DOI: 10.1148/rg.255055011
RadioGraphics 2005;25:1183-1195
© RSNA, 2005
Imaging of Chronic Granulomatous Disease in Children1
Geetika Khanna, MD,
Simon C. Kao, MD,
Patricia Kirby, MD and
Yutaka Sato, MD
1 From the Departments of Radiology (G.K., S.C.K., Y.S.) and Pathology (P.K.), University of Iowa College of Medicine, Iowa City. Recipient of a Certificate of Merit award for an education exhibit at the 2004 RSNA Annual Meeting. Received January 25, 2005; revision requested March 7 and received April 14; accepted April 19. All authors have no financial relationships to disclose. Supported by grant R43DK061079-01 from the National Institute of Mental Health; G.K. supported by grant K30HL04117-01A1 from the Iowa Scholars in Clinical Investigation Program.
Address correspondence to G.K., Department of Radiology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 (e-mail: geetika-khanna{at}uiowa.edu).
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Abstract
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Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder. The inability of phagocytic cells to kill catalase-positive organisms, such as Staphylococcus and Aspergillus species, causes recurrent infections, persistent inflammation, and granuloma formation. The imaging findings in nine cases of CGD were studied. Recurrent pulmonary infection was the most common abnormality (seven cases). Its complications included pulmonary abscesses, bronchiectasis, mediastinal abscesses, osteomyelitis, sepsis, and brain abscesses. Suppurative cervical adenitis was the second most common abnormality (four cases) and was also the presenting abnormality in the youngest patient (aged 31 days). Abdominal manifestations included hepatosplenomegaly, recurrent hepatic and splenic abscesses, necrotic mesenteric adenopathy, and gastric outlet obstruction. Osteomyelitis occurred in two cases secondary to hematogenous spread or spread of contiguous infection from the lung. Persistent infections led to formation of chronic inflammatory masses and granulomas in five cases. With improvements in therapy, the prognosis of CGD patients has improved and the general consensus is that most patients will survive into adulthood. Hence, radiologists are more likely to encounter the complications of CGD and should familiarize themselves with the spectrum of imaging findings.
© RSNA, 2005
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Introduction
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Chronic granulomatous disease (CGD) is an inherited disorder of neutrophil function, affecting one child per 200,000–250,000 live births in the United States (1). Although it is most commonly transmitted in an X-linked recessive manner, three autosomal recessive defects have also been identified. It is characterized by recurrent infections with catalase-positive organisms, such as Staphylococcus, Burkholderia cepacia, Nocardia, Mycobacteria, Serratia, Klebsiella, Pseudomonas species, and fungi, especially Aspergillus species and Candida. Recurrent bacterial and fungal infections result in lymphadenitis, abscesses, and granuloma formation, with most patients presenting within the first 2 years of life.
In this article, we summarize our experience with nine cases of CGD followed up for a total of 97 patient years and review the literature. Specific topics discussed are pathogenesis and epidemiology, the role of imaging, and manifestations of CGD.
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Study Population
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Nine cases of CGD were identified from the database of the Pediatric Immunodeficiency Clinic at our hospital. The patients have been followed up over the period 1983–2005. The most common initial presentation in this group was pulmonary infection. Lung infection was also the most common cause of morbidity, followed by suppurative adenitis. Other complications included liver abscesses, osteomyelitis, and gastric outlet obstruction. Two patients died of complicated pneumonia. The other seven patients are alive and currently free of major infections at age 1–21 years (mean, 11.9 years). The clinical characteristics of this population, including the initial presentation that led to the diagnosis of CGD, are summarized in the Table.
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Pathogenesis and Epidemiology
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CGD is caused by mutations in one of four genes encoding subunits of the phagocyte NADPH (nicotinamide adenine dinucleotide phosphate [reduced form]) oxidase (2). In the resting neutrophil, the NADPH oxidase lies dormant. Phagocytosis leads to activation of NADPH oxidase in the normal phagocyte, resulting in transfer of electrons to molecular oxygen, a process called "respiratory burst." This leads to the formation of free radical superoxide in the phagocytic vacuole (Fig 1). Oxygen radicals are the principal means by which microbial killing occurs in the phagosome.
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Figure 1. Activation of NADPH oxidase in a normal phagocyte. Phagocytosis of a microbe into a vacuole leads to activation of NADPH oxidase in the wall of the vacuole, generating oxygen radicals in the vacuole. Cytoplasmic granules also release enzymes into the vacuole, resulting in microbial killing.
