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LETTER TO THE EDITOR| Volume 99, ISSUE 12, P1620-1622, December 2005

Anti-tuberculosis treatment and infliximab

Open ArchivePublished:July 22, 2005DOI:https://doi.org/10.1016/j.rmed.2005.06.010
Anti-tuberculosis treatment and infliximab
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Next ArticleCOPD: What is the diagnosis?
      It was with considerable interest that I read the case report of Vlachaki et al.,
      • Vlachaki E.
      • Psathakis K.
      • Tsintiris K.
      • Iliopoulos A.
      Delayed response to anti-tuberculosis treatment in a patient on infliximab.
      Respir Med. 2005; 99: 648-652
      “Delayed response to anti-tuberculosis treatment in a patient on infliximab”, in the May 2005 issue of your journal. However, I believe the authors’ main conclusion, that the prolonged illness was due to prolonged anti-TNF activity of infliximab, is incorrect. Instead, I believe it is much more likely that it represents immune reconstitution inflammatory syndrome (IRIS) due to infliximab withdrawal.
      IRIS, or paradoxical worsening, typically presents as hectic fevers, lymphadenopathy, worsened pulmonary infiltrates, effusions, hypoxia, and occasionally, the evolution of new lesions not clinically apparent prior to starting treatment. IRIS occurs in its most complete form in persons starting treatment for both AIDS and tuberculosis,
      • Chien J.W.
      • Johnson J.L.
      Paradoxical reactions in HIV and pulmonary TB.
      Chest. 1998; 114: 933-936
      , 
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      , 
      • Navas E.
      • Martin-Davila P.
      • Moreno L.
      • Pintado V.
      • Casado J.L.
      • Fortun J.
      • et al.
      Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy.
      Arch Intern Med. 2002; 162: 97-99
      , 
      • Orlovic D.
      • Smego Jr, R.A.
      Paradoxical tuberculous reactions in HIV-infected patients.
      Int J Tuberc Lung Dis. 2001; 5: 370-375
      , 
      • Wanchu A.
      • Sud A.
      • Bambery P.
      • Singh S.
      Paradoxical reaction in HIV and tuberculosis coinfection.
      J Assoc Physicians India. 2002; 50: 588-589
      , 
      • Wendel K.A.
      • Alwood K.S.
      • Gachuhi R.
      • Chaisson R.E.
      • Bishai W.R.
      • Sterling T.R.
      Paradoxical worsening of tuberculosis in HIV-infected persons.
      Chest. 2001; 120: 193-197
      but has also been described in the context of other HIV-associated infections, and in patients with tuberculosis without HIV infection.
      • Hawkey C.R.
      • Yap T.
      • Pereira J.
      • Moore D.A.
      • Davidson R.N.
      • Pasvol G.
      • et al.
      Characterization and management of paradoxical upgrading reactions in HIV-uninfected patients with lymph node tuberculosis.
      Clin Infect Dis. 2005; 40: 1368-1371
      , 
      • Teoh R.
      • Humphries M.J.
      • O’Mahony G.
      Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: a report of 10 patients and review of the literature.
      Q J Med. 1987; 63: 449-460
      , 
      • Carter E.J.
      • Mates S.
      Sudden enlargement of a deep cervical lymph node during and after treatment for pulmonary tuberculosis.
      Chest. 1994; 106: 1896-1898
      In AIDS cases with tuberculosis, IRIS onset is closely related temporally to the initiation of antiretroviral therapy (ART).
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      Baseline risk factors for IRIS in AIDS/TB include disseminated or extrapulmonary tuberculosis, low initial CD4 count, and non-reactive tuberculin skin tests. Patients with a vigorous response to ART (as assessed by changes in viral load or CD4 count) are also at increased risk.
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      , 
      • Breton G.
      • Duval X.
      • Estellat C.
      • Poaletti X.
      • Bonnet D.
      • Mvondo M.D.
      • et al.
      Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy.
      Clin Infect Dis. 2004; 39: 1709-1712
      Little is known regarding the immunology of IRIS, except that nearly all cases convert to strongly reactive tuberculin skin tests as the syndrome evolves.
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      There are no specific diagnostic tests for IRIS. However, it is a clinical hallmark of IRIS that the magnitude of the host immune response is disproportionate to the burden of infection, which in TB-associated cases, usually has declined substantially by the time IRIS is diagnosed.
      Infliximab (anti-TNF monoclonal antibody) is licensed in the US for treatment of Crohn's disease and rheumatoid arthritis. It is administered periodically by intravenous infusion, usually every 4–6 weeks. In addition to blocking soluble TNF, infliximab inhibits T cell activation and interferon γ expression.

