Radiographic features of patients with chronic granulomatous disease

Patient 1, a previously healthy male, presented at 12 years of age with migratory arthritis, swelling of fingers and toes, mouth ulcers, decreased appetite, weight loss, and daily fevers. He was admitted to hospital where initial investigations showed signs of macrophage activation syndrome. He was treated with high dose prednisone, and his symptoms progressively resolved. Two months later, he was re-admitted with fevers, painful oral ulcers, cough, and pleuritic chest pain. Computed tomography (CT) scan of his chest showed bilateral pulmonary nodules with mediastinal and hilar lymphadenopathy (Figure 1). A bronchoalveolar lavage was positive for Aspergillus fumigatus. He was diagnosed with autosomal recessive CGD after genetic assessment revealed a mutation in NCF1.

Patient 2 presented at 1 year of age with prolonged fever and poor response to 1 course of antibiotics. Further evaluation revealed a right lower lobe cavitating pneumonia and hilar mediastinal lymphadenopathy, found to be positive for Enterovirus, Bocavirus, and Acinetobacter. His tuberculosis (TB) skin test was negative and gastric aspirate was twice negative. Follow up chest CT demonstrated worsening of the right lower lobe opacity with small confluent cavitation and associated hilar and mediastinal lymphadenopathy (Figure 2). He was treated with multiple courses of antimicrobials including meropenem. Genetic evaluation revealed a mutation in NCF2, confirming the diagnosis of autosomal recessive CGD. He later developed recurrent mouth ulcers on the inside of his lower lip, which resolved over 4–5 days without treatment. This remains an active issue for him.

Patient 3 is the only female patient in our case series. At 2 years of age, she had a history of afebrile cervical adenitis with spontaneous non-purulent drainage that resolved with a course of amoxicillin-clavulanate. Aside from 3 episodes of acute otitis media responsive to short course of antibiotics, there was no other significant infection history. She had oral aphthous lesions in childhood that resolved over years, as well as recurrent, prolonged fevers ranging from 6 days to 2 weeks. At 7 years of age, she presented with decreased appetite, abdominal pain and fullness, as well as generalized fatigue. These episodes were found to be associated with significant splenomegaly and moderate hepatomegaly as well as pan or bi-cytopenia. Infectious work up was persistently negative. Bone marrow biopsy showed mild fibrosis with no evidence of malignancy or hemophagocytosis. Her full body magnetic resonance imaging (MRI) and abdominal ultrasound revealed hepatosplenomegaly but no other abnormal finding. Splenic biopsy identified diffuse infiltrate with small, well-defined non-caseating granulomas. The patient was diagnosed with juvenile sarcoidosis, and ophthalmology assessment showed uveitis. She was subsequently started on oral prednisone (2 mg/kg), ocular prednisone, and methotrexate. This resulted in marked improvement, with resolution of cytopenia, fevers, hepatosplenomegaly, and uveitis. Given the presence of granulomas in the spleen and low NOBI (from 1.7 to 9.0) on 3 separate occasions, genetic testing was subsequently arranged. A mutation in NCF1 confirmed the diagnosis of autosomal recessive CGD. Antimicrobial and antifungal prophylaxis was initiated, however, with poor compliance. Upon cessation of immunosuppression, she had resurgence of mild cytopenia and hepatosplenomegaly. She had another flare of fever, splenomegaly, and abdominal pain a year later associated with severe headache and papilledema. Brain MRI and subsequent magnetic resonance venography (MRV) showed evidence of increased intracranial pressure, and abdominal MRI (Figure 3) showed an enlarged liver and spleen with with parenchymal heterogeneity in the periphery of the spleen, as well as some prominent periportal and peripancreatic enlarged lymph nodes. Lumbar puncture showed increased opening pressure (37) with benign cerebrospinal fluid (CSF) examination. She was started on acetazolamide with somewhat adequate response, and receives low dose steroids in case of flare-ups. The patient has not been transplanted, however, this is considered an option for her.

