Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data.

BACKGROUND: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation. METHODS: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742. FINDINGS: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23). INTERPRETATION: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.

Clinical recommendations for the inpatient management of lower respiratory tract infections in children and adolescents with severe neurological impairment in Germany.

Children and adolescents with severe neurological impairment (SNI) require specialized care due to their complex medical needs. In particular, these patients are often affected by severe and recurrent lower respiratory tract infections (LRTIs). These infections, including viral and bacterial etiology, pose a significant risk to these patients, often resulting in respiratory insufficiency and long-term impairments. Using expert consensus, we developed clinical recommendations on the management of LRTIs in children and adolescents with SNI. These recommendations emphasize comprehensive multidisciplinary care and antibiotic stewardship. Initial treatment should involve symptomatic care, including hydration, antipyretics, oxygen therapy, and respiratory support. In bacterial LRTIs, antibiotic therapy is initiated based on the severity of the infection, with aminopenicillin plus a beta-lactamase inhibitor recommended for community-acquired LRTIs and piperacillin-tazobactam for patients with chronic lung disease or tracheostomy. Ongoing management includes regular evaluations, adjustments to antibiotic therapy based on pathogen identification, and optimization of supportive care. Implementation of these recommendations aims to improve the diagnosis and treatment of LRTIs in children and adolescents with SNI. What is Known: • Children and adolescents with severe neurological impairment are particularly affected by severe and recurrent lower respiratory tract infections (LRTIs). • The indication and choice of antibiotic therapy for bacterial LRTI is often difficult because there are no evidence-based treatment recommendations for this heterogeneous but vulnerable patient population; the frequent overuse of broad-spectrum or reserve antibiotics in this patient population increases selection pressure for multidrug-resistant pathogens. What is New: • The proposed recommendations provide a crucial framework for focused diagnostics and treatment of LRTIs in children and adolescents with severe neurological impairment. • Along with recommendations for comprehensive and multidisciplinary therapy and antibiotic stewardship, ethical and palliative care aspects are taken into account.

[SARS-CoV-2 Exposure and Seroprevalence of SARS-CoV-2 Antibodies among Medical Students in the First Phase of the Pandemic 2020-2021]. / SARS-CoV-2 Exposition und Seroprävalenz von SARS-CoV-2-Antikörpern bei Medizinstudierenden in der ersten Phase der Pandemie, 2020­2021.

BACKGROUND: Due to their clinical training and secondary activities in the hospital, medical students are exposed to contact with SARS-CoV-2 infected people more often than the general population. We determined the seroprevalence of SARS-CoV-2 antibodies in medical students in clinical training at different times during the pandemic and asked participants about possible SARS-CoV-2 exposures in both medical and private settings. METHODS: From May 2020 to June 2021, medical students each in their 3rd year of training at the University Hospital Würzburg participated in the cross-sectional survey. All SARS-CoV-2 unvaccinated students were offered a determination of their SARS-CoV-2 serostatus. The blood samples were tested by an immunoassay (Elecsys, Roche) for IgG/IgM/IgA antibodies against the SARS-CoV-2 N antigen. Demographic data, SARS-CoV-2 disease and vaccination status, as well as possible SARS-CoV-2 exposures were collected using a questionnaire. RESULTS: Overall, 383 (86.1%) of 445 students took part in the cross-sectional survey (65% female; median age 22 years; IQR 21-24). Serostatus was determined in 223 (58.2% of 383) SARS-CoV-2 unvaccinated participants. In the period between the beginning of the pandemic in Germany (February 2020) and the time of the survey, 332 (86.7% of 383) students stated that they worked in the medical field, mainly in the context of clinical traineeships (76.8%) or secondary activities with patient contact (48.8%); 129 (33.7%) reported previous contact with a COVID-19 patient, of which 78.3% of contacts took place at a medical facility. Antibodies against SARS-CoV-2 were detected in 8 (3.6%) of the 223 unvaccinated participants tested, and in 3 infected persons an association between infection and contact in the course of medical activity seemed likely. CONCLUSION: Despite frequent patient contact and the associated increased risk of infection, medical students in their 3rd year of training did not show an increased seroprevalence compared to the general population and showed a lower or similar seroprevalence rate than medical students in other European countries in the first 18 months of the pandemic. This indicates sufficient protection of medical students at the beginning of clinical training through the hygiene and infection protection measures implemented at that time during medical activities.