      Wallis RS, Saliu OY, Sofer C, Stein DS, Schwander SK. Effect of TNF blockers on expression of mycobacterial immunity in vitro. In: International Conference on the Pathogenesis of Mycobacterial Infections, 2005. p. 6.

      , 
      • Zou J.
      • Rudwaleit M.
      • Brandt J.
      • Thiel A.
      • Braun J.
      • Sieper J.
      Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept.
      Ann Rheum Dis. 2003; 62: 561-564
      Its combined effects on TNF and IFNγ may account for the high risk infliximab poses for reactivation of latent TB infection, which has been estimated in Europe to be as high as 173 cases per 100,000 persons per year.
      • Gardam M.A.
      • Keystone E.C.
      • Menzies R.
      • Manners S.
      • Skamene E.
      • Long R.
      • et al.
      Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management.
      Lancet Infect Dis. 2003; 3: 148-155
      This risk is significantly greater than that of etanercept,
      • Wallis R.S.
      • Broder M.S.
      • Wong J.Y.
      • Beenhouwer D.O.
      Granulomatous infections due to tumor necrosis factor blockade: correction.
      Clin Infect Dis. 2004; 39: 1254-1256
      , 
      • Wallis R.S.
      • Broder M.
      • Wong J.
      • Lee A.
      • Hoq L.
      Reactivation of latent granulomatous infections by infliximab.
      Clin Infect Dis. 2005; 41: S194-S198
      a soluble TNF receptor that does not block IFNγ expression.
      • Zou J.
      • Rudwaleit M.
      • Brandt J.
      • Thiel A.
      • Braun J.
      • Sieper J.
      Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept.
      Ann Rheum Dis. 2003; 62: 561-564
      A recent retrospective study by Garcia Vidal et al.
      • Garcia Vidal C.
      • Fernandez S.R.
      • Lacasa J.M.
      • Salavert M.
      • Carballeira M.R.
      • Garau J.
      Paradoxical response to anti-tuberculous therapy in infliximab-treated patients with disseminated tuberculosis.
      Clin Infect Dis. 2005; 40: 756-759
      described typical IRIS-type paradoxical reactions due to withdrawal of infliximab following the diagnosis of tuberculosis in four patients with autoimmune diseases. All four patients presented with disseminated or extrapulmonary tuberculosis and subsequently had infliximab treatment discontinued. The interval until IRIS occurrence was from 5 to 16 weeks; however, this may have been influenced by the case definition, which required an interval of at least 4 weeks for inclusion in the study. Three of the four cases required corticosteroids or surgical intervention.
      In the present case report, Vlachaki attributes the delayed therapeutic response to “the long term immunosuppressive action of infliximab”. It is not clear how the authors made this assessment, since the tuberculin skin test was not repeated, nor were any in vitro tests performed to measure mycobacterial T cell responses. Indeed, the return of active spondylitis would appear to indicate a lack of prolonged effect. The authors implied that immunity is required for sterilization of mycobacterial infection, and that the delayed resolution of the granulomatous host response must therefore indicate delayed resolution of infection. However, they report the results of four bronchoscopic diagnostic procedures, performed at diagnosis, and after 20 days, 3 months, and 12 months of treatment. Specimens from the first procedure were positive for Mycobacterium tuberculosis by both stain and culture; those from the second, by culture only. Subsequent specimens were negative. This cannot be described as a delayed microbiologic response to therapy.
      More importantly, the concept that host immunity facilitates sterilization during TB chemotherapy is not likely correct. The capacity of human macrophages to kill virulent M. tuberculosis is very limited. Granulomas therefore serve to contain an infection that cannot otherwise be eradicated by host defenses. Mycobacteria contained within granulomas face a hostile microenvironment with low pH, oxygen, and other nutrients. Sequestered mycobacteria adapt to these harsh conditions with profound alterations in gene expression profiles, resulting in reduced replication and reduced aerobic metabolism.
      • Karakousis P.C.
      • Yoshimatsu T.
      • Lamichhane G.
      • Woolwine S.C.
      • Nuermberger E.L.
      • Grosset J.
      • et al.
      Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis within artificial granulomas in mice.
      J Exp Med. 2004; 200: 647-657
      This adaptation forms the basis of clinical latency in tuberculosis. Granulomas may thus paradoxically protect sequestered mycobacteria from administered chemotherapy by reducing drug penetration, and by reducing the level of expression of the molecular targets of these drugs. Experimental evidence indicating antagonism between immunity and sterilization in tuberculosis is summarized in Table 1. The report most pertinent to the case in question is that of Narita et al.,
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      a retrospective case-control study of AIDS/TB IRIS. The authors found that IRIS increased by six fold the subsequent risk of TB relapse.
