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Mycobacterium kansasii Infection in a Patient Receiving Biologic Therapy—Not All Reactive Interferon Gamma Release Assays Are Tuberculosis
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Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D.
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S0002-9629(16)30051-9 http://dx.doi.org/10.1016/j.amjms.2016.03.001 AMJMS126
To appear in:
Am J Med Sci
Cite this article as: Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D., Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis, Am J Med Sci, http://dx.doi.org/10.1016/j.amjms.2016.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Mycobacterium kansasii infection in a patient receiving biologic therapy not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Authors: Nasir Saleem M.D.1 Raya Saba M.D.1 Srikanth Maddika M.D.1 Mitchell Weinstein M.D.1
Affiliations: 1
Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, 2900 N Lake Shore Drive, Chicago, Illinois, 60657 Correspondence: Nasir Saleem M.D. Department of Internal Medicine, Presence Saint Joseph Hospital, 2900 N Lake Shore Drive, Chicago, Illinois, 60657 Email: [email protected] Phone: 312-843-2689 Disclosures: All authors have nothing to disclose.
Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D. Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois
Abstract: Mycobacterium kansasii (MK), a nontuberculous mycobacteria (NTM), can lead to lung disease similar to tuberculosis. Immunotherapeutic biologic agents predispose to infections with mycobacteria, including MK. T-cell mediated interferon gamma release assays (IGRAs) like Quantiferon-TB-Gold-Test (QFT) are widely used by clinicians for the diagnosis of infections with Mycobacterium tuberculosis (MTB), however, QFT may also be positive with certain NTM infections. We report a case of MK pulmonary infection, with a positive QFT, in an immunocompromised patient receiving prednisone, leflunomide and tocilizumab, a humanised anti-interleukin-6 receptor monoclonal antibody. This case highlights the risk of mycobacterial infections with the use of various biologic agents and the need for caution when interpreting the results of IGRAs.
Keywords: Mycobacterium kansasii, biologic therapy, tocilizumab, Quantiferon-TB
Introduction: Mycobacterial infections including Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM) have been reported in association with the use of biologic therapies that inhibit tumor necrosis factor (TNF-α), including infliximab, adalimumab and etanercept 1, 2. Tocilizumab is a humanised anti-interleukin-6 receptor monoclonal antibody which may similarly predispose to mycobacterial infections 3-6. Such agents are used increasingly in the management of various rheumatological diseases including rheumatoid arthritis and psoriatic arthritis. T-cell mediated interferon gamma release assays (IGRAs) like Quantiferon-TB-Gold-Test (QFT) detect specific mycobacterial peptide antigens. Although quite helpful clinically, these diagnostic tests may have limitations in differentiating MTB and certain NTM infections. Accurate differentiation is important in the management of these infections. In this report, we describe a case of Mycobacterial kansasii (MK) cavitary pneumonia in a patient receiving tocilizumab, leflunomide and prednisone with a positive QFT test and positive AFB smear.
Case report: A 61 year old female with a past medical history of psoriatic and rheumatoid arthritis was admitted to the hospital for evaluation of a right upper lobe pulmonary cavity seen on an outpatient chest x-ray. On admission she reported a 5-day history of cough productive of brown and bloody sputum, sore throat and exertional dyspnea, associated with 15-20 lbs weight loss, chills and night sweats, but no fevers. She had a long history of biologic immunotherapeutic therapy for severe psoriatic and rheumatoid arthritis including adalimumab, etanercept, tocilizumab, leflunomide and varying doses of prednisone (20-60 mg). At the time of admission she was on tocilizumab, leflunomide and prednisone (10 mg). She had been on tocilizumab for two months and her last dose was one month previously. A prior QFT fifteen months previously was negative. Physical exam including chest auscultation was benign. Chest x-ray revealed a right apical cavity (Fig. 1a). CT scan of the chest (Fig. 1b) confirmed a cavitary lesion measuring 5.7 x 5.2 x 6.6 cm with irregular thickened walls and multiple nodules in the upper lobe of right lung, along with right hilar and mediastinal lymphadenopathy. Quantiferon-TB-Gold-Test (QFT) was positive and sputum smear revealed many acid-fast bacilli. She was started empirically on isoniazid, rifampin, pyrazinamide, ethambutol and pyridoxine, the biologic agents were held, and she was placed in respiratory isolation for presumed tuberculosis. On day 4 of admission she was discharged home with instructions for home confinement. DNA probe was negative for MTB. Multiple sputa cultures subsequently grew MK. The isolate was shown to be susceptible to isoniazid, rifampin, clarithromycin and moxifloxacin and based on susceptibility testing the drug regimen was modified. Pyrazinamide was discontinued, the dose of ethambutol was lowered and clarithromycin was added. Due to intolerance, clarithromycin was later replaced by moxifloxacin and sputum cultures became negative at 4 months of therapy. A 12-18 month course is planned. Her inflammatory arthritis worsened and was managed with steroids and reinstitution of leflunomide with significant improvement. Tocilizumab was not resumed. Contact tracing and isolation measures were discontinued.
