Background:According to estimates, globally more than 200,000 pregnant women develop tuberculosis (TB) annually. Despite this, data on perinatal TB remain scarce. This study aimed to describe perinatal TB, comprising congenital (cTB) and postnatal (pTB) TB, in a European setting. Methods:Retrospective cohort study via the Paediatric Tuberculosis Network European Trials Group (ptbnet) capturing and comparing cases of cTB and pTB diagnosed at 104 participating European healthcare institutions between 1995 and 2019. Findings:Forty-six cases reported by 20 centres were included in the final analysis (cTB, n = 27; pTB, n = 19). Median age at symptom onset was one week in cTB (IQR: 0-1 weeks), and 12 weeks in pTB patients (IQR: 5-18 weeks). Prematurity was more common in cTB than pTB patients [57.9% (11/19); 95% CI: 36.3-76.9% vs. 21.1% (4/19); 95% CI: 8.5-43.3%; p = 0.049], and the average birth weight was significantly lower [1680 g; IQR: 932-2805 g vs. 2890 g; IQR: 2461-3400 g; p = 0.0043]. Microbiological confirmation was achieved in most patients [85.2% (23/27); 95% CI: 67.5-94.1% vs. 78.9% (15/19); 95% CI: 56.7-91.5%; p = 0.70]. The sensitivity of interferon-gamma release assays was poor in both groups [25.0% (3/12) 95% CI: 8.9-53.2% vs. 35.7% (5/14) 95% CI: 16.3-61.2%; p = 0.68]; in contrast, the sensitivity of the tuberculin skin tests (at 5 mm cut-off) was significantly higher in pTB patients [16.7% (2/12) 95% CI: 4.7-44.8% vs. 66.7% (10/15); 95% CI: 41.7-84.8%; p = 0.0185]. Approximately half of the patients required intensive care support [51.9% (14/27) 95% CI: 34.0-69.3% vs. 47.4% (9/19); 95% CI: 27.3-68.3%; p > 0.99]. Four (4/46; 8.7%) patients died, and four (4/46; 8.7%) had severe long-term sequelae. Interpretation:There was substantial mortality and morbidity in this patient cohort, despite the high-resource setting. cTB was associated with premature birth and low birth weight. In contrast to microbiological tests, immunological tests perform poorly in perinatal TB, and should therefore not be used as rule-out tests. Funding:No study-specific funding.

To the Editors: A 13-year-old boy of African descent presented with a 2-week history of progressively increasing right preauricular mass. The mass was associated with substantial pain upon mastication and nocturnal pain. Other symptoms were reduced appetite and 3-kg weight loss. Cough, fever and night sweats were not reported. Physical examination revealed slightly fluctuating swelling of the right temporomandibular joint (TMJ), in the absence of erythema, purulent discharge or facial nerve palsy. Biology showed microcytic anemia and inflammatory syndrome with high erythrocyte sedimentation rate. Medical history was unremarkable, and he tested negative for HIV. Computed tomography (CT)-scan of head and neck showed TMJ osteoarthritis and associated paratracheal lymph nodes, motivating the realization of a thoracic and mediastinal CT-scan. It revealed mediastinal necrotic lymph node as well as a parenchymal lesion (tree in bud) and a splenic lesion of 17 mm in diameter (Fig. 1).FIGURE 1.: A: Cervical CT-Scan: Partial destruction of the right condyle. B: Thoracic CT-Scan: Necrotic right-sided paratracheal, hilar and infracarinal lymph nodes and tree in bud lesion in the right upper lobe.At that time, tuberculosis (TB) disease was highly suspected, and after complete workup, classical quadrichemotherapy for TB was initiated. TB of the TMJ was confirmed by joint liquid as well as gastric lavage GeneXpert Mycobacterium tuberculosis-RIF and cultures. Culture-based first-line drug susceptibility testing revealed resistance to Pyrazinamide (PZA) only. Arthritis of the TMJ can have a traumatic, infectious, degenerative or inflammatory cause. Pain, swelling, limited movement and trismus’ sign are common findings. The clinical appearance of TB of the TMJ is nonspecific and may be similar to other etiologies.1 Diagnosis of osteoarticular TB in children is known to represent considerable diagnostic challenge due to nonspecific clinical manifestations and insidious disease course. Median diagnostic delay is several months. In addition, Mycobacterium tuberculosis smear and culture performance in children is poor.2 As osteoarticular TB usually involves the spine or large articulations, the diagnostic challenge was all the greater in this case, taking into account the rarity of TMJ involvement, with only a few cases reported in the literature. In our case, the stigmas of pulmonary TB on CT-scan, performed despite the absence of associated respiratory symptoms and signs, represented the key element pointing towards the diagnosis of TB in an early stage. In the pediatric population, destruction of the condyle results in mandibular growth disturbance and potential facial deformity; ankylosis may follow. The functional prognosis of the joint depends on the degree of destruction at the time of diagnosis and timing of treatment initiation, emphasizing the importance of early diagnosis.3 Finally, the patient’s African descent and the frequent ingestion of unpasteurized dairy products throughout his childhood, as well as the phenotypical monoresistance to PZA, were initially suggestive of Mycobacterium bovis as the causative agent. M. bovis intrinsic resistance to PZA is the consequence of a pcnA gene mutation but PZA monoresistance is not exclusive to M. bovis.4 This was illustrated by our case, as whole-genome sequencing was performed and detected wild-type Mycobacterium tuberculosis complex. Nevertheless, M. bovis should not be forgotten as a causative pathogen for osteoarticular TB, especially in the presence of PZA monoresistance.

