Infective endocarditis in pediatric patients: a decade of insights from a leading Spanish heart surgery reference center.

Infective endocarditis (IE) is a rare disease in children and is associated with significant morbidity and mortality. In recent years, significant changes have occurred in pediatric care that could have influenced the microbiology and presentation of IE. The aim of this work was to study epidemiological, microbiological, and clinical features of IE treated at a Pediatric Cardiac Surgery Reference Center located in Madrid (Spain) in a 10-years' period. A descriptive observational retrospective study was performed, including pediatric patients < 16 years old with definite or possible IE admitted to a reference center between January 2012 and December 2021. Thirty-two IE episodes were identified. Twenty-eight (87.5%) had congenital heart disease (CHD), 8 (25.0%) were preterm infants, 1 (3.1%) was immunocompromised and 6 (18.8%) had other chronic conditions; in 11 (34.4%) episodes more than one underlying condition was associated. In 20 (62.5%) episodes there was an indwelling central venous catheter (CVC); children with other comorbidities (preterm, immunocompromised, other chronic conditions) were more likely to have a CVC at diagnosis compared with patients with isolated CHD (p < 0.001). Thirty-six microbiological isolates were obtained in the 32 episodes; 4 (12.5%) episodes had 2 isolated microorganisms. Microbiological isolates were 20 (55.6%) Gram-positive bacteria (GPB), 10 (27.8%) non-HACEK Gram-negative bacteria (GNB), 1 (2.8%) HACEK-group bacterium, 4 (11.1%) fungi and 1 (2.8%) Coxiella burnetii. In 10 (31.3%) episodes, patients were colonized by multidrug-resistant bacteria (MDRB) and the etiology of IE in 3 (30.0%) of those episodes was the colonizing MDRB. MDRB colonization was associated with MDRB IE (p = 0.007). The most common complication was septic embolism: 11 (34.4%) episodes (9 pulmonary and 2 cerebral). In-hospital mortality was 6.3% (n = 2), all of them due to underlying conditions and not to IE or its complications. Clinical features and complications of IE episodes caused by non-HACEK GNB and those caused by GPB were compared, finding no statistically significant differences.    Conclusion: Risk factors for developing IE, the proportion of embolic complications, and mortality rate were consistent with previously published findings. Proportion of IE cases attributed to non-HACEK GNB was higher than previously reported, suggesting an evolving epidemiology of IE. One-third of children colonized with MDRB subsequently developed IE caused by the same MDRB strains, so empirical coverage of MDRB organisms must be considered when IE is suspected in MDRB colonized patients. No significant differences in clinical features and complications were observed when comparing IE episodes caused by non-HACEK GNB and those caused by GPB, however larger cohort studies are needed. What is Known: • Infective endocarditis (IE) is a rare disease in children, associated with significant morbidity and mortality. • The main risk factor for developing IE in children is an underlying congenital heart disease. What is New: • With current changing epidemiology in pediatric IE, a higher proportion of IE caused by non-HACEK Gram-negative bacteria should be expected. • A significant percentage of children colonized by multidrug-resistant bacteria can develop an IE due to those bacteria.

Treatments for multi-system inflammatory syndrome in children - discharge, fever, and second-line therapies.

Scarce evidence exists about the best treatment for multi-system inflammatory syndrome (MIS-C). We analyzed the effects of steroids, intravenous immunoglobulin (IVIG), and their combination on the probability of discharge over time, the probability of switching to second-line treatment over time, and the persistence of fever 2 days after treatment. We did a retrospective study to investigate the effect of different treatments on children with MIS-C from 1 March 2020 to 1 June 2021. We estimated the time-to-event probability using a Cox model weighted by propensity score to balance the baseline characteristics. Thirty of 132 (22.7%) patients were initially treated with steroids alone, 29/132 (21.9%) with IVIG alone, and 73/132 (55%) with IVIG plus steroids. The probability of early discharge was higher with IVIG than with IVIG plus steroids (hazard ratio [HR] 1.65, 95% CI 1.11-2.45, p = 0.013), but with a higher probability of needing second-line therapy compared to IVIG plus steroids (HR 3.05, 95% CI 1.12-8.25, p = 0.028). Patients on IVIG had a higher likelihood of persistent fever than patients on steroids (odds ratio [OR] 4.23, 95% CI 1.43-13.5, p = 0.011) or on IVIG plus steroids (OR 4.4, 95% CI 2.05-9.82, p < 0.001). No differences were found for this endpoint between steroids or steroids plus IVIG.    Conclusions: The benefits of each approach may vary depending on the outcome assessed. IVIG seemed to increase the probability of earlier discharge over time but also of needing second-line treatment over time. Steroids seemed to reduce persistent fever, and combination therapy reduced the need for escalating treatment. What is Known: • Steroids plus intravenous immunoglobulin, compared with intravenous immunoglobulin alone for multi-system inflammatory syndrome (MIS-C) might reduce the need for hemodynamic support and the duration of fever, but the certainty of the evidence is low. What is New: • Intravenous immunoglobulin, steroids, and their combination for MIS-C may have different outcomes. • In this study, intravenous immunoglobulin increased the probability of discharge over time, steroids reduced persistent fever, while combination therapy reduced the need for second-line treatments.

Clinical outcomes and antibody transfer in a cohort of infants with in utero or perinatal exposure to SARS-CoV-2 (Coronascope Study).

We aimed to describe the outcomes, focusing on the hearing and neurological development, of infants born to mothers with COVID-19 during pregnancy and to evaluate the persistence of maternal antibodies in the first months of life. An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers with COVID-19 during pregnancy between March and September 2020 was conducted. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on nasopharyngeal swab, and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age. Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected, and neurodevelopment was normal in 96% of the infants (median Z score: 0). CONCLUSION: In this cohort, the majority of infants born to mothers with COVID-19 during pregnancy were healthy infants with a normal cUS, no hearing loss, and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up. WHAT IS KNOWN: • Hearing loss and neurodevelopmental delay in infants born to mothers with COVID-19 during pregnancy has been suggested, although data is inconsistent. Maternal antibody transfer seems to be high, with a rapid decrease during the first weeks of life. WHAT IS NEW: • Most infants born to mothers with COVID-19 during pregnancy had normal hearing screening, cranial ultrasound, and neurodevelopmental status at 12 months of life. Antibodies against SARS-CoV-2 were only detected in 50% of the infants at two months of life.

Kawasaki disease in children younger than 6 months of age: characteristics of a Spanish cohort.

A retrospective study that compared children younger than 6 months versus older children of a Spanish cohort of patients diagnosed with Kawasaki disease between 2011 and 2016 (Kawa-Race study). From the 598 patients recruited, 42 patients were younger than 6 months (7%) and presented more frequently with an incomplete diagnosis of Kawasaki disease (52.4 vs 27.9%, p = 0.001). Cardiac abnormalities detected by echocardiography were more common in younger patients (52.4 vs 30%, p = 0.002). These younger patients presented with a higher proportion of coronary aneurysms as well (19 vs 8.6%, p < 0.001). Shock at diagnosis (9.5 vs 1.9%, p = 0.016) and admission to intensive care units (17.7 vs 4.1%, p = 0.003) were more frequent in patients younger than 6 months. There were no statistically significant differences in relation to infections, non-response to IVIG, or mid- or long-term outcomes.Conclusion: Data of the Spanish cohort are consistent with other American and Asian studies, although Spanish children younger than 6 months had a lower rate of non-response to IVIG and better clinical outcomes. A high index of suspicion should be considered for this population due to a higher risk of coronary abnormalities, presentation of shock, and admission to the intensive care unit. What is Known: •Children below 6 months of age with Kawasaki disease (KD) have different features compared to older. •Younger patients usually have an incomplete form of KD and coronary artery abnormalities. What is New: •Younger than 6 months with KD presented with shock and required admission to PICU more frequently compared to older. •Infections play a similar role in KD despite the age of the patients.

Ventricular Repolarization Parameters and Coronary Involvement in Kawasaki Disease.

