False Positive QuantiFERON TB- Gold test due to Mycobacterium gordonae Kiran Gajurel, Aruna K. Subramanian PII: DOI: Reference:
S0732-8893(15)00391-0 doi: 10.1016/j.diagmicrobio.2015.10.020 DMB 13940
To appear in:
Diagnostic Microbiology and Infectious Disease
Received date: Revised date: Accepted date:
21 April 2015 21 August 2015 24 October 2015
Please cite this article as: Gajurel Kiran, Subramanian Aruna K., False Positive QuantiFERON TB- Gold test due to Mycobacterium gordonae, Diagnostic Microbiology and Infectious Disease (2015), doi: 10.1016/j.diagmicrobio.2015.10.020
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Title: False Positive QuantiFERON TB- Gold test due to Mycobacterium gordonae Running Title: M. gordonae and false positive quantiferon
RI P
T
Word count (abstract): 60 Word count (body of the text): 1677
SC
Author Names and Affiliation:
Division of Infectious Diseases
MA
Stanford University School of Medicine,
NU
Kiran Gajurel MD and Aruna K. Subramanian MD
ED
Stanford, CA 94305
PT
Corresponding Author Kiran Gajurel MD
CE
300 Pasteur Drive; Lane -134
AC
Division of Infectious Diseases Stanford University School of Medicine Stanford, CA 94305
Telephone: 650-497-3492 Fax: 650-723-3474 Email: [email protected] or [email protected]
ACCEPTED MANUSCRIPT
Abstract
T
We report a case of QuantiFERON TB-Gold conversion caused by Mycobacterium gordonae in
RI P
an elderly male from an assisted living facility without known risk factors for tuberculosis. This
SC
knowledge of environmental mycobacteria causing positive quantiferon assays is important to avoid unnecessary treatment of false positive latent tuberculosis, especially in the absence of
NU
well-established positive predictive value of quantiferon conversion.
MA
Keywords
Interferon gamma release assay, latent tuberculosis, Mycobacterium gordonae, quantiferon,
ED
tuberculosis
PT
1. Introduction
CE
Interferon-gamma release assays (IGRAs) such as QuantiFERON-TB Gold (QFT) are used widely
AC
as diagnostic tools for latent tuberculosis (LTB) infection. In the interest of preventing tuberculosis in long-term care facilities, IGRAs are increasingly being used serially in elderly patients. However, there is little guidance on the interpretation and positive predictive value (PPV) of QFT conversion as serial testing has not been studied in the elderly. Placing elderly nursing home patients on airborne isolation and starting anti-tuberculous therapy both carry significant risks. We describe a case of an elderly patient with Parkinson’s disease who had a QFT conversion due to non-pathogenic Mycobacterium gordonae (M gordonae).
ACCEPTED MANUSCRIPT 2. Case Report An 83-year-old male with Parkinson’s disease was found to have a positive QFT (TB antigen – Nil
RI P
T
= 0.9, with a positive cut off at 0.35) in December 2013 during routine screening when he moved to a new assisted living facility. He reportedly had a negative QFT 2 years prior when
SC
moving into a previous long-term care facility. There was no prior history of skin test for
NU
tuberculosis. He was otherwise in his usual state of health without fevers, chills, cough, chest pain, hemoptysis, night sweats or increased dyspnea. There was no known contact with active
MA
tuberculosis and no prior history of tuberculosis.
ED
Chest X ray showed a small but a new left pleural effusion and a trace left base opacity. Repeat chest X ray done 2 months later revealed persistent left base effusion. Because of these findings
PT
on chest X ray and a positive quantiferon assay, the patient underwent left thoracentesis.
