Paul G. Quie

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%).

In Vitro Bactericidal Capacity of Human Polymorphonuclear Leukocytes: Diminished Activity in Chronic Granulomatous Disease of Childhood *

Diminished bactericidal capacity was found to be characteristic of polymorphonuclear leukocytes (PMN) from five children with the clinical syndrome of granulomatous disease of childhood. The PMN from these children demonstrated nearly normal phagocytic capacity, and the majority of viable bacteria, after 2 hours of incubation in the phagocytosis system, were found associated with leukocytes. The morphology of the unstimulated polymorphonuclear leukocytes from patients with chronic granulomatous disease was similar to those from normal persons of similar ages by light and electron microscopy. In addition, the total lysozyme and phagocytin activity of leukocyte extracts from these patients was similar to those from equal numbers of leukocytes from controls.A striking difference in the cytoplasmic response after phagocytosis characterized the PMN of the patients with granulomatous disease. Whereas degranulation, vacuole formation, and rapid bacterial digestion were the rule in the PMN from controls, little degranulation and persistence of intact bacteria in the cytoplasm characterized disease. The deficiency of bactericidal capacity and the minimal degranulation after active phagocytosis by the PMN of these children with an inherited syndrome suggest that separate metabolic processes are involved in phagocytosis and in intracellular digestion. Continuing study of the metabolic function of leukocytes from these children should provide an opportunity for increased understanding of the metabolic basis for degranulation and intracellular digestion in phagocytic cells.

Fungal Septicemia in Patients Receiving Parenteral Hyperalimentation

Abstract Thirty-three patients with fungal septicemia at the University of Minnesota Hospital were seen during an 18-month period, January, 1968, through August, 1969. Twenty-two of these 33 patients (67 per cent) had received parenteral hyperalimentation for severe gastrointestinal dysfunction. Fungal septicemia was not related to steroid therapy or immunologic deficiency i te patiets receiing hyperalimentation. However, a correlation with prolonged intravenous catheterization was found. More recently, during a prospective study of all patients receiving parenteral hyperalimentation, septicemia complicated the course of therapy in 13 of 49. In eight of these patients, Candida albicans was the causative microbial species.

Kinetics of staphylococcal opsonization, attachment, ingestion and killing by human polymorphonuclear leukocytes: A quantitative assay using [3H] thymidine labeled bacteria

A method has been developed for studying quantitatively the separate processes of bacterial opsonization, phagocytosis, and killing by human polymorphonuclear leukocytes using [3H]thymidine labeled Staphylococcus aureus. Phagocytosis is determined by assaying for leukocytes-associated radioactivity after differential centrifugation and washing the leukocytes. Opsonization is studied by incubating bacteria with an opsonic source for varying durations and then adding leukocytes. By treatment of samples with the muralytic enzyme, lysostaphin, the attachment and ingestion phases of phagocytosis can be separated. Sampling for colony forming units after disruption of the leukocytes permits the measurement of bacterial killing. Using this method, differences in the kinetics of staphylococcal opsonization by normal and C2 deficient sera were defined, opsonic influences on the attachment and ingestion phases of pH agocytosis were delineated, and the influences of different opsonins and leukocyte populations on killing were determined.

Chronic Granulomatous Disease in Females

Abstract Leukocyte glutathione peroxidase activity of two female patients with chronic granulomatous disease was shown to be significantly diminished as compared to the activity of control leukocyt...

Familial neutrophil chemotaxis defect, recurrent bacterial infections, mucocutaneous candidiasis, and hyperimmunoglobulinemia E.

A 20-year old women and her infant daughter had recurrent bacterial infections and chronic mucocutaneous candidiasis and were found to have extreme hyperimmunoglobulinemia E, defective neutrophil chemotaxis, and diminished lymphocyte responses to Candida antigen. Studies of members of the mothers family showed mild increases of IgE and mildly depressed chemotactic activity of neutrophils in a brother, the father, and the paternal grandfather. The recurrent bacterial infections in these two patients can be explained by the defective neutrophil chemotaxis. It is not known whether the mucocutaneous candidiasis is related to the neutrophil chemotaxis with the lymphocyte defect being secondary to the Candida infection or, alternatively, the Candida infection being secondary to the lymphocyte defect. Furthermore, the family data suggest a familial pattern of hyperimmunoglobulinemia E and defective neutrophil motility.

