Tuberculosis, Pulmonary Clinical Trial
Official title:
Observational Study to Compare IGRA and Mantoux Test in Children With Suspected Latent or Active TB Infection
The aim of this project is to analyze the potential contribution of IGRA test QuantiFERON-TB
Gold In Tube test (QTF-GIT, Cellestis Limited, Carnegie, Victoria, Australia) in the
diagnosis of tuberculosis (TB - active or latent) in pediatric subjects (0 and 17 year)s
recently exposed to infection (indicated as "contacts") or with clinical suspicion of active
TB, and to compare the results obtained with those of the TuberculinSkin Test (TST; gold
standard). The project is expected to enroll up to 50 pediatric patients over a 4-year
study. Children with access to Ambulatory structures or hospitalized at University
Infectious Diseases Clinic or Pediatric Clinic, University Hospital of Siena, or with access
to Ambulatory or hospitalized at Pediatric Clinic USL 9 Grosseto will be enrolled. Once
obtained the informed consent of patients' parents or legal guardians, patients will be
enrolled. The doctor will administer a clinical-anamnestic questionnaire, relative to the
country of birth and residence, date of arrival in Italy and any stays in the country of
origin (in case of foreign patient), travels abroad, risk factors for infectious diseases,
type of contact with any index case, previous vaccination with BCG, date and outcome of the
TST, clinical symptoms and signs suggestive of active TB, report of any instrumental
investigation. Together with the collection of blood samples for routine purposes, an
additional blood sample will be taken so to run IGRA test. Also patients for whom their
medical doctor will independently order to run QTF-GIT test as necessary tool for the
clinical diagnosis of TB will be included in the study.
A retrospective analysis will be performed on patient pertaining to participant Clinics,
from 1 January 2012 to 31 May 2015. Such analysis will be performed on those patients for
which their medical doctor requested both intradermal Mantoux and IGRA test.
Expected results:
- estimation of concordance between QuantiFERON-TB Gold In Tube and TST in pediatric
patients exposed to TB, with or without latent TB infection
- Evaluation of the sensitivity of the test QTF-GIT in patients with active tuberculosis
disease
- Evaluation of specificity of testQTF-GIT in not infected patients
- Evaluation on the possible use of QTF-GIT, together with TST, to improve the diagnosis
of tuberculosis latent or active infection in pediatric subjects.
- Evaluation of the possible diagnostic use of QTF-GIT in the child <5 years.
The diagnosis of tuberculosis in children is a complex procedure. The commonly used test is
the tuberculin skin test (TST), which shows significant limitations such as cross-reactivity
with the bacillus Calmette-Guerin (BCG) used for vaccination, and other environmental
mycobacteria, the possible influence of age and the immunological status of the patient, the
need to return to the hospital for the re-reading of the intradermal reaction. Since 2001,
the Food and Drug Administration approved the first of a series of new tests, called
Interferon-Gamma Release Assays (IGRAs), based on the release of interferon gamma by
sensitized lymphocytes in the blood of the patient. Among them, the QuantiFERON-TBGold In
Tube (QTF-GIT, Cellestis Limited, Carnegie, Victoria, Australia), is a highly specific test
that measures, through an ELISA assay, the release of interferon-gamma production by
lymphocytes in response to an antigenic challenge to Mycobacterium tuberculosis antigens.
The antigens used in the test QTF-GIT (ESAT-6, CFP-10 and the sequence of TB7.7) are in fact
absent from the vaccine strain BCG and in most nontuberculous mycobacteria, giving to the
QTF-GIT test greater specificity than TST. Moreover, being an in vitro test, it does not
require a return visit to the reading of the result (this is particularly important in
screening of contacts), which is instead carried out in an instrument (and therefore
objective) and, finally, thanks to the presence of an internal positive control, it is
possible to evaluate the performance of tests and reduce possible technical errors. The
QTF-GIT test gave significant results in adults in terms of sensitivity and specificity, as
demonstrated by a large scientific literature, and is currently used in many hospitals, in
combination with the TST, for the diagnosis of tuberculosis. Since September 2012, also the
Siena University Hospital introduced the QTF-GIT assay as a diagnostic test for tuberculosis
diagnosis in healthcare workers and in inpatient or outpatient tested positive TST requiring
detailed diagnostic investigation (eg. Previous BCG vaccination, suspected atypical
mycobacteriosis, eruptive events or other skin changes that contraindicate performing
intradermal reaction).