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

Hospitalizations due to respiratory syncytial virus (RSV) infections in Germany: a nationwide clinical and direct cost data analysis (2010-2019).

PURPOSE: Clinical and direct medical cost data on RSV-related hospitalizations are relevant for public health decision-making. We analyzed nationwide data on RSV-coded hospitalizations from Germany in different age and risk groups. METHODS: Assessment of RSV-coded hospitalizations (ICD-10-GM RSV-code J12.1/J20.5/J21.0 as primary discharge diagnosis) from 01/2010 to 12/2019, using remote data retrieval from the Hospital Statistics Database of the German Federal Statistical Office. RESULTS: Overall, 205,352 RSV-coded hospitalizations (198,139 children < 18 years, 1,313 adults, 5,900 seniors > 59 years) were reported (median age < 1 year, IQR 0; 1; 56% males, 32% with RSV pneumonia). Annual median RSV-coded hospitalization incidence was 24.8/100,000 persons (IQR 21.3; 27.5); children reported a median incidence of 145.8 (IQR 130.9; 168.3). Between 2010 and 2019, hospitalization incidence increased 1.7-fold/15.1-fold/103-fold in children/adults/seniors. Adults and seniors reported higher rates of underlying chronic conditions, complications, and intensive care treatment than children; of 612 in-hospital fatalities, 103/51/458 occurred in children/adults/seniors. Per-patient mean costs varied between 3286€ ± 4594 in 1-4-year-olds and 7215€ ± 13,564 among adults. Increased costs were associated with immune disorders (2.55-fold increase compared to those without), nervous system disorders (2.66-fold), sepsis (7.27-fold), ARDS (12.85-fold), intensive care (4.60-fold) and ECMO treatment (16.88-fold). CONCLUSION: The economic burden of RSV-related hospitalizations in Germany is substantial, even when only considering cases with RSV-coded as the primary discharge diagnosis. Children represented the vast majority of RSV-coded hospitalizations. However, adults and seniors hospitalized for RSV were at a higher risk of severe complications, required more costly treatments, and had higher fatality rates; although their RSV-coded hospitalization incidence showed a clear upward trend since 2017, their true hospitalization incidence is still likely to be underestimated due to lack of routine RSV testing in these age groups. Hence, new treatments and vaccines for RSV ideally should also target adults and seniors in addition to children.

Comparing SARS-CoV-2 variants among children and adolescents in Germany: relative risk of COVID-19-related hospitalization, ICU admission and mortality.

PURPOSE: SARS-CoV-2 infections cause COVID-19 and have a wide spectrum of morbidity. Severe disease courses among children are rare. To date, data on the variability of morbidity in relation to variant of concern (VOC) in children has been sparse and inconclusive. We compare the clinical severity of SARS-CoV-2 infection among children and adolescents in Germany during the Wildtype and Alpha combined, Delta and Omicron phases of the COVID-19 pandemic. METHODS: Comparing risk of COVID-19-related hospitalization, intensive care unit (ICU) admission and death due to COVID-19 in children and adolescents, we used: (1) a multi-center seroprevalence study (SARS-CoV-2-KIDS study); (2) a nationwide registry of pediatric patients hospitalized with SARS-CoV-2 infections; and (3) compulsory national reporting for RT-PCR-confirmed SARS-CoV-2 infections in Germany. RESULTS: During the Delta predominant phase, risk of COVID-19-related hospitalization among all SARS-CoV-2 seropositive children was 3.35, ICU admission 1.19 and fatality 0.09 per 10,000; hence about halved for hospitalization and ICU admission and unchanged for deaths as compared to the Wildtype- and Alpha-dominant period. The relative risk for COVID-19-related hospitalization and ICU admission compared to the alpha period decreased during Delta [0.60 (95% CI 0.54; 0.67) and 0.51 (95% CI 0.42; 0.61)] and Omicron [0.27 (95% CI 0.24; 0.30) and 0.06 (95% CI 0.05; 0.08)] period except for the < 5-year-olds. The rate of case fatalities decreased slightly during Delta, and substantially during Omicron phase. CONCLUSION: Morbidity caused by SARS-CoV-2 infections among children and adolescents in Germany decreased over the course of the COVID-19 pandemic, as different VOCs) emerged.

