Severe and invasive bacterial infections in infants aged less than 90 days with and without SARS-CoV-2 infection.

BACKGROUND: Fever in children represents one of the most common causes of medical evaluation. Infants younger than 90 days of age are at higher risk of severe and invasive bacterial infections (SBI and IBI). However, clinical signs and symptoms of viral and bacterial infections in young infants are frequently similar, and several studies have shown that the risk of SBIs remains non-negligible even in the presence of a positive point-of-care viral test. Our study aims to evaluate whether the proportion of SBIs and IBIs in febrile infants younger than 90 days during the COVID-19 pandemic was higher than that in the pre-pandemic period, and to describe the proportion of SBIs and IBIs in infants with and without SARS-CoV-2 infection. METHODS: This was a retrospective single-center cohort study conducted at the Children's Hospital of the University of Padua in Italy, involving febrile young infants evaluated in the Pediatric Emergency Department (PED) and admitted to Pediatric Acute Care Unit (PACU) between March 2017 to December 2022. Infants admitted before the COVID-19 pandemic were compared to infants admitted during the pandemic period and SARS-CoV-2 positive patients to the negative ones. RESULTS: 442 febrile infants younger than 90 days were evaluated in Padua PED and admitted to the wards. The proportion of SBIs and IBIS did not significantly change over the study periods, ranging between 10.8% and 32.6% (p = 0.117) and between 0% and 7.6%, respectively (p = 0.367). The proportion of infants with a diagnosis of SBIs and IBIs was higher in the SARS-CoV-2 negative group (30.3% and 8.2%, respectively) compared to the positive group (8.5% and 2.8%, respectively) (p < 0.0001). The most common diagnosis in both groups was UTI, mainly caused by E. coli. A similar proportion of blood and urine cultures were performed, whereas lumbar puncture was more frequently performed in SARS-CoV-2 negative infants (40.2% vs 16.9%, p = 0.001). CONCLUSIONS: Although the risk of concomitant serious bacterial infection with SARS-CoV-2 is low, it remains non-negligible. Therefore, even in SARS-CoV-2-positive febrile infants, we suggest that the approach to screening for SBIs remains cautious.

Diagnosis of urinary tract infection in infants under 3 months with fever without a source: reliability of urinalysis and urine culture.

BACKGROUND: Urinary tract infection (UTI) is infants' most common serious bacterial infection. This study aimed to investigate the reliability of urianalysis (UA) to predict UTI, to specify the colony forming units (CFU)/ml threshold for diagnosis, and to identify variables that help suspect bacteremia in infants under 3 months with UTI. METHODS: We reviewed clinical records of children under 3 months hospitalized for a fever without source and recorded age, sex, days of fever pre-consultation, temperature and severity at admission, discharge diagnoses, laboratory tests, and treatments. According to the discharge diagnosis, we divided them into UTIs (-) and (+) with or without bacteremia. RESULTS: A total of 467 infants were admitted: 334 with UTI and 133 without UTI. In UTIs (+), the pyuria had a sensitivity of 95.8% and bacteria (+) 88.3%; specificity was high, especially for nitrites (96.2%) and bacteria (+) (92.5%). Positive predictive value (PPV) for nitrites was 95.9%, for bacteria 96.7%, and oyuria 92.5%. Escherichia coli was present in 83.8% of urine and 87% of blood cultures. UTIs with bacteremia had inflammatory urinalysis, urine culture > 100,000 CFU/ml, and higher percentage of C reactive protein (CRP) > 50 mg (p= 0.002); 94.6% of the urine culture had > 50,000 CFU. CONCLUSIONS: The pyuria and bacteria (+) in urine obtained by catheterization predict UTI. The cut-off point for diagnosis was ≥ 50,000 CFU/ml. No variables to suspect bacteremia were identified in this study.

