Transient Viral Rebound in Children with Perinatally Acquired HIV-1 Induces a Unique Soluble Immunometabolic Signature Associated with Decreased CD4/CD8 Ratio.

BACKGROUND: To determine by multi-omic analysis changes in metabolites, lipids, and proteins as a consequence of transient viral rebound (tVR) in children with perinatally acquired HIV-1 (PHIV). METHODS: Plasma samples from children with PHIV and with tVR (first episode of transient RNA-HIV viral load >20 copies/ml followed by suppression) on the time-point immediately before (pre-tVR) and after (post-tVR) the tVR were assessed. Multi-omic analyses were performed using nLC-Orbitrap, GC-qTOF-MS, and LC-qTOF-MS. RESULTS: Comparing pre- and post-tVR time-points, HIV-1 children with tVR (n = 5) showed a trend to a decrease in ratio CD4/CD8 (p = 0.08) but no significant differences were observed in plasma metabolites, lipids, or proteins. Post-tVR condition was compared with a reference group of children with PHIV with persistent viral control (n = 9), paired by sex, age, and time under antiretroviral treatment. A total of 10 proteins, 8 metabolites, and 2 lipids showed significant differences (p < 0.05): serotransferrin, clusterin, kininogen-1, succinic acid, threonine, 2-hydroxyisovaleric acid, methionine, 2-hydroxyglutaric, triacylglyceride 50:0 (TG50:0), and diacylglyceride 34:1 (DG34:1) were upregulated while alpha-2-macroglobulin, apolipoprotein A-II, carboxylic ester hydrolase, apolipoprotein D, coagulation factor IX, peptidase inhibitor 16, SAA2-SAA4 readthrough, oleic acid, palmitoleic acid, and D-sucrose downregulated on post-tVR time-point compared to the reference group. Ratio CD4/CD8 correlated with apolipoprotein A-II, DG34:1, and methionine (p = 0.004; ρ = 0.71, p = 0.016; ρ = -0.63; and p = 0.032; ρ = -0.57, respectively). Nadir CD4+ correlated inversely with kininogen-1 (p = 0.022; ρ = -0.60) and positively with D-sucrose (p = 0.001; ρ = 0.77). CONCLUSIONS: tVR followed by suppression implies changes in soluble proteins, lipids, and metabolites that correlate with immunological parameters, mainly ratio CD4/CD8, that decreased after tVR. These distinct soluble biomarkers could be considered potential biomarkers of immune progression.

Clinical and Epidemiologic Characteristics of a Cohort of HIV-Infected Mother-Infant Pairs During 21 Years.

BACKGROUND: HIV infection continues to be a worldwide public health problem. After the introduction of effective preventive measures, perinatal transmission dramatically decreased. Our aim was to assess the sociodemographic changes in pregnant women living with HIV infection and trends in perinatal transmission rates over time. SETTING: The Madrid cohort of HIV-infected mother-infant pairs is a multicenter, prospective, observational, and cohort study that collects information on HIV-infected pregnant women and their children. METHODS: Information on clinical-epidemiological characteristics of HIV-infected pregnant women until delivery and their children from 9 public hospitals was included. Data were collected from a standardized questionnaire from medical records. The results were classified in 3 periods: period 1 (P1) 2000-2006, period 2 (P2) 2007-2013, and period 3 (P3) 2014-2020. RESULTS: A total of 1521 women living with HIV and 1548 newborns were included. In P1, most mothers (75.8%) were Spanish, whereas in P2 and P3 there was a predominance of foreign origin [62.8% and 70.5% respectively ( P < 0.01)]. The percentage of women with antiretroviral treatment before pregnancy increased significantly in P3 ( P < 0.01). The proportion of Caesarean sections decreased over time ( P < 0.01): 66.2% (n = 472) in P1, 54.9% (n = 245) in P2, and 46.7% (n = 141) in P3. The percentage of preterm and low birth weight newborns showed a statistically significant decrease. Even though there were no statistically significant differences ( P = 0.154), a decrease in cases of perinatal infection was observed (1.6% in P1, 1.3% in P2 and 0.3% in P3). CONCLUSIONS: The epidemiologic characteristics of pregnant women with HIV infection have changed over time in our setting, with an increase of non-Caucasian, heterosexual, and perinatally infected mothers. Although there are still perinatal infections, especially in vulnerable populations such as immigrant women, transmission rate has markedly decreased in recent years and is still of major concern. Prevention measures should be reinforced in the most socially disadvantaged groups.

SARS-CoV-2 Infection in Children and Adolescents Living With HIV in Madrid.