CE
Approximately 30 ml of clear, yellow transudative fluid was aspirated. Routine bacterial culture
AC
and acid-fast bacilli (AFB) stain and culture remained negative. Sputum induction was performed, as the patient was not coughing. One out of 3 sets of sputum, showed rare AFB on the fluorescent stain. The patient was placed in airborne isolation at the assisted living facility, based on the infection control policy. This caused the patient to become extremely depressed as he could not leave his room or see his elderly wife suffering from Alzheimer’s dementia. Anti-tuberculous therapy was considered while awaiting cultures, but was not started due to concern for toxicity. The 3 sputum specimens were found to be negative for Mycobacterium tuberculosis (MTB) by polymerase chain reaction (PCR). Three
ACCEPTED MANUSCRIPT more sputum specimens were tested over the next few weeks for AFB, one of which was read as suspicious for AFB on stain. A repeat QFT remained positive (TB Antigen – Nil = 1.17).
RI P
T
All 6 sputum specimens eventually grew M gordonae. Pleural fluid cultures remained negative. After much difficulty he was taken off of airborne isolation precautions. He was not treated for
SC
his pulmonary process and never developed cough or fever. Follow up chest imaging has
NU
improved.
The patient was born in the Midwestern United States and had no international travel. He
MA
worked as a university professor prior to his retirement. There was no history of smoking,
ED
alcohol use, drug abuse, homelessness, or incarceration. He was not on any immunosuppressive medications.
PT
His past medical history was remarkable for malignancy of the tongue with radiation treatment-
CE
currently in remission, benign prostatic hyperplasia, hypertension, coronary artery disease,
AC
atrial fibrillation, peripheral vascular disease, left carotid endarterectomy, chronic kidney disease, hypothyroidism and Parkinson’s disease. On initial presentation the patient appeared to be frail but was not in acute distress. He was afebrile and breathing comfortably. The remainder of the exam was unremarkable except for slightly decreased air entry at the left base. Because of the absence of significant findings on chest imaging (except persistent small pleural effusion) and asymptomatic clinical course he was thought to have colonization of the respiratory tract by M gordonae and was not offered treatment. Since he did not have risk factors for tuberculosis, the positive quantiferon test was attributed to M gordonae itself and was not treated for LTB as well.
ACCEPTED MANUSCRIPT
T
3. Discussion
RI P
About three decades ago Willian Stead described a high burden of tuberculosis while reporting
SC
the first outbreak of active disease among nursing home residents in the United States [1-3]. Unfortunately, despite the overall decline in the incidence of tuberculosis over the years it still
NU
remains disproportionately higher among elderly residents of long term care facilities
MA
compared to similar age group community dwellers [4]. Early detection of tuberculosis, preferably in the latent stage, will allow institution of timely therapy and may prevent an
ED
outbreak in this already frail population. Tuberculin skin test (TST) or IGRA against MTB specific proteins are recommended for the diagnosis of LTB [5]. However, the accuracy of these tests
PT
including the newer generation IGRAs (T spot and QuantiFERON-TB Gold In-Tube) in predicting
CE
progression to active tuberculosis is not clear, as there is no gold standard test in assessing sensitivity and specificity. Unlike TST, which measures a delayed hypersensitivity reaction to
AC
purified protein derivative (PPD) present in both MTB and other non-tubercular mycobacteria, IGRAs are in vitro tests that are more specific for MTB infection. They measure either the total amount of interferon gammaproduced (QuantiFERON –TB Gold test and QuantiFERON-TB Gold In-Tube) or the increase in the quantity of interferon gamma producing cells (T spot test) in response to MTB specific antigens. These tubercular antigens are early secretory antigenic target (ESAT-6), culture filtrate protein (CFP-10) and TB7.7 that are universally present in MTB but absent in Bacille Calmette-Guérin (BCG) and most of the non-tubercular mycobacteria. IGRAs hence seem to be more specific for MTB infection especially in BCG vaccinated
ACCEPTED MANUSCRIPT population with similar or slightly higher sensitivity compared to TST[6]. However, some tubercular (M africanum and M bovis but not the BCG strain) and a few non tubercular
RI P
T
mycobacteria also harbor ESAT- 6, CFP-10 and TB 7.7 and can potentially yield a positive quantiferon test thus confounding the diagnosis of LTB. In fact, M. kansasii, M. szulgai, M.
