Tuesday, 22 Oct 2019

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TB Management Questions

The following is a compilation of several frequently asked questions regarding tuberculosis (TB) testing or treatment in patients on a TNF inhibitor (TNFi) or other biologic agents.

Which Test Knows Best.  A nurse (born in Southeast Asia) needs a biologic and you wish to order a TB test. But the patient says she received BCG and prefers to be tested by CXR, as this is what her past doctors have done. Her last CXR was 10 months ago and was normal.  What do you recommend?
a.    Tuberculin skin test (PPD)
b.    Quantiferon (IGRA)
c.    CXR
d.    None of the above

The right answer is (b).  The answer is predicated on several facts: 1. most patients who have received BCG live in TB endemic areas.  PPD positivity after BCG is lost in the vast majority of those vaccinated.  Hence, someone coming from a foreign endemic area, now living in the USA (or UK, Canada, etc.) and who has a positive PPD test is far more likely to have latent TB infection (LTBI) than BCG-related PPD positivity.  The best way to arbitrate this would be to use an interferon gamma releasing assay (IGRA), which is unaffected by BCG use and thus a positive IGRA would be sign of prior infection.

Indeterminate IGRA. How do you handle the indeterminate IGRA result?  The frequency of indeterminate IGRA is 5-6.8% in patients with chronic inflammatory disease. Calabrese and Calabrese found that steroid use is likely to increase indeterminate findings and DMARDs may decrease such results (http://buff.ly/1TFzCIp).  Another study from Korea found that SLE, sulfasalazine or TNFi and manual ELISA IGRA were risk factors for IGRA results (http://buff.ly/1TFzCIp).  While the usual practice is to repeat the test, most will find an indeterminate result will be followed by another indeterminate result.  I consider such results as being akin to finding anergy with PPD testing – meaning that up to 10% of such patients may be infected and thus, you can proceed with treatment but observe closely for signs of TB infection.  Some people have taken to ordering a different IGRA test, but I do not find this to be particularly helpful. It is interesting that if the IGRA result is indeterminate and the patient goes on to receive a TNFi, repeat result is almost always negative, suggesting that inflammation is interfering with the assay.

Which do you believe? You do a PPD test and it comes back unexpectedly positive at 6 or 7 mm of induration.  Perplexed by the result, many people go ahead and order an IGRA test. If and when the IGRA comes back negative, many practitioners are satisfied that this is confirmation of safety and that they need not be concerned. Unfortunately, this is erroneous, finding either test positive (PPD or IGRA) is evidence of antecedent infection and needs to be treated.  If for good reason you believe that the PPD is not reliable you should repeat the PPD – if done within 1-3 weeks, the 2nd test would qualify as a 2-step PPD- and findings here are much more valid than the first (possibly equivocal test).  Another scenario would be to discover that the patient had or may have had BCG long ago. In this instance the IGRA test should be employed as it would not be affected by prior BCG vaccination. 

Already treated, never tested.  Surely you've encountered this scenario. A patient comes to you having been treated for several years with a TNF inhibitor, let's say Remicade. But you discover the patient has never been tested for TB.  If you find a positive PPD and she has no signs or symptoms of TB and has a negative CXR, she meets the definition for LTBI.  Hence, she has evidence of latent TB by testing but has been on a TNFi for 4 years. What do you do?  Should she receive a course of isoniazid prophylaxis or not?  I believe the patient has already passed the TB-TNFi stress test.  The vast majority of patients who are going to reactivate their TB on a TNFi are going to do so within the first 6 to 12 months of therapy; faster with infliximab and slower with etanercept.  After 4 years and no evidence of active TB or nontuberculous mycobacterial infection, I would culture the patients for mycobacterial infection (sputum, urine, etc.) and observe the patient without giving INH, but knowing this patient is still at higher risk of TB reactivation.

BCG for bladder cancer.  You need to be cautious using a TNFi (much more so than other non-TNFi biologics) in patients with bladder cancer who are receiving intravessicular BCG therapy.  There are numerous cases of BCG therapy leading to reactivation of TB (including death) while on anti-TNF therapy. The patient can safely receive oral DMARDs, including tofacitinib, while on BCG. The risk of TB reactivation with drugs like tofacitinib, abatacept, rituximab and tocilizumab is about 100 fold lower than with a TNF inhibitor. Thus the risk is much lower with these alternatives; but it’s not zero.  Hence, use the lowest doses and least number of drugs as possible to control their inflammatory disease and maintain this very low risk.  All of this advice weakens if the patient is incredibly immunosuppressed from cancer or other reasons, or if he had TB in the past or if he is on very high doses of steroids.

