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.

High burden of RSV and influenza in patients presenting with suspected pneumonia in the emergency room of a German tertiary hospital in fall of 2022.

PURPOSE: Bacterial pneumonia, a major cause of respiratory tract infections (RTI), can be challenging to diagnose and to treat adequately, especially when seasonal viral pathogens co-circulate. The aim of this study was to give a real-world snapshot of the burden of respiratory disease and treatment choices in the emergency department (ED) of a tertiary care hospital in Germany in the fall of 2022. METHODS: Anonymized analysis of a quality control initiative that prospectively documented all patients presenting to our ED with symptoms suggestive of RTI from Nov 7th to Dec 18th, 2022. RESULTS: 243 patients were followed at the time of their ED attendance. Clinical, laboratory and radiographic examination was performed in 92% of patients (224/243). Microbiological work-up to identify causative pathogens including blood cultures, sputum or urine-antigen tests were performed in 55% of patients (n = 134). Detection of viral pathogens increased during the study period from 7 to 31 cases per week, while bacterial pneumonias, respiratory tract infections without detection of a viral pathogen and non-infectious etiologies remained stable. A high burden of bacterial and viral co-infections became apparent (16%, 38/243), and co-administration of antibiotic and antiviral treatments was observed (14%, n = 35/243). 17% of patients (41/243) received antibiotic coverage without a diagnosis of a bacterial etiology. CONCLUSION: During the fall of 2022, the burden of RTI caused by detectable viral pathogens increased unusually early. Rapid and unexpected changes in pathogen distribution highlight the need for targeted diagnostics to improve the quality of RTI management in the ED.

Correction to: Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

An amendment to this paper has been published and can be accessed via the original article.

Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

In a study originally designed to find potential risk factors for bovine spongiform encephalopathy (BSE) we examined tissues from 403 Holstein Frisian cattle in total. These included 20 BSE cattle and their 236 birth- and feeding cohort animals plus 32 offspring, 103 age, breed and district-matched control cattle and further twelve cattle with neurological signs. In addition to the obex, we examined the celiac ganglion, cervical cranial ganglion, trigeminal ganglion and proximal ganglion of the vagus nerve using histological techniques. Unexpectedly, we found a high number of neurofibroma, a benign peripheral nerve sheath tumor consisting of Schwann cells, fibroblasts and perineural cells. The neurofibroma were present only in the celiac ganglion and found during histologic examination. With a frequency of 9.91% in BSE cattle and their cohorts (case animals) and 9.09% in the age, breed and district matched control animals there seems to be no correlation between the occurrence of BSE and neurofibroma. Benign peripheral nerve sheath tumors have been described more often in cattle than in other domestic animals. Usually, they are incidental macroscopic findings in the thoracic ganglia during meat inspection. To our knowledge, there are no previous systematic histologic studies including bovine celiac ganglia at all. The high incidence of celiac ganglia neurofibroma may play a role in the frequently occurring abomasal displacements in Holstein Frisian cattle as the tumors might cause a gastrointestinal motility disorder. At present a genetic predisposition for these neoplasms cannot be ruled out.

Impact of refugee influx on the epidemiology of late-presenting HIV-infected pregnant women and mother-to-child transmission: comparing a southern and northern medical centre in Germany.

PURPOSE: Due to early antenatal screening and treatment, HIV mother-to-child transmission (MTCT) rarely occurs in Germany. The study aimed to investigate the impact on prevalence of HIV infection in the antenatal population and the incidence of late-presenting HIV-infected mothers attributable to increased numbers of refugees. METHODS: Retrospective analysis and comparison were performed for all deliveries in HIV-infected pregnant women presenting to medical care in Munich (southern Germany) and Hamburg (northern Germany) covering two time periods, A (2010-2012) and B (2013-2015). RESULTS: In Munich, deliveries in HIV-infected pregnant women increased 1.6-fold from period A (n = 50) to B (n = 79) with late-presenting cases rising significantly from 2% (1/50) in period A to 13% (10/79) in B. In contrast, late-presenting cases in Hamburg decreased from 14% (14/100) in period A to 7% (7/107) in B, while the total number of HIV-infected women giving birth remained stable. From 2010 to 2015, one late-presenting pregnant woman transmitted HIV in Munich by presumed in utero mode of infection (case reviewed here), while no MTCT occurred in Hamburg. CONCLUSIONS: HIV infections diagnosed late in pregnancy and leading to delayed ART initiation are rising in Munich compared to Hamburg. Antenatal care of HIV-infected pregnant women in Munich appears to have been more affected by the recent refugee influx than Hamburg. Our study highlights the importance of screening all pregnant women for HIV early in pregnancy and providing timely health care access for pregnant refugees and asylum seekers to effectively prevent MTCT in Germany.