SC
marinum, M. flavescens, M gastri and M. riyadhense have been demonstrated to possess these antigens and the former 3 mycobacteria have been shown to cross react with IGRAs. [5,7-9].
NU
Some evidence suggests that M. avium also has homologous ESAT- 6 and CFP- 10 proteins and
MA
can test positive with IGRAs [10,11]. Other mycobacteria reported to occasionally induce a positive IGRA include M abscessus, M abscessus-chelonae, M fortuitum, and M celatum[12].
ED
M gordonae is a slow growing environmental mycobacterium and is generally regarded as a
PT
weak pathogen. Its isolation from non-sterile body sites like the lungs may represent
CE
colonization rather than true disease [13-15]. However, it occasionally causes serious diseases including disseminated infection in both immunocompetent and immunocompromised
AC
population [16-20]. Its cross reactivity with IGRAs has not been well described even though it has been reported to carry all three MTB specific tubercular antigens [8,9]. To the best of our knowledge, its association with a positive quantiferon test has been described only once by Welch et al. In their retrospective analysis of different diagnostic tests one QuantiFERON-TB Gold In-Tube positive sample was attributed to M gordonae infection [21]. It is possible that a few patients with M gordonae respiratory colonization in a Danish study on the performance of IGRA in non tuberculous mycobacteria also had a positive IGRA but no detailed description is provided [12]. Herein we describe another case of positive IGRA with M gordonae infection/colonization. The fact that our patient i) had a positive quantiferon test on 2
ACCEPTED MANUSCRIPT different occasions , ii) lacked risk factors for tuberculosis and iii) had repeated isolation of M gordonae from the respiratory sample support the notion that the positive quantiferon assay is
RI P
T
caused by M gordonae itself. However, because of the inherent limitations of IGRA in establishing a diagnosis of tuberculosis infection, our findings of an association between a
SC
positive QFT and M gordonae are suggestive but not definitive proof that M gordonae caused a false positive QFT. Also our patient likely had a respiratory colonization of M gordonae rather
NU
than true infection or disease. It isnot clear whether colonization itself can elicit a positive IGRA
MA
test. In a Danish study of performance of IGRA in non tuberculous mycobacterial infection, 15% of 49 patients with respiratory colonization yielded a positive IGRA. Surprisingly, a higher
ED
proportion of patients with respiratory colonization had a positive IGRA than those with definite disease leading the authors to speculate that these patients could have an undiagnosed
PT
LTB infection as well [12]. It is a remote possibility that our patient may have had a non-
CE
progressive LTB infection despite the lack of exposure or risk factors for tuberculosis.
AC
Moreover, the etiology of pleural effusion is not clear and the work up did not yield any pathogens. However, since it improved spontaneously, it is unlikely to be secondary to invasive mycobacterial infection.
This concept of environmental mycobacteria including M gordonae causing positive quantiferon assays is important to avoid unwarranted treatment of falsely positive LTB, especially without knowing the true PPV of QFT conversion. The cross reactivity with other environmental mycobacteria even with the newer generation quantiferon assays can lower the PPV of these tests. In a 5 year follow up of serially administered TST and QFT among 259 elderly nursing home residents in Taiwan, the PPVs for development of active TB of both baseline positive TST
ACCEPTED MANUSCRIPT and QFT were only 3% and 2.6% respectively. Even with QFT conversion the PPV was only 25% [22]. Thus QFT seems to be an ineffective tool in accurately predicting active tuberculosis in
RI P
T
elderly residents of long term care facilities. This puts a clinician into a dilemma- on one hand failure to treat a true LTB , especially recent conversion, can cause a dismal outcome with
SC
development of full blown active tuberculosis and a possible transmission in long term care facilities. On the other hand, overzealous treatment of all positive QFT (including QFT
NU
conversion) may be unwarranted because a vast majority may not progress to active
MA
tuberculosis and can be potentially harmful due to side effects such as hepatotoxicity and potential drug interactions. However, isolation of mycobacteria from clinical specimens that
ED
can cross react with QFT can help clinicians make a decision in not treating a positive QFT in the
CE
PT
absence of other risk factors for tuberculosis.
