Rationale: The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis–specific CD8+ T cells are generated in response to high bacillary loads occurring during tuberculosis. Objectives: To determine if M. tuberculosis–specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. Methods: Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis–specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8+ T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). Measurements and Main Results: The proportion of positive CD8+ T-cell assays and magnitude of CD8+ T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis–specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. Conclusions: Among young children, M. tuberculosis–specific CD8+ T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ–producing M. tuberculosis–specific CD8+ T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease.

The management of childhood tuberculosis (TB) is hampered by the low sensitivity and limited accessibility of microbiological testing. Optimizing clinical approaches is therefore critical to close the persistent gaps in TB case detection and prevention necessary to realize the child mortality targets of the End TB Strategy. In this review, we provide practical guidance summarizing the evidence and guidelines describing the use of symptoms and signs in decision making for children being evaluated for either TB preventive treatment (TPT) or TB disease treatment in high-TB incidence settings. Among at-risk children being evaluated for TPT, a symptom screen may be used to differentiate children who require further investigation for TB disease before receiving TPT. For symptomatic children being investigated for TB disease, an algorithmic approach can inform which children should receive TB treatment, even in the absence of imaging or microbiological confirmation. Though clinical approaches have limitations in accuracy, they are readily available and can provide valuable guidance for decision making in resource-limited settings to increase treatment access. We discuss the trade-offs in using them to make TB treatment decisions.

Neonatal CD4⁺ T cells have traditionally been viewed as deficient in their capacity to produce Th1 cytokines in response to polyclonal or Ag-specific stimuli. Thus, defining unique aspects of CD4⁺ T cell activation and development into Th1 effector cells in neonates is essential to the successful development of novel vaccines and immunotherapies to protect infants from intracellular pathogens. Using highly purified naive CD4⁺ T cells derived from cord and adult peripheral blood, we compared the impact of anti-CD3 stimulation plus costimulation through TLR-2 performed in the absence of APC on CD4⁺ T cell cytokine production, proliferation, and expression of activation markers. In both age groups, TLR-2 costimulation elicited activation of naive CD4⁺ T cells, characterized by robust production of IL-2 as well as key Th1-type cytokines IFN-γ and TNF-α. TLR-2 costimulation also dramatically reduced naive T cell production of the immunosuppressive cytokine IL-10. We observed that neonatal naive CD4⁺ T cells are uniquely sensitive to TLR-2–mediated costimulation, which enabled them to produce equivalent amounts of IFN-γ and more IL-2 when compared with adult responses. Thus, neonatal CD4⁺ T cells have a distinctive propensity to use TLR-2–mediated costimulation for development into proinflammatory Th1 effectors, and interventions that target CD4⁺ T cell TLR-2–mediated responses may be exploited to enhance neonatal adaptive immunity.

Background and objectives: Severe pneumonia is the leading cause of death among young children worldwide, disproportionately impacting children who lack access to advanced diagnostic imaging. Here our objectives were to develop and test the accuracy of an artificial intelligence algorithm for detecting features of pulmonary consolidation on point-of-care lung ultrasounds among hospitalized children. Methods: This was a prospective, multicenter center study conducted at academic Emergency Department and Pediatric inpatient or intensive care units between 2018–2020. Pediatric participants from 18 months to 17 years old with suspicion of lower respiratory tract infection were enrolled. Bedside lung ultrasounds were performed using a Philips handheld Lumify C5-2 transducer and standardized protocol to collect video loops from twelve lung zones, and lung features at both the video and frame levels annotated. Data from both affected and unaffected lung fields were split at the participant level into training, tuning, and holdout sets used to train, tune hyperparameters, and test an algorithm for detection of consolidation features. Data collected from adults with lower respiratory tract disease were added to enrich the training set. Algorithm performance at the video level to detect consolidation on lung ultrasound was determined using reference standard diagnosis of positive or negative pneumonia derived from clinical data. Results: Data from 107 pediatric participants yielded 117 unique exams and contributed 604 positive and 589 negative videos for consolidation that were utilized for the algorithm development process. Overall accuracy for the model for identification and localization of consolidation was 88.5%, with sensitivity 88%, specificity 89%, positive predictive value 89%, and negative predictive value 87%. Conclusions: Our algorithm demonstrated high accuracy for identification of consolidation features on pediatric chest ultrasound in children with pneumonia. Automated diagnostic support on an ultraportable point-of-care device has important implications for global health, particularly in austere settings.

Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters. TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.