Organ Dysfunction in Children With Blood Culture-Proven Sepsis: Comparative Performance of Four Scores in a National Cohort Study.

OBJECTIVES: Previous studies applying Sepsis-3 criteria to children were based on retrospective analyses of PICU cohorts. We aimed to compare organ dysfunction criteria in children with blood culture-proven sepsis, including emergency department, PICU, and ward patients, and to assess relevance of organ dysfunctions for mortality prediction. DESIGN: We have carried out a nonprespecified, secondary analysis of a prospective dataset collected from September 2011 to December 2015. SETTING: Emergency departments, wards, and PICUs in 10 tertiary children's hospitals in Switzerland. PATIENTS: Children younger than 17 years old with blood culture-proven sepsis. We excluded preterm infants and term infants younger than 7 days old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the 2005 International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Organ Dysfunction Information Update Mandate (PODIUM) scores, measured at blood culture sampling, to predict 30-day mortality. We analyzed 877 sepsis episodes in 807 children, with a 30-day mortality of 4.3%. Percentage with organ dysfunction ranged from 32.7% (IPSCC) to 55.3% (pSOFA). In adjusted analyses, the accuracy for identification of 30-day mortality was area under the curve (AUC) 0.87 (95% CI, 0.82-0.92) for IPSCC, 0.83 (0.76-0.89) for PELOD-2, 0.85 (0.78-0.92) for pSOFA, and 0.85 (0.78-0.91) for PODIUM. When restricting scores to neurologic, respiratory, and cardiovascular dysfunction, the adjusted AUC was 0.89 (0.84-0.94) for IPSCC, 0.85 (0.79-0.91) for PELOD-2, 0.87 (0.81-0.93) for pSOFA, and 0.88 (0.83-0.93) for PODIUM. CONCLUSIONS: IPSCC, PELOD-2, pSOFA, and PODIUM performed similarly to predict 30-day mortality. Simplified scores restricted to neurologic, respiratory, and cardiovascular dysfunction yielded comparable performance.

Structured Immune Workup in Healthy Children With a First Episode of Severe Bacterial Infection: A 7-year Single-Center Study.

BACKGROUND: Severe bacterial infections (SBIs) in otherwise healthy children are rare and may represent an underlying impairment of the immune system, including primary immunodeficiency. However, it is unclear whether and how children should be assessed. METHODS: We retrospectively analyzed data from hospital records of previously healthy children aged 3 days to 18 years with SBI, including pleuropneumonia, meningitis, and/or sepsis. Patients were diagnosed or immunologically followed up between 1 January 2013 and 31 March 2020. RESULTS: Among 432 children with SBI, findings could be analyzed in 360. Follow-up data were available for 265 children (74%), of whom 244 (92%) underwent immunological testing. Laboratory abnormalities were found in 51 of 244 patients (21%), with 3 deaths (1%). Fourteen children (6%) had immunodeficiency considered clinically relevant (3 complement deficiencies, 1 autoimmune neutropenia, 10 humoral immunodeficiencies), and 27 (11%) had milder humoral abnormalities or findings suggestive of delayed adaptive immune maturation. CONCLUSIONS: A substantial proportion of children with SBI may benefit from routine immunological testing, revealing (potentially) clinically relevant impaired immune function in 6%-17% of children. The identification of immune abnormalities allows for specific counseling of families and optimization of preventive measures, such as booster vaccinations, to avoid future SBI episodes.

Swiss consensus recommendations on urinary tract infections in children.