Conflict of Interest: None
Abbreviations:
AC
Acknowledgement: None
IGRA-Interferon-gamma release assay LTB- latent tuberculosis PCR-Polymerase chain reaction PPV- positive predictive value QFT- QuantiFERON - TBGold
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ACCEPTED MANUSCRIPT
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References:
Stead WW: Tuberculosis among elderly persons: An outbreak in a nursing home. Annals of internal medicine (1981) 94(5):606-610.
2.
Stead WW, Lofgren JP, Warren E, Thomas C: Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Engl J Med (1985) 312(23):1483-1487.
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Stead WW, To T, Harrison RW, Abraham JH, 3rd: Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons. Annals of internal medicine (1987) 107(6):843845.
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Thrupp L, Bradley S, Smith P, Simor A, Gantz N, Crossley K, Loeb M, Strausbaugh L, Nicolle L: Tuberculosis prevention and control in long-term-care facilities for older adults. Infection control and hospital epidemiology (2004) 25(12):1097-1108.
5.
Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K: Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection - united states, 2010. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports / Centers for Disease Control (2010) 59(Rr-5):1-25.
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Pai M, Zwerling A, Menzies D: Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An update. Annals of internal medicine (2008) 149(3):177-184.
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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. Journal of bacteriology (2009) 191(18):5865-5867.
8.
Kuznetcova TI, Sauty A, Herbort CP: Uveitis with occult choroiditis due to mycobacterium kansasii: Limitations of interferon-gamma release assay (igra) tests (case report and minireview on ocular non-tuberculous mycobacteria and igra cross-reactivity). International ophthalmology (2012) 32(5):499-506.
9.
Arend SM, de Haas P, Leyten E, Rosenkrands I, Rigouts L, Andersen P, Mijs W, van Dissel JT, van Soolingen D: Esat-6 and cfp-10 in clinical versus environmental isolates of mycobacterium kansasii. The Journal of infectious diseases (2005) 191(8):1301-1310.
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ACCEPTED MANUSCRIPT Hur YG, Crampin AC, Chisambo C, Kanyika J, Houben R, Ndhlovu R, Mzembe T, Lalor MK, Saul J, Branson K, Stanley C et al: Identification of immunological biomarkers which may differentiate latent tuberculosis from exposure to environmental nontuberculous mycobacteria in children. Clinical and vaccine immunology : CVI (2014) 21(2):133-142.
11.
Siddiqi UR, Chagan-Yasutan H, Nakajima C, Saitoh H, Ashino Y, Usami O, Shiratori B, Usuzawa M, Suzuki Y, Hattori T: Distinct clinical features in nontuberculous mycobacterial disease with or without latent tuberculosis infection. The Tohoku journal of experimental medicine (2012) 226(4):313-319.
12.
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(4):e93986.
13.
Del Giudice G, Iadevaia C, Santoro G, Moscariello E, Smeraglia R, Marzo C: Nontuberculous mycobacterial lung disease in patients without hiv infection: A retrospective analysis over 3 years. The clinical respiratory journal (2011) 5(4):203-210.
14.
Eckburg PB, Buadu EO, Stark P, Sarinas PS, Chitkara RK, Kuschner WG: Clinical and chest radiographic findings among persons with sputum culture positive for mycobacterium gordonae: A review of 19 cases. Chest (2000) 117(1):96-102.
15.