INTRODUCCIÓN: La infección del tracto urinario (ITU) es una infección bacteriana grave frecuente en lactantes. El objetivo de este trabajo fue investigar la fiabilidad del análisis de orina (AO) para predecirla, precisar el umbral de unidades formadoras de colonias (UFC)/ml para el diagnóstico y buscar variables que ayuden a sospechar de bacteriemia en lactantes menores de 3 meses con ITU. MÉTODOS: Se revisaron fichas clínicas de lactantes menores de 3 meses hospitalizados por fiebre sin foco evidente, registrando edad, sexo, días de fiebre preconsulta, temperatura y gravedad al ingreso, diagnósticos de egreso, exámenes de laboratorio y tratamientos. Según diagnóstico de egreso, se separaron en ITU (-) y (+), con o sin bacteriemia. RESULTADOS: Ingresaron 467 lactantes: 334 con ITU y 133 sin ITU. En ITU (+), la sensibilidad de la piuria fue de 95.8% y bacterias (+) 88.3%; la especificidad fue alta para nitritos (96.2%) y bacterias (+) (92.5%). El valor predictivo positivo (VPP) fue de 95.9% para nitritos, 96.7% para bacterias y 92.5% para piuria. Escherichia coli se encontró en el 83.8% de los urocultivos (UC) (+) y en el 87% de los hemocultivos (+). Las ITU con bacteriemia presentaron elementos inflamatorios, UC con ≥ 100,000 UFC/ml y mayor porcentaje de proteína C reactiva (PCR) > 50 mg/l (p= 0.002); el 94.6% de los UC (+) tuvo ≥ 50,000 UFC/ml. CONCLUSIONES: La piuria y bacterias (+) en el AO son excelentes para pronosticar ITU en orina obtenida con sonda vesical y el punto de corte para el diagnóstico debe ser ≥ 50,000 UFC/ml. No encontramos señales que ayudaran a sospechar ITU con bacteriemia.

Incidence and risk factors of neonatal bacterial infections: a community-based cohort from Madagascar (2018-2021).

BACKGROUND: Few studies on neonatal severe bacterial infection are available in LMICs. Data are needed in these countries to prioritize interventions and decrease neonatal infections which are a primary cause of neonatal mortality. The BIRDY project (Bacterial Infections and Antimicrobial Drug Resistant among Young Children) was initially conducted in Madagascar, Senegal and Cambodia (BIRDY 1, 2012-2018), and continued in Madagascar only (BIRDY 2, 2018-2021). We present here the BIRDY 2 project whose objectives were (1) to estimate the incidence of neonatal severe bacterial infections and compare these findings with those obtained in BIRDY 1, (2) to identify determinants associated with severe bacterial infection and (3) to specify the antibiotic resistance pattern of bacteria in newborns. METHODS: The BIRDY 2 study was a prospective community-based mother and child cohort, both in urban and semi-rural areas. All pregnant women in the study areas were identified and enrolled. Their newborns were actively and passively followed-up from birth to 3 months. Data on clinical symptoms developed by the children and laboratory results of all clinical samples investigated were collected. A Cox proportional hazards model was performed to identify risk factors associated with possible severe bacterial infection. FINDINGS: A total of 53 possible severe bacterial infection and 6 confirmed severe bacterial infection episodes were identified among the 511 neonates followed-up, with more than half occurring in the first 3 days. For the first month period, the incidence of confirmed severe bacterial infection was 11.7 per 1,000 live births indicating a 1.3 -fold decrease compared to BIRDY 1 in Madagascar (p = 0.50) and the incidence of possible severe bacterial infection was 76.3, indicating a 2.6-fold decrease compared to BIRDY 1 in Madagascar (p < 0.001). The 6 severe bacterial infection confirmed by blood culture included 5 Enterobacterales and one Enterococcus faecium. The 5 Enterobacterales were extended-spectrum ß-lactamases (ESBL) producers and were resistant to quinolones and gentamicin. Enterococcus faecium was sensitive to vancomycin but resistant to amoxicillin and to gentamicin. These pathogns were classified as multidrug-resistant bacteria and were resistant to antibiotics recommended in WHO guidelines for neonatal sepsis. However, they remained susceptible to carbapenem. Fetid amniotic fluid, need for resuscitation at birth and low birth weight were associated with early onset possible severe bacterial infection. CONCLUSION: Our results suggest that the incidence of severe bacterial infection is still high in the community of Madagascar, even if it seems lower when compared to BIRDY 1 estimates, and that existing neonatal sepsis treatment guidelines may no longer be appropriate in Madagascar. These results motivate to further strengthen actions for the prevention, early diagnosis and case management during the first 3 days of life.

