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Teresa del Rosal,1,2 Ana Méndez-Echevarría,1,2 Cesar Garcia-Vera,3 Luis Escosa-Garcia,1,2 Martin Agud,1 Fernando Chaves,4 Federico Román,5 José Gutierrez-Fernandez,6 Enrique Ruiz de Gopegui,7 Guillermo Ruiz-Carrascoso,8 Maria del Carmen Ruiz-Gallego,9 Albert Bernet,10 Sara Maria Quevedo,11 Ana Maria Fernández-Verdugo,12 Jesús Díez-Sebastian,13 Cristina Calvo1,2 On behalf of the COSACO Study Group1Pediatric Infectious and Tropical Diseases Department, Hospital Universitario La Paz, Madrid, Spain; 2Translational Research Network in Pediatric Infectious Diseases (RITIP), Institute for Health Research IdiPAZ, Madrid, Spain; 3“José Ramón Muñoz Fernández” Health Care Center, Aragón Health Service, Zaragoza, Spain; 4Department of Clinical Microbiology, Hospital Universitario 12 de Octubre, Madrid, Spain; 5Laboratory of Nosocomial Infections, Department of Bacteriology, CNM, Instituto de Salud Carlos III, Madrid, Spain; 6Department of Microbiology, Hospital Virgen de las Nieves, Granada, Spain; 7Department of Clinical Microbiology, Hospital Universitari Son Espases. Servicio de Microbiología, Palma de Mallorca, Spain; 8Department of Clinical Microbiology, Hospital Universitario La Paz, Madrid, Spain; 9Department of Microbiology, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 10Section of Microbiology, Arnau de Vilanova University Hospital, Lleida, Spain; 11Department of Microbiology, Hospital Universitario Severo Ochoa, Leganes, Spain; 12Department of Microbiology, Hospital Universitario Central de Asturias, Oviedo, Spain; 13Department of Preventive Medicine, Hospital Universitario La Paz, Madrid, SpainCorrespondence: Ana Méndez-Echevarría Pediatric Infectious and Tropical Diseases Department. Hospital La Paz-IdiPAZ, Paseo de la Castellana 261, Madrid 28046, SpainTel/Fax +34-917277479Email amendezes@yahoo.esObjective: To assess the prevalence and risk factors for S. aureus and methicillin-resistant S. aureus (MRSA) nasal colonization in Spanish children.Methods: Cross-sectional study of patients < 14 years from primary care centers all over Spain. Clinical data and nasal aspirates were collected from March to July 2018.Results: A total of 1876 patients were enrolled. Prevalence of S. aureus and MRSA colonization were 33% (95% CI 30.9– 35.1) and 1.44% (95% CI 0.9– 2), respectively. Thirty-three percent of the children (633/1876) presented chronic conditions, mainly atopic dermatitis, asthma and/or allergy (524/633). Factors associated with S. aureus colonization were age ≥ 5 years (OR 1.10, 95% CI 1.07– 1.12), male sex (OR 1.43, 95% CI 1.17– 1.76), urban setting (OR 1.46, 95% CI 1.08– 1.97) and the presence of asthma, atopic dermatitis or allergies (OR 1.25; 95% CI: 1.093– 1.43). Rural residence was the only factor associated with MRSA colonization (OR 3.62, 95% CI 1.57– 8.36). MRSA was more frequently resistant than methicillin-susceptible S. aureus to ciprofloxacin [41.2% vs 2.6%; p< 0.0001], clindamycin [26% vs 16.9%; p=0.39], and mupirocin [14.3% vs 6.7%; p=0.18]. None of the MRSA strains was resistant to tetracycline, fosfomycin, vancomycin or daptomycin.Conclusions: The main risk factors for S. aureus colonization in Spanish children are being above five years of age, male gender, atopic dermatitis, asthma or allergy, and residence in urban areas. MRSA colonization is low, but higher than in other European countries and is associated with rural settings.Keywords: S. aureus, MRSA, child, colonization

We describe the epidemiology, diagnosis, and management of nontuberculous mycobacterial lymphadenitis cases detailed in a 28-year (1996-2023) multicenter cohort from Spain. The case numbers remained stable during the initial prospective phase (2013-2020), but a sharp decline was observed during 2021-2022. Disease onset occurred during spring or June in 45.9% of cases. Mycobacterium avium complex (43.1%) and M. lentiflavum (39.9%) were the most common species detected. M. lentiflavum affected mostly younger children from central Spain. The most common treatment strategy was complete surgical resection with (n = 80) or without (n = 88) antimicrobial drug treatment, followed by antimicrobial drugs alone (n = 76). Facial palsy developed in 10.4% of surgical cases. Adverse events because of antimicrobial drugs were uncommon. New fistula formation during follow-up occurred more in children managed with observation alone than in those treated with antimicrobial drugs alone (relative risk 2.7 [95% CI 1.3-5.3]; p = 0.014).

