The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter (-135G>A [rs56061981] and -1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the -1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51-5.85, p = 0.021). In addition, individuals with the -1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the -1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34-22.29, p = 0.018). Furthermore, -135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05-0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the -1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males.

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CXCL10 Gene Promoter Polymorphism -1447A>G Correlates with Plasma CXCL10 Levels and is Associated with Male Susceptibility to Cerebral Malaria

Following the innovations and new discoveries of the last 10 years in the field of lung ultrasound (LUS), a multidisciplinary panel of international LUS experts from six countries and from different fields (clinical and technical) reviewed and updated the original international consensus for point‐of‐care LUS, dated 2012. As a result, a total of 20 statements have been produced. Each statement is complemented by guidelines and future developments proposals. The statements are furthermore classified based on their nature as technical (5), clinical (11), educational (3), and safety (1) statements.

New International Guidelines and Consensus on the Use of Lung Ultrasound

Background: Interferon-gamma release assays (IGRA) are well-established immunodiagnostic tests for tuberculosis (TB) in adults. In children these tests are associated with higher rates of false-negative and indeterminate results. Age is presumed to be one factor influencing cytokine release and therefore test performance. The aim of this study was to systematically review factors associated with indeterminate IGRA results in pediatric patients. Methods: Systematic literature review guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) searching PubMed, EMBASE, and Web of Science. Studies reporting results of at least one commercially available IGRA (QuantiFERON-TB, T-SPOT.TB) in pediatric patient groups were included. Random effects meta-analysis was used to assess proportions of indeterminate IGRA results. Heterogeneity was assessed using the I2 value. Risk differences were calculated for studies comparing QuantiFERON-TB and T-SPOT.TB in the same study. Meta-regression was used to further explore the influence of study level variables on heterogeneity. Results: Of 1,293 articles screened, 133 studies were included in the final analysis. These assessed QuantiFERON-TB only in 77.4% (103/133), QuantiFERON-TB and T-SPOT.TB in 15.8% (21/133), and T-SPOT.TB only in 6.8% (9/133) resulting in 155 datasets including 107,418 participants. Overall 4% of IGRA results were indeterminate, and T-SPOT.TB (0.03, 95% CI 0.02-0.05) and QuantiFERON-TB assays (0.05, 95% CI 0.04-0.06) showed similar proportions of indeterminate results; pooled risk difference was-0.01 (95% CI -0.03 to 0.00). Significant differences with lower proportions of indeterminate assays with T-SPOT.TB compared to QuantiFERON-TB were only seen in subgroup analyses of studies performed in Africa and in non-HIV-infected immunocompromised patients. Meta-regression confirmed lower proportions of indeterminate results for T-SPOT.TB compared to QuantiFERON-TB only among studies that reported results from non-HIV-infected immunocompromised patients (p < 0.001). Conclusion: On average indeterminate IGRA results occur in 1 in 25 tests performed. Overall, there was no difference in the proportion of indeterminate results between both commercial assays. However, our findings suggest that in patients in Africa and/or patients with immunocompromising conditions other than HIV infection the T-SPOT.TB assay appears to produce fewer indeterminate results.

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Risk Factors for Indeterminate Interferon-Gamma Release Assay for the Diagnosis of Tuberculosis in Children-A Systematic Review and Meta-Analysis.

Lung ultrasound has become increasingly used in both adult and pediatric populations, allowing the rapid evaluation of many lung and pleura diseases This popularity is due to several advantages of the method such as the low cost, rapidity, lack of ionizing radiation, availability of bedside and repeatability of the method These features are even more important after the outbreak of the SARS-CoV-2 pandemic, given the possibility of recognizing through ultrasound the signs of interstitial lung syndrome typical of pneumonia caused by the virus The purpose of this paper is to review the available evidence of lung ultrasound (LUS) in children and its main applications in pediatric diseases

Lung Ultrasound: Its Findings and New Applications in Neonatology and Pediatric Diseases

Transcriptome profiling and differential expression analysis of the immune-related genes during the acute phase of infection with Mycobacterium marinum in the goldfish (Carassius auratus L.)

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.

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

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.

[CXCL10/IP-10 as a new biomarker for Mycobacterium tuberculosis infection].

Objectives To assess whether children ≤5 years of age, produce sufficient amounts of interferon gamma (IFN-ɣ) 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-ɣ 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-ɣ levels in mitogen and TB antigen tubes in children ≤5 years and >5 years, and the correlation between IFN-ɣ 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-ɣ 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-ɣ 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-ɣ in response to TB antigens thus QFT-GIT might be a useful tool for TB diagnostics in this age group.

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

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.

[Tularaemia - a forgotten disease? Own experience].

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.

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Anna Komorowska-Piotrowska

Papers

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

[CXCL10/IP-10 as a new biomarker for Mycobacterium tuberculosis infection].

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

[Tularaemia - a forgotten disease? Own experience].

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