Gastrointestinal Involvement in Chronic Granulomatous Disease
* Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. Chronic granulomatous disease (CGD) is a rare disorder of phagocyte oxidative metabolism. In addition to infectious complications, granulomatous lesions often involve hollow viscera, especially the gastrointestinal (GI) tract. The objective of this study was to evaluate the clinical presentation, prevalence, and consequences of GI involvement in patients with CGD.
Methods. The medical records of 140 patients with CGD (67% X-linked) followed at the National Institutes of Health were reviewed and abstracted for GI manifestations. All available GI pathology was reviewed.
Results. GI involvement was recorded in 46 (32.8%) of 140 patients with CGD, 89% of whom had X-linked inheritance. The median age at the time of initial GI manifestations was 5 years (range: 0.8–30 years); 70% of the affected patients presented with GI involvement in the first decade of life. Abdominal pain was the most frequent symptom (100%), and hypoalbuminemia was the most frequent sign (70%). Prednisone controlled symptoms and signs in the majority of affected patients, but relapse of symptoms occurred in 71%. GI involvement had no effect on mortality and was unassociated with interferon-
use.
Conclusion. GI involvement is a common and recurring problem in CGD, especially in those with X-linked inheritance. Currently, there is no clear evidence for an infectious cause. The frequency of GI involvement is unaffected by the use of interferon- and does not affect mortality. GI involvement should be sought in patients who have CGD with abdominal pain, growth delay, or hypoalbuminemia.
Key Words: chronic granulomatous disease • inflammatory bowel disease • interferon- • colitis • obstruction • steroids
Abbreviations: CGD, chronic granulomatous disease • GI, gastrointestinal • NIH, National Institutes of Health • CI, confidence interval • IFN-, interferon- • OR, odds ratio
Chronic granulomatous disease (CGD) is a genetic immunodeficiency in which phagocytes are unable to kill certain bacteria and fungi as a result of reduced production of superoxide and hydrogen peroxide. Patients with CGD develop recurrent and life-threatening infections as well as granulomatous inflammation of hollow viscera.1 CGD is classified according to the mode of inheritance and the components of the reduced nicotinamide adenine dinucleotide phosphate oxidase affected. Approximately 65% of patients have X-linked disease as a result of defects in gp91phox; the remainder have an autosomal recessive pattern of inheritance as a result of defects in p47phox (30%), p67phox (<5%), or p22phox (<5%).1,2
The abnormal inflammatory responses in CGD lead to exuberant and persistent tissue granuloma formation.1,3 Granulomata can affect diverse organs, but involvement of the gut is the most common and can be present either at CGD diagnosis or later.4–7 Although gastrointestinal (GI) manifestations of CGD have been reported previously,8–12 the extent of GI tract involvement in patients with CGD as a whole is unknown, and the outcome of GI involvement in CGD is poorly characterized. Therefore, we undertook a comprehensive review of all patients who had CGD and were followed at the National Institutes of Health (NIH).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Medical records for 156 patients who had CGD and were treated on various research protocols at the NIH from 1988 to 2002 were reviewed retrospectively. All patients had the diagnosis of CGD confirmed either by nitroblue tetrazolium reduction or dihydrorhodamine oxidation. The specific gene defect was determined by immunoblotting or sequencing or both.
When available, data from before the initial NIH visit was also collected. Sixteen (10%) patients were excluded from analysis because of lack of follow-up or incomplete data. The distribution of patterns of inheritance in the analyzed 140 patients was consistent with those in the general population: 95 (67%) were X-linked; 45 (33%) were autosomal recessive; 118 (84%) were male. Nineteen (13.5%) patients died in the CGD cohort during the period of observation.
For the purposes of this review, GI involvement was defined as abdominal pain (persistent, unrelated to others causes), diarrhea (persistent, without an infectious cause; with or without blood in the stool), constipation, obstruction, or fistulas. Also included were involvement of the esophagus, stomach, or bowel confirmed by endoscopy and/or histopathology. Hepatic granulomata, hepatic abscesses, and all other GI involvement from proven causes, such as gastroenteritis or infectious colitis (eg, Clostridium difficile), were not included. Routine medically indicated laboratory testing was performed at the NIH Warren Grant Magnuson Clinical Center (Bethesda, MD).
The age at diagnosis of CGD was calculated in months; those whose CGD was diagnosed at birth as a result of a positive family history were given an age at diagnosis of 1 month. The age at diagnosis of GI tract involvement in CGD was defined as that age at which the diagnosis was made by endoscopy or the patient was begun on specific treatment.
Growth was assessed by plotting age versus height (in cm) and weight (in kg) on standard growth charts (Centers for Diseases Control and Prevention Growth Charts: www.cdc.gov/growthcharts). For providing maximal comparability to the 2000 Centers for Diseases Control and Prevention percentile curves, an "age-month" variable was calculated for each patient.
We examined the effect of oral steroid therapy on relapse and growth. For family clusters of CGD, we determined the numbers of sibling pairs concordant for a given variable versus those discordant.
Statistical Analysis
Results are expressed as mean ± standard deviation. Categorical variables were compared using 
2 test, Fisher exact test, or t test, as appropriate. Survival curves were plotted using the method of Kaplan and Meier and compared by log-rank test. All probabilities were 2-tailed. The level of statistical significance was set at .05. Adjusted relative risks and 95% confidence intervals (CIs) were calculated for the use of interferon- (IFN-). Odds ratios (ORs) and 95% CI using the approximation of Woolf were calculated for association with genotype. The prevalence of GI involvement among relatives with CGD at the time of study was calculated by dividing the total number of relatives with CGD by the number of CGD relatives affected.13,14
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Forty-six patients with CGD had documented GI involvement, for an overall prevalence of 33%; 44 (96%) were male. The median age at CGD diagnosis for those with bowel disease was 2 years (range: birth to 27 years). The median age at diagnosis of GI involvement was 5 years (range: 10 months to 30 years). The 46 patients with CGD and GI involvement were born between 1965 and 1996. Among affected patients, 32 (70%) had GI symptoms identified within the first decade of life, 9 (20%) in the second decade, and 5 (10%) in the third decade. In 8 (17%), GI manifestations preceded the diagnosis of CGD: 3 carried a formal diagnosis of Crohn's disease, and 5 had recurrent nonspecific GI manifestations antedating their CGD diagnoses.
At the time of this report, 87% of the affected patients were alive, 42% of whom were older than 18 years. Two patients from the same kindred have had GI symptoms as their only manifestation of CGD. All other patients eventually experienced severe infections. Within the affected cohort of 46 patients, 41 (89%) had X-linked inheritance, whereas only 5 (11%) had autosomal recessive (4 p47phox and 1 p22phox deficient). Therefore, the prevalence of GI involvement among all X-linked patients (0.43) was significantly higher than among autosomal recessive patients (0.11; P = .0001; OR: 6.07; 95% CI: 2–19.24; Fig 1). Six (13%) patients with GI involvement had died by the time of this report, compared with 19 (13.5%) of the patients without GI involvement (P = .71; hazard ratio: 1.19; 95% CI: 0.43–3.31). Even when the mortality analysis was restricted to the X-linked cohort, no significant difference was detected. The mean age at death for those with GI involvement was 13.83 ± 3.3 years (range: 5–25 years), compared with 19.23 ± 2.5 years (range: 5–39 years; P = .24) for those without. All deaths in the GI cohort were in X-linked patients, and all were attributable to severe infections. One patient with GI involvement died as a result of intra-abdominal catastrophe; another died from aspergillus pneumonia in the setting of high-dose steroid therapy and concomitant CMV colitis. Only 3 of the 6 patients in the GI involvement group who died had been on steroids; none of the patients who died had received cyclosporine, antimetabolites, or tumor necrosis factor inhibitors.
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Clinical Features
All patients with CGD and GI involvement complained of abdominal pain; it was the primary GI manifestation in 33%. The pain was often periumbilical, especially in children, but was often diffuse with lower abdominal cramping. Other symptoms associated with abdominal pain were diarrhea with or without blood in the stool (39%), nausea and vomiting (24%), and constipation (2%).
