IP-10 for the Diagnosis and Treatment Monitoring of Tuberculosis in Children.

PURPOSE: To determine the utility of interferon-gamma-inducible protein 10 (IP-10) for identifying active tuberculosis (TB) and TB infection (TBI) in children in BCG-vaccinated populations, establish its diagnostic performance characteristics, and evaluate changes in IP-10 level during anti-TB chemotherapy. METHODS: Concentrations of IP-10 and IFN-γ were measured in QuantiFERON-TB Gold (QFT) supernatants in children with suspected TB or due to recent TB contact. A total of 225 children were investigated: 33 with active TB, 48 with TBI, 83 TB contacts, 20 with suspected TB but other final diagnoses, and 41 controls. In 60 children, cytokine responses were evaluated at a follow-up visit after 2 months of anti-TB treatment. RESULTS: IP-10 expression was significantly higher in infected children (active TB and TBI cases) than in uninfected individuals. IP-10 proved effective in identifying TB infection at its optimal cut-off (>1084.5 pg/mL) but was incapable of differentiating between children with active TB and TBI. Combining IP-10 and IFN-γ increased the QFT sensitivity. IP-10 but not IFN-γ decreased significantly during anti-TB treatment in children with active TB (p = 0.003). CONCLUSION: IP-10 identifies TB infection and declines during anti-TB chemotherapy in children. Incorporating IP-10 into new immunodiagnostic assays could improve TB diagnosis and allow for treatment monitoring.

Lung Ultrasound in the Evaluation of Lung Disease Severity in Children with Clinically Stable Cystic Fibrosis: A Prospective Cross-Sectional Study.

With the increasing longevity of cystic fibrosis (CF), there is a growing need to minimise exposure to ionising radiation in patients who undergo regular imaging tests while monitoring the course of the lung disease. This study aimed to define the role of lung ultrasounds (LUS) in the evaluation of lung disease severity in children with clinically stable CF. LUS was performed on 131 patients aged 5 weeks to 18 years (study group) and in 32 healthy children of an equivalent age range (control group). Additionally, an interobserver study was performed on 38 patients from the study group. In CF patients, the following ultrasound signs were identified: I-lines; Z-lines; single, numerous and confluent B-lines; Am-lines; small and major consolidations; pleural line abnormalities and small amounts of pleural fluid. The obtained results were evaluated against an original ultrasound score. LUS results were correlated with the results of chest X-ray (CXR) [very high], pulmonary function tests (PFTs) [high] and microbiological status [significant]. The interobserver study showed very good agreement between investigators. We conclude that LUS is a useful test in the evaluation of CF lung disease severity compared to routinely used methods. With appropriate standardisation, LUS is highly reproducible.

Diagnostic Value of IP-10 Level in Plasma and Bronchoalveolar Lavage Fluid in Children with Tuberculosis and Other Lung Diseases.

OBJECTIVES: IP-10 has been proposed as a new diagnostic biomarker for Mycobacterium tuberculosis infection (MTBI). However, data on IP-10 concentration in bronchoalveolar lavage fluid (BALF) for pediatric tuberculosis are lacking. AIM: To determine IP-10 levels in unstimulated BALF and plasma in children with and without MTBI. METHODS: IP-10 concentrations in BALF and plasma were measured in children hospitalized with suspected tuberculosis or other respiratory disease and scheduled for bronchoscopy. Thirty-five children were enrolled: 13 with suspected tuberculosis and 22 controls. The association between IP-10 and age was examined. RESULTS: The IP-10 expression was increased in BALF compared to plasma (p = 0.008). We noticed higher BALF IP-10 levels in children with asthma, interstitial lung disease, and lung anomaly than in children with MTBI and other respiratory tract infections, but the differences were statistically insignificant. There was a moderate correlation between plasma and BALF IP-10 concentrations (rs = 0.46, p = 0.018). No correlation between IP-10 level and age was detected. CONCLUSIONS: IP-10 is detectable in unstimulated BALF in children with respiratory diseases, reaches higher concentrations in unstimulated BALF vs plasma, and does not correlate with age. However, it could not discriminate MTBI from other respiratory diseases.

