Changes in the epidemiology of invasive fungal disease in a Pediatric Hematology and Oncology Unit: the relevance of breakthrough infections.

BACKGROUND: Invasive fungal disease (IFD) is a significant cause of morbimortality in children under chemotherapy or hematopoietic stem cell transplant (HSCT). The purpose of this study is to describe the changes in the IFD epidemiology that occurred in a Pediatric Hematology-Oncology Unit (PHOU) with an increasing activity over time. METHODS: Retrospective revision of the medical records of children (from 6 months to 18 years old) diagnosed with IFD in the PHOU of a tertiary hospital in Madrid (Spain), between 2006 and 2019. IFD definitions were performed according to the EORTC revised criteria. Prevalence, epidemiological, diagnostic and therapeutic parameters were described. Comparative analyses were conducted using Chi-square, Mann-Whitney and Kruskal-Wallis tests, according to three time periods, the type of infection (yeast vs mold infections) and the outcome. RESULTS: Twenty-eight episodes of IFD occurred in 27 out of 471 children at risk (50% males; median age of 9.8 years old, [IQR 4.9-15.1]), resulting in an overall global prevalence of 5.9%. Five episodes of candidemia and 23 bronchopulmonary mold diseases were registered. Six (21.4%), eight (28.6%) and 14 (50%) episodes met criteria for proven, probable and possible IFD, respectively. 71.4% of patients had a breakthrough infection, 28.6% required intensive care and 21.4% died during treatment. Over time, bronchopulmonary mold infections and breakthrough IFD increased (p=0.002 and p=0.012, respectively), occurring in children with more IFD host factors (p=0.028) and high-risk underlying disorders (p=0.012). A 64% increase in the number of admissions in the PHOU (p<0.001) and a 277% increase in the number of HSCT (p=0.008) were not followed by rising rates of mortality or IFD/1000 admissions (p=0.674). CONCLUSIONS: In this study, we found that yeast infections decreased, while mold infections increased over time, being most of them breakthrough infections. These changes are probably related to the rising activity in our PHOU and an increase in the complexity of the baseline pathologies of patients. Fortunately, these facts were not followed by an increase in IFD prevalence or mortality rates.

Serologic evolution and follow-up to IgG antibodies of infants born to mothers with gestational COVID.

BACKGROUND: It is known that SARS-CoV-2 antibodies from pregnant women with SARS-CoV-2 infection during pregnancy cross the placenta but the duration and the protective effect of these antibodies in infants is scarce. METHODS: This prospective study included mothers with SARS-COV-2 infection during pregnancy and their infants from April 2020 to March 2021. IgG antibodies to SARS-CoV-2 spike protein were performed on women and infants at birth and at two and six months during follow-up. Anthropometrical measures and physical and neurological examinations and a clinical history of symptoms and COVID-19 diagnosis were collected. Simple linear regression was performed to compare categorical and continuous variables. To compare the mother's and infant's antibody titers evolution, a mixed linear regression model was used. A predictive model of newborn antibody titers at birth has been established by means of simple stepwise linear regression. RESULTS: 51 mother-infant couples were included. 45 (90%) of the mothers and 44 (86.3%) of the newborns had a positive serology al birth. These antibodies were progressively decreasing and were positive in 34 (66.7%) and 7 (13.7%) of infants at 2 and 6 months, respectively. IgG titers of newborns at birth were related to mothers' titers, with a positive moderate correlation (Pearson's correlation coefficient: 0.82, p < 0,001). Fetal/maternal antibodies placental transference rate was 1.3 (IQR: 0.7-2.2). The maternal IgG titers at delivery and the type of maternal infection (acute, recent, or past infection) was significantly related with infants' antibody titers at birth. No other epidemiological or clinical factors were related to antibodies titers. Neurodevelopment, psychomotor development, and growth were normal in 94.2% of infants in the third follow-up visit. No infants had a COVID-19 diagnosis during the follow-up period. CONCLUSIONS: Transplacental transfer of maternal antibodies is high in newborns from mothers with recent or past infection at delivery, but these antibodies decrease after the first months of life. Infant's IgG titers were related to maternal IgG titers at delivery. Further studies are needed to learn about the protective role of maternal antibodies in infants.