Panagiotou M, Papaioannou AI, Kostikas K, Paraskeua M, Velentza E, Kanellopoulou M, Filaditaki V, Karagiannidis N: The epidemiology of pulmonary nontuberculous mycobacteria: Data from a general hospital in athens, greece, 2007-2013. Pulmonary medicine (2014) 2014(894976.
16.
Mizoshita T, Tanida S, Mizushima T, Hirata Y, Murakami K, Shimura T, Mori Y, Kataoka H, Kamiya T, Joh T: A rare case of infectious colitis with ulcers in the cecum caused by mycobacterium gordonae. Internal medicine (Tokyo, Japan) (2011) 50(21):2583-2586.
17.
Verma N, Spencer D: Disseminated mycobacterium gordonae infection in a child with cystic fibrosis. Pediatric pulmonology (2012) 47(5):517-518.
18.
Asija A, Prasad A, Eskridge E: Disseminated mycobacterium gordonae infection in an immunocompetent host. American journal of therapeutics (2011) 18(3):e75-77.
19.
den Broeder AA, Vervoort G, van Assen S, Verduyn Lunel F, de Lange WC, de Sevaux RG: Disseminated mycobacterium gordonae infection in a renal transplant recipient. Transplant infectious disease : an official journal of the Transplantation Society (2003) 5(3):151-155.
20.
Weinberger M, Berg SL, Feuerstein IM, Pizzo PA, Witebsky FG: Disseminated infection with mycobacterium gordonae: Report of a case and critical review of the literature. Clinical
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CE
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ED
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T
10.
ACCEPTED MANUSCRIPT infectious diseases : an official publication of the Infectious Diseases Society of America (1992) 14(6):1229-1239. Welch RJ, Lawless KM, Litwin CM: Antituberculosis igg antibodies as a marker of active mycobacterium tuberculosis disease. Clinical and vaccine immunology : CVI (2012) 19(4):522526.
22.
Tsou PH, Huang WC, Huang CC, Lin CF, Wu KM, Hsu JY, Shen GH: Quantiferon tb-gold conversion can predict active tuberculosis development in elderly nursing home residents. Geriatrics & gerontology international (2014).
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CE
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ED
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T
21.
ACCEPTED MANUSCRIPT Highlights:
T
SC
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PT
ED
MA
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predictive value of IGRA conversion.
CE
Interferon gamma release assays (IGRAs) are widely used to diagnose latent tuberculosis but these assays have significant cross reactivity with some environmental mycobacteria and cannot accurately predict active tuberculosis. We report an association of Mycobacterium gordonae with a positive IGRA. Knowledge of mycobacteria that can cross react with IGRAs is important to avoid unwarranted treatment of latent tuberculosis in patients who do not have risk factors for tuberculosis especially without knowing the true positive
AC
S0732-8893(15)00391-0 doi: 10.1016/j.diagmicrobio.2015.10.020 DMB 13940
To appear in:
Diagnostic Microbiology and Infectious Disease
Received date: Revised date: Accepted date:
21 April 2015 21 August 2015 24 October 2015
Please cite this article as: Gajurel Kiran, Subramanian Aruna K., False Positive QuantiFERON TB- Gold test due to Mycobacterium gordonae, Diagnostic Microbiology and Infectious Disease (2015), doi: 10.1016/j.diagmicrobio.2015.10.020
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Title: False Positive QuantiFERON TB- Gold test due to Mycobacterium gordonae Running Title: M. gordonae and false positive quantiferon
RI P
T
Word count (abstract): 60 Word count (body of the text): 1677
SC
Author Names and Affiliation:
Division of Infectious Diseases
MA
Stanford University School of Medicine,
NU
Kiran Gajurel MD and Aruna K. Subramanian MD
ED
Stanford, CA 94305
PT
Corresponding Author Kiran Gajurel MD
CE
300 Pasteur Drive; Lane -134
AC
Division of Infectious Diseases Stanford University School of Medicine Stanford, CA 94305
Telephone: 650-497-3492 Fax: 650-723-3474 Email: [email protected] or [email protected]
ACCEPTED MANUSCRIPT
Abstract
T
We report a case of QuantiFERON TB-Gold conversion caused by Mycobacterium gordonae in
RI P
an elderly male from an assisted living facility without known risk factors for tuberculosis. This
SC
knowledge of environmental mycobacteria causing positive quantiferon assays is important to avoid unnecessary treatment of false positive latent tuberculosis, especially in the absence of
NU
well-established positive predictive value of quantiferon conversion.