OBJECTIVES: To evaluate electrocardiogram markers to predict coronary involvement in patients with Kawasaki disease by assessing measures of ventricular repolarization parameters on the 12-lead electrocardiogram. STUDY DESIGN: This cross-sectional study included 180 Spanish and Japanese patients ≤14 years of age with Kawasaki disease, with or without coronary involvement, from 2011 to 2016. We manually measured the Tp-Te/QT ratio and QTc interval (with Bazett's formula) in 12-lead electrocardiogram in the acute and recovery period and explored their potential association with coronary involvement. RESULTS: No association was found between Tp-Te/QT ratio obtained manually in V5 and V6 leads and coronary involvement in the acute (V5:0.25 [IQR, 0.21-0.27] vs 0.25 [IQR, 0.20-0.27], P = .80; V6:0.24 [IQR, 0.21-0.27] vs 0.25 [IQR, 0.20-0.27], P = .86) or the recovery (V5: 0.23 [IQR, 0.20-0.25] vs 0.23 [IQR, 0.19-0.25], P = .68; V6: 0.23 [IQR, 0.20-0.25] vs 0.23 [IQR, 0.17-0.25], P = .50) period. By contrast, QTc in V5 and V6 was significantly lower in patients with Kawasaki disease and coronary involvement in the acute period (V5: 378 ms [IQR, 364-395 ms] vs 390 ms [IQR, 371-411 ms], P = .04; V6: 377 ms [IQR, 364-392 ms] vs 390 ms [IQR, 371-410 ms], P = .01). A QTc interval of <385 ms in lead V6 was associated with a 2.5-fold increased risk of coronary involvement (OR, 2.5; 95% CI, 1.2-5.3; P = .02). CONCLUSIONS: Manually measured QTc interval may be a marker of coronary disease in the acute period of Kawasaki disease.

Rituximab as Second-Line Treatment in Anti-NMDAR Encephalitis after Herpes Simplex Encephalitis in Children.

The long-term response of two infants with anti-N-methyl-D-aspartate receptor (anti-NMDAR) post herpes simplex encephalitis treated with rituximab is reported here. Rituximab may improve the course of the disease and should be considered early as second-line treatment. Data on the long-term effect of rituximab in B cell depletion and immunoglobulins levels in infants are needed.

Risk scores for Kawasaki disease, a management tool developed by the KAWA-RACE cohort.

INTRODUCTION/OBJECTIVES: Asian scores developed to predict unresponsiveness to intravenous immunoglobulin (IVIG) or development of coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) are not appropriate in Western populations. The purpose of this study is to develop 2 scores, to predict unresponsiveness to IVIG and development of CAA, appropriate for Spanish population. METHOD: Data of 625 Spanish children with KD collected retrospectively (2011-2016) were used to identify variables to develop the 2 scores of interest: unresponsiveness to IVIG and development of CAA. A statistical model selected best variables to create the scores, and scores were validated with data from 98 patients collected prospectively. RESULTS: From 625 patients of the retrospective cohort, final analysis was performed in 439 subjects: 37 developed CAA, and 212 were unresponsive to IVIG. For the score to predict CAA, a cutoff ≥ 8 was considered for high risk, considering a score system with a different weight for each of the eight variables. External validation showed a sensitivity of 22% and a specificity of 75%. The score to predict unresponsiveness to IVIG established a cutoff ≥ 8 for high risk, considering a score system with a different weight for each of the nine variables. External validation showed a sensitivity of 78% and a specificity of 50%. CONCLUSIONS: Two risk scores for KD were developed from Spanish population, to predict development of CAA and unresponsiveness to IVIG; validation in other cohorts could help to implement these tools in the management of KD in other Western populations.

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.

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.

Prevalence and Clinical Manifestations of Congenital Cytomegalovirus Infection in a Screening Program in Madrid (PICCSA Study).

