Predictors of mortality and clinical characteristics among carbapenem-resistant or carbapenemase-producing Enterobacteriaceae bloodstream infections in Spanish children.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging problem in the paediatric population worldwide with high mortality rates in bloodstream infection (BSI). OBJECTIVES: To evaluate predictors of 30 day mortality in CRE BSI in a paediatric cohort. METHODS: A retrospective observational single-centre study (December 2005-August 2018) was conducted. Cases of CRE BSI in children 0 to 16 years were included. Microbiological identification (MALDI Biotyper) and antimicrobial susceptibility testing (Vitek2® and MicroScan panel NBC44) according to EUCAST breakpoints were performed. PCR OXVIKP® was used to confirm carbapenemase genes (OXA-48, VIM, KPC, NDM). Demographic characteristics, underlying diseases, source of bacteraemia, antimicrobial therapy and outcomes were collected from medical records. Survival analysis to establish predictors of 30 day mortality was performed. RESULTS: Thirty-eight cases were included; 76.3% were hospital-acquired infections and 23.7% related to healthcare. All patients had at least one underlying comorbidity and 52.6% were recipients of an organ transplant. VIM carbapenemase was the predominant mechanism (92.1%). Previous CRE colonization or infection rate was 52.6%. Intestinal tract (26.3%) and vascular catheter (21.1%) were the most common sources of infection. Crude mortality within 30 days was 18.4% (7/38); directly related 30 day mortality was 10.5%. Conditions associated with an increment in 30 day mortality were intensive care admission and inadequate empirical therapy (P < 0.05). Combination-antibiotic targeted treatment and a low meropenem MIC were not related to improved survival. CONCLUSIONS: CRE BSI mortality rate is high. The most important factor related to 30 day survival in our CRE BSI cohort in children was empirical treatment that included at least one active antibiotic.

[Congenital cytomegalovirus infection, is more prevalent in our country in newborns exposed to HIV?] / La infección congénita por citomegalovirus, ¿es más prevalente en nuestro medio en neonatos expuestos al VIH?

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) has been considered more prevalent among HIV-exposed children during pregnancy. Spanish national guidelines recommend the cCMV screening in these newborns. Nowadays, pregnant women have a better control of HIV infection compared to previous decades. We aim to analyze the prevalence and associated risk factors to cCMV in these children. METHODS: A retrospective cross-sectorial study was performed. All newborns exposed to HIV were assisted in a third-level hospital (2014-2020). Epidemiological and clinical data of the mother and newborn were recorded. Shell vial urine culture and/or CRP were performed along the two first weeks of life for the neonatal screening of cCMV. RESULTS: Overall 69 newborns were enrolled. A high proportion (82.4%) of the mothers had been diagnosed with HIV before getting pregnant. All women received ART during the pregnancy. Median T-CD4 lymphocytes before delivery was 641/mm3 (IQR: 480-865) and the viral load was undetectable in 83.6%. Serological test for CMV along the first trimester of pregnancy was performed in 73.5% (positive IgG in 96%). There were no congenital cases of HIV neither cCMV (CI 95%:0-5.3%). CONCLUSIONS: The cCMV prevalence in newborns exposed to HIV was 0%, lower than reported before, probably related to a better and earlier ART during pregnancy, leading to a better immunological status.

Intestinal giardiasis in children: Five years' experience in a reference unit.

BACKGROUND: Giardiasis is highly prevalent in children and is often mildly symptomatic. First-line treatment is metronidazole, but treatment failure is not uncommon. We describe a paediatric series, to identify risk factors for treatment failure and to analyse the safety and effectiveness of other treatment strategies. METHODS: Retrospective observational study, including children diagnosed with giardiasis from 2014 to 2019. Diagnosis was based on direct visualisation by microscopy after concentration using an alcohol-based fixative, antigen detection and/or DNA detection by polymerase chain reaction in stool. Treatment failure was considered when GI was detected 4 weeks after treatment. RESULTS: A total of 120 patients were included, 71.6% internationally adopted, median age 4.2 (2.3-7.3) years. Only 50% presented with symptoms, mainly diarrhoea (35%) and abdominal pain (14.1%); co-parasitism was frequent (45%). First-line treatment failure after a standard dose of metronidazole was 20%, lowering to 8.3% when a higher dose was administered (p < 0.001). Quinacrine was administered in 10 patients, with 100% effectiveness. Children <2 years were at higher risk of treatment failure (OR 3.49; 95% CI 1.06-11.53; p = 0.040). CONCLUSIONS: In children with giardiasis, treatment failure is frequent, especially before 2 years of age. Quinacrine can be considered as a second-line treatment. After treatment, eradication should be confirmed.

