Clinica Pediatrica dell'Università di Brescia, Brescia, Italy and
1 Sanquin Research at CLB, and Landsteiner Laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
SIR, Chronic granulomatous disease (CGD) is an inherited condition characterized by impairment of phagocyte microbicidal activity owing to a reduced ability of granulocytes to synthesize superoxide ions and hydrogen peroxide, leading to recurrent bacterial and fungal infections [1]. In addition to chronic complications, CGD patients may develop other inflammatory symptoms that affect gastrointestinal and urinary systems, and/or autoimmune diseases, including inflammatory bowel disease [1, 2]. Prevention of life-threatening infections with fungal and bacterial pathogens in CGD is based on prophylaxis with antibiotics and antifungal drugs combined with subcutaneous administration of interferon- [3]. Here we describe an 11-yr-old child affected by X-linked CGD who has been treated with interferon-
(50 µg/kg three times a week) from 6 to 10 yr of age, when he developed systemic lupus erythematosus (SLE).
Our patient is a male born in 1990 after an uneventful pregnancy. In 1995 he was referred to our hospital because of cough, respiratory distress and fever of acute onset that was refractory to cephalosporin treatment (ceftriaxone 50 mg/kg body weight per day). Because of the history of recurrent infections, including a previous pneumonia, and failure to thrive, we suspected a primary immunodeficiency. On the basis of a decreased respiratory burst of granulocytes stimulated by phorbol myristate acetate (PMA) we hypothesized that the child was affected by CGD. Diagnosis of X-linked CGD in the patient was confirmed by genetic analysis at the CYBB locus that demonstrated a point mutation at nucleotide 13 (ATG to GTG) which abolished the translation initiation codon.
Because CGD is characterized by a profound defect in the microbicidal activity of phagocytic cells, we started a prophylaxis regimen with trimethoprimsulphamethoxazole (TMPSMX) (5 mg/kg body weight per day), itraconazole (5 mg/kg body weight per day), and interferon- at 50 µg/m2 three times weekly. In November 1999, the mother noticed fever and anorexia after interferon-
administration and suspended the prophylaxis with interferon-
. After a few months, in February 2000, our patient was admitted to the hospital because of persisting weakness and loss of weight that were associated with pain at both wrists without heat or swelling of these joints. In the following days, the child presented with fever, abdominal pain and scrotal hydroceles without evidence of infection. Chest radiography demonstrated pleural effusion and enlargement of the cardiac silhouette. Further evaluation by echocardiography showed fluid accumulation in the pericardial sac, but normal systolic function without evidence of cardiac tamponade. On the basis of blood analyses that showed increased levels of C-reactive protein (up to 21 µg/ml), but normal leucocyte counts (white blood cell count 8700 /µl) and mild anaemia (haemoglobin was 9.5 g/dl), an empirical intravenous antibiotic therapy including teicoplanin and amphotericin B was started. In search of an autoimmune disorder, antinuclear antibodies (ANA) and serum complement concentrations were determined. Since the ANA test was strongly positive (1:800), and haemolytic activity, C3 and C4 levels were markedly decreased (24%, 35.2 mg/dl, 3.77 mg/dl, respectively), anti-dsDNA and anti-ssDNA levels were determined. Elevated levels of anti-dsDNA (82.18 IU/ml, normal values <4.2 IU/ml) and anti-ssDNA (44%, normal values <35%) antibodies confirmed the diagnosis of SLE without renal involvement and prompted us to initiate treatment with prednisone (1 mg/kg per day orally). In order to reduce the dosage of steroids, azathioprine (1 mg/kg per day orally) was added, leading to normalization of anti-dsDNA in the next 2 months. Since then, ANA have remained negative and the child has stayed in good health while receiving TMPSMX and itraconazole.
Because Chanock's group [2] have reported an increased risk of haematological/autoimmune disorders in patients with CGD who carry variant alleles of Fc- receptor-IIa genes, we investigated in this patient polymorphisms in FCGRIIA, FCGRIIIA and FCGRIIIB genes. We found that our patient is heterozygous for the allelic variants of Fc
RIIa (RH), Fc
RIIIa (VF) and Fc
RIIIb (NA1/NA2). Interestingly, the genes for these proteins reside at chromosome 1q23, a region linked to development of SLE [4, 5]. Moreover, the polymorphic variants of these proteins, RR or RH (Fc
RIIa) and VF (Fc
RIIIa), confer a reduced binding activity of phagocytic cells to IgG2 and IgG1, respectively, and to C-reactive protein, suggesting that susceptibility to SLE might be related to impairment in phagocytosis of immune complexes [46]. In addition, the mother presented with a discoid lupus-like disease, indicating that our patient might have inherited a genetic disposition to autoimmune disorders from the mother. While discoid lupus-like skin lesions have been frequently reported both in CGD patients and carriers [7], only three other cases of CGD patients who developed a systemic form of disease characterized by polyserositis, and positive antinuclear and anti-dsDNA antibodies have been described [810]. We propose that the allelic variants of FCGRIIA (RH), FCGRIIIA (VF) and FCGRIIIB (NA1/NA2) genes might contribute to development of SLE in CGD patients. Evaluation of the role of interferon-
treatment in the development of autoimmune complications emphasizes the need for controlled studies in CGD patients.
Notes
Correspondence to: R. Badolato, Clinica Pediatrica dell'Università di Brescia, c/o Spedali Civili, 25123 Brescia, Italy. E-mail: badolato{at}master.cci.unibs.it
References