Epidemiology and economic burden of meningococcal disease in Germany: A systematic review.

INTRODUCTION: Invasive meningococcal disease (IMD) is a notifiable disease in Germany and other European countries. Due to the high lethality of the disease and the risk of long-term consequences, IMD prevention is of high public health relevance despite the low number of cases in the population. This study aims to describe key epidemiological and economic parameters of IMD in Germany to support national decision-making processes for implementing enhanced prevention measures. METHODS: Based on a systematic literature review in PubMed and EMBASE, all publications on the burden of disease and costs of IMD published up to May 2020 were evaluated. Additionally, notification data were used to report the annual case numbers and incidence of IMD in Germany until the end of 2019. RESULTS: Thirty-six studies were included, of which 35 reported data on the epidemiological burden of disease and three reported data on economic aspects of IMD. The type of reported endpoints and results on the incidence of IMD differed widely by reporting year, population, and data source used. Most of the data are reported without specific information about a serogroup. Data on the economic burden of disease and healthcare resource use are scarce. Based on mandatory notification data, a decrease in the incidence of notified IMD cases has been observed since 2004. Currently, the nationwide annual incidence in Germany is at 0.3 cases per 100,000 persons and has gradually decreased. While the overall decline is mainly attributable to MenB, cases with MenY and MenW are the only ones that have increased on a low level in recent years. CONCLUSION: While IMD is a rare disease, high direct and indirect costs illustrate the relevance of the disease for patients, caregivers, as well as for the health care system. Future research should concentrate on quantifying the long-term economic burden and indirect costs of meningococcal disease. Integrated IMD surveillance with isolate characterisation remains crucial to inform public health policies.

[Coronavirus disease 2019 in childhood and adolescence]. / "Coronavirus disease 2019 (COVID­19)" im Kindes- und Jugendalter: Klinik, Epidemiologie und Impfprogramme.

The coronavirus disease 2019 (COVID­19) mostly occurs in children and adolescents as an asymptomatic infection. The course of the disease is usually mild or moderate. The estimated seroprevalence in Germany before the start of the vaccination program in children and adolescents was > 10%. Individual risk factors for a severe course are known. The COVID­19-associated pediatric inflammatory multisystem syndrome (PIMS) is a very rare and severe disease with a favorable prognosis if diagnosed early and treated appropriately. The data situation on long-COVID syndrome in children and adolescents is still insufficiently defined and the incidence is not known. The primary source of infections in children and adolescents are household contacts. Transmission in school settings and other day care facilities play a subordinate role, at least in Germany.Two mRNA vaccines are currently approved in Europe for the prevention of COVID­19 in children and adolescents above the age of 12 years. Except for the very rare occurrence of pericarditis/myocarditis in temporal association with the vaccination, especially in young men, the COVID­19 vaccines are considered effective and safe in the age group 12-17 years. The Standing Vaccination Commission (STIKO) issued a vaccination recommendation for all 12-17-year-olds on 19 August 2021.

High antibiotic prescription rates in hospitalized children with human metapneumovirus infection in comparison to RSV infection emphasize the value of point-of-care diagnostics.

BACKGROUND: Respiratory infections are the main causes for hospitalization in children and a common reason for the initiation of antibiotic treatment. Rapid antigen detection tests and point-of-care mPCR-based assays provide a fast detection of viral pathogens. Nonetheless, the prescription rate of antibiotics for respiratory infections is exceedingly high. In particular, human metapneumovirus (hMPV) infections frequently cause antibiotic treatment. METHODS: Children hospitalized in our clinic with an acute respiratory infection between January 2008 and January 2013 were included in the present study. Data of 3799 children were analyzed retrospectively for clinical symptoms, laboratory findings, and antibiotic and inhalation treatment. We performed an in-house m-RT-PCR-ELISA method for pathogen detection. RESULTS: Pathogen detection was possible in 2464 patients. In 6.3%, hMPV and, in 24.0%, RSV were detected. Patients positively tested for hMPV received inhalation therapy in 62.9%; patients positive for RSV in 73.8%. Patients positive for hMPV were treated with antibiotics in 62.3%. Patients with RSV infection received antibiotic treatment in 44.4%; all others in 43.5%. Notably, a positive result in RSV-RADT was associated with reduced number of antibiotic treatment. CONCLUSION: hMPV infections inherit a two times higher probability of antibiotic treatment. There was no significant difference in laboratory findings or body temperature between hMPV infection and infections caused by other pathogens. Clinical symptoms seem not to differ from those in RSV illness. Nonetheless, RSV infections triggered significantly lower antibiotic prescription rates. A considerate application of a POC-mPCR for patients with RSV-like symptoms and age of 1 year and older with a negative RSV-RADT might lead to higher detection rates of hMPV and a reduction in prescription of antibiotics.