Response to Comment on Jaworska, J. et al. Consensus on the Application of Lung Ultrasound in Pneumonia and Bronchiolitis in Children. Diagnostics 2020, 10, 935.

Thank you for the opportunity to respond to the issues raised by Nenna et al [...].

Consensus on the Application of Lung Ultrasound in Pneumonia and Bronchiolitis in Children.

This evidence-based consensus aims to establish the role of point-of-care lung ultrasound in the management of pneumonia and bronchiolitis in paediatric patients. A panel of thirteen experts form five Polish tertiary pediatric centres was involved in the development of this document. The literature search was done in PubMed database. Statements were established based on a review of full-text articles published in English up to December 2019. The development of this consensus was conducted according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluations)-adopted and Delphi method. Initially, 22 proposed statements were debated over 3 rounds of on-line discussion and anonymous voting sessions. A total of 17 statements were agreed upon, including four statements referring to general issues, nine referring to pneumonia and four to bronchiolitis. For five statements experts did not achieve an agreement. The evidence supporting each statement was evaluated to assess the strength of each statement. Overall, eight statements were rated strong, five statements moderate, and four statements weak. For each statement, experts provided their comments based on the literature review and their own experience. This consensus is the first to establish the role of lung ultrasound in the diagnosis and management of pneumonia and bronchiolitis in children as an evidence-based method of imaging.

Is secretion of IFN-gamma in response to Mycobacterium tuberculosis antigens in youngest children sufficient to play a role in TB diagnostics?

OBJECTIVES: To assess whether children ≤5 years of age, produce sufficient amounts of interferon gamma (IFN-É£) in response to phytohaemagglutinin (mitogen), and Mycobacterium tuberculosis antigens (TB antigens) in the QuantiFERON-TB Gold in-Tube test (QFT-GIT), (Cellestis Ltd., Australia). WORKING HYPOTHESIS: Is TB-antigen-induced IFN-É£ response in children ≤5 years sufficient to consider QFT-GIT a possible tool for TB diagnostics? Study design, patient-subject selection, and methods: We recruited children 0-17 years old suspected of TB infection to this cross-sectional study, in whom QFT-GIT and TST were performed. We analyzed the median IFN-É£ levels in mitogen and TB antigen tubes in children ≤5 years and >5 years, and the correlation between IFN-É£ level in both tubes and age. RESULTS: A total of 153 children were enrolled, age median was 7.8 (IQR:8), 45 (29.4%) aged ≤5 years (median 3.4, IQR:1.7), 108 > 5 years (median 10.55, IQR:5.93). In the mitogen tubes, the median IFN-É£ level was higher in children >5 years (median 17.87, IQR:2.1 vs 16.77, IQR:7.6), but surprisingly in the TB antigen tubes it was higher in the younger group (median 0.12, IQR:0.21vs 0.06, IQR:0.09, P = 0.04). We proved a positive correlation between IFN-É£ level and age in mitogen tubes (r = 0.18, P = 0.03) and a negative correlation in TB antigen tubes (r = -0.17, P = 0.04). In latent tuberculosis infection patients, the latter correlation was found to be even stronger (r = -0.39, P = 0.01). CONCLUSIONS: The youngest children release sufficient amount of IFN-É£ in response to TB antigens thus QFT-GIT might be a useful tool for TB diagnostics in this age group.

[The diagnosis of latent tuberculosis infection in children in XXI century. Is tuberculin skin test still up to date?]. / Wspólczesna diagnostyka zakazenia pratkiem gruzlicy u dzieci ­ czy nadal odczyn tuberkulinowy?

