Chronic granulomatous disease. Report on a national registry of 368 patients.

A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).

Chronic granulomatous disease and glutathione peroxidase deficiency, revisited.

We have restudied two kindreds that formed the basis of the original report of autosomal recessive chronic granulomatous disease (CGD) associated with leukocyte glutathione peroxidase deficiency. Case 1 from the original study and the surviving brother of the originally reported case 2 both have severe CGD, with no detectable respiratory burst activity in purified intact neutrophils. However, their leukocytes exhibit normal glutathione peroxidase enzyme activity and gene expression. Examination of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components known to be defective in CGD reveals no detectable cytochrome b558 nor any membrane activity in a cell-free NADPH oxidase assay system. Molecular analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a C-->T substitution at nucleotide 688 of the gene encoding the gp91-phox subunit of cytochrome b558, resulting in a termination signal in place of Arginine-226. Levels of gp91-phox mRNA are markedly decreased despite normal levels of gene transcription, indicating a post-transcriptional effect of the nonsense mutation on mRNA processing or stability. The X-linked form of CGD developed in this cytogenetically normal female due to the uniform inactivation of the normal X chromosome in her granulocytes, indicated by the expression in her granulocyte mRNA of only one allele of a glucose-6-phosphate dehydrogenase polymorphisms for which she is heterozygous in genomic DNA. Case 2 (of the present study) has distinct mutations in each allele of the p22-phox gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative metabolic products released from polymorphonuclear leukocytes in middle ear fluid during experimental pneumococcal otitis media.

To determine whether oxidative metabolic products of phagocytic cells are present in the middle ear during experimental pneumococcal otitis media, we measured the concentration of myeloperoxidase (MPO) in middle ear fluid (MEF) and the capacity of neutrophils isolated from MEF and peripheral blood to produce MPO and superoxide anion (O2-) after in vitro stimulation. Free MPO in MEF was significantly increased 24 and 48 h after either viable or nonviable pneumococci were inoculated into the middle ear. In vitro-stimulated production of MPO and O2- from middle ear neutrophils was significantly less than that from peripheral blood neutrophils 24 h after nonviable pneumococci were inoculated but similar to it after 48 h. Twenty-four hours after viable pneumococci were inoculated, middle ear neutrophils stimulated in vitro produced less MPO but the same amount of O2- as did blood neutrophils. Oxidative metabolic products, therefore, are released from phagocytic cells into the MEF during pneumococcal otitis media, and future studies will need to define the contribution of these products to acute and chronic middle ear tissue injury.

Antimicrobial defenses in the neonate.

Serious life-threatening neonatal infections with microbial species that are infrequently associated with infections in adults are related to the immature immune system of human newborn infants. The usually sterile intrauterine environment of the fetus is associated with a primed but inactive immune system at the time of birth. Sudden introduction into a complex microbial world stimulates the inflammatory system and an effective host defense rapidly develops. Defense mechanisms include innate phagocytic and complement systems, and specific adaptive immunity including antimicrobial antibodies. Fortunately, neonates have protective antibodies against many microbes at birth provided by their mothers via placental transfer of IgG. Specific antimicrobial antibody production by the newborn infant is delayed. Neutrophil numbers in the circulation are high in the normal neonate, but the bone marrow pool of cells is limited. Chemotactic responsiveness of circulating phagocytic cells is decreased in comparison with adult cells, although phagocytic and microbicidal activity of neonatal neutrophils and monocytes are normal. The newborn infant's lymphocyte system is relatively mature, and neonatal mononuclear cells have normal antigen-presenting and secretory function. T lymphocytes are present in normal numbers and although response of these cells to antigens is somewhat slower than in adult cells, a near normal response suggests intrauterine stimulation by maternally derived immunoregulators. B lymphocytes are also present in newborn human infants. However, maturation of B lymphocytes into antibody-producing plasma cells occurs gradually during the first weeks of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiphagocytic effect of the capsule of Staphylococcus simulans.