BACKGROUND: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Up to 15%-20% of infected newborns will develop long-term sequelae such as hearing loss and neurologic abnormalities. The aim of this study was to investigate the prevalence of congenital CMV infection (cCMV) and associated clinical abnormalities in Spain. METHODS: A prospective screening for cCMV by viral load in saliva was performed. Saliva samples were obtained within the first 72 hours of life in a maternity ward in Madrid (Spain), during a 1-year period. All positive screening tests were confirmed with viral load in urine. Clinical, laboratory, auditory, visual and cerebral imaging assessments were performed in all children with cCMV. RESULTS: Of the 4097 neonates born during the study period, 3190 (78%) were included. CMV viral load in saliva was detectable in 24/3190 (0.75%) children, and congenital infection was confirmed in 15/3190 (0.47%, CI 95%: 0.29%-0.77%). Positive predictive value was 62.5% (CI 95%: 46.5%-76.1%). Two infants presented symptoms at birth. Eight (53.3%) children showed abnormalities in magnetic resonance imaging; most of them isolated white matter abnormalities. Newborns with abnormalities in magnetic resonance imaging showed higher viral loads in blood and saliva (P = 0.04). CONCLUSIONS: One in 200 neonates born in our hospital presented a cCMV infection. CMV viral load in saliva has been shown to be a simple and highly accepted screening method but should be confirmed by CMV detection in urine. In spite of the fact that half of infected children had abnormalities in cerebral imaging, diagnosis during the neonatal period would have been impossible without a screening program in most cases.

Prevalence and Clinical Characteristics of SARS-CoV-2 Confirmed and Negative Kawasaki Disease Patients During the Pandemic in Spain.

Introduction: COVID-19 has a less severe course in children. In April 2020, some children presented with signs of multisystem inflammation with clinical signs overlapping with Kawasaki disease (KD), most of them requiring admission to the pediatric intensive care unit (PICU). This study aimed to describe the prevalence and clinical characteristics of KD SARS-CoV-2 confirmed and negative patients during the pandemic in Spain. Material and Methods: Medical data of KD patients from January 1, 2018 until May 30, 2020 was collected from the KAWA-RACE study group. We compared the KD cases diagnosed during the COVID-19 period (March 1-May 30, 2020) that were either SARS-CoV-2 confirmed (CoV+) or negative (CoV-) to those from the same period during 2018 and 2019 (PreCoV). Results: One hundred and twenty-four cases were collected. There was a significant increase in cases and PICU admissions in 2020 (P-trend = 0.001 and 0.0004, respectively). CoV+ patients were significantly older (7.5 vs. 2.5 yr) and mainly non-Caucasian (64 vs. 29%), had incomplete KD presentation (73 vs. 32%), lower leucocyte (9.5 vs. 15.5 × 109) and platelet count (174 vs. 423 × 109/L), higher inflammatory markers (C-Reactive Protein 18.5vs. 10.9 mg/dl) and terminal segment of the natriuretic atrial peptide (4,766 vs. 505 pg/ml), less aneurysm development (3.8 vs. 11.1%), and more myocardial dysfunction (30.8 vs. 1.6%) than PreCoV patients. Respiratory symptoms were not increased during the COVID-19 period. Conclusion: The KD CoV+ patients mostly meet pediatric inflammatory multisystem syndrome temporally associated with COVID-19/multisystem inflammatory syndrome in children criteria. Whether this is a novel entity or the same disease on different ends of the spectrum is yet to be clarified.

Previous or coincident infections with suspected Kawasaki disease. Should we change our approach?

INTRODUCTION: Kawasaki disease (KD) is a multisystem vasculitis associated with coronary artery abnormalities. Infections could be a trigger of the inflammation. The main aim of this study was to describe the presence of infections in children with KD, and to analyse the clinical characteristics and the presence of coronary abnormalities in these cases. PATIENTS AND METHODS: A retrospective study was performed within the Kawasaki Disease network (KAWA-RACE (2011-2016). An analysis was performed that included patients with positive microbiological findings (PMF) during the acute phase, as well as those with a previous recent infection (PRI) during the 4 weeks preceding KD diagnosis. RESULTS: The study included a total of 621 children with KD, with PMF being found in 101 (16.3%) patients, and a PRI in 107 (17.2%). Significantly less echocardiographic abnormalities were found in the group with a PRI, when compared to those without a PRI (23 vs. 35%, P = .01) and also a lower proportion of overall coronary artery lesions (16 vs. 25%, P = .054). No significant differences were found in the proportion of aneurysms in either of these groups (PRI or PMF) when compared to those without infection. CONCLUSIONS: In the present study, no differences were found in the incidence of coronary aneurysms in either of the groups, with or without PRI or PMF. Therefore, if KD is suspected, appropriate treatment should be started despite having a confirmed infection.

