Tuberculosis disease in immunocompromised children and adolescents: a pTBnet multi-centre case-control study.

BACKGROUND: In high-resource settings the survival of immunocompromised (IC) children has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools and outcome of IC children with TB in Europe. METHODS: Multicentre, matched case-control study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), capturing TB cases <18 years diagnosed 2000-2020. RESULTS: 417 TB cases were included, comprising 139 children with IC (HIV, inborn errors of immunity, drug-induced immunosuppression and other immunocompromising conditions) and 278 non-IC children as controls. Non-respiratory TB was more frequent among cases than controls (32.4% vs. 21.2%; p = 0.013). IC patients had an increased likelihood of presenting with severe disease (57.6% vs. 38.5%; p < 0.001; OR [95% CI]: 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs. 6.0%; p < 0.001) and QuantiFERON-TB Gold assay (30.0% vs. 7.3%; p < 0.001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs. 49.3%; p = 0.083). Although the mortality in IC children was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs. 6.1%; p = 0.004). CONCLUSIONS: IC children with TB disease in Europe have increased rates of non-respiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in IC patients, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.

Tuberculosis among children visiting friends & relatives.

BACKGROUND: Most paediatric tuberculosis (TB) cases in low-TB-incidence countries involve children born to migrant families. This may be partially explained by trips to their countries of origin for visiting friends and relatives (VFR). We aimed to estimate the risk of latent TB infection (LTBI) and TB in children VFR. METHODS: We conducted a prospective multicentric observational study in Catalonia (Spain) from 06/2017 to 12/2019. We enrolled children aged < 15 years with a negative tuberculin skin test (TST) at baseline and at least one parent from a high-TB-incidence country, and who had travelled to their parent's birth country for ≥21 days. TST and QuantiFERON-TB Gold Plus (QFT-Plus) were performed within 8-12 weeks post-return. LTBI was defined as a TST ≥5 mm and/or a positive QFT-Plus. RESULTS: Five hundred children completed the study, equivalent to 78.2 person-years of follow-up (PYFU). Thirteen children (2.6%) were diagnosed with LTBI (16.6/per100 PYFU,95%CI = 8.8-28.5), including two cases (0.4%) of TB (2.5/per100 PYFU, 95%CI = 0.3-9.3). LTBI incidence rates remained high after excluding BCG-vaccinated children (9.7/per100 PYFU,95%CI = 3.9-20.0). Household tobacco smoke exposure was associated with LTBI (aOR = 3.9, 95%CI = 1.1-13.3). CONCLUSIONS: The risk of LTBI in children VFR in high-TB-incidence countries may equal, or perhaps even exceed, the infection risk of the native population. The primary associated risk factor was the presence of smokers in the household. Furthermore, the incidence rate of active TB largely surpassed that of the countries visited. Children VFR in high-TB-incidence countries should be targeted for diagnostic and preventive interventions.

Management of paediatric soil-transmitted helminthiasis in a non-endemic area: experience in a reference international health unit.

Soil-transmitted helminth (STH) infections inflict disability worldwide, especially in the poorest communities. Current therapeutic options against STHs show limited efficacy, particularly against Trichuris trichiura. The empirical management of patients coming from high-prevalence areas has been suggested for non-endemic areas. This study aimed to describe the management of STH infections in a non-endemic setting using an individualised approach. We performed a retrospective, descriptive study of all patients up to 16 years of age with STH infections attended at an international health unit in a non-endemic area (2014-2018), including all T. trichiura, Necator americanus, Ancylostoma duodenale, and Ascaris lumbricoides infections diagnosed using a formol-ether concentration technique and direct visualisation. Patients were treated according to current international guidelines. Sixty-one stool samples from 48 patients testing positive for STHs were collected, with 96% (46/48) reporting a previous long-term stay in endemic areas. Cure rates with 3-day benzimidazole regimens were 72% for T. trichiura, 40% for hookworms, and 83% for A. lumbricoides. The results were not influenced by any reinfection risk due to the study being performed in a non-endemic area. Patients coming from STH-endemic areas should be evaluated with appropriate diagnostic tools and followed up until cure control results. Cure rates in our cohort were moderate to low, similar to those published in studies in endemic areas. The efficacy of current treatment options is insufficient to recommend a specific empirical approach in high-income countries' healthcare systems.

A longitudinal prospective study of active tuberculosis in a Western Europe setting: insights and findings.