Universal screening for latent and active tuberculosis (TB) in asylum seeking children, Bochum and Hamburg, Germany, September 2015 to November 2016.

BackgroundIn Germany, the incidence of tuberculosis (TB) in children has been on the rise since 2009. High numbers of foreign-born asylum seekers have contributed considerably to the disease burden. Therefore, effective screening strategies for latent TB infection (LTBI) and active TB in asylum seeking children are needed. Aim: Our aim was to investigate the prevalence of LTBI and active TB in asylum seeking children up to 15 years of age in two geographic regions in Germany. Methods: Screening for TB was performed in children in asylum seeker reception centres by tuberculin skin test (TST) or interferon gamma release assay (IGRA). Children with positive results were evaluated for active TB. Additionally, country of origin, sex, travel time, TB symptoms, TB contact and Bacille Calmette-Guérin (BCG) vaccination status were registered. Results: Of 968 screened children 66 (6.8%) had TB infection (58 LTBI, 8 active TB). LTBI prevalence was similar in children from high (Afghanistan) and low (Syria) incidence countries (8.7% vs 6.4%). There were no differences regarding sex, age or travel time between infected and non-infected children. Children under the age of 6 years were at higher risk of progression to active TB (19% vs 2% respectively, p=0,07). Most children (7/8) with active TB were asymptomatic at the time of diagnosis. None of the children had been knowingly exposed to TB. Conclusions: Asylum seeking children from high and low incidence countries are both at risk of developing LTBI or active TB. Universal TB screening for all asylum seeking children should be considered.

Delayed Induction of Noninflammatory SARS-CoV-2 Spike-Specific IgG4 Antibodies Detected 1 Year After BNT162b2 Vaccination in Children.

Humoral immune responses after BNT162b2 vaccination are predominantly composed of immunoglobulin (Ig) G1 and IgG3 subclass antibodies. As previously described in adults, S1-specific and receptor-binding domain-specific IgG4 levels increase significantly 1 year after the second BNT162b2 vaccination in children 5-11 years of age. Understanding mRNA vaccine-specific IgG4 responses in all age groups is crucial as more mRNA vaccines will reach licensure in the coming years.

Reduced Humoral and Cellular Immune Response to Primary COVID-19 mRNA Vaccination in Kidney Transplanted Children Aged 5-11 Years.

The situation of limited data concerning the response to COVID-19 mRNA vaccinations in immunocom-promised children hinders evidence-based recommendations. This prospective observational study investigated humoral and T cell responses after primary BNT162b2 vaccination in secondary immunocompromised and healthy children aged 5-11 years. Participants were categorized as: children after kidney transplantation (KTx, n = 9), proteinuric glomerulonephritis (GN, n = 4) and healthy children (controls, n = 8). Expression of activation-induced markers and cytokine secretion were determined to quantify the T cell response from PBMCs stimulated with peptide pools covering the spike glycoprotein of SARS-CoV-2 Wuhan Hu-1 and Omicron BA.5. Antibodies against SARS-CoV-2 spike receptor-binding domain were quantified in serum. Seroconversion was detected in 56% of KTx patients and in 100% of the GN patients and controls. Titer levels were significantly higher in GN patients and controls than in KTx patients. In Ktx patients, the humoral response increased after a third immunization. No differences in the frequency of antigen-specific CD4+ and CD8+ T cells between all groups were observed. T cells showed a predominant anti-viral capacity in their secreted cytokines; however, this capacity was reduced in KTx patients. This study provides missing evidence concerning the humoral and T cell response in immunocompromised children after COVID-19 vaccination.

[HIV infection and exposure in children and adolescents]. / HIV-Infektion und -Exposition bei Kindern und Jugendlichen: 25 Jahre antiretrovirale Prophylaxe und Therapie: Was ist erreicht?