Discussion: Non-tuberculous mycobacteria (NTM) are ubiquitous organisms found in the environment worldwide including soil, dust, and tap water 7, 8 with tap water likely the major reservoir for MK 9. They are opportunistic pathogens causing human disease especially in immunocompromised individuals 10. Human disease is suspected to be acquired from environmental exposures, although the specific source of infection usually cannot be identified 11. Person to person spread is not thought to be common and as such contact tracing and patient isolation is unnecessary. The potent TNF-α blocking antibodies infliximab and adalimumab and the soluble receptor etanercept are effective antiinflammatory agents and lead to relatively high rates of mycobacterial infections including active TB in those who are latently infected 1, 2. The risk of such infections seems to vary by the biologic agent 12. A recent nationwide survey of infectious disease consultants from the US suggested
that the majority of mycobacterial infections occurring in the context of anti-TNF-α and similar biologic therapy are attributable to NTM and not MTB 13. Tocilizumab is a humanised anti-interleukin-6 receptor monoclonal antibody that has demonstrated efficacy in rheumatoid arthritis patients who have an inadequate response to TNF antagonist treatment 14 . Although tocilizumab, in general, is well tolerated with an acceptable safety profile 15, there have also been reports of mycobacterial infections including both TB and various NTM infections with its use 3-6. A post-marketing surveillance report from Japan described 9 cases of NTM infections after treatment with tocilizumab, with no described breakdown of the individual species 15. However, to the best of our knowledge this is the first case report of MK infection associated with tocilizumab. Interferon-gamma release assays (IGRAs) are based on T-cell mediated IFN-γ release after stimulation with specific mycobacterial antigens. These tests have shown good specificity, less cross reactivity with most NTM 16, a lack of BCG cross reactivity and a higher sensitivity compared to tuberculin skin tests (TST) for the diagnosis of both active TB and LTBI 17, 18. The Quantiferon-TB-Gold-Test (QFT) is based on response to the MTB specific peptide antigens ESAT-6 (early secretory antigenic target-6), CFP-10 (culture filtrate protein-10) and TB7.7 which are located in a specific genomic area in MTB, called the region of difference (RD1). The RD1 is present in mycobacteria belonging to the M. tuberculosis complex (M. tuberculosis, M. africanum, M. bovis, M. canettii, M. caprae, M. microti, M. pinnipedii, M. mungi and M. orygis) 19 and very few NTM species (M. kansasii, M. marinum, M. szulgai, M. gastri and M. riyadhense) 16, 20, 21. Infection with these strains can potentially result in a positive QFT result 16. In the vaccine strain M. bovis BCG and in the majority of NTMs, however, the RD1 is absent. Thus, in BCGvaccinated and the vast majority of individuals infected with NTM, the QFT is negative. Due to this higher specificity, some studies have suggested using the QFT to discriminate between MTB and NTM infection 22-25. In a recent study conducted in Denmark to assess IGRA performance in patients with NTM disease in a low TB burden population, the overall positivity rate for QFT in patients with NTM disease was found to be 8% while a lower positivity rate of 4% was seen among patients with NTM without the RD1 region 10. Conversely, some authors have suggested using QFT as a rapid diagnostic method for pulmonary infection due to MK 26. Such disparate observations highlight the lack of consensus on interpretation of IGRAs in cases of NTM infections. The treatment of NTM infection is indicated in patients with compatible respiratory or constitutional symptoms with radiographic abnormalities plus either consistent isolation of NTM in moderate to high numbers from more than one specimen of pulmonary secretions or isolation from at least one specimen along with histologic evidence of pulmonary parenchymal