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Prolonged paradoxical response to anti-tuberculous treatment after infliximab
International Journal of Infectious Diseases 14S (2010) e333–e334
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
Prolonged paradoxical response to anti-tuberculous treatment after infliximab Sara Melboucy-Belkhir a,*, Gabriella Flexor a, Je´roˆme Stirnemann a, Anne-Sophie Morin a, Latifatou Boukari a, Claude Polliand b, Philippe Cruaud c, Olivier Fain a a
Service de Me´decine Interne, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, avenue du 14 Juillet, 93140 Bondy Cedex, France Service de Chirurgie, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, Bondy, France c Laboratoire de Microbiologie, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, Bondy, France b
A R T I C L E I N F O
S U M M A R Y
Article history: Received 1 November 2009 Received in revised form 11 March 2010 Accepted 14 March 2010
A 56-year-old woman with ankylosing spondylitis, treated for 3 months with infliximab, developed miliary tuberculosis with mediastinal lymphadenopathies and brain and splenic lesions. After initial improvement under anti-tuberculous therapy, she suffered an unexpectedly prolonged paradoxical worsening with several episodes of lymphadenopathy, including life-threatening ones, over a period of more than 14 months of follow-up. The outcome was favorable as a result of corticosteroid and surgical treatments. This phenomenon reflects a paradoxical reaction precipitated by infliximab withdrawal. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: Sheldon Brown, New York, USA Keywords: Tuberculosis Anti-TNF Cytokine Spondylarthritis Immunology
1. Introduction Infliximab is a monoclonal antibody inhibitor of tumor necrosis factor-alpha (TNF-a) used for the treatment of rheumatoid arthritis, spondylarthritis, and Crohn’s disease. However, it increases the risk of opportunistic infections, particularly tuberculosis (TB). Worsening of pre-existing TB lesions or the appearance of new TB lesions in patients whose state has initially improved with antiTB therapy defines a paradoxical reaction to anti-TB treatment.1 Most cases have been described in HIV patients2–4 for whom antiretroviral therapy was initiated simultaneously or within two months after starting anti-TB treatment. Cases occurring after infliximab therapy have rarely been reported.1,5,6 We report the case of a patient who experienced a paradoxical reaction that lasted more than 14 months after infliximab therapy and present a review of the literature to describe this phenomenon. 2. Case report A 56-year-old woman suffering from ankylosing spondylitis was treated with infliximab 5 mg/kg (275 mg) in November 2004.
* Corresponding author. Tel.: +33 673160891. E-mail address: [email protected] (S. Melboucy-Belkhir).
The second and third infusions were administered two and four weeks later. Her grandfather had had pulmonary and osteoarticular TB in 1953; her tuberculin skin test (TST) before starting infliximab was positive (10 mm), but she received no anti-TB treatment. At the end of January 2005, she complained of fever, cough, chest pain, sweats, weight loss, and headaches. A physical examination was normal except for a temperature of 38.2 8C. Chest and abdominal computed tomography (CT) scans showed miliary lesions, mediastinal lymphadenopathies, and splenic nodules. Magnetic resonance imaging revealed three brain nodules. The cerebrospinal fluid was normal; a mycobacterial culture was sterile. HIV serology was negative. Despite negative sputum smears for acid-fast bacilli, a four-drug regimen was started: rifampin (600 mg/day), isoniazid (250 mg/day), pyrazinamide (1500 mg/day) and ethambutol (750 mg/day). Infliximab was discontinued; long-term sputum cultures grew pan-sensitive Mycobacterium tuberculosis. From April 2005, only rifampin and isoniazid were prescribed. In May 2005, she developed an acute, inflammatory, right supraclavicular lymphadenopathy measuring 5 4 cm (Figure 1); standard and mycobacterial cultures of its purulent liquid content were negative. It diminished in size after adjunctive prednisone (1 mg/kg/day) therapy. The patient was re-hospitalized three months later, in July 2005, for respiratory distress, chest pain, and facial edema. A CT scan showed cervical and mediastinal
1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2010.03.002
[(Figure_1)TD$IG]
e334
S. Melboucy-Belkhir et al. / International Journal of Infectious Diseases 14S (2010) e333–e334
Figure 1. Acute inflammatory right supraclavicular lymphadenopathy appeared four months after starting anti-TB treatment.
