Incidence of Tuberculosis and the Predictive Value of ELISPOT and Mantoux Tests in Gambian Case Contacts

Abstract

BackgroundStudies of Tuberculosis (TB) case contacts are increasingly being utilised for understanding the relationship between M. tuberculosis and the human host and for assessing new interventions and diagnostic tests. We aimed to identify the incidence rate of new TB cases among TB contacts and to relate this to their initial Mantoux and ELISPOT test results.Methods and FindingsAfter initial Mantoux and ELISPOT tests and exclusion of co-prevalent TB cases, we followed 2348 household contacts of sputum smear positive TB cases. We visited them at 3 months, 6 months, 12 months, 18 months and 24 months, and investigated those with symptoms consistent with TB. Those who were diagnosed separately at a government clinic had a chest x-ray. Twenty six contacts were diagnosed with definite TB over 4312 person years of follow-up (Incidence rate 603/100,000 person years; 95% Confidence Interval, 370–830). Nine index and secondary case pairs had cultured isolates available for genotyping. Of these, 6 pairs were concordant and 3 were discordant. 2.5% of non-progressors were HIV positive compared to 12% of progressors (HR 6.2; 95% CI 1.7–22.5; p = 0.010). 25 secondary cases had initial Mantoux results, 14 (56%) were positive ; 21 had initial ELISPOT results, 11 (52%) were positive; 15 (71%) of 21 tested were positive by one or the other test. Of the 6 contacts who had concordant isolates with their respective index case, 4 (67%) were Mantoux positive at recruitment, 3 (50%) were ELISPOT positive; 5 (83%) were positive by one or other of the two tests. ELISPOT positive contacts, and those with discordant results, had a similar rate of progression to those who were Mantoux positive. Those negative on either or both tests had the lowest rate of progression.ConclusionsThe incidence rate of TB disease in Gambian TB case contacts, after screening for co-prevalent cases, was 603/100,000 person years. Since initial ELISPOT test and Mantoux tests were each positive in only just over half of cases, but 71% were positive by one or other test, positivity by either might be the best indication for preventive treatment. These data do not support the replacement of the Mantoux test by an ELISPOT test in The Gambia or similar settings.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

“…A single large prospective study has been published describing the risk of progression to tuberculosis after conversion to a positive ELISPOT assay in Gambian case contacts [88]. In this study, ELISPOT positive contacts had a similar rate of progression to those who were skin test positive, whereas those negative on either or both tests had the lowest rate of progression.…”

“…Others recommend that IGRAs completely replace the tuberculin skin test for identifying latent infection [85]. Today, some data from prospective studies are now emerging that look at the risk of tuberculosis in those with a positive IGRA [86,88,121,122].…”

“…If either test gives a positive result, this may be regarded as supportive evidence of infection [88], and the children should be offered preventive chemotherapy.…”

Diagnosis of tuberculosis infection using interferon-γ-based assays

“…Unexpectedly, TST was not predictive of TB, regardless of the cut-off point used. In a study with 2348 household contacts in Gambia, Hill et al 90 found that neither the TST nor the T-SPOT.TB predicted development of TB. The lack of predictive value was attributed to the high-burden of TB and recent transmission.…”

Spectrum of latent tuberculosis — existing tests cannot resolve the underlying phenotypes

“…Thus, none of the existing tests can accurately identify the subgroup that is at risk of progression to disease. This is borne out by the sobering fact that IGRAs have been shown to have only a modest predictive ability, and several studies show similar (and rather low) rates of progression among individuals with positive TST and IGRA results [2][3][4][5][6] . For example, the incidence rate of active disease in TB contacts with positive IGRA results was 9.2 per 1000 person-years (PY) in the Gambia 2 , 20.5 per 1000 PY in Turkey 4 and 7.7 per 1000 PY in Colombia 6 .…”