Tuberculosis in a Spanish cohort of children living with HIV: the CHOTIS study (Childhood HIV & TB study).

BACKGROUND: Tuberculosis (TB) is the leading opportunistic infection in children with human immunodeficiency virus (HIV), but is uncommon in low prevalence regions. We aim to describe the changing epidemiology and clinical presentation of TB-HIV co-infection in a cohort of HIV-infected children in Spain.METHODS: Children diagnosed with TB between 1995 and 2016 in the paediatric HIV cohort were identified. The incidence and clinical presentation were compared in three periods: 1995-1999 (P1, before initiation of combined antiretroviral therapy, cART), 2000-2009 (P2, increase in immigration), and 2010-2016 (P3, decrease in immigration).RESULTS: We included 29 TB cases among 1183 children aged <18 years (2.4%, 243/100 000 person-years). The proportion was stable in P1 and P2 (1.3%), but decreased in P3 (0.8%). The median age at TB diagnosis was 6.4 years (IQR 4-10.6); most children in P3 were aged >10 years (20% vs. 23.1% vs. 83.3%, P = 0.01). TB was diagnosed at HIV presentation in 11/29 children (37.9%). Foreign-born children accounted for respectively 0%, 8% and 67% of the total number of children in each period (P ≤ 0.0001). One third had extrapulmonary TB; four children died (13.8%).CONCLUSION: In our cohort, the incidence of TB-HIV co-infection decreased with decline in immigration. In regions with adequate cART coverage and low TB transmission, paediatric TB-HIV coinfection is uncommon, but associated with significant morbidity. Strategies for TB surveillance, diagnosis and treatment in this vulnerable population should be reinforced.

[Recommendations of the Spanish Society for Pediatric Infectious Diseases (SEIP) on the management of drug-resistant tuberculosis]. / Documento de consenso de la Sociedad Española de Infectología Pediátrica sobre la tuberculosis resistente a fármacos.

Drug resistant tuberculosis (TB-R), and in particular, multidrug resistant tuberculosis (MDR-TB) is a global public health problem, as well as a problem in our country. Cases of TB-R and MDR-TB have increased mainly in HIV, immigrant and socially disadvantaged populations, but a notable increase in the general population has also been observed. This aspect reinforces the need for a systematic study of sensitivity of all the isolates in a reference laboratory to optimally guide the treatment. Children are especially vulnerable to this severe disease due to the limited knowledge of second line anti-tuberculous drugs, in terms of their pharmacokinetic data, optimal doses, or their long term toxicity, all this eventually resulting in the compassionate use of drugs. Another aspect which further complicates the management of R-TB in children is the limited yield of cultures, which frequently leads to clinician designing drug combinations according to the sensitivity of the initial strain. The epidemiological pattern in our country has currently changed. There is a reported increase in isoniazid-resistant strains; therefore, a four drugs regime is mandatory for the initial period in children, until reliable sensitivity results are available. Treatment should be directly observed or at least supervised by paediatricians. The management of latent infections or exposure to a resistant TB case also requires an accurate, strict and prolonged supervision by expert paediatricians. Authorities and health care professionals who deal with TB should be prepared to face this new phenomenon with appropriate measures. The knowledge of second line drugs for children, as well as mechanisms to ensure the therapeutic adherence and long term control of disease, are essential.

[HIV-1 genetic variability in non Spaniard infected children]. / Identificación de las diferentes variantes geneticas del VIH-1 en niños de procedencia no española.