lymphadenopathies compressing the trachea and superior vena cava without thrombosis. Tinzaparin and methylprednisolone (500 mg/day for 3 days) gave substantial relief; prednisone was progressively tapered from 120 to 20 mg/day four months later, while anti-TB therapy was continued. In March 2006, despite her regimen of rifampin, isoniazid and prednisone (20 mg/day), her right supraclavicular lymphadenopathy reappeared, reaching 3–4 cm in size, and was surgically excised. Histopathological examination revealed caseating gigantocellular granulomas; cultures were negative. Two months later, another cervical lymph node, measuring 2 cm, appeared and was resolved with prednisone (60 mg/day for 2 weeks). Anti-TB treatment was stopped in June 2006. In January 2008, a new cervical lymphadenopathy appeared and was surgically excised. Again, histopathological examination revealed caseating gigantocellular granulomas and cultures were negative. In January 2009, the patient appeared to be cured of TB. 3. Discussion Clinical or radiological TB worsening, occurring at least four weeks after starting anti-TB therapy, in a patient whose clinical status initially improved, is known as a paradoxical reaction or immune reconstitution syndrome (IRIS).1 It has been well described in HIV patients with TB whose antiretroviral treatment was started simultaneously with or within the first few months of the onset of anti-TB agents.2,3 It has also been observed in non-HIVinfected patients.4 Different clinical pictures have been described, including fever, lymphadenopathy, pulmonary infiltrates, pleurisy, cerebral tuberculomas, and meningitis.2 Affected tissues have usually contained granulomas, but cultures have been negative.2 This phenomenon has coincided with increased lymphocyte counts and has been attributed to a hypersensitivity reaction to antigens released by M. tuberculosis killed by anti-TB treatment; this reaction reflects the rapid host immune reconstitution due to the efficacy of antiretroviral therapy.2,3 Infliximab, a monoclonal antibody inhibitor of TNF-a, has been used to treat spondylarthritis, but it has been shown to increase the risk of TB because TNF-a is critical for the formation and maintenance of granulomas, which prevent the systemic spread of M. tuberculosis. Our infliximab-treated patient was diagnosed with active miliary, splenic TB lesions, cerebral tuberculomas, and lymphadenopathies; her TB was probably latent and triggered by infliximab.
According to the guidelines,7,8 our patient with a TST result greater than 5 mm should have received prophylactic treatment for TB before infliximab onset. Although the risk of TB during anti-TNF therapy was known at that time, the threshold of the TST in France for the treatment of latent TB was 10 mm.9 Nevertheless, this case report highlights and reinforces the importance of the current guidelines for assessing the risks and for managing M. tuberculosis infection in patients due to start anti-TNF. The infliximab activity lasted 4–8 weeks; as a result IRIS occurred over the next few months after stopping infliximab in the presence of released TB antigens.1 The occurrence of a paradoxical reaction after stopping infliximab, when TB was diagnosed, has previously been reported.1,5,6 Between 1999 and 2003, Garcia Vidal et al.1 reviewed 284 infliximab-treated patients in three Spanish hospitals. Six (2.1%) of them had TB; of these, four (67%) developed paradoxical reactions that occurred 5–16 weeks after TB. Our patient presented unusually severe and prolonged paradoxical reactions marked by several flares during more than 14 months of follow-up; this is likely to reflect both a high antigenic load and the strength of the immune reconstitution after withdrawal of immunosuppression in an otherwise immunocompetent patient. Noncompliance, malabsorption, drug resistance, and opportunistic infections were ruled out. Paradoxical reactions are usually controlled by corticosteroids, sometimes surgery, continuation of anti-TB treatment, and withdrawal of anti-TNF.1,3 However, one case was recently reported in which anti-TNF therapy (adalimumab) was resumed to treat a life-threatening TB paradoxical reaction, with a prompt favorable outcome.6 In another case, infliximab was used to treat a steroid-resistant TB paradoxical reaction involving the central nervous system in a patient who had not previously been receiving anti-TNF therapy.10 Thus maintenance infliximab should be considered to avoid dramatic paradoxical worsening.1,5,10 In summary, this case illustrates unusually prolonged and severe TB paradoxical reactions precipitated by infliximab withdrawal and reinforces the importance of guidelines for assessing and managing TB before starting anti-TNF. Conflict of interest: No conflict of interest to declare. References 1. Garcia Vidal C, Rodrı´guez Ferna´ndez S, Martı´nez Lacasa J, Salavert M, Vidal R, Rodrı´guez Carballeira M, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 2005;40:756–9. 2. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933–6. 3. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIVinfected patients. Clin Infect Dis 2004;38:1159–66. 4. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803–9. 5. Belknap R, Reves R, Burman W. Immune reconstitution to Mycobacterium tuberculosis after discontinuing infliximab. Int J Tuberc Lung Dis 2005;9: 1057–8. 6. Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 2009;48:1429–32. 7. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005; 60: 800–5. 8. Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol 2008;59:209–17. 9. Treatment of latent tuberculosis infection: towards a change in practices in France. Rev Mal Respir 2003; 20:S41–4. 10. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis 2008;47:83–5.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