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In CGD patients, a dysfunctional NADPH oxidase prevents the normal respiratory burst. In addition, microbes with catalase—a hydrogen peroxide degrading enzyme—further impair the microbicidal action of phagocytes in CGD patients. Although the neutrophils can phagocytose these catalase-positive microbes, the lack of oxygen radicals renders the neutrophils unable to kill them. These microorganisms can then survive within the phagosome, leading to a chronic struggle of the immune system with the pathogen. Chronic inflammatory cell reactions result in granuloma formation in a variety of organs, hence the name "chronic granulomatous disease."
Laboratory diagnosis of CGD is based on the determination that the patient’s neutrophils are unable to express a respiratory burst, which can be measured in a variety of ways. The nitroblue tetrazolium (NBT) test and the dihydrorhodamine reduction flow cytometry test are the two commonly used tests for diagnosis of CGD. In the NBT test, incubation of activated neutrophils with the yellow dye NBT results in the accumulation within normal phagocytes of formazan, a dark blue pigment. Failure of the color to change indicates a diagnosis of CGD. An apparently normal result of the NBT test does not exclude the X-linked carrier state, and test results are also negative in carriers of the autosomal recessive forms of CGD. Genetic testing is currently used primarily for genetic counseling and prenatal diagnosis.
Most patients manifest symptoms within the 1st year of life. The disorder is much more common in males than females, with 86% of patients in the national registry being male (1). Most patients in this registry are white (83%), although the disease may have been underdiagnosed in other races. The major sites of infection are those that come into contact with the external environment: the lungs, skin, and gastrointestinal tract and the lymph nodes that drain these organs. Hematogenous seeding can lead to osteomyelitis and liver abscesses.
The prognosis for patients with CGD has continued to improve since the disease was initially described in the 1950s, when most patients died in childhood (3). In a retrospective study conducted between 1964 and 1989, Finn et al (4) reported that 50% of patients survived through the 3rd decade. With a multifaceted therapeutic approach comprising prophylactic antibiotics, early treatment of infections with parenteral antibiotics, percutaneous drainage, surgical intervention, and the use of granulocyte infusions and interferon 
therapy, most patients are now expected to survive into adulthood. The overall mortality of all patients with CGD in the United States has been estimated at 2%–5% per year, with pneumonia or sepsis due to Aspergillus species or B cepacia being the most common cause of death (1).
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Role of Imaging
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Over the past 2 decades, the role of imaging has significantly expanded from identifying the site of the infection and its complications to image-guided interventions that are used for both diagnosis and therapy of the complications. Image-guided aspiration of abscesses or biopsy of osteomyelitis sites can be used for isolating the organisms, and percutaneous drainage of abscesses can be performed under ultrasonographic (US) or computed tomographic (CT) guidance for therapeutic purposes. This is especially important in a population predisposed to recurrent infections, in which abscess drainage allows organ preservation by avoiding multiple surgeries.
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Manifestations of CGD
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Pleuropulmonary Manifestations
Recurrent pneumonia is the most common infection, occurring in approximately 80% of CGD patients (5). Common pathogens include Staphylococcus aureus, Aspergillus species, and enteric bacteria. Aspergillus is the most common isolated organism, as empiric antibiotic therapy may resolve infections caused by bacteria, such as Staphylococcus. B cepacia (previously called Pseudomonas cepacia) is being increasingly recognized as a significant and potentially lethal pathogen.
Pulmonary infection can manifest as focal consolidation or as a miliary pattern secondary to hematogenous spread (Fig 2). Pneumonia may be complicated by abscess formation or empyema in up to 20% of patients (Fig 3a). Lung infections in CGD patients tend to follow a protracted course and may be complicated by granulomatous inflammation, persistent hilar or mediastinal lymphadenopathy, pulmonary fibrosis, and honeycomb lung (Fig 3b, 3c). Pulmonary infection can involve previously scarred areas, which may delay radiographic detection. All pulmonary infections should be aggressively treated because of the risk of spread into the chest wall and osteomyelitis involving the ribs or vertebral bodies (6). In addition to aggressive medical management, surgical resection is frequently needed to eradicate infections in these patients (7).
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Figure 2a. Pulmonary infection in an 18-year-old patient with CGD who presented with B cepacia sepsis. Chest radiograph (a) and CT scan (b) show interstitial thickening and miliary nodules in both lungs, an appearance consistent with hematogenous spread of infection.
