TreatmentUpdate59; Vol 7, No. 5 - May 1995
Sean Hosein

As part of tuberculosis (TB) control programmes in the USA, public health workers perform a variety of tasks such as making sure that their patients take their antibiotics as instructed, providing counselling and testing their patients to see if they have been infected with the bacteria that cause TB. Nurses can inject a small amount of protein from TB-causing bacteria called PPD (purified protein derivative) and watch for a reaction 2 days later. This reaction is called delayed-type hypersensitivity (DTH). A reaction to PPD, swelling and redness indicates that the person has been exposed to TB-causing bacteria or has been vaccinated with the TB vaccine BCG. This reaction depends on one type of immune response called CMI (cell-mediated immunity).

* ANERGY

Under constant attack by HIV and other microbes over many years CMI weakens and infections grow out of control. In people with weak or 'exhausted' immune systems there may be no reaction to PPD or other proteins and these people are called 'anergic'. This lack of reaction to PPD creates problems for health care workers when trying to find out if their patients have been infected with TB. One way to try and deal with this problem of no reaction to PPD is to also inject them with 'at least 2 [other proteins that cause DTH reactions)'. In practice this means that health care workers inject patients with proteins from bacteria, fungi or viruses at the same time they receive PPD injections (each in its own spot on skin). In this way if patients react with swelling and redness to the other proteins but don't react to PPD, it is very likely that they have not been infected by TB-causing bacteria (these patients do not have symptoms of TB). To test this idea, researchers across the USA have been performing tests of DTH on a variety of subjects for which we provide details.

* STUDY DETAILS

Over a 1 6-month period researchers enrolled over 1,300 subjects and here is the subject profile at the start of the study:

- 86% male - 70% gay/bisexual - 25% injection drug users - 5% heterosexual women - 68% white, 24% black and 6% hispanic - 50% of HIV-infected subjects had a CD4+ cell count of 410 cells - For 50% of non-HIV-infected subjects the equivalent was 889 cells

Although most of the subjects were HIV-infected, researchers enrolled a smaller but similar group of non-HIV-infected subjects to use for comparison.

* RESULTS

- as expected, non-HIV-infected subjects were more likely to have DTH than HIV-infected subjects, a difference that was statistically significant

- HIV-infected and non-infected injection drug users had similar rates of DTH reactions to PPD

- Injection drug users (both HIV-infected and non- infected) were 3 times more likely to have a reaction to PPD than gay/bisexual men. This difference was statistically significant. - Among non-HIV-infected subjects, anergy (a lack of responses to the various proteins used) occurred in 44% of injection drug users and 16% of gay/bisexual men. This difference between the 2 groups was statistically significant - A lack of response to all 4 proteins (anergy) occurred in the same proportion of subjects across all groups of HIV-infected subjects. - About 11% of heterosexual women had DTH to PPD - non-HIV-infected gay/bisexual men were 3 times more likely to have DTH to PPD compared with similar HIV-infected men. This difference was also statistically significant.

* CD4+ AND DTH

There was a general trend for fewer DTH responses as CD4+ counts fell among HIV-infected subjects. This trend was statistically significant.

* FOCUS ON TB

In this study, among 716 subjects (who received all 4 microbial proteins) there was no link between responding to PPD and reactions to other proteins tested. Older subjects, and those who received the TB vaccine BCG or who had reacted to PPD in the past were more likely to have a 'positive' skin test result to PPD. No subject with less than 100 CD4+ cells reacted to PPD in this study.

* FOCUS ON AN EXHAUSTED IMMUNE SYSTEM (ANERGY)

The researchers in this study found that anergy was more likely to occur in:

- HIV-infected subjects - HIV-infected subjects with less than 200 CD4+

Anergy was less likely to occur in:

- HIV-infected subjects with at least 600 CD4+ cells - non-HIV infected subjects

The researchers found that 'overall, HIV-infected [injection] drug users were no more likely to be anergic than HIV-infected gay/bisexual men'. Women did not seem to be any more anergic than men. Interestingly, results from this study were similar to another which used data from over 2,000 Haitian subjects. There are problems comparing results from studies which used different tests and different ways of interpreting skin test results.

* DEVELOPING TB

According to the study doctors, results from earlier studies 'suggest that many HIV-infected people have a positive [reaction to PPD injections] months to years before [symptoms of TB appear].' They add that 'most cases of TB develop [when patients can react to skin tests using PPD].' They add that most cases of HIV-related TB are caused by reactivated and not new infections.

* WHAT TO DO?

Testing anergic subjects with other proteins might spare some people from being given anti-TB medication (assuming that these people had been TB-infected despite a negative reaction to PPD) isoniazid and its toxicities. The researchers found that subjects were likely to react to PPD regardless of any other reaction to other proteins. In this study, anergy to PPD started when subjects' CD+ cell counts fell below 400 cells. The study doctors suggest that in the absence of highly accurate tests that can predict who will get TB, better ways of detecting TB bacteria and less toxic therapies, early skin (in HIV-infected subjects) should be done on a regular basis 'even in patients with low CD+ cells'. Skin testing kits, such as the 'Multitest', sold by Pasteur-Mérieux Serum et Vaccins.

REFERENCES:

1. Markowitz N, Hansen NI, Wilcosky TC, et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Annals of Internal Medicine 1993;119(3):185-193.

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Copyright © 1995 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca