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Background. Chronic granulomatous disease (CGD) is a genetic disorder of the phagocyte NADPH oxidase, which predisposes patients to infections and inflammatory complications, including severe colitis. Management of CGD colitis is a challenge because standard immunosuppressive therapy increases the risk of infection in already immunocompromised hosts.
Methods. We report the use of infliximab in 5 patients with CGD.
Results. Infliximab administration predisposed patients to severe infections with typical CGD pathogens but not mycobacteria, as reported with infliximab in other conditions. In addition to infections, infliximab administration led to successful closure of fistulae, sometimes with other untoward consequences. Infliximab-associated complications were associated with 2 deaths.
Conclusions. Infliximab use in the treatment of CGD inflammatory bowel disease requires aggressive antimicrobial prophylaxis, assiduous surveillance for infection, and vigilance for untoward gastrointestinal complications. This experience suggests that infliximab therapy is effective but has untoward consequences in patients with CGD.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by defective NADPH oxidase activity occurring in at least 1 in 250,000 live births . CGD phagocytes are unable to create superoxide and its downstream metabolites hydrogen peroxide and hypochlorite. Patients with CGD have recurrent life-threatening infections with a relatively narrow spectrum of bacteria and fungi, including Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia species, and Aspergillus species. There are 5 genotypes of CGD, each due to a gene of the NADPH oxidase complex. gp91phox is on the X chromosome and accounts for ~65% of cases, the autosomal recessive defects in p47phox (25% of cases), p67phox (<5% of cases), p22phox (<5% of cases) , and p40phox (1 case) account for the remainder of cases [3, 4].
In addition to recurrent infections, patients with CGD may also experience exuberant inflammatory responses characterized by tissue granuloma formation. Symptomatic inflammatory bowel disease affects up to 50% of CGD patients and may occasionally be their presenting symptom . CGD-associated colitis is clinically and radiologically similar to Crohn colitis, with more rectal disease, patchier distribution, and denser granuloma formation [5, 6]. The rate of colitis in CGD does not correlate with prophylactic antifungals, antibacterials, or interferon gamma use but is markedly more common in the x-linked form than in the autosomal recessive varieties . Survival rates for patients with CGD with and without colitis are similar, with a mortality rate for patients with CGD of ~1.5% annually [5, 7].
Infliximab, a chimeric (mouse/human) monoclonal antibody to tumor necrosis factor-α (TNF-α) (human constant region  of immunoglobulin [Ig] G1 coupled to the variable regions [VK and VH] of mouse anti-TNF-α) binds either membrane-bound or soluble TNF-α. In Crohn colitis, infliximab closes fistulae and induces and maintains remission [8, 9]. Infectious consequences of infliximab treatment are due to the effective blockade of this cytokine, which is important to host defense against bacteria, mycobacteria, fungi, and viruses. Infliximab-associated infections may include reactivation of latent tuberculosis, nontuberculous mycobacterial infections, hepatitis B and C exacerbation , histoplasmosis , listeriosis , pulmonary actinomycosis , other serious bacterial infections , Pneumocystis jiroveci infection [15, 16], and disseminated cytomegalovirus (CMV) infection [17–19]. Pulmonary and invasive Aspergillus fumigatus has been reported with infliximab use [8,20–24]. In all these reports. corticosteroids or other immunosuppressive agents were concomitantly used, as is usually the case in the management of inflammatory bowel diseases and other inflammatory diseases.
We describe 5 patients with CGD treated with infliximab in addition to other agents to control severe CGD colitis. The complications of therapy included predisposition to CGD-specific infections, sometimes with fatal consequences.
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 (Table 1). 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 (Figure 1). 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.
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.
Infliximab and similar agents that selectively block TNF-α represent a major advance in the management of inflammatory bowel disease, especially those cases complicated by fistulae. As anticipated from the crucial role TNF-α plays in host defense, depression of microbial containment has led to recurring problems with infection in individuals treated with TNF-α blockade [25, 26]. In vivo, in vitro, and animal data suggest an exuberant TNF-α response to inflammation in CGD. In some situations, it has been suggested that TNF-α contributes to inappropriate tissue injury [27–29]. Although it may well be true that exaggerated TNF-α responses in CGD may be harmful, our human experience shows that neutralization of TNF-α is profoundly dangerous in CGD, suggesting that TNF-α is playing a more central role in CGD than previously appreciated.
