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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e3181bc9407
Concise Report

Peritoneal Tuberculosis Complicated by Immune Reconstitution Inflammatory Syndrome in a Patient Treated With Infliximab?: A Case for Adjuvant Immunosuppressive Therapy

Szerszen, Anita DO*; Gupta, Shilpi MD†; Seminara, Donna MD, FACP*; Jarrett, Mark MD, MBA, FACP, FACR‡; Goldstein, Mark MD, FACR‡

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From the *Division of Geriatrics, Department of Medicine, Staten Island University Hospital, Staten Island, NY; †Department of Medicine, Staten Island University Hospital, Staten Island, NY; and ‡Division of Rheumatology, Department of Medicine, Staten Island University Hospital, Staten Island, NY.

Correspondence: Anita Szerszen, DO, Division of Geriatrics, Department of Medicine, Staten Island University Hospital, 375 Seguine Ave, Staten Island, NY 10309. E-mail: aszerszen@aol.com or anita_szerszen@siuh.edu.

Infliximab is a monoclonal antibody against tumor necrosis factor alpha (TNF-α) approved for treatment of rheumatoid arthritis.1 The concern about the reactivation of latent tuberculosis (TB) in patients treated with TNF antagonists2,3 prompts the need to screen candidates for the therapy for previous TB exposure using the tuberculin skin test.4,5 According to current guidelines, upon diagnosis of TB, TNF-α inhibitor should be withheld until the active infection is treated.6 The optimal time for resuming the TNF-α antagonist is undetermined. Others suggest the possibility of continuation of anti-TNF therapy throughout the TB treatment and others still who recommend instituting a corticosteroid, a notion examined in our case report.3

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Case Presentation

A 70-year-old man with rheumatoid arthritis was treated with prednisone (8 mg/d), azathioprine, and infliximab. Tuberculin skin test prior to initiation of infliximab was negative, but the patient admitted to a family history of tuberculosis about 40 years ago. Five months after starting treatment he was admitted to the hospital for evaluation of dyspnea, night sweats, fever, and abdominal distension for about 1 month. The admission chest x-ray demonstrated left pleural effusion and thoracocentesis revealed exudative pleural effusion with negative acid fast stains and cultures. An abdominal computed tomography was performed and was significant for ascites and focal infiltration of the mesentery suspicious for bacterial peritonitis or malignancy. Peritoneal biopsy demonstrated multinucleated giant cell granulomas and acid fast bacteria, consistent with tuberculous peritonitis. This diagnosis was further confirmed by peritoneal fluid cultures and DNA PCR. Infliximab, prednisone, and azathioprine were discontinued and the patient was started on daily regimen of isoniazid 300 mg (with pyridoxine 50 mg/d), rifampin 600 mg, ethambutol 1.2 g, and pyrazinamide 1.5 g.

Within 4 days of initiation of antituberculous medications and discontinuation of immunosuppressants, we observed clinical deterioration. His temperature increased to 105°F, he had profound diaphoresis, increased dyspnea, generalized malaise, confusion, and lethargy. Repeated chest x-ray revealed reaccumulation of the pleural fluid. Cerebrospinal fluid (CSF) analysis including acid fast stain and cultures were negative. Morning cortisol level was normal. After excluding a multidrug resistant tuberculosis and drug fever, he was started on 60 mg/d of prednisone as a treatment for an immune reconstitution inflammatory response syndrome (IRIS). Fever, confusion, and lethargy resolved within 24 hours of initiation of the corticosteroid. The antituberculous therapy remained unchanged. After 4 days, prednisone was decreased to 50 mg per day. The patient continued to be stable and was discharged home on slow corticosteroid taper. Three weeks later, he was readmitted for recurring altered mental status. At that time of admission his prednisone dose was 15 mg. Full evaluation, together with CSF analysis, was again negative. The patient improved when the dose of prednisone was increased to 40 mg daily. He was discharged home to follow up with a primary care physician. Two months later, when his prednisone was already decreased to the maintenance dose of 8 mg daily, the patient was readmitted for a new onset of jaundice consistent with drug-induced hepatitis. Consequently, his antituberculous medications were changed to streptomycin and ethambutol. Liver function tests done the following month confirmed resolution of disease.