Despite the important results obtained with the test QTF-GIT in adults, studies of
specificity and sensitivity of the tests conducted in the pediatric age group are still
limited. Some studies have shown a high specificity, while the sensitivity appears lower
than the TST. The data are discordant, however, between the different studies, complicated
by the fact that there is no real-Gold standard for the diagnosis of latent TB, and hence,
further analysis is still needed.
While in adults the risk of progression from latent infection to active pulmonary disease is
about 5-10%, in infants (<1 year old) this value increases up to about 30-40%, therefore the
diagnosis and the treatment of latent infections is more than ever necessary to reduce the
risk of developing the disease. Thus an urgent need to identify specific and sensitive
diagnostic tools that would enable better diagnosis of TB in childhood, particularly in the
age group under 5 years, as clearly expressed also by the European Centre for Disease
Prevention and Control (ECDC) in guidelines "Use of Interferon-gamma release assays in
support of TB diagnosis" and by the resolution of the Regional Council of Tuscany Region n.
677 of 8.4.2014.
The aim of this project is to analyze the potential contribution of IGRA test,
QuantiFERON-TB Gold In Tube test (QTF-GIT, Cellestis Limited, Carnegie, Victoria, Australia)
in the diagnosis of tuberculosis (TB - active or latent) in pediatric subjects aged between
0 and 17 years recently exposed to infection (indicated as "contacts") or with clinical
suspicion of active TB, and to compare the results obtained with those of the TuberculinSkin
Test (TST), which is the gold standard. The research project is expected to enroll up to 50
pediatric patients (0- 17 years) over a 4-year study. Children with access to Ambulatory
structures or hospitalized at University Infectious Diseases Clinic or Pediatric Clinic,
University Hospital of Siena, or with access to Ambulatory or hospitalized at Pediatric
Clinic USL 9 Grosseto will be enrolled. Once obtained the informed consent of patients'
parents or legal guardians, patients will be enrolled. The doctor will administer a
clinical-anamnestic questionnaire (CRF), relative to the country of birth and residence,
date of arrival in Italy and any stays in the country of origin (in case of foreign
patient), travels abroad, risk factors for infectious diseases, type of contact with any
index case, previous vaccination with BCG, date and outcome of the TST, clinical symptoms
and signs suggestive of active TB, report of any instrumental investigation. Together with
the collection of blood samples for routine purposes, an additional blood sample will be
taken so to run experimental IGRA test. Also patients for whom their medical doctor will
independently order to run QTF-GIT test as necessary tool for the clinical diagnosis of TB
will be included in the study.
A retrospective analysis will be performed on patient pertaining to participant Clinics,
from 1 January 2012 to 31 May 2015. Such analysis will be performed on those patients for
which their medical doctor requested both intradermal Mantoux and IGRA test.
Main objectives:
1. Estimation of concordance between QuantiFERON-TB Gold In Tube and TST in pediatric
patients exposed to TB
2. Evaluation of the sensitivity of the test QTF-GIT in patients with active tuberculosis
disease
3. Evaluation of specificity of test QTF-GIT in not infected patients
Secondary objectives:
- Evaluation of the possible use of QTF-GIT, together with TST, to improve the diagnosis
of latent or active tuberculosis infection in pediatric subjects.
- Evaluation of the possible diagnostic use of QTF-GIT in the child, with special
attention to children <5 years.
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