Diagnosis of urinary tract infection in infants under 3 months with fever without a source: reliability of urinalysis and urine culture / Diagnóstico de infección del tracto urinario en lactantes menores de 3 meses con fiebre sin foco identificado: fiabilidad del análisis de orina y urocultivo

Abstract Background: Urinary tract infection (UTI) is infants´ most common serious bacterial infection. This study aimed to investigate the reliability of urianalysis (UA) to predict UTI, to specify the colony forming units (CFU)/ml threshold for diagnosis, and to identify variables that help suspect bacteremia in infants under 3 months with UTI. Methods: We reviewed clinical records of children under 3 months hospitalized for a fever without source and recorded age, sex, days of fever pre-consultation, temperature and severity at admission, discharge diagnoses, laboratory tests, and treatments. According to the discharge diagnosis, we divided them into UTIs (-) and (+) with or without bacteremia. Results: A total of 467 infants were admitted: 334 with UTI and 133 without UTI. In UTIs (+), the pyuria had a sensitivity of 95.8% and bacteria (+) 88.3%; specificity was high, especially for nitrites (96.2%) and bacteria (+) (92.5%). Positive predictive value (PPV) for nitrites was 95.9%, for bacteria 96.7%, and oyuria 92.5%. Escherichia coli was present in 83.8% of urine and 87% of blood cultures. UTIs with bacteremia had inflammatory urinalysis, urine culture > 100,000 CFU/ml, and higher percentage of C reactive protein (CRP) > 50 mg (p= 0.002); 94.6% of the urine culture had > 50,000 CFU. Conclusions: The pyuria and bacteria (+) in urine obtained by catheterization predict UTI. The cut-off point for diagnosis was ≥ 50,000 CFU/ml. No variables to suspect bacteremia were identified in this study.

Resumen Introducción: La infección del tracto urinario (ITU) es una infección bacteriana grave frecuente en lactantes. El objetivo de este trabajo fue investigar la fiabilidad del análisis de orina (AO) para predecirla, precisar el umbral de unidades formadoras de colonias (UFC)/ml para el diagnóstico y buscar variables que ayuden a sospechar de bacteriemia en lactantes menores de 3 meses con ITU. Métodos: Se revisaron fichas clínicas de lactantes menores de 3 meses hospitalizados por fiebre sin foco evidente, registrando edad, sexo, días de fiebre preconsulta, temperatura y gravedad al ingreso, diagnósticos de egreso, exámenes de laboratorio y tratamientos. Según diagnóstico de egreso, se separaron en ITU (-) y (+), con o sin bacteriemia. Resultados: Ingresaron 467 lactantes: 334 con ITU y 133 sin ITU. En ITU (+), la sensibilidad de la piuria fue de 95.8% y bacterias (+) 88.3%; la especificidad fue alta para nitritos (96.2%) y bacterias (+) (92.5%). El valor predictivo positivo (VPP) fue de 95.9% para nitritos, 96.7% para bacterias y 92.5% para piuria. Escherichia coli se encontró en el 83.8% de los urocultivos (UC) (+) y en el 87% de los hemocultivos (+). Las ITU con bacteriemia presentaron elementos inflamatorios, UC con ≥ 100,000 UFC/ml y mayor porcentaje de proteína C reactiva (PCR) > 50 mg/l (p= 0.002); el 94.6% de los UC (+) tuvo ≥ 50,000 UFC/ml. Conclusiones: La piuria y bacterias (+) en el AO son excelentes para pronosticar ITU en orina obtenida con sonda vesical y el punto de corte para el diagnóstico debe ser ≥ 50,000 UFC/ml. No encontramos señales que ayudaran a sospechar ITU con bacteriemia.

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study.

INTRODUCTION: The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. METHODS: The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. RESULTS: Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. CONCLUSION: We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. TRIAL REGISTRATION: BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

The Incidence of Serious/Invasive Bacterial Diseases in Infants 90 Days Old or Younger at an Emergency Hospital in Japan.