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Figure 2b. Pulmonary infection in an 18-year-old patient with CGD who presented with B cepacia sepsis. Chest radiograph (a) and CT scan (b) show interstitial thickening and miliary nodules in both lungs, an appearance consistent with hematogenous spread of infection.
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Figure 3a. Pulmonary infection in an 8-year-old patient with CGD who presented with a fever and respiratory distress. (a) Frontal radiograph shows consolidation in the left lung with an air-fluid level in the left lower lobe (arrow), a finding suggestive of an abscess. (b) CT scan obtained 4 years later shows severe volume loss in the left lung and a honeycomb pattern in the parenchyma (arrow). Note the mosaic attenuation of the right lung with associated pleural thickening (*) and calcified hilar lymph nodes (arrowhead). (c) Lung section obtained at autopsy shows scarring in the lower lobe with hilar fibrosis (arrows) and consolidation (arrowhead).
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Figure 3b. Pulmonary infection in an 8-year-old patient with CGD who presented with a fever and respiratory distress. (a) Frontal radiograph shows consolidation in the left lung with an air-fluid level in the left lower lobe (arrow), a finding suggestive of an abscess. (b) CT scan obtained 4 years later shows severe volume loss in the left lung and a honeycomb pattern in the parenchyma (arrow). Note the mosaic attenuation of the right lung with associated pleural thickening (*) and calcified hilar lymph nodes (arrowhead). (c) Lung section obtained at autopsy shows scarring in the lower lobe with hilar fibrosis (arrows) and consolidation (arrowhead).
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Figure 3c. Pulmonary infection in an 8-year-old patient with CGD who presented with a fever and respiratory distress. (a) Frontal radiograph shows consolidation in the left lung with an air-fluid level in the left lower lobe (arrow), a finding suggestive of an abscess. (b) CT scan obtained 4 years later shows severe volume loss in the left lung and a honeycomb pattern in the parenchyma (arrow). Note the mosaic attenuation of the right lung with associated pleural thickening (*) and calcified hilar lymph nodes (arrowhead). (c) Lung section obtained at autopsy shows scarring in the lower lobe with hilar fibrosis (arrows) and consolidation (arrowhead).
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Contiguous extension of disease from the lungs to the pleura or chest wall has been reported in up to one-third of patients with CGD and Aspergillus pneumonia (Fig 4). This can manifest clinically with local pain and tenderness, but the erythema and edema frequently seen with acute osteomyelitis are rarely seen in these patients. Detection of chest wall invasion with conventional radiography is limited due to underlying parenchymal disease in the lung, but technetium-labeled bone scans and cross-sectional imaging with CT or magnetic resonance (MR) imaging can be used to effectively diagnose this complication. CT will demonstrate osseous erosion with periosteal or endosteal reaction. MR imaging features of osteomyelitis include abnormal bone marrow signal intensity, abnormal periosteum, cortical destruction, and surrounding soft-tissue inflammation. Cross-sectional imaging can also be used to perform diagnostic biopsy and plan surgical intervention.
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Figure 4a. Pulmonary infection in a 20-year-old man with known CGD who presented with back pain. (a) Chest CT scan shows focal consolidation in the posterior lower lobe of the right lung (arrow). A specimen of the infiltrate obtained with CT-guided biopsy showed growth of Aspergillus. (b) Follow-up CT scan obtained 1 year later shows persistent pleural thickening (*) with associated periostitis of the adjacent rib (arrow), a finding suggestive of osteomyelitis. (c) Photomicrograph (original magnification, x40; hematoxylineosin stain) of a specimen from the rib shows osseous trabeculae with chronic and granulomatous inflammation replacing the marrow (arrows). (d) Photomicrograph (original magnification, x400; Grünwald-Masson stain) shows fungal hyphae within a granuloma (arrows).
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Figure 4b. Pulmonary infection in a 20-year-old man with known CGD who presented with back pain. (a) Chest CT scan shows focal consolidation in the posterior lower lobe of the right lung (arrow). A specimen of the infiltrate obtained with CT-guided biopsy showed growth of Aspergillus. (b) Follow-up CT scan obtained 1 year later shows persistent pleural thickening (*) with associated periostitis of the adjacent rib (arrow), a finding suggestive of osteomyelitis. (c) Photomicrograph (original magnification, x40; hematoxylineosin stain) of a specimen from the rib shows osseous trabeculae with chronic and granulomatous inflammation replacing the marrow (arrows). (d) Photomicrograph (original magnification, x400; Grünwald-Masson stain) shows fungal hyphae within a granuloma (arrows).