involvement 9. In contrast to standard therapy for susceptible MTB infection, treatment of most pulmonary NTM pathogens, such as MAC and MK, is longer and involves at least 12 months after negative sputum cultures while on therapy 9. As well, choice of antimicrobial agents differ; specifically MK is generally susceptible to isoniazid, rifampin, ethambutol, streptomycin, amikacin, clarithromycin and fluoroquinolones and isolates are resistant to pyrazinamide. ATS guidelines recommend as first line a regimen of isoniazid, rifampin, and ethambutol (15 mg/kg) continued 12 months after sputum conversion, with additional options for use of macrolides, moxifloxacin, and sulfamethoxazole in rifampin resistant isolates 9. The macrolides and fluoroquinolones obviously represents a difference from first line TB treatment. There are no guidelines regarding the safety of resuming anti-TNF-α and other biologic therapy during or after treatment for MTB or NTM infections. In most cases biologic agents are stopped when infection is diagnosed. Anecdotal experience and case reports have reported reinstitution of biologic agents at varying times 27, 28. A recent study from South Korea suggested that resuming anti-TNF-α therapy in
patients undergoing adequate concomitant treatment for TB might be safe 29. There is even some data that initiating TNF-α inhibitors may be useful therapeutically for immune reconstitution syndrome associated with mycobacterial infections 30. The American College of Rheumatology recommends resumption of biologics after completion of TB treatment 31. Expert opinion regarding NTM infections is that patients with active NTM diseases should receive TNF-α blocking agents only if they are also receiving adequate therapy for the NTM diseases 9. Further studies are clearly needed to better clarify optimal usage of biologic agents after mycobacterial infections. Our patient had a positive QFT with test conversion due to infection with MK, a NTM species that contains the RD1 genomic area, in the setting of biologic treatment with tocilizumab, leflunomide and prednisone. This case illustrates the risk of infection with NTM in immunocompromised patients receiving biologic therapy. The precise risk and role of tocilizumab in predisposing to MK infection is not well defined, but our case suggests caution with this agent, and requires further research. It also highlights the need for caution when interpreting results of IGRAs, such as QFT, in patients suspected of having MTB or NTM infections, as this differentiation has important bearing on various aspects of management including the choice, dosage and duration of antimycobacterial therapy. This distinction also has implications for in-hospital isolation, contact tracing and confinement or isolation of index cases which is not required for NTM infections. Our case also illustrates a limit in the specificity of IGRAs due to the presence of shared antigens in MTB and certain NTM, including MK, and strengthens the role of direct diagnostic methods, such as culture and nucleic acid testing for accurate diagnosis.
Disclosures: The authors declare that they have no conflict of interest.
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Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098-1104. Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis. 2004;39:300-302. Kobayashi D, Ito S, Hirata A, et al. Mycobacterium abscessus Pulmonary Infection under Treatment with Tocilizumab. Intern Med. 2015;54:1309-1313. Nakahara H, Kamide Y, Hamano Y, et al. A case report of a patient with rheumatoid arthritis complicated with Mycobacterium avium during tocilizumab treatment. Mod Rheumatol. 2011;21:655-659. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13:R141. Inayama M, Shinohara T, Hosokawa E, Machida H, Iwahara Y, Ogushi F. [A case of pulmonary nontuberculous mycobacteriosis induced by tocilizumab treatment for rheumatoid arthritis]. Kansenshogaku Zasshi. 2011;85:523-526. Falkinham JO, 3rd. Nontuberculous mycobacteria in the environment. Clin Chest Med. 2002;23:529-551.