[Retinal bleeding and venous stasis in a 10-month-old infant after a fall?]. / Retinale Blutungen und venöse Stase bei einem 10 Monate alten Säugling nach Sturz?

This report describes the case of a 10-month-old infant, who was delivered to our hospital by the emergency physician intubated and in an unclear unconscious state. The father reported that the child had fallen from the couch to the ground. The consulted ophthalmologist reported venous stasis in both eyes including intraretinal and preretinal bleeding in all four quadrants, a diffuse vitreous hemorrhage in the right eye and temporal retinal wrinkling in both eyes. Based on these particular clinical findings a shaken baby syndrome was suspected. This report demonstrates the importance of recognizing and correctly interpreting the typical ophthalmological signs of physical child abuse in order to detect and prevent further mistreatment of children; moreover, the increasing importance of photographic documentation and histological work-up of the findings for forensic reasons are emphasized.

[Endogenous Candida lens abscess in a premature infant]. / Endogener Candida-Linsenabszess bei Frühgeborenem.

BACKGROUND: This case report describes an extremely rare Candida lens abscess in a premature infant (gestational age 24 weeks at birth). CASE REPORT: After birth the infant suffered from Candida sepsis which was successfully treated with an antifungal medication. The patient was referred at the age of 6 months because of greyish alterations in the pupils but an absence of other symptoms. The examination with the patient under general anesthesia revealed a grey pupillary membrane and behind it a whitish swollen lens. A lensectomy was performed. The vitreous body was inconspicuous. Candida albicans was identified microbiologically. CONCLUSIONS: In preterm infants dissemination of pathogens into the lens through the vascular coat of the lens is possible, which after regression of the coat is no longer accessible to systemic treatment and may thus be manifested as delayed abscess formation.

[The polyglandular autoimmune syndrome--quality of life and family clustering]. / Das polyglanduläre Autoimmunsyndrom--Lebensqualität und familiäre Beteiligung.

BACKGROUND AND AIM: For patients with polyglandular autoimmune syndrome (PGA), data pertaining to familial clustering and quality of life are missing. Therefore, we performed a prospective and controlled study to collect this information. PATIENTS AND METHODS: Clinical and serological evaluation of 75 consecutively recruited patients with PGA (mean age 47,5 ± 15,3 years; 65,3% women) and their 108 relatives (mean age 33,13 ± 20,08 years; 65,7% women) was performed. Three validated questionnaires for psychosocial evaluation (quality of life short form 36 [SF-36], hospital anxiety and depression scale [HADS] and the Gießener Beschwerdebogen [GBB]) were answered by patients and relatives. RESULTS: 47 (62%) patients with PGA had type 1 diabetes and autoimmune thyroid disease. 56 (52%) of their relatives had an autoimmune disease whereas Hashimoto's thyroiditis and type-A-gastritis were the most prevalent endocrine and non-endocrine components. Thyroid peroxidase autoantibodies were most prevalent in patients and involved relatives. Compared to a German reference group, all scales of the SF-36 were markedly decreased in patients and involved relatives (p < 0.001). Anxiety and depression scales were pathologically increased in patients and relatives (p < 0.001). Also, all GBB scales were elevated for patients and relatives (p < 0.001). Patients with both glandular and non-glandular autoimmune diseases showed the most pathological psychosocial results. CONCLUSION: Familial clustering is high in patients with PGA. Quality of life and psychosocial status are poor in patients and involved relatives. Multidisciplinary management of the multiplex families in specialized centers is warranted.