Tuberculosis morbidity rates in Poland have been gradually decreasing. Nevertheless, there are approximately 8 thousand cases being registered annually, which includes almost 3 thousand massively infectious patients. In the last 3 years, around 100 cases/year have been reported among children below 14 years of age. Infection with Mycobacterium tuberculosis should be considered in all patients who present symptoms suggesting tuberculosis, have had recent contact with a person suffering from lung tuberculosis or are planned to undergo an immunosuppressive treatment. HIV infected patients are also supposed to have screening tests for M. tuberculosis infection performed. For over a 100 years tuberculin skin test (TST) was the only test capable of confirming tuberculous infection. TST is based on the assessment of skin reaction to intracutaneous injection of tuberculin. Due to cross-reaction to the injected tuberculin in BCG vaccinated individuals, the correct interpretation of the test is difficult. Since 13 years new immunological assays have been available. They are based on detecting interferon gamma (Interferon Gamma Release Assay - IGRA) concentration in blood serum, which has previously been incubated with Mycobacterium tuberculosis antigens absent in the BCG strain. In infected individuals interferon gamma is intensively produced by memory cells in reaction to the contact with previously met Mycobacterium antigens. Many trials have proved IGRA's high sensitivity and, higher than TST, specificity. Recent guidelines promote the usage of IGRAs, even in children.

[Tularaemia - a forgotten disease? Own experience]. / Tularaemia - choroba zapomniana? Doswiadczenia wlasne.

Tularaemia is an acute, animal-born disease, caused by Gram-negative aerobic bacilli - Francisella tularensis. Due to its high infectiousness and virulence it remains an epidemiological issue in some countries. The prevalence rate of tularaemia in the Scandinavian region, where most of the cases among European countries have been reported, it has remained stable since 2006, whereas in Poland a small, but stable increase has been observed. The first case of tularaemia in Poland was diagnosed in 1949 and since then more than 600 cases have been reported, mainly in the north-eastern and north-western regions of the country. In the majority of cases the infection has been transmitted by ixode bites or through direct contact with infected animals. Depending on the route of transmission, tularaemia can develop in different forms with a characteristic sudden onset of high fever and local lymphadenopathy. In Europe 95% of cases account for the ulceroglandular type, which characteristically presents with skin ulceration and inflammation of regional tissues and lymph nodes. This is the reason why it should always be taken into consideration in differential diagnosis of lymphadenitis, especially if its course is atypical or it does not respond to antibiotic therapy. The above mentioned atypical course of the disease and resistance to empirical treatment contribute to the challenge encountered by physicians in the process of diagnosis and treatment. The aim of the study is to present the most important data on tularaemia as an animal-born, infectious disease and to convince physicians to take it into consideration in the differential diagnosis of ymphadenopathy. We illustrate this article with the case of ulceroglandular type of tularemia diagnosed in a 5 year-old boy and describe the encountered diagnostic and therapeutic problems.

[CXCL10/IP-10 as a new biomarker for Mycobacterium tuberculosis infection]. / Zastosowanie CXCL10/IP-10 jako nowego biomarkera zakazenia Mycobacterium tuberculosis.

In low prevalence countries, where identification and treatment of latent TB infection (LTBI) are basis of national programmes against tuberculosis, the diagnosis is focused mainly on tuberculin skin test (TST) and interferon gamma release assay (IGRA), both of which seem to be imperfect. This is why searches for a new, more specific biomarker for TB infection have been conducted. A promising candidate for the new marker is interferon gamma induced protein (IP-10). IP-10 is a chemokine, which can be detected in increased amounts in patients with active tuberculosis, latent TB infection and in individuals who had contact with an index case. It has been commonly suggested that a simultaneous analysis of IGRA and IP-10 level increases the effectiveness of IGRA, however it is still not certain whether measurement of IP-10 level might help distinguish between the above mentioned forms of tuberculous infection. Hopes are high as the protein is proved to be a good marker for treatment monitoring in adults, though there is no available data on its usefulness in monitoring therapy in paediatric population. More studies are still needed to fully assess the benefits of IP-10 level measurement as a biomarker for tuberculous infection, especially in children.