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Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytes in which defective production of microbicidal oxidants leads to severe recurrent infections. CGD is caused by mutations in any of 4 genes encoding components of nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase, the multisubunit enzyme that produces the precursor of these oxidants, superoxide. Approximately 5% of CGD patients have an autosomal recessive form of disease caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the oxidase that appears to regulate electron transport within the enzyme. Here we report the biochemical and molecular characterization of 6 unrelated kindreds with p67-phox deficiency. These studies show that, as in gp91-phox and p22-phox deficiencies, the p67-phox CGD patients show a high degree of heterogeneity in the genetic defects that underlie their disease. Five different mutant alleles were identified: (1) a nonsense mutation in exon 4 (C304 → T); (2) a 5-nucleotide (nt) deletion in exon 13 (nts 1169-1173); (3) a splice mutation in the first nucleotide of intron 4 (G → A); (4) a deletion of 1 nt in exon 9 (A728); and (5) a 9-nt in-frame deletion in exon 2 (nts 55-63). The splice mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 apparently unrelated families (both of Palestinian origin). Homozygosity was present in 4 of the kindreds, 2 of which had consanguineous parentage. In the isolated neutrophils of each of the affected patients in the 6 kindreds, there was no measurable respiratory burst activity and no p67-phox protein detected by immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot studies. Thus, this heterogeneous group of mutations in p67-phox all lead to marked instability of mRNA or protein (or both) that results in the complete loss of NADPH oxidase activity.

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Lung puncture-aspiration is simple and generally innocuous. For the study of acute pneumonia it is superior to examination of nasopharyngeal, throat or laryngeal cultures and gives more positive results than does blood culture. It can be extremely useful in investigational studies and with selected patients in whom identification of the precise pathogen is necessary for optimal antibiotic therapy. ETIOLOGIC diagnosis of lower respiratory tract infections has always been a vexing problem. Commonly employed diagnostic procedures, such as cultures taken from the upper respiratory tract, have little usefulness and clinical and radiologic investigation of the patient seldom indicate the specific etiology. In general, the bacteria recovered from the nasopharynx, throat and sputum are not the same as the true pathogens obtained from pulmonary tissues in cases of acute pneumonia.1-8 Sometimes a blood culture is helpful, but one encounters bacteremia in no more than 30 per cent of pneumococcal pneumonias and iñ ~ per cent or less of those due to streptococcus or staphylococcus. Only in pneumonia due to Hemophilus a~xflue~z~~e does one frequently find positive blood cultures.9-12 For these reasons we decided to use lung puncture-aspiration as a means of obtaining reliable specimens for bacteriologic study in pneumonias of infancy and childhood. HistoryLung puncture-aspiration was first employed by Leyden in 1882. 13 In 1909 Horder 14, 15 recommended its use with any patient having signs of consolidation if the course of illness was unfavorable and with pulmonary abscess and bronchiectasis in order to recover pathogenic bacteria unmixed with the throat flora. He