[Update of the guidelines of the Israeli Association of Rheumatology for the prevention of tuberculosis in patients treated with TNF-alpha blockers].

The use of TNFalpha blockers is associated with reactivation of tuberculosis (TB). The previous guidelines of the Israeli Association of Rheumatology were based on the tuberculin skin test (TST), chest X ray and a questionnaire on possible previous exposure to TB. The growing use of Interferon-gamma released assay (IGRA) has prompted the need for an update to these guidelines. All patients who are candidates to receive TNFalpha blockers should be screened for active or Latent tuberculosis. The screening includes: Tuberculin Skin Test (TST), interferon-gamma release assays (IGRA), chest X-ray and a questionnaire about possible exposure to tuberculosis. TST > or = 10 mm is considered positive; TST < or = 5 is negative; in case of TST = 0, a 2-step screening is recommended. If TST is > or = 5 mm but < 10 mm or in heavy immunosuppressed patients with TST = 0, an IGRA test should be performed and the diagnosis of latent TB taken accordingly. If the IGRA test is indeterminate, the decision should be taken based on the TST and patient's characteristics. Patients with a TST less than 5 mm. should be questioned about prior exposure to tuberculosis. Latent tuberculosis should be treated with a 9 month course of isoniazid (300 mg/d) or a 4 month course of rifampicin (600 mg/d) or for 3 months with a combination of 300 mg. isoniazid and 600 mg. rifampicin daily. The committee recommends postponing treatment with TNFalpha blockers until completion of anti-tuberculosis therapy. If the clinical condition requires the urgent use of TNFalpha blockers, these may be initiated one month after starting treatment for latent tuberculosis.

Increased Th1 and Th2 type cytokine production in patients with active tuberculosis.

BACKGROUND: The global spread of tuberculosis necessitates the development of an effective vaccine and new treatment modalities. That requires a better understanding of the differences in regulation of the immune responses to Mycobacterium tuberculosis between individuals who are susceptible or resistant to the infection. Previous immune studies in young Ethiopian immigrants to Israel did not demonstrate anergy to purified protein derivative or a Th2-like cytokine profile. OBJECTIVES: To evaluate the profile of Th1 and Th2 cytokine production in immigrant TB patients, in comparison with asymptomatic control subjects. METHODS: The present study included (part 1): 39 patients with acute TB (group 1), 34 patients with chronic relapsing TB (group 2), 39 Mantoux-positive asymptomatic TB contacts (group 3), and 21 Mantoux-negative asymptomatic controls (group 4). Patients were mainly immigrants from Eastern Europe and Ethiopia. Levels of interferon gamma, interleukin 2 receptor, IL-6 and IL-10 were measured in serum and in non-stimulated and PPD-stimulated peripheral blood mononuclear cell culture supernatants, using commercial ELISA kits. In addition (part 2), levels of IFNgamma and IL-12p40 were evaluated in 31 immigrant Ethiopian patients and 58 contact family members. RESULTS: Patients with acute disease tended to secrete more cytokines than contacts, and contacts more than chronic patients and controls, without a specific bias. None of the patients showed in vitro anergy. Discriminant probability analysis showed that from the total of 12 available parameters, a cluster of 6 (IFNgamma-SER, IFNgamma-PPD, IL-2R-SER, IL-10-SER, IL-10-NS and IL-6-PPD) predicted an 84% probability to become a TB contact upon exposure, 71% a chronic TB patient and 61% an acute TB patient. Family-specific patterns of IFNgamma were demonstrated in the second part of the study. CONCLUSIONS: Firstly, no deficiency in cytokine production was demonstrated in TB patients. Secondly, acute TB patients secreted more cytokines than contacts, and contacts more than unexposed controls. Thus, neither anergy nor a cytokine dysregulation explains susceptibility to acute TB disease in our cohort, although chronic TB patients produced less cytokines than did acute patients and less than asymptomatic contacts. Thirdly, a certain cytokine configuration may predict a trend of susceptibility to acquire, or not acquire, clinical TB. It is presently unclear whether this finding may explain the disease spread in large populations. Finally, the familial association of IFNgamma secretion levels probably points towards a genetic regulation of the immune response to Mycobacterium tuberculosis.

[Guidelines of the Israeli association of rheumatology for the prevention of tuberculosis in patients treated with TNF-alpha blockers].

The use of TNFalpha blockers is associated with reactivation of tuberculosis. The Israeli Association of Rheumatology nominated a committee to determine guidelines for the prevention of tuberculosis in patients taking TNFalpha blockers. The risk of reactivation of tuberculosis is higher with monoclonal antibodies to TNFalpha (infliximab, adalimumab) in comparison with the soluble receptor of TNFalpha (etanercept). All patients who are candidates to receive TNFalpha blockers should be screened for active or latent tuberculosis. The screening includes: Tuberculin Skin Test (TST), chest X-ray and a questionnaire about possible exposure to tuberculosis. Two-step screening should be used as recommended by the Ministry of Health. The reaction elicited in the second test (if applied) should be used. In the general population latent tuberculosis is diagnosed when the TST response is 15 mm. or above; a reaction of 10 mm. or above is positive in populations with a history of definite or probable exposure to TB and 5 mm. is the threshold for populations who are immunosuppressed or if chest radiography reveals old tuberculosis without clear documentation of previous treatment. Patients with a TST less than 5 mm. should be questioned about prior exposure to tuberculosis. Latent tuberculosis should be treated with a 9 month course of isoniazid (300mg/d) or a 4 month course of rifampicin (600mg/d) or for 3 months with a combination of 300 mg. isoniazid and 600 mg. rifampicin daily. The committee recommends postponing treatment with TNFalpha blockers until completion of anti-tuberculosis therapy. If the clinical condition requires the urgent use of TNFalpha blockers, these may be initiated one month after starting treatment for latent tuberculosis.

Mortality of patients hospitalized for active tuberculosis in Israel.

BACKGROUND: Pulmonary tuberculosis continues to cause of mortality, particularly in developing countries. Despite modern anti-TB treatment, the elderly and immigrants from TB-endemic countries are at risk. Multidrug resistance has yet to be resolved.. OBJECTIVES: To determine the mortality rate and predictors of mortality among patients hospitalized with TB in Israel. METHODS: We evaluated the medical records of 461 patients with active pulmonary TB who were hospitalized in the respiratory care department during the 5 year period 2000-2004. Data included demographic, clinical, laboratory and radiological findings, drug resistance as well as adverse reactions to anti-TB treatment. RESULTS: Three main ethno-geographic groups were observed: 253 patients from the former USSR, 130 from Ethiopia, and 54 of Israeli origin (as well as 24 residents of other countries). Of the 461 patients 65 (13%) died in hospital. The factors that were best predictors of mortality were older age, ischemic heart disease, cachexia, prior corticosteroid treatment, hypoalbuminemia and pleural effusion (P < 0.005 for all). The ethno-geographic factor and the presence of multidrug-resistant bacteria had no significant effect on mortality in our study group. CONCLUSIONS: The mortality rate in our study was relatively low, and there was no significant difference between the three ethno-geographic groups.