Background The incidence of severe bacterial infections (SBIs) in infants aged ≤90 days is thought to have decreased because of widespread vaccination programs. However, relevant epidemiological data in Japan are scarce. Materials and methods This observational, single-center study investigated the epidemiology of fever in infants aged ≤90 days. SBI was defined as the presence of meningitis, urinary tract infections (UTIs), or bacteremia. Invasive bacterial infection (IBI) was defined as the presence of meningitis, bacteremic UTI, or bacteremia. We determined the incidence of UTIs, bacteremia, meningitis, SBIs, and IBIs in the following three age groups: 0-28, 29-60, and 61-90 days. We subsequently calculated the relative incidence for the groups aged 29-60 and 61-90 days, using the group aged 0-28 days as the reference group.  Results Herein, 58, 124, and 166 infants were included in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively. Of the total number of patients, 15.5%, 8.9%, and 16.9% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with SBI. The relative incidences were 1 for the 0-28 days group (reference group), 0.67 for the 29-60 days group (95% confidence interval [CI], 0.39-1.15), and 1.08 for the 61-90 days group (95% CI, 0.58-2.00). Of the total number of patients, 10.3%, 3.2%, and 0.6% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with IBI. Relative incidences were 1 (reference group), 0.50 (95% CI, 0.29-0.88), and 0.28 (95% CI, 0.19-0.41) for the 0-28 days, 29-60 days, and 61-90 days age groups, respectively. All cases of IBI were caused by Group B streptococcus (GBS), except for two cases of bacteremia, which were caused by Haemophilus influenzae.  Conclusion The incidence of SBI was similar in the 0-28 days and 61-90 days age groups. However, the incidence of IBI decreased with increasing age. The incidence of UTIs was highest in the 61-90 days age group, and that of meningitis and bacteremia decreased with increasing age.

Low incidence of severe bacterial infections in hospitalised patients with COVID-19: A population-based registry study.

BACKGROUND: Bacterial infections complicating COVID-19 are rare but present a challenging clinical entity. The aim of this study was to evaluate the incidence, aetiology and outcome of severe laboratory-verified bacterial infections in hospitalised patients with COVID-19. METHODS: All laboratory-confirmed patients with COVID-19 admitted to specialised healthcare hospitals in the Capital Province of Finland during the first wave of COVID-19 between 27 February and 21 June 2020 were retrospectively studied. We gathered the blood and respiratory tract culture reports of these patients and analysed their association with 90-day case-fatality using multivariable regression analysis. RESULTS: A severe bacterial infection was diagnosed in 40/585 (6.8%) patients with COVID-19. The range of bacteria was diverse, and the most common bacterial findings in respiratory samples were gram-negative, and in blood cultures gram-positive bacteria. Patients with severe bacterial infection had longer hospital stay (mean 31; SD 20 days) compared to patients without (mean 9; SD 9 days; p < 0.001). Case-fatality was higher with bacterial infection (15% vs 11%), but the difference was not statistically significant (OR 1.38 CI95% 0.56-3.41). CONCLUSIONS: Severe bacterial infection complicating COVID-19 was a rare occurrence in our cohort. Our results are in line with the current understanding that antibiotic treatment for hospitalised COVID-19 patients should only be reserved for situations where a bacterial infection is strongly suspected. The ever-evolving landscape of the pandemic and recent advances in immunomodulatory treatment of COVID-19 patients underline the need for continuous vigilance concerning the possibility and frequency of nosocomial bacterial infections.

The risk of serious bacterial infections among young ex-premature infants with fever.

Background and Objectives: To determine the rate of serious-bacterial-infections (SBI) in young ex-premature infants with fever, and to develop a risk-stratification algorithm for these patients. Methods: A retrospective cohort study including all infants who presented to the pediatric emergency department (ED) of a tertiary-care university-hospital between 2010 and 2020 with fever (≥38°C), were born prematurely (<37-weeks), had post-conception age of <52-weeks, and had available blood, urine, or CSF cultures. The rates of SBI by age-of-birth and age-at-visit were calculated and compared to a cohort of matched full-term controls. Results: The study included a total of 290 ex-premature cases and 290 full-term controls. There were 11 cases (3.8%) with an invasive bacterial infection (IBI) of either bacteremia, meningitis or both and only six controls (2.1%) with IBI (p = 0.32). Over 28-days chronologic-age, there were 10 (3.6%) IBIs among cases and no IBIs among the controls (p = 0.02). There were eight (3%) cases and three (1%) controls with IBI who were well-appearing on physical examination (p = 0.19). All eight well-appearing ex-premature infants were under 60-days adjusted-age, seven of whom (88%) were also under 28-days adjusted-age. There were 28 (10.6%) cases and 34 (12%) controls with urinary tract infection (UTI) (p = 0.5). Among cases under 60-days adjusted-age, urinalysis was not reliable to exclude UTI (50% negative). Conclusions: Well-appearing ex-preterm infants have a significant risk for IBI until the adjusted age of 28-days and for UTI until the adjusted age of 60-days. Further studies are needed to evaluate the approach to fever in this unique population.