MA
Keywords
Interferon gamma release assay, latent tuberculosis, Mycobacterium gordonae, quantiferon,
ED
tuberculosis
PT
1. Introduction
CE
Interferon-gamma release assays (IGRAs) such as QuantiFERON-TB Gold (QFT) are used widely
AC
as diagnostic tools for latent tuberculosis (LTB) infection. In the interest of preventing tuberculosis in long-term care facilities, IGRAs are increasingly being used serially in elderly patients. However, there is little guidance on the interpretation and positive predictive value (PPV) of QFT conversion as serial testing has not been studied in the elderly. Placing elderly nursing home patients on airborne isolation and starting anti-tuberculous therapy both carry significant risks. We describe a case of an elderly patient with Parkinson’s disease who had a QFT conversion due to non-pathogenic Mycobacterium gordonae (M gordonae).
ACCEPTED MANUSCRIPT 2. Case Report An 83-year-old male with Parkinson’s disease was found to have a positive QFT (TB antigen – Nil
RI P
T
= 0.9, with a positive cut off at 0.35) in December 2013 during routine screening when he moved to a new assisted living facility. He reportedly had a negative QFT 2 years prior when
SC
moving into a previous long-term care facility. There was no prior history of skin test for
NU
tuberculosis. He was otherwise in his usual state of health without fevers, chills, cough, chest pain, hemoptysis, night sweats or increased dyspnea. There was no known contact with active
MA
tuberculosis and no prior history of tuberculosis.
ED
Chest X ray showed a small but a new left pleural effusion and a trace left base opacity. Repeat chest X ray done 2 months later revealed persistent left base effusion. Because of these findings
PT
on chest X ray and a positive quantiferon assay, the patient underwent left thoracentesis.
CE
Approximately 30 ml of clear, yellow transudative fluid was aspirated. Routine bacterial culture
AC
and acid-fast bacilli (AFB) stain and culture remained negative. Sputum induction was performed, as the patient was not coughing. One out of 3 sets of sputum, showed rare AFB on the fluorescent stain. The patient was placed in airborne isolation at the assisted living facility, based on the infection control policy. This caused the patient to become extremely depressed as he could not leave his room or see his elderly wife suffering from Alzheimer’s dementia. Anti-tuberculous therapy was considered while awaiting cultures, but was not started due to concern for toxicity. The 3 sputum specimens were found to be negative for Mycobacterium tuberculosis (MTB) by polymerase chain reaction (PCR). Three
ACCEPTED MANUSCRIPT more sputum specimens were tested over the next few weeks for AFB, one of which was read as suspicious for AFB on stain. A repeat QFT remained positive (TB Antigen – Nil = 1.17).
RI P
T
All 6 sputum specimens eventually grew M gordonae. Pleural fluid cultures remained negative. After much difficulty he was taken off of airborne isolation precautions. He was not treated for
SC
his pulmonary process and never developed cough or fever. Follow up chest imaging has
NU
improved.
The patient was born in the Midwestern United States and had no international travel. He
MA
worked as a university professor prior to his retirement. There was no history of smoking,
ED
alcohol use, drug abuse, homelessness, or incarceration. He was not on any immunosuppressive medications.
