Schistosomiasis in migrant children and adolescents in a paediatric tropical referral unit in Spain: diagnosis and long-term management challenges.

Globalisation and population movement have led to an increasing number of migrant children residing in areas non-endemic for schistosomiasis. However, diagnosing and managing schistosomiasis in children remain controversial. This study aims to investigate the prevalence of schistosomiasis in migrant children and to describe the diagnostic approach and management strategies, including long-term follow-up, to explore the potential role of serological tests in evaluating treatment response. We conducted a retrospective descriptive study spanning from January 2014-July 2021 at a referral unit for Paediatric Tropical Diseases in Madrid (Spain). The study included patients under 18 years diagnosed with schistosomiasis. Of 679 children screened for schistosomiasis, 73 (10.8%) tested positive. The median age was 16.3 years [IQR 9-17.6], 74% male. The majority originated from Sub-Saharan Africa (47%) and Asia (47%). Only 40% presented with symptoms, with gastrointestinal (18%) and cutaneous (17%) manifestations being the most common. Eosinophilia was observed in 43% (median [IQR]: 1103/mm3 [671-1536]), and ova were visualised in the urine of 2/50 (4.0%). Praziquantel treatment was administered to 92%, and 5 patients required retreatment. Follow-up data were available for 58 (80%) over a median period of 9 months [IQR 6-19.8], revealing a progressive decline in eosinophil count, IgE titres, and ELISA optical density.    Conclusion: In this series, the prevalence of schistosomiasis among migrant children was significant (10%), highlighting the importance of including serological tests in migrant health screening. The disease is largely asymptomatic, eosinophilia is often absent, and visualisation of ova in urine is exceedingly rare. Eosinophil count, IgE titres, and ELISA optical density could prove valuable as an initial approach for monitoring inflammation during follow-up assessments. What is Known: • The burden of disease related to schistosomiasis is significant, particulary in children, and it is advisable to screen this vulnerable population. What is New: • Eosinophilia may not be present in parasitic infections, so serological tests are crucial for screening migrant children. • Serological monitoring facilitates long-term management of migrant children with schistosomiasis.

Mental Health in Children, Adolescents, and Youths Living with Perinatally Acquired HIV: At the Crossroads of Psychosocial Determinants of Health.

Here, we aim to describe mental health (MH) in a cohort of children, adolescents, and young adults living with perinatally acquired HIV (PHIV) in Spain and explore the treatment gap for mental disorders. We also aim to analyze the potential association between MH issues to psychosocial risk factors (PSRFs) and identify management priorities. We conducted a descriptive transversal study that included all cases of PHIV under follow-up in a reference hospital in Madrid. The study included patients undergoing follow-up in the pediatric outpatient clinic and youths transferred from pediatric to adult care units after 1997. Epidemiological, clinical, immunovirological, and treatment-related data were collected, including PSRF and adverse childhood experiences (ACEs). Of the 72 patients undergoing follow-up, 43 (59.7%) had already been transferred to the adult outpatient clinic. The patients' median age was 25 years (IQR 18-29), and 54.2% were women. Most patients were undergoing treatment (94.6%) and were virologically suppressed (84.7%). Although MH issues were present in 30 patients (41.7%), only 17 (56.7%) had been referred for evaluation to the Department of Mental Health, and only 9 (30%) had received a MH diagnosis. PSRFs were common (32% of participants had at least one PSRF) and were associated with MH issues and adherence issues (all p < 0.05). A multidisciplinary approach to address the psychological factors and social determinants of health is urgently needed, particularly during important life development stages, such as adolescence.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. CONCLUSION: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. WHAT IS KNOWN: • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. WHAT IS NEW: • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

Nutritional Supplementation to Increase Influenza Vaccine Response in Children Living With HIV: A Pilot Clinical Trial.

Aims: Vaccine response is poor among children living with HIV. The gut microbiota has been identified as a potential target to improve vaccine immunogenicity, but data are scarce in the context of HIV infection. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected children were randomized to receive a mixture of symbiotics, omega-3/6 fatty acids, and amino acids or placebo for 4 weeks, each in combination with ART, and were then immunized against influenza. Vaccine response and safety of the nutritional supplementation were the primary outcomes. Results: Eighteen HIV-infected children completed the follow-up period (mean age 11.5 ± 4.14 years, 61% female). The nutritional supplement was safe but did not enhance the response to the influenza vaccine. A 4-fold rise in antibody titers was obtained in only 37.5% of participants in the intervention arm vs. 40% in the placebo. No immunological or inflammatory predictors of vaccine response were identified. Conclusions: In this exploratory study, a 4-week course of symbiotics did not increase influenza vaccine immunogenicity in HIV-infected children. Larger studies are warranted to address the potential of modulating the microbiome in children living with HIV.