INTRODUCTION: The prevalence of HIV-1 non-B subtypes (HIV-NBS) is increasing in Europe, because of emigration from countries where genetic variants are endemic. Although HIV-NBS could have a different clinical evolution and could respond differently to antiretrovirals (AR) than B-subtypes, these variant's response remain undocumented. AIMS: To identify HIV-1 genetic variants and to determine clinical evolution in a non-Spaniard children infected with HIV-1. PATIENTS AND METHOD: Children with HIV-1 infection from endemic countries were tested for HIV-1 subtypes between 1-1-1988 and 31-12-2006. Twelve children less than 18 years old and born abroad were selected. RESULTS: HIV-NBS were isolated in 5 children (42%): CRF2_AG recombinant in 3 cases (Equatorial Guinea), Subtype C in one (Equatorial Guinea) and CRF13_cpx in last one (India). DISCUSSION: Because of the increasing frequency of patients with HIV-NBS and their unknown long-term evolution, all children from endemic countries should be tested for HIV subtypes. We believe new studies with more patients during longer times could reveal differences in these patient's clinical, immunological and virological evolution.

[Antiretroviral drug toxicity in human immunodeficiency virus infected children]. / Toxicidad de fármacos antirretrovirales en niños infectados por el virus de la inmunodeficiencia humana.

Paediatric Human Immunodeficiency Virus infection (HIV) nowadays is a chronic disease with an excellent long term prognosis, but lifelong combined antiretroviral treatment is required. However, an improved quality of life in this population is limited by adverse drug effects. The highest risk of treatment toxicity is developing a complete metabolic syndrome including: Hyperlipemia, lipodystrophy, insulin resistance, lactic acidosis, osteopenia, hypertension, and specific system and organ toxicity, such as the kidney, liver, CNS or bone marrow. The risk of cardiovascular disease adult life and also definitive bone mass damage are the most significant metabolic costs that have to paid for increased survival. Most of these toxicities were able to be adequately treated but, pharmacological interferences, patient intolerance and the high number of drugs are the problems that limit the adherence to treatment, which is essential for a good therapeutical efficacy. In this article, we present four HIV paediatric patients who presented with almost the whole range of metabolic toxicities, and a practical overview of therapeutical management.

[Exposure to multiresisant tuberculosis: study and follow-up of nine children]. / Exposición a tuberculosis multirresistente: estudio y seguimiento de nueve niños.

A world increase in multidrug-resistant tuberculosis (MDR-TB) has been reported over the last few years. A larger number of diagnoses are being seen in Spain, due to the increase of immigration from high endemic TB countries. Articles published on this are anecdotal in children, and there is no clear directives for treatment of MDR-TB, or latent tuberculosis infection (ITBL) or on prophylaxis after exposure to active pulmonary MDR-TB. We present the initial management and progression of nine children after close contact exposure to an Ecuadorian woman diagnosed with active pulmonary TB, resistant to Isoniazid, Rifampicin and Pyrazinamide.

[Imported dengue: an emerging arbovirosis in Spain]. / Dengue importado: arbovirosis emergente en España.

Dengue is caused by one of 4 serotypes of dengue virus. Only imported cases have been reported in Spain. The main clinical findings are fever and exanthema, although there may be severe forms, particularly in secondary infections. Five children with a primary, non severe dengue infection are presented. The diagnosis was based on clinical suspicion and epidemiological history, and confirmed by immunochromatography and ELISA tests. The outcome was favourable in all cases. It is important to consider this diagnosis in international travellers that present with fever within the 14 days of returning from an endemic area, in order to get an early diagnosis, adequate treatment and a good prognosis.

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (i): Epidemiology and diagnosis. Congenital tuberculosis]. / Guía de la Sociedad Española de Infectología Pediátrica sobre tuberculosis en la embarazada y el recién nacido (I): epidemiología y diagnóstico. Tuberculosis congénita.

Tuberculosis (TB) screening in pregnancy using tuberculin skin test (TST) is recommended in case of symptoms of TB disease, close contact with a patient with infectious TB, or high risk of developing active disease. The new interferon gamma release assay (IGRA) tests are recommended in BCG-vaccinated pregnant women with positive TST and no known risk factors for TB, and in those immunocompromised, with clinical suspicion of TB but negative TST. TB diagnosis is difficult due to the non-specific symptoms, the increased frequency of extrapulmonary disease, the delay in radiological examinations, and the high rate of tuberculin anergy. Neonatal TB can be acquired in utero (congenital TB), or through airborne transmission after delivery (postnatal TB). Congenital TB is extremely rare and does not cause fetal malformations. It may be evident at birth, although it usually presents after the second week of life. In newborns with no family history of TB, the disease should be considered in cases of miliary pneumonia, hepatosplenomegaly with focal lesions, or lymphocytic meningitis with hypoglycorrhachia, especially in those born to immigrants from high TB-burden countries. TST is usually negative, and IGRAs have lower sensitivity than in older children. However, the yield of acid-fast smear and culture is higher, mostly in congenital TB. Molecular diagnosis techniques enable early diagnosis and detection of drug resistance mutations. There is a substantial risk of disseminated disease and death.