PT
His past medical history was remarkable for malignancy of the tongue with radiation treatment-
CE
currently in remission, benign prostatic hyperplasia, hypertension, coronary artery disease,
AC
atrial fibrillation, peripheral vascular disease, left carotid endarterectomy, chronic kidney disease, hypothyroidism and Parkinson’s disease. On initial presentation the patient appeared to be frail but was not in acute distress. He was afebrile and breathing comfortably. The remainder of the exam was unremarkable except for slightly decreased air entry at the left base. Because of the absence of significant findings on chest imaging (except persistent small pleural effusion) and asymptomatic clinical course he was thought to have colonization of the respiratory tract by M gordonae and was not offered treatment. Since he did not have risk factors for tuberculosis, the positive quantiferon test was attributed to M gordonae itself and was not treated for LTB as well.
ACCEPTED MANUSCRIPT
T
3. Discussion
RI P
About three decades ago Willian Stead described a high burden of tuberculosis while reporting
SC
the first outbreak of active disease among nursing home residents in the United States [1-3]. Unfortunately, despite the overall decline in the incidence of tuberculosis over the years it still
NU
remains disproportionately higher among elderly residents of long term care facilities
MA
compared to similar age group community dwellers [4]. Early detection of tuberculosis, preferably in the latent stage, will allow institution of timely therapy and may prevent an
ED
outbreak in this already frail population. Tuberculin skin test (TST) or IGRA against MTB specific proteins are recommended for the diagnosis of LTB [5]. However, the accuracy of these tests
PT
including the newer generation IGRAs (T spot and QuantiFERON-TB Gold In-Tube) in predicting
CE
progression to active tuberculosis is not clear, as there is no gold standard test in assessing sensitivity and specificity. Unlike TST, which measures a delayed hypersensitivity reaction to
AC
purified protein derivative (PPD) present in both MTB and other non-tubercular mycobacteria, IGRAs are in vitro tests that are more specific for MTB infection. They measure either the total amount of interferon gammaproduced (QuantiFERON –TB Gold test and QuantiFERON-TB Gold In-Tube) or the increase in the quantity of interferon gamma producing cells (T spot test) in response to MTB specific antigens. These tubercular antigens are early secretory antigenic target (ESAT-6), culture filtrate protein (CFP-10) and TB7.7 that are universally present in MTB but absent in Bacille Calmette-Guérin (BCG) and most of the non-tubercular mycobacteria. IGRAs hence seem to be more specific for MTB infection especially in BCG vaccinated
ACCEPTED MANUSCRIPT population with similar or slightly higher sensitivity compared to TST[6]. However, some tubercular (M africanum and M bovis but not the BCG strain) and a few non tubercular
RI P
T
mycobacteria also harbor ESAT- 6, CFP-10 and TB 7.7 and can potentially yield a positive quantiferon test thus confounding the diagnosis of LTB. In fact, M. kansasii, M. szulgai, M.
SC
marinum, M. flavescens, M gastri and M. riyadhense have been demonstrated to possess these antigens and the former 3 mycobacteria have been shown to cross react with IGRAs. [5,7-9].
NU
Some evidence suggests that M. avium also has homologous ESAT- 6 and CFP- 10 proteins and
MA
can test positive with IGRAs [10,11]. Other mycobacteria reported to occasionally induce a positive IGRA include M abscessus, M abscessus-chelonae, M fortuitum, and M celatum[12].