SBI is uncommon in the absence of paediatricians' gut feeling and abnormal respiratory pattern.

AIM: According to the Italian national statistical institute, severe bacterial infections (SBI) in Italy are responsible for 1.7% of mortality under 5 years of age and their recognition is often challenging, especially in the first stages of the disease. We tried to estimate the prevalence of SBI in our target population and to identify signs and symptoms that could guide in the initial evaluation of a child with a possible SBI. METHODS: We designed a prospective, multicentre study and enrolled patients aged 0-14 years at the first evaluation to the emergency department with an acute illness lasting a maximum of 5 days. The presence of variables suggestive of SBI was collected for every enrolled patient. One week after the enrolment, every patient was followed up by telephone. RESULTS: SBI is more likely to be detected with the 'gut feeling' in both univariate and multivariate models (univariate OR: 7.16, 95% CI: 4.08-12.56; multivariate OR: 5.34, 95% CI: 2.78-10.25), while abnormal breathing pattern resulted significative only in univariate model (OR 3.83, 95% CI: 1.98-7.40). Nevertheless, their associated sensitivity is low. CONCLUSION: SBI is uncommon in the absence of paediatricians' gut feeling and abnormal respiratory pattern.

Severe bacterial infections in people who inject drugs: the role of injection-related tissue damage.

BACKGROUND: In the context of the current U.S. injection drug use epidemic, targeted public health harm reduction strategies have traditionally focused on overdose prevention and reducing transmission of blood-borne viral infections. Severe bacterial infections (SBI) associated with intravenous drug use have been increasing in frequency in the U.S. over the last decade. This qualitative study aims to identify the risk factors associated with SBI in hospitalized individuals with recent injection drug use. METHODS: Qualitative analysis (n = 15) was performed using an in-depth, semi-structured interview of participants admitted to Bellevue Hospital, NYC, with SBI and recent history of injection drug use. Participants were identified through a referral from either the Infectious Diseases or Addition Medicine consultative services. Interviews were transcribed, descriptively coded, and analyzed for key themes. RESULTS: Participants reported a basic understanding of prevention of blood-borne viral transmission but limited understanding of SBI risk. Participants described engagement in high risk injection behaviors prior to hospitalization with SBI. These practices included polysubstance use, repetitive tissue damage, nonsterile drug diluting water and multipurpose use of water container, lack of hand and skin hygiene, re-use of injection equipment, network sharing, and structural factors leading to an unstable drug injection environment. Qualitative analysis led to the proposal of an Ecosocial understanding of SBI risk, detailing the multi-level interplay between individuals and their social and physical environments in producing risk for negative health outcomes. CONCLUSIONS: Structural factors and injection drug use networks directly impact drug use, injection drug use practices, and harm reduction knowledge, ultimately resulting in tissue damage and inoculation of bacteria into the host and subsequent development of SBI. Effective healthcare and community prevention efforts targeted toward reducing risk of bacterial infections could prevent long-term hospitalizations, decrease health care expenditures, and reduce morbidity and mortality.

Impact of early kangaroo mother care versus standard care on survival of mild-moderately unstable neonates <2000 grams: A randomised controlled trial.

BACKGROUND: Understanding the effect of early kangaroo mother care on survival of mild-moderately unstable neonates <2000 g is a high-priority evidence gap for small and sick newborn care. METHODS: This non-blinded pragmatic randomised clinical trial was conducted at the only teaching hospital in The Gambia. Eligibility criteria included weight <2000g and age 1-24 h with exclusion if stable or severely unstable. Neonates were randomly assigned to receive either standard care, including KMC once stable at >24 h after admission (control) versus KMC initiated <24 h after admission (intervention). Randomisation was stratified by weight with twins in the same arm. The primary outcome was all-cause mortality at 28 postnatal days, assessed by intention to treat analysis. Secondary outcomes included: time to death; hypothermia and stability at 24 h; breastfeeding at discharge; infections; weight gain at 28d and admission duration. The trial was prospectively registered at www.clinicaltrials.gov (NCT03555981). FINDINGS: Recruitment occurred from 23rd May 2018 to 19th March 2020. Among 1,107 neonates screened for participation 279 were randomly assigned, 139 (42% male [n = 59]) to standard care and 138 (43% male [n = 59]) to the intervention with two participants lost to follow up and no withdrawals. The proportion dying within 28d was 24% (34/139, control) vs. 21% (29/138, intervention) (risk ratio 0·84, 95% CI 0·55 - 1·29, p = 0·423). There were no between-arm differences for secondary outcomes or serious adverse events (28/139 (20%) for control and 30/139 (22%) for intervention, none related). One-third of intervention neonates reverted to standard care for clinical reasons. INTERPRETATION: The trial had low power due to halving of baseline neonatal mortality, highlighting the importance of implementing existing small and sick newborn care interventions. Further mortality effect and safety data are needed from varying low and middle-income neonatal unit contexts before changing global guidelines.