Multicenter study designed to describe epidemiologic and clinical characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive cases registered among children and adolescents living with HIV (CALWH). SARS-CoV-2 infection was confirmed in 13.3% of CALWH, with all patients presenting mild symptoms, and the outcome was good in all patients. None of the HIV- and antiretroviral treatment-related variables studied were associated with greater infection risk or could be considered protective.

New diagnosis of mother-to-child transmission of HIV in 8 Latin-American countries during 2018.

BACKGROUND: Important prevention efforts have led to a reduction in mother-to-child transmission of HIV (MTCT) globally. However, new cases of paediatric HIV infections still occur. Early diagnosis of new HIV infections is essential to start an appropriate antiretroviral treatment to avoid childhood morbidity and mortality related to infection. The aim of this study was to describe the new cases of MTCT in Latin-American referral hospitals. METHODS: A retrospective, multicentre and descriptive study of the new cases of MTCT diagnosed during 2018 in 13 referral hospitals from 8 Latin-American countries (Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama) belonging to PLANTAIDS (Paediatric Network for Prevention, Early Detection and Treatment of HIV in Children), was conducted. PLANTAIDS is included in CYTED (Ibero-American Programme of Science and Technology for Development). RESULTS: Eighty-one children (40.7% males) were included, median age at diagnosis of 2.33 years (IQR:0.7-4.7). Less than 3% of women knew their HIV diagnosis before pregnancy. More than 80% of them were diagnosed after delivery, 8.7% during pregnancy, and 2.9% at delivery. Only one patient underwent antiretroviral therapy (ART) prior to pregnancy. At diagnosis, 50.0% of the children presented with an advanced stage of disease (stage C following the current CDC classification for HIV infection), and 34.4% had less than 15% CD4+ cells/mm3. The time elapsed between delivery and the maternal diagnosis was correlated with the age of children at diagnosis, ρ = 0.760, p < 0.001. Younger age at diagnosis (p = 0.03), a smaller number of previous hospitalizations (p < 0.01), and better immunovirological status (p < 0.01) were found in children whose mothers knew their HIV status at delivery, compared to mothers who were not aware of it. CONCLUSIONS: Although MTCT in Latin America has declined in recent years, our series shows there are still cases that indicate some failures in prevention, being a critical point to improve an earlier diagnosis of pregnant women. Half of the children were diagnosed in an advanced stage of disease and the delay in maternal diagnosis entailed a worse clinical and immunological child' prognosis.

Etiology and outcome of febrile children coming from the tropics.

INTRODUCTION: International travelers have grown significantly over last years, as well as imported diseases from tropical areas. Information in pediatric population is scarce. We describe demographic and clinical characteristics of febrile children coming from the tropics. METHODS: Retrospective review of patients under 18 years old, presenting at a tertiary hospital and surrounding primary health care centers between July 2002 and July 2018 with a stay in a tropical region during the previous year. Patients were selected from microbiological charts of thick smears for malaria or dengue serologies. RESULTS: 188 patients were studied: 52.7% were born in Spain with a median age of 3.0 years old (IQR 1.5-8.0). Main regions of stay were Sub-Saharan Africa (54.8%) and Latin America (29.8%), mostly for visiting their friends and relatives (56.3%), followed by recent arrival migrants (32.4%). Only 34% of travelers attended pre-travel consultation. More than 80% of these febrile children attended directly the Emergency Room. The most frequent diagnoses were febrile syndrome without source (56.4%), respiratory condition (15.4%) and acute diarrhea (11.7%). Around a half (52.1%) were managed as outpatients, but 46.2% were hospitalized and 7.4% were admitted to Intensive Care Unit. No specific diagnosis was achieved in 24% of cases. However, 29.7% were diagnosed with malaria. CONCLUSION: Children with fever coming from tropical areas were at risk of severe infectious diseases. Malaria was diagnosed in one out of four and 7% required admission in PICU. This information emphasizes the need of reinforcing training about tropical diseases among first line physicians.

Safety and Experience With Combined Antiretroviral Prophylaxis in Newborn at High-risk of Perinatal HIV Infection, in a Cohort of Mother Living With HIV-infant Pairs.

