Search

BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

Liver abscesses in chronic granulomatous disease (CGD) are typically difficult to treat and often require surgery. We describe 9 X-linked CGD patients with staphylococcal liver abscesses refractory to conventional therapy successfully treated with corticosteroids and antibiotics. Corticosteroids may have a role in treatment of Staphylococcus aureus liver abscesses in CGD.

Chronic granulomatous disease (CGD) is a rare inherited disorder involving defective nicotinamide adenine dinucleotide phosphate oxidase function, which leads to defective production of antimicrobial superoxide anion and related oxygen intermediates critical for host defense [1]. Clinically, CGD patients develop recurrent life-threatening infections and extensive tissue granuloma formation, autoimmune diseases, and inflammatory bowel disease, which may require immunosuppressive or immunomodulatory therapy. The pathogens that commonly cause infection in CGD include the bacteria Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, and Nocardia species and the fungi Aspergillus species, especially Aspergillus fumigatus and Aspergillus nidulans [2]. Other less common fungi, such as Paecilomyces species and Trichosporon inkin, are encountered more frequently in patients with CGD than among the general population, highlighting the fact that patients with CGD have a unique susceptibility pattern [1]. New pathogens are continually being identified as a result of improvements in microbiologic culture and identification techniques. The use of genomic sequencing and the increasing number of sequences available in databases have permitted identification of emerging pathogens (eg, Granulibacter bethesdensis) [3] in CGD patients, as well as the reassignment of misidentified pathogens (eg, Neosartorya udagawae) [4, 5] to their correct taxa. Here we describe, to our knowledge, the first report of invasive mycoses caused by another emerging pathogen, Geosmithia argillacea, in 7 CGD patients. This disease was aggressive, involving invasion across tissue planes or metastatic dissemination in 3 patients. As shown by genomic sequencing of stored fungal isolates, isolates from 4 of these patients had been misidentified originally as Paecilomyces variotii, which resembles G. argillacea morphologically. Correct identification has important therapeutic and prognostic implications.

Background Chronic granulomatous disease (CGD) is associated with multiple and recurrent infections. In patients with CGD, invasive pulmonary infection with Aspergillus species remains the greatest cause of mortality and is typically insidious in onset. Acute fulminant presentations of fungal pneumonia are catastrophic. Methods Case records, radiograph findings, and microbiologic examination findings of patients with CGD who had acute presentations of dyspnea and diffuse pulmonary infiltrates caused by invasive fungal infection were reviewed and excerpted onto a standard format. Results From 1991 through 2004, 9 patients who either were known to have CGD or who received a subsequent diagnosis of CGD presented with fever and new onset dyspnea. Eight patients were hypoxic at presentation; bilateral pulmonary infiltrates were noted at presentation in 6 patients and developed within 2 days after initial symptoms in 2 patients. All patients received diagnoses of invasive filamentous fungi; 4 patients had specimens that also grew Streptomyces species on culture. All patients had been exposed to aerosolized mulch or organic material 1-10 days prior to the onset of symptoms. Cases did not occur in the winter. Five patients died. Two patients, 14 years of age and 23 years of age, who had no antecedent history of recognized immunodeficiency, were found to have p47(phox)-deficient CGD. Conclusions Acute fulminant invasive fungal pneumonia in the absence of exogenous immunosuppression is a medical emergency that is highly associated with CGD. Correct diagnosis has important implications for immediate therapy, genetic counseling, and subsequent prophylaxis.

Chronic granulomatous disease (CGD) is characterized by life-threatening bacterial and fungal infections. Treatment with posaconazole led to a complete response in 7 of 8 patients with CGD with invasive mold infections (7 proven cases and 1 possible case) after failure or intolerance of treatment with standard antifungal agents. In this preliminary study, salvage treatment with posaconazole was safe and effective.

Background Chronic granulomatous disease (CGD) is a rare disorder of phagocytes in which absent production of superoxide and hydrogen peroxide in phagocytes predisposes patients to bacterial and fungal infections. Infections are dramatically reduced by prophylaxis with antibiotics, antifungals, and interferon- gamma (IFN-gamma ). Methods Seventy-six patients with CGD were enrolled in an uncontrolled, open-label follow-up study to assess the long-term clinical safety and efficacy of IFN-gamma therapy. Patients received IFN-gamma subcutaneously 3 times per week. Results We observed patients for up to 9 years, for a total observation period of 328.4 patient-years. The incidence of serious infections was 0.30 infections per patient-year; for serious bacterial infections, the incidence was 0.18 cases per patient-year, and for serious fungal infections, it was 0.12 cases per patient-year. Thirty-seven percent of patients reported an adverse event, the most common of which was fever. Twenty-six patients withdrew from the study (3 because of adverse events, 15 because of patient preference, and 8 because of transfer to another trial). There were no life-threatening IFN-gamma-related adverse events and no discernible effects on growth. The overall mortality rate was 1.5% per patient-year. Conclusion IFN-gamma prophylaxis for CGD appears to be effective and well tolerated over a prolonged period of time.