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Figure 4c. Pulmonary infection in a 20-year-old man with known CGD who presented with back pain. (a) Chest CT scan shows focal consolidation in the posterior lower lobe of the right lung (arrow). A specimen of the infiltrate obtained with CT-guided biopsy showed growth of Aspergillus. (b) Follow-up CT scan obtained 1 year later shows persistent pleural thickening (*) with associated periostitis of the adjacent rib (arrow), a finding suggestive of osteomyelitis. (c) Photomicrograph (original magnification, x40; hematoxylineosin stain) of a specimen from the rib shows osseous trabeculae with chronic and granulomatous inflammation replacing the marrow (arrows). (d) Photomicrograph (original magnification, x400; Grünwald-Masson stain) shows fungal hyphae within a granuloma (arrows).
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Figure 4d. Pulmonary infection in a 20-year-old man with known CGD who presented with back pain. (a) Chest CT scan shows focal consolidation in the posterior lower lobe of the right lung (arrow). A specimen of the infiltrate obtained with CT-guided biopsy showed growth of Aspergillus. (b) Follow-up CT scan obtained 1 year later shows persistent pleural thickening (*) with associated periostitis of the adjacent rib (arrow), a finding suggestive of osteomyelitis. (c) Photomicrograph (original magnification, x40; hematoxylineosin stain) of a specimen from the rib shows osseous trabeculae with chronic and granulomatous inflammation replacing the marrow (arrows). (d) Photomicrograph (original magnification, x400; Grünwald-Masson stain) shows fungal hyphae within a granuloma (arrows).
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Involvement of Lymph Nodes
Suppurative adenitis is the second most common infection and is more common in the X-linked recessive form of the disease than the autosomal recessive form. The cervical chain of lymph nodes is most commonly involved (Figs 5, 6), although involvement of the femoral, inguinal, mediastinal, and hilar lymph nodes has also been described. Lymph node involvement may be suppurative with abscess formation or nonsuppurative with granuloma formation due to chronic inflammation. Staphylococcus species are the most common microorganisms isolated from suppurative adenitis.
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Figure 5a. Lymph node involvement in a 10-year-old boy with known CGD who presented with swelling of the right side of the neck and a fever. (a) Contrast-enhanced CT scan shows a large abscess with enhancing septa in the right side of the neck (arrow). The abscess displaces the carotid space medially (arrowhead) and the sternocleido-mastoid muscle posteriorly (*). A specimen from the abscess showed growth of Haemophilus aphrophilus. (b) Follow-up CT scan obtained 2 years later shows persistence of the hypoattenuating fluid collection (arrow) deep to the sternocleidomastoid muscle despite aggressive management with drainage and antibiotics. Seven milliliters of pus was drained, which again showed growth of H aphrophilus.
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Figure 5b. Lymph node involvement in a 10-year-old boy with known CGD who presented with swelling of the right side of the neck and a fever. (a) Contrast-enhanced CT scan shows a large abscess with enhancing septa in the right side of the neck (arrow). The abscess displaces the carotid space medially (arrowhead) and the sternocleido-mastoid muscle posteriorly (*). A specimen from the abscess showed growth of Haemophilus aphrophilus. (b) Follow-up CT scan obtained 2 years later shows persistence of the hypoattenuating fluid collection (arrow) deep to the sternocleidomastoid muscle despite aggressive management with drainage and antibiotics. Seven milliliters of pus was drained, which again showed growth of H aphrophilus.
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Figure 6a. Lymph node involvement in a 6-week-old boy with a persistent fever and diffuse swelling of the neck. (a) US scan shows enlarged lymph nodes (arrows). (b) CT scan of the neck shows parapharyngeal (*) and posterior triangle (arrowhead) abscesses. Blood cultures were positive for Candida. (c) Photomicrograph (original magnification, x100; hematoxylineosin stain) of a lymph node shows effacement of normal lymph node architecture by a large necrotizing granuloma (arrows).
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Figure 6b. Lymph node involvement in a 6-week-old boy with a persistent fever and diffuse swelling of the neck. (a) US scan shows enlarged lymph nodes (arrows). (b) CT scan of the neck shows parapharyngeal (*) and posterior triangle (arrowhead) abscesses. Blood cultures were positive for Candida. (c) Photomicrograph (original magnification, x100; hematoxylineosin stain) of a lymph node shows effacement of normal lymph node architecture by a large necrotizing granuloma (arrows).