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von Reyn CF, Waddell RD, Eaton T, et al. Isolation of Mycobacterium avium complex from water in the United States, Finland, Zaire, and Kenya. J Clin Microbiol. 1993;31:3227-3230. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. Hermansen TS, Thomsen VO, Lillebaek T, Ravn P. Non-tuberculous mycobacteria and the performance of interferon gamma release assays in Denmark. PLoS One. 2014;9:e93986. von Reyn CF, Arbeit RD, Horsburgh CR, et al. Sources of disseminated Mycobacterium avium infection in AIDS. J Infect. 2002;44:166-170. Singh JA, Cameron C, Noorbaloochi S, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386:258-265. Winthrop KL, Yamashita S, Beekmann SE, Polgreen PM, Infectious Diseases Society of America Emerging Infections N. Mycobacterial and other serious infections in patients receiving antitumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis. 2008;46:1738-1740. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516-1523. Koike T, Harigai M, Inokuma S, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011;70:2148-2151. van Ingen J, de Zwaan R, Dekhuijzen R, Boeree M, van Soolingen D. Region of difference 1 in nontuberculous Mycobacterium species adds a phylogenetic and taxonomical character. J Bacteriol. 2009;191:5865-5867. Diel R, Goletti D, Ferrara G, et al. Interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J. 2011;37:88-99. Sester M, Sotgiu G, Lange C, et al. Interferon-gamma release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011;37:100-111. van Ingen J, Rahim Z, Mulder A, et al. Characterization of Mycobacterium orygis as M. tuberculosis complex subspecies. Emerg Infect Dis. 2012;18:653-655. Harboe M, Oettinger T, Wiker HG, Rosenkrands I, Andersen P. Evidence for occurrence of the ESAT-6 protein in Mycobacterium tuberculosis and virulent Mycobacterium bovis and for its absence in Mycobacterium bovis BCG. Infect Immun. 1996;64:16-22. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol. 1996;178:1274-1282. Detjen AK, Keil T, Roll S, et al. Interferon-gamma release assays improve the diagnosis of tuberculosis and nontuberculous mycobacterial disease in children in a country with a low incidence of tuberculosis. Clin Infect Dis. 2007;45:322-328. Kobashi Y, Mouri K, Yagi S, et al. Clinical evaluation of the QuantiFERON-TB Gold test in patients with non-tuberculous mycobacterial disease. Int J Tuberc Lung Dis. 2009;13:1422-1426. Lein AD, von Reyn CF, Ravn P, Horsburgh CR, Jr., Alexander LN, Andersen P. Cellular immune responses to ESAT-6 discriminate between patients with pulmonary disease due to Mycobacterium avium complex and those with pulmonary disease due to Mycobacterium tuberculosis. Clin Diagn Lab Immunol. 1999;6:606-609. Riazi S, Zeligs B, Yeager H, et al. Rapid diagnosis of Mycobacterium tuberculosis infection in children using interferon-gamma release assays (IGRAs). Allergy Asthma Proc. 2012;33:217-226.
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Kobashi Y, Mouri K, Miyashita N, Oka M. Clinical usefulness of QuantiFERON TB-2G test for the early diagnosis of pulmonary Mycobacterium kansasii disease. Jpn J Infect Dis. 2009;62:239-241. Dare JA, Jahan S, Hiatt K, Torralba KD. Reintroduction of etanercept during treatment of cutaneous Mycobacterium marinum infection in a patient with ankylosing spondylitis. Arthritis Rheum. 2009;61:583-586. Matsumoto T, Tanaka T, Kawase I. Infliximab for Rheumatoid Arthritis in a Patient with Tuberculosis. New England Journal of Medicine. 2006;355:740-741. Kim YJ, Kim YG, Shim TS, et al. Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors. Rheumatology (Oxford). 2014;53:1477-1481. Hsu DC, Faldetta KF, Pei L, et al. A Paradoxical Treatment for a Paradoxical Condition: Infliximab Use in Three Cases of Mycobacterial IRIS. Clin Infect Dis. 2016;62:258-261. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.