HIV HGM biobank as a research platform for paediatric infectious diseases and COVID-19 pandemic.

AIM: The initial cases of COVID-19 appeared in December 2019 and Spain was one of the most affected countries during the first wave (March to June). Since then, HIV HGM BioBank has been restructured as an established Paediatrics and Adults HIV_COVID-19 BioBank that aims at the long-term storage of samples obtained from not only HIV-1, but also from COVID-19 patients and HIV-1_COVID-19 coinfected patients. METHODS: HIV HGM BioBank holds high quality biological samples from newborns, children, adolescents and adults with their associated clinical data. Research groups trying to establish large networks focused on research on specific clinical problems in epidemiology, biology, routes of transmission and therapies, are potential users of the clinical samples and of associated data of HIV-1_COVID-19 HGM BioBank. RESULTS: The HIV HGM BioBank is an academic and ethical enterprise complying with all the legal regulatory rules to provide service to the society. HIV_COVID-19 HGM BioBank has been repurposed to offer an important resource for global research of COVID-19 in newborns, children, adolescents, adults and elders to study the biological effect of the pandemic. CONCLUSION: Herein, we present a description of how HIV HGM BioBank has rapidly become an indispensable structure in modern biomedical research, including COVID-19 research.

Targeting the Gut Microbiota of Vertically HIV-Infected Children to Decrease Inflammation and Immunoactivation: A Pilot Clinical Trial.

Aims: Children with HIV exhibit chronic inflammation and immune dysfunction despite antiretroviral therapy (ART). Strategies targeting persistent inflammation are needed to improve health in people living with HIV. The gut microbiota likely interacts with the immune system, but the clinical implications of modulating the dysbiosis by nutritional supplementation are unclear. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected on ART were randomized to supplementation with a daily mixture of symbiotics, omega-3/6 fatty acids and amino acids, or placebo four weeks, in combination with ART. We analyzed inflammatory markers and T-cell activation changes and their correlations with shifts in fecal microbiota. Results: Twenty-four HIV-infected children were recruited and randomized to receive a symbiotic nutritional supplement or placebo. Mean age was 12 ± 3.9 years, 62.5% were female. All were on ART and had HIV RNA < 50/mL. We did not detect changes in inflammatory (IL-6, IL-7, IP-10), microbial translocation (sCD14), mucosal integrity markers (IFABP, zonulin) or the kynurenine to tryptophan ratio, or changes in markers of the adaptive immune response in relation to the intervention. However, we found correlations between several key bacteria and the assessed inflammatory and immunological parameters, supporting a role of the microbiota in immune modulation in children with HIV. Conclusions: In this exploratory study, a four-week nutritional supplementation had no significant effects in terms of decreasing inflammation, microbial translocation, or T-cell activation in HIV-infected children. However, the correlations found support the interaction between gut microbiota and the immune system.

Screening for parasites in migrant children.

BACKGROUND: Globalization has pushed population movements in the last decades, turning imported diseases into the focus. Due to behavioral habits, children are at higher risk of acquiring parasitosis. This study aims to investigate the prevalence of parasites in migrant children and factors associated with parasitic diseases. METHOD: Retrospective cross-sectional study (2014-2018) including children diagnosed with parasitosis. The diagnosis was based on serology and/or microscopic stool-sample evaluation. Epidemiological and clinical data were recorded. RESULTS: Out of 813 migrant children screened, 241 (29.6%) presented at least one parasite, and 89 (10.9%) more than one. The median age was 6.6 years (IQR: 3.1-11.9) and 58.9% were males. Most cases were referred for a health exam; only 52.3% of children were symptomatic, but 43.6% had eosinophilia. The most common diagnosis were giardiasis (35.3%), schistosomiasis (19.1%), toxocariasis (15.4%), and strongyloidiasis (9.1%). After the multivariate analysis, African origin and presenting with eosinophilia were the main risk factors for parasitism. CONCLUSIONS: parasitosis are frequent among migrant children. Children are often asymptomatic, and thus active screening for parasitosis should be considered among high-risk populations. Eosinophilia can be useful to guide complimentary tests, as well as geographical origin, but normal eosinophil count does not exclude parasitosis.

