Tuberculosis Case Detection and Guideline Adherence among Child Contacts in Switzerland: A Retrospective Observational Study.

BACKGROUND: Children exposed to a tuberculosis (TB) index case are at risk of TB infection and disease. OBJECTIVES: The aim of this study was to describe the proportion of child contacts who developed TB infection or disease after exposure and to assess the diagnostic pathways and adherence to current guidelines. METHODS: Retrospective observational study including children ≤16 years of age who had contact to a TB index case between January 2019 and July 2021. Analysis was stratified by age groups 0-4, 5-11, and 12-16 years. RESULTS: Of 401 TB-exposed children, data were available for 380 (95%). Of those, 7 (2%) were diagnosed with TB disease and 35 (9%) with TB infection. We identified several deviations in the management compared to recommendations in national Swiss guidelines: In the children aged 0-4 years, only 82% were examined with an immunodiagnostic test or a chest radiography within 2 weeks after last contact. Recommended prophylactic treatment was prescribed in 66% of the children only. In the children aged 5-11 years, 64% were tested with an immunodiagnostic test in a first examination and 75% in a second examination, 2 weeks and 2 months after last contact, respectively. CONCLUSIONS: Contact investigations of children exposed to a TB index case identified a significant proportion of children with TB infection and disease in a low TB incidence setting. We observed significant deviations from the guidelines in the contact investigations suggesting the need for improved implementation.

Monocyte, Lymphocyte and Neutrophil Ratios - Easy-to-Use Biomarkers for the Diagnosis of Pediatric Tuberculosis.

BACKGROUND: The neutrophil-to-lymphocyte-ratio (NLR), neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) and monocyte-to-lymphocyte-ratio (MLR) may have diagnostic potential for tuberculosis (TB). METHODS: Data of two prospective multicenter studies in Switzerland were used, which included children <18 years with TB exposure, infection or disease or with febrile non-TB lower-respiratory-tract infection (nTB-LRTI). RESULTS: Of the 389 children included 25 (6.4%) had TB disease, 12 (3.1%) TB infection, 28 (7.2%) were healthy TB exposed and 324 (83.3%) nTB-LRTI. Median (IQR) NLR was highest with 2.0 (1.2, 2.2) in children with TB disease compared to TB exposed [0.8 (0.6, 1.3); P = 0.002] and nTB-LRTI [0.3 (0.1, 1.0); P < 0.001]. Median (IQR) NMLR was highest with 1.4 (1.2, 1.7) in children with TB disease compared to healthy exposed [0.7 (0.6, 1.1); P = 0.003] and children with nTB-LRTI [0.2 (0.1, 0.6); P < 0.001). Receiver operating characteristic curves to detect TB disease compared to nTB-LRTI for NLR and NMLR had an area under the curve of 0.82 and 0.86, the sensitivity of 88% and 88%, and specificity of 71% and 76%, respectively. CONCLUSION: NLR and NMLR are promising, easy-to-obtain diagnostic biomarkers to differentiate children with TB disease from other lower respiratory tract infections. These results require validation in a larger study and in settings with high and low TB endemicity.

Malaria in Refugee Children Resettled to a Holoendemic Area of Sub-Saharan Africa.

BACKGROUND: Malaria is a leading cause of morbidity and mortality in refugee children in high-transmission parts of Africa. Characterizing the clinical features of malaria in refugees can inform approaches to reduce its burden. METHODS: The study was conducted in a high-transmission region of northern Zambia hosting Congolese refugees. We analyzed surveillance data and hospital records of children with severe malaria from refugee and local sites using multivariable regression models and geospatial visualization. RESULTS: Malaria prevalence in the refugee settlement was similar to the highest burden areas in the district, consistent with the local ecology and leading to frequent rapid diagnostic test stockouts. We identified 2197 children hospitalized for severe malaria during the refugee crisis in 2017 and 2018. Refugee children referred from a refugee transit center (n = 63) experienced similar in-hospital mortality to local children and presented with less advanced infection. However, refugee children from a permanent refugee settlement (n = 110) had more than double the mortality of local children (P < .001), had lower referral rates, and presented more frequently with advanced infection and malnutrition. Distance from the hospital was an important mediator of the association between refugee status and mortality but did not account for all of the increased risk. CONCLUSIONS: Malaria outcomes were more favorable in refugee children referred from a highly outfitted refugee transit center than those referred later from a permanent refugee settlement. Refugee children experienced higher in-hospital malaria mortality due in part to delayed presentation and higher rates of malnutrition. Interventions tailored to the refugee context are required to ensure capacity for rapid diagnosis and referral to reduce malaria mortality.

Performance of QuantiFERON-TB Gold Plus assays in paediatric tuberculosis: a multicentre PTBNET study.

RATIONALE: In 2016, a new interferon-gamma release assay (IGRA) was introduced, QuantiFERON-TB Gold Plus (QFT-Plus), claimed to have improved sensitivity in active tuberculosis (TB). OBJECTIVES: This study aimed to determine the performance of QFT-Plus, compared with previous generation IGRAs and the tuberculin skin test (TST), in children with TB in Europe. METHODS: Multicentre, ambispective cohort study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), a dedicated paediatric TB research network comprising >300 members, capturing TB cases <18 years-of-age diagnosed between January 2009 and December 2019. MEASUREMENTS AND MAIN RESULTS: 1001 TB cases from 16 countries were included (mean age (IQR) 5.6 (2.4-12.1) years). QFT-Plus was performed in 358, QFT Gold in-Tube (QFT-GIT) in 600, T-SPOT.TB in 58 and TST in 636 cases. The overall test sensitivities were: QFT-Plus 83.8% (95% CI 80.2% to 87.8%), QFT-GIT 85.5% (95% CI 82.7% to 88.3%), T-SPOT.TB 77.6% (95% CI 66.9% to 88.3%) and TST (cut-off ≥10 mm) 83.3% (95% CI 83.3% to 86.2%). There was a trend for tests to have lower sensitivity in patients with miliary and/or central nervous system (CNS) TB (73.1%, 70.9%, 63.6% and 43.5%, respectively), and in immunocompromised patients (75.0%, 59.6%, 45.5% and 59.1%, respectively). CONCLUSIONS: The results indicate that the latest generation IGRA assay, QFT-Plus, does not perform better than previous generation IGRAs or the TST in children with TB disease. Overall, tests performed worse in CNS and miliary TB, and in immunocompromised children. None of the tests evaluated had sufficiently high sensitivity to be used as a rule-out test in children with suspected TB.

Associations between salivary cytokines and oral health, age, and sex in healthy children.

Human saliva is a complex fluid containing proteins such as salivary cytokines, which can be used for diagnostic purposes, particularly among the pediatric population. This study aimed to assess the concentrations of salivary cytokines in healthy children and adolescents and determine their associations with age, sex, and oral and dental findings. Healthy children and adolescents aged 4-18 years were enrolled in this cross-sectional study. The concentrations of the following salivary cytokines were measured by Luminex technology: IFN-γ, IL-1α, IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IP-10, TNF-α, and VEGF-A. Additionally, oral and dental parameters were recorded using a standardized protocol. A total of 128 participants (mean age, 10.7 years; males, 50.8%) were enrolled. The levels of 1ß, IL-6, IL-8, and IL-10 were significantly higher in those with gingivitis. Increased salivary flow rates were negatively correlated with IL-1α, IL-1ß, IL-6, IL-8, IL-10, TNF-α, and VEGF-A concentrations. The findings of this study showed that the concentrations of most of the salivary cytokines were positively correlated with age and the presence of oral pathologies (such as gingivitis and caries) and negatively correlated with salivary flow rate.

Towards Accurate Point-of-Care Tests for Tuberculosis in Children.

In childhood tuberculosis (TB), with an estimated 69% of missed cases in children under 5 years of age, the case detection gap is larger than in other age groups, mainly due to its paucibacillary nature and children's difficulties in delivering sputum specimens. Accurate and accessible point-of-care tests (POCTs) are needed to detect TB disease in children and, in turn, reduce TB-related morbidity and mortality in this vulnerable population. In recent years, several POCTs for TB have been developed. These include new tools to improve the detection of TB in respiratory and gastric samples, such as molecular detection of Mycobacterium tuberculosis using loop-mediated isothermal amplification (LAMP) and portable polymerase chain reaction (PCR)-based GeneXpert. In addition, the urine-based detection of lipoarabinomannan (LAM), as well as imaging modalities through point-of-care ultrasonography (POCUS), are currently the POCTs in use. Further to this, artificial intelligence-based interpretation of ultrasound imaging and radiography is now integrated into computer-aided detection products. In the future, portable radiography may become more widely available, and robotics-supported ultrasound imaging is currently being trialed. Finally, novel blood-based tests evaluating the immune response using "omic-"techniques are underway. This approach, including transcriptomics, metabolomic, proteomics, lipidomics and genomics, is still distant from being translated into POCT formats, but the digital development may rapidly enhance innovation in this field. Despite these significant advances, TB-POCT development and implementation remains challenged by the lack of standard ways to access non-sputum-based samples, the need to differentiate TB infection from disease and to gain acceptance for novel testing strategies specific to the conditions and settings of use.