The kidneys and the urinary tract are a common source of infection in children of all ages, especially infants and young children. The main risk factors for sequelae after urinary tract infections (UTI) are congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction. UTI should be considered in every child with fever without a source. The differentiation between upper and lower UTI is crucial for appropriate management. Method of urine collection should be based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. Treatment of UTI should be based on practical considerations regarding age and presentation with adjustment of the initial antimicrobial treatment according to antimicrobial sensitivity testing. All children, regardless of age, should have an ultrasound of the urinary tract performed after pyelonephritis. In general, antibiotic prophylaxis is not recommended.Conclusion: Based on recent data and in line with international guidelines, multidisciplinary Swiss consensus recommendations were developed by members of Swiss pediatric infectious diseases, nephrology, and urology societies giving the clinician clear recommendations in regard to diagnosis, type and duration of therapy, antimicrobial treatment options, indication for imaging, and antibiotic prophylaxis. What is Known: • Urinary tract infections (UTI) are a common and important clinical problem in childhood. Although children with pyelonephritis tend to present with fever, it can be difficult on clinical grounds to distinguish cystitis from pyelonephritis, particularly in young children less than 2 years of age. • Method of urine collection is based on age and risk factors. The diagnosis of UTI requires urine analysis and significant growth of a pathogen in culture. What is New: • Vesicoureteric reflux (VUR) remains a risk factor for UTI but per se is neither necessary nor sufficient for the development of renal scars. Congenital anomalies of the kidney and urinary tract (CAKUT) and bladder-bowel dysfunction play a more important role as causes of long-term sequelae. In general, antibiotic prophylaxis is not recommended. • A switch to oral antibiotics should be considered already in young infants. Indications for invasive imaging are more restrictive and reserved for patients with abnormal renal ultrasound, complicated UTI, and infections with pathogens other than E. coli.

Improved Diagnostics Help to Identify Clinical Features and Biomarkers That Predict Mycoplasma pneumoniae Community-acquired Pneumonia in Children.

BACKGROUND: There are no reliable signs or symptoms that differentiate Mycoplasma pneumoniae (Mp) infection in community-acquired pneumonia (CAP) from other etiologies. Additionally, current diagnostic tests do not reliably distinguish between Mp infection and carriage. We previously determined that the measurement of Mp-specific immunoglobulin M antibody-secreting cells (ASCs) by enzyme-linked immunospot assay allowed for differentiation between infection and carriage. Using this new diagnostic test, we aimed to identify clinical and laboratory features associated with Mp infection. METHODS: This is a prospective cohort study of children, 3-18 years of age, with CAP from 2016 to 2017. Clinical features and biomarkers were compared between Mp-positive and -negative groups by Mann-Whitney U test or Fisher exact test, as appropriate. Area under the receiver operating characteristic curve (AUC) differences and optimal thresholds were determined by using the DeLong test and Youden J statistic, respectively. RESULTS: Of 63 CAP patients, 29 were Mp-positive (46%). Mp positivity was statistically associated with older age (median, 8.6 vs 4.7 years), no underlying disease, family with respiratory symptoms, prior antibiotic treatment, prolonged prodromal respiratory symptoms and fever, and extrapulmonary (skin) manifestations. Lower levels of C-reactive protein, white blood cell count, absolute neutrophil count, and procalcitonin (PCT), specifically PCT <0.25 µg/L, were statistically associated with Mp infection. A combination of age >5 years (AUC = 0.77), prodromal fever and respiratory symptoms >6 days (AUC = 0.79), and PCT <0.25 µg/L (AUC = 0.81) improved diagnostic performance (AUC = 0.90) (P = .05). CONCLUSIONS: A combination of clinical features and biomarkers may aid physicians in identifying patients at high risk for Mp CAP.

Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study.

BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS: We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS: There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Impact of rapid enterovirus polymerase chain reaction testing on management of febrile young infants < 90 days of age with aseptic meningitis.

BACKGROUND: Diagnostic evaluation of febrile young infants is challenging. Empirical antimicrobial treatment is therefore common practice in this setting despite high percentage of causative viral infections. The objective of this study was to investigate the impact of rapid enterovirus cerebrospinal fluid polymerase chain reaction (CSF EV PCR) test on hospital length of stay (LOS) and antimicrobial treatment duration in young febrile infants. METHODS: Retrospective observational study comparing duration of antimicrobial treatment and hospital LOS before (May 1, 2014 - May 30, 2015, untested group) and after (June 1, 2015 - June 30, 2017, tested group) the introduction of rapid CSF EV PCR testing in infants < 90 days of age presenting with fever and CSF pleocytosis at the University Children's Hospital Zurich. Additionally, the same variables were compared after test introduction between CSF EV PCR positive and negative children. RESULTS: One hundred twenty-eight children were enrolled in the study, 58 before and 70 after the introduction of rapid CSF EV PCR testing. Duration of antimicrobial treatment was significantly shortened in EV positive (n = 42) compared to both EV negative (n = 28) (median 18 h and 48 h, respectively, p < 0.001) and untested patients (n = 58) (median 18 h and 48 h, respectively, p < 0.001), and also in tested compared to untested group patients (median 36 vs 48 h, p < 0.001). Hospital LOS was significantly shortened in EV positive compared to EV negative patients (median 3 days and 4 days respectively, p = 0.013), while an overall reduction was not observed between tested and untested group patients. CONCLUSIONS: In this study we demonstrate that antimicrobial treatment duration could be significantly shortened in neonates and young infants < 90 days of age with aseptic meningitis after the introduction of a rapid CSF EV PCR test compared to untested patients before test introduction.

Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjugate Vaccines: A Prospective Population-based Cohort Study.

BACKGROUND: Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study. METHODS: The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS). RESULTS: Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7-2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4-19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1-7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (ß coefficient 0.2, 95% CI .1-1.1; P = .01). CONCLUSIONS: The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity.

Neonatal Sepsis of Early Onset, and Hospital-Acquired and Community-Acquired Late Onset: A Prospective Population-Based Cohort Study.

OBJECTIVE: To assess the epidemiology of blood culture-proven early- (EOS) and late-onset neonatal sepsis (LOS). STUDY DESIGN: All newborn infants admitted to tertiary care neonatal intensive care units in Switzerland and presenting with blood culture-proven sepsis between September 2011 and December 2015 were included in the study. We defined EOS as infection occurring <3 days after birth, and LOS as infection ≥3 days after birth. Infants with LOS were classified as having community-acquired LOS if onset of infection was ≤48 hours after admission, and hospital-acquired LOS, if onset was >48 hours after admission. Incidence was estimated based on the number of livebirths in Switzerland and adjusted for the proportion of admissions at centers participating in the study. RESULTS: We identified 444 episodes of blood culture-proven sepsis in 429 infants; 20% of cases were EOS, 62% hospital-acquired LOS, and 18% community-acquired LOS. The estimated national incidence of EOS, hospital-acquired LOS, and community-acquired LOS was 0.28 (95% CI 0.23-0.35), 0.86 (0.76-0.97), and 0.28 (0.23-0.34) per 1000 livebirths. Compared with EOS, hospital-acquired LOS occurred in infants of lower gestational age and was more frequently associated with comorbidities. Community-acquired LOS was more common in term infants and in male infants. Mortality was 18%, 12%, and 0% in EOS, hospital-acquired LOS, and community-acquired LOS, and was higher in preterm infants, in infants with septic shock, and in those requiring mechanical ventilation. CONCLUSIONS: We report a high burden of sepsis in neonates with considerable mortality and morbidity. EOS, hospital-acquired LOS, and community-acquired LOS affect specific patient subgroups and have distinct clinical presentation, pathogens and outcomes.

Mycoplasma pneumoniae intrathecal antibody responses in Bickerstaff brain stem encephalitis.

The pathogenesis of Mycoplasma pneumoniae encephalitis is not established. We report, for the first time, the case of a patient with severe Bickerstaff brain stem encephalitis in whom we detected intrathecal production of M. pneumoniae-specific antibodies, contrasting the findings in another patient with less severe encephalitis in whom we detected intrathecal M. pneumoniae DNA but no specific antibodies. Our observations suggest that intrathecal M. pneumoniae-specific antibody responses may contribute to a more severe course of M. pneumoniae encephalitis.

Clinical Characteristics and Management of Children and Adolescents Hospitalized With Pyomyositis.

