My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

The weight of the evidence to date suggests that immunosuppressive therapy, including steroids, other oral immunosuppressants and anti-tumor-necrosis factor (TNF) agents, may negatively impact IGRA results.1

In some ways the finding of false-negative IGRA in the setting of immunosuppression is intuitive since many immunosuppressive agents are potent inhibitors of T cells and interferon-gamma response. 1,2 Despite this, the initial reports have been somewhat conflicting which makes a 2016 meta-analysis of the effect of immunosuppressive therapy on IGRA results in patient with autoimmune diseases (eg, rheumatoid arthritis, lupus, inflammatory bowel disease) particularly timely. 1

This meta-analysis found a significantly lower positive IGRA results among patients on immunosuppressive therapy ( O.R. 0.66, 95% C.I. 0.53-0.83). Breakdown by IGRA test showed a significant association between QuantiFERON-TB Gold In-Tube and lower positive results and a trend toward the same with T-SPOT though the latter did not reach statistical significance with fewer evaluable studies (O.R. 0.81, 95% C.I 0.6-1.1).   Breakdown by type of immunosuppressant showed significantly negative impact of corticossteroids, other oral immunosuppressants, and anti-TNF agents for all. Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 3,4

So, whenever possible, testing for latent TB should be performed before immunosuppressants are initiated.

Bonus Pearl: Did you know that an estimated one-third of the world’s population may have latent TB?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Sester U, Wilkens H, van Bentum K, et al. Impaired detection of Mycobacterium tuberculosis immunity in patents using high levels of immunosuppressive drugs. Eur Respir J 2009;34:702-10. https://erj.ersjournals.com/content/34/3/702
  3. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  4. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

Think of invasive pulmonary aspergillosis (IPA) in your patient when she or he has a COPD exacerbation that appears refractory to broad-spectrum antibiotics and high doses of steroids. Heighten your suspicion even more in patients with severe-steroid dependent COPD, presence of a new pulmonary infiltrate or isolation of Aspergillus spp from respiratory cultures. 1

It’s worth remembering that although dyspnea and bronchospasm are found in most COPD patients with IPA, in contrast to haematological patients, fever, chest pain and hemoptysis are usually absent in this patient population.1

Diagnosis of IPA in this patient population is challenging for several reasons including: 1. A definitive or “proven” diagnosis requires histopathologic evidence of Aspergillus invasion of lung tissue which is not possible without subjecting an already fragile patient to invasive procedures (eg, lung aspiration or biopsy); 2. In contrast to IPA in highly susceptible immunocompromised patients with cancer and recipients of hematopoietic stem cell transplants, standardized definition of IPA in patients with COPD is lacking; 1,3 and 3. Frequent colonization of the respiratory tract of COPD patients with Aspergillus spp (16.3 per 1000 COPD admission in 1 study) 4,5, makes it difficult to diagnose IPA based on cultures alone.

Aside from respiratory cultures, another non-invasive test, serum galactomannan (GM, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp and released into the blood during its growth phase 6) may have some utility in suggesting IPA in COPD patients, albeit with a mediocre sensitivity (~30-60%) but respectable specificity (>80 %). In contrast, bronchoalveolar lavage fluid GM may have better sensitivity  (~75%-90%) with similar specificity as that of serum GM in the diagnosis of IPA in these patients 7-8

Bonus pearl: Did you know that the incidence of IPA appears to be increasing in COPD patients requiring ICU admission, with reported mortality rates of 67% to 100%? 7