      Table 1Experimental evidence of antagonism between immunity and sterilization during tuberculosis treatment.
      AuthorStudy designMain findings
      Karakousis et al.
      • Karakousis P.C.
      • Yoshimatsu T.
      • Lamichhane G.
      • Woolwine S.C.
      • Nuermberger E.L.
      • Grosset J.
      • et al.
      Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis within artificial granulomas in mice.
      J Exp Med. 2004; 200: 647-657
      		Murine M. tuberculosis infection in subcutaneously implanted permeable hollow fibersGranuloma formation decreased the bactericidal effect of isoniazid
      Dhillon and Mitchison.
      • Dhillon J.
      • Mitchison D.A.
      Influence of BCG-induced immunity on the bactericidal activity of isoniazid and rifampicin in experimental tuberculosis of the mouse and guinea-pig.
      Br J Exp Pathol. 1989; 70: 103-110
      		Guinea pig M. tuberculosis infection with or without prior BCG vaccinationPrior BCG vaccination decreased the bactericidal effect of isoniazid
      Wallis et al.
      • Wallis R.S.
      • Song H.Y.
      • Whalen C.
      • Okwera A.
      TB chemotherapy: antagonism between immunity and sterilization.
      Am J Respir Crit Care Med. 2004; 169: 771-772
      		Human whole blood culture model of intracellular M. tuberculosis infectionImmune control of intracellular M. tuberculosis growth decreased the intracellular bactericidal effect of ofloxacin
      Johnson et al.
      • Johnson J.L.
      • Ssekasanvu E.
      • Okwera A.
      • Mayanja H.
      • Hirsch C.S.
      • Nakibali J.G.
      • et al.
      Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis.
      Am J Respir Crit Care Med. 2003; 168: 185-191
      		Prospective randomized clinical trial of IL-2 vs. placebo during first month of TB therapy in 110 HIV uninfected subjectsIL-2 delayed the clearance of viable M. tuberculosis from sputum and delayed sputum culture conversion
      Wallis et al.
      • Wallis R.S.
      • Kyambadde P.
      • Johnson J.L.
      • Horter L.
      • Kittle R.
      • Pohle M.
      • et al.
      A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis.
      AIDS. 2004; 18: 257-264
      		Prospective controlled clinical trial of etanercept vs. placebo during first month of TB therapy in subjects with HIV infection and CD4 >200/ml in 16 subjects and 42 controlsAnti-TNF therapy with etanercept (soluble TNF receptor) accelerated sputum culture conversion by 1 week
      Mayanja-Kizza et al.
      • Mayanja-Kizza H.
      • Jones-Lopez E.C.
      • Okwera A.
      • Wallis R.S.
      • Ellner J.J.
      • Mugerwa R.D.
      • et al.
      Immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone: a phase II clinical trial in Uganda.
      J Infect Dis. 2005; 191: 856-865
      		Prospective controlled clinical trial of high dose prednisolone vs. placebo during the first month of TB therapy in 189 subjects with HIV infection and CD4 >200/mlAnti-TNF therapy with prednisolone 2.75mg/kg/d accelerated sputum culture conversion by 1 month
      Sonnenberg et al.
      • Sonnenberg P.
      • Murray J.
      • Glynn J.R.
      • Shearer S.
      • Kambashi B.
      • Godfrey-Faussett P.
      HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers.
      Lancet. 2001; 358: 1687-1693
      		Prospective case control study of recurrent tuberculosisIn the absence of ART, HIV infection increased the risk of recurrence due to reinfection but decreased the risk of RFLP-confirmed relapse
      Weiner et al.
      • Weiner M.
      • Burman W.
      • Vernon A.
      • Khan K.
      TB Trials Consortium
      Effect of HIV coinfection on two month sputum culture conversion and its associations with TB treatment outcomes.
      Proc Am Thorac Soc. 2005; 2A20
      		Prospective TB Trials Consortium clinical trialTwo month sputum culture conversion was superior in HIV-infected TB cases
      Narita et al.
      • Narita M.
      • Ashkin D.
      • Hollender E.S.
      • Pitchenik A.E.
      Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
      Am J Respir Crit Care Med. 1998; 158: 157-161
      		Retrospective case control study of IRIS in HIV+TBTB relapse risk was increased 6 fold in patients with IRIS
      el Sadr et al.
      • el Sadr W.M.
      • Perlman D.C.
      • Matts J.P.
      • Nelson E.T.
      • Cohn D.L.
      • Salomon N.
      • et al.
      Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG).
      Clin Infect Dis. 1998; 26: 1148-1158
      		Prospective ACTG/CPCRA clinical trialHIV infection increased the rate of 2 month sputum culture conversion and decreased the risk of relapse compared to historic controls
      Based on this evidence, there is reason to believe that infliximab may hasten, rather than delay, the clinical and microbiologic response to tuberculosis therapy,
      • Wallis R.S.
      Reconsidering adjuvant immunotherapy for tuberculosis.
      Clin Infect Dis. 2005; 41: 201-208
      and that its withdrawal at the time of TB diagnosis may be problematic. Further studies of the management of tuberculosis in patients on infliximab therapy are warranted.