BACKGROUND: Pyomyositis, a bacterial muscle infection, is an important differential diagnosis in children and adolescents with musculoskeletal pain. In contrast to tropical regions, it is rarely recognized in temperate countries, but incidence is increasing and major studies are missing. METHODS: This retrospective multicenter study included patients <18 years of age hospitalized with pyomyositis in 11 Swiss children's hospitals between January 2010 and December 2022. Cases were identified by ICD-10 code (Myositis; M60-M60.9), and data was extracted from electronic hospital records. RESULTS: Of 331 patients identified, 102 fulfilled the case definition. Patient age at presentation ranged from 2 weeks to 17 years (median 8 years). The majority had no underlying illness and all presented with fever and localized pain. At the respective site of pyomyositis, 100 (98%) had impaired movement and 39 (38%) presented with local swelling. Pelvic (57%) and leg (28%) muscles were mostly affected. Blood or tissue cultures were obtained in 94 (92%) and 59 (57%) patients, respectively. Of those, 55 (58%) blood and 52 (88%) tissue cultures were positive, mainly for Staphylococcus aureus (35 and 19, respectively) and Streptococcus pyogene s (12 and 15, respectively). All patients received antibiotic treatment during hospitalization for a median of 10 days (interquartile range: 7-17), followed by outpatient treatment for a further median of 16 days (interquartile range: 11-22) in 95 (93%) patients. Fifty-nine (57%) patients required surgery. CONCLUSIONS: Pyomyositis is a challenging diagnosis that requires a high level of awareness. Blood and/or tissue cultures revealed S. aureus and S. pyogenes as the predominant causative agents.

Sensitivity of ICD coding for sepsis in children-a population-based study.

Background: International Classification of Diseases 10th edition (ICD-10) is widely used to describe the burden of disease. Aim: To describe how well ICD-10 coding captures sepsis in children admitted to the hospital with blood culture-proven bacterial or fungal infection and systemic inflammatory response syndrome. Methods: Secondary analysis of a population-based, multicenter, prospective cohort study on children with blood culture-proven sepsis of nine tertiary pediatric hospitals in Switzerland. We compared the agreement of validated study data on sepsis criteria with ICD-10 coding abstraction obtained at the participating hospitals. Results: We analyzed 998 hospital admissions of children with blood culture-proven sepsis. The sensitivity of ICD-10 coding abstraction was 60% (95%-CI 57-63) for sepsis; 35% (95%-CI 31-39) for sepsis with organ dysfunction, using an explicit abstraction strategy; and 65% (95%-CI 61-69) using an implicit abstraction strategy. For septic shock, the sensitivity of ICD-10 coding abstraction was 43% (95%-CI 37-50). Agreement of ICD-10 coding abstraction with validated study data varied by the underlying infection type and disease severity (p < 0.05). The estimated national incidence of sepsis, inferred from ICD-10 coding abstraction, was 12.5 per 100,000 children (95%-CI 11.7-13.5) and 21.0 per 100,000 children (95%-CI 19.8-22.2) using validated study data. Conclusions: In this population-based study, we found a poor representation of sepsis and sepsis with organ dysfunction by ICD-10 coding abstraction in children with blood culture-proven sepsis when compared against a prospective validated research dataset. Sepsis estimates in children based on ICD-10 coding may thus severely underestimate the true prevalence of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s44253-023-00006-1.

[Baby on board - recommendations for pediatric travel consultation]. / Baby on board ­ ein Beratungsleitfaden für Reisen mit Kindern.

Traveling with babies and children is challenging for parents and the doctor providing travel medicine advice. Especially pediatric VFR (visiting friends and relatives) travelers have a higher risk for infectious diseases due to lower risk perception and higher exposure. Being well prepared helps in exploring the world while staying healthy. Topics to be discussed in pediatric travel consultation are travel vaccinations, mosquito repellents, malaria prophylaxis, thorough sun protection, rehydration for gastroentritis, avoidance of rabies exposure, an agetailored travel pharmacy and more. We provide a guide to the most important topics for pediatric travel consultations.

Neonates with SARS-CoV-2 infection: spectrum of disease from a prospective nationwide observational cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can be more severe in infants than in older children. To date, only a few case series have reported data on neonates with COVID-19, including mostly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection. This study summarises nationwide epidemiological data, clinical characteristics, treatment and outcomes of neonates presenting with symptomatic SARS-CoV-2 infection. METHODS: Data were prospectively collected through the Swiss Paediatric Surveillance Unit from hospitalised neonates with laboratory-confirmed SARS-CoV-2 infection (positive polymerase chain reaction on a respiratory sample) from 1 March 2020 to 31 September 2021. All 29 paediatric hospitals in Switzerland reported cases. RESULTS: In total, 73 neonates were included; 7 (10%) were preterm. The median age at presentation was 17 days (interquartile range [IQR] 11-23); 40 (55%) were female. The majority of neonates (64, 88%) were admitted from home. Nine (12%) had a pre-existing medical condition. Overall, the most common symptom recorded was fever in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%). Twenty (27%) neonates presented with fever without a source. Seven (10%) neonates were admitted to an intensive care unit (5 for respiratory failure and 2 for monitoring). One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3-5). Two (3%) were treated with corticosteroids and 1 (1%) with remdesivir. In total, 60 (82%) neonates had contact with a known or suspected SARS-CoV-2 index case. All of the 71 neonates for whom data were available were discharged to their homes without symptoms. CONCLUSION: In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short period of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, the presence of SARS-CoV-2 should not deter from the search for a serious bacterial infection. Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