GI involvement in 30 (65%) patients was either granulomatous or ulcerative involving the colon. Ulcerative colitis was diagnosed in 3 patients; Crohn's-like inflammatory bowel disease was diagnosed in 5 (11%). Two patients who initially had a diagnosis of Crohn's disease required a diverting colostomy and repair of a rectovesical fistula, respectively. At intervals of 11 years and 4 years from their surgeries, the patients who had diagnoses of isolated Crohn's disease were identified as having CGD during a family evaluation; 3 other patients received a diagnosis of Crohn's disease after the diagnosis of CGD, 2 of whom presented initially with severe fistulas.
Obstruction was present in 16 (35%) patients: 7 gastric, 3 esophageal, 3 duodenal, and 3 other bowel obstructions. One patient with gastric outlet obstruction developed protein-losing enteropathy. Seven patients with GI involvement also had involvement of the genitourinary tract, including the bladder, ureters, and urethra.
Symptomatic relapses occurred in 71% after reduction or cessation of therapy. It is interesting that relapses were not the same as at the onset of the GI involvement (Table 1). Five patients had unremitting symptoms, 3 had recurrent obstruction, and 2 had colitis. Infliximab was transiently successful and allowed tapering of prednisone in 1 boy. No malignancies were found.
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Laboratory findings are presented in Table 2. In general, an abnormal hemogram was uncommon, but the majority had hypoalbuminemia at the onset of GI involvement. In comparison, only 25% of patients without GI involvement had low albumins.
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Histopathology
Pathology from procedures involving the GI tract was available from 15 patients. These included biopsies from 18 lower endoscopies (10 patients), 14 upper endoscopies (11 patients), 1 segmental resection of the colon, and 1 incidental appendectomy. Tissue sections from these procedures were reviewed systematically to identify patterns of injury. In general, most of the changes were in the colon and were mild. Focal active colitis (Fig 2), with focal cryptitis and some architectural changes, was seen in 12 of 18 colonoscopic specimens. Granulomata were seen in only 6 of the 18 procedures (4 of 10 patients). In contrast to the poorly formed granulomata typical of Crohn's disease, the granulomata in CGD colitis were sharply defined aggregates of epithelioid histiocytes surrounded by a cuff of dense lymphocytic inflammation. Evidence of chronic colitis, including Paneth cell metaplasia, crypt shortening, and thickened muscularis mucosa, was seen in only 5 of the 18 colonoscopies.
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The sigmoid resection was performed for strictures associated with deep fissures and ulcerations. There was a fibrinous exudate on the serosal surface without perforations. Multiple necrotizing and nonnecrotizing granulomata were large, with irregular borders, and were associated with fissures. Crypt abscesses and cryptitis were rarely seen. The lamina propria was expanded by chronic inflammation, and the crypts showed changes of chronic colitis. Although the inflammation mainly involved the mucosa and submucosa, nonnecrotizing granulomata and chronic inflammatory infiltrates were seen in the serosa and in the mesenteric fat, and perivascular lymphoid infiltrates were present in the muscularis. The incidental appendectomy was entirely normal.
Growth
In this GI involvement cohort, 15 (32%) patients had at least 1 height measurement below the fifth percentile, and 10 (22%) patients had at least 1 weight measurement below the fifth percentile for age at least once during this period; 5 (11%) patients had a diagnosis of growth delay. Thyroid hormone levels for these patients were normal. In 2 patients, height was already low before they clearly manifested GI involvement.
At the time of this report, 23 patients were still younger than 18 years. Although there was no clear statistical difference in height associated with GI involvement (P = .08; Fig 3), more children had fallen off their growth curves in the GI involvement group than in the unaffected patients.
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Treatment
General Medical Management
All patients received trimethoprim-sulfamethoxazole for prophylaxis, and 50% were also on itraconazole. Although the majority (89%) of the GI involvement cohort received IFN-
prophylaxis, in 46%, GI involvement began before initiation of IFN-, and 11% had never received IFN-. IFN- was unassociated with GI involvement, because the same proportion of those with (89%) and without (81%) GI involvement had received it (P = .49; relative risk: 1.3; 95% CI: 0.6–2.6). However, in 3 patients, IFN- therapy was discontinued because of GI or genitourinary granulomata.