Documented or not?  I often get questions about what to do when a patient claims to have a prior history of either latent TB or active TB and you wish to give a TNF inhibitor.   Often there is little or no knowledge of treatments received and there is no documentation of such treatment.  As such patients are likely to be positive for either skin testing (PPD) or IGRA, testing does not provide any useful evidence of what to do. I base my decision on how well the patient can provide or recite evidence of prior treatments. Meaning that if they can say they took an antibiotic, or isoniazid, for greater than six months and it was the only drug they took and they didn't drink alcohol during this period.  I would accept that as prima facie evidence of “adequate treatment”.  Likewise if they said that they took several antibiotic, or TB drugs, at a time for more than four months then I would also accept this in lieu of documents proving prior treatment.  Without any documentation or a good history of documentation you either have to treat for TB or a less risky biological agent (anakinra, tofacitinib, abatacept, rituximab, tocilizumab).

IGRA vs. PPD?  Turns out that both tests are recommended by the CDC and have been shown to be reliable screening tests for TB.   Which you prefer or use is often dependent upon what is available at your locale. The advantages of IGRAs include the following: 1) can be done in a single patient visit 2) not associated with potential booster phenomenon (a concern with repeated PPD testing); 3) results are not subject to human interpretation or error; 4) results can be available within 24 hours; and 5) results are unaffected by BCG and most nontuberculous mycobacteria.  Limitations include A) availability; B) experienced proper processing; C) reliability in certain groups (such as children < 5 years, persons recently exposed to TB, immunocompromised, those needing serial testing).  Hence IGRAs are preferred in patients who are unreliable and patients who have received BCG vaccination.  The TST is the preferred method for testing for children under the age of 5 years.   The CDC warns that routine testing with both TST and IGRAs is NOT recommended (http://buff.ly/1Tz3y7L)

How long to wait?  Patients found to have evidence of latent tuberculosis infection (LTBI) must have anti-tuberculous prophylaxis begun before starting a TNFi.  There is considerable confusion and spin on what "before" means and how long someone should be on INH before starting their biologic.  Anyone who mandates 1 month, 2 months, 6 months or 9 months, is (by their numbers) increasingly inventive and speculative.  Look at the product label for the drug you wish to begin.  All of them have the same carefully worded languages that states, "prophylaxis BEFORE TNFi initiation".  That means 2 minutes after the first INH tablet is injested or a day or a week later.  Each meets the expert guided wording of before.  As does the recommendations to wait 2 months or 6 months. However, I would assume that someone sick enough to get a TNFi or biologic should needed sooner and without delay.  Here are some facts that may give you some comfort in doing as I do (give the TNFi immediately after the INH):

  • All of the TNFi developmental trials had the same inclusion criteria language found in the product label. Hence I had a patient who was to be randomized into the early RA ASPIRE trial and because she had a 16mm +PPD and negative CXR (LTBI) she was given 300 mg of oral isoniazid, followed by her first infusion of infliximab.  This was the policy for that trial and many other TNFi and biologic trials.  These policies and rules were carefully devised by TB experts and FDA reviewers in consultation with the CDC (the biggest division in the CDC is their TB division)
  • There are no reports of patients suddenly dying from rapid disseminated TB soon after starting both INH and a TNFi. 
  • The primary reason to wait after starting INH is to be sure that INH is well tolerated and not hepatoxic.  But there should be no confusing INH toxicity with any side effects associated with TNFi initiation.
  • There are many reports of highly active TB infection treated with high dose corticosteroids without additional hazard.
  • There are reports of HIV+ persons infected with active TB who started multi-drug TB therapy with or without etanercept.  Yes etanercept.  TNFi probably work by causing breakdown of granulomas and apoptosis of TB infected cells. Patients on the TNFi had better pulmonary and TB outcomes.  Hence giving the TNFi seemed to be a more effective way of delivering the bug to the drug.  
Disclosures: 
The author has no conflicts of interest to disclose related to this subject

Rheumatologists' Comments

I thought etanercept was less effective at breaking down granulomas than TNF MAB treatment . Why would have researches used Etanercept if this was the proposed mechanism of benefit in treating active TB
It is less effective than other MAB anti-TNFi, but yet it is as effective (in RA AS and PsA) as all the others, but in Psoriasis and IBD its not as effective. Clearly there are differential mechanisms that are meaningful. Its not so clear that its related to apoptosis potential alone. JJC

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