A 3-week-old female infant presented with fever, cough and dyspnea of several days duration. She had been born at term with a birth weight of 2.6 kg and developed transient tachypnea during the first 2 days of life, with a normal chest radiograph. Her healthy parents are cousins. She has six siblings who are well with the exception of an older sister with a history of recurrent lymphadenitis starting during early childhood. There was no history of exposure to tuberculosis.
On physical examination there were no dysmorphic features, temperature was 40°C, respiratory rate was 60/min, blood pressure was 90/30 mm Hg and weight was 2.75 kg. Crackles were heard on auscultation in both lung fields. The rest of the examination was normal. A chest radiograph showed a left upper lobe consolidation with multiple bilateral nodular infiltrates. Computerized tomographic scan of the chest showed multiple bilateral pulmonary nodules with early cavitation (Fig. 1). No mediastinal or hilar lymphadenopathy was seen.
Blood count showed a white blood cell count of 23 100/mm,3 with 40% segmented neutrophils, 50% lymphocytes and normal hemoglobin and platelets. Several blood cultures showed no bacterial or fungal growth. Sputum cultures obtained by pharyngeal aspirate after a cough episode or during chest physiotherapy showed only normal upper respiratory tract bacterial flora. Nasopharyngeal aspirate was negative for respiratory syncytial virus. Tuberculin skin testing, HIV serology and gastric aspirate for acid-fast bacilli were negative. Renal and liver function tests, urinary catecholamines and a sweat chloride test were normal. Other tests with normal values included serum immunoglobulins (IgG, IgA, IgM, IgE), IgG subclasses, B and T lymphocyte phenotyping with monoclonal antibodies, complement C3, C4 and CH50. Abdominal ultrasonography was normal. A diagnostic lung biopsy was declined by the parents.
Treatment with intravenous ampicillin and cefotaxime was started, to which were empirically added several days later trimethoprim-sulfamethoxazole and erythromycin. Although the symptoms and signs resolved after 2 weeks of treatment, radiologic normalization was seen only after a few months. Further tests at 18 months of age when she presented with cervical lymphadenitis revealed the diagnosis.
Hassib Narchi, F.R.C.P.
Sultan Gammoh, M.D.
Al Hasa Specialty Services Division; Saudi Aramco-Al-Hasa Health Center; Saudi Aramco Medical Services Organization; Mubarraz, Kingdom of Saudi Arabia
For denouement see p. 485.
DENOUEMENT-CONTINUED FROM P. 471
At 18 months of age the patient presented with cervical adenitis. Before this time she had had a gluteal abscess and another episode of cervical lymphadenitis, all caused by Staphylococcus aureus. During this admission the following studies were performed. Neutrophil function tests included chemotaxis (in vitro assay with patient and control sera), myeloperoxidase stain, flow cytometry measurement of surface glycoproteins and L-selectin and degranulation tests which were all normal. However, neutrophil chemiluminescence was absent on phagocytosis, indicating a reduction in the phagocytic oxidative metabolic burst. Leukocyte bactericidal activity against catalase-producing organisms was decreased and the nitroblue tetrazolium (NBT) dye reduction test was markedly reduced at 5%, diagnostic of chronic granulomatous disease (CGD).
CGD is a rare inherited disease in which phagocytic cells are able to ingest but unable to produce the normal respiratory burst to kill catalase-producing bacteria and fungi. The reduced nicotinamide adenine dinucleotide phosphate oxidase that catalyzes that burst, by reducing oxygen to superoxide anion to hydrogen peroxide, becomes activated by opsonized organisms and chemotactic peptides which excite a transmembrane electron transport system. The latter has two subunits of 91 kDa and 22 kDa and requires two cytosolic protein components of 47 kDa and 67 kDa. The diversity of the genetic defects in these subunits accounts for the clinical and genetic heterogeneity of CGD.1, 2 Deletions, insertions and point mutations have been identified. The most common form of CGD (50 to 55%) is X-linked and caused by a cytochrome b 91 kDa subunit expression defect (X chromosome). Autosomal recessive forms occur (30 to 40%) and are caused by an expression defect in the 47-kDa (chromosome 7), 67-kDa (chromosome 1) or 22-kDa (chromosome 16) subunits.3
Catalase-positive organisms such as Staphylococcus aureus, Klebsiella, Escherichia coli, Salmonella, Shigella, Pseudomonas, Serratia marcescens, Candida albicans and Aspergillus produce chronic and recurrent pyogenic infections with abscesses or granulomas involving lymph nodes, lungs, skin, digestive tract and liver. Obstructive lesions of the gastrointestinal and genitourinary tract, caused by granuloma formation, may occur.
Pulmonary aspergillosis with chronic nodular pneumonia is common with chronic peripheral alveolar opacities and localized pleural thickening.4, 5 Pulmonary coin lesions may also be caused by Neisseria mucosa.6 Pseudosequestration and honeycomb lung changes have also been reported, as well as persistent lung cysts.
In addition to the NBT dye test, flow cytometric methods are used in the diagnosis.7, 8
Genetic counseling is indicated and quantitative NBT assays are used to screen carriers. The carriers of the X-linked form have 50% of their neutrophils affected (Lyon hypothesis) whereas the carriers of the autosomal recessive forms have normal results on NBT tests. Prenatal diagnosis is available by NBT test on fetal blood granulocytes or amniotic fibroblasts and by polymerase chain reaction or restriction fragment length polymorphism studies on fetal blood to detect the mutant DNA sequence.
Prophylactic and curative antibacterial therapy require antimicrobials with good intracellular penetration and activity against catalase-positive organisms, such as clindamycin, trimethoprim-sulfamethoxazole and rifampin. Prophylactic use of trimethoprim-sulfamethoxazole is recommended.9 Acute infections require rapid bacteriologic diagnosis and appropriate intravenous antibiotics. Short term granulocyte transfusions may also be required during these episodes.10, 11 Before blood transfusion the patients should be tested for the presence of the Kell-associated red blood cell antigen, as the lack of that antigen (McLeod phenotype), the locus of which is close to the CGD locus on chromosome X, increases the risk of serious transfusion reactions. Subcutaneous interferongamma therapy reduces the frequency of infections, by mechanisms other than improvement in respiratory burst function.12 Surgery for diagnosis, drainage or resection of localized infections may be needed. Bone marrow transplantation has been performed with variable success. Therapeutic gene transfer trials are in progress, involving the cloned product interferon-gamma or somatic gene transfer therapy.
CGD should always be considered in children with nodular pulmonary infiltrates, regardless of their sex, especially if recurrent infections by catalase-positive organisms occur in different organs.
Acknowledgments. We acknowledge the use of Saudi Aramco Medical Services Organization facilities for the data and study that resulted in this article. The authors were employed by Saudi Aramco during the time the study was conducted and the article was written.
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