Bacillus Calmette-Guérin Skin Reaction Predicts Enhanced Mycobacteria-Specific T-Cell Responses in Infants: A Post Hoc Analysis of a Randomized Controlled Trial.

Rationale: Scar formation following bacillus Calmette-Guérin (BCG) vaccination has been associated with lower all-cause mortality; the relation between scar and mycobacteria-specific protection against tuberculosis is debated. Objectives: To evaluate the association between BCG skin reaction and mycobacteria-specific immune responses. Methods: A post hoc analysis was done among 214 infants in Australia randomized to vaccination with one of three BCG vaccine strains (BCG-Denmark, BCG-Japan, or BCG-Russia) given at birth or BCG-Denmark given at 2 months of age. Measurements and Main Results: BCG skin reaction size and characteristics 10 weeks after vaccination were related to the in vitro mycobacteria-specific immune responses measured in stimulated whole blood. The size and characteristics of the skin reaction correlated positively with in vitro immune responses, even after adjusting for BCG vaccine strain and age at vaccination. Specifically, the reaction size and characteristics correlated with the proportion of mycobacteria-specific polyfunctional CD4+ T cells after stimulation with BCG and PPD and, to a lesser extent, after stimulation with Mycobacterium tuberculosis or Mycobacterium ulcerans. A similar correlation was observed with concentrations of IFN-γ, IL-2, tumor necrosis factor, and IL-13 in the supernatant after stimulation with BCG, PPD, and M. tuberculosis and to some degree for the proportions of mycobacteria-specific polyfunctional CD8+ T cells and CD107+ cytotoxic cells. Conclusions: BCG skin reaction correlated with the magnitude of mycobacteria-specific T-cell responses. As T-cell responses play a key role in defense against mycobacteria, the relationship between BCG scar formation and protection against tuberculosis should be revisited. This may also extend to the need for BCG revaccination in scar-negative individuals.Clinical trial registered with www.australianclinicaltrials.gov.au/clinical-trial-registries (ACTRN12608000227392).

Subclinical Tuberculosis in Children: Diagnostic Strategies for Identification Reported in a 6-year National Prospective Surveillance Study.

BACKGROUND: Subclinical tuberculosis (TB) is well recognized and defined as a disease state with absent or nonrecognized symptoms. The study identifies factors associated with subclinical TB and diagnostic strategies in a low-burden, high-resource country. METHODS: Data were collected between December 2013 and November 2019 through the Swiss Pediatric Surveillance Unit (SPSU). Children with culture/molecular confirmed TB, or who were treated with ≥3 antimycobacterial drugs, were included. RESULTS: A total of 138 (80%) children with TB disease were included in the final analysis, of which 43 (31%) were subclinical. The median age of children with subclinical compared to symptomatic TB was 3.7 (interquartile range [IQR] 2.2-7) and 9.7 (IQR 2.7-14.3) years, respectively (P = .003). The cause of investigation for TB was recorded in 31/43 (72.1%) of children with subclinical TB and included contact exposure in 25 (80.6%) of children. In children with subclinical TB, diagnosis was made by a combination of the following abnormal/confirming results: culture/molecular + immunodiagnostic + chest radiography in 12 (27.9%) cases, immunodiagnostic + chest radiography in 19 (44.2%) cases, culture/molecular + chest radiography in 2 (4.7%) cases, culture + immunodiagnostic in 1 (2.3%) case, chest radiography only in 8 (18.6%) cases, and immunodiagnostic only in 1 (2.3%) case. CONCLUSIONS: A notable proportion of children with TB had subclinical disease. This highlights the importance of non-symptom-based TB case finding in exposed children and refugees from high-TB-prevalence settings. TB screening in these asymptomatic children should therefore include a combination of immunodiagnostic testing and imaging followed by culture and molecular testing.

Pediatric Tuberculosis Disease during Years of High Refugee Arrivals: A 6-Year National Prospective Surveillance Study.