BACKGROUND: Perinatal transmission of HIV has dramatically decreased in high-income countries in the last few years with current rates below 1%, but it still occurs in high-risk situations, mainly pregnant women with late diagnosis of infection, poor antiretroviral adherence and a high viral load (VL). In these high-risk situations, many providers recommend combined neonatal prophylaxis (CNP). Our aim was to evaluate the safety and toxicity of CNP in infants deemed at high-risk of HIV infection among mother-infant pairs in the Madrid Cohort. MATERIALS AND METHODS: Prospective, multicenter, observational cohort study between years 2000 and 2019. The subgroup of newborns on CNP and their mothers were retrospectively selected (cohort A) and compared with those who received monotherapy with zidovudine (cohort B). Infants with monotherapy were classified according to treatment regimes in long (6 weeks) and short (4 weeks) course. RESULTS: We identified 227 newborns (33.3% preterm and 7 sets of twins) with CNP. A maternal diagnosis of HIV-1 infection was established during the current pregnancy in 72 cases (36.4%) and intrapartum or postpartum in 31 cases (15.7%). Most infants received triple combination antiretroviral therapy (65.6%; n = 149). The perinatal transmission rate in cohort A was 3.5% (95% confidence interval: 1.13%-5.92%). Infants from cohort A developed anemia (26.1% vs. 19.4%, P = 0.14) and neutropenia more frequently at 50-120 days (21.4% vs. 10.9%, P < 0.01), without significant differences in grade 3 and 4 anemia or neutropenia between the two cohorts. There were no differences in increased alanine aminotransferase. Neutropenia was more common in the long zidovudine regimes. CONCLUSIONS: Our findings provide further evidence of the safety of CNP in infants with high-risk of HIV-1 perinatal transmission.

Etiology and outcome of febrile children coming from the tropics.

INTRODUCTION: International travelers have grown significantly over last years, as well as imported diseases from tropical areas. Information in pediatric population is scarce. We describe demographic and clinical characteristics of febrile children coming from the tropics. METHODS: Retrospective review of patients under 18 years old, presenting at a tertiary hospital and surrounding primary health care centers between July 2002 and July 2018 with a stay in a tropical region during the previous year. Patients were selected from microbiological charts of thick smears for malaria or dengue serologies. RESULTS: 188 patients were studied: 52.7% were born in Spain with a median age of 3.0 years old (IQR 1.5-8.0). Main regions of stay were Sub-Saharan Africa (54.8%) and Latin America (29.8%), mostly for visiting their friends and relatives (56.3%), followed by recent arrival migrants (32.4%). Only 34% of travelers attended pre-travel consultation. More than 80% of these febrile children attended directly the Emergency Room. The most frequent diagnoses were febrile syndrome without source (56.4%), respiratory condition (15.4%) and acute diarrhea (11.7%). Around a half (52.1%) were managed as outpatients, but 46.2% were hospitalized and 7.4% were admitted to Intensive Care Unit. No specific diagnosis was achieved in 24% of cases. However, 29.7% were diagnosed with malaria. CONCLUSION: Children with fever coming from tropical areas were at risk of severe infectious diseases. Malaria was diagnosed in one out of four and 7% required admission in PICU. This information emphasizes the need of reinforcing training about tropical diseases among first line physicians.

Tuberculosis in the paediatric population of Madrid in the last 26 years. / Enfermedad tuberculosa en población pediátrica en Madrid en los últimos 26 años.

INTRODUCTION: Tuberculosis (TB) continues to be a serious public health problem and establishing a definitive diagnosis among children is extremely challenging. Pulmonary tuberculosis is the most prevalent form, with children under the age of 2 years being at greatest risk of severe and disseminated forms. The aim of this study was to describe TB among children in Spain in recent years. PATIENTS AND METHODS: A retrospective study of paediatric patients diagnosed with TB in two hospitals of the Community of Madrid over a 26-year period (1991-2017). Epidemiological and clinical variables, additional tests and treatments received were analysed. RESULTS: 170 children were included. The two most-affected age groups were infancy and adolescence. 42.9% of patients were immigrant children (South-America or Morocco). The main reasons for consultation were TB contact (20.6%) and fever (15.3%). At diagnosis, 61.8% of cases referred an epidemic environment, and 30.6% were asymptomatic. The Mantoux tuberculin skin test was positive in 92.2% of patients and IGRA was positive in 70.6%. Pulmonary TB was identified in 91.8% of children vs. 8.2% with extrapulmonary forms. Gastric juice culture was positive in 36.9% of cases and three strains resistant to isoniazid were isolated. All patients were cured without complications except one who died. CONCLUSIONS: Pulmonary TB continues to be the most prevalent form among children and presumptive diagnosis (symptoms consistent with positive Mantoux test or suggestive X-ray) is the most common form of diagnosis. It is important to conduct a contact investigation in order to control the spread of TB.

[Evaluation of an Xpert EV (Cepheid®) molecular diagnostic technique for enteroviral meningitis]. / Evaluación de una técnica de diagnóstico molecular Xpert EV (Cepheid®) en la meningitis por enterovirus.