The 2009 pandemic influenza A(H1N1) coincides with changes in the epidemiology of other viral pathogens causing acute respiratory tract infections in children.

BACKGROUND: In Germany, the outbreak of the novel pandemic 2009 influenza A(H1N1) virus A(H1N1)pdm09 caused a wave of high activity between November 2009 and January 2011. The aim of this study was to investigate the prevalence of 19 respiratory pathogens in children hospitalized for lower respiratory tract infections during the winter influenza seasons of 2009/2010 and 2010/2011 and to observe a possible impact of influenza A(H1N1)pdm09 on the epidemiology of other epidemic viruses. MATERIALS AND METHODS: Specimens were nasopharyngeal aspirates which had been collected from children admitted to the participating hospitals in the area of Mainz, Wiesbaden, and Kiel, Germany, with acute community-acquired lower respiratory tract infections. The specimens were subjected to a previously described multiplex reverse transcription PCR assay to detect the following microorganisms: enterovirus, influenza virus types A and B, respiratory syncytial virus (RSV), parainfluenzavirus types 1-4, adenovirus, Mycoplasma pneumoniae, Chlamydophila pneumoniae, rhinovirus, human metapneumovirus (hMPV), coronavirus OC43 and 229E, influenza A(H1N1)pdm09, Bordetella pertussis, Bordetella parapertussis, and Legionella pneumophila. RESULTS: A total of 3,998 clinical specimens were collected from July 2009 to March 2011, of which 296 were positive for A(H1N1)pdm09. An epidemic of seasonal influenza A or B was not observed in the 2009/2010 season, but a minor epidemic of seasonal influenza B was observed in January/February 2011. Influenza A(H1N1)pdm09 coincided with the absence of the seasonal influenza A of former years. The RSV and hMPV epidemics of 2009/2010 erupted several weeks later than expected based on data collected in the PID-ARI-Network during the past 10 years, whereas in the 2010/2011 influenza season they occurred as expected. CONCLUSIONS: The emergence of the novel influenza A(H1N1)pdm09 virus may have been influenced the epidemiology of other epidemic viruses, such as the RSV and hMPV. No epidemic of seasonal influenza was observed in the 2009/2010 influenza season.

[Tonsillectomy and tonsillotomy: ENT surgeon and pediatric viewpoints]. / Tonsillektomie und Tonsillotomie: HNO-ärztliche und pädiatrische Sicht.

Tonsillotomy and tonsillectomy are most frequently performed interventions during childhood. There is a need for a critical assessment of indication by using selected criteria. The collaboration of pediatricians and ENT surgeons is essential. Tonsillotomy in children < 6 years of age is associated with lower rates of postoperative bleeding.

Validation of a multiplex reverse transcriptase PCR ELISA for the detection of 19 respiratory tract pathogens.

INTRODUCTION: Since acute respiratory tract infections inflict a high burden of disease in children worldwide, a multiplex reverse transcription polymerase chain reaction combined with a microwell hybridization assay (m-RT-PCR-ELISA) to detect 19 different respiratory pathogens was developed and validated. METHODS: A total of 430 respiratory specimens were retrospectively tested in parallel by both the advanced 19-valent m-RT-PCR-ELISA as well as by culture or individual RT-PCR assays used in clinical routine. RESULTS: The mean (median) sensitivity of the m-RT-PCR-ELISA in the retrospective test was 93.3% (95.1%; range 83.3-100 %), and the mean (median) specificity was 99.8 and 100 % (range 98.6-100 %), respectively. The mean positive predictive value was 99.3 % (range 93.4-100 %) and the mean negative predictive value was 95.3 % (range 98.4-100 %). Feasibility and clinical value of the 19-valent method was prospectively shown on 16,231 incoming clinical specimens from patients between 0 and 16 years of age with acute respiratory tract infections admitted to pediatric hospitals or private practices from October 2003 to June 2010 in three regions in Germany (Kiel, Mainz, Freiburg; Freiburg to June 2007 only). At least one microorganism was detected in 10,765 of 16,231 (66.3 %) clinical specimens: 5,044 RV, 1,999 RSV, 1,286 AV, 944 EV, 737 seasonal IVA, 173 pandemic IVA H1N1-2009, 899 MPV, 518 CV, 383 PIV3, 268 PIV1, 259 Mpn, 205 IVB, 164 PIV2, 144 PIV4, 103 Bp, 29 Cpn and 29 Bpp, while reovirus and Lpn were not present in these specimens from a pediatric population. More than one organism could be detected in 13.4 % of the specimens. CONCLUSIONS: The m-RT-PCR-ELISA evaluated here improves the spectrum for diagnosing respiratory infections and is a feasible instrument for individual diagnostic and epidemiological studies.