Prolonged paradoxical response to anti-tuberculous treatment after infliximab Sara Melboucy-Belkhir a,*, Gabriella Flexor a, Je´roˆme Stirnemann a, Anne-Sophie Morin a, Latifatou Boukari a, Claude Polliand b, Philippe Cruaud c, Olivier Fain a a
Service de Me´decine Interne, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, avenue du 14 Juillet, 93140 Bondy Cedex, France Service de Chirurgie, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, Bondy, France c Laboratoire de Microbiologie, Hoˆpital Jean-Verdier, Assistance Publique–Hoˆpitaux de Paris, Universite´ Paris 13, Bondy, France b
A R T I C L E I N F O
S U M M A R Y
Article history: Received 1 November 2009 Received in revised form 11 March 2010 Accepted 14 March 2010
A 56-year-old woman with ankylosing spondylitis, treated for 3 months with infliximab, developed miliary tuberculosis with mediastinal lymphadenopathies and brain and splenic lesions. After initial improvement under anti-tuberculous therapy, she suffered an unexpectedly prolonged paradoxical worsening with several episodes of lymphadenopathy, including life-threatening ones, over a period of more than 14 months of follow-up. The outcome was favorable as a result of corticosteroid and surgical treatments. This phenomenon reflects a paradoxical reaction precipitated by infliximab withdrawal. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: Sheldon Brown, New York, USA Keywords: Tuberculosis Anti-TNF Cytokine Spondylarthritis Immunology
1. Introduction Infliximab is a monoclonal antibody inhibitor of tumor necrosis factor-alpha (TNF-a) used for the treatment of rheumatoid arthritis, spondylarthritis, and Crohn’s disease. However, it increases the risk of opportunistic infections, particularly tuberculosis (TB). Worsening of pre-existing TB lesions or the appearance of new TB lesions in patients whose state has initially improved with antiTB therapy defines a paradoxical reaction to anti-TB treatment.1 Most cases have been described in HIV patients2–4 for whom antiretroviral therapy was initiated simultaneously or within two months after starting anti-TB treatment. Cases occurring after infliximab therapy have rarely been reported.1,5,6 We report the case of a patient who experienced a paradoxical reaction that lasted more than 14 months after infliximab therapy and present a review of the literature to describe this phenomenon. 2. Case report A 56-year-old woman suffering from ankylosing spondylitis was treated with infliximab 5 mg/kg (275 mg) in November 2004.
* Corresponding author. Tel.: +33 673160891. E-mail address: [email protected] (S. Melboucy-Belkhir).
The second and third infusions were administered two and four weeks later. Her grandfather had had pulmonary and osteoarticular TB in 1953; her tuberculin skin test (TST) before starting infliximab was positive (10 mm), but she received no anti-TB treatment. At the end of January 2005, she complained of fever, cough, chest pain, sweats, weight loss, and headaches. A physical examination was normal except for a temperature of 38.2 8C. Chest and abdominal computed tomography (CT) scans showed miliary lesions, mediastinal lymphadenopathies, and splenic nodules. Magnetic resonance imaging revealed three brain nodules. The cerebrospinal fluid was normal; a mycobacterial culture was sterile. HIV serology was negative. Despite negative sputum smears for acid-fast bacilli, a four-drug regimen was started: rifampin (600 mg/day), isoniazid (250 mg/day), pyrazinamide (1500 mg/day) and ethambutol (750 mg/day). Infliximab was discontinued; long-term sputum cultures grew pan-sensitive Mycobacterium tuberculosis. From April 2005, only rifampin and isoniazid were prescribed. In May 2005, she developed an acute, inflammatory, right supraclavicular lymphadenopathy measuring 5 4 cm (Figure 1); standard and mycobacterial cultures of its purulent liquid content were negative. It diminished in size after adjunctive prednisone (1 mg/kg/day) therapy. The patient was re-hospitalized three months later, in July 2005, for respiratory distress, chest pain, and facial edema. A CT scan showed cervical and mediastinal
1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2010.03.002
[(Figure_1)TD$IG]
e334
S. Melboucy-Belkhir et al. / International Journal of Infectious Diseases 14S (2010) e333–e334
Figure 1. Acute inflammatory right supraclavicular lymphadenopathy appeared four months after starting anti-TB treatment.