Clinical Burden of Respiratory Syncytial Virus in Hospitalized Children Aged ≤5 Years (INSPIRE Study).

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of hospitalizations in children (≤5 years of age); limited data compare burden by age. METHODS: This single-center retrospective study included children (≤5 years of age) hospitalized for >24 hours with reverse-transcription polymerase chain reaction (RT-PCR)-confirmed RSV infection (2015-2018). Hospital length of stay (LOS), intensive care unit (ICU) admissions, ICU LOS, supplemental oxygen, and medication use were assessed. Multivariate logistic regression analyses identified predictors of hospital LOS >5 days. RESULTS: Three hundred twelve patients had RSV infection (ages 0 to <6 months [35%], 6 to <12 months [15%], 1 to <2 years [25%], and 2-5 years [25%]); 16.3% had predefined comorbidities (excludes preterm infants). Median hospital LOS was 5.0 days and similar across age; 5.1% (16/312) were admitted to ICU (ICU LOS, 5.0 days), with those aged 0 to <6 months admitted most frequently (10/108 [9.3%]). Supplemental oxygen was administered in 57.7% of patients, with similar need across ages. Antibiotics were administered frequently during hospitalization (43.6%). Predictors of prolonged LOS included pneumonia (odds ratio [OR], 2.33), supplemental oxygen need (OR, 5.09), and preterm births (OR, 3.37). High viral load (RT-PCR RSV cycle threshold value <25) was associated with greater need for supplemental oxygen. CONCLUSIONS: RSV causes substantial burden in hospitalized children (≤5 years), particularly preterm infants and those aged <6 months.

Similar severity of influenza primary and re-infections in pre-school children requiring outpatient treatment due to febrile acute respiratory illness: prospective, multicentre surveillance study (2013-2015).

BACKGROUND: Influenza virus infections in immunologically naïve children (primary infection) may be more severe than in children with re-infections who are already immunologically primed. We compared frequency and severity of influenza virus primary and re-infections in pre-school children requiring outpatient treatment. METHODS: Influenza-unvaccinated children 1-5 years of age presenting at pediatric practices with febrile acute respiratory infection < 48 h after symptom onset were enrolled in a prospective, cross-sectional, multicenter surveillance study (2013-2015). Influenza types/subtypes were PCR-confirmed from oropharyngeal swabs. Influenza type/subtype-specific IgG antibodies serving as surrogate markers for immunological priming were determined using ELISA/hemagglutination inhibition assays. The acute influenza disease was defined as primary infection/re-infection by the absence/presence of influenza type-specific immunoglobulin G (IgG) and, in a second approach, by the absence/presence of subtype-specific IgG. Socio-demographic and clinical data were also recorded. RESULTS: Of 217 influenza infections, 178 were due to influenza A (87 [49%] primary infections, 91 [51%] re-infections) and 39 were due to influenza B (38 [97%] primary infections, one [3%] re-infection). Children with "influenza A primary infections" showed fever with respiratory symptoms for a shorter period than children with "influenza A re-infections" (median 3 vs. 4 days; age-adjusted p = 0.03); other disease characteristics were similar. If primary infections and re-infections were defined based on influenza A subtypes, 122 (87%) primary infections (78 "A(H3N2) primary infections", 44 "A(H1N1)pdm09 primary infections") and 18 (13%) re-infections could be classified (14 "A(H3N2) re-infections" and 4 "A(H1N1)pdm09 re-infections"). Per subtype, primary infections and re-infections were of similar disease severity. Children with re-infections defined on the subtype level usually had non-protective IgG titers against the subtype of their acute infection (16 of 18; 89%). Some patients infected by one of the influenza A subtypes showed protective IgG titers (≥ 1:40) against the other influenza A subtype (32/140; 23%). CONCLUSIONS: Pre-school children with acute influenza A primary infections and re-infections presented with similar frequency in pediatric practices. Contrary to expectation, severity of acute "influenza A primary infections" and "influenza A re-infections" were similar. Most "influenza A re-infections" defined on the type level turned out to be primary infections when defined based on the subtype. On the subtype level, re-infections were rare and of similar disease severity as primary infections of the same subtype. Subtype level re-infections were usually associated with low IgG levels for the specific subtype of the acute infection, suggesting only short-time humoral immunity induced by previous infection by this subtype. Overall, the results indicated recurring influenza virus infections in this age group and no or only limited heterosubtypic antibody-mediated cross-protection.