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Figure 6c. Lymph node involvement in a 6-week-old boy with a persistent fever and diffuse swelling of the neck. (a) US scan shows enlarged lymph nodes (arrows). (b) CT scan of the neck shows parapharyngeal (*) and posterior triangle (arrowhead) abscesses. Blood cultures were positive for Candida. (c) Photomicrograph (original magnification, x100; hematoxylineosin stain) of a lymph node shows effacement of normal lymph node architecture by a large necrotizing granuloma (arrows).
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Skeletal Manifestations
Osteomyelitis occurs in approximately one-third of CGD patients. Common sites of involvement include the ribs, vertebrae, and small bones of the feet and hands (8). This is in contrast to non-CGD patients, in whom the metaphyses of long bones are most frequently involved. Osteomyelitis in children with CGD may develop from contiguous extension of infection or may result from hematogenous spread. Ribs and vertebrae are usually involved due to contiguous spread of infection from the lung or liver (Fig 7), with Aspergillus species being the most common organism (8). Small bones of the hands and feet may also be involved due to direct extension of skin infections (Fig 8). Osteomyelitis due to hematogenous spread most commonly involves the extremities (Fig 9) and is caused by microorganisms, such as Staphylococcus, Serratia, and Nocardia.
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Figure 7a. Osteomyelitis in a 13-year-old boy with CGD who presented with a fever and right shoulder pain. (a) Magnified radiograph of the right side of the upper chest shows pleural thickening at the lung apex with widening of the second rib (arrow). (b) Technetium 99m–methylene diphosphonate bone scan (anterior view) shows increased uptake in the right second rib (thick arrow) and adjacent vertebral body (arrowhead), findings suggestive of osteomyelitis. Mild increased uptake is also noted in the right third rib (thin arrow). (c) CT scan shows a moth-eaten appearance of the right second rib (arrow) with associated involvement of the vertebral body (arrowhead), findings indicative of osteomyelitis. Underlying pleural thickening is also noted (*).
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Figure 7b. Osteomyelitis in a 13-year-old boy with CGD who presented with a fever and right shoulder pain. (a) Magnified radiograph of the right side of the upper chest shows pleural thickening at the lung apex with widening of the second rib (arrow). (b) Technetium 99m–methylene diphosphonate bone scan (anterior view) shows increased uptake in the right second rib (thick arrow) and adjacent vertebral body (arrowhead), findings suggestive of osteomyelitis. Mild increased uptake is also noted in the right third rib (thin arrow). (c) CT scan shows a moth-eaten appearance of the right second rib (arrow) with associated involvement of the vertebral body (arrowhead), findings indicative of osteomyelitis. Underlying pleural thickening is also noted (*).
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Figure 7c. Osteomyelitis in a 13-year-old boy with CGD who presented with a fever and right shoulder pain. (a) Magnified radiograph of the right side of the upper chest shows pleural thickening at the lung apex with widening of the second rib (arrow). (b) Technetium 99m–methylene diphosphonate bone scan (anterior view) shows increased uptake in the right second rib (thick arrow) and adjacent vertebral body (arrowhead), findings suggestive of osteomyelitis. Mild increased uptake is also noted in the right third rib (thin arrow). (c) CT scan shows a moth-eaten appearance of the right second rib (arrow) with associated involvement of the vertebral body (arrowhead), findings indicative of osteomyelitis. Underlying pleural thickening is also noted (*).
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Figure 8a. Osteomyelitis in a previously healthy 32-month-old boy with a history of recurrent subcutaneous abscesses on his leg. (a) Bone scan shows increased uptake in the right calcaneus (arrow). (b) Plain radiograph shows a lytic area in the calcaneus with surrounding sclerosis (arrow), an appearance suggestive of osteomyelitis. Serratia marcescens was cultured from a biopsy specimen of the calcaneus.
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Figure 8b. Osteomyelitis in a previously healthy 32-month-old boy with a history of recurrent subcutaneous abscesses on his leg. (a) Bone scan shows increased uptake in the right calcaneus (arrow). (b) Plain radiograph shows a lytic area in the calcaneus with surrounding sclerosis (arrow), an appearance suggestive of osteomyelitis. Serratia marcescens was cultured from a biopsy specimen of the calcaneus.
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Figure 9a. Osteomyelitis in a 4-year-old patient with known CGD who presented with a limp. Anteroposterior (a) and lateral (b) radiographs of the lower leg show a lytic lesion with surrounding sclerosis in the tibial diaphysis (arrow). Osteomyelitis was proved at tibial biopsy.