An encapsulated strain of Staphylococcus simulans was observed to be more resistant to phagocytosis by human granulocytes than was a nonencapsulated strain. Phagocytosis of the encapsulated strain was enhanced by antisera to S. simulans, but opsonic activity of antisera was removed by absorption with S. simulans capsular material. The encapsulated strain of S. simulans was also more invasive than the nonencapsulated S. simulans in vivo. More encapsulated than nonencapsulated S. simulans were found in heart blood when equal numbers of organisms were injected intraperitoneally into mice. Invasion of the bloodstreams of mice by encapsulated S. simulans was prevented by passive immunization (rabbit antiserum). Thus, the capsule of S. simulans inhibited phagocytosis in vitro and contributed to virulence in vivo.

Chemiluminescence response of human polymorphonuclear and mononuclear phagocytic cells induced by Staphylococcus saprophyticus, lectinophagocytosis versus opsonophagocytosis.

Two strains of Staphylococcus saprophyticus with well characterized cell surface structures were studied to determine the contribution of lectinophagocytosis versus opsonophagocytosis exerted by human phagocytic cells from five healthy donors. The luminol specific chemiluminescence assay was used to evaluate the response of phagocytes. Human polymorphonuclear leukocytes (PMNL) were demonstrated to have surface lectin receptors, since the chemiluminescence response towards both S. saprophyticus strains was inhibited by lectin-specific glycoconjugates for those organisms. Phagocytosis of S. saprophyticus by mononuclear cells was not inhibited by microbial lectin-specific glycoconjugates but was inhibited by D-mannose, suggesting that human monocytes express D-mannose specific lectins on their surface.

Urinary tract disorders in patients with chronic granulomatous disease.

Twelve of the 25 patients with chronic granulomatous disease treated at our institution between 1957 and 1987 were found to have urinary tract disorders. All 12 patients were male and 22 years of age or younger when chronic granulomatous disease was diagnosed. Six patients had hydroureteronephrosis in association with recurrent episodes of pyelonephritis, retroperitoneal lymphadenitis, and granuloma formation. The other six patients had genital lesions or dysuria. Among the six patients with hydroureteronephrosis, a nephrectomy was performed in two, ureterolysis was used to relieve obstruction in one, and hydroureteronephrosis resolved after antibiotic therapy alone in three. We conclude that complications involving the genitourinary system occur frequently in patients with chronic granulomatous disease. Periodic imaging of the urinary tract may detect asymptomatic hydroureteronephrosis or other treatable genitourinary abnormalities in these patients.

Granulocyte activation by a cell surface complex of Staphylococcus saprophyticus: a receptor-mediated phenomenon.

High molecular weight cell surface complex (CSC) from Staphylococcus saprophyticus strain S 1 could be shown to be a potent stimulator of human polymorphonuclear leukocyte (PMN) chemiluminescence whereas human monocytes were not activated. Heating of the CSC (100 degrees C for 5 min) as well as protease treatment significantly (p less than 0.001) inhibited the PMN activating process suggesting that the protein part of the molecule mediates its biological activity. Data on the biochemical character of the CSC are given. Preincubation of PMNs with CSC inhibited another chemiluminescence response to this substance and to homologous opsonized S. saprophyticus, respectively. However, restimulation with formylmethionyl peptides (fMLP) or non-opsonized staphylococci suggested that the PMN function is a receptor-mediated phenomenon. These data were substantiated since fMLP activated PMNs could be evidently re-stimulated with CSC but not with analogue peptides. Evaluation of the bactericidal capacity of human PMNs yielded comparable results.

Granulocyte activating factor released from Propionibacterium acnes. A possible mediator of inflammation in acne vulgaris.

Incubation of Propionibacterium acnes but not of Propionibacterium granulosum or Propionibacterium avidum (for 30 min at 37 degrees C in physiological saline) released a soluble factor that produced enhanced chemiluminescence response of human granulocytes as well as increased chemotactic motility of these cells. Sephadex G-25 filtration of the granulocyte activating factor (GAF) revealed its low molecular weight and apparent peptide character. Thus, GAF may be a stimulus for inflammation in acne vulgaris since low molecular weight chemotactic factors can be expected to penetrate follicular walls.