[A rare manifestation of sarcoidosis]. / Seltene Manifestation einer Sarkoidose.

This article reports the case of a 14-year-old boy who was presented in the case conference with symptoms of decreased visual acuity, scintillating scotomas and photophobia. Physical examination revealed right facial paralysis, parotid gland swelling, high fever and poor general condition. Ophthalmoscopy revealed anterior and posterior uveitis including macular edema and chorioretinal infiltrates. Angiography revealed a dense pattern of hyperfluorescent lesions and these observations resulted in the diagnosis of Heerfordt syndrome. Under systemic prednisolone therapy, symptoms were reduced and visual acuity recovered.

Prediction of pneumococcal conjugate vaccine effectiveness against invasive pneumococcal disease using opsonophagocytic activity and antibody concentrations determined by enzyme-linked immunosorbent assay with 22F adsorption.

We compared the abilities of two serological readouts, antipolysaccharide IgG antibody concentrations and opsonophagocytic activity (OPA) titers, to predict the clinical effectiveness of the 7-valent pneumococcal conjugate vaccine (7vCRM) against invasive pneumococcal disease (IPD). We also assessed the accuracy of the previously established thresholds for GlaxoSmithKline's enzyme-linked immunosorbent assay with 22F adsorption (22F-ELISA) (≥0.2 µg/ml) and OPA assay (titer, ≥8) in predicting effectiveness. We showed that following a 3-dose 7vCRM primary vaccination, the serological response rates as determined using thresholds of ≥0.2 µg/ml IgG and an OPA titer of ≥8 corresponded well with overall effectiveness against IPD. In addition, the OPA assay seemed to better predict serotype-specific effectiveness than enzyme-linked immunoassay. Finally, when applied to post-dose-2 immune responses, both thresholds also corresponded well with the overall IPD effectiveness following a 2-dose 7vCRM primary vaccination. These results support the importance of the OPA assay in evaluating immune responses to pneumococcal conjugate vaccines.

A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children.

Meningococcal disease incidence is highest in young children, yet a tetravalent conjugate vaccine is currently not available for this age group. This study evaluated a single dose of four different ACWY-TT conjugate vaccine formulations in 240 toddlers (12-14 months) and 268 children (3-5 years) compared to licensed age-appropriate control vaccines. In toddlers, rSBA-MenC GMTs for the selected formulation were statistically higher than after monovalent-MenC-conjugate vaccine. In children, rSBA-GMTs against each serogroup were statistically higher than after tetravalent polysaccharide vaccine. The safety profile was comparable to licensed controls. The new ACWY-TT conjugate vaccine promises high seroprotection levels against meningococcal disease from 1 year of age.

[Preparation of a compatibility chart for intravenous drug therapy in neonatal and pediatric intensive care units]. / Erstellung einer Kompatibilitätstabelle für die intravenöse Pharmakotherapie auf neonatologischen und pädiatrischen Intensivstationen.