Investigation of primary immune deficiency after severe bacterial infection in children: A population-based study in western France.

BACKGROUND: Infectious diseases are still an important cause of morbidity and mortality in high-income countries and may preferentially affect predisposed children, especially immunocompromised children. We aimed to evaluate the frequency of recommended immunological tests in children with community-onset severe bacterial infection (COSBI) admitted to a pediatric intensive care unit. We also assessed the frequency and described the typology of diagnosed primary immune deficiency (PID). METHODS: We conducted a retrospective observational epidemiological study in six university hospitals in western France. All children from 1 month to 16 years of age admitted to hospital for bacterial meningitis, purpura fulminans, or meningococcal disease between August 2009 and January 2014 were included. We analyzed the frequency, type, and results of the immunological tests performed on children with meningitis, purpura fulminans, or a meningococcemia episode. RESULTS: Among the 143 children included (144 episodes), 84 (59%) and 60 (41%) had bacterial meningitis and purpura fulminans or meningococcemia, respectively: 72 (50%) had immunological tests and 8% had a complete immunological investigation as recommended. Among the 72 children examined for PID, 11 (15%) had at least one anomaly in the immunological test results. Two children had a diagnosis of PID (one with C2 deficit and the other with C8 deficit) and seven other children had possible PID. Thus, the prevalence of a definite or possible diagnosis of PID was 12% among the children examined. CONCLUSION: PID is rarely investigated after COSBI. We raise awareness of the need for immunological investigations after a severe infection requiring PICU admission.

Clinical utility of procalcitonin in febrile infants younger than 3 months of age visiting a pediatric emergency room: a retrospective single-center study.

BACKGROUND: Fever in infants under 90 days of age is highly likely to be caused by a severe bacterial infection (SBI) and it accounts for a large number of patients visiting the pediatric emergency room. In order to predict the bacterial infection and reduce unnecessary treatment, the classic classification system is based on white blood cell (WBC) count, urinalysis, and x-ray, and it is modified and applied at each center by incorporating recently studied biomarkers such as c-reactive protein (CRP) or procalcitonin (PCT). This study analyzed the usefulness of PCT in predicting SBI when applied along with the existing classification system, including CRP, among infants less than 90 days old who visited with a fever at a single institution pediatric emergency center. METHODS: We retrospectively reviewed the medical records of patients younger than 3 months of age who presented with fever at the Seoul Asan Medical Center pediatric emergency room between July 2017 and October 2018. RESULTS: A total of 317 patients were analyzed, and 61 were diagnosed with SBI, among which urinary tract infection (UTI) accounted for the largest proportion (55/61, 90.2%). There were differences in WBC, neutrophil proportion, CRP, and PCT between the SBI group and the non-SBI group, and the AUC values of WBC, CRP, and PCT were 0.651, 0.804, and 0.746, respectively. When using the cut-off values of CRP and PCTs as 2.0 mg/dL and 0.3 ng/mL, respectively, the sensitivity and specificity for SBI were 49.2/89.5, and 54.1/87.5, respectively. WBC, CRP, and PCT were statistically significant for predicting SBI in multivariate analysis (odds ratios 1.066, 1.377, and 1.291, respectively). When the subjects were classified using the existing classification criteria, WBC and CRP, the positive predictive value (PPV) and negative predictive value (NPV) were 29.3 and 88.7%, respectively, and when PCT was added, the PPV and NPV were 30.7 and 92%, respectively, both increased. CONCLUSION: PCT is useful for predicting SBI in children aged 3 months or less who visit the emergency room with a fever. It is useful as a single biomarker, and when used in conjunction with classic biomarkers, its diagnostic accuracy is further increased.