DNA fingerprinting of Streptococcus zooepidemicus (Lancefield group C) as an aid to epidemiological study.

A collection of Streptococcus zooepidemicus strains from human and animal infections was examined for DNA banding patterns after nuclease digestion and agarose gel electrophoresis. The large variety of DNA fingerprints found revealed the complexity of the species but showed that isolates from clusters of outbreaks had identical prints. The results confirmed the specificity of bacteriocin and bacteriophage typing of S. zooepidemicus; the technique also gave useful profiles on untypable strains. Strains with common bacteriocin and biotyping patterns from sporadic infections could be differentiated by their DNA fingerprints. In several outbreaks and incidents, more than one strain of S. zooepidemicus were encountered, and the importance of carefully interpreting typing data is stressed. Chromosomal DNA fingerprinting is a very efficient technique for demonstrating differences between strains of S. zooepidemicus, and its use is recommended for future epidemiological studies of this infectious agent.

Granulocyte transfusion kinetics measured by chemiluminescence, nitroblue tetrazolium reduction, and recovery of indium-111-labeled granulocytes.

A 20-year-old man with chronic granulomatous disease (CGD) and who was receiving granulocyte transfusions for a refractory liver abscess was studied to compare the kinetics of 111In-labeled granulocytes with those of two functional granulocyte assays, nitroblue tetrazolium reduction and chemiluminescence. Transfused granulocytes were eliminated in both rapid and slow phases. Peak recovery was noted in the first sample, which was obtained 10 minutes after transfusion for each assay. The elimination kinetics were similar over 24 hours. These results confirm the value of using 111In-labeled granulocytes as a marker of transfused granulocytes. These data also confirm that the oxidative metabolic function of granulocytes prepared by continuous-flow leukapheresis remains intact while in the recipient's circulation. The response of the patient adds support for the use of granulocyte transfusions in certain patients with CGD.

The white cells: use of granulocyte transfusions.

Since serious infections are major complications in patients with fewer than 200 phagocytic cells per microliter or in patients with dysfunctional phagocytes, granulocyte transfusions have been used in an attempt to improve clinical outcome. After two decades of trial and clinical use, the role of granulocyte transfusions for therapy of serious infections has not been clearly established. The methods of harvest, storage, and transfusion of granulocytes are acceptable; however, the quantities that are obtained from donors restrict numbers of cells that may be transfused. Limited clinical response has diminished enthusiasm for the use of granulocyte transfusions as therapy, and their use as prophylaxis has been ineffective. Reported clinical data suggest that patients with persisting granulocytopenia with sepsis due to gram-negative bacteria and patients with chronic granulomatous disease with life-threatening infections unresponsive to aggressive antimicrobial therapy may benefit from granulocyte transfusions.

Interference with granulocyte function by Staphylococcus epidermidis slime.

The interaction of Staphylococcus epidermidis slime with human neutrophils (PMN) was examined by using isolated slime and allowing bacteria to elaborate slime and other extracellular products in situ. S. epidermidis slime was found to contain a chemoattractant. Incubation of PMN with 50 micrograms or more of slime per ml inhibited subsequent chemotaxis of the PMN to n-formyl-methionyl-leucyl-phenylalanine by 27% and to zymosan-activated serum by 44 to 67% with increasing slime concentrations. S. epidermidis slime stimulated little degranulation of untreated PMN. After pretreatment of PMN with 5 micrograms of cytochalasin b per ml, slime predominantly induced release of specific granule contents (33.8% lactoferrin release by 250 micrograms of slime per ml versus 10% myeloperoxidase release by 250 micrograms of slime per ml). By a surface phagocytosis assay, PMN uptake of radiolabeled S. epidermidis which were incubated for 18 h on a plastic surface for slime expression was less than that for S. epidermidis adhered to the plastic for 2 h or grown in unsupplemented nutrient broth. These results suggest that S. epidermidis slime interaction with PMN may be potentially detrimental to host defense and may contribute to the ability of this organism to persist on surfaces of foreign bodies in the vascular or central nervous system.