BACKGROUND: Modern neonatal and pediatric intensive care includes a sophisticated pharmacotherapy with numerous drugs, mainly administered intravenously. Often, despite the use of multi-lumen central venous lines, more peripheral venous accesses are required. To reduce the necessity of numerous venous lines on one hand and on the other hand to avoid complications from incompatibilities of the administered drugs, we compiled a compatibility chart, encompassing more substances than covered in previously available charts. METHODS: Information on compatibility of commonly prescribed drugs was collected by analysis of manufacturers' information, medical and pharmaceutical handbooks, and a literature research. RESULTS: Available data on compatibility of 78 drugs were displayed in a two-dimensional chart. Beside the pH of each drug, compatibility of drug combinations was encoded for simultaneous infusion. Special emphasis was on security of the therapy. CONCLUSION: The compatibility chart gives quick reference for Data on compatibility of intravenously administered drugs in neonatal and pediatric intensive care.

Identification of a novel compound heterozygote SCO2 mutation in cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy.

UNLABELLED: Fatal infantile cardioencephalomyopathy (OMIM No. 604377) is a disorder of the mitochondrial respiratory chain and is characterised by neonatal progressive muscular hypotonia and cardiomyopathy because of severe Cytochrome c oxidase deficiency. Here we report a novel mutation in the Cytochrome c oxidase assembly gene SCO2 in an infant with fatal infantile cardioencephalomyopathy despite normal initial metabolic screening. CONCLUSION: In newborns with unexplained muscular hypotonia and cardiomyopathy genetic testing of mitochondrial respiratory chain disorders might be helpful to establish a final diagnosis and guide treatment decisions.

[Impact of universal varicella vaccination in Germany: an epidemiological and economic analysis]. / Effektivität einer universellen Varizellen-Schutzimpfung in Deutschland: Eine epidemiologische und gesundheitsökonomische Analyse.

Varicella is a highly contagious viral disease which mainly affects young children and usually is perceived as infection with a mild disease course. However, there is increasing evidence indicating that the morbidity and mortality as well as the economic impact associated with varicella are significant. While universal childhood vaccination against varicella is currently not recommended in Germany, the availability of safe and efficacious vaccines offers the opportunity for preventive intervention. Detailed and reliable data on the consequences of varicella and the possible impact of a universal vaccination program are missing to date for Germany. In order to generate this information, we conducted a comprehensive evaluation. The objective was to quantify the medical consequences and the economic impact of varicella on third-party payers and the society by means of a model analysis, and particularly to assess the effects of various universal vaccination strategies. The study confirms that varicella represents a significant health and economic burden in Germany. Following mathematical modelling, universal varicella vaccination for children at the age of 12-18 months could prevent more than 82 % of cases and complications on average per year. Economically, universal vaccination would lead to net cost savings not only for the society but also for the third-party payers. From these findings it can be concluded that universal varicella vaccination is a strategy which should be encouraged, from a medical, epidemiological, but also economic viewpoint.

Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life.