Epidemiology and direct healthcare costs of Influenza-associated hospitalizations - nationwide inpatient data (Germany 2010-2019).

INTRODUCTION: Detailed and up-to-date data on the epidemiology and healthcare costs of Influenza are fundamental for public health decision-making. We analyzed inpatient data on Influenza-associated hospitalizations (IAH), selected complications and risk factors, and their related direct costs for Germany during ten consecutive years. METHODS: We conducted a retrospective cost-of-illness study on patients with laboratory-confirmed IAH (ICD-10-GM code J09/J10 as primary diagnosis) by ICD-10-GM-based remote data query using the Hospital Statistics database of the German Federal Statistical Office. Clinical data and associated direct costs of hospital treatment are presented stratified by demographic and clinical variables. RESULTS: Between January 2010 to December 2019, 156,097 persons were hospitalized due to laboratory-confirmed Influenza (J09/J10 primary diagnosis). The annual cumulative incidence was low in 2010, 2012 and 2014 (1.3 to 3.1 hospitalizations per 100,000 persons) and high in 2013 and 2015-2019 (12.6 to 60.3). Overall direct per patient hospitalization costs were mean (SD) 3521 EUR (± 8896) and median (IQR) 1805 EUR (1502; 2694), with the highest mean costs in 2010 (mean 8965 EUR ± 26,538) and the lowest costs in 2012 (mean 2588 EUR ± 6153). Mean costs were highest in 60-69 year olds, and in 50-59, 70-79 and 40-49 year olds; they were lowest in 10-19 year olds. Increased costs were associated with conditions such as diabetes (frequency 15.0%; 3.45-fold increase compared to those without diabetes), adiposity (3.3%; 2.09-fold increase) or immune disorders (5.6%; 1.88-fold increase) and with Influenza-associated complications such as Influenza pneumonia (24.3%; 1.95-fold), bacterial pneumonia (6.3%; 3.86-fold), ARDS (1.2%; 10.90-fold increase) or sepsis (2.3%; 8.30-fold). Estimated overall costs reported for the 10-year period were 549.6 Million euros (95% CI 542.7-556.4 million euros). CONCLUSION: We found that the economic burden of IAH in Germany is substantial, even when considering solely laboratory-confirmed IAH reported as primary diagnosis. The highest costs were found in the elderly, patients with certain underlying risk factors and patients who required advanced life support treatment, and median and mean costs showed considerable variations between single years. Furthermore, there was a relevant burden of disease in middle-aged adults, who are not covered by the current vaccination recommendations in Germany.

Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011-2017.

BACKGROUND: The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. METHODS: During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. RESULTS: A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6%) were infected with RSV-A, 235 (39.0%) with RSV-B, and one child (0.2%) with both RSV-A and RSV-B; in 26 (4.3%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4%), NA1 in 92 (26.9%), and GA5 in 2 children (0.6%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7-12 vs. 7 days, IQR 5-9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4-9 vs. 4 days, IQR 2-6; p = 0.03) for children infected with RSV-A ON1. CONCLUSIONS: In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.

Secondary haemophagocytic lymphohistiocytosis triggered by postnatally acquired cytomegalovirus infection in a late preterm infant.

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition with impairment of cytotoxic T-cells and natural killer cells. Causes in infants are mostly hereditary immune defects as well as various infectious triggering factors, amongst these cytomegalovirus (CMV). Vertical CMV transmission may occur in utero, during birth, and by breast feeding. Usually, a CMV infection transmitted via breast milk is symptomatic only in very immature preterm infants. We report on a late preterm infant born after 35 + 5 weeks of gestation with a birth weight of 1840 g, being admitted to our intensive care unit at the age of 9 weeks with acute enteritis and severe dehydration. After a prolonged recovery, the infant developed a sepsis-like condition with hyperpyrexia, hepatosplenomegaly, and pancytopenia. Combination with high ferritin levels (2809 µg/l), hypertriglyceridaemia (481 mg/dl), elevated soluble IL-2 receptor (sCD25, 9120 U/ml), and reduced perforin expression allowed diagnosis of HLH, caused by an acute CMV infection. Since connatal CMV infection had been ruled out earlier, we report the rare case of secondary HLH triggered by a postnatally acquired symptomatic CMV infection in an immunocompetent infant, most likely transmitted via breast milk. The infant was successfully treated with ganciclovir without need for immunosuppressive therapy.