Fig. 1a: Chest x-ray posteroanterior view showing a right apical cavitary lesion Fig. 1b: CT chest showing a large cavitary lesion in the right upper lobe with thick, irregular walls along with areas of airspace opacification
Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D.
www.amjmedsci.com
PII: DOI: Reference:
S0002-9629(16)30051-9 http://dx.doi.org/10.1016/j.amjms.2016.03.001 AMJMS126
To appear in:
Am J Med Sci
Cite this article as: Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D., Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis, Am J Med Sci, http://dx.doi.org/10.1016/j.amjms.2016.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Mycobacterium kansasii infection in a patient receiving biologic therapy not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Authors: Nasir Saleem M.D.1 Raya Saba M.D.1 Srikanth Maddika M.D.1 Mitchell Weinstein M.D.1
Affiliations: 1
Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, 2900 N Lake Shore Drive, Chicago, Illinois, 60657 Correspondence: Nasir Saleem M.D. Department of Internal Medicine, Presence Saint Joseph Hospital, 2900 N Lake Shore Drive, Chicago, Illinois, 60657 Email: [email protected] Phone: 312-843-2689 Disclosures: All authors have nothing to disclose.
Mycobacterium kansasii infection in a patient receiving biologic therapy - not all reactive interferon-gamma release assays (IGRAs) are tuberculosis Nasir Saleem M.D., Raya Saba M.D., Srikanth Maddika M.D., Mitchell Weinstein M.D. Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois
Abstract: Mycobacterium kansasii (MK), a nontuberculous mycobacteria (NTM), can lead to lung disease similar to tuberculosis. Immunotherapeutic biologic agents predispose to infections with mycobacteria, including MK. T-cell mediated interferon gamma release assays (IGRAs) like Quantiferon-TB-Gold-Test (QFT) are widely used by clinicians for the diagnosis of infections with Mycobacterium tuberculosis (MTB), however, QFT may also be positive with certain NTM infections. We report a case of MK pulmonary infection, with a positive QFT, in an immunocompromised patient receiving prednisone, leflunomide and tocilizumab, a humanised anti-interleukin-6 receptor monoclonal antibody. This case highlights the risk of mycobacterial infections with the use of various biologic agents and the need for caution when interpreting the results of IGRAs.
Keywords: Mycobacterium kansasii, biologic therapy, tocilizumab, Quantiferon-TB
Introduction: Mycobacterial infections including Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM) have been reported in association with the use of biologic therapies that inhibit tumor necrosis factor (TNF-α), including infliximab, adalimumab and etanercept 1, 2. Tocilizumab is a humanised anti-interleukin-6 receptor monoclonal antibody which may similarly predispose to mycobacterial infections 3-6. Such agents are used increasingly in the management of various rheumatological diseases including rheumatoid arthritis and psoriatic arthritis. T-cell mediated interferon gamma release assays (IGRAs) like Quantiferon-TB-Gold-Test (QFT) detect specific mycobacterial peptide antigens. Although quite helpful clinically, these diagnostic tests may have limitations in differentiating MTB and certain NTM infections. Accurate differentiation is important in the management of these infections. In this report, we describe a case of Mycobacterial kansasii (MK) cavitary pneumonia in a patient receiving tocilizumab, leflunomide and prednisone with a positive QFT test and positive AFB smear.
