Letters Screening tests for TB before biological therapy

Limitations of current tuberculosis screening tests in immunosuppressed patients

BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2226 (Published 28 April 2015) Cite this as: BMJ 2015;350:h2226
  1. Vanessa Clifford, research fellow1,
  2. Marc Tebruegge, NIHR clinical lecturer in paediatric infectious diseases and immunology2,
  3. Nigel Curtis, professor of paediatric infectious diseases3
  1. 1Murdoch Children’s Research Institute, Royal Children’s Hospital Melbourne, Parkville, Australia
  2. 2Academic Unit of Clinical and Experimental Medicine, Faculty of Medicine and Respiratory Biomedical Research Unit and Institute for Life Sciences, University of Southampton, Southampton, UK
  3. 3Department of Paediatrics, University of Melbourne, Parkville
  1. nigel.curtis{at}rch.org.au

We agree that a combination of an interferon γ release assay (IGRA; QuantiFERON-TB Gold in-Tube (QFT-IT) or TSPOT.TB) and a tuberculin skin test is the most sensitive approach to screening for latent tuberculosis infection in patients with rheumatological diseases before starting biological drugs.1

The authors note that skin tests can be false-negative in patients receiving corticosteroids. However, IGRAs, which are designed primarily to achieve high specificity (versus high sensitivity), are also prone to false negative results in this setting.

A recent meta-analysis found no significant reduction in positive IGRA results in patients on corticosteroids, but the design and reported outcomes of included studies varied greatly.2

QFT-IT assays rely on detecting interferon γ induced by stimulation with tuberculosis specific antigens. QFT-IT produces “indeterminate” results if the interferon γ concentration in the negative control sample exceeds a predefined threshold or the interferon γ response in the positive control sample is insufficient.3 Our ex vivo study found that therapeutic levels of dexamethasone significantly reduce tuberculosis antigen induced interferon γ responses in the QFT-IT assay, without significantly reducing positive control responses (thereby not producing indeterminate results).4 Thus, patients receiving corticosteroids are at increased risk of false negative QFT-IT results.

Interestingly, we found that interferon γ inducible protein 10 was a more sensitive marker of latent tuberculosis in the presence of dexamethasone,4 which is consistent with a recent clinical study in immunosuppressed patients with rheumatoid arthritis.5

Until more robust and more accurate immune based tuberculosis tests become available, we strongly endorse the recommendation that a combination of tuberculin skin test and IGRA should be used to determine the tuberculosis infection status of immunosuppressed patients.1 Even this cautious approach cannot definitively exclude the presence of latent tuberculosis in this setting.


Cite this as: BMJ 2015;350:h2226


  • Competing interests: We have no commercial or other association that might pose a conflict of interest. MT is supported by a clinical lectureship provided by the UK National Institute for Health Research (NIHR).

  • Full response at: www.bmj.com/content/350/bmj.h1060/rr.


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