A Systematic Review on Novel Mycobacterium tuberculosis Antigens and Their Discriminatory Potential for the Diagnosis of Latent and Active Tuberculosis

Background: Current immunodiagnostic tests for tuberculosis (TB) are based on the detection of an immune response toward mycobacterial antigens injected into the skin or following an in-vitro simulation in interferon gamma-release assays. Both tests have limited sensitivity and are unable to differentiate between tuberculosis infection (LTBI) and active tuberculosis disease (aTB). To overcome this, the use of novel Mycobacterium tuberculosis (M. tuberculosis) stage-specific antigens for the diagnosis of LTBI and aTB has gained interest in recent years. This review summarizes current evidence on novel antigens used for the immunodiagnosis of tuberculosis and discrimination of LTBI and aTB. In addition, results on measured biomarkers after stimulation with novel M. tuberculosis antigens were also reviewed.Methods: A systematic literature review was performed in Pubmed, EMBASE and web of science searching articles from 2000 up until December 2017. Only articles reporting studies in humans using novel antigens were included.Results: Of 1,533 articles screened 34 were included in the final analysis. A wide range of novel antigens expressed during different stages and types of LTBI and aTB have been assessed. M. tuberculosis antigens Rv0081, Rv1733c, Rv1737c, Rv2029c, Rv2031 and Rv2628, all encoded by the dormancy of survival regulon, were among the most widely studied antigens and showed the most promising results. These antigens have been shown to have best potential for differentiating LTBI from aTB. In addition, several studies have shown that the inclusion of cytokines other than IFN-γ can improve sensitivity.Conclusion: There is limited evidence that the inclusion of novel antigens as well as the measurement of other biomarkers than IFN-γ may improve sensitivity and may lead to a discrimination of LTBI from aTB

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

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

Chikungunya Fever During Pregnancy and in Children: An Overview on Clinical and Research Perspectives

Chikungunya fever (CF) is an arboviral disease in worldwide expansion due to the plasticity of its pathogen and vector. Chikungunya virus (CHIKV), a positive-sense, single-stranded RNA alphavirus, is transmitted by Aedes (Stegomyia) aegypti and Aedes albopictus mosquitoes, two hegemonic anthropophilic day-biting mosquitoes capable of colonizing very different environments. This expert review discusses the molecular epidemiology, pathophysiology, clinical features, diagnosis, management, and prevention of CF during pregnancy, infancy, and childhood. Specifically, it will focus not only on the issue and challenges of perinatal mother-to-child transmission of CHIKV, its pathogenesis, and effects on neurodevelopment, but also on CHIKV-associated central nervous system disease in children, two previously ill-characterized features of the infection

Preventable admissions and emergency-department-visits in pediatric asylum-seeking and non-asylum-seeking patients

Background Migrant health has become an essential part of public health. According to the World Health Organization, many health systems in Europe have not yet adapted adequately to the needs of asylum-seekers, which might result in untimely and inefficient health care for asylum-seeking patients. The aim of this study was to assess the number of preventable hospital admissions and emergency department visits in asylum-seeking and non-asylum-seeking pediatric patients. Methods This is a retrospective, hospital-based study. The study was done at the University Children’s Hospital Basel in Switzerland. Patients admitted or presenting to the emergency department were included and split into the groups of asylum-seeking and non-asylum-seeking patients. All admissions and emergency-department visits were extracted from the administrative electronic health records from 1st Jan 2016-31st Dec 2017. The main outcome was the proportion of admissions due to ambulatory-care-sensitive conditions (which refer to conditions for which admission can be prevented by early interventions in primary care) in asylum-seeking and non-asylum-seeking patients. Ambulatory-care-sensitive conditions were defined by a validated list of ICD-10 codes. The secondary objective was to assess the number of preventable emergency-department visits by asylum-seeking patients defined as proportion of visits with a non-urgent triage score. Results A total of 75′199 hospital visits were included, of which 63′405 were emergency department visits and 11′794 were admissions. Ambulatory-care-sensitive conditions accounted for 12.1% (18/149) of asylum-seeking and 10.9% (1270/11645) of non-asylum seeking patients’ admissions. Among the emergency department visits by asylum-seeking patients, non-urgent conditions accounted for 82.2% (244/297). Conclusions Admissions due to ambulatory-care-sensitive conditions are comparable in asylum-seeking and non-asylum-seeking children, suggesting few delayed presentations to ambulatory care facilities. Strategies to prevent non-urgent visits at pediatric emergency department facilities are needed.publishedVersio

Health care provided to recent asylumseeking and non-asylum-seeking pediatric patients in 2016 and 2017 at a Swiss tertiary hospital - a retrospective study