Acute Epstein-Barr virus infection: Diagnostic challenge in young children, risk factors for hospitalisation and cytomegalovirus co-detection.

AIM: Acute Epstein-Barr virus (aEBV) and cytomegalovirus (CMV) infections frequently have similar manifestations. We aim to evaluate the characteristics of aEBV infection, risk factors for hospitalisation and differences according to CMV IgM detection (EBV-CMV co-detection) in children. METHODS: Retrospective, single-centre study including patients <16 years diagnosed with aEBV infection (positive anti-EBV IgM/Paul-Bunnell test and acute symptomatology). EBV-CMV co-detection was defined as positive CMV IgM. Factors associated with age, hospitalisation and EBV-CMV co-detection were analysed in a multivariate analysis. RESULTS: A total of 149 patients were included (median age 4.6 years). Most frequent manifestations were fever (77%), cervical lymphadenopathy (64%) and elevated liver enzymes (54%). Younger children had lower rate of positive Paul-Bunnell test (35% vs. 87%; p < 0.01), but higher rate of EBV-CMV co-detection (54% vs. 29%; p = 0.03). These children tended to have less typical symptoms of infectious mononucleosis and higher hospitalisation rate. The overall antibiotic prescription was 49%. Hospitalisation (27 children; 18%) was independently associated with prior antibiotic therapy and anaemia. Sixty-two cases (42%) had EBV-CMV co-detection, which was independently associated with elevated liver enzymes and younger age. CONCLUSION: In this study, younger children with aEBV infection presented more frequently with atypical clinical symptoms, had higher EBV-CMV co-detection rates and were more often hospitalised. Hospitalisation was associated with prior antibiotic prescription.

Risk-score based strategy to minimize antibiotic exposure in children with sickle cell disease and fever.

Severe bacterial infections (SBI) have become less frequent in children with sickle cell disease (SCD) in the last decades. However, because of their potential risk of SBI, they usually receive empirical therapy with broad-spectrum antibiotics when they develop fever and are hospitalized in many cases. We performed a prospective study including 79 SCD patients with fever [median age 4.1 (1.7-7.5) years, 78.5% males; 17 of the episodes were diagnosed with SBI and 4 of them were confirmed] and developed a risk score for the prediction of SBI. The optimal score included CRP > 3 mg/dl, IL-6 > 125 pg/ml and hypoxemia, with an AUC of 0.91 (0.83-0.96) for the prediction of confirmed SBI and 0.86 (0.77-0.93) for possible SBI. We classified the patients in 3 groups: low, intermediate and high risk of SBI. Our risk-score-based management proposal could help to safely minimize antibiotic treatments and hospital admissions in children with SCD at low risk of SBI.

Interleukin 6 as a marker of severe bacterial infection in children with sickle cell disease and fever: a case-control study.

BACKGROUND: Etiological diagnosis of fever in children with sickle cell disease (SCD) is often challenging. The aim of this study was to analyze the pattern of inflammatory biomarkers in SCD febrile children and controls, in order to determine predictors of severe bacterial infection (SBI). METHODS: A prospective, case-control study was carried out during 3 years, including patients younger than 18 years with SCD and fever (cases) and asymptomatic steady-state SCD children (controls). Clinical characteristics and laboratory parameters, including 10 serum proinflammatory cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17a, IFN-γ and TNF-α) and comparisons among study subgroups were analyzed. RESULTS: A total of 137 patients (79 cases and 58 controls) were included in the study; 78.5% males, median age 4.1 (1.7-7.5) years. Four cases were diagnosed with SBI, 41 viral infection (VI), 33 no proven infection (NPI) and 1 bacterial-viral coinfection (the latter excluded from the subanalyses). IL-6 was significantly higher in patients with SBI than in patients with VI or NPI (163 vs 0.7 vs 0.7 pg/ml, p < 0.001), and undetectable in all controls. The rest of the cytokines analyzed did not show any significant difference. The optimal cut-off value of IL-6 for the diagnosis of SBI was 125 pg/mL, with high PPV and NPV (PPV of 100% for a prevalence rate of 5, 10 and 15% and NPV of 98.7%, 97.3% and 95.8% for those prevalences rates, respectively). CONCLUSION: We found that IL-6 (with a cut-off value of 125 pg/ml) was an optimal marker for SBI in this cohort of febrile SCD children, with high PPV and NPV. Therefore, given its rapid elevation, IL-6 may be useful to early discriminate SCD children at risk of SBI, in order to guide their management.