Case report: A 61 year old female with a past medical history of psoriatic and rheumatoid arthritis was admitted to the hospital for evaluation of a right upper lobe pulmonary cavity seen on an outpatient chest x-ray. On admission she reported a 5-day history of cough productive of brown and bloody sputum, sore throat and exertional dyspnea, associated with 15-20 lbs weight loss, chills and night sweats, but no fevers. She had a long history of biologic immunotherapeutic therapy for severe psoriatic and rheumatoid arthritis including adalimumab, etanercept, tocilizumab, leflunomide and varying doses of prednisone (20-60 mg). At the time of admission she was on tocilizumab, leflunomide and prednisone (10 mg). She had been on tocilizumab for two months and her last dose was one month previously. A prior QFT fifteen months previously was negative. Physical exam including chest auscultation was benign. Chest x-ray revealed a right apical cavity (Fig. 1a). CT scan of the chest (Fig. 1b) confirmed a cavitary lesion measuring 5.7 x 5.2 x 6.6 cm with irregular thickened walls and multiple nodules in the upper lobe of right lung, along with right hilar and mediastinal lymphadenopathy. Quantiferon-TB-Gold-Test (QFT) was positive and sputum smear revealed many acid-fast bacilli. She was started empirically on isoniazid, rifampin, pyrazinamide, ethambutol and pyridoxine, the biologic agents were held, and she was placed in respiratory isolation for presumed tuberculosis. On day 4 of admission she was discharged home with instructions for home confinement. DNA probe was negative for MTB. Multiple sputa cultures subsequently grew MK. The isolate was shown to be susceptible to isoniazid, rifampin, clarithromycin and moxifloxacin and based on susceptibility testing the drug regimen was modified. Pyrazinamide was discontinued, the dose of ethambutol was lowered and clarithromycin was added. Due to intolerance, clarithromycin was later replaced by moxifloxacin and sputum cultures became negative at 4 months of therapy. A 12-18 month course is planned. Her inflammatory arthritis worsened and was managed with steroids and reinstitution of leflunomide with significant improvement. Tocilizumab was not resumed. Contact tracing and isolation measures were discontinued.
Discussion: Non-tuberculous mycobacteria (NTM) are ubiquitous organisms found in the environment worldwide including soil, dust, and tap water 7, 8 with tap water likely the major reservoir for MK 9. They are opportunistic pathogens causing human disease especially in immunocompromised individuals 10. Human disease is suspected to be acquired from environmental exposures, although the specific source of infection usually cannot be identified 11. Person to person spread is not thought to be common and as such contact tracing and patient isolation is unnecessary. The potent TNF-α blocking antibodies infliximab and adalimumab and the soluble receptor etanercept are effective antiinflammatory agents and lead to relatively high rates of mycobacterial infections including active TB in those who are latently infected 1, 2. The risk of such infections seems to vary by the biologic agent 12. A recent nationwide survey of infectious disease consultants from the US suggested
that the majority of mycobacterial infections occurring in the context of anti-TNF-α and similar biologic therapy are attributable to NTM and not MTB 13. Tocilizumab is a humanised anti-interleukin-6 receptor monoclonal antibody that has demonstrated efficacy in rheumatoid arthritis patients who have an inadequate response to TNF antagonist treatment 14 . Although tocilizumab, in general, is well tolerated with an acceptable safety profile 15, there have also been reports of mycobacterial infections including both TB and various NTM infections with its use 3-6. A post-marketing surveillance report from Japan described 9 cases of NTM infections after treatment with tocilizumab, with no described breakdown of the individual species 15. However, to the best of our knowledge this is the first case report of MK infection associated with tocilizumab. Interferon-gamma release assays (IGRAs) are based on T-cell mediated IFN-γ release after stimulation with specific mycobacterial antigens. These tests have shown good specificity, less cross reactivity with most NTM 16, a lack of BCG cross reactivity and a higher sensitivity compared to tuberculin skin tests (TST) for the diagnosis of both active TB and LTBI 17, 18. The Quantiferon-TB-Gold-Test (QFT) is based on response to the MTB specific peptide antigens ESAT-6 (early secretory antigenic target-6), CFP-10 (culture filtrate protein-10) and TB7.7 which are located in a specific genomic area in MTB, called the region of difference (RD1). The RD1 is present in mycobacteria belonging to the M. tuberculosis complex (M. tuberculosis, M. africanum, M. bovis, M. canettii, M. caprae, M. microti, M. pinnipedii, M. mungi