Defective Polymorphonuclear-Leukocyte Function and Chronic Granulomatous Disease in Two Female Children

Abstract In vitro studies of polymorphonuclear-leukocyte function in two female patients with clinical and pathological features of chronic granulomatous disease of childhood showed defective bacte...

The pattern of genetic transmission of the leukocyte defect in fatal granulomatous disease of childhood

The leukocyte-phagocytic function test which was found to be abnormal in boys with fatal granulomatous disease of childhood has been found to be abnormal to an intermediate extent in their mothers. Nine of nine mothers were shown to be abnormal, whereas none of eight fathers and none of five healthy brothers exhibited a defect. 10 of 16 female siblings were abnormal to the same degree as their mothers, as were all three maternal grandmothers available for study. Assuming that this intermediate functional defect represents the heterozygous state, the nine family pedigrees are entirely compatible with the concept that the trait is transmitted on the X-chromosome.A tetrazolium dye-phagocytosis histochemical test was also abnormal in the carrier females and provided independent confirmation of the selection of the female siblings suspected of being carriers for the trait. In addition, this procedure gives indirect evidence that the gene in question is subject to the random inactivation that appears to affect many X-linked genes in mammalian females. The family members were also studied with two of the metabolic assays that have been shown to be abnormal in the cells of affected boys. One assay, the oxidation of the first carbon of glucose-1-(14)C by the isolated leukocytes, was significantly abnormal in the cells of carrier females. The other assay, the oxidation of formate-(14)C by leukocytes of heterozygotes was not significantly different from control values. The practical problem of diagnosing patients would appear to be best solved with a tetrazolium dye procedure, whereas the more subtle abnormality in carrier females is best detected with the leukocyte function test. Improved methods for the function test are being developed.

Impaired leukotactic responsiveness in patients with juvenile diabetes mellitus.

The neutrophil leukocytes of 30 patients with juvenile onset diabetes mellitus were tested for leukotactic activity and compared with 30 age-matched controls to determine whether patients with uncomplicated juvenile diabetes mellitus have abnormal leukotactic responsiveness. The mean leukotactic index of patients with juvenile onset diabetes mellitus was significantly lower than that of controls (p < 0.001). The leukotactic defect was not related to the duration of diabetes, or to the degree of control. Following incubation of the neutrophils of juvenile diabetics with insulin, the mean leukotactic index increased to normal levels. The leukotactic activity of control leukocytes after incubation with insulin remained unchanged. Random mobility and nitroblue tetrazolium dye reduction by the neutrophils of juvenile diabetic patients did not differ from that of controls. Leukotactic responsiveness in patients with uncomplicated juvenile onset diabetes is similar to that described in patients with adult onset diabetes and may explain, at least in part, the severity and chronicity of infections suffered by diabetic patients.

Hyperactivity of Neutrophil Leukotactic Responses during Active Bacterial Infection

To determine if changes in neutrophil leukocyte function occur during active bacterial infection, the neutrophils of 25 patients with active bacterial infection and 25 age-matched controls were compared for leukotactic activity, random mobility, and nitroblue tetrazolium reduction. The neutrophil leukocytes of patients with bacterial infection were hyperactive in unidirectional movement toward a chemotactic stimulus as measured in the leukotactic assay and usually had increased nitroblue tetrazolium reduction. The mean leukotactic index was 165+/-56 in patients with bacterial infection and 70+/-11 in controls (P < 0.001). After 7-10 days of appropriate therapy with clinical and bacteriological response, leukotactic activity returned to normal values. A hyperactive leukotactic response continued, however, in patients with persisting bacterial infection. The hyperactive leukotactic response of circulating neutrophils appears to be an early and sensitive event in the inflammatory cycle stimulated by bacterial infection and may aid in the localization of invading bacteria.