Effect of an intervention to improve the prescription of antifungals in pediatric hematology-oncology.

BACKGROUND: The use of antifungals has expanded in pediatric hematology-oncology, and the need to develop pediatric-based surveillance and education activities is becoming crucial. The aims of this study were to evaluate the impact of a multidisciplinary protocol on the adequacy of antifungal prescription in a pediatric hematology-oncology unit and to assess the effect of an educational intervention to improve the knowledge of prescribing pediatricians over time. METHODS: A multidisciplinary team established a protocol for the management of invasive fungal disease (IFD). The use of antifungals before (January 2012-May 2013) and after the protocol (June 2013-December 2015) was evaluated. Prescribing pediatricians attended a training course on IFD and were evaluated before 0, 6, and 12 months after the intervention. RESULTS: During the study period, antifungal agents were used in 185 episodes (56 children, 39.3% females), and were administered as prophylaxis (58.9%), empiric (34.6%), or targeted therapy (6.5%). Antifungal prescriptions were inadequate in 7% of the episodes, related to drug selection (53.8%), dosage (38.5%) and route of administration (7.7%). After protocol implementation, inadequate prescriptions decreased 9.9% (15.2% vs 5.3%; P = .04). Following the educational activity, the percentage of adequate responses to the questionnaire improved significantly compared to baseline, and persisted over time (19.7% improvement at 0 months [P < .0001]; 21.1% at 6 months [P < .0001]; 16.6% at 12 months [P = .002]). CONCLUSIONS: The establishment of multidisciplinary protocols and education activities improved the quality of antifungal prescription and the knowledge of prescribers regarding antifungal therapy. Therefore, these activities may be important for the implementation of antifungal stewardship programs in pediatrics.

Low-risk factors for severe bacterial infection and acute chest syndrome in children with sickle cell disease.

INTRODUCTION: The rate of bacterial infections in children with sickle cell disease (SCD) has decreased in recent years, mainly due to penicillin prophylaxis and vaccination. OBJECTIVES: To determine the rate of severe bacterial infection (SBI) in a cohort of children with SCD and to describe low-risk factors for confirmed SBI (CSBI) and acute chest syndrome (ACS). METHODS: This 11-year retrospective cohort study included children with febrile SCD admitted to a reference hospital in Spain. A case-control study was performed comparing patients diagnosed with SBI to those without SBI, and subanalyses for groups with CSBI and ACS were carried out. RESULTS: A total of 316 febrile episodes were analyzed; 69 (21.8%) had confirmed or possible SBI. Thirteen of those had CSBI (4.1%), eight urinary tract infection, and five bacteremia/sepsis. Among the cases of possible SBI, the majority had ACS (54/56; 96.4%). Age >3 years, absence of central venous catheter, hemodynamic stability, and procalcitonin <0.6 ng/ml were low-risk factors for CSBI, whereas normal oxygen saturation and C-reactive protein <3 mg/dl were low-risk factors for ACS, with negative predictive values (NPV) of 98.3%, 97.4%, 96%, 97.2%, 87.5%, and 85.8%, respectively. CONCLUSION: In this cohort of children with SCD who were well vaccinated and received adequate prophylaxis, we found a low rate of bacteremia and CSBI. We described several low-risk factors for CSBI and ACS, all of them with a high NPV. These findings may help to develop a risk score to safely select the patients that could be managed with a more conservative approach.

Consensus document on the management of febrile neutropenia in paediatric haematology and oncology patients of the Spanish Society of Pediatric Infectious Diseases (SEIP) and the Spanish Society of Pediatric Hematology and Oncology (SEHOP).