Among the challenges in controlling tuberculosis, a rapid and accurate diagnostic test for the detection of Mycobacterium tuberculosis complex (MTBc) and its resistance to first line therapies is crucial. We evaluated the performance of the Xpert MTB/RIF Ultra assay (Xpert Ultra) for the rapid detection of MTBc and rifampicin resistance (RR) in 1120 pulmonary and 461 extra-pulmonary clinical specimens and compared it with conventional phenotypic techniques. The Xpert Ultra assay detected MTBc in 223 (14.1%) samples with an overall sensitivity and specificity, using culture as the "gold standard", of 91.1% (95% CI, 85.6-95.1) and 94.5% (95% CI, 93.1-95.6), respectively. The sensitivity of the Xpert Ultra test for smear-negative extra-pulmonary specimens was high (87.1%), even higher than with smear-negative pulmonary specimens (81.8%). But this enhanced sensitivity came with a low overall specificity of smear-negative extra-pulmonary specimens (66.7%). For 73 patients, 79/1423 (3.4%) negative mycobacterial culture samples were found to be positive with Xpert Ultra. Clinical data was necessary to correctly interpret potential false-positive results, especially trace-positive results. Sensitivity of the Xpert Ultra to detect RR compared to drug susceptibility testing was 100% (95% CI, 29.2-100) and specificity was 99.2% (95% CI, 95.8-100). We concluded that the Xpert Ultra test is able to provide a reliable TB diagnosis within a significantly shorter turnaround time than culture. This is especially true for paucibacillary samples such as smear-negative pulmonary specimens and extra-pulmonary specimens.

Introduction: Belgium is a country with low incidence of tuberculosis (TB) and a very low number of TB cases in children. Children in contact with an adult smear-positive TB case are at high risk of transmission. Early diagnosis is important as young children have a significant predisposition of developing TB disease. In this paper, we describe two outbreaks after exposure to, respectively, two teachers with smear-positive pulmonary TB: one in a primary school, a nursery teacher, and another in a private language school. Methods: An exposure investigation was carried out in both index cases household and school, according to the stone-in-the-pond principle. The tuberculin skin test (TST) was used a screening tool. The time elapsed between TB diagnosis in the index case and contact investigation was, respectively, 1 and 3 weeks. If this initial test was negative, it was repeated after a “window period” of ≥8 weeks. Results: Index cases showed a transmission rate of, respectively, 13 and 40% in their classes at school, defined as casual contacts. The proximity of contact increased the risk of infection. TB disease was observed in, respectively, 4 and 11% of all the casual contacts; all of them were children younger than 5 years old. TB-infected and children with active TB disease had good compliance with recommended treatment. Uptake of chemoprophylaxis during the “window period” was poor, respectively, only 32–42%, in children under 5 years with an initially negative TST. Discussion: The World Health Organization recommends to screen all young children (<5 years old) who have close contact with a person affected by pulmonary TB and to initiate Latent tuberculosis infection treatment even before infection can be demonstrated, after ruling out active TB disease. Despite this knowledge, a small percentage of the children younger than 5 years with no proof of infection was treated with the proposed chemoprophylactic treatment, in both cases. Conclusion: This exposure investigation of two teachers detects high transmission among family contacts and school casual contacts. Recommendations for chemoprophylactic treatment in children <5 years showed low compliance, reflecting the difficulty of communication to staff, parents, and children in a school outbreak. It is essential to develop a new approach for this vulnerable group of patients. This approach could be improved, applied, and evaluated by National TB Control Programs, involving public and private health services. Public health authorities play a role in raising public awareness about the risks of TB for young children.

A young child, 19 months of age, presented with a second episode of tuberculosis after full recovery from initial tuberculosis disease 6 months earlier. Mycobacterium tuberculosis strains isolated from both episodes were genotyped and differed from one another. We present the first case of proven tuberculosis reinfection in a likely immunocompetent child, living in a high-risk environment favorable for exposition to M. tuberculosis but in a low-incidence country.