CGD is characterized by heightened susceptibility to infection, as well as aberrant inflammation. Colitis is a major manifestation and complication of CGD, with at least 50% of patients developing symptomatic bowel disease, including anal fissures, perirectal abscesses, fistulae, bowel obstruction, cramping, and diarrhea [5, 30–33]. The consequences of this include iron deficiency, growth retardation, fatigue, and discomfort. Importantly, bone marrow transplantation seems to be curative of CGD and colitis . Infliximab has been suggested previously as a possible therapeutic agent in CGD . Its use has been mentioned in CGD inflammatory bowel disease, but no detailed report of efficacy or complications has been presented . We resorted to the use of infliximab because of refractory inflammatory bowel disease despite aggressive management. The combination of steroids, 6-mercaptopurine, and infliximab substantially improved our patients' colitis. However, despite prophylaxis beyond the norm, including increased antibacterials and posaconazole or voriconazole, we failed to prevent infections. Importantly, the infections that our patients developed were largely those typical in CGD and not some of the infections reported in the general population receiving TNF-03b1 blockade, such as mycobacteria. In addition, the time to the development of a serious infection was relatively short, ranging from 3 to 12 infusions of infliximab. The infections that were identified were usually different from those that had been cultured from the patients previously, indicating that their infections were likely due to intercurrent infections and not derepression of latent ones. Although the closure of enteroenteric fistulae is beneficial, the occlusion of tracts leading to undrained abscesses had untoward consequences, as evidenced in patients 2 and 4, in whom the disease courses were further complicated.
Most of the experience in treating inflammatory bowel disease is derived from Crohn disease and ulcerative colitis, both of which are chronic relapsing conditions that often require lifetime care. Although the initial response to steroids is favorable in these conditions, the long-term response is less than satisfactory because of either the complications of prolonged steroid use or loss of effect. For this reason, alternative immune modulators have been sought to complement steroids and to diminish their prolonged use. TNF-α blockers are used in combination with other immune modifiers, such as corticosteroids, methotrexate, cyclosporine, azathioprine, or 6-mercaptopurine, agents that reduce the likelihood of antibody formation toward infliximab. They additionally benefit control of inflammation in combination regimens and facilitate stable long-term, antiinflammatory effects [37, 38]. Anti-TNF-α therapies have gained much popularity in other immunodeficiencies, such as the granulomatous complications of common variable immunodeficiency. Although granulomas appear to be pathologic in Crohn disease, where their obliteration is good, in CGD granulomas may reflect a more physiologic, albeit intrusive, response. Therefore, although TNF-α may be pathologically dysregulated in CGD, blocking it appears to do more harm than in the non-CGD population.
Interestingly, there are several reports of invasive aspergillosis in adults with Crohn disease treated with infliximab [8, 20–24]. Because Crohn-like colitis can be the initial or sole manifestation of CGD in some cases, it is possible that these cases may actually represent undiagnosed CGD. Therefore, we suggest that CGD be considered as one cause of inflammatory bowel disease before the initiation of TNF-α blockade.
Infliximab was highly effective in the treatment of refractory CGD-associated colitis but was associated with serious bacterial and fungal infections, including 2 deaths. If TNF-α blockade is deemed necessary in CGD, it should be used with extreme caution, if at all. It seems prudent to increase patient and staff awareness of risk, to maximize prophylaxis, and to augment the usual surveillance for infection in CGD. The number of serious infections and complications occurring in 5 CGD patients receiving TNF-α blockade, despite aggressive prophylaxis, was high. These cases suggest that TNF-α-mediated immunity is central to the residual immunity in CGD and should be retained whenever possible.
Financial support. The Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Potential conflicts of interest. All authors: no conflicts.
The views expressed in this article are those of the authors and do not reflect the official policy of the US government.