Bronchiolitis before and after the SARS-CoV-2 pandemic: Twelve years of experience in a Spanish paediatric hospital.

INTRODUCTION: Acute bronchiolitis is the main cause of hospitalization in children under 2 years of age, with a regular seasonality, mostly due to the respiratory syncytial virus. OBJECTIVES: To describe the epidemiology of bronchiolitis hospitalizations in our center in the last 12 years, and analyze the changes in clinical characteristics, microbiology, and adverse outcomes during the SARS-CoV-2 pandemic. METHODS: Observational study including patients admitted for bronchiolitis between April 2010 and December 2021 in a Spanish tertiary paediatric hospital. Relevant demographic, clinical, microbiological, and adverse outcome variables were collected in an anonymized database. The pandemic period (April 2020 to December 2021) was compared to 2010-2015 seasons using appropriate statistical tests. RESULTS: There were 2138 bronchiolitis admissions, with a mean of 195.6 per year between 2010 and 2019 and a 2-4-month peak between November and March. In the expected season of 2020, there was a 94.4% reduction of bronchiolitis hospitalizations, with only 11 cases admitted in the first year of the pandemic. Bronchiolitis cases increased from the summer of 2021 during a 6-month long peak, reaching a total of 171 cases. Length of stay was significantly shorter during the pandemic, but no differences were found in clinical and microbiological characteristics or other adverse outcomes. CONCLUSIONS: The SARS-CoV-2 pandemic has modified the seasonality of bronchiolitis hospitalizations, with a dramatic decrease in cases during the expected season of 2020-2021, and an extemporaneous summer-autumn peak in 2021 with longer duration but similar patient characteristics and risk factors.

Infective endocarditis in paediatric patients from Andalusia (Spain), 2008-2020.

INTRODUCTION: Paediatric infective endocarditis (IE) is a serious condition associated with significant mortality. Information in Spain is limited and comes from case series from single centres. The aim was to describe the epidemiology, clinical features, microbiology and outcome of paediatric IE in Andalusia. PATIENTS AND METHODS: Multi-centre descriptive observational retrospective study of patients <18 years old with a diagnosis of IE who were admitted to six Andalusian hospitals during 2008-2020. RESULTS: 44 episodes of IE (41 patients) with a median age of 103 months (IQR 37-150 months) were identified. Congenital heart disease (CHD) was the main predisposing factor, identified in 34 cases (77%). A total of 21 (48%) episodes of IE occurred in patients with prosthetic material. These had higher rate of CHD (p = 0.002) and increased end organ dysfunction (p = 0.04) compared to those with native valve. Fever was an almost universal symptom, associated in 23% of the episodes with heart failure. Staphylococcus aureus (25%) followed by coagulase-negative staphylococci (18%) and Streptococcus viridans (14%) were the most frequently isolated microorganisms, and three (7%) patients with central venous catheters had a fungal infection. Thromboembolic events were observed in 30% of the episodes, surgical intervention was required in 48% of cases. Mortality rate was 9%. Prosthetic material and CRP > 140 mg/L were independent predictors of complicated IE. CONCLUSIONS: Our findings emphasize the high morbidity of paediatric IE. The information provided could be useful for the identification of epidemiological and clinical profiles of children with IE and complicated forms.

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.

Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations.

PURPOSE: STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients' cells. METHODS: Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients. RESULTS: DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient' cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients. CONCLUSION: In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations.

Clinical characteristics, health care resource utilization and direct medical costs of Rotavirus hospitalizations in Spain (2013-2018).