Background Asylum-seeking children represent an increasing and vulnerable group of patients whose health needs are largely unmet. Data on the health care provision to asylum-seeking children in European contexts is scarce. In this study we compare the health care provided to recent asylum-seeking and non-asylum-seeking children at a Swiss tertiary hospital. Methods We performed a cross-sectional retrospective study in a pediatric tertiary care hospital in Basel, Switzerland. All patients and visits from January 2016 to December 2017 were identified, using administrative and medical electronic health records. The asylum-seeking status was systematically assessed and the patients were allocated accordingly in the two study groups. Results A total of 202,316 visits by 55,789 patients were included, of which asylum-seeking patients accounted for 1674 (1%) visits by 439 (1%) individuals. The emergency department recorded the highest number of visits in both groups with a lower proportion in asylum-seeking compared to non-asylum-seeking children: 19% (317/1674) and 32% (64,315/200,642) respectively. The median number of visits per patient was 1 (IQR 1–2) in the asylum-seeking and 2 (IQR 1–4) in the non-asylum-seeking children. Hospital admissions were more common in asylum-seeking compared to non-asylum-seeking patients with 11% (184/1674) and 7% (14,692/200,642). Frequent visits (> 15 visits per patient) accounted for 48% (807/1674) of total visits in asylum-seeking and 25% (49,886/200,642) of total visits in non-asylum-seeking patients. Conclusions Hospital visits by asylum-seeking children represented a small proportion of all visits. The emergency department had the highest number of visits in all patients but was less frequently used by asylum-seeking children. Frequent care suggests that asylum-seeking patients also present with more complex diseases. Further studies are needed, focusing on asylum-seeking children with medical complexity.publishedVersio

Risk factors for allergic bronchopulmonary aspergillosis and sensitisation to Aspergillus fumigatus in patients with cystic fibrosis

An increasing incidence of allergic bronchopulmonary aspergillosis (ABPA) as a complication in patients with cystic fibrosis (CF) is reported. The objective of this retrospective case-control study was to assess potential risk factors for ABPA and for Aspergillus fumigatus sensitisation (AFS). In a group of 160 CF patients, 11 (7%) fulfilled the diagnostic criteria for ABPA and 20 (13%) had evidence of AFS. They were compared to 62 control CF patients (25 for ABPA and 37 for AFS group) without evidence of ABPA or AFS using extended matching for sex, age and weight. AFS patients had received significantly higher cumulative doses of inhaled corticosteroids than their respective controls (OR 8.0; 95% CI 1.74-63). Bronchial colonisation with Stenotrophomonas maltophilia was strongly and independently associated with ABPA (OR 20; 95% CI 2.8- infinity). A longer duration of Pseudomonas aeruginosa colonisation was independently associated with AFS (OR per year 1.50; 95% CI 1.12- infinity). Conclusion: Cystic fibrosis patients with allergic bronchopulmonary aspergillosis have a more frequent isolation of S. maltophilia in their sputum than their controls. Longer duration of colonisation with P. aeruginosa is a risk factor for Aspergillus fumigatus sensitisation. Higher cumulative doses of inhaled corticosteroids are associated with Aspergillus fumigatus sensitisation and their role as a risk factor needs to be clarifie

Risk factors for indeterminate interferon-gamma release assay for the diagnosis of tuberculosis in children : a systematic review and meta-analysis

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 0.03-0.00). 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

Aerococcus urinae - significance of detection in the paediatric urinary tract: a case series

Aerococcus urinae (A. urinae) is primarily recognized as a common pathogen in the geriatric population, causing urinary tract infection (UTI), sepsis, and endocarditis, predominantly in female patients. In the paediatric population, only a few case reports exist suggesting A. urinae causes malodorous urine in otherwise healthy boys. In this study, we investigated the spectrum of clinical and laboratory presentations of A. urinae detection in children. A retrospective, single-centre, case series including all patients with the detection of A. urinae during a 7-year study period. Patients with detection of A. urinae only in non-urogenital skin swabs were excluded. A total of 40 samples from 33 patients were identified of which 20 patients were included in the final analysis. The median (IQR) age was 6.8 (2.9-9.5) years; 18 (90%) patients were boys. Four patients were diagnosed with a UTI, six had malodorous urine without UTI, three were diagnosed with balanitis and seven showed A. urinae colonization in the urine culture. Urogenital disorders were present in 12 patients. Additional pathogens were detected in 13 patients. Recurrence of detection during our study period was observed in four (20%) patients. Conclusion: Beyond malodorous urine, A. urinae detection is associated with more severe presentations including UTI in the paediatric population. Pre-existing urogenital disorders were frequent, and therefore, a nephro-urological investigation should be considered in all cases of A. urinae detection in the paediatric population. What is Known: • Aerococcus urinae (A. urinae) is known to be a common pathogen in the geriatric population, causing urinary tract infection (UTI), sepsis, and endocarditis, predominantly in female patients. • In the paediatric population, A. urinae is mainly described as a low-grade pathogen. Some case reports describe A. urinae as the cause of extraordinary malodorous urine in otherwise healthy boys. What is New: • Beyond malodorous urine, A. urinae detection is associated with more severe presentations including UTI in the paediatric population. • A. urinae was mainly detected in boys with pre-existing urogenital disorders; therefore, a nephro-urological investigation should be considered in cases of A. urinae detection in the paediatric population. Keywords: CAKUT; Children; Malodorous; Pyelonephritis; Urinary tract infection; Urogenital disorder