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (ii): Prophylaxis and treatment]. / Guía de la Sociedad Española de Infectología Pediátrica sobre tuberculosis en la embarazada y el recién nacido (ii): profilaxis y tratamiento.

In pregnant women who have been exposed to tuberculosis (TB), primary isoniazid prophylaxis is only recommended in cases of immunosuppression, chronic medical conditions or obstetric risk factors, and close and sustained contact with a patient with infectious TB. Isoniazid prophylaxis for latent tuberculosis infection (LTBI) is recommended in women who have close contact with an infectious TB patient or have risk factors for progression to active disease. Otherwise, it should be delayed until at least three weeks after delivery. Treatment of TB disease during pregnancy is the same as for the general adult population. Infants born to mothers with disseminated or extrapulmonary TB in pregnancy, with active TB at delivery, or with postnatal exposure to TB, should undergo a complete diagnostic evaluation. Primary isoniazid prophylaxis for at least 12 weeks is recommended for those with negative diagnostic tests and no evidence of disease. Repeated negative diagnostic tests are mandatory before interrupting prophylaxis. Isoniazid for 9 months is recommended in LTBI. Treatment of neonatal TB disease is similar to that of older children, but should be maintained for at least 9 months. Respiratory isolation is recommended in congenital TB, and in postnatal TB with positive gastric or bronchial aspirate acid-fast smears. Separation of mother and infant is only necessary when the mother has received treatment for less than 2 weeks, is sputum smear-positive, or has drug-resistant TB. Breastfeeding is not contraindicated, and in case of mother-infant separation expressed breast milk feeding is recommended.

[Update on antiretroviral treatment in HIV infection]. / Actualización en el tratamiento antirretroviral en la infección por el virus de la inmunodeficiencia humana.

In recent years, major advances have been made in the care of HIV-infected children, particularly in antiretroviral treatment, which have dramatically improved survival and quality of life. The goal of highly active antiretroviral therapy (HAART), which includes at least three potent drugs, is the maximal and most durable suppression of viral replication possible, which is often not achieved despite clear immunologic and clinical improvement. There are still major barriers to achieving this goal, mainly the difficulty of permanent adherence to complex regimens and treatment-related toxicities. Adverse events are frequent, including a high prevalence of metabolic complications with unknown consequences in the future. These drawbacks of antiretroviral treatment are leading to a more conservative initial approach, as well as to research into simpler and less toxic therapeutic options. New strategies should continue to be developed to overcome the still important limitations of current antiretroviral treatment.

[Interpretation of the tuberculin test in children with CD4 lymphocyte cell mediated immunity changes]. / Interpretación de la prueba de tuberculina en niños con alteración de la inmunidad celular mediada por linfocitos CD4.

Immunosuppression could be a cause of a false negative tuberculin skin test (TST) result. A cross-sectional study was performed on a population of immigrants and internationally adopted children to analyse whether CD4 cell counts could modify the TST results. A total of 1074 children were included between January 2003 and December 2008. CD4 cell counts were performed on 884 children, in whom 5.3% had CD4 values <25%. There were no differences in TST results among children with normal and pathological CD4 cell counts. Several studies, including this one, have shown that there is no direct association between the CD4 value and the TST results. These results should be confirmed with larger series and with a higher percentage of children with CD4 values <25%.

[Results from the 2012-2013 paediatric national survey on off-label drug use in children in Spain (OL-PED study)]. / Conocimiento sobre el uso de fármacos off-label en Pediatría. Resultados de una encuesta pediátrica nacional 2012-2013 (estudio OL-PED).

