Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

Molecular epidemiology of paediatric invasive pneumococcal disease in Andalusia, Spain.

This study aimed to assess the impact of the introduction of pneumococcal conjugate vaccine 13 (PCV13) on the molecular epidemiology of invasive pneumococcal disease (IPD) in children from Andalusia. A population-based prospective surveillance study was conducted on IPD in children aged <14 years from Andalusia (2018-2020). Pneumococcal invasive isolates collected between 2006 and 2009 in the two largest tertiary hospitals in Andalusia were used as pre-PCV13 controls for comparison of serotype/genotype distribution. Overall IPD incidence rate was 3.55 cases per 100 000 in 2018; increased non-significantly to 4.20 cases per 100 000 in 2019 and declined in 2020 to 1.69 cases per 100 000 (incidence rate ratio 2020 vs. 2019: 0.40, 95% confidence interval (CI) 0.20-0.89, P = 0.01). Proportion of IPD cases due to PCV13 serotypes in 2018-2020 was 28% (P = 0.0001 for comparison with 2006-2009). Serotypes 24F (15%) and 11A (8.3%) were the most frequently identified non-PCV13 serotypes (NVT) in 2018-2020. Penicillin- and/or ampicillin-resistant clones mostly belonged to clonal complex 156 (serotype 14-ST156 and ST2944 and serotype 11A-ST6521). The proportion of IPD cases caused by PCV13 serotypes declined significantly after the initiation of the PCV13 vaccination programme in 2016. Certain NVT, such as serotypes 24F and 11A, warrant future monitoring in IPD owing to invasive potential and/or antibiotic resistance rates.

Cystic echinococcosis in a Moroccan boy: a silent and neglected disease among refugee and migrant children.

We report the unusual case of a 5-year-old migrant boy from a rural area of Morocco with an almost-giant lung hydatid cyst that was an incidental finding on a chest X-ray performed during routine visa procedures. Echinococcus granulosus serology test was initially negative with subsequent positive seroconversion. Albendazole was started at 4 weeks before surgery and maintained for 4 months, with a favourable outcome. Cystic echinococcosis (CE) is considered a neglected tropical disease and affects more than one million people worldwide, mostly from a lower socioeconomic background. Preventive measures have been limited in underdeveloped regions. Children with CE are especially vulnerable, due not only to the high pathogenic potential of the disease but also to their frequent involvement in challenging socioeconomic situations, including migration. The incidence of CE is increasing in Europe because of high immigration flows from endemic countries. Nevertheless, CE is not covered by current migrant screening protocols.

Distinct Laboratory and Clinical Features of Secondary Hemophagocytic Lymphohistiocytosis in Pediatric Visceral Leishmaniasis: A Retrospective Analysis of 127 Children in Andalusia, Spain (2004-2019).

BACKGROUND: Visceral leishmaniasis (VL) is an endemic in Southern Europe. However, details regarding disease burden, clinical presentations, laboratory markers, management and outcome in children are scarce. METHODS: Medical records of children (<14 years) admitted with VL to 10 pediatric units in Andalusia (2004-2019) were retrospectively reviewed. VL diagnosis was based on clinical presentation, serology, microscopy and molecular methods. Diagnosis of secondary hemophagocytic lymphohistiocytosis (sHLH) was established using the hemophagocytic lymphohistiocytosis-2004 criteria. RESULTS: A total of 127 patients were identified. Median age was 14.5 months; the main clinical presentations were fever and splenomegaly (95.3% each). Cytopenias were the most common laboratory abnormalities. Diagnostics as well as treatment regimens varied over time and the participating centers. Liposomal amphotericin B was prescribed in 97.6%; relapses as well as adverse events were rarely observed (3.1% each). Thirty-seven patients, diagnosed with sHLH required longer hospital admission (P = 0.001), an increased number of platelet (P < 0.006) and red blood cell (P = 0.0001) transfusions and pediatric intensive care unit admission (P = 0.007). Monocytopenia (P = 0.011) and high C-reactive protein levels (P = 0.031), variables not included in the hemophagocytic lymphohistiocytosis-2004 criteria, were associated with sHLH. One patient deceased in the context of the Leishmania infection. CONCLUSIONS: We report data on the largest pediatric VL cohort from Europe, commonly associated with sHLH. Raised C-reactive protein levels and monocytopenia appear to be associated with sHLH. The latter may help to identify these patients and to guide decisions regarding need of additional supportive clinical care and immunomodulatory therapies. The observed high rate of heterogeneity in terms of diagnosis and management warrants the establishment of appropriate guidelines.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Descripción de datos clínico-epidemiológicos de pacientes pediátricos con diarrea por Aeromonas spp. y estudio de la sensibilidad antibiótica de dicho agente / Epidemiological data description of pediatric patients with diarrhea by Aeromonas spp. and the antibiotic susceptibility of this agent

