Barbara Maria Bergamini

Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study

BACKGROUND Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. METHODS We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. FINDINGS Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p<0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p<0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p<0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). INTERPRETATION T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.

Performance of commercial blood tests for the diagnosis of latent tuberculosis infection in children and adolescents

BACKGROUND. The accurate diagnosis of latent tuberculosis infection reduces the risk of progression to severe disseminated disease. However, in young children, a major limitation of the standard tuberculin skin test is that false-negative results cannot be detected. The new interferon-γ release assays QuantiFERON-TB Gold (Cellestis Carnegie Victoria, Australia), QuantiFERON-TB In-Tube (Cellestis), and T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) show promise of greater accuracy, but they may also be affected by impaired cellular immunity, resulting in indeterminate results (ie, insufficient response in positive-control wells). OBJECTIVE. To evaluate the impact of age on the performance of interferon-γ release assays when used in a routine hospital setting among children tested for suspected active or latent TB infection. METHODS. We retrospectively studied 496 children 0 to 19 years of age who had been tested with the tuberculin skin test and at least 1 interferon-γ release assay: 181 with QuantiFERON-TB Gold and 315 with QuantiFERON-TB In-Tube. In 154 of the children, paired interferon-γ release assay testing was available: 87 with QuantiFERON-TB Gold/T-SPOT.TB and 67 with QuantiFERON-TB In-Tube/T-SPOT.TB. RESULTS. Compared with T-SPOT.TB, the rates of indeterminate results were significantly higher for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. QuantiFERON-TB Gold and QuantiFERON-TB In-Tube also gave indeterminate results more frequently in children <4 years of age than in those ≥4 years of age. Indeterminate results were associated with younger age for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube but not for T-SPOT.TB. Considering age as a binary variable (<4 and ≥4 years of age), a significantly higher concentration of phytohaemagglutinin-produced interferon-γ was observed in older children with both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. CONCLUSIONS. Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children <4 years of age.

T-cell-based diagnosis of neonatal multidrug-resistant latent tuberculosis infection.

Young children exposed to tuberculosis have a high risk of progression to severe tuberculosis disease, but diagnosis of recent infection is hindered by the poor sensitivity of the tuberculin skin test. Whether new blood tests can detect latent infection in this vulnerable group is unknown because there is no gold standard. We monitored a tuberculin skin test–negative infant whose mother had infectious multidrug-resistant tuberculosis with enzyme-linked immunospot, a blood test that enumerates Mycobacterium tuberculosis–specific T cells. The enzyme-linked immunospot test became persistently positive by 6 months, and 18 months later the child developed active tuberculosis despite appropriate chemoprophylaxis. At this point, the magnitude of the enzyme-linked immunospot response increased >10-fold. Our findings demonstrate that this blood test detected latent infection with dormant, yet viable, bacilli and illustrate how enzyme-linked immunospot could improve diagnosis of childhood tuberculosis infection.

Performance of interferon-γ release assay for the diagnosis of active or latent tuberculosis in children in the first 2 years of age: a multicenter study of the Italian Society of Pediatric Infectious Diseases.

Background: The diagnosis of latent or active tuberculosis in children is often challenging. Recently, interferon-&ggr; release assays have been licensed, but their diagnostic accuracy in young children remains questionable as frequent false-negative or indeterminate results have been reported. Methods: We performed a multicenter, retrospective study in children 0–24 months of age who were tested at least once with QuantiFERON-TB Gold-in-tube (QTF-IT) ± tuberculin skin test (TST), to analyze its use and performance in clinical practice. Results: Eight-hundred and twenty-three children (449 males, median age 13.5 months) were enrolled. QTF-IT sensitivity and specificity for active tuberculosis were 92.4% and 98.6%, respectively. Indeterminate tests (4.2 %) were not related to age (P = 0.838) or gender (P = 0.223); 32 children (91.4 %) with an indeterminate QTF-IT ultimately resulted uninfected. In the 616 subjects with valid paired results of QTF-IT and TST, sensitivity and specificity were comparable (91.1% vs. 85.1% and 98.1% vs. 97.9%, respectively). Diagnostic concordance between tests was higher in Bacillus Calmétte-Guerin nonvaccinated children (&kgr; = 0.802). A high rate of discordant tests was observed in latent infections. Conclusions: QTF-IT showed good sensitivity and specificity, and a low rate of indeterminate results in the first 2 years of life, supporting its use at this age. However, considering costs and the similar performance between QTF-IT and TST, it is reasonable to suggest the latter as first-line testing in young children. The complementary use of TST and interferon-&ggr; release assays may be considered in selected cases to improve the accuracy of testing.

Prior tuberculin skin testing does not boost QuantiFERON-TB results in paediatric contacts

To the Editors: We read with interest the paper by Leyten et al. 1, which appeared in the June 2007 issue of the European Respiratory Journal ( ERJ ). Leyten et al. 1 showed that prior tuberculin skin tests (TST) do not induce false-positive QuantiFERON®-TB Gold in-tube (QFT-GIT) assay results when evaluated in the days immediately following TST administration. In the same issue of the ERJ , Naseer et al. 2 reported the results of a study of 10 subjects without risk for tuberculosis infection, who were tested with QFT-GIT and the T-SPOT. TB assay (Oxford Immunotec, Abingdon, UK) before, 48 h and 6 weeks after TST administration. Naseer et al. 2 confirmed the results of Leyten et al. 1 in the first days following skin testing; however, after 6 weeks, three out of nine individuals turned from negative to positive with QFT-GIT, and none of the subjects turned from negative to positive with T-SPOT. TB . On this basis, Naseer …

Alternaria spores at different heights from the ground

Background:  Alternaria tenuis (Alt) is one of the main allergens in pediatric age. In temperate climates, airborne Alt spores are detectable from May to November with peaks in late summer and autumn. Sensitized children display symptoms even in the absence of airborne Alt spores. Alt spore concentration, as well as pollen, is usually detected by fixed devices located on the roof of a building at a height of 10–20 m. The aim of the current study is to find out whether ground‐level (50 cm) Alt spore concentrations are different from those at roof‐top level, even during low‐concentration periods.

Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children

Erdosteine has positive effects on mucus rheology and transport due to the active metabolite (Metabolite I) which contains a free thiol group. Erdosteine inhibits bacterial adhesiveness and has antioxidant properties. A synergistic effect of erdosteine with various antibiotics has been demonstrated in pharmacological and clinical studies. The present study was multicenter, randomized, double-blind and placebo-controlled. The aims of the study were to compare a combination of erdosteine with amoxicillin against an amoxicillin-placebo combination in pediatric patients with acute lower respiratory tract disease. A total of 158 patients (78 in the erdosteine group and 80 in the placebo group) were treated for 7 +/- 2 days. The efficacy parameters were cough (primary), polypnea, rhonchi, rales and body temperature (all measured at baseline, on Day 3 and at the end of treatment). Safety was assessed by strictly monitoring the occurrence of adverse events and using standard laboratory parameters. The results of the intention-to-treat analysis showed that the severity of cough was decreased by 47% at Day 3 in the erdosteine group with a statistically significant difference compared to placebo, the difference was still significant at the final visit. The decrease in the severity of rales was significantly greater at Day 3 in the erdosteine group than in the placebo group. The incidence of polypnea and rhonchi in the two groups showed similar decreases, an improvement mainly due to the antibiotic. No adverse events occurred and no adverse changes in laboratory parameters were observed. It is concluded that the combination of erdosteine and amoxicillin is a safe medication which is clinically superior to that of the antibiotic combined with placebo, especially in regard to the effects on cough.

Pediatric Tuberculosis in Italian Children: Epidemiological and Clinical Data from the Italian Register of Pediatric Tuberculosis

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries.

Tracheobronchial anomalies in chromosome 22q11.2 microdeletion

The 22q11.2 microdeletion syndrome consists of several manifestations including congenital heart defects (CHD), velopharyngeal insufficiency, cleft palate, thymus aplasia-hypoplasia, craniofacial anomalies, and hypoparathyroidism. These phenotypic features can occur in many combinations, and the clinical spectrum varies greatly in severity, ranging from life-threatening problems to hypernasal speech [Ryan et al., 1997]. Phenotypic variability is a striking aspect of the 22q11.2 microdeletion and to date the basis of it remains unclear [Yamagishi, 2002]. The 22q11.2 deletion syndrome encompasses the DiGeorge anomaly (DGA), velocardiofacial (VCFS) and conotruncal anomaly face syndromes (CAFS). In addition to the main clinical features several other defects have been reported with the syndrome, including learning difficulties and psychiatric disorders, eye defects, renal and urological anomalies [Wilson et al., 1993; Devriendt et al., 1996; Hong, 1998; Scambler, 2000]. The 22q11.2 microdeletion syndrome, with an incidence of 1/4,000 live births, is the most frequent interstitial deletion known in humans [Scambler, 2000]. Most of 22q11.2 microdeletions are due to ‘‘de novo’’ mutations while from 12% up to 28% are inherited [Rayan et al., 1997; Vantrappen et al., 1999]. It is suggested that it represents a ‘‘contiguous gene syndrome’’ in which many genes can be lost in several more or less visible deletions [Hall, 1993]. Isolated cases of DGA with no microdeletion (12%) may be ascribed to epigenetic factors such as alcohol or retinoic acid ingestion during pregnancy and maternal diabetes [Driscoll et al., 1993]. Structures primarily affected in 22q11.2 patients are derivatives of pharyngeal arches, pharyngeal arch arteries, and the conotruncal region of the heart (craniofacial features, thyroid, parathyroid, thymus, aortic arch, andheart outflow tract). Neural crest cells migrate in these regions during the 4th week of embryogenesis and constitute, along with paraxial mesoderm, the mesenchyme of these complex embryonic structures. Experiments of neural crest ablation on chick embryos and other animal models have shown that failure in migration/survival/differentiation of neural crest derived cells or imperfect epithelial–mesenchymal interaction in the development of pharyngeal arches, generate phenocopies of 22q11.2 deletion syndrome [Bockman et al., 1987; Frank et al., 2002; Hutson and Kirby, 2003]. Recent research found that genes mapping in the human DGA-critical region are expected to play an important function in controlling the development of neural crest derived cells or in their interaction with endodermal or mesodermal cells in the branchial arch system [Yamagishi, 2002]. In this report we describe a child who showed both 22q11.2 deletion syndrome features and two supernumerary tracheal bronchi. Bronchial branching anomalies are uncommon findings, mainly represented by supernumerary tracheal bronchus (STB) and displaced tracheal bronchus, whereas bridging bronchus, supernumerary esophageal bronchus and esophageal lung are more exceptional observations [Evans, 1990]. STB is defined as an adjunctive bronchus that originates from the tracheal lateral wall (segmentary), mostly on the right, or from the main bronchus (subsegmentary), and directs to the ipsilateral upper lobe territory [Ghaye et al., 2001]. A causal connection between 22q11.2 microdeletion and STB is plausible on the basis of the timing of embryo development. In fact the respiratory system