Prospective study of loss of health-related quality adjusted life years in children and their families due to uncomplicated and hospitalised varicella.

INTRODUCTION AND AIMS: Although usually benign, varicella can lead to serious complications and sometimes long-term sequelae. Vaccines are safe and effective but not yet included in immunisation programmes in many countries. We aimed to quantify the impact on health-related quality of life (HRQoL) in terms of quality-adjusted life years (QALY) in children with varicella and their families, key to assessing cost-utility in countries with low mortality due to this infection. METHODS: Children with varicella in the community and admitted to hospitals in Portugal were included over 18 months from January 2019. Children's and carers' HRQoL losses were assessed prospectively using standard multi-attribute utility instruments for measuring HRQoL (EQ-5D and CHU9D), from presentation to recovery, allowing the calculation of QALYs. RESULTS: Among 109 families with children with varicella recruited from attendees at a pediatric emergency service (community arm), the mean HRQoL loss/child was 2.0 days (95 % CI 1.9-2.2, n = 101) (mean 5.4 QALYs/1000 children (95 % CI 5.3-6.1) and 1.3 days/primary carer (95 % CI 1.2-1.6, n = 103) (mean 3.6 QALYs /1000 carers (95 % CI 3.4-4.4). Among 114 families with children admitted to hospital because of severe varicella or a complication (hospital arm), the mean HRQoL loss/child was 9.8 days (95 % CI 9.4-10.6, n = 114) (mean 26.8 QALYs /1000 children (95 % CI 25.8-29.0) and 8.5 days/primary carer (95 % CI 7.4-9.6, n = 114) (mean 23.4 QALYs/1000 carers (95 % CI 20.3-26.2). Mean QALY losses/1000 patients were particularly high for bone and joint infections [67.5 (95 % CI 43.9-97.6)]. Estimates for children's QALYs lost using the CHU9D tool were well correlated with those obtained using EQ-5D, but substantially lower. CONCLUSIONS: The impact of varicella on HRQoL is substantial. We report the first measurements of QALYs lost in hospitalised children and in the families of children both in the community and admitted to hospital, providing important information to guide vaccination policy recommendations.

Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand.

BACKGROUND: Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. METHODS: Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. RESULTS: 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months (n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start (n=83) was 147 [16, 267] cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens-Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. CONCLUSION: Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis.

INTRODUCTION: Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. METHODS: Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10-17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. RESULTS: A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from <3 years in North America and Europe to >7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3 . Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3 . This decline was observed across all regions, in males and females. CONCLUSIONS: Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood.

Children living with HIV in Europe: do migrants have worse treatment outcomes?

OBJECTIVES: To assess the effect of migrant status on treatment outcomes among children living with HIV in Europe. METHODS: Children aged < 18 years at the start of antiretroviral therapy (ART) in European paediatric HIV observational cohorts where ≥ 5% of children were migrants (defined as born abroad) were included. Three outcomes were considered: (i) severe immunosuppression-for-age; (ii) viraemic viral load (≥ 400 copies/mL) at 1 year after ART initiation; and (iii) AIDS/death after ART initiation. The effect of migrant status was assessed using univariable and multivariable logistic and Cox models. RESULTS: Of 2620 children included across 12 European countries, 56% were migrants. At ART initiation, migrant children were older than domestic-born children (median 6.1 vs. 0.9 years, p < 0.001), with slightly higher proportions being severely immunocompromised (35% vs. 33%) and with active tuberculosis (2% vs. 1%), but a lower proportion with an AIDS diagnosis (14% vs. 19%) (all p < 0.001). At 1 year after beginning ART, a lower proportion of migrant children were viraemic (18% vs. 24%) but there was no difference in multivariable analysis (p = 0.702), and no difference in severe immunosuppression (p = 0.409). However, there was a trend towards higher risk of AIDS/death in migrant children (adjusted hazard ratio = 1.51, 95% confidence interval: 0.96-2.38, p = 0.072). CONCLUSIONS: After adjusting for characteristics at ART initiation, migrant children have virological and immunological outcomes at 1 year of ART that are comparable to those who are domestic-born, possibly indicating equity in access to healthcare in Europe. However, there was some evidence of a difference in AIDS-free survival, which warrants further monitoring.

[Case Series of 103 Children with SARS-CoV-2 Infection in Portugal]. / Série de Casos de 103 Crianças com Infeção por SARS-CoV-2 em Portugal.