PURPOSE: This study investigates the potential of inflammatory parameters (IP), symptoms, and patient-related outcome measurements as biomarkers of severity and their ability to predict tuberculosis (TB) evolution. METHODS: People with TB were included prospectively in the Stage-TB study conducted at five clinical sites in Barcelona (Spain) between April 2018 and December 2021. Data on demographics, epidemiology, clinical features, microbiology, and Sanit George Respiratory Questionnaire (SGRQ) and Kessler-10 as Health-Related Quality of Life (HRQoL) were collected at three time points during treatment. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil/lymphocyte, and monocyte/lymphocyte ratios (NLR and MLR), complement factors C3, C4, and cH50, clinical and microbiological data, and HRQoL questionnaires were assessed at baseline, 2 months, and 6 months. Their ability to predict sputum culture conversion (SCC) and symptom presence after 2 months of treatment was also analysed. RESULTS: The study included 81 adults and 13 children with TB. The CRP, ESR, NLR, and MLR values, as well as the presence of symptoms, decreased significantly over time in both groups. Higher IP levels at baseline were associated with greater bacillary load and persistent symptoms. Clinical severity at baseline predicted a delayed SCC. Kessler-10 improved during follow-up, but self-reported lung impairment (SGRQ) persisted in all individuals after 6 months. CONCLUSIONS: IP levels may indicate disease severity, and sustained high levels are linked to lower treatment efficacy. Baseline clinical severity is the best predictor of SCC. Implementing health strategies to evaluate lung function and mental health throughout the disease process may be crucial for individuals with TB.

Prevalence and morbidity of urogenital schistosomiasis among pre-school age children in Cubal, Angola.

BACKGROUND: Schistosomiasis is one of the most important neglected tropical diseases, with a great impact on public health and more than 200,000 deaths annually. Schistosoma haematobium causes urinary tract (UT) morbidity. Since schistosomiasis morbidity control programs focus on children older than 5 years, pre-school age children (PSAC) morbidity is not well known. METHODS: We conducted a cross-sectional study in Cubal (Angola) among 245 PSAC with the objective of evaluating the prevalence of S. haematobium infection, the intensity of infection, and associated morbidity. For this purpose, urine filtration test followed by microscopic visualization and ultrasound examinations were performed. RESULTS: The estimated overall prevalence of urogenital schistosomiasis was 30.2% (CI 95%; 24.5-35.9), with 20.3% (CI 95%; 15.3-25.3) of the samples analysed showing a high intensity of infection. A total of 54.5% (CI 95%; 47.6-61.8) of infected children presented UT lesions, showing a significant association between schistosomiasis infection and UT morbidity (p-value < 0.001). Bladder wall thickening was the most common lesion, being present in 100% of abnormal ultrasounds. We found that anaemia and severe malnutrition were not significantly associated with the development of UT lesions. CONCLUSIONS: S. haematobium infection in PSAC causes great UT detectable morbidities. Therefore, there is an evident need of including them in mass drug administration (MDA) campaigns and consequently the development of an adapted praziquantel treatment dosage for children under 2 years of age.

The Value of the Second QuantiFERON-TB Gold-Plus Antigen Tube at Diagnosis and at Treatment Completion in Spanish Children With Tuberculosis.

We studied 295 children (tuberculosis disease, n = 159; latent tuberculosis infection, n = 136) with positive QuantiFERON-TB Gold-Plus assay results. No significant differences between first and second antigen tube interferon-gamma responses were detected, irrespective of patient and disease characteristics at diagnosis. Of patients with a repeat assay after treatment completion (n = 65), only 16.9% converted to negative results.

Prevalence and Clinical Characteristics of Children With Nonsevere Tuberculosis in Spain.