ED
M gordonae is a slow growing environmental mycobacterium and is generally regarded as a
PT
weak pathogen. Its isolation from non-sterile body sites like the lungs may represent
CE
colonization rather than true disease [13-15]. However, it occasionally causes serious diseases including disseminated infection in both immunocompetent and immunocompromised
AC
population [16-20]. Its cross reactivity with IGRAs has not been well described even though it has been reported to carry all three MTB specific tubercular antigens [8,9]. To the best of our knowledge, its association with a positive quantiferon test has been described only once by Welch et al. In their retrospective analysis of different diagnostic tests one QuantiFERON-TB Gold In-Tube positive sample was attributed to M gordonae infection [21]. It is possible that a few patients with M gordonae respiratory colonization in a Danish study on the performance of IGRA in non tuberculous mycobacteria also had a positive IGRA but no detailed description is provided [12]. Herein we describe another case of positive IGRA with M gordonae infection/colonization. The fact that our patient i) had a positive quantiferon test on 2
ACCEPTED MANUSCRIPT different occasions , ii) lacked risk factors for tuberculosis and iii) had repeated isolation of M gordonae from the respiratory sample support the notion that the positive quantiferon assay is
RI P
T
caused by M gordonae itself. However, because of the inherent limitations of IGRA in establishing a diagnosis of tuberculosis infection, our findings of an association between a
SC
positive QFT and M gordonae are suggestive but not definitive proof that M gordonae caused a false positive QFT. Also our patient likely had a respiratory colonization of M gordonae rather
NU
than true infection or disease. It isnot clear whether colonization itself can elicit a positive IGRA
MA
test. In a Danish study of performance of IGRA in non tuberculous mycobacterial infection, 15% of 49 patients with respiratory colonization yielded a positive IGRA. Surprisingly, a higher
ED
proportion of patients with respiratory colonization had a positive IGRA than those with definite disease leading the authors to speculate that these patients could have an undiagnosed
PT
LTB infection as well [12]. It is a remote possibility that our patient may have had a non-
CE
progressive LTB infection despite the lack of exposure or risk factors for tuberculosis.
AC
Moreover, the etiology of pleural effusion is not clear and the work up did not yield any pathogens. However, since it improved spontaneously, it is unlikely to be secondary to invasive mycobacterial infection.
This concept of environmental mycobacteria including M gordonae causing positive quantiferon assays is important to avoid unwarranted treatment of falsely positive LTB, especially without knowing the true PPV of QFT conversion. The cross reactivity with other environmental mycobacteria even with the newer generation quantiferon assays can lower the PPV of these tests. In a 5 year follow up of serially administered TST and QFT among 259 elderly nursing home residents in Taiwan, the PPVs for development of active TB of both baseline positive TST
ACCEPTED MANUSCRIPT and QFT were only 3% and 2.6% respectively. Even with QFT conversion the PPV was only 25% [22]. Thus QFT seems to be an ineffective tool in accurately predicting active tuberculosis in
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elderly residents of long term care facilities. This puts a clinician into a dilemma- on one hand failure to treat a true LTB , especially recent conversion, can cause a dismal outcome with
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development of full blown active tuberculosis and a possible transmission in long term care facilities. On the other hand, overzealous treatment of all positive QFT (including QFT
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conversion) may be unwarranted because a vast majority may not progress to active
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tuberculosis and can be potentially harmful due to side effects such as hepatotoxicity and potential drug interactions. However, isolation of mycobacteria from clinical specimens that
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can cross react with QFT can help clinicians make a decision in not treating a positive QFT in the
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absence of other risk factors for tuberculosis.
Conflict of Interest: None
Abbreviations:
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Acknowledgement: None
IGRA-Interferon-gamma release assay LTB- latent tuberculosis PCR-Polymerase chain reaction PPV- positive predictive value QFT- QuantiFERON - TBGold
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ACCEPTED MANUSCRIPT Highlights:
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predictive value of IGRA conversion.
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Interferon gamma release assays (IGRAs) are widely used to diagnose latent tuberculosis but these assays have significant cross reactivity with some environmental mycobacteria and cannot accurately predict active tuberculosis. We report an association of Mycobacterium gordonae with a positive IGRA. Knowledge of mycobacteria that can cross react with IGRAs is important to avoid unwarranted treatment of latent tuberculosis in patients who do not have risk factors for tuberculosis especially without knowing the true positive
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