Febrile neutropenia is one of the main infectious complications experienced by paediatric patients with blood or solid tumours, which, despite the advances in diagnosis and treatment, are still associated with a significant morbidity and mortality. These patients have several risk factors for infection, chief of which are chemotherapy-induced neutropenia, the disruption of cutaneous and mucosal barriers and the use of intravascular devices. Early diagnosis and treatment of febrile neutropenia episodes based on the patient's characteristics is essential in patients with blood and solid tumours to improve their outcomes. Therefore, it is important to develop protocols in order to optimise and standardise its management. In addition, the rational use of antibiotics, with careful adjustment of the duration of treatment and antimicrobial spectrum, is crucial to address the increase in antimicrobial drug resistance. The aim of this document, developed jointly by the Spanish Society of Pediatric Infectious Diseases and the Spanish Society of Pediatric Hematology and Oncology, is to provide consensus recommendations for the management of febrile neutropenia in paediatric oncology and haematology patients, including the initial evaluation, the stepwise approach to its treatment, supportive care and invasive fungal infection, which each facility then needs to adapt to the characteristics of its patients and local epidemiological trends.

Use of Monoclonal Antibodies in a Pediatric Patient With Severe Combined Immunodeficiency and Persistent SARS-CoV-2 Infection.

We describe the use of monoclonal antibodies for the treatment of persistent SARS-CoV-2 infection in a pediatric patient with severe combined immunodeficiency who required urgent stem cell transplantation to cure his 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.

Case Report: Severe ARDS in a Pediatric Hematopoietic Stem-Cell Transplantation Recipient Caused by Disseminated Toxoplasmosis.

Toxoplasma gondii infection is a severe complication of hematopoietic stem-cell transplantation (HSCT) recipients that can remain unnoticed without a high clinical suspicion. We present the case of a 6-year-old patient with acute lymphoblastic leukemia and HSCT recipient who was admitted to the Pediatric Intensive Care Unit (PICU) on post-transplantation day +39 with fever, hypotension, severe respiratory distress and appearance of a lumbar subcutaneous node. She developed severe Acute Respiratory Distress Syndrome (ARDS) and underwent endotracheal intubation and early mechanical ventilation. Subsequently, she required prone ventilation, inhaled nitric oxide therapy and high-frequency oscillatory ventilation (HFOV). An etiologic study was performed, being blood, urine, bronchoalveolar lavage and biopsy of the subcutaneous node positive for Toxoplasma gondii by Polymerase Chain Reaction (PCR). Diagnosis of disseminated toxoplasmosis was established and treatment with pyrimethamine, sulfadiazine and folinic acid started. The patient showed clinical improvement, allowing weaning of mechanical ventilation and transfer to the hospitalization ward after 40 days in the PICU. It is important to consider toxoplasmosis infection in immunocompromised patients with sepsis and, in cases of severe respiratory distress, early mechanical ventilation should be started using the open lung approach. In Toxoplasma IgG positive patients, close monitoring and appropriate anti-infectious prophylaxis is needed after HSCT.

[Invasive meningococcal disease in children and adults in a tertiary level hospital. Recent epidemiology and prognostic factors]. / Enfermedad meningocócica invasiva en niños y adultos en un hospital terciario: epidemiología reciente y factores pronósticos.

INTRODUCTION: Invasive meningococcal disease (IMD) has a high morbidity and mortality in children and adults. The aim of this study was to describe the clinical and epidemiological characteristics of patients with IMD, to compare them among children and adults, and to determine prognostic factors and changes in epidemiology during a 14-year period. METHODS: A retrospective study was conducted on patients admitted to a third level hospital with IMD between 2004 and 2017. An analysis was made of the clinical, epidemiological and microbiological data. RESULTS: A total of 84 patients were diagnosed with IMD, of which 50 (59.5%) were children. Median age was 2 years (IQR 0.7-7.5) for children and 41.2 years (IQR 26.4-69.3) for adults. Diagnosis was bacteraemia in 47 patients (56%), meningitis in 24 (28.6%), and both in 13 (15.5%). Serogroup B (MenB) was the most common cause of IMD (40.5%), followed by serogroup C (MenC) in 15.5%, which was more common among adults (26.5% vs 8%, P=.022). Incidence rate decreased between 2004-2010 and 2011-2017, from 3.14 to 1.33 cases/100.000 emergencies attended in the study hospital (P<.001). Eighty-four percent of children had received≥1 dose of vaccine against MenC, with none against MenB. Children had higher proportion of ICU admissions (78% vs 44.1%, P=.001). Mortality was slightly higher in adults (11.8% vs 2.0%, P=.153). Adverse outcomes (sequelae or mortality) were independently associated with intubation and thrombocytopenia, while disease severity with leukopenia and purpuric rash. CONCLUSIONS: IMD incidence has decreased in our setting, with MenB being the most common serogroup. The higher prevalence of MenC in adults was probably related to lower vaccination coverage. According to this study, thrombocytopenia, leukopenia, and purpuric rash were parameters associated with worse outcome.