Prevalence of nonalcoholic fatty liver disease using noninvasive techniques among children, adolescents, and youths living with HIV.

OBJECTIVE: The prevalence of subclinical liver abnormalities is high among people with HIV, but data regarding perinatally HIV-infected children and adolescents (PHIV) are scarce. Noninvasive image techniques offer an opportunity to address nonalcoholic fatty liver disease (NAFLD) in a population in which the scores validated for adults have not been tested. DESIGN: Prospective cross-sectional study including PHIV and uninfected controls. METHODS: Noninvasive imaging techniques for the diagnosis of NAFLD and/or fibrosis were performed, and four scores to predict NAFLD were evaluated. RESULTS: Seventy-six participants (59.2% women) with a median of 19 years old (interquartile range: 15.5-25.6) were included, 38 were PHIV and 38 were age and sex-matched controls. All HIV participants were on ART at the moment of inclusion, and 86.8% were virologically suppressed. A total of 11 PHIV and three controls were diagnosed with NAFLD (28.9% vs. 7.9%; P = 0.02) by noninvasive imaging techniques. The performance of scores based on clinical and analytical parameters was very poor. Although nonsignificant, overweight was more common among participants with NAFLD, who had a significantly higher BMI. Differences in HIV-related parameters between the groups were nonsignificant, except for the CD4+/CD8+ T-cells ratio, decreased among PHIV diagnosed with NAFLD (P = 0.04). CONCLUSIONS: The prevalence of NAFLD was high (28.9%) among PHIV, and only partially explained by overweight and metabolic syndrome defining factors. The scores based on clinical and analytical parameters did not accurately identify participants at risk. Therefore, liver ultrasound assessment should be considered for the screening of NAFLD among PHIV in routine clinical practice.

Eosinophilia in Migrant Children: How Should We Proceed?

BACKGROUND: The diagnostic approach to eosinophilia is complex, given the numerous reported etiologies. Intestinal parasites (especially helminths) are a concern in children from high-burden settings. We describe the diagnostic approach and clinical management of eosinophilia in a cohort of migrant children. METHODS: We conducted a retrospective observational study that included children diagnosed with eosinophilia at a reference center for pediatric tropical diseases from 2014 to 2018. All patients were screened according to a unified protocol, including direct microbiologic and serologic tests. RESULTS: A total of 163 children presented with eosinophilia during the study period [median age, 7.7 years (4.1-12.2); 57.1% boys], mostly from Asia (27.6%) and South America (22.1%). Most were internationally adopted children (43.6%) or migrants (26.4%). Only 34.4% of the children were symptomatic, and the main etiology for eosinophilia was helminths (56.4%). After a sequential diagnostic approach, no etiology was found for 40.5% of the patients. The independent risk factors for an unexplained etiology were younger age (≤2 years: odds ratio, 3.6; 95% CI, 1.3-10.2; P = 0.015), absence of symptoms (odds ratio, 4.8; 95% CI, 1.8-12.5; P = 0.001) and mild eosinophilia (<1000/µL: odds ratio, 4.2; 95% CI, 4.5-11.7; P = 0.005). Only 6 children were treated empirically. In those children with an identified cause and in those treated empirically, the eosinophilia resolved in 52% in a median of 7 months (5-9). CONCLUSIONS: Helminths are the main cause of eosinophilia in migrant children and need to be hunted, especially in older children with eosinophil counts >1000 eosinophils/µL.

Impact of Coronavirus Pandemic on Tuberculosis and Other Imported Diseases Screening among Migrant Minors in Spain.

