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Tuberculosis (TB) notification rates in New Zealand are around 7/100,000 with highest rates in those of non-European ethnicity.1 Primary pulmonary infection is often asymptomatic with conversion of a tuberculin skin test or interferon gamma release assay (IGRA) the only evidence of infection.Active tuberculosis refers to patients with replicating organisms.1 The diagnosis of active tuberculosis can be difficult because of the low sensitivity of sputum microscopy and the prolonged culture required.2IGRAs are increasingly being used as a screening test to rule out TB infection. A positive IGRA result does not distinguish between latent and active disease and importantly false negative results can occur.3–6We describe a case of active tuberculosis associated with a negative IGRA at presentation that seroconverted following treatment.Case reportA 29-year-old man of Indian origin presented with 7 weeks of an unproductive cough, unexplained weight loss and supraclavicular lymphadenopathy. He was born in India, lived in New Zealand since 2006 and had frequent visits to India. His sister-in-law was being investigated for active TB. He had no significant past medical history and HIV serology was negative.Examination was unremarkable besides small non-tender supraclavicular lymphadenopathy on the right. His chest radiograph showed a 30mm opacity in the right upper lobe. His interferon gamma release assay (QuantiFERON-TB Gold in-tube assay, Cellestis Ltd., Victoria, Australia) was negative with a value of 0.23 IU/ml.A computed tomography scan of his chest showed low attenuation centre consolidation in the right upper lobe with some associated ground glass and lymph nodes at the right hilum extending up the mediastinum to the root of the neck on the right hand side. These nodes showed low attenuation centres. He then underwent bronchoscopy with right upper lobe lavage as well as a fine needle aspirate of a supraclavicular node. Both were negative for acid-fast bacilli on Ziehl-Neeson stain.Nucleic acid amplification with the GeneXpert (Cepheid, California, USA) detectedMycobacterium tuberculosis DNA. The organism was subsequently cultured and proved to be fully sensitive. He was treated with six months of standard combination anti-tuberculous therapy. His symptoms resolved and his chest radiograph normalised. His repeat IGRA was positive with a value of 0.86 IU/ml.DiscussionNew Zealand's prevalence of TB is around 7-10/100,000; it is a low prevalence country but cases are concentrated in migrants.1 A highly sensitivity test is required to rule out tuberculosis in a low prevalence setting. IGRAs indicate a cellular immune response toMycobacterium tuberculosis antigens and therefore infection; they have been proposed as appropriate tests to rule out TB.7One study has shown the T-spot.TB to be more sensitive than QuantiFERON-TB Gold in-tube assay, but a recent meta-analysis showed a sensitivity of approximately 80% for both the QuantiFERON-TB Gold in-tube assay (Cellestis Ltd., Carnegie, Australia) and the T-Spot.TB (Oxford Immunotec Ltd., Abingdon, UK).3,8This may be due to a window period (up to 22 weeks) from infection to IGRA conversion, immunosupression such as HIV as well as impaired T cell activity from immune anergy caused by active TB infection.39,10 The low sensitivity of IGRA results in a low negative predictive value in situations such as this case when there is a high clinical suspicion of tuberculosis.This case serves as a reminder that even in low prevalence countries such as New Zealand, a negative IGRA does not rule out active tuberculosis when the clinical suspicion is high. Current guidelines conclude that IGRA should not be part of routine investigation for active tuberculosis but contribute only supplementary information . 1, 4,5

Summary

Abstract

This report describes a patient with pulmonary tuberculosis in whom the interferon gamma release assay (IGRA) was negative at presentaion. It became positive following treatment. This illustrates that this test cannot be used to rule out tuberculosis, even in a low incidence country.

Aim

Method

Results

Conclusion

Author Information

Michael Maze, Advanced Trainee in Respiratory Medicine; Lutz Beckert, Respiratory Physician; Respiratory Medicine; Canterbury District Health Board, Christchurch

Acknowledgements

Correspondence

Lutz Beckert, Respiratory Medicine, Christchurch Hospital, PO Box 4345, Christchurch 8041, New Zealand.