      References

        • Vlachaki E.
        • Psathakis K.
        • Tsintiris K.
        • Iliopoulos A.
        Delayed response to anti-tuberculosis treatment in a patient on infliximab.
        Respir Med. 2005; 99: 648-652
        View in Article
        • Chien J.W.
        • Johnson J.L.
        Paradoxical reactions in HIV and pulmonary TB.
        Chest. 1998; 114: 933-936
        View in Article
        • Narita M.
        • Ashkin D.
        • Hollender E.S.
        • Pitchenik A.E.
        Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.
        Am J Respir Crit Care Med. 1998; 158: 157-161
        View in Article
        • Navas E.
        • Martin-Davila P.
        • Moreno L.
        • Pintado V.
        • Casado J.L.
        • Fortun J.
        • et al.
        Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy.
        Arch Intern Med. 2002; 162: 97-99
        View in Article
        • Orlovic D.
        • Smego Jr, R.A.
        Paradoxical tuberculous reactions in HIV-infected patients.
        Int J Tuberc Lung Dis. 2001; 5: 370-375
        View in Article
        • Wanchu A.
        • Sud A.
        • Bambery P.
        • Singh S.
        Paradoxical reaction in HIV and tuberculosis coinfection.
        J Assoc Physicians India. 2002; 50: 588-589
        View in Article
        • Wendel K.A.
        • Alwood K.S.
        • Gachuhi R.
        • Chaisson R.E.
        • Bishai W.R.
        • Sterling T.R.
        Paradoxical worsening of tuberculosis in HIV-infected persons.
        Chest. 2001; 120: 193-197
        View in Article
        • Hawkey C.R.
        • Yap T.
        • Pereira J.
        • Moore D.A.
        • Davidson R.N.
        • Pasvol G.
        • et al.
        Characterization and management of paradoxical upgrading reactions in HIV-uninfected patients with lymph node tuberculosis.
        Clin Infect Dis. 2005; 40: 1368-1371
        View in Article
        • Teoh R.
        • Humphries M.J.
        • O’Mahony G.
        Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: a report of 10 patients and review of the literature.
        Q J Med. 1987; 63: 449-460
        View in Article
        • Carter E.J.
        • Mates S.
        Sudden enlargement of a deep cervical lymph node during and after treatment for pulmonary tuberculosis.
        Chest. 1994; 106: 1896-1898
        View in Article
        • Breton G.
        • Duval X.
        • Estellat C.
        • Poaletti X.
        • Bonnet D.
        • Mvondo M.D.
        • et al.
        Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy.
        Clin Infect Dis. 2004; 39: 1709-1712
        View in Article

      12. Wallis RS, Saliu OY, Sofer C, Stein DS, Schwander SK. Effect of TNF blockers on expression of mycobacterial immunity in vitro. In: International Conference on the Pathogenesis of Mycobacterial Infections, 2005. p. 6.