This study conducted in Madrid, Spain between 2018 and 2023 shows a significant decrease in the pediatric bacterial community-acquired pneumonia cases during the COVID-19 pandemic, followed by a notable postpandemic increase surpassing prepandemic incidence. Streptococcus pneumoniae remains predominant, with an increasing prevalence of serotype 3, while Streptococcus pyogenes was the second most common pathogen., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients., Methods: Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases., Results: In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40-62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4-42] versus 11 [3-21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died., Conclusions: NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Splicing is the molecular mechanism to produce mature messenger RNA (mRNA) before its translation into protein. It is estimated that 50% of disease-causing mutations disrupt splicing, mostly of them affecting canonical positions. However, variants occurring in coding regions or deep-intronic variants can also affect splicing. In these cases, interpretation of the results may be challenging and molecular validation is required., Methods: The study includes 23 patients with splicing variants out of a cohort of 187 patients diagnosed with inborn errors of immunity (IEI). Clinical features and immunophenotypes are shown. Reverse transcription-polymerase chain reaction (RT-PCR) is the molecular assay employed for pathogenicity validation., Results: We detected 23 patients of 20 pedigrees with splicing variants in IEI genes, which constitutes the 12.3% of our cohort. In total, 21 splicing variants were analyzed, 10 of which had previously been reported in the literature and 11 novel ones. Among the 23 patients, 16 showed variants at canonical splice sites. Molecular validation was required only in the cases of genes of uncertain significance (GUS), high homology pseudogenes or incompatible clinical phenotype. Seven patients showed variants outside canonical positions. All of them needed molecular validation, with the exception of two patients, whose variants had previously been well characterized in the medical literature., Conclusion: This study shows the proportion of splicing variants in a cohort of IEI patients, providing their clinical phenotypic characteristics and the methodology used to validate the splicing defects. Based on the results, an algorithm is proposed to clarify when a splicing variant should be validated by complementary methodology and when, by contrast, it can be directly considered disease causing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Miguel Berenguel, Gianelli, Matas Pérez, del Rosal, Méndez Echevarría, Robles Marhuenda, Feito Rodríguez, Caballero Molina, Magallares García, Sánchez Garrido, Hita Díaz, Allende Martínez, Nozal Aranda, Cámara Hijón, López Granados, Rodríguez Pena and Bravo García-Morato.)

Objective: The objective of this study was to assess the role of T-lymphocyte immune responses in newborns with congenital cytomegalovirus (CMV) infection (cCMV) and their potential association with the development of long-term sequelae., Study Design: A multicenter, prospective study from 2017 to 2022 was conducted across 8 hospitals in Spain. Blood samples were collected within the first month of life from neonates diagnosed with cCMV. Intracellular cytokine staining was employed to evaluate the presence of CMV-specific interferon-gamma (IFN-γ)-producing CD8 + and CD4 + T lymphocytes (CMV-IFN-γ-CD8 + /CD4 + ) using flow cytometry. The development of sequelae, including hearing loss and neurologic impairment, was assessed during follow-up., Results: In total, 64 newborns were included; 42 infants (65.6%) had symptomatic cCMV. The median age at the last follow-up visit was 25.3 months (IQR 20.1-34.4). Eighteen infants had long-term sequelae (28.1%), predominantly hearing loss (20.3%) and neurologic disorders (15.6%). No relationship was observed between total count or percentage of CMV-specific IFN-γ-CD8 + or CD4 + lymphocytes and long-term sequelae. Multivariable analysis demonstrated an association between lower total lymphocyte count and long-term sequelae (aOR 0.549, 95% CI: 0.323-0.833), which requires further study., Conclusions: CMV-specific IFN-γ-CD4 + and CD8 + T-lymphocyte responses in neonates with cCMV were not predictive of long-term sequelae., Competing Interests: Declaration of Competing Interest DBG received fees from MSD as speaker in educational activities. JSL received fees from Biomerieux as speaker. None of the remaining authors have any conflict of interests to declare. This work was supported by projects PI 16/00807, PI 19/01333, and PI 22/01540, from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) and co-funded by the European