INTRODUCTION: The North Lisbon University Hospital Center was activated for referral of SARS-CoV-2 infected patients on the 11th March 2020. The aim of this study is to describe the experience at the Department of Pediatrics in the approach and the clinical outcomes of infected children. MATERIAL AND METHODS: A descriptive observational study was performed. Children and adolescents (0 to 18 years) with SARS-CoV-2 infection, diagnosed in the emergency room or admitted to the Department of Pediatrics between March 11th and June 18th, were included. Hospital records and Trace COVID-19 platform were reviewed and patient caregivers were interviewed to assess follow up. RESULTS: Among 103 diagnosed children, 83% had a known previous contact with an infected patient, 43% presented fever and 42% presented respiratory symptoms. Ten percent had risk factors and 21% were aged under one year old. Ten percent were hospitalised, one needing intensive care, with paediatric inflammatory multisystem syndrome. Blood tests were performed in 9% and chest radiograph in 7%. No children required ventilation, antiviral therapy or underwent thoracic computed tomography scan. Eight percent of children returned to the emergency room and one child was hospitalised. The clinical outcome is known in 101 patients and is favourable in all. DISCUSSION: Most children had an epidemiological link and little clinical repercussion, even during the first year of life. The expected mild severity in children justified the use of established clinical criteria and recommendations for similar conditions, regarding tests and hospitalizations. No antiviral treatments were given due to lack of evidence of its benefits. CONCLUSION: This strategy contributed to a low consumption of hospital resources and proved safe in this series.

Introdução: O Centro Hospitalar Universitário Lisboa Norte foi ativado para referência de doentes com infeção SARS-CoV-2 em 11 de março de 2020. O objetivo deste estudo é descrever a experiência do Departamento de Pediatria na abordagem e evolução clínica de crianças infetadas.Material e Métodos: Realizámos um estudo observacional descritivo. Incluímos as crianças e adolescentes (0 aos 18 anos) com infeção por SARS-CoV-2 diagnosticados na urgência e internamento do nosso departamento entre 11 de março e 18 de junho de 2020. Consultámos registos internos e a plataforma Trace COVID-19 e contactámos os cuidadores para avaliação de seguimento.Resultados: De 103 crianças diagnosticadas, 83% tiveram contacto prévio identificado com doente infetado, 43% doentes apresentaram febre e 42% sintomas respiratórios. Em 10% havia fatores de risco; 21% tinham idade inferior a um ano. Foram internadas 10% das crianças, uma em cuidados intensivos com síndrome inflamatória multissistémica pediátrica. Foi efetuada avaliação laboratorial em 9%, radiografia torácica em 7%. Nenhum recebeu suporte ventilatório, terapêutica antiviral ou realizou tomografia computorizada torácica. Foram reobservadas em serviço de urgência 8% das crianças, sendo internada uma. A evolução foi conhecida em 101 casos sendo favorável em todos.Discussão: A maioria dos doentes tinha link epidemiológico familiar e pouca repercussão clínica, mesmo no primeiro ano de vida. A menor gravidade esperada na criança motivou a adoção de critérios habituais noutros quadros clínicos semelhantes para a realização de exames complementares de diagnóstico e internamento hospitalar. Não foi administrada terapêutica antiviral em nenhum doente por se considerar haver pouca evidência de benefício.Conclusão: Esta estratégia traduziu-se num baixo consumo de recursos hospitalares e revelou-se segura nesta série.

[Correction to the article "Case Series of 103 Children with SARS-CoV-2 Infection in Portugal", published on Acta Med Port 2020 Dec;33(12):795-802]. / Errata ao artigo "Série de Casos de 103 Crianças com Infeção por SARS-CoV-2 em Portugal", publicado em Acta Med Port 2020 Dec;33(12):795-802.

On page 801, fifth, where it reads: "No início da pandemia, teorizou-se que a vacina BCG pudesse ter um efeito protetor relativamente à COVID-19,27,28 mas não se encontrou até à data evidência para tal, não estando atualmente recomendada a vacinação BCG na prevenção da COVID-19.28,29 No nosso estudo, a maioria dos doentes (76%) tinha sido vacinada. Analisámos separadamente o subgrupo de crianças nascidas após janeiro de 2016, altura em que passaram a ser vacinadas apenas as crianças pertencentes a grupos de risco.30 A taxa de vacinação neste grupo foi de 51%, sendo superior à taxa de 30,1% estimada para crianças nascidas em Portugal com um ano de idade referido a 2019.31" It should read: "No início da pandemia, teorizou-se que a vacina BCG pudesse ter um efeito protetor relativamente à COVID-19,27,28 mas não se encontrou até à data evidência para tal, não estando atualmente recomendada a vacinação BCG na prevenção da COVID-19.28 No nosso estudo, a maioria dos doentes (76%) tinha sido vacinada. Analisámos separadamente o subgrupo de crianças nascidas após janeiro de 2016, altura em que passaram a ser vacinadas apenas as crianças pertencentes a grupos de risco.29 A taxa de vacinação neste grupo foi de 51%, sendo superior à taxa de 30,1% estimada para crianças nascidas em Portugal com um ano de idade referido a 2019.30" Paper published with errors: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/14537.