Rotavirus (RV) is the most common cause of severe gastroenteritis (GE) in infants and young children worldwide and is associated with a significant clinical and economic burden. The objective of this study was to analyze the characteristics, healthcare resource utilization and the direct medical costs related to RVGE hospitalizations in Spain. An observational, multicenter, cross-sectional study was conducted from June 2013 to May 2018 at the pediatric departments of 12 hospitals from different Spanish regions. Children under 5 years of age admitted to the hospital with a confirmed diagnosis of RVGE were selected. Data on clinical characteristics, healthcare resource use and costs were collected from patient records and hospital databases. Most children hospitalized for RVGE did not have any previous medical condition or chronic disease. Forty-seven percent had previously visited the Emergency Room (ER), 27% had visited a primary care pediatrician, and 15% had received pharmacological treatment prior to hospital admission due to an RVGE episode. The average length of a hospital stay for RVGE was 5.6 days, and the mean medical costs of RVGE hospitalizations per episode ranged from 3,940€ to 4,100€. The highest direct medical cost was due to the hospital stay. This study showed a high burden of health resource utilization and costs related to the management of cases of RVGE requiring hospitalization. RV vaccination with high coverage rates should be considered to minimize the clinical and economic impacts of this disease on the health-care system.

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

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

Skin lesions in children during the first wave of the SARS-CoV-2 pandemic.

BACKGROUND: Cutaneous manifestations have been included in COVID-19 patients' clinical spectrum. Our objective was to determine the association between skin lesions in children and SARS-CoV2 infection, analyzing others possible infectious/autoimmune etiologies. MATERIAL AND METHODS: Observational, multicenter, cross-sectional study, about children with skin manifestations from April to May 2020. The diagnosis of SARS-CoV2 was performed by PCR in nasopharyngeal exudate and/or presence of antibodies by serology. RESULTS: Sixty-two children were included, 9 (14.5%) presented positive antibodies to SARS-CoV-2, with no positive PCR to SARS-Cov-2 in those patients in whom it was made. Patients with positive serology to SARS-CoV-2 presented chilblains and/or vesicular-bullous skin lesions more frequently (66.7% vs. 24.5%, p = 0.019). Generalized, urticarial and maculopapular rash was more common in patients with negative antibodies (37.7 vs. 0%, p = 0.047), others pathogens were isolated in 41.5% of these patients. There were no significant differences in the positivity for autoantibodies between both groups. CONCLUSION: In our study, the presence of chilblains-like and/or vesicular lesions were significantly related to SARS-CoV2 previous contact.

INTRODUCCIÓN: Las manifestaciones cutáneas se han incluido en el espectro clínico de los pacientes con COVID-19. Nuestro objetivo fue determinar la asociación entre las lesiones cutáneas observadas en niños durante la primera ola de la pandemia y la infección por SARS-CoV-2, analizando otras posibles etiologías infecciosas o autoinmunes. MATERIAL Y MÉTODOS: Estudio observacional, multicéntrico, de corte transversal, desarrollado en niños con manifestaciones cutáneas desde abril hasta mayo de 2020. La determinación de SARS-CoV-2 se realizó mediante PCR en exudado nasofaríngeo y/o serología. RESULTADOS: Se seleccionó a 62 niños; 9 (14,5%) presentaron serología positiva para SARS-CoV-2, siendo la PCR negativa en todos los casos en los que se realizó. Los pacientes con serología positiva para SARS-CoV-2 presentaron con más frecuencia lesiones pernióticas y/o vesiculosas (66,7 vs. 24,5%; p = 0,019). El exantema generalizado, urticarial y maculopapuloso fue más habitual en el grupo de pacientes con serología negativa (37,7 vs. 0%; p = 0,047); se aislaron otros patógenos en el 41,5%. No hubo diferencias significativas en cuanto a la positividad de autoanticuerpos entre ambos grupos. CONCLUSIÓN: En nuestro estudio, las lesiones de tipo perniosis o vesiculosas se relacionaron significativamente con el contacto previo con SARS-CoV-2.

Clinical-epidemiological characteristics of Pneumocystis jirovecii pneumonia in a tertiary hospital in Spain.

