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.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). The patients’ susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2–4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.

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.

Tuberculosis (TB) in young children differs from adult TB in that the risk of rapid progression to active TB (aTB) is higher in children than in adults. The reasons for this increased risk are not fully understood. Early differentiation remains difficult between children at risk to develop aTB from those who will remain healthy and develop a latent TB infection (LTBI). Biomarkers to differentiate aTB from LTBI in children, especially in very young children, are urgently needed. To identify M. tuberculosis-specific functional T cell subsets related to clinical manifestations in children, we enrolled 87 children exposed to M. tuberculosis. After standard clinical assessment, the children were classified as aTB, LTBI, or uninfected. Their CD4+ T cell cytokine profiles (IFN-γ, TNF-α, IL-2, IL-17) were analyzed at the single-cell level by flow cytometry after stimulation with three mycobacterial antigens, purified protein derivative (PPD), early-secreted-antigenic target-6 (ESAT-6), or heparin-binding hemagglutinin (HBHA). This approach identified age-related discriminative markers between aTB and LTBI. Whereas among the 3- to 15-year-old children, an excellent discrimination between aTB and LTBI was provided by comparing the ratio between the proportions of ESAT-6-induced IFN-γsingle+ and ESAT-6-induced TNF-αsingle+CD4+ T lymphocytes, this was not the case for children younger than 3 years. By contrast, in this group (<3years), the analysis of HBHA-induced IL-17single+CD4+ T lymphocytes allowed us to identify children with LTBI by the high proportion of this cellular lymphocyte subset, whereas this was not the case for children with aTB. The analysis at the single-cell level of T cell immune responses induced by mycobacterial antigens are, thus, different in infected children younger or older than 3 years of age. HBHA-induced IL-17 production by CD4+ T lymphocytes was associated with protection only in children under 3 years who are at high risk for rapid progression to aTB. This suggests that the HBHA-induced IL-17 production by CD4+ T lymphocytes is a potential new correlate of protection against M. tuberculosis in humans, and that the distinction between children with LTBI and those with aTB is possible based on age-related diagnostic markers.

Young children with persistent wheezing pose a diagnostic and therapeutical challenge to the pediatrician.