BACKGROUND: To assess the prevalence and characteristics of nonsevere TB among children in Spain. It has been recently demonstrated that these children can be treated with a 4-month regimen instead of the classical 6-month treatment regimen, with the same effectivity and outcomes, decreasing toxicity and improving adherence. METHODS: We conducted a retrospective cohort study in a cohort of children ≤16 years of age with TB. Nonsevere TB cases included smear-negative children with respiratory TB confined to 1 lobe, with no significant airway obstruction, no complex pleural effusion, no cavities and no signs of miliary disease, or with peripheral lymph-node disease. The remaining children were considered to have severe TB. We estimated the prevalence of nonsevere TB and compared the clinical characteristics and outcomes between children with nonsevere and severe TB. RESULTS: A total of 780 patients were included [46.9% males, median age 5.5 years (IQR: 2.6-11.1)], 477 (61.1%) of whom had nonsevere TB. Nonsevere TB was less frequent in children <1 year (33% vs 67%; P < 0.001), and >14 years of age (35% vs 65%; P = 0.002), mostly diagnosed in contact tracing studies (60.4% vs 29.2%; P < 0.001) and more frequently asymptomatic (38.3% vs 17.7%; P < 0.001). TB confirmation in nonsevere disease was less frequent by culture (27.0% vs 57.1%; P < 0.001) and by molecular tests (18.2% vs 48.8%; P < 0.001). Sequelae were less frequent in children with nonsevere disease (1.7 vs 5.4%; P < 0.001). No child with nonsevere disease died. CONCLUSIONS: Two-thirds of children had nonsevere TB, mostly with benign clinical presentation and negative microbiologic results. In low-burden countries, most children with TB might benefit from short-course regimens.

Performance of QuantiFERON-TB Gold Plus assays in paediatric tuberculosis: a multicentre PTBNET study.

RATIONALE: In 2016, a new interferon-gamma release assay (IGRA) was introduced, QuantiFERON-TB Gold Plus (QFT-Plus), claimed to have improved sensitivity in active tuberculosis (TB). OBJECTIVES: This study aimed to determine the performance of QFT-Plus, compared with previous generation IGRAs and the tuberculin skin test (TST), in children with TB in Europe. METHODS: Multicentre, ambispective cohort study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), a dedicated paediatric TB research network comprising >300 members, capturing TB cases <18 years-of-age diagnosed between January 2009 and December 2019. MEASUREMENTS AND MAIN RESULTS: 1001 TB cases from 16 countries were included (mean age (IQR) 5.6 (2.4-12.1) years). QFT-Plus was performed in 358, QFT Gold in-Tube (QFT-GIT) in 600, T-SPOT.TB in 58 and TST in 636 cases. The overall test sensitivities were: QFT-Plus 83.8% (95% CI 80.2% to 87.8%), QFT-GIT 85.5% (95% CI 82.7% to 88.3%), T-SPOT.TB 77.6% (95% CI 66.9% to 88.3%) and TST (cut-off ≥10 mm) 83.3% (95% CI 83.3% to 86.2%). There was a trend for tests to have lower sensitivity in patients with miliary and/or central nervous system (CNS) TB (73.1%, 70.9%, 63.6% and 43.5%, respectively), and in immunocompromised patients (75.0%, 59.6%, 45.5% and 59.1%, respectively). CONCLUSIONS: The results indicate that the latest generation IGRA assay, QFT-Plus, does not perform better than previous generation IGRAs or the TST in children with TB disease. Overall, tests performed worse in CNS and miliary TB, and in immunocompromised children. None of the tests evaluated had sufficiently high sensitivity to be used as a rule-out test in children with suspected TB.

Neurological Short-Term Outcomes of a Cohort of Children Born to Zika Virus-Infected Mothers in Barcelona.

Zika virus (ZIKV) is a vector-borne flavivirus with a known teratogenic effect, yet the full spectrum has not been delineated. Studies on endemic areas tried to characterize the clinical outcomes of ZIKV intrauterine exposure. We aimed to describe early neurodevelopmental outcomes on prenatally ZIKV-exposed children in a non-endemic ZIKV area. This is a prospective observational cohort study conducted from May 2016 to December 2021 at Hospital Universitari Vall d'Hebron in Barcelona, Catalonia, Spain. We monitored for up to 24 months 152 children extracted from a pregnant women cohort with suspected ZIKV infection; eleven women (11/150; 7.3%) fulfilled the criteria for a confirmed ZIKV infection. Among the 152 children included, we describe two cases of congenital ZIKV syndrome (CZS) born from women with a confirmed ZIKV infection. Additionally, we describe five cases of other potentially ZIKV-related outcomes (OPZROs), all with normal birth cranial circumference and born to women with probable ZIKV infection. The low exposed prevalence of adverse outcomes in asymptomatic children at birth in a non-endemic area suggests that close follow-up should be addressed by primary care pediatricians instead of pediatric specialists. Further studies are needed to assess the effects of ZIKV intrauterine exposure beyond two years of life.