Correspondence Email

Lutz.Beckert@cdhb.health.nz

Competing Interests

Ministry of Health. Guidelines for Tuberculosis Control in New Zealand. 2010. Wellington: Ministry of Health.Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis. 2006;6:664-74.Sester M, Sotgiu G, Lange C, et al. Interferon-\u03b3-release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011;37(1):100.Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-\u03b3-release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis . J Infect Dis. 2011;204 Suppl 4:S1120.Centers for Disease Control and Prevention. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection - United States, 2010. MMWR 2010;59(No. RR-5).European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC; 2011.van Leeuwen RML, Bossink AWJ, Thijsen SFT. Exclusion of active Mycobacterium tuberculosis complex infection with the T-SPOTTM.TB assay. Eur Respir J. 2007;29:605-607.Lai CC, Tan CK, Lin SH, et al. Diagnostic performance of whole-blood interferon-gamma assay and enzyme-linked immunospot assay for active tuberculosis. Diagn Microbiol Infect Dis. 2011 Oct;71(2):139-43. Epub 2011 Aug 15.Lee SW, Oh DK, Lee SH, et al . Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis. Eur Respir J. 2011;37(6):1447.Kabeer BSA, Sikhamani R, Swaminathan S, et al. Role of Interferon Gamma Release Assay in Active TB Diagnosis among HIV Infected Individuals. PLoSOne. 2009;4 (5):e5718.

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Tuberculosis (TB) notification rates in New Zealand are around 7/100,000 with highest rates in those of non-European ethnicity.1 Primary pulmonary infection is often asymptomatic with conversion of a tuberculin skin test or interferon gamma release assay (IGRA) the only evidence of infection.Active tuberculosis refers to patients with replicating organisms.1 The diagnosis of active tuberculosis can be difficult because of the low sensitivity of sputum microscopy and the prolonged culture required.2IGRAs are increasingly being used as a screening test to rule out TB infection. A positive IGRA result does not distinguish between latent and active disease and importantly false negative results can occur.3–6We describe a case of active tuberculosis associated with a negative IGRA at presentation that seroconverted following treatment.Case reportA 29-year-old man of Indian origin presented with 7 weeks of an unproductive cough, unexplained weight loss and supraclavicular lymphadenopathy. He was born in India, lived in New Zealand since 2006 and had frequent visits to India. His sister-in-law was being investigated for active TB. He had no significant past medical history and HIV serology was negative.Examination was unremarkable besides small non-tender supraclavicular lymphadenopathy on the right. His chest radiograph showed a 30mm opacity in the right upper lobe. His interferon gamma release assay (QuantiFERON-TB Gold in-tube assay, Cellestis Ltd., Victoria, Australia) was negative with a value of 0.23 IU/ml.A computed tomography scan of his chest showed low attenuation centre consolidation in the right upper lobe with some associated ground glass and lymph nodes at the right hilum extending up the mediastinum to the root of the neck on the right hand side. These nodes showed low attenuation centres. He then underwent bronchoscopy with right upper lobe lavage as well as a fine needle aspirate of a supraclavicular node. Both were negative for acid-fast bacilli on Ziehl-Neeson stain.Nucleic acid amplification with the GeneXpert (Cepheid, California, USA) detectedMycobacterium tuberculosis DNA. The organism was subsequently cultured and proved to be fully sensitive. He was treated with six months of standard combination anti-tuberculous therapy. His symptoms resolved and his chest radiograph normalised. His repeat IGRA was positive with a value of 0.86 IU/ml.DiscussionNew Zealand's prevalence of TB is around 7-10/100,000; it is a low prevalence country but cases are concentrated in migrants.1 A highly sensitivity test is required to rule out tuberculosis in a low prevalence setting. IGRAs indicate a cellular immune response toMycobacterium tuberculosis antigens and therefore infection; they have been proposed as appropriate tests to rule out TB.7One study has shown the T-spot.TB to be more sensitive than QuantiFERON-TB Gold in-tube assay, but a recent meta-analysis showed a sensitivity of approximately 80% for both the QuantiFERON-TB Gold in-tube assay (Cellestis Ltd., Carnegie, Australia) and the T-Spot.TB (Oxford Immunotec Ltd., Abingdon, UK).3,8This may be due to a window period (up to 22 weeks) from infection to IGRA conversion, immunosupression such as HIV as well as impaired T cell activity from immune anergy caused by active TB infection.39,10 The low sensitivity of IGRA results in a low negative predictive value in situations such as this case when there is a high clinical suspicion of tuberculosis.This case serves as a reminder that even in low prevalence countries such as New Zealand, a negative IGRA does not rule out active tuberculosis when the clinical suspicion is high. Current guidelines conclude that IGRA should not be part of routine investigation for active tuberculosis but contribute only supplementary information . 1, 4,5