INTRODUCTION: Polymerase chain reaction (PCR) assays have shown to be useful and quick for the diagnosis of enterovirus in aseptic meningitis. The aim of our study was to analyse the changes in clinical practice after the introduction of a real-time polymerase chain reaction (RT-PCR) technique using the Xpert EV (Cepheid®) assay for the qualitative detection of enterovirus RNA in cerebrospinal fluid specimens from children with suspected viral meningitis. METHODS: A retrospective study was performed in children older than 1year, diagnosed with enterovirus meningitis in a third level hospital from November 2006 to February 2013. The first period, before the availability of Xpert EV (Cepheid®) (Group1, November 2006-August 2010) was compared with the later period (Group2, September 2010-February 2013). Clinical characteristics, the mean length of stay, and the cost per inpatient cases, were compared between the 2periods. RESULTS: Forty-one patients (60.9% male) were included, with a median age of 64 months (interquartile range 28-96). Twenty-six patients (63.4%) were included in Group2. There were non-statistically significant differences in the epidemiological, disease severity, and laboratory characteristics between both periods of study. A significant difference was observed in the mean length of stay, with it being shorter in Group2 (48hours vs 40.5hours, P=.039), and a significant lower inpatient cost per case (€779.77 vs €656.05, P<.05). CONCLUSION: Xpert EV (Cepheid®) assay was useful for decreasing the length of hospital stay and the costs associated with hospitalisation in children with enterovirus meningitis.

[Early diagnosis of human immunodeficiency virus-1 in infants: The prevention of mother-to-child transmission program in Equatorial Guinea]. / Diagnóstico precoz de la infección por el virus de la inmunodeficiencia humana-1 en niños: programa de prevención de la transmisión maternoinfantil en Guinea Ecuatorial.

BACKGROUND: Great efforts have been made in the last few years in order to implement the prevention of mother-to-child transmission (PMTCT) program in Equatorial Guinea (GQ). The aim of this study was to evaluate the rates of mother-to-child HIV transmission based on an HIV early infant diagnosis (EID) program. METHODS: A prospective observational study was performed in the Regional Hospital of Bata and Primary Health Care Centre Maria Rafols, Bata, GQ. Epidemiological, clinical, and microbiological characteristics of HIV-1-infected mothers and their exposed infants were recorded. Dried blood spots (DBS) for HIV-1 EID were collected from November 2012 to December 2013. HIV-1 genome was detected using Siemens VERSANT HIV-1 RNA 1.0 kPCR assay. RESULTS: Sixty nine pairs of women and infants were included. Sixty women (88.2%) had WHO clinical stage 1. Forty seven women (69.2%) were on antiretroviral treatment during pregnancy. Forty five infants (66.1%) received postnatal antiretroviral prophylaxis. Age at first DBS analysis was 2.4 months (IQR 1.2-4.9). One infant died before a HIV-1 diagnosis could be ruled out. Two infants were HIV-1 infected and started HAART before any symptoms were observed. The rate of HIV-1 transmission observed was 2.9% (95%CI 0.2-10.5). CONCLUSIONS: The PMTCT rate was evaluated for the first time in GQ based on EID. EID is the key for early initiation of antiretroviral therapy and to reduce the mortality associated with HIV infection.

[Characteristics of a cohort of pregnant women with human immunodeficiency virus infection]. / Características de una cohorte materna con infección por el virus de la inmunodeficiencia humana.

BACKGROUND: Mother-to-child transmission (MTCT) during pregnancy, delivery or breastfeeding, is the main route of HIV infection in children. Strategies aimed at promoting the health of HIV infected pregnant women and MTCT prevention have reduced transmission to below 2%. This paper presents the clinical and epidemiological features of a cohort from Madrid and compares foreign-born with Spanish-born women. METHOD: Retrospective, observational and descriptive study on HIV infected pregnant women from South Madrid (n=70) and their offspring (n=78) who were born during the study period from August 1992 to January 2010. RESULTS: Most pregnant women were infected by heterosexual transmission (51%). Most Spanish-born women (66%) were diagnosed before pregnancy (81%), while foreign-born women (34%) were diagnosed during pregnancy (70%). Foreign-born women had less obstetric check-ups (67%) than Spanish-born women (97%). The MTCT rate was 1.3% during the last ten years. CONCLUSIONS: Heterosexual transmission is the primary mode of acquisition of HIV infection both for Spanish-born and foreign-born pregnant women. However, the HIV infection was diagnosed earlier in Spanish-born women. There were no differences in the effectiveness of antiretroviral therapy as a preventive measure against MTCT when it is started at an early stage.