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DISCUSSION

It has been postulated that use of immunosuppressants (azathioprine, corticosteroids, TNF-antagonists) may increase the risk of developing tuberculosis, although small doses of prednisone, less than 15 mg daily, have not been associated with this infection.7 One theoretical explanation for the increased risk for reactivation of latent TB in patients on TNF-α antagonists is that TNF-α is expressed at the site of the infection in patients newly diagnosed with tuberculosis8 and is thought to play a role in host defense mechanisms, including granuloma formation and phagocytosis of mycobacteria by macrophages.9 Interestingly, however, recent studies showed benefit of anti-TNF therapy in immune-compromised patients treated for tuberculosis to prevent an immune reconstitution inflammatory syndrome (IRIS) and to decrease culture conversion time.10,11

In HIV patients, addition of etanercept to the quadruple anti-TB therapy resulted in earlier conversion of sputum cultures as well as superior resolution of lung infiltrates and lung cavities.10 Even greater effect was observed in HIV patients treated with high doses of methylprednisolone (2.75 mg/kg/d) during first month of standard antituberculous therapy. Half of them had negative sputum cultures after 1 month, as compared with only 10% of patients in placebo group.11

Corticosteroid and, potentially, TNF antagonist administration may also be useful in prevention of paradoxical reaction seen in immunocompromised patients, especially with HIV infection, following commencement of antituberculous therapy.12,13 This reaction, called immune reconstitution inflammatory syndrome (IRIS), usually occurs in patients with extrapulmonary or disseminated TB. Patients have recurrence of symptoms related to tuberculosis infection like worsened fever, malaise, increased pulmonary infiltrates, or lymphadenopathy. There are several published case reports of similar reactions seen in infliximab-treated patients after cessation of immunosuppressive regimen.14 It is postulated that a dysregulated delayed-type hypersensitivity reaction underlies the pathogenesis of the IRIS12 and, possibly, in patients treated with TNF blockers it is a consequence of an induction of the immune response upon their discontinuation. The onset of symptoms related to IRIS is variable; usually symptoms occur within 2 to 3 months after initiation of antituberculous treatment, however, they may appear as early as a few days of beginning of the therapy.12,13

Due to lack of a diagnostic test, IRIS should be considered after excluding other diagnoses such as the multidrug resistant strain of Mycobacterium tuberculosis and hypersensitivity drug reaction as a cause of fever and worsening symptoms during antituberculous therapy. A prospective evaluation of patients treated with TNF blockers, who develop tuberculosis, is needed and should include consideration for IRIS to clarify its influence on the treatment of tuberculosis.

Based on current knowledge and lack of clear guidelines, consideration should be given to a possible continuance of TNF-α antagonist, perhaps at lower dose, and the judicious use of corticosteroids in patients who develop tuberculosis while on anti-TNF therapy.3,15

This course of action may not only prevent IRIS but also aide in treatment of the infection itself. Etanercept may be useful in this setting as it only blocks the soluble TNF-α receptor and leaves free the transmembrane receptor thought to play an integral role in infectious defense of the body.15 Moreover, as a TNF antagonist, infliximab may disrupt established granulomas and allow for active replication of tuberculous bacilli.3 Interestingly, it is known that actively replicating bacilli are more sensitive to treatment with INH. Infliximab is thought to be a more potent blocker then etanercept and, as it is associated with the highest rates of reactivation of tuberculosis,3 it may also at the same time be more effective in antituberculous treatment.

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CONCLUSION

According to current guidelines once the diagnosis of TB is made, the TNF-α inhibitor has to be withheld during the course of active infection. This case supports the claim that patients treated with infliximab who develop tuberculosis should be considered for adjuvant immunosuppressive therapy. Tapering of the TNF-α inhibitor or addition of corticosteroid may diminish the risk for significant immunologic reconstitution symptoms upon sudden discontinuation of immune modulating treatment. Moreover, adjuvant treatment with immunosuppressants, especially corticosteroids, is associated with higher culture conversion rates as compared with those without such treatment. Further studies are needed in face of the growing population of patients treated with anti-TNF therapy.

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REFERENCES

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10. Wallis RS, Kyambadde P, Johnson JL, et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1- associated tuberculosis. AIDS. 2004;18:257–264.

11. Mayanja-Kizza H, Jones-Lopez EC, Okwera A, et al. Immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone: a phase II clinical trials in Uganda. J Infect Dis. 2005;191:856–865.

12. McIlleron H, Meintjes G, Burman WJ, et al. Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. J Infect Dis. 2007;196(suppl 1):S63–S75.

13. Wright ME, Suzman DL, Csaky KG, et al. Extensive retinal neovascularization as a late finding in human immunodeficiency virus-infected patients with immune recovery uveitis. Clin Infect Dis. 2003;36.

14. Garcia Vidal C, Rodríguez Fernández S, Martínez Lacasa J, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. CID. 2005;40:756–759.

15. Szymkowski D. Innovative Therapies in Autoimmune Diseases. In the proceedings of American College of Rheumatology (March 2002–April 2007), 2007. Arlington, VA.

© 2009 Lippincott Williams & Wilkins, Inc.

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