Patient 4 developed idiopathic serous pericardial effusion with tamponade at age 19 months, requiring pericardiocentesis. At 3 years of age, he had significant episodes of vomiting, abdominal pain, and severe obstruction. Ultrasound and CT scan of the abdomen was suggestive of multiple sites of inflammation from the esophagus including the small and large bowel (Figure 4). Biopsies revealed focal eosinophilic abscess in the duodenum but no granulomas, as well as multiple pigmented macrophages in the lamina propria. He was started on omeprazole and ketotifen for eosinophilic gastroenteritis, but his weight loss and vomiting persisted. Repeat upper and lower gastrointestinal (GI) endoscopies and biopsies of the colon and rectum revealed positive Periodic acid-Schiff (PAS) staining of macrophages in the rectum, raising the possibility of CGD. Vomiting was explained by gastric outlet obstruction, a gastrojejunal tube was inserted for feeding, and he was started on steroids for the GI inflammation. The patient had abnormal NOBI on 2 occasions at levels of 1.0 and 1.7, while the patient’s mom was found to have 2 populations of neutrophils with normal and abnormal NOBI. Genetic testing was confirmatory of X-linked CGD with a point mutation in CYBB. He was subsequently started on antimicrobial and antifungal prophylaxis. The patient had brain MRI and angiography due to refractory and persistent vomiting which showed irregular asymmetric dilatation of basilar artery (Figure 5). No intervention was necessary. He had flare ups of abdominal pain 4–5 times a year which responded well to steroids. Although he had a human leukocyte antigen (HLA)-matched sibling, the family did not consent to HSCT. He was lost to follow-up for several years, and was admitted at the age of 12 years to the intensive care unit with septicemia secondary to small bowel microperforations requiring small bowel resection and ileostomy. The resected portion of small bowel, as well as biopsies from other GI sites, showed non-necrotizing granulomas. The procedure was later complicated with an abdominal abscess. Subsequent MRI of the pelvis revealed persistent bowel inflammation mimicking IBD. A CT scan of his chest showed multiple nodules/granulomas in his right lung. The patient later died due to sepsis and respiratory failure.

Patient 5 presented at 2 months of age with cervical lymphadenopathy on the left side requiring excision and debridement due to abscess formation. Cultures grew Staphylococcus aureus and the tissue showed granuloma formation. He presented again at 4.5 months of age with bilateral neck lymphadenopathy (Figure 6) and fever. Cultures again grew S. aureus and the microscopic description was consistent with granulomatous inflammation. NOBI was low at 1.3, and alongside the presence of granuloma and frequent lymphadenitis, this lead to the diagnosis of X-linked CGD. A novel mutation in CYBB encoding for gp91^phox was identified. Given the persistence of fever, a CT of his chest was performed which showed multiple small pulmonary nodules (Figure 7) and an abdominal ultrasound was also performed which demonstrate multiple hypoechoic splenic lesions in a mildly enlarged spleen (Figure 8). Once his lymphadenitis and fever improved, he was started on trimethoprim-sulfamethoxazole and itraconazole for bacterial and fungal prophylaxis. He underwent a successful matched sibling donor HSCT at 9 months of age and has full immune reconstitution.

Patient 6 presented at 18 months of age with a history of diarrhea and fever. An abdominal ultrasound and CT scan were performed, showing 2 hypoechoic lesions in his liver (Figures 9A and 9B). He was treated with cefotaxime, ampicillin, and flagyl, then subsequently switched to cloxacillin and ciprofloxacin. Biopsy of the lesions showed non-necrotizing granulomatous inflammation. He continued to have persistent fevers and was eventually found to have Serratia marcescens in a urine culture. Further imaging with an abdominal CT showed diffuse large bowel wall thickening (Figure 9C). An upper and lower endoscopy revealed severe colitis, particularly in the proximal bowel. He was given mesalamine as well as interferon gamma 3 times a week while he was admitted in hospital. A CT of his chest showed scattered small lesions in the posterior area of both lungs (Figure 10). He had 2 low NOBI and subsequent genetic testing confirmed X-linked CGD due to mutation in the CYBB gene. His mother was identified as a carrier. Once the infections were controlled, he underwent a successful matched sibling donor HSCT. Unfortunately, he had multiple issues post-transplant, including hypothyroidism, short stature, bronchiolitis obliterans requiring steroid treatment, ADHD, learning disability, recurrence of his colitis, bilateral lichen sclerosis atrophicus of axilla, and plasmacytoma of his tongue. He also had disseminated measles after MMR vaccination that required hospital admission. The patient remains partially engrafted.

