T-Cell Immune Responses in Newborns and Long-Term Sequelae in Congenital Cytomegalovirus Infection (CYTRIC Study).

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.

Severe Impairment of T-cell Immunity and Pulmonary GvHD Are Major Risk Factors for Nontuberculous Mycobacterial Infection After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

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.

Multiplex PCR and Antibiotic Use in Children with Community-Acquired Pneumonia.

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® 2plus, 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.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

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.

Adenovirus Infection in Hematopoietic and Solid Organ Paediatric Transplant Recipients: Treatment, Outcomes, and Use of Cidofovir.

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.

Update on the diagnosis and treatment of tuberculosis.

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.

Bloodstream Infection in Children With Epidermolysis Bullosa.

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.

Torque Teno Virus in Nasopharyngeal Aspirate of Children With Viral Respiratory Infections.

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.

A challenging differential diagnosis in a patient with autosomal dominant STAT3 deficiency.

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.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

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.

Acute bronchiolitis during the COVID-19 pandemic.

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.

Uncommon Cause of Hemoptysis in a 15-Year-Old Boy.

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.

Norovirus-associated White Matter Injury in a Term Newborn With Seizures.

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.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity.

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.

Acute bronchiolitis during the COVID-19 pandemic.

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.

Introducción: La epidemia de bronquiolitis de otoño e invierno prácticamente desapareció durante el primer año de la pandemia de COVID-19.Nuestros objetivos eran caracterizar la bronquiolitis durante el cuarto trimestre de 2020 y determinar el papel desempeñado por el virus SARS-CoV-2. Métodos: Estudio multicéntrico prospectivo realizado en Madrid (España) entre los meses de octubre y diciembre de 2020, que incluyó a todos los niños ingresados con bronquiolitis aguda. Se recogieron los datos clínicos y se realizó una PCR múltiple para virus respiratorios. Resultados: Se hospitalizó a treinta y tres pacientes con bronquiolitis durante el periodo del estudio: 28 correspondieron a rinovirus, 4 a SARS-CoV-2 y uno presentaba ambos tipos de infección. Las bronquiolitis por SAR-CoV-2 fueron comparables a las bronquiolitis por rinovirus, salvo por una estancia hospitalaria más corta. Se detectó una reducción significativa en la tasa de ingresos por bronquiolitis y no se aisló VSR. Conclusión: Es raro que la infección por SARS-CoV-2 cause bronquiolitis aguda y no se asocia a una evolución clínica grave. Durante la pandemia de COVID-19 se produjo un descenso pronunciado de los casos de bronquiolitis.

Preseptal Versus Orbital Cellulitis in Children: An Observational Study.

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.