Documento de consenso de manejo de neutropenia febril en el paciente pediátrico oncohematológico de la Sociedad Española de Infectología Pediátrica (SEIP) y la Sociedad Española de Hematología y Oncología Pediátrica (SEHOP) / Consensus document on the management of febrile neutropenia in paediatric haematology and oncology patients of the Spanish Society of Pediatric Infectious Diseases (SEIP) and the Spanish Society of Pediatric Hematology and Oncology (SEHOP)

La neutropenia febril es una de las principales complicaciones infecciosas que sufren los pacientes pediátricos oncohematológicos, y a pesar los avances en diagnóstico y tratamiento, siguen condicionando una mortalidad y morbilidad significativa. Estos pacientes agrupan una serie de factores de riesgo de infección, donde destaca la neutropenia asociada a quimioterapia, la disrupción de barreras cutáneo-mucosas y el uso de dispositivos intravasculares. El abordaje diagnóstico y terapéutico precoz de los episodios de neutropenia febril en los pacientes oncohematológicos, ajustado a las características individuales de cada paciente, es fundamental para mejorar su pronóstico. Por ello, diseñar protocolos de abordaje, que sistematicen su atención, permite optimizar y homogeneizar su abordaje. Además, racionalizar el uso de los antimicrobianos, ajustando la duración y el espectro de los mismos, es crucial para hacer frente al incremento de resistencias a antimicrobianos. El objetivo de este documento, elaborado entre la Sociedad Española de Infectología Pediátrica y la Sociedad Española de Hematología y Oncología Pediátrica, es dar recomendaciones de consenso sobre el manejo de la neutropenia febril en el paciente oncohematológico, respecto al abordaje inicial, terapia secuencial y de soporte e infección fúngica invasiva, que cada centro debe adaptar a las características de sus pacientes y epidemiología local. (AU)

Febrile neutropenia is one of the main infectious complications experienced by paediatric patients with blood or solid tumours, which, despite the advances in diagnosis and treatment, are still associated with a significant morbidity and mortality. These patients have several risk factors for infection, chief of which are chemotherapy-induced neutropenia, the disruption of cutaneous and mucosal barriers and the use of intravascular devices. Early diagnosis and treatment of febrile neutropenia episodes based on the patient's characteristics is essential in patients with blood and solid tumours to improve their outcomes. Therefore, it is important to develop protocols in order to optimise and standardise its management. In addition, the rational use of antibiotics, with careful adjustment of the duration of treatment and antimicrobial spectrum, is crucial to address the increase in antimicrobial drug resistance. The aim of this document, developed jointly by the Spanish Society of Pediatric Infectious Diseases and the Spanish Society of Pediatric Hematology and Oncology, is to provide consensus recommendations for the management of febrile neutropenia in paediatric oncology and haematology patients, including the initial evaluation, the stepwise approach to its treatment, supportive care and invasive fungal infection, which each facility then needs to adapt to the characteristics of its patients and local epidemiological trends. (AU)

Histoplasmosis aguda importada en un adolescente con sospecha de síndrome linfoproliferativo / Imported Acute Histoplasmosis in an Adolescent with Suspected Lymphoproliferative Syndrome