A national survey of private-sector outpatient care of sick infants and young children in Nepal.

BACKGROUND: Previous research has documented that across South Asia, as well as in some countries in Sub-Saharan Africa, the private sector is the primary source of outpatient care for sick infants and children and, in many settings, informal providers play a bigger role than credentialed health professionals (particularly for the poorer segments of the population). This is the case in Nepal. This study sought to characterize medicine shop-based service providers in rural areas and small urban centers in Nepal, their role in the care and treatment of sick infants and children (with a particular focus on infants aged < 2 months), and the quality of the care provided. A secondary objective was to characterize availability and quality of such care provided by physicians in these settings. METHODS: A nationally representative sample of medicine shops was drawn, in rural settings and small urban centers in Nepal, from 25 of the 75 districts in Nepal, using multi-stage cluster methodology, with a final sample of 501 shops and 82 physician-run clinics. Face-to-face interviews were conducted. RESULTS: Most medicine shops outside urban areas were not registered with the Department of Drug Administration (DDA). Most functioned as de facto clinics, with credentialed paramedical workers (having 2-3 years of training) diagnosing patients and making treatment decisions. Such a role falls outside their formally sanctioned scope of practice. Quality of care problems were identified among medicine shop-based providers and physicians, including over-use of antibiotics for treating diarrhea, inaccurate weighing technique to determine antibiotic dose, and inappropriate use of injectable steroids for treating potentially severe infections in young infants. CONCLUSIONS: Medicine shop-based practitioners in Nepal represent a particular type of informal provider; although most have recognized paramedical credentials, they offer services falling outside their formal scope of practice. Nevertheless, given the large proportion of the population served by these practitioners, engagement to strengthen quality of care by these providers and referral to the formal health sector is warranted.

Neonatal care and community-level treatment seeking for possible severe bacterial infection (PSBI) in Amhara, Ethiopia.

BACKGROUND: In Ethiopia, neonatal mortality accounts for approximately 54% of under-five deaths with the majority of these deaths driven by infections. Possible Severe Bacterial Infection (PSBI) in neonates is a syndromic diagnosis that non-clinical health care providers use to identify and treat newborns with signs of sepsis. In low- and middle-income countries, referral to a hospital may not be feasible due to transportation, distance or finances. Growing evidence suggests health extension workers (HEWs) can identify and manage PSBI at the community level when referral to a hospital is not possible. However, community-based PSBI care strategies have not been widely scaled-up. This study aims to understand general determinants of household-level care as well as household care seeking and decision-making strategies for neonatal PSBI symptoms. METHODS: We conducted eleven focus group discussions (FGDs) to explore illness recognition and care seeking intentions from four rural kebeles in Amhara, Ethiopia. FGDs were conducted among mothers, fathers and households with recruitment stratified among households that have had a newborn with at least one symptom of PSBI (Symptomatic Group), and households that have had a newborn regardless of the child's health status (Community Group). Data were thematically analyzed using MAXQDA software. RESULTS: Mothers were described as primary caretakers of the newborn and were often appreciated for making decisions for treatment, even when the father was not present. Type of care accessed was often dependent on conceptualization of the illness as simple or complex. When symptoms were not relieved with clinical care, or treatments at facilities were perceived as ineffective, alternative methods were sought. Most participants identified the health center as a reliable facility. While designed to be the first point of access for primary care, health posts were not mentioned as locations where families seek clinical treatment. CONCLUSIONS: This study describes socio-contextual drivers for PSBI treatment at the community level. Future programming should consider the role community members have in planning interventions to increase demand for neonatal care at primary facilities. Encouragement of health post utilization could further allow for heightened accessibility-acceptability of a simplified PSBI regimen.

Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial.

BACKGROUND: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum). METHODS/DESIGN: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival. DISCUSSION: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine. TRIAL REGISTRATION: EudraCT, 2016-001788-34; ClinicalTrials.gov, NCT03334006 . Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).

Vaccine-preventable severe morbidity and mortality caused by meningococcus and pneumococcus: A population-based study in France.