        View in Article
        • Zou J.
        • Rudwaleit M.
        • Brandt J.
        • Thiel A.
        • Braun J.
        • Sieper J.
        Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept.
        Ann Rheum Dis. 2003; 62: 561-564
        View in Article
        • Gardam M.A.
        • Keystone E.C.
        • Menzies R.
        • Manners S.
        • Skamene E.
        • Long R.
        • et al.
        Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management.
        Lancet Infect Dis. 2003; 3: 148-155
        View in Article
        • Wallis R.S.
        • Broder M.S.
        • Wong J.Y.
        • Beenhouwer D.O.
        Granulomatous infections due to tumor necrosis factor blockade: correction.
        Clin Infect Dis. 2004; 39: 1254-1256
        View in Article
        • Wallis R.S.
        • Broder M.
        • Wong J.
        • Lee A.
        • Hoq L.
        Reactivation of latent granulomatous infections by infliximab.
        Clin Infect Dis. 2005; 41: S194-S198
        View in Article
        • Garcia Vidal C.
        • Fernandez S.R.
        • Lacasa J.M.
        • Salavert M.
        • Carballeira M.R.
        • Garau J.
        Paradoxical response to anti-tuberculous therapy in infliximab-treated patients with disseminated tuberculosis.
        Clin Infect Dis. 2005; 40: 756-759
        View in Article
        • Karakousis P.C.
        • Yoshimatsu T.
        • Lamichhane G.
        • Woolwine S.C.
        • Nuermberger E.L.
        • Grosset J.
        • et al.
        Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis within artificial granulomas in mice.
        J Exp Med. 2004; 200: 647-657
        View in Article
        • Wallis R.S.
        Reconsidering adjuvant immunotherapy for tuberculosis.
        Clin Infect Dis. 2005; 41: 201-208
        View in Article
        • Dhillon J.
        • Mitchison D.A.
        Influence of BCG-induced immunity on the bactericidal activity of isoniazid and rifampicin in experimental tuberculosis of the mouse and guinea-pig.
        Br J Exp Pathol. 1989; 70: 103-110
        View in Article
        • Wallis R.S.
        • Song H.Y.
        • Whalen C.
        • Okwera A.
        TB chemotherapy: antagonism between immunity and sterilization.
        Am J Respir Crit Care Med. 2004; 169: 771-772
        View in Article
        • Johnson J.L.
        • Ssekasanvu E.
        • Okwera A.
        • Mayanja H.
        • Hirsch C.S.
        • Nakibali J.G.
        • et al.
        Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis.
        Am J Respir Crit Care Med. 2003; 168: 185-191
        View in Article
        • Wallis R.S.
        • Kyambadde P.
        • Johnson J.L.
        • Horter L.
        • Kittle R.
        • Pohle M.
        • et al.
        A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis.
        AIDS. 2004; 18: 257-264
        View in Article
        • Mayanja-Kizza H.
        • Jones-Lopez E.C.
        • Okwera A.
        • Wallis R.S.
        • Ellner J.J.
        • Mugerwa R.D.
        • et al.
        Immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone: a phase II clinical trial in Uganda.
        J Infect Dis. 2005; 191: 856-865
        View in Article
        • Sonnenberg P.
        • Murray J.
        • Glynn J.R.
        • Shearer S.
        • Kambashi B.
        • Godfrey-Faussett P.
        HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers.
        Lancet. 2001; 358: 1687-1693
        View in Article
        • Weiner M.
        • Burman W.
        • Vernon A.
        • Khan K.
        • TB Trials Consortium
        Effect of HIV coinfection on two month sputum culture conversion and its associations with TB treatment outcomes.
        Proc Am Thorac Soc. 2005; 2A20
        View in Article
        • el Sadr W.M.
        • Perlman D.C.
        • Matts J.P.
        • Nelson E.T.
        • Cohn D.L.
        • Salomon N.
        • et al.
        Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG).
        Clin Infect Dis. 1998; 26: 1148-1158
        View in Article

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      Published online: July 22, 2005

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      DOI: https://doi.org/10.1016/j.rmed.2005.06.010

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