Background: Improved diagnostic tests are needed for the early identification of Mycobacterium tuberculosis-infected young children exposed to an active TB (aTB) index case. We aimed to compare the diagnostic accuracy of new blood-based tests to that of the tuberculin skin test (TST) for the identification of all infected children and for a potential differentiation between aTB and latent TB infection (LTBI). Methods: 144 children exposed to a patient with aTB were included, and those who met all inclusion criteria (130/144) were classified in three groups based on results from classical investigations: non-infected (NI: n = 69, 53%, median age 10 months), LTBI (n = 28, 22%, median age 96 months), aTB disease (n = 33, 25%, median age 24 months). The first whole blood assay consisted of a 7-days in vitro stimulation of blood with four different mycobacterial antigens (40 μl/condition), followed by flow cytometric measurement of the proportions of blast cells appearing among lymphocytes as a result of their specific activation. Thresholds of positivity were determined by Receiver Operating Characteristic (ROC) curve analysis (results of NI children vs. children with LTBI/aTB) in order to identify infected children in a first stage. Other cut-offs were determined to discriminate subgroups of infected children in a second step (results from children with aTB/LTBI). Analysis of blood monocytes and dendritic cell subsets was performed on 100 μl of blood for 25 of these children as a second test in a pilot study. Results: Combining the results of the blast-induced CD3+ T lymphocytes by Heparin-Binding Haemagglutinin and by Culture Filtrate Protein-10 identified all but one infected children (sensitivity 98.2% and specificity 86.9%, compared to 93.4 and 100% for the TST). Further identification among infected children of those with aTB was best achieved by the results of blast-induced CD8+ T lymphocytes by purified protein derivative (sensitivity for localized aTB: 61.9%, specificity 96.3%), whereas high proportions of blood type 2 myeloid dendritic cells (mDC) were a hallmark of LTBI. Conclusions: New blood-based tests requiring a very small volume allow the accurate identification of M. tuberculosis-infected young children among exposed children and are promising to guide the clinical classification of children with aTB or LTBI.

Introduction: Interferon Gamma Release Assay (IGRA) has proven to be a useful test to evaluate the immune response to Mycobacterium tuberculosis antigens in children over the age of 5 years as an alternative to tuberculin skin testing (TST). Much less is known about its performance in younger children, who are at higher risk for developing tuberculosis (TB) disease after exposure. We aimed to evaluate the accuracy of using IGRA in TB screening in this population. Methods: Children below the age of 5 years at high risk for TB infection were prospectively enrolled, to compare the performance of TST and the QuantiFERON-TB Gold-In-Tube test (QFT). Children were treated in accordance with the diagnosis made at baseline and followed-up for 12 months. Results: We included a total of 60 children of which 97 blood samples were available for analysis. There was 90.72% agreement between TST and QFT (Kappa test 0.59, moderate agreement). With TST as a reference, the QFT positive predictive value was 0.72 and the negative predictive value 0.93. Discordant results were observed with 6% TST+/QFT- paired tests. When we restricted the comparison of TST and QFT to non-BCG-vaccinated children, the degree of agreement was more substantial (95%, Kappa test 0.75) and the negative predictive value was 0.99. We observed 3% discordant TST-/QFT+ results. All children with active TB disease had concordant positive QFT results, with QFT values above 4.00 IU/ml. Conclusion: In a low TB prevalence country, serial testing of QFT was found to produce a moderate agreement with TST results. False positive QFT results would have been eliminated by using a higher cutoff without misdiagnosing the children with TB disease. Some of the false negative QFT results could be explained by false positive TST results on consecutive testing. For now the most prudent approach would be to consider discordant QFT-/TST+ results as false negative QFT results, taking into account the young age of our population and the potential risk for evolution to active TB disease.

Background: Multidrug-resistant (MDR) tuberculosis (TB) treatment requires long and potentially toxic drug regimens. In children, TB is hampered by sampling difficulties and few studies report data on MDR-TB in low incidence countries. Aim: We describe the epidemiology, clinical presentation and outcome of pediatric MDR-TB in Belgium. Methods: This retrospective multicentric study included all children ≤15 years with confirmed MDR-TB in Belgium from 2001 to 2016. Patients were identified from a national database (BELTA-TBnet registry) and data were abstracted retrospectively from medical records. Results: Out of 249 cases of MDR-TB recorded in Belgium, 9 were children (3,6%), representing 0,8% of belgian pediatric TB diseases. Median age at diagnosis was 6,6 years (range 1,3-14,6). There were 5 boys and 4 girls. All children had a foreign origin and no child was infected with HIV. Three children (30%) had a history of treated TB and one a history of MDR contact. Five patients presented with pulmonary and 4 with extrapulmonary disease (miliary, meningitis, sub-cutaneous and osteoarticular TB). The oldest patient had an extensively drug-resistant (XDR) strain and a 18 months-old child a pre-XDR one. Patients were treated with different 2nd-line medications according to available guidelines and individual DST results. One child (11% of this group) died from TB meningitis with massive intracranial haemorrhage. Out of 8 children who completed treatment, 5 children (62.5%) who received aminoglycosides developed sensorineural hearing loss and one (12.5%) a peripheral neuropathy. Conclusion: MDR-TB is a rare condition in children in Belgium and treatment is associated with high rates of adverse reactions.