lymphadenopathies compressing the trachea and superior vena cava without thrombosis. Tinzaparin and methylprednisolone (500 mg/day for 3 days) gave substantial relief; prednisone was progressively tapered from 120 to 20 mg/day four months later, while anti-TB therapy was continued. In March 2006, despite her regimen of rifampin, isoniazid and prednisone (20 mg/day), her right supraclavicular lymphadenopathy reappeared, reaching 3–4 cm in size, and was surgically excised. Histopathological examination revealed caseating gigantocellular granulomas; cultures were negative. Two months later, another cervical lymph node, measuring 2 cm, appeared and was resolved with prednisone (60 mg/day for 2 weeks). Anti-TB treatment was stopped in June 2006. In January 2008, a new cervical lymphadenopathy appeared and was surgically excised. Again, histopathological examination revealed caseating gigantocellular granulomas and cultures were negative. In January 2009, the patient appeared to be cured of TB. 3. Discussion Clinical or radiological TB worsening, occurring at least four weeks after starting anti-TB therapy, in a patient whose clinical status initially improved, is known as a paradoxical reaction or immune reconstitution syndrome (IRIS).1 It has been well described in HIV patients with TB whose antiretroviral treatment was started simultaneously with or within the first few months of the onset of anti-TB agents.2,3 It has also been observed in non-HIVinfected patients.4 Different clinical pictures have been described, including fever, lymphadenopathy, pulmonary infiltrates, pleurisy, cerebral tuberculomas, and meningitis.2 Affected tissues have usually contained granulomas, but cultures have been negative.2 This phenomenon has coincided with increased lymphocyte counts and has been attributed to a hypersensitivity reaction to antigens released by M. tuberculosis killed by anti-TB treatment; this reaction reflects the rapid host immune reconstitution due to the efficacy of antiretroviral therapy.2,3 Infliximab, a monoclonal antibody inhibitor of TNF-a, has been used to treat spondylarthritis, but it has been shown to increase the risk of TB because TNF-a is critical for the formation and maintenance of granulomas, which prevent the systemic spread of M. tuberculosis. Our infliximab-treated patient was diagnosed with active miliary, splenic TB lesions, cerebral tuberculomas, and lymphadenopathies; her TB was probably latent and triggered by infliximab.
According to the guidelines,7,8 our patient with a TST result greater than 5 mm should have received prophylactic treatment for TB before infliximab onset. Although the risk of TB during anti-TNF therapy was known at that time, the threshold of the TST in France for the treatment of latent TB was 10 mm.9 Nevertheless, this case report highlights and reinforces the importance of the current guidelines for assessing the risks and for managing M. tuberculosis infection in patients due to start anti-TNF. The infliximab activity lasted 4–8 weeks; as a result IRIS occurred over the next few months after stopping infliximab in the presence of released TB antigens.1 The occurrence of a paradoxical reaction after stopping infliximab, when TB was diagnosed, has previously been reported.1,5,6 Between 1999 and 2003, Garcia Vidal et al.1 reviewed 284 infliximab-treated patients in three Spanish hospitals. Six (2.1%) of them had TB; of these, four (67%) developed paradoxical reactions that occurred 5–16 weeks after TB. Our patient presented unusually severe and prolonged paradoxical reactions marked by several flares during more than 14 months of follow-up; this is likely to reflect both a high antigenic load and the strength of the immune reconstitution after withdrawal of immunosuppression in an otherwise immunocompetent patient. Noncompliance, malabsorption, drug resistance, and opportunistic infections were ruled out. Paradoxical reactions are usually controlled by corticosteroids, sometimes surgery, continuation of anti-TB treatment, and withdrawal of anti-TNF.1,3 However, one case was recently reported in which anti-TNF therapy (adalimumab) was resumed to treat a life-threatening TB paradoxical reaction, with a prompt favorable outcome.6 In another case, infliximab was used to treat a steroid-resistant TB paradoxical reaction involving the central nervous system in a patient who had not previously been receiving anti-TNF therapy.10 Thus maintenance infliximab should be considered to avoid dramatic paradoxical worsening.1,5,10 In summary, this case illustrates unusually prolonged and severe TB paradoxical reactions precipitated by infliximab withdrawal and reinforces the importance of guidelines for assessing and managing TB before starting anti-TNF. Conflict of interest: No conflict of interest to declare. References 1. Garcia Vidal C, Rodrı´guez Ferna´ndez S, Martı´nez Lacasa J, Salavert M, Vidal R, Rodrı´guez Carballeira M, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 2005;40:756–9. 2. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933–6. 3. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIVinfected patients. Clin Infect Dis 2004;38:1159–66. 4. Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803–9. 5. Belknap R, Reves R, Burman W. Immune reconstitution to Mycobacterium tuberculosis after discontinuing infliximab. Int J Tuberc Lung Dis 2005;9: 1057–8. 6. Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 2009;48:1429–32. 7. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005; 60: 800–5. 8. Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol 2008;59:209–17. 9. Treatment of latent tuberculosis infection: towards a change in practices in France. Rev Mal Respir 2003; 20:S41–4. 10. Blackmore TK, Manning L, Taylor WJ, Wallis RS. Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes. Clin Infect Dis 2008;47:83–5.