BACKGROUND: In recent decades, the increase in population movements has turned the focus to imported diseases. The COVID-19 pandemic has negatively impacted the access to health care systems, especially in highly vulnerable populations. We address the effects of the pandemic on the health screening of migrant unaccompanied minors (UM) in Spain. METHOD: Retrospective cross-sectional study including UM screened for imported diseases with a unified protocol at a pediatric reference unit for tropical and infectious diseases in Madrid, Spain. We compared the pre-pandemic (2018-2019) and post-pandemic periods (2020-2021). RESULTS: A total of 192 minors were screened during the study period, with a drop in UM's referral to our center in the post-pandemic years (140 in 2018-2019 vs. 52 in 2020-2021). Out of 192, 161 (83.9%) were diagnosed with at least one medical condition. The mean age was 16.8 years (SD 0.8) and 96.9% were males. Most cases were referred for a health exam; only 38% of children were symptomatic. Eosinophilia was present in 20.8%. The most common diagnosis were latent tuberculosis infection (LTBI) (72.9%), schistosomiasis (15.1%), toxocariasis (4.9%) and strongyloidiasis (4.9%). The prevalence of LTBI did not vary significantly (69.3% vs. 82.7%, p = 0.087). A total of 38% of the patients diagnosed with LTBI never started treatment or were lost to follow-up, as were two out of three patients with active pulmonary tuberculosis. CONCLUSIONS: In this series, the number of UM referred for health screening has dropped dramatically after the COVID pandemic, and two years after the beginning of the pandemic, access to care is still limited. Lost to follow-up rates are extremely high despite institutionalization. Specific resources, including multidisciplinary teams and accessible units are needed to improve diagnoses and linkage to care in this vulnerable population.

Clinical spectrum of COVID-19 and risk factors associated with severity in Spanish children.

We aimed to identify the spectrum of disease in children with COVID-19, and the risk factors for admission in paediatric intensive care units (PICUs). We conducted a multicentre, prospective study of children with SARS-CoV-2 infection in 76 Spanish hospitals. We included children with COVID-19 or multi-inflammatory syndrome (MIS-C) younger than 18 years old, attended during the first year of the pandemic. We enrolled 1200 children. A total of 666 (55.5%) were hospitalised, and 123 (18.4%) required admission to PICU. Most frequent major clinical syndromes in the cohort were mild syndrome (including upper respiratory tract infection and flu-like syndrome, skin or mucosae problems and asymptomatic), 44.8%; bronchopulmonary syndrome (including pneumonia, bronchitis and asthma flare), 18.5%; fever without a source, 16.2%; MIS-C, 10.6%; and gastrointestinal syndrome, 10%. In hospitalised children, the proportions were 28.5%, 25.7%, 16.5%, 19.1% and 10.2%, respectively. Risk factors associated with PICU admission were age in months (OR: 1.007; 95% CI 1.004 to 1.01), MIS-C (OR: 14.4, 95% CI 8.9 to 23.8), chronic cardiac disease (OR: 4.8, 95% CI 1.8 to 13), asthma or recurrent wheezing (OR: 2.5, 95% CI 1.2 to 5.2) and after excluding MIS-C patients, moderate/severe liver disease (OR: 8.6, 95% CI 1.6 to 47.6). However, asthmatic children were admitted into the PICU due to MIS-C or pneumonia, not due to asthma flare.Conclusion: Hospitalised children with COVID-19 usually present as one of five major clinical phenotypes of decreasing severity. Risk factors for PICU include MIS-C, elevation of inflammation biomarkers, asthma, moderate or severe liver disease and cardiac disease. What is Known: • All studies suggest that children are less susceptible to serious SARS-CoV-2 infection when compared to adults. Most studies describe symptoms at presentation. However, it remains unclear how these symptoms group together into clinically identifiable syndromes and the severity associated with them. What is New: • We have gathered the primary diagnoses into five major syndromes of decreasing severity: MIS-C, bronchopulmonary syndrome, gastrointestinal syndrome, fever without a source and mild syndrome. Classification of the children in one of the syndromes is unique and helps to assess the risk of critical illness and to define the spectrum of the disease instead of just describing symptoms and signs.

Combined treatment with immunoglobulin and valaciclovir in pregnant women with cytomegalovirus infection and high risk of symptomatic fetal disease.

INTRODUCTION: Congenital cytomegalovirus (CMV) infection is one of the most common during pregnancy. The infection, particularly in the first trimester, is associated with important sequelae in up to half of the children. Valaciclovir and immunoglobulin have been tested separately for the treatment of fetal CMV infection with relative success. Nevertheless, there is no experience with the simultaneous use of both therapies. METHODS: combination therapy (oral valaciclovir 2 g/6h until the end of pregnancy and intravenous hyperimmune gamma globulin 200 UI/kg) was offered to pregnant women with CMV infection acquired during pregnancy and viral load (VL) in amniotic fluid above 105 copies/ml and/or brain injuries in the ultrasonography. Additional immunoglobulin monthly doses were used in case of ultrasonography or MRI evidence of persistent fetal involvement. Neurological and hearing evaluations of infants were performed at birth and every 3 months during follow-up. RESULTS: 15 pregnant women were enrolled: primary infection, 14, non-primary infection, 1; first trimester, 11, second trimester, 4. Mean gestational age at the start of combination treatment were 23.2 weeks and 29.3 weeks, depending on the infection being diagnosed in the first or the second trimester, respectively. Median VL of CMV-DNA in amniotic fluid was 62.5 × 105 copies/ml. Intrauterine progression of fetal brain lesions was only observed in two cases in which the dose of CMV-HIG was repeated, slowing their progression. Although the treatment has failed to reverse ultrasound fetal lesions, only 3 children were born with hearing impairment and their psychomotor development was consistent with chronological age in all patients but one. Combination therapy was not associated with adverse effects in either the mothers or the fetuses. CONCLUSION: Combination therapy with immunoglobulin and valaciclovir may be a useful alternative in CMV fetal infection, particularly if changes in cerebral echography or high VL in the amniotic fluid are present.