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Enfermedad meningocócica invasiva en niños y adultos en un hospital terciario: epidemiología reciente y factores pronósticos / Invasive meningococcal disease in children and adults in a tertiary level hospital. Recent epidemiology and prognostic factors

Introducción: La enfermedad meningocócica invasiva (EMI) supone una causa importante de morbimortalidad en niños y adultos. Objetivo principal: describir las características clínicas y epidemiológicas de los pacientes con EMI. Objetivos secundarios: describir las diferencias entre niños y adultos, factores pronósticos y cambios epidemiológicos en los últimos 14 años. Métodos: Estudio retrospectivo realizado en un hospital terciario. Se incluyeron los pacientes diagnosticados de EMI entre 2004 y 2017, recogiéndose datos epidemiológicos, clínicos y microbiológicos. Resultados: Fueron diagnosticados 84 pacientes con EMI, 50 (59,5%) niños. Edad mediana en niños 2 años (RIC: 0,7-7,5) y adultos 41,2 años (RIC: 26,4-69,3). Bacteriemia en 47 casos (56%), meningitis en 24 (28,6%) y ambas en 13 (15,5%). Predominio del serogrupo B (MenB), en el 40,5%, seguido del serogrupo C (MenC), en el 15,5%, con mayor proporción de MenC en adultos (26,5 vs. 8%; p = 0,022). Disminución en la incidencia de 2004-2010 a 2011-2017, pasando de 3,14 a 1,33 casos/100.000 urgencias en el centro de estudio (p < 0,001). El 84% de los niños había recibido ≥ 1 dosis de vacuna frente a MenC, ninguno frente a MenB. Mayor proporción de ingreso en UCI en niños (78 vs. 44,1%; p = 0,001). Tendencia a mayor letalidad en adultos (11,8 vs. 2%; p = 0,153). La intubación y la trombocitopenia fueron factores de riesgo independientes de desenlace adverso, y la leucopenia y el exantema purpúrico de gravedad. Conclusiones: Se objetivó un descenso en la incidencia de EMI, siendo MenB el mayoritario. El mayor porcentaje de MenC en adultos probablemente esté relacionado con una menor cobertura vacunal. La trombocitopenia, la leucopenia y el exantema purpúrico fueron factores de riesgo relacionados con peor pronóstico

Introduction: Invasive meningococcal disease (IMD) has a high morbidity and mortality in children and adults. The aim of this study was to describe the clinical and epidemiological characteristics of patients with IMD, to compare them among children and adults, and to determine prognostic factors and changes in epidemiology during a 14-year period. Methods: A retrospective study was conducted on patients admitted to a third level hospital with IMD between 2004 and 2017. An analysis was made of the clinical, epidemiological and microbiological data. Results: A total of 84 patients were diagnosed with IMD, of which 50 (59.5%) were children. Median age was 2 years (IQR 0.7-7.5) for children and 41.2 years (IQR 26.4-69.3) for adults. Diagnosis was bacteraemia in 47 patients (56%), meningitis in 24 (28.6%), and both in 13 (15.5%). Serogroup B (MenB) was the most common cause of IMD (40.5%), followed by serogroup C (MenC) in 15.5%, which was more common among adults (26.5% vs 8%, P = .022). Incidence rate decreased between 2004-2010 and 2011-2017, from 3.14 to 1.33 cases/100.000 emergencies attended in the study hospital (P < .001). Eighty-four percent of children had received ≥ 1 dose of vaccine against MenC, with none against MenB. Children had higher proportion of ICU admissions (78% vs 44.1%, P = .001). Mortality was slightly higher in adults (11.8% vs 2.0%, P = .153). Adverse outcomes (sequelae or mortality) were independently associated with intubation and thrombocytopenia, while disease severity with leukopenia and purpuric rash. Conclusions: IMD incidence has decreased in our setting, with MenB being the most common serogroup. The higher prevalence of MenC in adults was probably related to lower vaccination coverage. According to this study, thrombocytopenia, leukopenia, and purpuric rash were parameters associated with worse outcome

Brote de infección por enterovirus causantes de afectación neurológica grave en un hospital terciario / Infection outbreak due to an enterovirus causing severe neurological complications in a tertiary hospital

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