BACKGROUND: The incidence of local reactions to diphtheria-, tetanus and acellular pertussis (DTaP-) vaccines in infants and toddlers increases with each subsequent dose, and entire thigh swellings (ETS) have been reported. Lowering the amount of antigen or of adjuvant may decrease the reactogenicity of DTaP while maintaining a protective immune response. OBJECTIVES: Following priming with three doses of a DTaP vaccine during infancy, the safety, reactogenicity and immunogenicity of nine different candidate DTaP-vaccines with reduced amounts of antigen and/or adjuvant given as fourth (booster) dose were evaluated. METHODS: Study participants were healthy infants aged 15-27 months at the time of booster vaccination. Each participant had received three doses of a DTaP vaccine (Infanrixtrade mark, GlaxoSmithKline, Rixensart, Belgium; "reference DTaP") at age 3, 4, and 5 months as part of a previous clinical trial. More than 20,000 children were eligible for participation in the current study protocol at the time. In a first phase at a University hospital-based vaccination study center, nine sequential cohorts of 63-119 study subjects received one of nine different candidate vaccines. Patients and study personal were blinded with regard to which vaccine was currently in use. Reactogenicity was solicited from parents using diary cards. Blood was drawn prior to and 4 weeks after vaccination and immediately centrifuged. The serum was stored at -20 degrees C until serology was performed by ELISA tests. As soon as the first candidate vaccine with adequate reactogenicity and immunogenicity profile was identified in the first study phase, a second study phase was initiated in parallel, to evaluate the safety and reactogenicity of the respective candidate vaccine in private practices in large cohorts (1613-2095 study subjects per group). RESULTS: In the first study phase, DTaP with no aluminum induced the highest frequency of ETS and fever. All other candidate vaccines caused lower rates of local and general reactions than the reference DTaP. As a general rule, vaccines with less antigen induced fewer reactions, although there was no strict dose-response effect and the difference, e.g. between a one-tenth and a one-fifth DTaP dose (DTaP 1/5; DTaP 1/10) was not clinically relevant. Separate injections of Td and aP caused fewer general reactions than the respective TdaP combination and local reactions were higher at the aP than at the Td injection site. Again, as a general rule, reduced amounts of antigen induced lower antibody concentrations, although all vaccines induced "protective" anti-tetanus and anti-diphtheria antibody responses. A total of 92-100% of children showed seroresponses to pertussis antigens even when vaccinated with reduced amounts of the respective pertussis antigen. Elimination of aluminum from DTaP vaccine induced higher anti-tetanus-antibody concentrations and so did a reduction of the amount of diphtheria antigen. Additional examples for antigen interaction were increased antibody concentrations, observed with injection of Td and aP into different limbs. In the second study phase, all three vaccines evaluated (one with a reduced amount of diphtheria antigen, TdaP; one with reduced amounts of all antigens, tdap; and one with a fifth dose of the reference vaccine (DTaP 1/5)) were safe and had an acceptable reactogenicity profile in a total of 4871 study subjects. CONCLUSIONS: Local reactions due to DTaP booster doses in the second year of life can be reduced by reducing the amount of antigen in the respective vaccine while an adequate immunogenicity is maintained. Aluminum-free vaccines induced ETS and fever most commonly. Any changes in vaccine composition should lead to a full evaluation of the new product.

Immunogenicity, reactogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a DTPa-HBV-IPV/Hib combination vaccine in healthy infants.

BACKGROUND: To evaluate immunogenicity, reactogenicity, and safety of a hexavalent combination vaccine diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) when coadministered with a 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: Infants received either a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-H. influenzae type b vaccine concomitantly with PCV7 or DTPa-HBV-IPV/Hib alone infants were vaccinated at 2, 3 and 4 months (primary immunization) and 12-15 months of age (booster dose). Local and systemic reactions and adverse events were monitored following each dose and compared between groups. Blood was obtained prior to dose 1, one month after dose 3, immediately prior to and 1 month following the booster dose to measure antibody responses to each of the antigens. RESULTS: Two hundred and fifty-three subjects (PCV7, 127; Control, 126) were enrolled. Antibody responses were compared in 226 subjects for the primary immunization and 212 for the booster dose (per-protocol (PP) population). Although there were some differences in geometric mean concentrations (GMCs) to the DTPa-HBV-IPV/Hib antigens after the primary series, GMCs for all antigens after the booster dose were similar in both groups, except for diphtheria which was significantly higher in the PCV7 group (PCV7, 7.41 IU/mL; Control, 5.78 IU/mL). Reactogenicity and safety data were compared in 252 infants receiving primary immunization and 235 children receiving the booster dose. Site reactions were similar in both groups. Fever >or=38.0 degrees C following each vaccination was reported more frequently in the PCV7 group (28.3-50.0%) than in the Control group (15.6-33.6%) whereas fever >39.0 degrees C occurred only in a few cases and to the same extent in both groups (PCV7, 0.8-2.7%; Control, 1.6-4.1%). Only one reported serious adverse event was characterized as being related to the study vaccines: control subject was hospitalized with a fever. CONCLUSION: DTPa-HBV-IPV/Hib and PCV7 were highly immunogenic, well-tolerated and safe when coadministered at 2, 3 and 4 months of age with a booster dose at 12-15 months of age. These results support the coadministration of PVC7 with DTPa-HBV-IPV/Hib as part of the routine immunization schedule for infants and children.