INTRODUCTION: HIV infection was the main risk of suffering Pneumocystis jirovecii pneumonia (PJP). The clinical-epidemiological characteristics of PJP have currently changed, with there being few studies on this. METHODS: A retrospective observational study was carried out on paediatric patients diagnosed with PJP over a 17 year period in a third level hospital in Spain. RESULTS: A total of 23 patients were included, of whom 7/23 (47.8%) suffered a haematological disease, 5/23 (21.7%) a primary immunodeficiency, and 4/23 (17.4%) an HIV infection. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) was received by 11/23 (47.8%) patients. All were treated with TMP-SMX and 18/23 (78.3%) with systemic glucocorticoids. There were six (26.1%) deaths, of which one of them (16.7%) suffered an HIV infection. A higher mortality was seen in the non-HIV patients with greater leucocytosis, greater CO2 retention, and a higher heart rate at onset, differences not observed in HIV patients. No differences were found in mortality in relation to the predisposing factor, use of pTMP-SMX, or treatment with glucocorticoids. CONCLUSIONS: Paediatric patients with haematological cancers are currently the main risk group of developing PJP in this age group. No differences were found in mortality between patients with or without HIV infection as predisposing factor. The mortality among non-HIV patients was higher in those that had greater leucocytosis, greater CO2 retention, and increased heart rate at onset. A better prognosis was not seen in patients that received prophylaxis with TMP-SMX prior to the development of the PJP, or in those that received glucocorticoids as part of the treatment.

[Skin lesions in children during the first wave of the SARS-CoV-2 pandemic]. / Lesiones cutáneas en niños durante la primera ola de la pandemia por SARS-CoV-2.

BACKGROUND: Cutaneous manifestations have been included in COVID-19 patients' clinical spectrum. Our objective was to determine the association between skin lesions in children and SARS-CoV-2 infection, analyzing others possible infectious/autoimmune etiologies. MATERIAL AND METHODS: Observational, multicenter, cross-sectional study, about children with skin manifestations from April to May 2020. The diagnosis of SARS-CoV-2 was performed by PCR in nasopharyngeal exudate and/or presence of antibodies by serology. RESULTS: Sixty-two children were included, 9 (14.5%) presented positive antibodies to SARS-CoV-2, with no positive PCR to SARS-Cov-2 in those patients in whom it was made. Patients with positive serology to SARS-CoV-2 presented chilblains and/or vesicular-bullous skin lesions more frequently (66.7% vs. 24.5%, p=0.019). Generalized, urticarial and maculopapular rash was more common in patients with negative antibodies (37.7 vs. 0%, p=0.047), others pathogens were isolated in 41.5% of these patients. There were no significant differences in the positivity for autoantibodies between both groups. CONCLUSION: In our study, the presence of chilblains-like and/or vesicular lesions were significantly related to SARS-CoV-2 previous contact.

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.

Skin manifestations during the COVID-19 pandemic in the pediatric emergency department.

BACKGROUND: The role of SARS-CoV-2 as the cause of chilblains in children remains a matter of debate but it is important to elucidate it for patient isolation and contact tracing. We sought to define the etiology, clinical presentation, time course, and outcomes of children presenting to the emergency department (ED) with cutaneous manifestations shortly after the first pandemic peak of COVID-19 in Spain. METHODS: A prospective, observational study in children <15 years of age evaluated for skin lesions in the EDs of three pediatric hospitals. Children underwent a comprehensive work-up including tests for SARS-CoV-2 antibodies and polymerase chain reaction (PCR), and serology and PCR tests for other viruses and bacteria. A 1 month follow-up visit was conducted. RESULTS: From April 14 through May 8, 2020, we enrolled 62 children. Of those, 34 had acro-ischemic skin lesions and 28 had a variety of skin rashes. Overall, 40% of children had mild systemic symptoms. Children with chilblains were older, had pain more frequently and a more prolonged duration of skin lesions, while those with non-specific rashes had fever more frequently. Lesions were resolved in 75% of children at follow up. Five patients demonstrated SARS-CoV-2 antibodies, and none tested positive with PCR. Three additional patients tested positive with PCR for rhinovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae. CONCLUSIONS: The number of ED visits for chilblains, which are rare in pediatrics, was high soon after the first peak of COVID-19 in Spain. The disease course was self-limited, outcomes were favorable, and the possibility of viral transmission was negligible as all patients tested negative for SARS-CoV-2 by PCR.

[Recommendations on the diagnosis and treatment of urinary tract infection]. / Recomendaciones sobre el diagnóstico y tratamiento de la infección urinaria.

