires a high degree of suspicion, together with a knowledge of their clinical presentation and the limitations of diagnostic modalities. Apart from administration of appropriate antifungal agents, successful management often requires the addition of surgical intervention. Adjunctive immunotherapy may be considered, although this has not been systematically studied. Prophylactic interferon-γ and itraconazole administration have been shown to reduce the risk of IFIs in patients with chronic granulomatous disease; however, the possibility of infections with azole-resistant organisms following long-term itraconazole prophylaxis should not be overlooked.

Fungal antioxidant pathways promote survival against neutrophils during infection

“…Similar findings were obtained in experimental A. fumigatus lung infections in which NOX but not MPO or iNOS were found to be required to control fungal growth (21,23,25,68). Our findings are also in agreement with the enhanced susceptibility of CGD patients, but not MPO-deficient patients, to filamentous fungal infections (2,32). However, our findings differ from a study showing no role for NOX in killing A. nidulans in vitro (27).…”

“…Pathogenic fungi, such as Aspergillus and Fusarium species, can cause lethal pulmonary and systemic disease in immune-suppressed individuals, including those with HIV infection (1,2). These organisms are also a major cause of infectious blindness and corneal ulcers in immunocompetent individuals, and in contrast to individuals with systemic and pulmonary fungal infections, there is no indication that fungal keratitis patients are other than fully immunocompetent (3,4).…”

“…NOX is an enzyme complex required for reduction of molecular O 2 to O 2 - (31). Superoxide is the limiting reagent in subsequent reactions, leading to the transient synthesis of ROS with greater oxidative and fungal killing potential (21), and individuals with CGD due to impaired NOX function are unable to control microbial infections and often succumb to filamentous fungal infections in the lung (2,32).…”

“…Similarly, neutrophils are the first cells recruited to the corneal stroma in murine models of Aspergillus and Fusarium keratitis (19,20), indicating that neutrophils are the main effector cells required for killing fungal hyphae. A role for neutrophils in control of fungal infection is also suggested by the increased incidence of systemic and pulmonary fungal infections in patients with neutropenia (2).…”

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

“…NETs are extracellular structures of chromatin and antimicrobial proteins that are released from activated neutrophils and can bind to the pathogen (17). These antimicrobial features enable MPO to participate directly in the defense of fungal (16,18) and various bacterial infections (17,19,20). In addition, MPO further activates neutrophils (21) and promotes their recruitment (22), leading to an enhanced proinflammatory immune response.…”