Na página 801, quinto parágrafo, onde se lê: "No início da pandemia, teorizou-se que a vacina BCG pudesse ter um efeito protetor relativamente à COVID-19,27,28 mas não se encontrou até à data evidência para tal, não estando atualmente recomendada a vacinação BCG na prevenção da COVID-19.28,29 No nosso estudo, a maioria dos doentes (76%) tinha sido vacinada. Analisámos separadamente o subgrupo de crianças nascidas após janeiro de 2016, altura em que passaram a ser vacinadas apenas as crianças pertencentes a grupos de risco.30 A taxa de vacinação neste grupo foi de 51%, sendo superior à taxa de 30,1% estimada para crianças nascidas em Portugal com um ano de idade referido a 2019.31" Deverá ler-se: "No início da pandemia, teorizou-se que a vacina BCG pudesse ter um efeito protetor relativamente à COVID-19,27,28 mas não se encontrou até à data evidência para tal, não estando atualmente recomendada a vacinação BCG na prevenção da COVID-19.28 No nosso estudo, a maioria dos doentes (76%) tinha sido vacinada. Analisámos separadamente o subgrupo de crianças nascidas após janeiro de 2016, altura em que passaram a ser vacinadas apenas as crianças pertencentes a grupos de risco.29 A taxa de vacinação neste grupo foi de 51%, sendo superior à taxa de 30,1% estimada para crianças nascidas em Portugal com um ano de idade referido a 2019.30"Artigo publicado com erros: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/14537.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study.

BACKGROUND: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. METHODS AND FINDINGS: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. CONCLUSIONS: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

Propionibacterium Acnes: Cause of Cerebrospinal Fluid Shunt Infection.

Infection after implantation of ventriculo-peritoneal shunts is associated with significant morbidity and mortality. We describe a 9-year-old girl with Propionibacterium acnes shunt infection with negative cerebrospinal fluid cultures, diagnosed by broad-range 16S-rRNA gene polymerase chain reaction. This case supports the use of this molecular diagnostic technique in shunt infections, where the offending pathogens are difficult to culture using traditional methods.

Ptosis, miosis and cats.

Horner's syndrome (HS) is caused by a disruption in the oculosympathetic pathway. Both congenital and acquired HS are unusual in children. Acquired HS can be caused by trauma, surgical intervention, tumours, vascular malformations or infection.We describe the case of a 6-year-old boy who was brought to our emergency department with ptosis, miosis, painful cervical lymphadenopathy and a cat scratch on a hand. The diagnosis of a cat scratch disease was confirmed by serology. A full recovery was observed on antibiotic treatment and cervical lymphadenomegaly reduction 3 weeks later.

Congenital malaria in a European country.

A newborn of 26 days, born in Lisbon, Portugal, presented with fever, anaemia and thrombocytopaenia. She was admitted considering neonatal sepsis, but Plasmodium vivax was identified in the second peripheral blood smear performed. Parenteral quinine was started with good evolution. Despite clinicians' unfamiliarity with congenital malaria in non-endemic areas, this diagnosis, although rare, should not be forgotten in the evaluation of newborns/infants born to women from endemic areas or with recent trip to these areas.

Biological control of the size and reactivity of catalytic Pd(0) produced by Shewanella oneidensis.

The interaction between Shewanella oneidensis MR-1 and the soluble metal Pd(II) during the reductive precipitation of Pd(0) determined the size and properties of the precipitated Pd(0) nanoparticles. Assessment of cell viability indicated that the bioreduction of Pd(II) was a detoxification mechanism depending on the Pd(II) concentration and on the presence and properties of the electron donor. The addition of H(2) in the headspace allowed S. oneidensis to resist the toxic effects of Pd(II). Interestingly, 25 mM formate was a less effective electron donor for bioreductive detoxification of Pd(II), since there was a 2 log reduction of culturable cells and a 20% decrease of viable cells within 60 min, followed by a slow recovery. When the ratio of Pd:cell dry weight (CDW) was below 5:2 at a concentration of 50 mg l(-1) Pd(II), most of the cells remained viable. These viable cells precipitated Pd(0) crystals over a relatively larger bacterial surface area and had a particle area that was up to 100 times smaller when compared to Pd(0) crystals formed on non-viable biomass (Pd:CDW ratio of 5:2). The relatively large and densely covering Pd(0) crystals on non-viable biomass exhibited high catalytic reactivity towards hydrophobic molecules such as polychlorinated biphenyls, while the smaller and more dispersed nanocrystals on a viable bacterial carrier exhibited high catalytic reactivity towards the reductive degradation of the anionic pollutant perchlorate.