The Kynurenine/Tryptophan Ratio Is a Sensitive Biomarker for the Diagnosis of Pediatric Tuberculosis Among Indian Children

ObjectivesPediatric tuberculosis (TB) remains difficult to diagnose. The plasma kynurenine to tryptophan ratio (K/T ratio) is a potential biomarker for TB diagnosis and treatment response but has not been assessed in children.MethodsWe performed a targeted diagnostic accuracy analysis of four biomarkers: kynurenine abundance, tryptophan abundance, the K/T ratio, and IDO-1 gene expression. Data were obtained from transcriptome and metabolome profiling of children with confirmed tuberculosis and age- and sex-matched uninfected household contacts of pulmonary tuberculosis patients. Each biomarker was assessed as a baseline diagnostic and in response to successful TB treatment.ResultsDespite non-significant between-group differences in unbiased analysis, the K/T ratio achieved an area under the receiver operator characteristic curve (AUC) of 0.667 and 81.5% sensitivity for TB diagnosis. Kynurenine, tryptophan, and IDO-1 demonstrated diagnostic AUCs of 0.667, 0.602, and 0.463, respectively. None of these biomarkers demonstrated high AUCs for treatment response. The AUC of the K/T ratio was lower than biomarkers identified in unbiased analysis, but improved sensitivity over existing commercial assays for pediatric TB diagnosis.ConclusionsPlasma kynurenine and the K/T ratio may be useful biomarkers for pediatric TB. Ongoing studies in geographically diverse populations will determine optimal use of these biomarkers worldwide.

Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer nonspecific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here, we demonstrate that intravenous, but not subcutaneous, inoculation of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 (SCV2) and results in reduced viral loads in non-transgenic animals infected with an α variant. The observed increase in host resistance was associated with reductions in SCV2-induced tissue pathology, inflammatory cell recruitment, and cytokine production that multivariate analysis revealed as only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and ensuing immunopathology. While intravenous BCG vaccination is not a clinically acceptable practice, our findings provide an experimental model for identifying mechanisms by which nonspecific stimulation of the pulmonary immune response promotes host resistance to SCV2 lethality.

Plasma chemokines as immune biomarkers for diagnosis of pediatric tuberculosis

Background Diagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis. Methods We conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines. Results Baseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment. Conclusion Thus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge

Early events in the host response to SARS-CoV-2 are thought to play a major role in determining disease severity. During pulmonary infection, the virus encounters both myeloid and epithelioid lineage cells that can either support or restrict pathogen replication as well as respond with host protective versus detrimental mediators. In addition to providing partial protection against pediatric tuberculosis, vaccination with bacille Calmette-Guérin (BCG) has been reported to confer non-specific resistance to unrelated pulmonary pathogens, a phenomenon attributed to the induction of long-lasting alterations within the myeloid cell compartment. Here we demonstrate that prior intravenous, but not subcutaneous, administration of BCG protects human-ACE2 transgenic mice against lethal challenge with SARS-CoV-2 and results in reduced viral loads in non-transgenic animals infected with an alpha variant. The observed increase in host resistance was associated with reductions in SARS-CoV-2-induced tissue pathology, inflammatory cell recruitment and cytokine production that multivariate analysis revealed to be only partially related to diminished viral load. We propose that this protection stems from BCG-induced alterations in the composition and function of the pulmonary cellular compartment that impact the innate response to the virus and the ensuing immunopathology.

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

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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). <b><i>Results:</i></b> 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 &#x3e;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 (<i>p</i> = 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 &#x3e;10 years, presence of fever, or weight loss were independent factors associated with confirmed TB. <b><i>Conclusion:</i></b> 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.

Pulmonary lesions in visceral toxocariasis in children in the phthisiatric practice (clinical case)

Background. The clinical and radiological picture of pulmonary tuberculosis has many common features with a large number of diseases. Therefore, differential diagnosis is very important when detecting tuberculosis. The purpose of the work: on the example of a clinical case to present the complexity of the differential diagnosis between pulmonary lesion in visceral toxocariasis and tuberculosis in children. Results. The child was diagnosed with an infiltrate in the third segment of the left lung with lesions of the intrathoracic lymph nodes, which is characteristic of the primary tuberculosis. The volatility of the infiltrate was not determined. All general blood test hadn’t shown an increase in eosinophils and white blood cells. According to the literature data, the appearance of persistent and prolonged eosinophilia with the development of eosinophilic leukemoid reactions of the blood, an increase in the level of leukocytes are the main and one of the constant manifestations of toxocariasis. The child was diagnosed with moderate hepatomegaly, which is cha­racteristic for both diseases. The patient was registered at a pediatric tuberculosis clinic due to a shift in tuberculin tests. At the time of hospitalization, there were not reasons to suspect visceral toxocariasis. Due to the examination data, first of all the absence of bacterial excretion and negative tuberculin tests, and the pre­sence in the child’s house of the dogs and cats, it was decided to recommend the consultation of the infectionist to exclude any parasitic disease. At the end, the correct diagnosis was established in this child at time and the necessary treatment was prescribed. Conclusions. This clinical case demonstrates the difficulties of differential diagnosis of visceral toxocariasis in lung lesion and tuberculosis. First of all, this is due to the asymptomatic clinical picture of toxocariasis, the diagnosis of which was established by X-ray data, blood test for IgG antibodies to Toxocara and epidemiological history. Given the fact that toxocariasis includes a large spectrum of masks of various diseases, and children who are infected by Toxocara do not have specific clinical symptoms, doctors should remember to prescribe the additional examination for the presence of parasitic diseases, including toxocariasis, especially if pets live in the child’s home.