Health and Vaccination Status of Unaccompanied Minors After Arrival in a European Border Country: A Cross-sectional Study (2017-2020).

BACKGROUND: Unaccompanied and separated children (UASC) are a high-risk group for infectious diseases and information on their vaccination status is scarce. Different approaches are used to screen newly arrived minors in Europe. The aim of this study was to describe the health status and serological protection against different vaccine-preventable diseases among UASC to inform public health decision-making. METHODS: Retrospective study of all UASC seen at an international health reference center in Barcelona (Spain) between January 2017 and February 2020. Screening results were analyzed using binary logistic regression with adjustment for symptoms, geographic origin, and time since arrival. RESULTS: We studied 289 UASC (88.9% males; median age, 17 years). At least one infection was diagnosed in 136 minors (47.1%). There was a high prevalence of intestinal parasites (22.8%), latent tuberculosis infection (22.5%), and hepatitis B (5.2%), even in asymptomatic individuals, and especially among UASC from sub-Saharan Africa (odds ratio, 2.5; 95% confidence interval, 1.5-4.0, P < 0.001). We did not observe a significant association between clinical symptoms and the presence of infection or differences in the prevalence of different infections according to number of months since arrival. Protection against hepatitis B virus (36%), measles (80%), and varicella (83%) was suboptimal. CONCLUSIONS: Our results highlight the importance of screening and vaccination programs for UASC arriving in Europe, especially border countries. Protocols should be adjusted according to geographic origin. Absence of symptoms does not necessarily rule out infection, highlighting the importance of screening in asymptomatic minors. These programs are a public health priority and should not be neglected during the current COVID-19 pandemic.

MDR Tuberculosis Treatment.

Multidrug-resistant (MDR) tuberculosis (TB), resistant to isoniazid and rifampicin, continues to be one of the most important threats to controlling the TB epidemic. Over the last few years, there have been promising pharmacological advances in the paradigm of MDR TB treatment: new and repurposed drugs have shown excellent bactericidal and sterilizing activity against Mycobacterium tuberculosis and several all-oral short regimens to treat MDR TB have shown promising results. The purpose of this comprehensive review is to summarize the most important drugs currently used to treat MDR TB, the recommended regimens to treat MDR TB, and we also summarize new insights into the treatment of patients with MDR TB.

Treatment of Complex Cutaneous Leishmaniasis with Liposomal Amphotericin B.

BACKGROUND: There is no consensus for the best treatment of complex cutaneous leishmaniasis (CL). We aimed to describe a cohort of CL, focusing on liposomal amphotericin B (L-AmB) treatment outcome. METHODS: We performed a retrospective study in Vall d'Hebron University Hospital (Barcelona, Spain). All patients with parasitologically proven CL diagnosed from 2012 to 2018 were included. RESULTS: The analysis included 41 patients with CL. The median age was 39 years (IQR 12- 66); 12 (29%) were children, and 29 (71%) were men. Regarding treatment, 24 (59%) received local treatment, whereas 17 (41%) had complex CL and were offered intravenous systemic treatment. Sixteen patients received L-AmB; eight (50%) had adverse events, and three (19%) discontinued treatment for safety reasons. All cases were considered cured within the first year post-treatment. CONCLUSIONS: L-AmB for complex CL showed no treatment failures, offering an alternative treatment option for patients with complex CL. Clinicians should pay close attention to the potential adverse events of L-AmB and adopt an active drug safety surveillance scheme to rapidly detect reversible side effects.

QuantiFERON-TB Gold Plus Assay Specificity in Children and Adolescents With Suspected Tuberculosis-A Multicenter Cross-sectional Study in Spain.

In this cross-sectional study of 284 children and adolescents with clinically or radiologically suspected tuberculosis in a low-endemic country, the QuantiFERON-TB Gold Plus assay specificity, sensitivity, positive predictive value and negative predictive value were 91.5%, 87.3%, 86.4%, and 91.2%, respectively. The specificity was higher than that observed in tuberculin skin tests performed simultaneously, but similar to previous-generation interferon-gamma release assays.

Zika Virus Infection in Tourists Travelling to Thailand: Case Series Report.

