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Systemic Mycobacterium avium Complex Infection During Antitumor Necrosis Factor-α Therapy in Pediatric Crohn Disease

Jordan, Nicole*; Waghmare, Alpana; Abi-Ghanem, Alain S.; Moon, Aeri§; Salvatore, Christine M.||

Journal of Pediatric Gastroenterology and Nutrition: February 2012 - Volume 54 - Issue 2 - p 294–296
doi: 10.1097/MPG.0b013e31822938c3
Case Reports

*Department of Pediatrics, Division of Gastroenterology and Nutrition

Department of Pediatrics

Department of Radiology, Division of Nuclear Medicine, Weill Cornell Medical College, New York, NY

§Division of Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, MA

||Department of Pediatrics, Division of Infectious Diseases, Weill Cornell Medical College, New York, NY.

Address correspondence and reprint requests to Christine M. Salvatore, MD, Assistant Professor of Pediatrics, Department of Pediatrics, Division of Infectious Diseases, Weill Cornell Medical College, New York Presbyterian Hospital, 505 E 70th St, 3rd Floor, PO Box 578, New York, NY 10065 (e-mail:

Received 13 January, 2011

Accepted 14 June, 2011

The authors report no conflicts of interest.

Tumor necrosis factor-α (TNF-α) is a cytokine involved in systemic inflammation. Anti-TNF-α therapy neutralizes the biological activity of TNF-α and is presently used for maintaining clinical remission in moderately to severely active Crohn disease (CD) (1–3). This therapy has been associated with serious and sometimes fatal infections, including tuberculosis (TB) (4). It is recommended that patients be evaluated for TB before initiating anti-TNF-α therapy (5). The risk is less clear for nontuberculous mycobacterial infections such as Mycobacterium avium complex (MAC) (4). To the best of our knowledge, we present the first pediatric case report of MAC infection after anti-TNF-α therapy in a pediatric patient with CD who had been on anti-TNF-α regimens.

An 11-year-old girl was diagnosed with CD in December 2007 at another institution after presenting with a long history of poor growth and anemia 3 months earlier. At the time of her initial diagnosis, her inflammatory bowel disease (IBD) serology showed positive anti-OmpC and anti-CBir1 antibodies, 26.6 EU/mL and 40.2 EU/mL, respectively. Biopsy slides from her initial diagnosis were reviewed at our institution and noted for chronic inactive gastritis, active duodenitis, and active inflammation in the right, transverse, left, and sigmoid colons; there were no granulomas found in the biopsy samples. Based on the above, her Montreal classification (6) at the time of diagnosis was A1, L2/L4, B1, and her Paris classification (6) was A1b, L2/L4a, B1, G1. Initially, her symptoms resolved after a short course of oral steroids; she was thus maintained on low-dose 5-aminosalicylic acid (5-ASA). For approximately 3 months, she experienced recurrent flares requiring several short courses of oral corticosteroids and higher dosing of 5-ASA. As of April 2008, a steroid-sparing agent, 6-mercaptopurine (6-MP), was added to her medical therapy; however, she started complaining of joint pain consistent with inflammatory bowel disease (IBD) arthropathy. In August 2008, infliximab was started and 6-MP discontinued. Before initiating infliximab, she was screened for TB. She did not have known risk factors for TB, including but not limited to an underlying immunodeficiency syndrome, travel outside the United States, living or working in a shelter, jail, or residential care facility, or close contact with anyone who lived or worked in a shelter, jail, or residential care facility. She was also found to have a negative tuberculin skin test (TST) and a normal chest x-ray. She received the standard induction course of infliximab (5 mg/kg body weight at weeks 0, 2, and 6) with suboptimal clinical improvement. In November 2008, she was hospitalized with recurrent high fevers, abdominal pain, and elevated inflammatory markers (erythrocyte sedimentation rate [ESR] 90 mm/hour and C-reactive protein [CRP] 2.93 mg/dL). A gallium scan and blood and urine cultures were negative. An abdominal computed tomography showed terminal ileal inflammation. Upper and lower endoscopies were performed. Endoscopically, she was noted to have white linear plaques and exudates in the upper esophagus, gastric erosions, a nodular antrum, and increased vascularity of the rectosigmoid colon. Histologically, biopsies of the esophagus, stomach, duodenum, terminal ileum, and entire colon were normal. Based on the above, she was thought to have possible adverse reactions to infliximab. Therefore, infliximab was discontinued and adalimumab at 80 mg was started with planned maintenance dosing of 40 mg every 2 weeks. Repeat chest x-ray and TST before initiating adalimumab were negative. Subsequently, at the end of January 2009, given her persistent disabling arthralgia, her adalimumab dosing frequency was shortened to weekly. Her clinical improvement was remarkable with reduction of ESR (50 mm/hour) and CRP (0.88 mg/dL), complete resolution of her arthralgia, and improvement in her appetite and weight gain (3 kg). At the end of March 2009, however, she developed impressive bilateral, tender, firm, nonfixed cervical, supraclavicular and axillary lymphadenopathy. There was no history of fever, weight loss, night sweats, fatigue, abdominal pain, diarrhea, or vomiting. Her laboratory findings showed a normal complete blood count, renal function, lactate dehydrogenase, and uric acid, ESR 85 mm/hour, and CRP 5.82 mg/dL. Fused positron emission tomography and computed tomography scan using 2-(18fluorine) fluoro-2-deoxy-D-glucose showed multiple hypermetabolic and enlarged lymph nodes within the neck, chest, abdomen, and pelvis (Fig. 1). She underwent an excisional biopsy of a cervical lymph node; histology was negative for lymphoma, but the histiocytes showed focal formation of small, loose granulomas. Microbiological analysis of the node showed a negative acid-fast stain. Because she had been on anti-TNF-α therapy and her previous TSTs were negative, an interferon-γ release assay (IGRA) (QuantiFeron-TB Gold [QFT-G]; Cellestis Ltd, Carnegie, Australia) was performed on 2 separate occasions (April and May 2009) and both times the assay was reported as abnormal, being the presence of interferon-γ detected (normal laboratory reference value = not detected). Immunosuppressive treatment with adalimumab was discontinued, and she was empirically started on antituberculosis therapy. A diagnosis of systemic MAC infection was established 2 weeks later after the lymph node culture became positive. Because of these results, inquiries did not reveal previous risk factors for MAC infection. The modification of the therapeutic regimen to ethambutol, clarithromycin, and rifampin led over time to a complete clinical resolution of the systemic adenopathy in December 2009.