BACKGROUND: In a context of suboptimal vaccination coverage and increasing vaccine hesitancy, we aimed to study morbidity and mortality in children related to missing or incomplete meningococcal C and pneumococcal conjugate vaccines. METHODS: We conducted a prospective, observational, population-based study from 2009 to 2014 in a French administrative area that included all children from age 1 month to 16 years who died before admission or were admitted to an intensive care unit for a community-onset bacterial infection. Vaccine-preventable infection was defined as an infection with an identified serotype included in the national vaccine schedule at the time of infection and occurring in a non- or incompletely vaccinated child. Death and severe sequelae were studied at hospital discharge. Frequencies of vaccine-preventable morbidity and mortality caused by meningococcus and pneumococcus were calculated. RESULTS: Among the 124 children with serotyped meningococcal (n = 75) or pneumococcal (n = 49) severe infections included (median age 26 months), 20 (16%) died and 12 (10%) had severe sequelae. Vaccine-preventable infections accounted for 18/124 infections (15%, 95% CI 9, 22), 5/20 deaths (25%, 95% CI 9, 49), and 3/12 severe sequelae cases (25%, 95% CI 0, 54). The vaccine schedule for meningococcal C and pneumococcal conjugate vaccinations was incomplete for 71/116 (61%) children targeted by at least one of these two vaccination programs. CONCLUSIONS: Mortality and morbidity rates related to vaccine-preventable meningococcal or pneumococcal infection could be reduced by one quarter with better implementation of immunisation programs. Such information could help enhance the perception of vaccine benefits and fight vaccine hesitancy.

[Suboptimal care and severe bacterial infection in the French Caribbean area]. / Soins sub-optimaux et infections bactériennes sévères communautaires aux Antilles françaises.

OBJECTIVE: To study the frequency and types of suboptimal care in initial management of children suffering from a severe bacterial infection (SBI), in a French region where little is known about pediatric SBI epidemiology. METHOD: Retrospective single-center study over a 6-year period. Children between 3 months and 15 years of age, deceased or surviving and admitted to the pediatric intensive care unit of the university-affiliated hospital of Martinique for a community-onset SBI were included in this study. The optimality of the medical care before admission to the pediatric intensive care unit was assessed in a blinded fashion by two independent experts. RESULTS: Twenty-nine of the 30 children suffering from SBI could be analyzed. The median age was 3.7 years (IQR: 1.7-10.4); the mortality rate was 14 % (95 % CI: 1-27 %). Most frequently infections were pulmonary infections (48 %; 95 % CI: 29-67 %), followed by septic shock (44 %; 95 % CI: 25-63 %). Microbiological cultures were positive in 55 % (95 % CI, 36-74 %) (n=16) of the cases, with five pneumococcus and four Streptococcus pyogenes. Of the 29 children included in the study, 72 % (95 % CI: 55-89 %) (n=21) had received at least one episode of suboptimal care. Suboptimal care comprised delay in diagnosis (identification of serious symptoms) in 65 % (95 % CI: 47-83 %), a delay in seeking care in 41 % (95 % CI: 22-60 %), and a delay in the initiation of antibiotics or hemodynamic support in 45 % (95 % CI: 26-64 %) and 38 % (95 % CI: 20-56 %) of the cases, respectively. CONCLUSION: Suboptimal care was frequent in the initial management of SBI, particularly because of a delay in seeking care and the failure of physicians to recognize early signs of SBI. A large public information campaign, focusing on healthcare accessibility and better education of physicians in the early recognition of SBIs are means of improvement that need to be explored.

Outcomes of Immunocompetent Children Presenting with Fever and Neutropenia.

BACKGROUND: Neutropenia may alarm clinicians and prompt extensive evaluation in children with fever, even in immunocompetent patients. OBJECTIVE: Our aim was to determine outcomes in previously healthy febrile children presenting to the emergency department with severe neutropenia. METHODS: We reviewed data from infants and children aged 3-36 months with fever and severe neutropenia, defined as a peripheral neutrophil count <500 × 103/µL, at our institution between January 1, 2012 and December 31, 2015. We compared our results to those from a similar study of children with a peripheral neutrophil count of 500-1000 × 103/µL. RESULTS: Severe neutropenia was recorded in 52 patients; severe bacterial infection (SBI) was found in 1 (1.9%), but none had a positive blood culture. Incidence of SBI was not different from that found in a study of similar patients with moderate neutropenia. CONCLUSIONS: Immunocompetent patients with fever and severe neutropenia do not carry a higher risk for SBI compared to patients with fever and moderate neutropenia. Such patients could potentially be followed closely with serial blood counts to ensure bone marrow recovery, without the use of antibiotics.