Background: Since 1997 an effective prevention and treatment of infections with human immunodeficiency virus (HIV) have been available in the form of antiretroviral combination therapy. Objective: What has been achieved during this time by transmission prophylaxis and treatment of HIV infections in children in Germany? Material and methods: Presentation of the development of transmission prophylaxis and the epidemiological surveys of the Robert Koch Institute, presentation of drug development and guidelines for antiretroviral therapy in children and adolescents and presentation of surveys of the German pediatric and adolescent HIV cohort (GEPIC). Results: The introduction of HIV testing of pregnant women has made regular antiretroviral treatment of HIV positive pregnant women and the introduction of transmission-reducing measures possible. This has reduced the risk of vertical transmission from about 30% to < 1%. Currently, it is being investigated whether children exposed to HIV can be breastfed without risk. Antiretroviral therapy in children has decisively improved the survival rates and the physical and cognitive development of HIV positive children. New active substances have a more favorable side effect profile. In Germany, the World Health Organization (WHO) target of achieving complete suppression of the viral load in 90% of the children has been achieved. A delayed diagnosis in children and adolescents is still associated with severe infections. An HIV infection remains a disease with a stigma and is therefore usually kept secret from the children and their environment. Conclusion: With the transmission prophylaxis and therapy that are now available, it is possible to prevent transmission to a large extent and with a timely diagnosis to enable HIV positive children to lead a largely healthy life. The goal of children being able to know and name their disease without fear has still not been achieved.

Cross-sectional seroprevalence surveys of SARS-CoV-2 antibodies in children in Germany, June 2020 to May 2021.

The rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections.

Similarities between forms of sheep scrapie and Creutzfeldt-Jakob disease are encoded by distinct prion types.

Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.

Fatal familial insomnia: Clinical features and early identification.

Our aim was to develop a detailed clinical description of fatal familial insomnia in a large patient group with respect to the M129V genotype. Data on 41 German fatal familial insomnia patients were analyzed. Clinical features, 14-3-3 proteins in the cerebrospinal fluid, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, polysomnography, and electroencephalography were studied. Age at disease onset, disease duration, and clinical syndrome varied depending on the codon 129 genotype. Because the sensitivity of the most diagnostic tests is low in fatal familial insomnia, detailed clinical investigation is extremely important. Polysomnography may help to support the diagnosis.

Reducing Hematologic Toxicity With Short Course Postexposure Prophylaxis With Zidovudine for HIV-1 Exposed Infants With Low Transmission Risk.

Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receiving 2-week (short course) versus longer duration zidovudine postexposure prophylaxis. Short course resulted in lower hematologic toxicity without evidence of increased vertical transmission risk.

Intravenous Artesunate for Imported Severe Malaria in Children Treated in Four Tertiary Care Centers in Germany: A Retrospective Study.

BACKGROUND: Intravenous artesunate (ivA) is the standard treatment for severe malaria. Data systematically evaluating the use of ivA in pediatric patients outside malaria-endemic regions are limited. The aim of this case series was to summarize efficacy and safety of ivA for imported severe malaria in children in Germany. METHODS: Our retrospective case series included pediatric patients with imported severe malaria treated with at least 1 dose of ivA (Artesun, Guilin Pharmaceutical; Shanghai, China) at 4 German tertiary care centers. Severe malaria was defined according to World Health Organization criteria. RESULTS: Between 2010 and 2018, 14 children with a median [interquartile range (IQR)] age of 6 (1;9.5) years were included. All children were of African descent. All but 2 patients had Plasmodium falciparum malaria; 1 child had P. vivax malaria and 1 child had P. falciparum and P. vivax co-infection. Median (IQR) parasitemia at admission in patients with P. falciparum was 9.5% (3;16.5). Patients were treated with 1-10 [median (IQR) 3 (3;4)] doses ivA. All but one patient received a full course of oral antimalarial treatment. Parasite clearance was achieved within 2-4 days, with the exception of 1 patient with prolonged clearance of peripheral parasitemia. Three patients experienced posttreatment hemolysis but none needed blood transfusion. Otherwise ivA was safe and well tolerated. CONCLUSIONS: ivA was highly efficacious in this pediatric cohort. We observed episodes of mild to moderate posttreatment hemolysis in approximately one-third of patients. The legal status and usage of potentially lifesaving ivA should be evaluated in Europe.

Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation.

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNÉ£ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/É£-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.