Specific Treatment
All patients with GI manifestations were treated with steroids as previously suggested.15,16 Typically, for patients who were treated at the NIH, prednisone (1 mg/kg/day) was begun when granulomata were confirmed by endoscopy. Steroids were usually gradually tapered to 
0.25 mg/kg every other day over 12 to 20 weeks. Corticosteroids markedly and rapidly decreased symptoms and induced clinical remission in most patients. Two patients developed transient hypertension. One patient developed steroid-induced cataracts.
Relapse occurred in 71% after discontinuation of corticosteroids, requiring retreatment. Low-dose prednisone (range: 2.5 mg every other day to 5 mg/day in patients 15–60 kg) was maintained for >1 year in 43%. No steroid refractory cases were recorded, even among the patients who had a diagnosis of Crohn's-like disease. Sulfasalazine was used in 5 patients with persistent colitis, with modest improvement. Infliximab was used in 1 patient with gastric outlet obstruction with improvement; granulocyte colony stimulating factor was used in another. Bowel resection was required in 3 patients; 2 patients needed surgery as a result of bowel obstruction. Bone marrow transplantation was performed in 3 patients who had GI involvement, all of whom have had complete and stable remission of their GI manifestations.
Family Analysis
These 46 patients CGD and GI involvement were members of 40 different kindreds. The concordance of GI involvement among members of affected kindreds was 85%, but symptoms were variable. Three patients with CGD developed GI manifestations, whereas their CGD-affected siblings did not.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Inflammatory GI involvement is a chronic, relapsing, and remitting condition with 2 overlapping phenotypes, ulcerative colitis and Crohn's disease.17–20 Inflammatory bowel disease that was clinically and radiographically indistinguishable from Crohn's disease was reported in patients with CGD soon after it was first described.21,22 Although the inflammatory process in the gut in CGD may be different from that in idiopathic inflammatory bowel disease, the phenotypes seem similar in many ways.23 In general, the GI pathology was more similar to Crohn's disease than ulcerative colitis,24 with a patchy distribution and well-formed granulomata, neither of which is typical for Crohn's disease.
The inflammatory manifestations of CGD have not been affected demonstrably by the wide use of prophylactic antibiotics, antifungals, and IFN-.25–28 These exuberant inflammatory lesions have been hypothesized to be attributable to inapparent infections, but the lack of change in the rate of those lesions coupled with the fact that steroids have successfully treated these lesions, often without additional antibiotics, suggests that the GI granulomas are not of infectious cause but rather represent dysregulated, exuberant inflammatory responses.29,30
Failure to thrive is a hallmark of chronic inflammatory bowel disease,31 and 30% of our patients had delayed growth. Confounding this observation is that growth is often delayed in patients with CGD in general but may pick up in late adolescence.32 It is hard to discern the effects of steroids from the effects of inflammatory bowel disease per se, but GI involvement in CGD may be an independent risk for failure to achieve normal height in these patients.
Treatment of CGD colitis is not well defined.15,16,33–35 Our own approach has been heavily dependent on corticosteroids, and at the doses that we use (0.25 mg/kg every other day), we have seen no discernible effect on infection susceptibility.
Treatment with IFN- decreases the frequency of serious infections in CGD in both humans and mice.28,36 However, because it is a potent proinflammatory cytokine involved in granuloma formation, it might exacerbate inflammatory disorders. We found no association between use of IFN- and the development of GI inflammatory involvement. Therefore, IFN- does not seem to be a risk factor for inflammatory bowel disease, at least not in CGD.
The rate of GI involvement is much higher in gp91phox deficiency than in the autosomal recessive forms.37 In addition, a positive family history of CGD GI involvement was common. This intrafamilial correlation may reflect a variety of genetic and environmental factors, which cannot be distinguished in this sort of retrospective study. The current study does not address directly the possibility that patients who had a diagnosis of Crohn's disease or ulcerative colitis may in fact have undiagnosed CGD. However, that 2 patients in this cohort were identified by family screening alone and that they have remained free of characteristic infections for several years suggest that this may be the case. Detection of these cases will be aided by family history, infection history, and the tighter granulomata seen in CGD GI involvement. Prospective studies will be needed to determine the true frequency of CGD in the inflammatory bowel disease population.