Summary

Abstract

This report describes a patient with pulmonary tuberculosis in whom the interferon gamma release assay (IGRA) was negative at presentaion. It became positive following treatment. This illustrates that this test cannot be used to rule out tuberculosis, even in a low incidence country.

Aim

Method

Results

Conclusion

Author Information

Michael Maze, Advanced Trainee in Respiratory Medicine; Lutz Beckert, Respiratory Physician; Respiratory Medicine; Canterbury District Health Board, Christchurch

Acknowledgements

Correspondence

Lutz Beckert, Respiratory Medicine, Christchurch Hospital, PO Box 4345, Christchurch 8041, New Zealand.

Correspondence Email

Lutz.Beckert@cdhb.health.nz

Competing Interests

Ministry of Health. Guidelines for Tuberculosis Control in New Zealand. 2010. Wellington: Ministry of Health.Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis. 2006;6:664-74.Sester M, Sotgiu G, Lange C, et al. Interferon-\u03b3-release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011;37(1):100.Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-\u03b3-release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis . J Infect Dis. 2011;204 Suppl 4:S1120.Centers for Disease Control and Prevention. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection - United States, 2010. MMWR 2010;59(No. RR-5).European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC; 2011.van Leeuwen RML, Bossink AWJ, Thijsen SFT. Exclusion of active Mycobacterium tuberculosis complex infection with the T-SPOTTM.TB assay. Eur Respir J. 2007;29:605-607.Lai CC, Tan CK, Lin SH, et al. Diagnostic performance of whole-blood interferon-gamma assay and enzyme-linked immunospot assay for active tuberculosis. Diagn Microbiol Infect Dis. 2011 Oct;71(2):139-43. Epub 2011 Aug 15.Lee SW, Oh DK, Lee SH, et al . Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis. Eur Respir J. 2011;37(6):1447.Kabeer BSA, Sikhamani R, Swaminathan S, et al. Role of Interferon Gamma Release Assay in Active TB Diagnosis among HIV Infected Individuals. PLoSOne. 2009;4 (5):e5718.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Tuberculosis (TB) notification rates in New Zealand are around 7/100,000 with highest rates in those of non-European ethnicity.1 Primary pulmonary infection is often asymptomatic with conversion of a tuberculin skin test or interferon gamma release assay (IGRA) the only evidence of infection.Active tuberculosis refers to patients with replicating organisms.1 The diagnosis of active tuberculosis can be difficult because of the low sensitivity of sputum microscopy and the prolonged culture required.2IGRAs are increasingly being used as a screening test to rule out TB infection. A positive IGRA result does not distinguish between latent and active disease and importantly false negative results can occur.3–6We describe a case of active tuberculosis associated with a negative IGRA at presentation that seroconverted following treatment.Case reportA 29-year-old man of Indian origin presented with 7 weeks of an unproductive cough, unexplained weight loss and supraclavicular lymphadenopathy. He was born in India, lived in New Zealand since 2006 and had frequent visits to India. His sister-in-law was being investigated for active TB. He had no significant past medical history and HIV serology was negative.Examination was unremarkable besides small non-tender supraclavicular lymphadenopathy on the right. His chest radiograph showed a 30mm opacity in the right upper lobe. His interferon gamma release assay (QuantiFERON-TB Gold in-tube assay, Cellestis Ltd., Victoria, Australia) was negative with a value of 0.23 IU/ml.A computed tomography scan of his chest showed low attenuation centre consolidation in the right upper lobe with some associated ground glass and lymph nodes at the right hilum extending up the mediastinum to the root of the neck on the right hand side. These nodes showed low attenuation centres. He then underwent bronchoscopy with right upper lobe lavage as well as a fine needle aspirate of a supraclavicular node. Both were negative for acid-fast bacilli on Ziehl-Neeson stain.Nucleic acid amplification with the GeneXpert (Cepheid, California, USA) detectedMycobacterium tuberculosis DNA. The organism was subsequently cultured and proved to be fully sensitive. He was treated with six months of standard combination anti-tuberculous therapy. His symptoms resolved and his chest radiograph normalised. His repeat IGRA was positive with a value of 0.86 IU/ml.DiscussionNew Zealand's prevalence of TB is around 7-10/100,000; it is a low prevalence country but cases are concentrated in migrants.1 A highly sensitivity test is required to rule out tuberculosis in a low prevalence setting. IGRAs indicate a cellular immune response toMycobacterium tuberculosis antigens and therefore infection; they have been proposed as appropriate tests to rule out TB.7One study has shown the T-spot.TB to be more sensitive than QuantiFERON-TB Gold in-tube assay, but a recent meta-analysis showed a sensitivity of approximately 80% for both the QuantiFERON-TB Gold in-tube assay (Cellestis Ltd., Carnegie, Australia) and the T-Spot.TB (Oxford Immunotec Ltd., Abingdon, UK).3,8This may be due to a window period (up to 22 weeks) from infection to IGRA conversion, immunosupression such as HIV as well as impaired T cell activity from immune anergy caused by active TB infection.39,10 The low sensitivity of IGRA results in a low negative predictive value in situations such as this case when there is a high clinical suspicion of tuberculosis.This case serves as a reminder that even in low prevalence countries such as New Zealand, a negative IGRA does not rule out active tuberculosis when the clinical suspicion is high. Current guidelines conclude that IGRA should not be part of routine investigation for active tuberculosis but contribute only supplementary information . 1, 4,5