Paediatric refugees from Ukraine: guidance for health care providers.

BACKGROUND: With the invasion of Ukraine by the Russian Army in February 2022, refugees, the majority of whom are women and children, started fleeing the war to neighbouring countries. Even before the current escalation, the conflict in the eastern part of Ukraine has led to the internal displacement of more than 200,000 children, and many others have experienced attacks, e.g. on schools. This inevitably leads to limitations in health care delivery. During transit, overcrowding, poor shelter and vulnerability may further put refugees at increased risk for infectious diseases. This consensus document aims to provide information and guidance regarding health issues that paediatricians and general practitioners may face when caring for Ukrainian children. METHODS: Members of the Migrant Health Reference Group of Paediatrics Switzerland and the Paediatric Infectious Disease Group in Switzerland developed this recommendation between March and April 2022 in a modified Delphi process. RESULTS: A total of 50 recommendations were agreed on with a ≥80% consensus. These include the following topics: i) general aspects, including interpreter services, urgent health needs, personal history and general check-ups; ii) mental health, including how to search for signs of psychological distress without going into traumatic details; iii) vaccinations, including recommendations for evaluation and catch-up; iv) screening for tuberculosis, human immunodeficiency virus, and hepatitis B and C; and v) providing age-appropriate preventive and health service information. CONCLUSION: This document provides current evidence and guidance when caring for paediatric refugees from Ukraine. The recommendations focus on Switzerland but may well be used in other countries. These are based on current evidence and may need to be adapted to individual situations and once further evidence becomes available.

Low secondary attack rate after prolonged exposure to sputum smear positive miliary tuberculosis in a neonatal unit.

BACKGROUND: Several neonatal intensive care units (NICU) have reported exposure to sputum smear positive tuberculosis (TB). NICE guidelines give support regarding investigation and treatment intervention, but not for contact definitions. Data regarding the reliability of any interferon gamma release assay (IGRA) in infants as a screening test for TB infection is scarce. We report an investigation and management strategy and evaluated the viability of IGRA (T-Spot) in infants and its concordance to the tuberculin skin test (TST). METHODS: We performed an outbreak investigation of incident TB infection in a NICU after prolonged exposure to sputum smear positive miliary TB by an infant's mother. We defined individual contact definitions and interventions and assessed secondary attack rates. In addition, we evaluated the technical performance of T-Spot in infants and compared the results with the TST at baseline investigation. RESULTS: Overall, 72 of 90 (80%) exposed infants were investigated at baseline, in 51 (56.7%) of 54 (60%) infants, follow-up TST at the age of 6 months was performed. No infant in our cohort showed a positive TST or T-Spot at baseline. All blood samples from infants except one responded to phytohemagglutinin (PHA), which was used as a positive control of the T-Spot, demonstrating that cells are viable and react upon stimulation. 149 of 160 (93.1%) exposed health care workers (HCW) were investigated. 1 HCW was tested positive, having no other reason than this exposure for latent TB infection. 5 of 92 (5.5%) exposed primary contacts were tested positive, all coming from countries with high TB incidences. In total, 1 of 342 exposed contacts was newly diagnosed with latent TB infection. The secondary attack rate in this study including pediatric and adult contacts was 0.29%. CONCLUSION: This investigation highlighted the low transmission rate of sputum smear positive miliary TB in a particularly highly susceptible population as infants. Our expert definitions and interventions proved to be helpful in terms of the feasibility of a thorough outbreak investigation. Furthermore, we demonstrated concordance of T-Spot and TST. Based on our findings, we assume that T-Spot could be considered a reliable investigation tool to rule out TB infection in infants.