Thailand is a popular tourist destination where Zika virus (ZIKV) transmission is currently active. To our knowledge, there are no reports of ZIKV infection imported from Thailand and affecting children. Here, we describe the clinical and microbiological findings in three cases of vector-borne ZIKV infection: An 11-year-old boy, a 2-year-old girl, and her pregnant mother, this last case leading to the prenatal exposure of her second baby to ZIKV in the second trimester of pregnancy. All patients were diagnosed after traveling to Thailand between September 2019 and January 2020. No complications were detected in any patient at follow-up, and the prenatally exposed fetus showed no abnormalities during intensive antenatal health care monitoring. On postnatal study, there were no clinical signs or microbiological findings of mother-to-child ZIKV transmission. ZIKV IgG was initially positive, but seroreversion occurred at 4 months of life. This report describes the clinical and serological evolution of vector-borne ZIKV infection occurring in dengue-naïve tourists returning from Thailand. The World Health Organization currently recommends that pre-travel advice to prevent arbovirus infection should be maintained in travelers to Southeast Asia.

Adverse Events Associated With New Injectable-Free Multidrug-Resistant Tuberculosis Drug Regimens / Efectos adversos asociados a los nuevos tratamientos farmacológicos sin inyectables contra la tuberculosis multirresistente

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Tuberculosis infection in children visiting friends and relatives in countries with high incidence of tuberculosis: A study protocol.

INTRODUCTION: Tuberculosis (TB) is a global infectious disease. In low-incidence countries, paediatric TB affects mostly immigrant children and children of immigrants. We hypothesize that these children are at risk of exposure to Mycobacterium tuberculosis when they travel to the country of origin of their parents to visit friends and relatives (VFR). In this study, we aim to estimate the incidence rate and risk factors associated to latent tuberculosis infection (LTBI) and TB in VFR children. METHODS AND ANALYSIS: A prospective study will be carried out in collaboration with 21 primary health care centres (PCC) and 5 hospitals in Catalonia, Spain. The study participants are children under 15 years of age, either immigrant themselves or born to immigrant parents, who travel to countries with high incidence of TB (≥ 40 cases/100,000 inhabitants). A sample size of 492 children was calculated. Participants will be recruited before traveling, either during a visit to a travel clinic or to their PCC, where a questionnaire including sociodemographic, epidemiological and clinical data will be completed, and a tuberculin skin test (TST) will be performed and read after 48 to 72 hours; patients with a positive TST at baseline will be excluded. A visit will be scheduled eight to twelve-weeks after their return to perform a TST and a QuantiFERON-TB Gold Plus test. The incidence rate of LTBI will be estimated per individual/month and person/year per country visited, and also by age-group. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Ethics Committee of the Hospital Universitari Mútua Terrassa (code 02/16) and the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (code P16/094). Articles will be published in indexed scientific journals. TRIAL REGISTRATION: Clinical-Trials.gov: NCT04236765.

Manifestaciones cutáneas en contexto del brote actual de enfermedad por coronavirus 2019 / Cutaneous manifestations in the current pandemic of coronavirus infection disease (COVID 2019)

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Clinical Outcomes of a Zika Virus Mother-Child Pair Cohort in Spain.

BACKGROUND: Zika virus (ZIKV) infection has been associated with congenital microcephaly and other neurodevelopmental abnormalities. There is little published research on the effect of maternal ZIKV infection in a non-endemic European region. We aimed to describe the outcomes of pregnant travelers diagnosed as ZIKV-infected in Spain, and their exposed children. METHODS: This prospective observational cohort study of nine referral hospitals enrolled pregnant women (PW) who travelled to endemic areas during their pregnancy or the two previous months, or those whose sexual partners visited endemic areas in the previous 6 months. Infants of ZIKV-infected mothers were followed for about two years. RESULTS: ZIKV infection was diagnosed in 163 PW; 112 (70%) were asymptomatic and 24 (14.7%) were confirmed cases. Among 143 infants, 14 (9.8%) had adverse outcomes during follow-up; three had a congenital Zika syndrome (CZS), and 11 other potential Zika-related outcomes. The overall incidence of CZS was 2.1% (95%CI: 0.4-6.0%), but among infants born to ZIKV-confirmed mothers, this increased to 15.8% (95%CI: 3.4-39.6%). CONCLUSIONS: A nearly 10% overall risk of neurologic and hearing adverse outcomes was found in ZIKV-exposed children born to a ZIKV-infected traveler PW. Longer-term follow-up of these children is needed to assess whether there are any later-onset manifestations.