Regional Development Fund. DBG was supported by the Spanish Ministry of Science and Innovation - Instituto de Salud Carlos III and by Fondos FEDER “Contratos para la intensificación de la actividad investigadora en el Sistema Nacional de Salud, 2020 INT20/00  086 and 2023 INT23/00  039”. The study was approved by the Ethics Committee of Hospital Universitario 12 de Octubre. Paula Rodríguez-Molino was funded by the Spanish Ministry of Science and Innovation-Instituto de Salud Carlos III and Fondos FEDER (Contrato Río Hortega CM21/00  174)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplant recipients are prone to infectious complications. Infections caused by nontuberculous mycobacteria have increased in adults but literature in children is scarce. We report 6 episodes of disseminated or pulmonary nontuberculous mycobacteria infection among 5 pediatric hematopoietic stem cell transplant recipients. All but one were caused by Mycobacterium avium complex. Four patients died, 2 related to nontuberculous mycobacteria infection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Antibiotics are frequently prescribed to children with pneumonia, although viruses are responsible for most cases. We aimed to evaluate the impact of multiplex polymerase chain reaction (mPCR) on antibiotic use. We conducted a prospective study of children under 14 years of age admitted for suspected viral pneumonia, from October 2019 to June 2022 (except March-November 2020). A mPCR respiratory panel (FilmArray ® 2 plus , bioMérieux, Marcy-l'Étoile, France) was performed within 72 h of admission. Patients with positive reverse transcription PCR for respiratory syncytial virus, influenza, or SARS-CoV-2 were excluded. We compared the patients with historical controls (2017-2018) who had suspected viral pneumonia but did not undergo an aetiological study. We included 64 patients and 50 controls, with a median age of 26 months. The respiratory panel detected viral pathogens in 55 patients (88%), including 17 (31%) with co-infections. Rhinovirus/enterovirus ( n = 26) and human metapneumovirus ( n = 22) were the most common pathogens, followed by adenovirus and parainfluenza ( n = 10). There were no statistically significant differences in the total antibiotic consumption (83% of cases and 86% of controls) or antibiotics given for ≥72 h (58% vs. 66%). Antibiotics were prescribed in 41% of the cases and 72% of the controls at discharge ( p = 0.001). Ampicillin was the most commonly prescribed antibiotic among the patients (44% vs. 18% for controls, p = 0.004), while azithromycin was the most commonly prescribed among the controls (19% vs. 48% for patients and controls, respectively; p = 0.001). Our findings underscore the need for additional interventions alongside molecular diagnosis to reduce antibiotic usage in paediatric community-acquired pneumonia.

Background: There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols., Methods: A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild., Results: A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases., Conclusions: The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: human adenovirus (hAdV) infection constitutes an important cause of morbidity and mortality in transplant recipients, due to their immune status. Among drugs currently available, cidofovir (CDF) is the most prescribed., Methods: Retrospective study of hAdV infection in paediatric transplant recipients from a tertiary paediatric centre, describing characteristics, management, and outcomes, and focused on the role of CDF., Results: 49 episodes of infection by hAdV were detected during a four-year period: 38 episodes in patients that received allogeneic hematopoietic stem cell transplantation (77.6%) and 11 in solid organ transplant recipients (22.4%). Twenty-five patients (52.1%) were symptomatic, presenting mainly fever and/or diarrhoea. CDF was prescribed in 24 patients (49%), with modest results. CDF use was associated with the presence of symptoms resulting in lower lymphocyte count, paediatric intensive care unit admission, and high viral load. Other therapeutic measures included administration of intravenous immunoglobulin, reducing immunosuppression, and T-lymphocyte infusion. Despite treatment, 22.9% of patients did not resolve the infection and there were three deaths related to hAdV infection. All-cause mortality was 16.7% (8 episodes) by 30 days, and 32.7% (16 episodes) by 90 days, of which, 3 episodes (3/16, 18.8%) were attributed to hAdV directly., Conclusions: hAdV infection had high morbidity and mortality in our series. CDF use is controversial, and available therapeutic options are limited. Transplant patients with low lymphocyte count are at higher risk of persistent positive viremias, and short-term survival of these patients was influenced by the resolution of hAdV infection.