Summary

Abstract

This report describes a patient with pulmonary tuberculosis in whom the interferon gamma release assay (IGRA) was negative at presentaion. It became positive following treatment. This illustrates that this test cannot be used to rule out tuberculosis, even in a low incidence country.

Aim

Method

Results

Conclusion

Author Information

Michael Maze, Advanced Trainee in Respiratory Medicine; Lutz Beckert, Respiratory Physician; Respiratory Medicine; Canterbury District Health Board, Christchurch

Acknowledgements

Correspondence

Lutz Beckert, Respiratory Medicine, Christchurch Hospital, PO Box 4345, Christchurch 8041, New Zealand.

Correspondence Email

Lutz.Beckert@cdhb.health.nz

Competing Interests

Ministry of Health. Guidelines for Tuberculosis Control in New Zealand. 2010. Wellington: Ministry of Health.Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis. 2006;6:664-74.Sester M, Sotgiu G, Lange C, et al. Interferon-\u03b3-release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011;37(1):100.Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-\u03b3-release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis . J Infect Dis. 2011;204 Suppl 4:S1120.Centers for Disease Control and Prevention. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection - United States, 2010. MMWR 2010;59(No. RR-5).European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: ECDC; 2011.van Leeuwen RML, Bossink AWJ, Thijsen SFT. Exclusion of active Mycobacterium tuberculosis complex infection with the T-SPOTTM.TB assay. Eur Respir J. 2007;29:605-607.Lai CC, Tan CK, Lin SH, et al. Diagnostic performance of whole-blood interferon-gamma assay and enzyme-linked immunospot assay for active tuberculosis. Diagn Microbiol Infect Dis. 2011 Oct;71(2):139-43. Epub 2011 Aug 15.Lee SW, Oh DK, Lee SH, et al . Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis. Eur Respir J. 2011;37(6):1447.Kabeer BSA, Sikhamani R, Swaminathan S, et al. Role of Interferon Gamma Release Assay in Active TB Diagnosis among HIV Infected Individuals. PLoSOne. 2009;4 (5):e5718.

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