Heterogeneity in coverage for measles and varicella vaccination in toddlers - analysis of factors influencing parental acceptance.

BACKGROUND: In 2004, routine varicella vaccination was introduced in Germany for children aged 11-14 months. Routine measles vaccination had already been introduced in 1973 for the same age group, but coverage is still too low (<95%) in some areas to eliminate measles. The present study assessed varicella and measles vaccination coverage and determinants of parental acceptance in two study regions, situated in Northern and Southern Bavaria (Germany). METHODS: From 2009 to 2011, annual cross-sectional parent surveys were performed on random samples of 600 children aged 18-36 months in the Bavarian regions of both Munich and Würzburg. Logistic regression models were used to identify factors associated with varicella and measles vaccination. RESULTS: In 2009, 2010 and 2011, vaccination coverage was lower in Munich than in Würzburg, for both varicella (Munich 53%, 67%, 69% vs. Würzburg 72%, 81%, 83%) and for measles (Munich 88%, 89%, 91% vs. Würzburg 92%, 93%, 95%). Recommendation by the physician was the main independent factor associated with varicella vaccination in both regions (adjusted odd ratios (OR) with 95% confidence interval (CI): Munich OR 19.7, CI 13.6-28.6; Würzburg OR 34.7, CI 22.6-53.2). Attendance at a childcare unit was positively associated with a higher acceptance of varicella vaccination in Munich (OR 1.5, CI 1.1-2.2). Regarding measles vaccination, attendance at a childcare unit was positively associated in both regions (Munich OR 2.0; CI 1.3-3.0; Würzburg OR 1.8; CI 1.1-3.1), and a higher level of parental school education was negatively associated in Würzburg (OR 0.5, CI 0.3-0.9). CONCLUSIONS: Vaccination rates differed between regions, with rates constantly higher in Würzburg. Within each region, vaccination rates were lower for varicella than for measles. Measles vaccination status was mainly dependent upon socio-demographic factors (attendance at a childcare unit, parental school education), whereas for the more recently introduced varicella vaccination recommendation by the physician had the strongest impact. Hence, different strategies are needed to further improve vaccination rates for both diseases.

Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects.

Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use 2 distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized C albicans was found to be dependent on complement receptor 3 (CR3) and the signaling proteins phosphatidylinositol-3-kinase and caspase recruitment domain-containing protein 9 (CARD9), but was independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The second mechanism for the killing of opsonized C albicans was strictly dependent on Fcγ receptors, protein kinase C (PKC), and reactive oxygen species production by the NADPH oxidase system. Each of the 2 pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensable for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency, or chronic granulomatous disease.

Varicella in pediatric oncology patients in the post-vaccine era-Analysis of routine hospital data from Bavaria (Germany), 2005-2011.

Varicella in oncology patients can result in serious complications. We analyzed trends in hospitalization rates and characteristics of pediatric oncology and non-oncology patients hospitalized with varicella during the first 7 years after introduction of routine varicella vaccination. Our data included children <17 years of age with an International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) main or secondary discharge diagnosis of varicella identified by annual database queries in 22-29 pediatric hospitals in Bavaria (Germany) in 2005-2011. Of a total of 1,245 varicella-associated hospitalizations, 42 children (median age 4 years, interquartile range 3-5) had an underlying malignancy (67% with acute lymphoblastic leukemia). Overall, additional diagnoses potentially associated with varicella were reported less often in oncology than in non-oncology varicella patients (62% vs. 77%, p = 0.041), suggesting earlier hospitalization of high-risk patients. Acute hematological diagnoses (29% vs. 3%, p < 0.001) and coinfections (invasive 12% vs. 2%, p = 0.001; noninvasive 19% vs. 8%, p = 0.019) were more frequent, whereas neurological (5% vs. 19%, p = 0.023) and upper respiratory tract diagnoses (2% vs. 16%, p = 0.014) were less frequent in oncology compared to non-oncology varicella patients. Oncology varicella patients showed a longer hospital stay (median 5 vs. 3 days, p < 0.001). Hospitalization rates in non-oncology varicella patients declined constantly since 2006, from 114.8 (2006) to 30.5 (2011) per 1,000 pediatric beds. The rates of varicella-associated hospitalizations in oncology patients indicated an overall decreasing trend (3.8, 1.9, 4.6, 3.5, 0.4, 2.1 and 0.6 cases per 1,000 pediatric beds in 2005-2011). Thus, pediatric oncology patients potentially profit from herd protection effects, resulting from increasing vaccine coverage in the general population.

