High rate of Quantiferon positive and tuberculin negative tests in infants born at a large Italian University Hospital in 2011: a cautionary hypothesis

Abstract

In the summer of 2011, an outbreak of Mycobacterium tuberculosis infection was suspected, and widely publicized, to have occurred in a maternity ward of an Italian University Hospital based on a case of tuberculosis in a nurse and another case in a newborn. More than 1300 newborns in the Hospital were surveyed for the occurrence of latent TB by the use of interferon-gamma released assays, which was positive in 118 newborns, all negative at the tuberculin skin test. We present here several theoretical arguments and literature data suggesting caution in interpreting the interferon-gamma released assays positivity alone as indication of latent TB infection in newborns.

Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children

“…More recently, interferon- release assays (IGRAs) have been developed to replace the TST for detecting LTBI, and while their intended use is not to diagnose active TB, some studies suggested their usefulness to identify childhood TB [ 5 ]. The sensitivity and specificity of the TST and IGRAs were shown to be similar for diagnosing active TB, while it remains difficult to determine their accuracy in detecting LTBI, given the lack of gold standards in children and adults [ 6 ] and the somehow controversial definition of LTBI [ 7 , 8 ]. In this regard, the Paediatric Tuberculosis Network European Trials group (PTBNET) has recently defined LTBI as ‘a positive immunological test result (either TST or IGRA) in the absence of active TB’[ 9 ].…”

Tuberculosis: Medico-Legal Aspects

“…One phenomenon is positivity due to laboratory or testing error, which for the QTF test can reach values of 30% of positive results that, spontaneously, i.e., in the absence of potentially confounding factors, convert within three months to a negative result 30. Additionally, a positive Mantoux test may be the result of a confounding circumstance, such a previous BCG vaccination or infection by other mycobacteria28 and also the observation, for some categories of subjects tested, of the interference of known immunological factors 31. These include “chimerism” (the presence of maternal T cells, possibly specific for tuberculosis mycobacterium, in mothers positive to the Mantoux test, which cross the hemo-placental barrier and can circulate in a new born infant for several months or even years) and “trogocytosis” (i.e., the “vampirisation” of foetal/neonatal cells by maternal immune cells specific for the mycobacterium).…”

“… 30 Additionally, a positive Mantoux test may be the result of a confounding circumstance, such a previous BCG vaccination or infection by other mycobacteria 28 and also the observation, for some categories of subjects tested, of the interference of known immunological factors. 31 These include “chimerism” (the presence of maternal T cells, possibly specific for tuberculosis mycobacterium, in mothers positive to the Mantoux test, which cross the hemo-placental barrier and can circulate in a new born infant for several months or even years) and “trogocytosis” (i.e., the “vampirisation” of foetal/neonatal cells by maternal immune cells specific for the mycobacterium). Both occurrences are potentially responsible for a true positive result, but are descriptive of an immune response temporarily transmitted by the actually sensitised subject to a subject testing positive, but in the absence of exposure (e.g.…”