Background: Epidermolysis bullosa (EB) is frequently complicated by skin infection, which can lead to bacteremia. However, bloodstream infections (BSI) in patients with EB have not been well described., Methods: Retrospective study of BSI in children 0-18 years with EB from a national reference unit in Spain, in 2015-2020., Results: Among 126 children with EB, we identified 37 BSI episodes in 15 patients (14 recessive dystrophic EB, 1 junctional EB). The most frequent microorganisms were Pseudomonas aeruginosa (n = 12) and Staphylococcus aureus (n = 11). Five P. aeruginosa isolates were ceftazidime-resistant (42%), 4 of which were also resistant to meropenem and quinolones (33%). As for S. aureus , 4 (36%) were methicillin-resistant and 3 (27%) clindamycin-resistant. In 25 (68%) BSI episodes skin cultures had been performed in the previous 2 months. The most frequent isolates were also P. aeruginosa (n = 15) and S. aureus (n = 11). In 13 cases (52%), smear and blood cultures grew the same microorganism, with the same antimicrobial resistance pattern in 9 isolates. Twelve patients (10%) died during follow-up (9 RDEB and 3 JEB). BSI was the cause of death in 1 case. In patients with severe RDEB, a history of BSI was associated with higher mortality (OR 6.1, 95% CI: 1.33-27.83, P = 0.0197)., Conclusions: BSI is an important cause of morbidity in children with severe forms of EB. The most frequent microorganisms are P. aeruginosa and S. aureus , with high rates of antimicrobial resistance. Skin cultures can help guide treatment decisions in patients with EB and sepsis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

According to World Health Organization estimates, more than 1 million patients aged less than 15 years develop tuberculosis (TB) each year worldwide. In some regions, up to 25% of new TB cases are caused by drug-resistant strains. Although Spain is considered a low-incidence country, several hundred children and adolescents develop TB each year. The importance of paediatric TB has been minimized for years due to the lack of microbiological confirmation in many patients and because these patients are not usually contagious. Nevertheless, in the past 15 years there have been major improvements in the epidemiological reporting of TB in children and adolescents, new immunodiagnostic tests have been developed, molecular methods that allow rapid microbiological diagnosis and detection of variants associated with drug resistance have become available, novel second-line antituberculosis drugs have been discovered, including for paediatric use, and the results of clinical trials have validated shorter courses of treatment for some patients. This document, developed by a group of experts from the Sociedad Española de Infectología Pediátrica and the Sociedad Española de Neumología Pediátrica, updates and complements the previous guidelines for the diagnostic and therapeutic management of children with TB in Spain based on the newly available scientific evidence., (Copyright © 2023 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Torque teno virus (TTV) is a ubiquitous anellovirus responsible for persistent infections and is considered a marker of immune function. The role of TTV as a facilitator of respiratory infections (RIs) is unknown., Objectives: Our aim was to estimate, in a prospective study, the prevalence of TTV in the nasopharyngeal aspirate (NPA) of hospitalized children <5 years old, with RIs and correlate them with outcomes and immune response., Patients and Methods: NPA was taken for testing of 16 respiratory viruses by reverse transcription-polymerase chain reaction (PCR), TTV PCR, and immunologic study., Results: Sixty hospitalized children with an RI were included. A total of 51/60 patients had positive common respiratory viral (CRV) identification. A total of 23/60 (38.3%) children were TTV+ in NPA. TTV+ patients had other CRVs in 100% of cases versus 78.3% in TTV- ( P = 0.029). The TTV+ patients tended to be older, have fever, and to need pediatric intensive care unit admission more often than TTV- patients. Abnormal chest radiograph was more frequent in the TTV+ patients, odds ratios 2.6 (95% CI: 1.3-5.2). The genetic expression of filaggrin (involved in epithelial barrier