Resumen El objetivo de nuestro estudio fue describir las características clínico-epidemiológicas de los pacientes pediátricos con diarrea por Aeromonas spp. y estudiar lasensibilidad antibiótica de dicho agente, a partir del análisis de casos ocurridos en un períodode 7 anos. Aeromonas caviae fue identificada en 93 muestras de heces recuperadas de ninos,el 52,2% de ellos fueron varones y el 85,6% menores de 36 meses. La estación del ano conmenor cantidad de aislamientos fue el invierno (14,4%). Hubo coinfección con otros microorganismos diarreogénicos en el 31,1% de esas muestras. El mayor número de muestras procediódel servicio de urgencias de nuestro hospital (45,6%). El 43,3% de los pacientes presentaronfiebre; el 87,8%, diarrea (43% con productos patológicos) y el 67,8%, vómitos. El 73,3% de lospacientes no precisó ingreso hospitalario. Se encontró una sensibilidad superior al 87% frentea trimetoprima-sulfametoxazol, ciprofloxacina, cefotaxima y cefepime. Todos los pacientessuperaron el proceso infeccioso aun cuando el 63,3% no recibió ningún tratamiento antibiótico.Concluimos que el tratamiento antibiótico estaría indicado en casos seleccionados, cuandoexiste gravedad clínica.© 2019 Asociacion Argentina de Microbiologıa. Publicado por Elsevier Espana, S.L.U. Este es unartıculo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract The aim of our study was to describe the epidemiological features of pediatric patients with diarrhea caused by Aeromonas spp. and to study the antibiotic susceptibility of this agent during a seven-year period. Aeromonas caviae was identified in 93 stool samples from 52.2% males and 85.6% patients younger than 36 months. The season with the lowest number of isolates was winter (14.4%). Coinfection with other diarrheagenic microorganisms was observed in 31.1% of the cases. The largest number of isolates was obtained from Emergency Department samples (45.6%); 43.3% of the patients presented with fever, 87.8% with diarrhea (43% of these cases were associated with pathological products) and 67.8% with vomiting, while 73.3% of the patients did not require hospital admission. Susceptibility higher than 87% was observed to trimethoprim-sulfamethoxazole, ciprofloxacin, cefotaxime and cefepime. All the patients overcame the infectious process and 63.3% of them did not receive any antibiotic treat-ment during the process. A. caviae was the isolated species associated with intestinal infection. Antibiotic treatment would be specifically indicated in cases selected for their clinical severity. © 2019 Asociación Argentina de Microbiología. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

[Epidemiological data description of pediatric patients with diarrhea by Aeromonas spp. and the antibiotic susceptibility of this agent]. / Descripción de datos clínico-epidemiológicos de pacientes pediátricos con diarrea por Aeromonas spp. y estudio de la sensibilidad antibiótica de dicho agente.

The aim of our study was to describe the epidemiological features of pediatric patients with diarrhea caused by Aeromonas spp. and to study the antibiotic susceptibility of this agent during a seven-year period. Aeromonas caviae was identified in 93 stool samples from 52.2% males and 85.6% patients younger than 36 months. The season with the lowest number of isolates was winter (14.4%). Co-infection with other diarrheagenic microorganisms was observed in 31.1% of the cases. The largest number of isolates was obtained from Emergency Department samples (45.6%); 43.3% of the patients presented with fever, 87.8% with diarrhea (43% of these cases were associated with pathological products) and 67.8% with vomiting, while 73.3% of the patients did not require hospital admission. Susceptibility higher than 87% was observed to trimethoprim-sulfamethoxazole, ciprofloxacin, cefotaxime and cefepime. All the patients overcame the infectious process and 63.3% of them did not receive any antibiotic treatment during the process. A. caviae was the isolated species associated with intestinal infection. Antibiotic treatment would be specifically indicated in cases selected for their clinical severity.

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

Expanding the Clinical and Genetic Spectra of Primary Immunodeficiency-Related Disorders With Clinical Exome Sequencing: Expected and Unexpected Findings.

Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.