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Figure 9b. Osteomyelitis in a 4-year-old patient with known CGD who presented with a limp. Anteroposterior (a) and lateral (b) radiographs of the lower leg show a lytic lesion with surrounding sclerosis in the tibial diaphysis (arrow). Osteomyelitis was proved at tibial biopsy.
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Pain and tenderness are reliable signs of infection, although the findings of erythema and swelling seen with typical acute osteomyelitis are generally absent. As the early stages of osteomyelitis in CGD may be clinically occult, by the time radiographic evaluation is performed considerable osseous abnormality may be present. Although osteomyelitis predominantly causes osteolysis early on, sclerotic changes predominate in the later stages. In the small bones of the hands and feet, bone expansion with sclerosis can mimic tuberculous dactylitis (9).
Gastrointestinal Manifestations
CGD can involve the gastrointestinal tract from the esophagus to the rectum (10). Narrowing of the gastric antrum is a distinctive manifestation of CGD (Figs 10, 11), occurring in up to 16% of patients with CGD (11). Gastric outlet obstruction is more common in the X-linked recessive forms of the disease than in the autosomal recessive forms. The mean age at presentation with gastric outlet obstruction has been reported as 44 months, with an age range of 18 months to 10 years (12).
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Figure 11. Gastric outlet obstruction in a symptomatic 9-year-old boy with CGD. Image from a barium study shows marked narrowing and elongation of the pyloric channel (arrow) with thickening of the gastric folds (arrowhead).
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A child suspected of having gastric outlet obstruction can be evaluated with an upper gastrointestinal series or US (13). The upper gastrointestinal series will demonstrate concentric antral narrowing and also help evaluate gastric emptying. Esophageal motility and peristalsis can also be evaluated, as involvement of the esophagus has also been reported in this patient population (14). Sonographic evaluation demonstrates circumferential wall thickening at the antrum. The imaging findings are nonspecific, with a differential diagnosis of peptic ulcer disease, Crohn disease, and eosinophilic gastritis, but in the appropriate clinical setting are suggestive of this process.
The exact etiology of the thickening of the antral folds is unclear and is believed to be noninfectious. At gross examination, there is gross thickening of the antral wall. Histologically, there is inflammation with granuloma formation and infiltration of lipid-laden histiocytes involving the lamina propria, submucosa, smooth muscle, and serosa. No organisms are usually isolated from these lesions. Most patients respond in a few weeks to conservative medical management with nutritional support, steroids, and antibiotics (12,13).
Granulomatous inflammation has been reported to involve the wall of the intestine, and patients may present with abdominal pain, diarrhea, fever, weight loss, or bowel obstruction. This may lead to the erroneous diagnosis of Crohn disease or ulcerative colitis (15). Intra-abdominal infections such as peritonitis, lymphadenitis, and abscesses have been described in the literature (Fig 12a). Commonly isolated organisms include S aureus and gram-negative organisms such as Escherichia coli, Salmonella, and Klebsiella. Chronic inflammation with granuloma formation can lead to intraabdominal calcifications in the lymph nodes, liver, and spleen (Fig 12b, 12c). Perirectal abscesses have been reported in up to 16% of patients with CGD at some time during the course of their disease.
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Figure 12a. Intraabdominal infection in a previously healthy 2-month-old child with a fever of unknown origin and a protuberant abdomen. (a) Contrast-enhanced CT scan shows multiple hypoattenuating mesenteric lymph nodes (arrows) that displace the bowel loops around them. Blood cultures were positive for Candida. (b, c) Follow-up abdominal radiograph (b) and CT scan (c) obtained at 5 years of age show multiple calcified mesenteric lymph nodes (arrows).
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Figure 12b. Intraabdominal infection in a previously healthy 2-month-old child with a fever of unknown origin and a protuberant abdomen. (a) Contrast-enhanced CT scan shows multiple hypoattenuating mesenteric lymph nodes (arrows) that displace the bowel loops around them. Blood cultures were positive for Candida. (b, c) Follow-up abdominal radiograph (b) and CT scan (c) obtained at 5 years of age show multiple calcified mesenteric lymph nodes (arrows).