Patient 7 presented at 1 year of age with cervical lymphadenitis requiring excision. At 3 years of age he developed multiple left axillary enlarged lymph nodes with surrounding inflammatory changes (Figure 11) and an erythematous nodule on his left arm. This lymph node was excised and grew Aspergillus. This finding raised the suspicion of CGD. Further laboratory testing and genetic work up confirmed the diagnosis of X-linked CGD due to mutation in CYBB. A CT scan of his chest demonstrated mediastinal and hilar lymphadenopathy as well as extensive nodular lung disease (Figure 12). He was treated with amphotericin and later with voriconazole and itraconazole, with excellent response to therapy after 4 months. Repeat imaging showed complete resolution of the axillary lesion and a significant decrease in the number of lung lesions. Six months later, abdominal ultrasound showed multiple splenic lesions and splenomegaly (Figure 13). He was treated again with amphotericin and caspofungin, however, the lesions did not improve and continued to wax and wane over the following months. A laparoscopic biopsy was then performed, which was negative for fungi or bacteria but showed non-necrotizing granulomas. He was started on weekly interferon gamma therapy and eventually received a matched sibling donor HSCT. He was fully engrafted and all lesions completely resolved. Unfortunately, he developed rhabdomyosarcoma of the left posterior fossa which was treated with surgery, chemotherapy and radiation. Subsequently, he developed hypothyroidism and is being treated with thyroid hormone replacement therapy.

Patient 8 presented at 6 months of age with severe skin impetigo that was treated with antibiotics. He has had 2 episodes of left sided cervical lymphadenitis (Figure 14). The first was at 8 months of age and required operative management. Cultures grew methicillin sensitive Staphylococcus aureus (MSSA). The second lymphadenitis was at 19 months old, however, no pathogen was identified. His most recent NOBI result was 5.9. Genetic testing confirmed X-linked CGD due to mutation in CYBB. He later underwent successful HSCT from a 9/10 HLA-matched unrelated donor.

Patient 9 presented at 3 months of age with fever, poor weight gain, and irritability. Hospital admission and investigations revealed septicemia (blood culture grew MSSA), bilateral neck lymphadenitis (Figure 15) and liver abscess (Figure 16). His liver abscess was biopsied and showed granuloma inflammation as well as positive culture for MSSA. For this, he was treated with a prolonged course of antibiotics. The patient’s NOBI test result was abnormally low and subsequent genetic testing identified a mutation in CYBB, confirming X-linked CGD. He received HSCT from 9/10 HLA-matched unrelated donor. His post-transplant course was complicated with liver and GI graft versus host disease (GvHD), requiring multiple immunosuppressive treatments to control his symptoms. To date, the patient’s GI GvHD has not flared for over a year, however, he is still receiving immunosuppression for his liver GvHD.

Patient 10 presented at 3 days of age with diarrhea and severe eczema, and was diagnosed with eosinophilic gastroenteritis. At 10 months of age, he developed bilateral cervical lymphadenitis. Lymph node excision showed granulomatous inflammation with no organism identified. Subsequent genetic testing revealed mutation in CYBB, confirming the diagnosis of X-linked CGD. The patient was started on prophylactic antibiotic, antifungals, and interferon gamma, however, he experienced recurrent mouth ulcers and intermittent anal fissures, as well as recurrent skin infections and abscesses. The patient decided to discontinue interferon gamma at 11 years of age, and prophylactic antibiotic and antifungals at 14 years of age. At 15, he was admitted with an abscess of his right foot, right thigh, and right lung. A CT scan of his lungs revealed consolidation of the right middle and lower lobes with mild pleural effusion, as well as mediastinal and hilar lymphadenopathy (Figure 17). Follow up chest MRI showed progression of the lung consolidation to an intrapulmonary abscess extending to the thoracic wall (Figure 18). A lung biopsy revealed Aspergillus. MRI of lower extremity showed an inflammatory/infective process in his right thigh (Figure 19). Skin biopsies from his right foot and from his right thigh revealed abscesses with granulomatous inflammation without any microorganism identified.