and M. orygis) 19 and very few NTM species (M. kansasii, M. marinum, M. szulgai, M. gastri and M. riyadhense) 16, 20, 21. Infection with these strains can potentially result in a positive QFT result 16. In the vaccine strain M. bovis BCG and in the majority of NTMs, however, the RD1 is absent. Thus, in BCGvaccinated and the vast majority of individuals infected with NTM, the QFT is negative. Due to this higher specificity, some studies have suggested using the QFT to discriminate between MTB and NTM infection 22-25. In a recent study conducted in Denmark to assess IGRA performance in patients with NTM disease in a low TB burden population, the overall positivity rate for QFT in patients with NTM disease was found to be 8% while a lower positivity rate of 4% was seen among patients with NTM without the RD1 region 10. Conversely, some authors have suggested using QFT as a rapid diagnostic method for pulmonary infection due to MK 26. Such disparate observations highlight the lack of consensus on interpretation of IGRAs in cases of NTM infections. The treatment of NTM infection is indicated in patients with compatible respiratory or constitutional symptoms with radiographic abnormalities plus either consistent isolation of NTM in moderate to high numbers from more than one specimen of pulmonary secretions or isolation from at least one specimen along with histologic evidence of pulmonary parenchymal involvement 9. In contrast to standard therapy for susceptible MTB infection, treatment of most pulmonary NTM pathogens, such as MAC and MK, is longer and involves at least 12 months after negative sputum cultures while on therapy 9. As well, choice of antimicrobial agents differ; specifically MK is generally susceptible to isoniazid, rifampin, ethambutol, streptomycin, amikacin, clarithromycin and fluoroquinolones and isolates are resistant to pyrazinamide. ATS guidelines recommend as first line a regimen of isoniazid, rifampin, and ethambutol (15 mg/kg) continued 12 months after sputum conversion, with additional options for use of macrolides, moxifloxacin, and sulfamethoxazole in rifampin resistant isolates 9. The macrolides and fluoroquinolones obviously represents a difference from first line TB treatment. There are no guidelines regarding the safety of resuming anti-TNF-α and other biologic therapy during or after treatment for MTB or NTM infections. In most cases biologic agents are stopped when infection is diagnosed. Anecdotal experience and case reports have reported reinstitution of biologic agents at varying times 27, 28. A recent study from South Korea suggested that resuming anti-TNF-α therapy in
patients undergoing adequate concomitant treatment for TB might be safe 29. There is even some data that initiating TNF-α inhibitors may be useful therapeutically for immune reconstitution syndrome associated with mycobacterial infections 30. The American College of Rheumatology recommends resumption of biologics after completion of TB treatment 31. Expert opinion regarding NTM infections is that patients with active NTM diseases should receive TNF-α blocking agents only if they are also receiving adequate therapy for the NTM diseases 9. Further studies are clearly needed to better clarify optimal usage of biologic agents after mycobacterial infections. Our patient had a positive QFT with test conversion due to infection with MK, a NTM species that contains the RD1 genomic area, in the setting of biologic treatment with tocilizumab, leflunomide and prednisone. This case illustrates the risk of infection with NTM in immunocompromised patients receiving biologic therapy. The precise risk and role of tocilizumab in predisposing to MK infection is not well defined, but our case suggests caution with this agent, and requires further research. It also highlights the need for caution when interpreting results of IGRAs, such as QFT, in patients suspected of having MTB or NTM infections, as this differentiation has important bearing on various aspects of management including the choice, dosage and duration of antimycobacterial therapy. This distinction also has implications for in-hospital isolation, contact tracing and confinement or isolation of index cases which is not required for NTM infections. Our case also illustrates a limit in the specificity of IGRAs due to the presence of shared antigens in MTB and certain NTM, including MK, and strengthens the role of direct diagnostic methods, such as culture and nucleic acid testing for accurate diagnosis.
Disclosures: The authors declare that they have no conflict of interest.
References: 1. 2. 3. 4.
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Fig. 1a: Chest x-ray posteroanterior view showing a right apical cavitary lesion Fig. 1b: CT chest showing a large cavitary lesion in the right upper lobe with thick, irregular walls along with areas of airspace opacification