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Since its approval in the late 1990s, infliximab — a chimeric monoclonal antibody directed against tumour necrosis factor (TNF-α) — has revolutionised our approach to moderate-to-severe IBD.1-3 To date, over 1 million patients worldwide with IBD, rheumatoid arthritis, psoriasis and other inflammatory conditions have received infliximab therapy.
Adverse effects of infliximab therapy include infusion reactions, serum sickness-like disease and the development of auto-antibodies (particularly anti-nuclear antibodies), rarely complicated by a lupus-like syndrome.3 Several years after it was initially approved for use in rheumatoid arthritis and Crohn’s disease, it was recognised that reactivation of tuberculosis could develop soon after treatment with infliximab.
Subsequent screening for latent tuberculous infection or active disease before initiating infliximab therapy was advised and this has seen a significant reduction in the number of cases of tuberculosis.4
However, while early studies reported low rates of serious adverse effects in patients treated with infliximab,5 subsequent studies and Safety Registry data point toward infrequent but serious opportunistic infections and sepsis.3,6,7 Over the past 15 years, several severe and occasionally fatal opportunistic infections have been reported following infliximab and adalimumab therapy, including listeria, pneumocystis, pulmonary aspergillosis, histoplasmosis, severe candida infections, coccidioidomycosis, cryptococcosis, cytomegalovirus, varicella-zoster virus and Epstein-Barr virus infections.5,9-16
Data from the ACCENT 1 trial3 and the Mayo Clinic6 in Rochester, Minnesota, US, have shown that 32 per cent and 8.2 per cent of IBD patients developed infections on infliximab therapy, respectively. However, serious infections, including sepsis, occurred in approximately 4 per cent of patients treated in both studies.3,6 While there appears to be no correlation between the number of infusions and the rate of infectious events, the most serious infections after infliximab treatment occurred after three or fewer infusions.3,6,9,18
The real risk of developing opportunistic infections following anti-TNF therapy is difficult to assess, as all of the reported patients with IBD were receiving concomitant corticosteroids or immunomodulators such as azathioprine or 6-mercaptopurine, which are also independently associated with opportunistic infections.17-21,22 While the extent to which concomitant corticosteroids and immunomodulator drugs contribute to serious opportunistic infections in patients with IBD who receive infliximab is not clear, a study by Toruner et al from the Mayo Clinic reported that immunosuppressive medications, especially when used in combination and older age, are associated with a significantly increased risk of opportunistic infections in patients with IBD.23
Listeria monocytogenes is a gram-positive, intra-cellular bacterium. Transmission occurs via contaminated food such as unpasteurised milk, soft cheeses, coleslaw, undercooked meats and raw vegetables.8 Human disease generally occurs at the extremes of life (younger than two months or older than 60 years of age) or in the setting of pregnancy or immunosuppression, and manifests itself as a systemic illness associated with bacteraemia, sepsis, meningitis and other systemic complications.9 Case mortality has been estimated to be 27 per cent, and unless recognised and treated promptly, many patients who develop listeria meningitis are left with significant neurological sequelae.9
Infections caused by Listeria monocytogenes complicating infliximab treatment for Crohn’s disease were first described in 2000.17 A review by the Food and Drug Administration’s Adverse Event Reporting Programme reported three CD patients on infliximab who developed listeria septicaemia and/or meningitis,18 one of whom died. All patients were receiving concurrent immunosuppressive drugs, including a 17-year-old girl reported by Kamath et al.19 In addition, meningitis caused by Listeria monocytogenes has been reported in three patients with CD treated with infliximab.7, 20, 21
TNF-α plays a pivotal role in the pathogenesis of IBD and a marked increase of this cytokine is found in the intestinal mucosa of patients with CD and UC.24 However, apart from its proinflammatory role, TNF-α also plays an important role in the defence against microbial infections. The interaction between listeria infection and the host response is complex,25 but there is good evidence suggesting that TNF-α plays an important role in host defence against Listeria monocytogenes. The presence of this cytokine and its receptor, p55, seems to be critical for resistance against primary infection by this intracellular pathogen.26 While the anti-TNF-α effects of infliximab are undoubtedly of great benefit to patients with moderate-to-severe IBD, unfortunately anti-TNF therapy predisposes a very small number of patients to potentially serious opportunistic infections, including listeriosis, as in our case. This appears to have a class effect, as cases have been reported in patients on adalimumab, which is another medication in this class.27
Consequently, the manufacturers of anti-TNF therapies have addressed this potentially serious complication by issuing a warning regarding the possible increased occurrence of opportunistic infections, including listeria.16 Clinicians should be aware of this complication after anti-TNF therapy and should consider aggressive investigation, including a low threshold for performing a lumbar puncture in all patients on anti-TNF therapy who develop headache, fever and/or new-onset neurological symptoms and signs with prompt empirical antibiotic treatment in all patients with suspected meningitis.
Patients receiving anti-TNF therapy should be advised to avoid foods such as soft cheeses and unpasteurised dairy products and reheat (until steaming) processed meats such as hot dogs.19,23 In 2011, the FDA added a boxed warning about the risk of Legionella and listeria infection for the entire class of TNF-α inhibitors.28 The acquisition of listeria through the ingestion of contaminated foods emphasises the importance of educating patients regarding food preparation and safety and this message should be included in the patient education packs and reinforced by healthcare professionals.
