Patients 1–4 were observed at the National Institutes of Health (Bethesda, MD) and enrolled in a natural history protocol (93-I-0119) approved by the institutional review board. All patients or their parents provided informed assent or consent. Patient 5 was observed at the Children's Hospital of Philadelphia for standard care. All work was conducted in accordance with the Declaration of Helsinki principles. We initiated a standard dose of 5 mg/kg of infliximab for all patients. The first dose was given on day 1, the second dose was given 1 week later, and subsequent doses were given every 4 weeks thereafter.
Patient 1. A white girl presented with disseminated B. cepacia infection due to p47phox deficiency at 3 years of age (). At the age of 12 years, abdominal discomfort, cramping, increased stooling, and failure to thrive led to a diagnosis of CGD colitis. Initially, oral antibiotics, salicylic acid derivatives, and oral steroids controlled her symptoms. At 15 years she developed a painful rectovaginal fistula with increased cramping, frequency, anal tags, and rectal bleeding. When the rectovaginal fistula became patent, infliximab treatment was started. Trimethoprim- sulfamethoxazole, metronidazole, ciprofloxacin, and voriconazole were provided for infection prophylaxis. Her antiinflammatory regimen was prednisone (<0.5 mg/kg daily), aminosalicylic acid, and 6-mercaptopurine in addition to infusions of infliximab every 4 weeks. After her eighth infliximab dose, she was admitted to the hospital with a low-grade fever, rightside chest pain, and mild dyspnea due to a new large right upper lobe consolidation, the biopsy of which yielded B. cepacia complex. Infliximab was held for 8 weeks and antibiotics administered. After her 12th dose of infliximab, sigmoidoscopy showed significant improvement of her colitis and closure of the rectovaginal fistula (). Her gastrointestinal symptoms resolved and biochemical markers improved, but she was unable to tolerate less frequent infliximab infusions. After 2 years of taking infliximab (15 subsequent doses), she underwent matched related bone marrow transplantation, which has been complicated by significant graft-versus-host disease.
Demographic Characteristics of Patients
Figure 1 Perianal disease in patient 1. A, Extensive perianal disease showing severe anal inflammation with undermining and formation of small tissue flaps and sinus tracts. B, Improvement after infliximab treatment. C, Burkholderia pneumonia after the eighth (more ...)
Patient 2. A white boy was diagnosed as having gp91phox-deficient CGD at the age of 1 year after recurrent staphylococcal cellulitis and cervical lymphadenitis. He was referred for management of longstanding perianal abscesses and fistulae with active inflammatory bowel disease despite high-dose oral steroids. He had weight loss, bloody stools, and frequent bowel movements (13-14 times daily) along with severe cramping, abdominal pain, and urgency. Perianal fistulae were actively draining. High-dose prednisone had no effect at the end of 3 months. Colonoscopy showed friable mucosa throughout the entire gastrointestinal tract, with pseudopolyps and edema in the sigmoid colon and deep rectosigmoid ulcers with exudates. Treatment with infliximab and 6-mercaptopurine was begun. Immediately after starting infliximab treatment, he had symptomatic relief. After the third dose of infliximab, there was marked healing of his perianal fistulae: 2 of the 3 fistulae had healed completely, whereas 1 was patent with minimal serous drainage. After the fifth dose, the draining fistula closed but led to an entrapped fistula tract in the buttock, which then developed into abscess with associated inguinal lymphadenitis. A lymph node aspirate yielded Candida lusitaniae. Infliximab treatment was stopped. Drainage of the abscess and broadspectrum antibiotics were successful. Colonoscopy showed a friable, edematous, and congested colon with loss of normal vascular pattern and haustral markings with deep ulcers throughout the sigmoid colon with spontaneous bleeding. He received maintenance therapy with antibiotics, 6-mercaptopurine, and prednisone. Infliximab treatment was not reinitiated. After 2 years, his persistent fistula worsened, leading to ileostomy and subtotal colectomy. His perianal fistula and colitis symptoms have been under control since, while he continues to take antibiotics and 6-mercaptopurine.
Patient 3. A white infant boy had scrotal staphylococcal infections. At 2 years of age, he had S. marcescens furunculosis of the buttocks. Cervical adenitis at 3 years of age led to the diagnosis of CGD. Granulomatous cystitis with hydronephrosis responded to prednisone. Fungal pneumonia at 7 years of age was treated with amphotericin B. Nocardia and Aspergillus pneumonias led to left upper lobectomy. At 9 and 12 years of age, CGD colitis was treated with intermittent pulse steroids followed by prolonged low-dose steroids. At 16 years of age, 4 liver abscesses were successfully treated with radiofrequency ablation. A symptomatic rectovesicle fistula at that time extended 7 cmproximal to the anal margin with a 4-cm abscess posterior to the bladder attached to the sigmoid loop superiorly and the bladder inferiorly. For fistulizing inflammatory bowel disease, he received his first dose of infliximab, which remitted his symptoms and reduced the fistula almost immediately. However, after his third dose of infliximab, Burkholderia multivorans sepsis led to critical illness. An episode of uveitis prompted a search for standard inflammatory bowel disease features, yielding positivity for HLA B27. For persistent pelvic abscess and sepsis he underwent abdominal exploration with appendectomy, partial sigmoidectomy with Hartman pouch, and an end colostomy. The ostomy was severely complicated by peristomal pyoderma gangrenosum. Postoperatively, 2 more doses of infliximab led to functional closure of the fistula. After the fifth dose of infliximab, an asymptomatic pneumonia was found, the biopsy of which yielded Paecilomyces variotti. Treatment with posaconazole was successful. The peristomal pyoderma improved with topical treatments and subcutaneous IgG infusions. After not taking infliximab for 8 months, colonoscopy revealed atrophic, erythematous, friable, inflamed, nodular, and ulcerated mucosa. These findings along with worsening severe pyoderma at the stoma site led to reinitiation of infliximab therapy. After his eighth infliximab infusion, the stoma site had improved.
After 16 cumulative doses of infliximab, he was admitted with fever, abdominal pain, drug-induced pancytopenia, and ecthyma gangrenosum. Cultures of the ecthyma yielded Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii. A mucoid P. aeruginosa was repeatedly isolated from the wound along with Candida glabrata. A nodular infiltrate was found in the right lung, and the biopsy was uninformative. Treatment with appropriate antibiotics and voriconazole was started empirically, but neutropenia and colitis escalated with pneumatosis intestinalis. Total colectomy, distal ileal resection, and colostomy takedown showed granulomatous inflammation and CMV colitis. CMV was also detected in blood (18,000 CMV genome equivalents/mL). Progressive multiple organ failure was fatal. Autopsy revealed pneumonia due to P. aeruginosa and A. baumannii and pulmonary vascular invasive septate hyphae consistent with aspergillus.
Patient 4. A white boy with a congenital solitary right kidney had poor wound healing and wound dehiscence after ureteral reimplantation, leading to the diagnosis of X-linked CGD. At 14 years of age, he developed abdominal pain and diarrhea due to CGD colitis. Treatment with adalimumab led to no improvement. He received maintainence therapy with oral steroids. At 16 years of age, a fistula extending from the left splenic flexure to the omentum and abdominal wall was identified, prompting the initiation of infliximab treatment. Treatment with prednisolone, 1 mg/kg, 6-mercaptopurine, and mesalamine was continued, as was use of his prophylactic trimethoprim-sulfamethoxazole, posaconazole, amoxicillin-clavulanic acid, metronidazole, and ciprofloxacin. His colitis symptoms improved significantly. When the fistula intermittently closed, the remnant abscess caused high temperatures and flank pain. After his sixth dose of infliximab, a diverting loop ileostomy was performed. At 17 years of age, 8 weeks after his last infliximab treatment and 6 weeks after his ileostomy, multiple hepatic microabscesses were identified while he was receiving intravenous levofloxacin and ertapenem. Cultures of 2 separate liver lesions were nondiagnostic. Treatment for presumed methicillin-resistant S. aureus infection led to resolution.
Patient 5. A white girl developed multiple S. aureus liver abscesses at 22 months of age. She was diagnosed as having autosomal recessive CGD at 27 months of age. At 10 years of age, periumbilical and low abdominal pain, cramping, tenesmus, and diarrhea led to colonoscopy demonstration of friability and colonic ulcers. She was treated with prednisone, 6- mercaptopurine, mesalamine, metronidazole, itraconazole, and trimethoprim-sulfamethoxazole. At 15 years of age, she had herpes zoster of her left arm and shoulder. At 19 years of age, multiple pelvic abscesses and fistulae with rectovaginal extension followed development of rectal strictures, which required dilatations. At 20 years of age, infliximab infusions were started every 6-8 weeks. She continued to take infliximab for the next 16 months with resolution of her pelvic abscesses and rectovaginal fistulae. At 21 years of age, after taking infliximab for more than 16 months, she presented in respiratory distress with pleural effusions. Blood cultures yielded B. cepacia. During the ensuing 2 months she had polymicrobial bloodstream infections, including S. aureus, Candida krusei, Candida albicans, and Aspergillus terreus. She died of multiorgan failure.