Urinary tract infection (UTI) is defined as the growth of microorganisms in a sterile urine culture in a patient with compatible clinical symptoms. The presence of bacteria without any symptoms is known as asymptomatic bacteriuria, and does not require any treatment. In neonates and infants, fever is the guiding sign to suspecting a UTI. Classic urinary tract symptoms become more important in older children. Urine cultures collected before starting antibiotics is always required for diagnosis. Clean-catch (midstream) specimens should be collected for urine culture. In the case of non-toilet-trained children, specimens must be obtained by urinary catheterisation, or suprapubic puncture in neonates and infants. Specimens collected by urine bag should not be used for urine culture. There are no significant differences in the clinical evolution and prognosis between oral versus short intravenous followed by oral antibiotic. Empirical antibiotic therapy should be guided by local susceptibility patterns. Second-generation cephalosporin (children under 6 years) and fosfomycin trometamol (over 6 years), are the empiric therapy recommended in this consensus. In the case of pyelonephritis, recommended antibiotic treatment are third-generation cephalosporins (outpatient care) or, if admission is required, aminoglycosides. Ampicillin should be added in infants less than 3 months old. Antibiotic de-escalation should be always practiced once the result of the urine culture is known.

[Renal scarring in children under 36 months hospitalised for acute pyelonephritis]. / Cicatrices renales en menores de 36 meses ingresados por pielonefritis aguda.

INTRODUCTION: Acute pyelonephritis (APN) is one of the most common causes of serious bacterial infection in infants. Renal scarring is the most prevalent long-term complication. OBJECTIVES: To review the incidence of renal scarring within 6 months after an episode of APN in children under 36 months and its relationship with imaging studies, clinical settings, and bacteriology. METHOD: A retrospective study of previously healthy patients aged one to 36 months, admitted for a first episode of APN, with a minimum follow-up of 6 months. Demographic and clinical variables were collected along with bacteriology, renal and bladder ultrasound scan, voiding cystourethrography, DMSA-scintigraphy, and re-infection events. RESULTS: A total of 125 patients were included in the study, of which 60% were male, the large majority (92%) febrile, and due to E. coli (74.6%). There was a history of prenatal ultrasound scan changes in 15.4%. Ultrasound scan found dilation of the urinary tract in 22.1%. Voiding cystourethrography was performed on 70 patients: 54.3% no abnormalities, 12.8% vesicoureteral reflux (VUR) grade i-iii, and 32.9% iv-v grade VUR. Six patients had iv-v grade VUR with a normal ultrasound scan. Adherence to DMSA-scintigraphy at 6 months was only 61% of that indicated. Renal scarring was found in 44.3% of those in which it was performed (60 cases). CONCLUSIONS: Almost half (44%) DMSA-scintigraphy in children aged one to 36 months hospitalised for APN show renal scarring at 6 months, which was found to be associated with the re-infection events and the iv-v grade VUR. There was no relationship between scarring and the bacteriology or the elevations of inflammatory biochemical markers.

Paradoxical reaction in immunocompetent children with tuberculosis.

BACKGROUND: A paradoxical reaction (PR) during anti-tuberculosis treatment is a phenomenon that is poorly studied in immunocompetent children. It is defined as a clinical or radiological worsening of pre-existing tuberculosis (TB) disease. METHODS: A retrospective descriptive study of children younger than 14 years of age was performed; these children developed PR during the years 2009 to 2014, following a diagnosis of TB. Demographic characteristics, microbiological results, treatment and outcome data were collected. RESULTS: Of 51 children diagnosed with TB, five (9.8%) developed a PR; four of these children had pulmonary TB and the remaining patient had miliary TB with central nervous system involvement. The PR occurred at a median of 42 days (range 23-53 days) after initiating therapy. Corticosteroids were started when PR was suspected, at a median dose of 1mg/kg/day. Clinical and radiological improvement was noted in all cases, with a median clinical regression time of 10.5 days (range 3-15 days) and a median radiological regression time of 45 days (range 26-105 days). No sequelae were described in any patient. CONCLUSIONS: PR in immunocompetent children during anti-tuberculosis treatment is not such an unusual reaction. Treatment with corticosteroids may be useful for the resolution of PR.