Primary Immunodeficiencies and Fungal Infections

A. Warris

Author address: 

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands


Phagocytic cells are the first line of host defense directed against the development of invasive fungal infections. Consequently, patients with primary immunodeficiencies characterized by phagocytic disorders do have an increased risk for invasive fungal infections. Most well known are patients with chronic granulomatous disease (CGD) with a life-time incidence of invasive aspergillosis of 25 to 40%. Furthermore, invasive aspergillosis is the cause of death in about 35% of these patients. Invasive candidiasis is less often seen in CGD patients and is associated with a mortality of about 6%. CGD is a rare (birth prevalence 1/250.000) inherited disorder of the reduced nicotinamide dinucleotide phosphatase oxidase complex (NADPH) in which phagocytes fail to generate the microbicidal reactive oxidant superoxide anion and its metabolites, hydrogen peroxide, hydroxyl anion, and hypohalous acid. These oxygen derivatives play a critical role in the killing of fungi. Clinically, as a result of the defect in the key innate host defense pathway, CGD patients suffer from recurrent lifethreatening fungal infections. The clinical epidemiology of invasive aspergillosis infections in CGD patients differs remarkably when compared with the hemato-oncology or post-HSCT patients. Symptoms are insidious, one-third of the infections are localized in the bones, A. nidulans is the causative fungus in 25% (in osteomyelitis up to 50%), diagnostic measures as characteristic laesions on a HRCT-thorax and the presence of galactomannan are often not detectable. In patients with the hyper-IgE-syndrome, occasional reports can be found of invasive aspergillosis and they do have problems with candida infections. Hyper-IgE-syndrome (Job's syndrome) is a rare primary immunodeficiency characterized by recurrent and often severe pulmonary infections, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for the majority of cases. STAT3 deficiency leads to the absence of IL-17 production by T-cells, and IL-17 producing T-cells (Th17-cells) are an important subset of Th-cells in the clearance of fungal pathogens. A small case serie reports invasive A. fumigatus infections as an important cause of death in these patients. Patients with myeloperoxidase (MPO) deficiency shows a mild predispostion to invasive infections with Aspergillus and Candida spp, although MPO-deficient persons are usually healthy. Myeloperoxidase is located within neutrophils capable of producing hypochlorous acid being active in vitro against fungi. The risk of invasive fungal infections in congenital neutropenia and other syndromes with neutropenia is not known. Incidental case reports can be found describing invasive fungal infections in patients with leukocyte adhesions deficiency, defects in the interferon-gamma/IL-12 pathway, DiGeorge syndrome, X-linked hyper-IgM syndrome and Wiskott-Aldrich syndrome.

abstract No: 


Full conference title: 

4th Trends in Medical Mycology
    • TIMM 4th (2012)