BACKGROUND: In Europe, surveillance and monitoring of pediatric tuberculosis (TB) remains important, particularly in the light of migration in recent years. The aim of the study was to evaluate incidence rates of childhood TB and detailed diagnostic pathways and treatment. METHODS: Data were collected through the Swiss Pediatric Surveillance Unit (SPSU) from December 2013 to November 2019. Monthly -notifications are obtained from the 33 pediatric hospitals in the SPSU, and a detailed questionnaire was sent out upon notification. Inclusion criteria were children and adolescents aged up to 15 years with culture- or molecular-confirmed TB disease or for whom a treatment with ≥3 antimycobacterial drugs had been initiated. Data were compared with age-matched notification data from the Swiss Federal Office of Public Health (FOPH). RESULTS: Of the 172 cases notified to SPSU, a detailed questionnaire was returned for 161 (93%) children, of which 139 met the inclusion criteria. Reasons for exclusion were age >15 years, double reporting, and not fulfilling the criteria for TB disease. During the same time period, 172 pediatric TB cases were reported to the FOPH, resulting in an incidence of 2.1 per 100,000, ranging from 1.4 to 2.8 per year, without a clear trend over time. In the 64 (46.0%) foreign-born children, incidence rates were higher and peaked in 2016, with 13.7 per 100,000 (p = 0.018). The median interval between arrival in Switzerland and TB diagnosis was 5 (IQR 1-21) months, and 80% were diagnosed within 24 months of arrival. In 58% of the cases, TB disease was confirmed by culture or molecular assays. Age >10 years, presence of fever, or weight loss were independent factors associated with confirmed TB. CONCLUSION: The annual pediatric TB incidence rate only varied among foreign-born children and was highest in 2016 when refugee influx peaked in Europe. Importantly, most foreign-born children with TB were diagnosed within 2 years after arrival in Switzerland. Thus, the early period after arrival in Switzerland is associated with a higher risk of TB disease in children, and this should be considered for screening guidance in refugees.

Cytokines in saliva as biomarkers of oral and systemic oncological or infectious diseases: A systematic review.

Recent evidence suggests that salivary cytokines provide information about both oral conditions and systemic diseases. This review summarizes evidence for the use of salivary cytokines as biomarkers for oral and systemic diseases. We included studies in adults and children with a focus on the latter, due to the importance of non-invasive diagnostic methods in the paediatric age group. A systematic review was performed using Medline and Web of Science covering the period of January 1996 to December 2019 according to the preferred reporting items for systematic reviews. Thirty-four studies were included in the final analysis, for a total of 2407 patients and healthy controls. Pro-inflammatory cytokines including interleukin (IL)-1ß, IL-2, IL-6 and tumor necrosis factor (TNF)-α were associated with the severity of oral mucosal tissue damage in patients with cancer, and IL-1ß may be an early marker of graft-versus-host disease. Salivary interferon-γ levels were correlated with oral complications and the presence of the underlying disease in HIV-infected individuals, and salivary cytokine patterns may be useful for diagnosing tuberculosis. In summary, current data illustrate that salivary cytokines are associated with oral inflammation, making them potential biomarkers for disease diagnosis and treatment efficacy. Because of the simplicity of saliva collection, this method may be useful in pediatric studies and in resource-limited settings.

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects.

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.

Influence of core body temperature on Tryptophan metabolism, kynurenines, and estimated IDO activity in critically ill patients receiving target temperature management following cardiac arrest.

BACKGROUND/AIMS: Temperature control improves neurological prognosis in comatose cardiac arrest (CA) survivors. Previous reports demonstrate that most affected patients show signs of significant systemic inflammation. In an effort to better characterize potential temperature-related effects on key inflammatory pathways, we investigate the course of Tryptophan (Trp) levels, Tryptophan catabolites (including kynurenines) and indoleamine-2,3-dioxygenase (IDO)-activity in post CA patients. MATERIAL/METHODS: In an observational blinded endpoint analysis, a total of n=270 serial samples from 20 post CA patients (63.1±16.6 yrs., 45% shockable rhythm, mean time to return of spontaneous circulation (ROSC) 26.6±16.0min) treated with target temperature management (TTM) were analyzed. Core body temperatures, course of Trp, Trp catabolites (incl. kynurenines), and estimated IDO-activity were followed up for a maximum of 7 days after ROSC. Patients were followed up until hospital discharge or death and functional outcome was recorded. RESULTS: Over the 7-day observational interval, marked changes in Trp serum levels and IDO-activity were noted. In general, Trp serum levels but not IDO-activity seemed to parallel with the course of core body temperature. In explorative analyses, a correlation of Trp (rho=0.271 (95%-CI: 0.16-0.38, p<0.0001) and IDO-activity (rho=-0.155, 95%-CI: -0.27 to -0.037, p=0.01) with core body temperature was observed. Linear mixed effect models revealed a positive significant association of core body temperature with Trp serum levels (Likelihood ratio test χ(2)=6.35, p=0.012). In patients with good (vs. unfavorable) outcome, a tendency toward higher Trp serum levels, lower IDO-activity, and lower Kynurenic acid levels was noted. CONCLUSIONS: We observed significant changes in Trp catabolism and IDO-activity that appeared temperature associated in post CA patients. Under hypothermia, decreased serum levels of Trp and increased IDO-activity were noted. We speculate from our data that IDO-induction during hypothermia contributes to the previously described increased susceptibility to infection or sepsis under reduced temperatures.