Background: Paradoxical reaction (PR) during antituberculosis (TB) therapy, defined as clinical or radiologic worsening of preexisting TB lesions or the development of new lesions, has not been widely studied in immunocompetent children.Methods: All children (<17 years) with the diagnosis of TB who sought care at our center between 1994 and 2007 were included in this retrospective study. Data on demographic characteristics, bacteriologic results, medical imaging, treatment regimens and outcomes were abstracted from medical records. Patients with and without PR were compared.Results: Of 115 TB cases, 12 (10.3%) developed PR. Children with PR were younger than those with TB without complication: median age at diagnosis was 26 months (range, 5-148) compared with 66 months (range, 6-205) for those without complications (P = 0.013). None of the children in the PR group had received Calmette-Guerin bacillus vaccination, compared with 34 of 103 (33%) children without PR (P = 0.017). Children with a diagnosis of PR were more frequently symptomatic at diagnosis of TB disease when compared with children without PR (P = 0.028). PR occurred at a median interval of 39 days (range, 15-75) after initiation of antituberculosis treatment. The most common PR was worsening of preexisting pulmonary lesions (75%). New lesions in anatomical sites other than those observed at initial presentation developed in 3 children.Conclusion: Paradoxical deterioration during treatment of TB disease is common in immunocompetent children. Young age and absence of Calmette-Guerin bacillus vaccination appeared to be associated with PR.

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacteriumtuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.

Treatment with paromomycin (25–35 mg/kg/d for 7 days) was evaluated prospectively in 15 children with Dientamoeba fragilis infection after 1-month follow-up. At the end of the study, parasitologic effectiveness and clinical improvement were observed in 12/15 (80%) and 13/15 (87%) patients, respectively. Paromomycin appears to be an effective drug for treatment of D. fragilis infection in children.

Despite absence of clear proof of efficacy, the use of inhaled corticosteroids (ICS) is widespread in cystic fibrosis (CF) patients. Therefore, the effect of ICS on lung function and other clinical variables was studied in 27 prepubertal CF children with mild to moderate lung disease. In a prospective double-blind case-controlled study, fluticasone propionate 500 μg or placebo were administered twice daily during 12 months. The mean (standard error of the mean, SEM) patient age was 8.2 (0.6) years in the placebo group and 9.0 (0.5) years in the fluticasone group. The mean (SEM) forced expiratory volume in 1 s (FEV1) was 91% (4%) in the placebo group and 86% (4%) in the fluticasone group. There was no statistically significant difference in the evolution of lung function and the number of respiratory exacerbations between groups. However, longitudinal growth in fluticasone patients was significantly slower than in placebo patients: 3.96 (0.29) cm versus 5.49 (0.38) cm [p<0.005, analysis of variance (ANOVA)] over the 12-month study duration. This resulted in a significant change in height standard deviation score (SDS) of –0.38 (0.09) in the fluticasone group versus –0.01 (0.07) in the placebo group (p<0.003, ANOVA). No catch-up growth was noted 1–2 years after discontinuation of inhaled steroids. The use of high-dose ICS in CF patients with mild lung disease may lead to persistent growth impairment.

OBJECTIVE: To assess the extent of nosocomial transmission of tuberculosis among infants, family members, and healthcare workers (HCWs) who were exposed to a 29-week-old premature infant with congenital tuberculosis, diagnosed at 102 days of age.DESIGN: A prospective exposure investigation using tuberculin skin test (TST) conversion was conducted. Contacts underwent two skin tests 10 to 12 weeks apart. Clinical examination and chest radiographs were performed to rule out disease. Isoniazid prophylaxis was administered to exposed infants at higher risk.SETTING: A neonatal intensive care unit in an urban hospital in Brussels, Belgium.PARTICIPANTS: Ninety-seven infants, 139 HCWs, and 180 visitors.RESULTS: Newly positive TST results occurred in HCWs who had been in close contact with the infant. Six (19%) of 32 primary care nurses and physicians had TST conversions and received treatment. Among the 97 exposed infants, 85 were screened and 34 were identified as at higher risk of infection. Of these, 27 received preventive isoniazid. None of the infants and none of the 93 other infants' family members evaluated were infected.CONCLUSIONS: Congenital tuberculosis in an infant poses a risk for nosocomial transmission to HCWs. Delayed diagnosis of this rare disease and close proximity are the most important factors related to transmission.