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Figure 12c. Intraabdominal infection in a previously healthy 2-month-old child with a fever of unknown origin and a protuberant abdomen. (a) Contrast-enhanced CT scan shows multiple hypoattenuating mesenteric lymph nodes (arrows) that displace the bowel loops around them. Blood cultures were positive for Candida. (b, c) Follow-up abdominal radiograph (b) and CT scan (c) obtained at 5 years of age show multiple calcified mesenteric lymph nodes (arrows).
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Hepatic and Splenic Manifestations
Hepatosplenomegaly can be present in up to 90% of patients with CGD (16). Abscesses may occur in the spleen (Fig 13) or liver, with hepatic and perihepatic abscesses described in up to 55% of cases (Fig 14). Because hepatic abscesses are relatively uncommon in children, their presence should raise suspicion for CGD (17). The clinical manifestations of liver abscess are nonspecific including fever, abdominal pain, fatigue, weight loss, and night sweats. In a series of 22 cases of CGD with hepatic abscesses reported from the National Institutes of Health, only about 50% of cases had abdominal findings of tenderness or hepatomegaly (17). In this series, 62% of cases had more than one abscess in the liver, and the size of the abscess ranged from 1 to 6 cm. Micro-abscesses can also occur in the liver or spleen as a result of fungemia (Fig 13). The liver may be simultaneously involved with both purulent and granulomatous processes, which can mimic each other at radiography.
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Figure 13. Splenic abscesses in a 6-week-old boy with sepsis. US scan of the spleen shows multiple hypoechoic lesions, findings suggestive of fungal abscesses. Blood cultures were positive for Candida; this result led to a diagnosis of CGD.
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Figure 14a. Hepatic abscesses in a 10-year-old patient with CGD. (a, b) Contrast-enhanced CT scans (a obtained at a higher level than b) show multiple hypoattenuating, peripherally enhancing lesions located predominantly in the right hepatic lobe (arrow), findings consistent with abscesses. Culture of a specimen from an abscess was positive for S aureus. (c) Transverse US scan obtained 3 months later shows lack of flow in the right portal vein (cursors), a finding consistent with thrombosis. Resection of the right hepatic lobe was performed. (d) CT scan obtained at 18 years of age shows compensatory hypertrophy of the left hepatic lobe. Multiple recurrent abscesses are noted in the left lobe (arrows). Also note the thickening of the gastric wall, predominantly at the antrum (arrowhead). (e) Photomicrograph (original magnification, x40; hematoxylineosin stain) of the liver shows hepatic lobules (bottom part of image) with fairly abrupt fibrosis (arrows) and multiple large necrotizing granulomas (arrowheads).
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Figure 14b. Hepatic abscesses in a 10-year-old patient with CGD. (a, b) Contrast-enhanced CT scans (a obtained at a higher level than b) show multiple hypoattenuating, peripherally enhancing lesions located predominantly in the right hepatic lobe (arrow), findings consistent with abscesses. Culture of a specimen from an abscess was positive for S aureus. (c) Transverse US scan obtained 3 months later shows lack of flow in the right portal vein (cursors), a finding consistent with thrombosis. Resection of the right hepatic lobe was performed. (d) CT scan obtained at 18 years of age shows compensatory hypertrophy of the left hepatic lobe. Multiple recurrent abscesses are noted in the left lobe (arrows). Also note the thickening of the gastric wall, predominantly at the antrum (arrowhead). (e) Photomicrograph (original magnification, x40; hematoxylineosin stain) of the liver shows hepatic lobules (bottom part of image) with fairly abrupt fibrosis (arrows) and multiple large necrotizing granulomas (arrowheads).
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Figure 14c. Hepatic abscesses in a 10-year-old patient with CGD. (a, b) Contrast-enhanced CT scans (a obtained at a higher level than b) show multiple hypoattenuating, peripherally enhancing lesions located predominantly in the right hepatic lobe (arrow), findings consistent with abscesses. Culture of a specimen from an abscess was positive for S aureus. (c) Transverse US scan obtained 3 months later shows lack of flow in the right portal vein (cursors), a finding consistent with thrombosis. Resection of the right hepatic lobe was performed. (d) CT scan obtained at 18 years of age shows compensatory hypertrophy of the left hepatic lobe. Multiple recurrent abscesses are noted in the left lobe (arrows). Also note the thickening of the gastric wall, predominantly at the antrum (arrowhead). (e) Photomicrograph (original magnification, x40; hematoxylineosin stain) of the liver shows hepatic lobules (bottom part of image) with fairly abrupt fibrosis (arrows) and multiple large necrotizing granulomas (arrowheads).