INTRODUCCIÓN: La enfermedad de Kawasaki (EK) es una vasculitis multisistémica asociada a lesiones en las arterias coronarias. Las infecciones podrían ser un desencadenante de la inflamación. Nuestro objetivo fue describir la presencia de infecciones en los niños con EK y analizar las características clínicas y la presencia de alteraciones coronarias en estos casos. PACIENTES Y MÉTODOS: Análisis retrospectivo de los pacientes incluidos en la red KAWA-RACE entre 2011 y 2016. Se estudió tanto a los pacientes que tuvieron una identificación microbiológica confirmada (IMC) en el periodo agudo como a los que presentaron antecedente de infección previa reciente (IPR) las 4 semanas anteriores. RESULTADOS: Se incluyó a un total de 621 niños, de los cuales 101 (16,3%) tuvieron una IMC y 107 (17,2%) una IPR. Encontramos una significativa menor afectación ecocardiográfica en el grupo de IPR respecto a los niños sin infección previa (23 vs. 35%; p 0,01), con menor proporción no significativa de las alteraciones coronarias globales (16 vs. 25%; p 0,054). Sin embargo, no se detectaron diferencias en la proporción de aneurismas en ninguno de los 2 grupos (IMC o IPR) respecto al resto de los pacientes sin infecciones asociadas. CONCLUSIONES: En nuestro estudio no encontramos diferencias en la incidencia de aneurismas coronarios en niños con y sin IMC o IPR, por lo que ante la sospecha de EK debe iniciarse siempre tratamiento, aunque se tenga infección confirmada microbiológicamente.

[Previous or coincident infections with suspected Kawasaki disease. Should we change our approach?] / Infecciones previas o coincidentes con la sospecha de enfermedad de Kawasaki ¿debemos cambiar nuestra actitud?

INTRODUCTION: Kawasaki disease (KD) is a multisystem vasculitis associated with coronary artery abnormalities. Infections could be a trigger of the inflammation. The main aim of this study was to describe the presence of infections in children with KD, and to analyse the clinical characteristics and the presence of coronary abnormalities in these cases. PATIENTS AND METHODS: A retrospective study was performed within the Kawasaki Diseases Network (KAWA-RACE (2011-2016). An analysis was performed that included patients with positive microbiological findings (PMF) during the acute phase, as well as those with a previous recent infection (PRI) during the 4 weeks preceding KD diagnosis. RESULTS: The study included total of 621 children with KD, with PMF being found in 101 (16.3%) patients, and a PRI in 107 (17.2%). Significantly less echocardiographic abnormalities were found in the in the group with a PRI, when compared to those without a PRI (23 vs. 35%, P=.01) and also a lower proportion of overall coronary artery lesions (16 vs. 25%, P=.054). No significant differences were found in the proportion of aneurysms in either of these groups (PRI or PMF) when compared to those without infection. CONCLUSIONS: In the present study, no differences were found in the incidence of coronary aneurysms in either of the groups, with or without PRI or PMF. Therefore, if KD is suspected, appropriate treatment should be started despite having a confirmed infection.

Epidemiological and clinical features of Kawasaki disease in Spain over 5 years and risk factors for aneurysm development. (2011-2016): KAWA-RACE study group.