integrity) was lower in TTV+ patients; however, the levels of filaggrin in the NPA were increased., Conclusions: TTV infection is common in children with RI and could be associated with abnormal imaging in radiograph, greater severity and an alteration in filaggrin gene expression and protein release., Competing Interests: There are no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors., Methods: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections., Results: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection., Conclusions: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors., Competing Interests: Potential conflicts of interest. C. M. C. reports the following grants or contracts unrelated to this work: Centers for Disease Control and Prevention (CDC) subaward from Johns Hopkins University to the Washington University in St. Louis (funding by the CDC grant number 1U54CK000617-01-00), vendor/individual agreement with Wayne State University for a case registry, and Associate Editor for Open Forum Infectious Diseases (1 May 2022 through 30 April 2023). D. F. P. reports payment or honoraria as a speaker for an antibiotic course for UMC Utrecht and as a teacher for Hospital Pharmacists in training for PAO; and participation on DSMB for the COBRA trial (Very short-course versus standard course antibiotic therapy in patients with acute Cholangitis after adequate endoscopic biliaRy drainage) in the Netherlands. M. J. M. reports consulting fees from Insmed and Biomerieux; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Microsoft Diagnostics (MSD), Insmed, and Teva; support for attending meetings and/or travel from MSD, Berlin Chemie; and participation on a Data Safety Monitoring Board or Advisory Board for Biomerieux, Insmed, MSD. J. T. S. reports payment or honoraria for manuscript writing for Gilead on subjects not related to this manuscript. M. B. reports support from Pfizer for attending a congress. N. K. reports royalties or licenses from Up To Date; consulting fees from Astellas, AstraZeneca, Biotest, ExeViR, Hansa, Merck Sharp and Dohme, Glasgow Smith Kline, Novartis Pharma, Takeda; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Astellas, Biotest, CSL Behring, Chiesi, Novartis Pharma, Sanofi, Sandoz, Takeda; and support for attending meetings and/or travel from Astellas, Novartis Pharma, Takeda. N. J. M. reports support for attending meetings and/or travel paid to author from Biotest; unpaid participation on a Data Safety Monitoring Board or Advisory Board for a CTX3 Study and paid participation on Advisory Boards for Takeda, MSD, and Pfizer. N. M. T. reports payment or honoraria for guest lecture for Boston Medical Center and Beth Israel Medical Center; payment for expert testimony for record review for Ficksman & Conley, LLP, in Boston, Massachusetts; participation on a Data Safety Monitoring Board or Advisory Board for United Network for Organ Sharing HIV Organ, Policy Equity (HOPE) Act Safety Review, and Workgroup (unpaid); role as Chair of the American Society of Transplantation and leadership or fiduciary role with Infectious Diseases Community of Practice (unpaid). O. M. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from MSD; and participation on a Data Safety Monitoring Board or Advisory Board for MSD. S. Be. reports grants or contracts unrelated to this work from Vancouver Costal Health Research Institute and Transplant Research Foundation of BC; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Merck; and participation on an Advisory Board for Evusheld (AstraZeneca). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by loss-of-function (LOF) mutations in the Signal Transducer and Activator of Transcription 3 (STAT3) gene. In these patients, performing a correct differential diagnosis of pulmonary infections is difficult and challenging, as they usually have atypical presentations. However, establishing a correct diagnostic and therapeutic approach is essential, as pulmonary complications are responsible for high morbidity and mortality rates in these patients. We report the case of a teenage girl with AD-HIES and respiratory symptoms and fever in whom performing a correct differential diagnosis was challenging., (© 2022 Wiley Periodicals LLC.)