GI involvement in CGD is surprisingly common, especially among those with the X-linked form of the disease. Falling off the growth curve may be an early indicator of GI involvement or chronic infection, as well as hypoalbuminemia.12,38 The prognosis for patients with CGD has changed dramatically since the first descriptions of the disease. Now that survival into adulthood is the norm, aspects beyond infections must be anticipated and managed.39 Additional cellular and molecular understanding of the causes of GI involvement in CGD may shed considerable light on the underlying causes of inflammatory bowel disease in the general population.
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FOOTNOTES |
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Received for publication Aug 7, 2003; Accepted Dec 2, 2003.
Reprint requests to (S.M.H.) Bldg 10/11N103, 10 Center Dr, MSC 1886, Bethesda, MD 20892-1886. E-mail: smh{at}nih.gov
Drs Marciano and Rosenzweig's current affiliation is Department of Pediatrics, Hospital Nacional de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.
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REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
- Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore).2000; 79 :170 –200[CrossRef][Medline]
- Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore).2000; 79 :155 –169[CrossRef][Medline]
- Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol.2001; 8 :17 –22[CrossRef][Web of Science][Medline]
- Ament ME, Ochs HD. Gastrointestinal manifestations of chronic granulomatous disease. N Engl J Med.1973; 288 :382 –387
- Griscom NT, Kirkpatrick JA Jr, Girdany BR, Berdon WE, Grand RJ, Mackie GG. Gastric antral narrowing in chronic granulomatous disease of childhood.
Pediatrics.1974; 54
:456
–460
[Abstract/Free Full Text] - Werlin SL, Chusid MJ, Caya J, Oechler HW. Colitis in chronic granulomatous disease. Gastroenterology.1982; 82 :328 –331[Web of Science][Medline]
- Lindahl JA, Williams FH, Newman SL. Small bowel obstruction in chronic granulomatous disease. J Pediatr Gastroenterol Nutr.1984; 3 :637 –640[Web of Science][Medline]
- Markowitz JF, Aronow E, Rausen AR, Aiges H, Silverberg M, Daum F. Progressive esophageal dysfunction in chronic granulomatous disease. J Pediatr Gastroenterol Nutr.1982; 1 :145 –149[Web of Science][Medline]
- Mulholland MW, Delaney JP, Simmons RL. Gastrointestinal complications of chronic granulomatous disease: surgical implications. Surgery.1983; 94 :569 –575[Web of Science][Medline]
- Johnson FE, Humbert JR, Kuzela DC, Todd JK, Lilly JR. Gastric outlet obstruction due to X-linked chronic granulomatous disease. Surgery.1975; 78 :217 –223[Web of Science][Medline]
- Barton LL, Moussa SL, Villar RG, Hulett RL. Gastrointestinal complications of chronic granulomatous disease: case report and literature review.
Clin Pediatr (Phila).1998; 37
:231
–236
[Abstract/Free Full Text] - Schappi MG, Smith VV, Goldblatt D, Lindley KJ, Milla PJ. Colitis in chronic granulomatous disease.
Arch Dis Child.2001; 84
:147
–151
[Abstract/Free Full Text] - Szudek J, Joe H, Friedman JM. Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol.2002; 23 :150 –164[CrossRef][Web of Science][Medline]
- Zhao Y, Kumar RA, Baser ME, et al. Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2). Genet Epidemiol.2002; 23 :245 –259[CrossRef][Web of Science][Medline]
- Quie PG, Belani K. Corticosteroids for chronic granulomatous disease. J Pediatr.1987; 111 :393 –394[CrossRef][Web of Science][Medline]
- Chin TW, Stiehm ER, Falloon J, Gallin JI. Corticosteroids in treatment of obstructive lesions of chronic granulomatous disease. J Pediatr.1987; 11 :349 –352
- Hendrickson BA, Gokhale R, Cho JH. Clinical aspects and pathophysiology of inflammatory bowel disease.