BACKGROUND: Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology affecting mainly children less than 5 years of age. Risk factors for cardiac involvement and resistance to treatment are insufficiently studied in non-Japanese children. OBJECTIVE: This study aimed to investigate the epidemiology, clinical features and risk factors for resistance to treatment and coronary artery lesions (CAL) in KD in Spain. METHODS: Retrospective study (May 2011-June 2016) of all patients less than 16 years of age diagnosed with KD included in KAWA-RACE network (84 Spanish hospitals). RESULTS: A total of 625 cases were analyzed, 63% were males, 79% under 5 year-olds and 16.8% younger than 12 months. On echocardiographic examination CAL were the most frequent findings (23%) being ectasia the most common (12%). Coronary aneurysms were diagnosed in 9.6%, reaching 20% in infants under 12 months (p<0.001). A total of 97% of the patients received intravenous immunoglobulin (IVIG) with a median number of days from fever onset to IVIG administration of 7.2. A second dose was given to 15.7% and steroids to 14.5% patients. Only 1.4% patients received infliximab. No deaths were reported. A multivariate analysis identified anemia, hypoalbuminemia, hyponatremia, higher creatinine and procalcitonin as independent risk factors for treatment failure and length under 103 cm, hemoglobin < 10.2 mg/dL, platelets > 900,000 cells/mm3, maximum temperature < 39.5°C, total duration of fever > 10 days and fever before treatment ≥ 8 days as independent risk factors for developing coronary aneurysms. CONCLUSIONS: In our population, children under 12 months develop coronary aneurysms more frequently and children with KD with anemia and leukocytosis have high risk of cardiac involvement. Adding steroids early should be considered in those patients, especially if the treatment is not started before 8 days of fever. A score applicable to non-Japanese children able to predict the risk of aneurysm development and IVIG resistance is necessary.

[National consensus on the cardiological treatment and follow-up of Kawasaki disease]. / Consenso nacional sobre diagnóstico, tratamiento y seguimiento cardiológico de la enfermedad de Kawasaki.

Kawasaki disease is a self-limiting acute vasculitis that affects small and medium-sized vessels, and is the most common cause of acquired heart disease in children in our environment. Up to 25% of untreated patients develop coronary aneurysms. It is suspected that an infectious agent may be the trigger of the disease, but the causative agent is still unknown. Based on the previous evidence, recommendations are proposed for the diagnosis, treatment of acute disease, and the long-term management of these patients, in order to unify criteria. The diagnosis must be quick, based on easy-to-use algorithms and with the support of complementary tests. This document includes the indication of available imaging techniques, as well as the planning of cardiological examinations based on the initial involvement. Intravenous immunoglobulin is the basis of the initial treatment. The role of corticosteroids is still controversial, but there are studies that support its use as adjuvant treatment. A multidisciplinary working group has developed a scheme with different treatment guidelines depending on the risk factors at diagnosis, the patient's clinical situation, and response to previous treatment, including indications for thromboprophylaxis in patients with coronary involvement. The stratification of risk for long-term treatment is essential, as well as the recommendations on the procedures based on the initial cardiological involvement and its progression. Patients with coronary aneurysms require continuous and uninterrupted cardiological monitoring for life.

Impact of lopinavir-ritonavir exposure in HIV-1 infected children and adolescents in Madrid, Spain during 2000-2014.

BACKGROUND: The most-used protease-inhibitor in children is Lopinavir-ritonavir (LPV/r), which provides durable suppression of viral load and increases CD4+T-counts. This study describes the virological outcome of the HIV-1-infected paediatric population exposed to LPV/r during 15 years in Spain. METHODOLOGY: Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different line therapy during 2000-2014 were selected. The baseline epidemiological-clinical features, viral suppression, changes in CD4+T-CD8+T cell counts and drug susceptibility were recorded before and during LPV/r exposure. Drug resistance mutations (DRM) were identified in viruses from samples collected until 2011. We predicted drug susceptibility to 19 antiretrovirals among those carrying DRM using the Stanford's HIVdb Algorithm. RESULTS: A total of 199 (37.3%) of the 534 patients from the cohort were exposed to LPV/r during 2000-2014 in first (group 1), second (group 2) or more line-therapies (group 3). Patients were mainly Spaniards (81.9%), perinatally infected (96.5%) with subtype-B (65.3%) and HIV-diagnosed before year 2000 (67.8%). The mean age at first LPV/r exposure was 9.7 years. After protease-inhibitor exposure, viral suppression was higher in groups 1 and 2 than in group 3. Viral suppression occurred in 87.5%, 68.6% and 64.8% patients from groups 1, 2 and 3, respectively. Among the 64 patients with available resistance data during LPV/r treatment, 27(42.3%) carried DRM to protease-inhibitor, 28 (58.3%) to reverse-transcriptase-inhibitors and 21 (43.7%) to non-reverse-transcriptase-inhibitors. Darunavir/ritonavir, atazanavir-ritonavir and tipranavir/ritonavir presented the highest susceptibility and nelfinavir the lowest. CONCLUSIONS: A better lymphocyte recovering occurred when protease-inhibitor was taken as part of a first-line regimen and a higher number of patients reached viral suppression. The least compromised antiretrovirals for rescue antiretroviral regimens, according to DRM in the LPV/r-exposed-paediatric cohort, were mainly the new protease inhibitors.