Introduction: The autumn and winter bronchiolitis epidemics have virtually disappeared in the first year of the COVID-19 pandemic. Our objectives were characterised bronchiolitis during fourth quarter of 2020 and the role played by SARS-CoV-2., Methods: Prospective multi-centre study performed in Madrid (Spain) between October and December 2020 including all children admitted with acute bronchiolitis. Clinical data were collected and multiplex PCR for respiratory viruses were performed., Results: Thirty-three patients were hospitalised with bronchiolitis during the study period: 28 corresponded to rhinovirus (RV), 4 to SARS-CoV-2, and 1 had both types of infection. SAR-CoV-2 bronchiolitis were comparable to RV bronchiolitis except for a shorter hospital stay. A significant decrease in the admission rate for bronchiolitis was found and no RSV was isolated., Conclusion: SARS-CoV-2 infection rarely causes acute bronchiolitis and it is not associated with a severe clinical course. During COVID-19 pandemic period there was a marked decrease in bronchiolitis cases., (Copyright © 2021 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001)., Conclusion: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI., What Is Known: • Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT). • Active viral infections at the time of HSCT lead to worse prognosis., What Is New: • In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease. • In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neonatal seizures with white matter injury have been associated with rotavirus, enterovirus and parechovirus. Neurological symptoms caused by norovirus have been occasionally reported in older children. We describe a case of a neonate with seizures and white matter lesions, with detection of human norovirus in stool samples from the patient and her mother., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Case Presentation: A 15-year-old boy presented with three acute episodes of self-limited hemoptysis. He was being followed by the pediatric pulmonology department for necrotizing pneumonia and a right upper lobe lung abscess with residual pneumatocele 5 years earlier. He had also experienced recurrent perianal abscesses and more than 15 acute suppurative otitis media throughout his life, even after myringotomy and transtympanic drainage; methicillin-sensitive Staphyloccocus aureus was found in a culture of otic exudate. He had no known allergies and was not taking any drugs. The patient's father had presented with more than 20 skin abscesses and was carrier of methicillin-resistant S aureus. After necrotizing pneumonia and along with his family history, the patient had undergone a neutrophil oxidative burst test excluding chronic granulomatous disease; immunoglobulin levels and lymphocyte populations were within normal range., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Preseptal and orbital cellulitis are two types of infection surrounding the orbital septum with very different potential outcomes. Our aim was to describe key differential features of both conditions, laying special emphasis on diagnostic and therapeutic tools., Methods: A retrospective review of patients admitted to a tertiary hospital over a 15-year period (January 2004-October 2019) was conducted. We included 198 patients with preseptal and 45 with orbital cellulitis. Descriptive statistics were performed to examine the available information., Results: Statistically significant differences were found between patients with preseptal and orbital cellulitis regarding age (3.9 ± 2.14 vs. 7.5 ± 4.24 years), presence of fever (51.5% vs. 82.2%), and preexisting sinusitis (2% vs. 77.8%) (all P < 0.001). Diplopia, ophthalmoplegia and proptosis were only present in orbital cellulitis (P < 0.001). Median values of C-reactive protein were significantly higher among children with orbital involvement [136.35 mg/L (IQR 74.08-168.98) vs. 17.85 (IQR 6.33-50.10), P < 0.0001]. A CRP>120 mg/L cut-off point for orbital cellulitis was obtained. Early CT scans were performed in 75.6% of suspected orbital cellulitis and helped detecting complications at an early stage. Abscesses were revealed in 70.6% of cases, especially medial subperiosteal abscesses (58.8%). All patients received intravenous antibiotics, whereas corticosteroids were preferred in patients with orbital implication (8.6% vs. 73.3%, P < 0.001). Only 26.7% of patients required additional surgery., Conclusions: Clinical presentation and CRP are extremely sensitive for differential diagnosis of preseptal and orbital cellulitis. Prompt initiation of intravenous antibiotics is mandatory and can prevent surgical procedures even in cases with incipient abscesses., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To characterize the Staphylococcus aureus strains colonizing healthy Spanish children., Methods: Between March and July 2018, 1876 Spanish children younger than 14 years attending primary healthcare centers were recruited from rural and urban areas. Staphylococcus aureus colonization of the anterior nostrils was analyzed. MecA and mecC genes, antibiotic susceptibility, and genotyping according to the spa were determined in all strains, and the following toxins were examined: Panton-Valentine leucocidin (pvl), toxic shock syndrome toxin (tst), and exfoliative toxins (eta, etb, etd). Multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing were performed on methicillin-resistant Staphylococcus aureus (MRSA) strains, as well as pulsed-field gel electrophoresis (PFGE)., Results: 619 strains were isolated in 1876 children (33%), and 92% of them were sent for characterization