Clin Microbiol Rev.2002; 15
:79
–94
[Abstract/Free Full Text] - Falconi M, Pederzoli P The relevance of gastrointestinal fistulae in clinical practice: a review. Gut.2001; 49(suppl 4) :2 –10
- Oliva-Hemker M, Fiocchi C. Etiopathogenesis of inflammatory bowel disease: the importance of the pediatric perspective. Inflamm Bowel Dis.2002; 8 :112 –128[CrossRef][Web of Science][Medline]
- Bonen DK, Cho J. The genetics of inflammatory bowel disease. Gastroenterology.2003; 124 :521 –536[CrossRef][Web of Science][Medline]
- Isaacs D, Wright VM, Shaw DG, Raafat F, Walker-Smith JA. Chronic granulomatous disease mimicking Crohn's disease. J Pediatr Gastroenterol Nutr.1985; 4 :498 –501[Web of Science][Medline]
- Mitomi H, Mikami T, Takahashi H, et al. Colitis in chronic granulomatous disease resembling Crohn's disease: comparative analysis of CD68-positive cells between two disease entities. Dig Dis Sci.1999; 4 :452 –456[CrossRef]
- Schappi MG, Klein NJ, Lindley KJ, et al. The nature of colitis in chronic granulomatous disease. J Pediatr Gastroenterol Nutr.2003; 36 :623 –631[CrossRef][Web of Science][Medline]
- Fisher JE, Khan AR, Heitlinger L, Allen JE, Afshani E. Chronic granulomatous disease of childhood with acute ulcerative colitis: a unique association. Pediatr Pathol.1987; 7 :91 –96[Medline]
- Margolis DM, Melnick DA, Alling DW, Gallin JI. Trimethoprim-sulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis.1990; 162 :723 –726[Web of Science][Medline]
- Tsuji S, Taniuchi S, Hasui M, Yamamoto A, Kobayashi Y. Increased nitric oxide production by neutrophils from patients with chronic granulomatous disease on trimethoprim-sulfamethoxazole. Nitric Oxide.2002; 7 :283 –288[CrossRef][Web of Science][Medline]
- Gallin JI, Alling DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease.
N Engl J Med.2003; 348
:2416
–2422
[Abstract/Free Full Text] - A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med.1991; 324 :509 –516[Abstract]
- Brown JR, Goldblatt D, Buddle J, Morton L, Thrasher AJ. Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD).
J Leukoc Biol.2003; 73
:591
–599
[Abstract/Free Full Text] - Segal BH, Kuhns DB, Ding L, Gallin JI, Holland SM. Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47 (phox): complement, leukotrienes, and reactive oxidants in acute inflammation.
J Leukoc Biol.2002; 71
:410
–416
[Abstract/Free Full Text] - Stephens M, Batres LA, Ng D, Baldassano R. Growth failure in the child with inflammatory bowel disease. Semin Gastrointest Dis.2000; 12 :253 –262
- Buescher ES, Gallin JI. Stature and weight in chronic granulomatous disease. J Pediatr.1984; 104 :911 –913[Web of Science][Medline]
- Myrup B, Valerius NH, Mortensen PB. Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor.
Gut.1998; 42
:127
–130
[Abstract/Free Full Text] - Stopyrowa J, Fyderek K, Sikorska B, Kowalczyk D, Zembala M. Chronic granulomatous disease of childhood: gastric manifestation and response to salazosulfapyridine therapy. Eur J Pediatr.1989; 149 :28 –30[CrossRef][Web of Science][Medline]
- Rosh JR, Tang HB, Mayer L, Groisman G, Abraham SK, Prince A. Treatment of intractable gastrointestinal manifestations of chronic granulomatous disease with cyclosporine. J Pediatr.1995; 126 :143 –145[CrossRef][Web of Science][Medline]
- Jackson SH, Miller GF, Segal BH, et al. IFN-gamma is effective in reducing infections in the mouse model of chronic granulomatous disease (CGD). J Interferon Cytokine Res.2001; 21 :567 –573[CrossRef][Web of Science][Medline]
- Foster CB, Lehrnbecher T, Mol F, et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest.1998; 102 :2146 –2155[Web of Science][Medline]
- Fitzgerald JF, Troncone R, Sabri M, Khan S. Clinical quiz. Chronic granulomatous disease. J Pediatr Gastroenterol Nutr.2002; 34 :198 , 223[CrossRef][Medline]
- Liese JG, Jendrossek V, Jansson A, et al. Chronic granulomatous disease in adults. Lancet.1996 :27 ,347:220 –223
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