Epidemiology and Management of Acute, Uncomplicated Septic Arthritis and Osteomyelitis: Spanish Multicenter Study.

BACKGROUND: Acute osteoarticular infection (OAI) is a potentially severe disease. The aim of this study was to evaluate the etiology, clinical characteristics and therapeutic approach of OAI in children in Spain. METHODS: Medical records from children <14 years with OAI from 25 hospitals between 2008 and 2012 were reviewed. Confirmed osteomyelitis (OM) and septic arthritis (SA) required a positive bacterial isolate; otherwise, they were considered probable. Probable SA with <40,000 cells/mm in joint fluid was not included. RESULTS: A total of 641 children were evaluated. Two hundred and ninety-nine cases (46%) were OM, 232 (36%) SA, 77 (12%) osteoarthritis and 33 (5%) spondylodiscitis. Children with OM were older (63 vs. 43 months for SA; P < 0.001). Magnetic resonance imaging and bone scintigraphy had the highest yield for OM diagnosis (94%). Arthrocentesis was performed in 96% of SA. A microorganism was isolated in 246 patients (38%: 33% OM vs. 55% SA; P < 0.001): Staphylococcus aureus was the most common (63%), followed by Kingella kingae (15%) and Streptococcus pyogenes (9%). Ninety-five percent of children initially received IV antibiotics, mostly cefotaxime + cloxacillin (60%) or cloxacillin (40%). Total treatment duration was 38 (±31) days for OM and 28 (±16) days for SA (P < 0.0001). Twenty percent of children with OM (46% because of complications) and 53% with SA (95% initial arthrotomy) underwent surgery. Patients with SA were compared according to initial arthrotomy (n = 123) versus arthrocentesis (n = 109), and no clinical differences were observed, except for higher rate of hip SA in the former (50% vs. 9%; P < 0.001). Children with arthrocentesis had less sequelae [6.6% vs. 1%; P = 0.03, odds ratio = 0.58 (95% confidence interval: 0.45-0.76)], but not in the multivariate analysis. CONCLUSIONS: This is the largest pediatric cohort of OAI in Spain. S. aureus was the most common isolate, although K. kingae was recovered in a high proportion of cases. Conservative management was applied in half of the patients. There was a low rate of sequelae, even with nonsurgical approaches.

Description and consequences of prescribing off-label antiretrovirals in the Madrid Cohort of HIV-infected children over a quarter of a century (1988-2012).

BACKGROUND: Licensing data for paediatric dosing is often sparse and subsequent studies may result in changes to recommended doses. We measured the extent and consequences of off-label antiretroviral (ARV) use in an HIV-infected paediatric cohort. METHODS: In this multicentre cohort study involving 318 HIV-infected children and adolescents from the Madrid Cohort, all off-label prescriptions from March 1988 to March 2012 were recorded from the clinical records. The reasons for prescribing ARV off-label, the side effects and the consequences of incorrect dosing of ARVs are discussed. RESULTS: Among the 318 patients of the cohort, 221 (69%) received off-label ARVs according to EMA licensing at the time of prescription, representing 23% (540) of the 2,353 prescribed ARVs. The main reason for starting an off-label drug was treatment failure. Adverse events led to treatment discontinuation in 12% of the prescriptions. Problems taking the drug led to withdrawal in 5%, more likely when formulation was not suitable for age (P<0.05). Up to 10% were overdosed and 10% underdosed, defined as 25% above or below the current recommended dose, respectively. Treatment failure occurred significantly more frequently among underdosed compared to overdosed patients (50% versus 26%; P<0.05). CONCLUSIONS: Off-label use of ARVs was common in our HIV-1 paediatric patients. Adverse events were common but rarely led to withdrawal. Suitable formulation is important in younger children. Pharmacokinetic studies are needed as frequent incorrect dosing may occur when prescribing off-label and underdosing may lead to treatment failure.