Continued high incidence of children with severe influenza A(H1N1)pdm09 admitted to paediatric intensive care units in Germany during the first three post-pandemic influenza seasons, 2010/11-2012/13.

BACKGROUND: Previous influenza surveillance at paediatric intensive care units (PICUs) in Germany indicated increased incidence of PICU admissions for the pandemic influenza subtype A(H1N1)pdm09. We investigated incidence and clinical characteristics of influenza in children admitted to PICUs during the first three post-pandemic influenza seasons, using active screening. METHODS: We conducted a prospective surveillance study in 24 PICUs in Bavaria (Germany) from October 2010 to September 2013. Influenza cases among children between 1 month and 16 years of age admitted to these PICUs with acute respiratory infection were confirmed by PCR analysis of respiratory secretions. RESULTS: A total of 24/7/20 influenza-associated PICU admissions were recorded in the post-pandemic seasons 1/2/3; incidence estimates per 100,000 children were 1.72/0.76/1.80, respectively. Of all 51 patients, 80% had influenza A, including 65% with A(H1N1)pdm09. Influenza A(H1N1)pdm09 was almost absent in season 2 (incidence 0.11), but dominated PICU admissions in seasons 1 (incidence 1.35) and 3 (incidence 1.17). Clinical data was available for 47 influenza patients; median age was 4.8 years (IQR 1.6-11.0). The most frequent diagnoses were influenza-associated pneumonia (62%), bronchitis/bronchiolitis (32%), secondary bacterial pneumonia (26 %), and ARDS (21%). Thirty-six patients (77 %) had underlying medical conditions. Median duration of PICU stay was 3 days (IQR 1-11). Forty-seven per cent of patients received mechanical ventilation, and one patient (2%) extracorporeal membrane oxygenation; 19% were treated with oseltamivir. Five children (11%) had pulmonary sequelae. Five children (11%) died; all had underlying chronic conditions and were infected with A(H1N1)pdm09. In season 3, patients with A(H1N1)pdm09 were younger than in season 1 (p = 0.020), were diagnosed more often with bronchitis/bronchiolitis (p = 0.004), and were admitted to a PICU later after the onset of influenza symptoms (p = 0.041). CONCLUSIONS: Active screening showed a continued high incidence of A(H1N1)pdm09-associated PICU admissions in the post-pandemic seasons 1 and 3, and indicated possible underestimation of incidence in previous German studies. The age shift of severe A(H1N1)pdm09 towards younger children may be explained by increasing immunity in the older paediatric population. The high proportion of patients with underlying chronic conditions indicates the importance of consistent implementation of the current influenza vaccination recommendations for risk groups in Germany.

The epidemiological impact of childhood influenza vaccination using live-attenuated influenza vaccine (LAIV) in Germany: predictions of a simulation study.

BACKGROUND: Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. METHODS: A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. RESULTS: In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. CONCLUSIONS: Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.

Empiric Antibiotic Therapy in 1402 Children With Parapneumonic Effusion/Pleural Empyema in Germany: A Long-term Surveillance Study.