Human Microbiome in Children, at the Crossroad of Social Determinants of Health and Personalized Medicine.

The evolving field of microbiome research offers an excellent opportunity for biomarker identification, understanding drug metabolization disparities, and improving personalized medicine. However, the complexities of host-microbe ecological interactions hinder clinical transferability. Among other factors, the microbiome is deeply influenced by age and social determinants of health, including environmental factors such as diet and lifestyle conditions. In this article, the bidirectionality of social and host-microorganism interactions in health will be discussed. While the field of microbiome-related personalized medicine evolves, it is clear that social determinants of health should be mitigated. Furthermore, microbiome research exemplifies the need for specific pediatric investigation plans to improve children's health.

Establishment of a miRNA profile in paediatric HIV-1 patients and its potential as a biomarker for effectiveness of the combined antiretroviral therapy.

miRNAs have been extensively studied in pathological conditions, including viral infections, such as those provoked by HIV-1. Several cellular and circulating miRNAs are altered during HIV-1 infection, with either beneficial effects on host defenses or enhanced virus infectivity. Blood samples were collected in sterile EDTA tubes and plasma was separated and stored, as were PBMCs. RNA was isolated and reverse-transcribed. Finally, the miRNA gene expression profile was assessed using TaqMan Array Human microRNA Card A v2.0. A comprehensive statistical analysis was performed on the results obtained. This is the first study on miRNAs in HIV-1 paediatric patients, and a miRNA profile differentiating patients starting combination antiretroviral therapy (cART) at different times after HIV-1 diagnosis was established. Thirty-four miRNAs were observed to have different expression levels between the control group and the cART group. The data indicates the need to start cART as soon as possible after the establishment of HIV-1 infection to assure the best outcome possible. Finally, the selected 34 miRNAs may be used as biomarkers for prognosis and assessing therapy effectiveness. However, more research must be conducted to establish adequate quantitative correlations.

Acute bronchiolitis and respiratory syncytial virus seasonal transmission during the COVID-19 pandemic in Spain: A national perspective from the pediatric Spanish Society (AEP).

INTRODUCTION AND OBJECTIVES: The COVID-19 pandemic and the widespread associated use of non-pharmaceutical interventions have impacted viral circulation and the incidence of respiratory tract infections. We compared Pediatric Emergency Department visits, bronchiolitis admissions, and respiratory syncytial virus (RSV) cases in 2020 with those documented for the preceding four years. METHODS: This was a retrospective multicentric national survey study, driven by the Pediatric Spanish Society, and gathering monthly data from Spanish hospitals between 1st January 2016 and 31st December 2020. An Interrupted Time Series Analysis and Poisson regression models were performed for each index. RESULTS: Thirty-eight hospitals representing most of the different regions of Spain participated. Compared to the preceding four years, in 2020, Pediatric emergency department visits significantly decreased immediately after initiation of the national lockdown. The median number of visits averted per month was 39,754 (IQR 26,539-50,065). RSV diagnoses during the 2020 winter season nearly disappeared with only 21 cases being documented among participating hospitals. The expected seasonal peak of bronchiolitis hospitalizations never occurred. The median number of admissions in 2020 averted per month was 100 (IQR 37-185) compared to 2016-2019. Only 3 hospitalized cases were RSV-confirmed. Reopening of schools and kindergarten was not associated with a remarkable increase in RSV cases or bronchiolitis hospitalizations. CONCLUSION: A dramatic reduction of bronchiolitis admissions and near disappearance of RSV cases was observed in Spanish hospitals coinciding with the peak of the COVID-19 pandemic.