INTRODUCTION: Off-label drug use is a common practice in paediatrics. The aim of the present study was to estimate the knowledge of Spaniard paediatricians on off-label use. MATERIAL AND METHODS: Cross-sectional, multicentre, descriptive and national study from July 2012 to March 2013 using an on-line questionnaire on off-label use in children. An e-mail was sent to paediatricians who were members of the Spanish Association of Paediatrics (AEP) or its Regional or Paediatric Specialties Societies. RESULTS: Out of 673 responses were received, 75.1% of Spanish paediatricians knew the meaning of off-label use, 61% of them prescribed medicines outside the conditions authorised in their Summary of Product Characteristics (SPC) and 47% knew of the importance of noting the off-label use in the medical record. However, just under half of paediatricians informed parents, and only 22% wrote it down in the medical record. CONCLUSIONS: Most Spanish paediatricians do not meet current regulations regarding off-label use. This regulation demands: justifying the decisions when off-label use is needed, and to write down in the medical record that, at least an oral consent from the parents has been obtained. This study reveals a fact that Spanish paediatricians must change. Meanwhile, it is a priority to continue with the implementation of consensus and clinical guidelines, to obtain more data on the efficacy and safety of off-label drug use in children, and to incorporate them into the SPC.

[Pediamécum: one year of experience]. / Pediamécum: un año de experiencia.

In 2011, the Spanish Association of Pediatrics decided to support the most ambitious project of its newly created Committee for Medicinal Products: Pediamécum. This is the first free on-line database with information on medicinal products for pediatric use in Spain. The web page http://pediamecum.es/ started on December 17 December 2012. One year later, Pediamécum includes 580 registered drugs. The website achieved more than one million page views by the end of 2013. Because of the first anniversary of Pediamécum, a survey was performed to request the feeling of users. Four hundred eighty-three responses were obtained. Ninety-five percent believed that it is easy to navigate through the web, and 74% said that their doubts about the use of medicines in children were always resolved. The overall rating of Pediamécum is 7.5/10. The aims of Pediamécum are being accomplished; which is reflected essentially due to it becoming a useful tool for all professionals who care for children in their daily clinical practice.

[Results from the 2012 Paediatric National Survey on Empirical Use of Antibiotics in Children in Spain (ABES Study)]. / Uso empírico de antibióticos en niños en España. Resultados de una Encuesta Pediátrica Nacional 2012 (Estudio ABES).

INTRODUCTION: There are currently several national guidelines on the appropriate empirical use of antibiotics in Spanish children. But, do the Spanish paediatricians use these guidelines when prescribing antimicrobials? MATERIAL AND METHODS: A national study from was conducted from April to June 2012 using an on-line questionnaire on the empirical selection of antibiotics in children. An e-mail was sent to paediatrician members of the Spanish Association of Paediatrics (AEP) or its Regional or Paediatric Specialties Societies. Current guidelines and consensus documents were used to determine the appropriateness of the responses. RESULTS: A total of 1214 responses were received. Eighty five per cent of the treatments selected by Spanish paediatricians were adjusted to guidelines. The least appropriate responses were obtained in those infectious diseases with no national consensus document at the time of the survey (73% in this case). CONCLUSIONS: Spanish paediatricians mainly select empirical antibiotics in accordance with current guidelines. However, there are features that could be improved in our country. The preparing and implementation of national consensus documents on the management of paediatric infectious diseases should be continued. We propose to regularly perform these kinds of surveys, including real prescription studies, and to also extend it to other paediatric specialities, in order to promote appropriateness of use of all the paediatric drugs in our country.

[Experience in the diagnosis of hepatitis E in a tropical infectious diseases unit]. / Experiencia en el diagnóstico de hepatitis E en una unidad de enfermedades infecciosas tropicales.

The hepatitis E virus (HEV) is endemic in some developing countries. It produces acute hepatitis in sporadic cases or epidemics. The main transmission route is faecal-oral by contaminated waters. In developed countries the cases described are more and more frequent, mainly due to population movement (travellers, immigrants, international adoptions), although there have also been increases in the local population. We currently have serological and molecular techniques for the diagnosis of this infection. We describe the experience in the diagnosis of the infection by HEV in a Paediatric Tropical Infectious Diseases Unit in Madrid.