to the Spanish National Centre of Microbiology (n = 572). Twenty (3.5%) of these strains were mecA-positive. Several spa types were detected among MRSA, being t002 the most frequently observed (30%), associating with SCCmec IVc. Among MSSA, 33% were positive for tst, while only 0.73% were positive for pvl. The 20 MRSA strains were negative for pvl, and 6 (30%) harbored the tst gene., Conclusions: methicillin-resistant Staphylococcus aureus nasal colonization in Spanish children is rare, with t002 being the most observed spa type, associated with SCCmec IVc. None of the MRSA strains produced pvl, but up to 30% of S. aureus strains were positive for tst., (© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Background: The impact of respiratory virus infection in patients diagnosed with ataxia-telangiectasia (A-T) has not been well studied., Methods: A prospective case control study was performed at a National Reference Unit for Primary Immunodeficiency in Spain (from November 2018 to July 2019), including patients younger than 20 years. Symptom questionnaires and nasopharyngeal swabs from multiple respiratory viruses' polymerase chain reaction were collected monthly, and between visits in case of symptoms., Results: Twenty-two individuals were included (11 patients; 11 controls); 164 samples were obtained (81 patients; 84 controls). Patients presented respiratory symptoms more frequently compared with controls (26.5% vs. 3.5%; p < 0.01). Viral detection was observed in 23 (27.3%) episodes in patients and in 15 (17.8%) episodes in controls ( p = 0.1). Rhinovirus was the most frequent virus in patients and controls (60% and 53.3%, respectively). Episodes with positive viral detection had associated symptoms in 54% of patients and 18% of controls ( p = 0.07). However, patients with A-T presented a similar rate of symptoms during episodes with positive and negative viral detection (26% vs. 27%). The median points given for each questionnaire during symptomatic episodes with negative viral detection were 13/23 points, and during symptomatic positive detection, 7.5/23 points ( p = 0.1). In the control group, all but two were asymptomatic during positive viral episodes (score: 2/23 and 3/23 points). Symptomatic episodes, with either positive or negative viral detection, were associated with lower IgA and higher IgM titers and higher CD8+ counts ( p < 0.05), particularly when these episodes were moderate/severe., Conclusions: Patients with A-T more frequently present symptomatic viral infections than controls, especially those with lower IgA and higher IgM titers and higher CD8+ counts.

Our study describes more than 100 children hospitalized with pneumonia during lockdown in the first pandemic wave with only 20% attributable to SARS-CoV-2. The serologic study during follow-up only helped to detect 4%. Other etiologies were common. Older age, presence of headache, vomiting, lymphopenia and thrombopenia were associated with COVID-19 pneumonia., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: After the introduction of pneumococcal conjugate vaccines, community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae has decreased whereas Staphylococcus aureus and Streptococcus pyogenes could be increasing. These bacteria have been associated with high rates of complications. Aims: (1) To describe the characteristics of pediatric bacterial CAP requiring hospitalization. (2) To compare outcomes according to causative microorganisms. (3) To analyze changes in bacterial CAP rate and etiology over time. Patients and Methods: Retrospective single-center study of inpatients aged 1 month-16 years with culture-confirmed bacterial CAP in 2010-2018 in Madrid, Spain. Results: We included 64 cases (42 S. pneumoniae , 13 S. pyogenes and 9 S. aureus ). Culture-confirmed CAP represented 1.48-2.33/1,000 all-cause pediatric hospital admissions, and its rate did not vary over time. However, there was a significant decrease in pneumococcal CAP in the last 3 years of the study (78% of CAP in 2010-2015 vs. 48% in 2016-18, p = 0.017). Median hospital stay was 10.5 days (interquartile range 5-19.5), 38 patients (59%) developed complications and 28 (44%) were admitted to the intensive care unit. Outcomes were similar among children with S. pneumoniae and S. aureus CAP, whereas S. pyogenes was associated with a higher risk for complications (OR 8 [95%CI 1.1-57.2]) and ICU admission (OR 7.1 [95%CI 1.7-29.1]) compared with pneumococcal CAP. Conclusion: In a setting with high PCV coverage, culture-confirmed bacterial CAP did not decrease over time and there was a relative increase of S. pyogenes and S. aureus . Children with CAP caused by S. pyogenes were more likely to develop complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 del Rosal, Caminoa, González-Guerrero, Falces-Romero, Romero-Gómez, Baquero-Artigao, Sainz, Méndez-Echevarría, Escosa-García, Aracil and Calvo.)

Competing Interests: Competing interests: None declared.

We present a pediatric case series describing false-positive QuantiFERON-TB Gold In-tube (QFT-GIT) assay (QIAGEN, Germany) results observed in a tertiary hospital in Spain (2013-2018). During the study period, 7 of 737 test results were considered false-positives: 4 children with chronic medical conditions, 1 Mycobacterium lentiflavum lymphadenitis, 1 infant born to a mother with pulmonary tuberculosis, and 1 child exposed to a noninfectious tuberculosis patient. Data regarding interferon-gamma release assays false-positive results in children are scarce, and more studies are necessary to determine the rates of false-positive results in low-prevalence settings.