Because of a recrudescence of her clinical symptoms, she resumed adalimumab. A few weeks before restarting adalimumab, she was started on MAC prophylaxis with weekly azithromycin. At the present time (December 2010), she remains completely asymptomatic while receiving bimonthly adalimumab.

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In 2001, Keane et al (7) reported an association between infliximab use and an increase in TB infection; since then all of the anti-TNF-α agents have been found to pose a risk for reactivation of latent TB and maybe also for newly acquired TB infections. Tuberculous and nontuberculous mycobacterial infections have been reported in patients on anti-TNF-α therapy (4). For this reason, the present practice is to screen for TB before initiating anti-TNF-α therapy. TB screening may include a TST, a chest x-ray, and/or the recently available IGRAs. Mow et al (8) found a high incidence of anergy in patients with IBD, especially if they were taking immunosuppressive medications, concluding that the TST may not be an adequate screen for TB. IGRAs use TB-specific antigens found in the M tuberculosis genome, proteins ESAT-6 and CFP-10, to stimulate the release of interferon-γ in blood samples and have been found to be highly specific for active TB and latent TB diagnoses (9). These TB-specific antigens are, however, deleted from the genome of M bovis and M avium complex; therefore, IGRAs should not be influenced by Bacillus Calmette-Guérin vaccination, which is derived from M bovis or MAC infection. Schoepfer et al (10) evaluated the agreement between TST versus QFT-G In-Tube (QFT-G-IT), which is one of the IGRAs, in detecting latent TB in patients with IBD. The present study found poor concordance between TST and QFT-G-IT and showed that TST is negatively influenced by immunosuppressive medications and vaccination status. The authors suggested that TST should thus be replaced by the IGRAs for TB screening in immunosuppressed patients with IBD. The Centers for Disease Control and Prevention caution that only limited data are available regarding the use of IGRAs for testing immunocompromised patients (11). Furthermore, as with the TST, the sensitivity of QFT-G-IT may be decreased in this population (12). In children younger than 5 years, the sensitivity and specificity of IGRAs have not been fully evaluated. It is difficult to interpret the persistently positive result of the QFT-G in our patient, being the culture from the node biopsy positive only for MAC and given the complete resolution on a therapeutic regimen that would not have treated TB. It is still possible, however, that she has latent TB, which has never expressed itself.

If the TB screening test is positive, it is highly recommended that patients complete TB therapy with isoniazid before initiating anti-TNF-α therapy, always weighing the risks and benefits of delaying anti-TNF-α therapy. Less is known about the risk of onset and progression of nontuberculous mycobacterial infection while on anti-TNF-α therapy; no screening test is available at this time for atypical mycobacteria and there are no official guidelines on how to manage patients with active infection. Griffith et al (13) states that anti-TNF-α therapy should be continued in patients with active nontuberculous mycobacterial infection if concurrent with therapy for the nontuberculous mycobacterial infection. We elected to discontinue our patient's adalimumab until complete resolution of her MAC infection.

There are a few reports of MAC infection in adult patients with IBD on anti-TNF-α therapy (4). To our knowledge, this is the first case report of systemic MAC infection in a pediatric patient with CD on anti-TNF-α therapy, namely adalimumab. More epidemiological studies are needed to evaluate the real incidence of nontuberculous mycobacteria infection while receiving anti-TNF-α therapy in children with IBD. In the settings of an acute clinical presentation, such as systemic adenopathy, a high index of suspicion for this opportunistic infection is warranted given the lack of effective screening tests.

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