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Figure 14d. Hepatic abscesses in a 10-year-old patient with CGD. (a, b) Contrast-enhanced CT scans (a obtained at a higher level than b) show multiple hypoattenuating, peripherally enhancing lesions located predominantly in the right hepatic lobe (arrow), findings consistent with abscesses. Culture of a specimen from an abscess was positive for S aureus. (c) Transverse US scan obtained 3 months later shows lack of flow in the right portal vein (cursors), a finding consistent with thrombosis. Resection of the right hepatic lobe was performed. (d) CT scan obtained at 18 years of age shows compensatory hypertrophy of the left hepatic lobe. Multiple recurrent abscesses are noted in the left lobe (arrows). Also note the thickening of the gastric wall, predominantly at the antrum (arrowhead). (e) Photomicrograph (original magnification, x40; hematoxylineosin stain) of the liver shows hepatic lobules (bottom part of image) with fairly abrupt fibrosis (arrows) and multiple large necrotizing granulomas (arrowheads).
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Figure 14e. Hepatic abscesses in a 10-year-old patient with CGD. (a, b) Contrast-enhanced CT scans (a obtained at a higher level than b) show multiple hypoattenuating, peripherally enhancing lesions located predominantly in the right hepatic lobe (arrow), findings consistent with abscesses. Culture of a specimen from an abscess was positive for S aureus. (c) Transverse US scan obtained 3 months later shows lack of flow in the right portal vein (cursors), a finding consistent with thrombosis. Resection of the right hepatic lobe was performed. (d) CT scan obtained at 18 years of age shows compensatory hypertrophy of the left hepatic lobe. Multiple recurrent abscesses are noted in the left lobe (arrows). Also note the thickening of the gastric wall, predominantly at the antrum (arrowhead). (e) Photomicrograph (original magnification, x40; hematoxylineosin stain) of the liver shows hepatic lobules (bottom part of image) with fairly abrupt fibrosis (arrows) and multiple large necrotizing granulomas (arrowheads).
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Urinary Tract Manifestations
Genitourinary infections in patients with CGD are relatively rare, although recurrent urinary tract infections, cystitis, and renal and perinephric abscesses have been reported. Urinary tract infections account for 5%–15% of all infections in this patient population (16). Involvement of the lower urinary tract is thought to be more common than upper tract involvement, with chronic inflammation of the bladder causing granulomatous cystitis, bladder wall thickening, pseudotumor, and secondary hydroureteronephrosis. Patients may present with dysuria, penile pain, and urinary frequency. The radiologic findings of granulomatous cystitis may mimic eosinophilic cystitis and include bladder wall thickening that may be diffuse or focal secondary to formation of pseudotumors (18).
Involvement of the Central Nervous System
Involvement of the central nervous system is very rare in CGD and accounts for less than 5% of all infections with no predominant organism apparent (1). Meningitis or meningoencephalitis can occur as an isolated event or due to generalized sepsis. Patients with CGD have been reported to have a predisposition to primary Candida meningitis (19). Central nervous system involvement due to a granulomatous process is unusual, unless it is as part of a disseminated granulomatous reaction. Brain abscesses have been described secondary to hematogenous spread of infections, such as Aspergillus (Fig 15).
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Figure 15a. Brain abscesses in an 8-year-old patient with known CGD and a history of Aspergillus pneumonia who presented with diplopia and headaches. Axial contrast-enhanced T1-weighted MR images show multiple ring-enhancing lesions primarily located at the gray matter–white matter junction, findings suggestive of abscesses. Aspergillus was cultured from a biopsy specimen.
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Figure 15b. Brain abscesses in an 8-year-old patient with known CGD and a history of Aspergillus pneumonia who presented with diplopia and headaches. Axial contrast-enhanced T1-weighted MR images show multiple ring-enhancing lesions primarily located at the gray matter–white matter junction, findings suggestive of abscesses. Aspergillus was cultured from a biopsy specimen.
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Conclusions
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The manifestations of CGD are protean, with a wide range of infectious and inflammatory findings. The diagnosis of CGD should be considered when a child presents with atypical infections such as chest wall infection secondary to pneumonia, osteomyelitis of the small bones of the hands and feet, persistent lymphadenitis, or inflammatory obstruction of the gastrointestinal or urinary tract.
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Footnotes
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Abbreviations: CGD= chronic granulomatous disease, NADPH = nicotinamide adenine dinucleotide phosphate (reduced form)
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References
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Abstract
Introduction