Infection is the leading cause of non-relapse-related mortality after allogeneic haematopoietic stem cell transplantation (HSCT). Altered functions of immune cells in nasal secretions may influence post HSCT susceptibility to viral respiratory infections. In this prospective study, we determined T and NK cell numbers together with NK activation status in nasopharyngeal aspirates (NPA) in HSCT recipients and healthy controls using multiparametric flow cytometry. We also determined by polymerase chain reaction (PCR) the presence of 16 respiratory viruses. Samples were collected pre-HSCT, at day 0, +10, +20 and +30 after HSCT. Peripheral blood (PB) was also analyzed to determine T and NK cell numbers. A total of 27 pediatric HSCT recipients were enrolled and 16 of them had at least one viral detection (60%). Rhinovirus was the most frequent pathogen (84% of positive NPAs). NPAs of patients contained fewer T and NK cells compared to healthy controls (p = 0.0132 and p = 0.120, respectively). Viral PCR + patients showed higher NK cell number in their NPAs. The activating receptors repertoire expressed by NK cells was also higher in NPA samples, especially NKp44 and NKp46. Our study supports NK cells relevance for the immune defense against respiratory viruses in HSCT recipients.

Objective: Respiratory tract infections are among the most common causes of morbidity and mortality worldwide. Acute bronchiolitis (AB) is the leading cause of hospital admission among infants. Clinical scores have proven to be inaccurate in predicting prognosis. Our aim was to build a score based on findings of lung ultrasound (LU) performed at admission, to stratify patients at risk of needing respiratory support (non-invasive and invasive ventilation)., Study Design: Prospective, multicenter study including infants <6 months of age admitted with AB. Point-of-care LU was performed on admission, and a score was calculated based on ultrasound findings (presence and localization of B lines, B line confluence and/or consolidations) and clinical data. Main outcome was need of respiratory support., Results: A total of 145 patients were included in the study, with a median age of 1.7 months [IQR: 1.2-2.8], 47.6% were female. Mean duration of symptoms prior to admission was 3.1 days (SD 1.8). Fifty-six patients (39%) required non-invasive ventilation (NIV), 14 (9.7%) were transferred to PICU, and 3 needed invasive ventilation (3/145). Identification of at least one posterior consolidation >1 cm was the main factor associated to NIV (RR 4.4; [CI95%1.8-10.8]) The LU score built according to the findings on admission showed an AUC: 0.845(CI95%:0.78-0.91). A score ≥3.5 showed a sensitivity of 89.1% (CI95%:78.2-94.9%) and specificity of 56% (CI95%: 45.3-66.1%) CONCLUSIONS: Among infants below 6 months of age admitted with AB, point-of-care LU was a helpful tool to identify patients at risk of needing respiratory support., (© 2019 Wiley Periodicals, Inc.)

Background: In recent years, there is an increasing interest in the use of linezolid for the treatment of tuberculosis (TB)., Methods: Patients less than 18 years of age who received linezolid within the Spanish Pediatric TB Network from 2001 to 2016 were retrospectively included. Treatment characteristics, adverse events (AEs) and outcomes were analyzed., Results: Fifteen children were included (53% male) with a median age of 3.6 years [interquartile range (IQR): 1.6-6.2]. Median follow-up was 54 months (IQR: 38-76). The reasons for linezolid use were drug-resistant TB in 8 (53%) patients, drug-induced liver injury in 5 (33%) patients and chronic liver disease in 2 (13%) patients. Four children (26%) were on immunosuppressive therapy when TB was diagnosed. Five children (33%) were diagnosed with extrapulmonary TB. The median duration of linezolid treatment was 13 months (IQR: 7.5-17). Nine patients had 13 linezolid-related AEs. Hematologic toxicity was observed in 8 patients (53%) and gastrointestinal intolerance in 3 patients (20%). In 2 patients, linezolid dose was reduced, and in 2 patients, linezolid was discontinued because of AEs. A 2-year-old girl went back to her country of birth and was lost to follow-up. No relapses were observed among the other 14 patients (93%)., Conclusions: Linezolid may be considered when treating children with drug-resistant TB but also in the cases of patients with chronic liver disease or drug-induced liver injury. However, AEs should be closely monitored. Further studies are needed to determine the optimum dosage and the optimal duration of linezolid treatment in children.

Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection., Materials and Methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009-2015, CMV-HIG (Cytotect ® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy., Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38-40) and two children (5.5%) were premature (born at 28 and 34 weeks' gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3-1185; p = .007)., Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.