OBJECTIVE: This study investigated empiric antibiotic treatment (EAT), guideline adherence, antibiotic streamlining and clinical outcomes in 1402 hospitalized children with pediatric parapneumonic effusion/pleural empyema (PPE/PE). METHODS: A nationwide surveillance study collected data on EAT, clinical course/outcome, pathogens, susceptibility testing and antibiotic streamlining of children with PPE/PE in Germany between 2010 and 2018. Subgroups were compared using χ2 test/Fisher exact test, Mann-Whitney U test and linear regression analysis adjusting for patient age where appropriate. RESULTS: Complete data on EAT were available for 1402 children. In children with monotherapy (n = 567) and in children with combination therapy of 2 antibiotics (n = 589), the most commonly used antibiotics were aminopenicillin/beta-lactamase inhibitor [138/567 (24.3%) and 102/589 (17.3%)] and cefuroxime [291/567 (51.3%) and 294/589 (49.9%)]. The most common combinations with these beta-lactams were macrolides, aminoglycosides and clindamycin. We observed no difference in clinical severity/outcome between EAT with aminopenicillin/beta-lactamase inhibitor and cefuroxime, neither when used in monotherapy nor when used in combination therapy of 2 antibiotics. Species diagnosis of Streptococcus pneumoniae (n = 192), Streptococcus pyogenes (n = 111) or Staphylococcus aureus (n = 38) in polymerase chain reaction or culture from pleural fluid or blood resulted in a switch to an appropriate narrow-spectrum beta-lactam therapy in 9.4%, 18.9 % and 5.2% of children. In a subset of children with reported bacterial susceptibility testing, penicillin resistance was reported in 3/63 (4.8%) of S. pneumoniae and methicillin resistance in S. aureus was reported in 10/32 (31.3%) of children. CONCLUSION: This study points to antibiotic overtreatment in children with PPE/PE, particularly the frequent use of combinations of antibiotics. Children receiving combinations of antibiotics did not show differences in clinical outcomes. The low rate of children with streamlined antibiotic therapy even upon pathogen detection indicates a necessity for antibiotic stewardship measures in PPE/PE and the need of investigating other potential therapeutic strategies as anti-inflammatory therapy.

Varicella routine vaccination and the effects on varicella epidemiology - results from the Bavarian Varicella Surveillance Project (BaVariPro), 2006-2011.

BACKGROUND: In 2004, routine varicella vaccination was recommended in Germany for children 11-14 months of age with one dose, and since 2009, with a second dose at 15-23 months of age. The effects on varicella epidemiology were investigated. METHODS: Data on varicella vaccinations, cases and complications were collected from annual parent surveys (2006-2011), monthly paediatric practice surveillance (Oct 2006 - Sep 2011; five varicella seasons) and paediatric hospital databases (2005-2009) in the area of Munich (about 238,000 paediatric inhabitants); annual incidences of cases and hospitalisations were estimated. RESULTS: Varicella vaccination coverage (1st dose) in children 18-36 months of age increased in two steps (38%, 51%, 53%, 53%, 66% and 68%); second-dose coverage reached 59% in the 2011 survey. A monthly mean of 82 (62%) practices participated; they applied a total of 50,059 first-dose and 40,541 second-dose varicella vaccinations, with preferential use of combined MMR-varicella vaccine after recommendation of two doses, and reported a total of 16,054 varicella cases <17 years of age. The mean number of cases decreased by 67% in two steps, from 6.6 (95%CI 6.1-7.0) per 1,000 patient contacts in season 2006/07 to 4.2 (95%CI 3.9-4.6) in 2007/08 and 4.0 (95%CI 3.6-4.3) in 2008/09, and further to 2.3 (95%CI 2.0-2.6) in 2009/10 and 2.2 (95%CI 1.9-2.5) in 2010/11. The decrease occurred in all paediatric age groups, indicating herd protection effects. Incidence of varicella was estimated as 78/1,000 children <17 years of age in 2006/07, and 19/1,000 in 2010/11. Vaccinated cases increased from 0.3 (95%0.2-0.3) per 1,000 patient contacts in 2006/07 to 0.4 (95%CI 0.3-0.5) until 2008/09 and decreased to 0.2 (95%CI 0.2-0.3) until 2010/11. The practices treated a total of 134 complicated cases, mainly with skin complications. The paediatric hospitals recorded a total of 178 varicella patients, including 40 (22.5%) with neurological complications and one (0.6%) fatality due to varicella pneumonia. Incidence of hospitalisations decreased from 7.6 per 100,000 children <17 years of age in 2005 to 4.3 in 2009, and from 21.0 to 4.7 in children <5 years of age. CONCLUSIONS: Overall, the results show increasing acceptance and a strong impact of the varicella vaccination program, even with still suboptimal vaccination coverage.