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References

  1. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Res J 2007;30:782-800. https://www.ncbi.nlm.nih.gov/pubmed/17906086
  2. Bulpa P, Bihin B, Dimopoulos G, et al. Which algorithm diagnoses invasive pulmonary aspergillosis best in ICU patietns with COPD? Eur Resir J 2017;50:1700532 https://www.ncbi.nlm.nih.gov/pubmed/28954783
  3. Barberan J, Garcia-Perez FJ, Villena V, et al. Development of aspergillosis in a cohort of non-neutropenic, non-transplant patients colonized by Aspergillus spp. BMC Infect Dis 2017;17:34. https://link.springer.com/article/10.1186/s12879-016-2143-5
  4. Guinea J, Torres-Narbona M, Gijon P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010; 16:870-77. https://www.sciencedirect.com/science/article/pii/S1198743X14617432
  5. Blot Stijn I, Taccone FS, Van den Abeele A-M, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 202;186:56-64. https://www.atsjournals.org/doi/full/10.1164/rccm.201111-1978OC
  6. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417-27. https://academic.oup.com/cid/article/42/10/1417/278148
  7. He H, Ding L, Sun B, et al. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Critical Care 2012;16:R138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066034/
  8. Zhou W, Li H, Zhang Y, et al. Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid samples from patients with nonneutropenic invasive pulmonary aspergillosis. J Clin Microbiol 2017;55:2153-61. https://www.ncbi.nlm.nih.gov/pubmed/28446576
When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

The presence of hepatitis B surface antibody (HBsab) in patients who also test positive for core antibody does not necessarily confer full protection against hepatitis B virus (HBV) reactivation during immunosuppression (incidence 4.3%). 1 This is because despite having HBsab and no HB surface antigen,  a small portion of patients continue to have detectable HBV DNA in the serum and are therefore at risk of reactivation during severe immunosuppression. 2

In fact, the American Gastroenterological Association recommends against using anti-HBs status to guide antiviral prophylaxis in anti-HBc-positive patients. 1

Overall, antiviral prophylaxis may reduce the risk of HBV reactivation by 87% (C.I. 70%-94%). Antiviral drugs with a high barrier to resistance (eg, entecavir) are preferred over lamivudine.

Immunosuppressants often requiring HBV prophylaxis include: 1-3

  • B cell-depleting agents (eg, rituximab, ofatumumab)
  • Anthracycline derivatives (eg, doxorubicin, epirubicin)
  • Prednisone (4 weeks or more)
  • Tumor necrosis factor inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)
  • Other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

Traditional immunosuppressive agents such as azathioprine, 6-mercaptopurine and methotrexate are often considered “low-risk” and do not generally require prophylaxis. 1

Fun Fact: Did you know that hepatitis B virus is very old and probably originated in birds when dinosaurs roamed the earth? 4

References

  1. Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute Guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215-19. https://www.ncbi.nlm.nih.gov/pubmed/25447850
  2. Gigi E, Georgiou T, Mougiou D, et al. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab. HIPPOKATRIA 2013;17:91-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738290/
  3. Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat 2008;40:36-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699087/
  4. Suh A, Brosius J, Schmitz J, et al. The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B virus. Nature Communications 2013; Article no. 1791. http://www.nature.com/articles/ncomms2798
Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

Does corticosteroid therapy impact the results of interferon-gamma release assays—IGRAs— in patients screened for latent tuberculosis?

 

The weight of the evidence to date suggests that immunosuppressive therapy, including corticosteroids, other oral immunosuppressants and anti-tumor-necrosing factor (TNF) drugs, may negatively impact IGRA results.1-5

Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 2-4 In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone.4

A meta-analysis of the performance of IGRAs (including T-SPOT.TB) in patients with inflammatory bowel disease concluded that these assays were negatively affected by immunosuppressive therapy.5

So, be cautious in interpreting a negative or indeterminate results of IGRAs in patients on corticosteroid therapy or other immunosuppressants.

See also a related P4P post: https://pearls4peers.com/2020/01/20/my-patient-with-rheumatoid-arthritis-might-have-been-exposed-to-tuberculosis-does-immunosuppressive-therapy-affect-the-results-of-interferon-gamma-release-assay-igra-testing-for-latent-tuberculosis/

Bonus Pearl: Did you know that IGRA is not affected by prior Bacillus Calmette-Guerin (BCG) vaccination, a significant advantage over PPD skin tests?

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Subscribe to Blog via Email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  3. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
  4. Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349. https://academic.oup.com/ibdjournal/article/17/11/2340/4631016 
  5.  Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042. https://www.researchgate.net/publication/265093409_Performance_of_Interferon-gamma_Release_Assay_for_Tuberculosis_Screening_in_Inflammatory_Bowel_Disease_Patients
Does corticosteroid therapy impact the results of interferon-gamma release assays—IGRAs— in patients screened for latent tuberculosis?