A 37-year-old man presented with a two-month history of abdominal cramps and bloody diarrhoea. He reported a 4kg weight loss over the preceding 10 days. On examination, he was dehydrated, hypotensive and had diffuse abdominal tenderness and was admitted to hospital for intravenous fluids. Investigations showed raised inflammatory markers but stool-testing for bacterial pathogens, Clostridium difficile toxins and parasites were negative. CT scan of the abdomen showed pancolitis. Flexible sigmoidoscopy revealed a severe continuous colitis extending to the point of insertion of the scope and biopsies were consistent with ulcerative colitis. After failing to respond to maximum doses of oral 5-aminosalicylic acid (5-ASA) and intravenous steroids (hydrocortisone 100mg QID), he was commenced on a 5mg/kg infliximab infusion.
Ten days later and 20 days into his hospital admission, he developed an occipital headache with fever. Neurological examination showed no focal motor or sensory deficit and absence of papilledema on fundoscopy. There was no neck stiffness and negative Kerning’s and Brzezinski’s signs. He underwent a non-contrast CT brain scan, which was reported as normal. A lumbar puncture was then performed, which yielded clear fluid with the following results:
Steroids were stopped on confirmation of diagnosis and the patient received intravenous Amoxicillin 2gm qds and Gentamicin 80mgs tds for 10 days. He recovered completely without any neurological sequelae. Further anti-TNFα therapy was considered inappropriate and a subtotal colectomy, which confirmed ulcerative colitis, was performed on completion of his antibiotic treatment.
- Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumour necrosis factor for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029-35. [PubMed]
- Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398-405. [PubMed].
- Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002;359:1541-9. [PubMed].
- Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumour necrosis factor-neutralising agent. N Engl J Med 2001;345:1098-104. [PubMed].
- Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: The first 100 patients. Am J Gastroenterol 2001;96:722-9. [PubMed].
- Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn’s disease: The Mayo clinic experience in 500 patients. Gastroenterology 2004;126:19-31. [PubMed]
- Ljung T, Karlen P, Schmidt D, et al. Infliximab in inflammatory bowel disease: Clinical outcome in a population-based cohort from Stockholm County. Gut 2004;53:849-53. [PMC free article] [PubMed]
- Greenberg HB, Matsui SM, Holodniy M. Small intestine: Infections with common bacterial and viral pathogens. In: Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, eds. Textbook of gastroenterology, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 1999:1530-60.
- Hamer DH, Gorbach SL. Infectious diarrhoea and bacterial food poisoning. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 7th edn. Philadelphia: WB Saunders Company, 2002:1864-1913.
- Tai TL, O’Rourke KP, McWeeney M, Burke CM, Sheehan K, Barry M. Pneumocystis carinii pneumonia following a second infusion of infliximab. Rheumatology (Oxford) 2002;41:951-2. [PubMed]
- Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001;344:1099-100. [PubMed]
- Keenan GF, Schaible TF, Boscia JA. Invasive pulmonary aspergillosis associated with infliximab therapy (reply). N Engl J Med 2001;344:1100.
- Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumour necrosis factor antagonists infliximab and etanercept. Arthritis Rheum 2002;46:2565-70. [PubMed]
- Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002;112:78. [PubMed]
- Diamanti A, Papadatou B, Knafelz D, Gambarara M, Ferretti F, Castro M. Complications of infliximab therapy in children and adolescents affected by Crohn’s disease. Am J Gastroenterol 2003;98:2812-3. [PubMed]
- Remicade (infliximab) for IV injection. Package Insert. Pennsylvania: Centocor Inc, 2003.
- Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000;95:841-2. [PubMed]
- Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumour necrosis factor-neutralising agents. Arthritis Rheum 2003;48:319-24. [PubMed]
- Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002;34:410-2. [PubMed]
- Joosten AA, van Olffen GH, Hageman G. Meningitis due to Listeria monocytogenes as a complication of infliximab therapy. Ned Tijdschr Geneeskd 2003;147:1470-2. [PubMed]
- Tweezer-Zaks N, Shiloach E, Spivak A, Rapoport M, Novis B, Langevitz P. Listeria monocytogenes sepsis in patients treated with anti-tumour necrosis factor. Isr Med Assoc J 2003;5:829-30. [PubMed]
- Bowie VL, Snella KA, Gopalachar AS, Bharadwaj P. Listeria meningitis associated with infliximab. Ann Pharmacother 2004;38:58-61. [PubMed]
- Toruner M et al. Rsk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134: 929-936.
- Cappello M, Keshav S, Prince C, Jewell DP, Gordon S. Detection of mRNAs for macrophage products in inflammatory bowel disease by in situ hybridisation. Gut 1992;33:1214-9. [PMC free article] [PubMed]
- Edelson BT, Unanue ER. Immunity to Listeria infection. Curr Opin Immunol 2000;12:425-31. [PubMed]
- White DW, Badovinac VP, Fan X, Harty JT. Adaptive immunity against listeria monocytogenes in the absence of type I tumour necrosis factor receptor p55. Infect Immun 2000;68:4470-6. [PMC free article] [PubMed]
- Willson KJ1, Jacob A, Shetti MP, Bhatia R, Yee K, Osler W. Listeria monocytogenes infection in Crohn’s disease treated with adalimumab. Med J Aust. 2012 Oct 15;197(8):466-7.
- FDA Drug Safety Communication: Drug labels for the tumour necrosis factor — (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria.