SARS-CoV-2 variants and the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 among children in Germany.

PURPOSE: To investigate the relationship between the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in children and the predominance of different SARS-CoV-2 variants of concern (VOC) over time. METHODS: In relation to the Alpha, Delta, and Omicron VOC phases of the pandemic, the risk of developing PIMS-TS was calculated by analyzing data for rtPCR-confirmed SARS-CoV-2 infections reported to the German statutory notification system, along with data captured by a separate, national PIMS-TS registry. Both overall infection rates and age group-specific ratios of PIMS-TS during the different pandemic phases were calculated using the Alpha period as the baseline. RESULTS: The PIMS-TS rate changed significantly over time. When the Alpha VOC was dominant [calendar week (CW) 11 in March-CW 31 in August 2021], the PIMS-TS rate was 6.19 [95% confidence intervals (95% CI) 5.17, 7.20]. When Delta prevailed (CW 32 in August 2021-CW 4 in January 2022), the rate decreased to 1.68 (95% CI 1.49, 1.87). During the Omicron phase (CW 5 in January-CW 16 in April 2022), the rate fell further to 0.89 (95% CI 0.79, 1.00). These changes correspond to a decreased PIMS-TS rate of 73% (rate ratio 0.271, 95% CI 0.222; 0.332) and 86% (rate ratio 0.048, 95% CI 0.037; 0.062), respectively, in comparison to the Alpha period. Rate ratios were nearly identical for all age groups. CONCLUSION: The data strongly suggest an association between the risk for PIMS-TS and the prevailing VOC, with highest risk related to Alpha and the lowest to Omicron. Given the uniformity of the decreased risk across age groups, vaccination against SARS-CoV-2 does not appear to have a significant impact on the risk of children developing PIMS-TS.

[German S1 Guideline Long-/Post-COVID]. / S1-Leitlinie Long-/Post-COVID.

The German Society of Pneumology initiated 2021 the AWMF S1 guideline Long COVID/Post-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendations describe current Long COVID/Post-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an explicit practical claim and will be developed and adapted by the author team based on the current increase in knowledge.

Breastfeeding and vitamin D supplementation reduce the risk of Kawasaki disease in a German population-based case-control study.

BACKGROUND: In Kawasaki disease (KD), a vasculitis of unknown etiology, the most serious complication is the development of coronary artery aneurysm (CAA). To date, the exact pathomechanism of KD is unknown. Both environmental and genetic factors seem to be associated with the development of the disease. METHODS: Data on KD patients recruited from the population-based German Pediatric Surveillance Study during 2012-2014 were used to evaluate the impact of various factors from the perinatal and infancy period on the development of KD. The study design was a matched case-control study with respect to age, sex and place of residence (n = 308 KD cases, n = 326 controls). All KD patients were individually re-evaluated; all fulfilled the international diagnostic KD criteria. A standardized questionnaire was used to review breastfeeding practices, vitamin D supplementation and birth characteristics. Logistic regression analyses were performed to obtain odds ratios (OR) for various risk factors among the case-control pairs. Simple measures of association were used to assess the impact of these factors on the clinical course. RESULTS: There was no difference in lengths of gestation, birth weight or parturition between KD patients and controls, but independently from each other vitamin D supplementation and breastfeeding were negatively associated with KD, even when adjusted for age, place of residence and sex. The duration of vitamin D was significantly shorter among children with KD than among children without KD (p = 0.039, OR = 0.964, 95% CI: 0.931-0.998), as was the duration of breastfeeding (p = 0.013, OR = 0.471, 95% CI: 0.260-0.853). Comparing KD patients with and without breastfeeding and/or vitamin D supplementation, there were no differences regarding developing CAA, being refractory to intravenous immunoglobulin treatment, age at onset of the disease and levels of inflammatory laboratory values. CONCLUSION: Our findings indicate breastfeeding and vitamin D supplementation to have protective effects in association with KD in our study population; however, these seem not to influence the natural course of the disease. Although the overall effects were relatively small, they nevertheless underline the overall benefit of both interventions. TRIAL REGISTRATION: Clinical Trial Registration: German clinical trial registration, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00010071 . Date of registration was 26. February 2016. The trial was registered retrospectively.

Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2×10

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ν_{e} candidates and seven anti-ν_{e} candidates are observed, while 67.5 and 9.0 are expected for δ_{CP}=0 and normal mass ordering. The obtained 2σ confidence interval for the CP-violating phase, δ_{CP}, does not include the CP-conserving cases (δ_{CP}=0, π). The best-fit values of other parameters are sin^{2}θ_{23}=0.526_{-0.036}^{+0.032} and Δm_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3} eV^{2}/c^{4}.

Prevalence and molecular diversity of invasive Streptococcus dysgalactiae and Streptococcus pyogenes in a German tertiary care medical centre.

Prevalence of invasive ß-haemolytic streptococci (BHS) at a tertiary care hospital and molecular diversity of S. pyogenes and S. dysgalactiae was studied. Between 2012 and 2016, all blood culture sets (n = 55,839), CSF (n = 8413) and soft tissue (n = 20,926) samples were analysed for BHS positivity using HYBASE software. Molecular profiles of 99 S. pyogenes and S. dysgalactiae were identified by sequencing of M protein genes (emm types) and multiplex PCR typing of 20 other virulence determinants. Streptococci contributed to 6.2% of blood, 10.7% of CSF and 14.5% of soft tissue isolates, being among the most common invasive isolates. The overall rates of invasive S. pyogenes, S. agalactiae, S. dysgalactiae and S. pneumoniae were 2.4, 4.4, 2.1, and 5.3%. Whereas S. pneumoniae was 1.5% more common in CSF samples, BHS isolates were 2-fold and 11-fold higher in bacteraemia and invasive soft tissue infections. Genetic BHS typing revealed wide molecular diversity of invasive and noninvasive group A and group G BHS, whereas one emm-type (stG62647.0) and no other virulence determinants except scpA were detected in invasive group C BHS. BHS were important invasive pathogens, outpacing S. pneumoniae in bacteraemia and invasive soft tissue infections. The incidence of S. dysgalactiae infections was comparable to that of S. pyogenes even with less diversity of molecular virulence. The results of this study emphasise the need for awareness of BHS invasiveness in humans and the need to develop BHS prevention strategies.

[DreKiP - an outpatient treatment program for children and adolescents with headache]. / DreKiP ­ ein ambulantes Therapieprogramm für Kinder und Jugendliche mit Kopfschmerzen.

Headaches are a frequent health problem among children and adolescents. The ocurrence of headaches and the resulting impairments in the quality of life and activities of daily living are modulated by biopsychosocial interactions, which necessitate a complex treatment program. The Dresden Childrens Headache Program (DreKiP) is a multidisciplinary therapy program consisting of eight modules for children and adolescents: education, stress relief, relaxation techniques, physical fitness, climbing therapy, art therapy and sensory training. In addition, there are six modules containing parallel workshops for parents. This outpatient program lasts 2-3 months and is performed parallel to the daily and school routine. Therapy groups consist of 6-8 patients in each age group. In total patients receive 15 h and the parents 7 h of therapy. Concomitant with the program, headache-associated data, such as headache frequency, medication use and school absence are documented. So far 32 children and adolescents in groups of 11, 14-15, 14-16, 17 and 17-18 years old completed the program. Of the 32 patients 19 presented with migraine and tension type headache, 6/32 with migraine and 7/32 with tension type headache only. The median number of headache days was 15 per month and 4 official school absence days per month. Preliminary results 6 months after the end of the therapy program showed reduced frequency of headaches in three quarters of our patients. The headache frequency was reduced from an initial median of 15 days per month to a median of 8 days per month after the program. The multidisciplinary program DreKiP improves the use of therapeutic means in children and adolescents with primary headaches. Children and adolescents with headache-related impairment in activities of daily life in school and leisure times constitute the target group of this therapy.

[Genetic methods for analysis of autoinflammatory diseases]. / Genetische Methoden für die Analyse autoinflammatorischer Erkrankungen.

Over the past years the phenotypic and genetic spectrum of autoinflammatory diseases has continuously increased. Moreover, several monogenic autoinflammatory disorders have now been identified where febrile episodes are not among the leading symptoms and which can be accompanied by autoimmune phenomena and susceptibility to infections. Autoinflammatory conditions that are characterized by uncontrolled activity of cytokines, such as interleukin-1 beta (IL1ß), tumor necrosis factor alpha (TNF-α) and type 1 interferons (1-IFN), are amenable to specific therapeutic interventions. Thus, identification of the underlying genetic cause is important. During diagnostic work-up, genetic testing of a patient with autoinflammation should be carried out depending on the clinical presentation. If a distinct disorder is suspected, sequencing of the causative gene should be performed. Genetic tests using next generation sequencing (NGS), such as panel sequencing, exome sequencing and array comparative genomic hybridization (CGH) can be carried out if symptoms cannot be assigned to a specific disease entity.

Molecular epidemiology of Staphylococcus aureus from Lambaréné, Gabon.

While there is an abundance of data on the epidemiology and molecular typing of Staphylococcus aureus, especially those carrying Panton-Valentine leucocidin (PVL) genes or mecA from Western Europe, Northern America and Australia, comparably few studies target African strains. In this study, we characterised genes associated with virulence and resistance, as well the phylogenetic background of S. aureus from healthy carriers and outpatients in Gabon. In total, 103 isolates from 96 study participants were characterised. Seventy-nine isolates originated from throat swabs and 24 isolates from skin lesions. Three isolates carried mecA, although only one, belonging to CC8-MRSA-IV [PVL+] 'USA300', was found to be phenotypically oxacillin-resistant; two CC88-MRSA-IV isolates appeared to be oxacillin-susceptible. PVL genes were common, with a total of 44 isolates (43 %) found to be PVL-positive. CC15-MSSA [PVL+] (n = 29) and CC152-MSSA [PVL+] (n = 9) were the predominant clones among the PVL-positive isolates. Among PVL-negative isolates, CC5-MSSA (n = 12), CC101-MSSA (n = 10) and CC15 (n = 9) were the most frequent. A hitherto undescribed multilocus sequence type of S. schweitzeri was detected twice in unrelated patients. The data emphasise a need for further studies on the role of PVL in African populations and the clinical significance of S. schweitzeri.

Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children.

Historically, osteomyelitis was considered an infectious disorder. More recently, inflammatory mechanisms were recognized causing a significant proportion of pediatric osteomyelitis. This study was to compare characteristics of children with chronic non-bacterial (CNO) and bacterial osteomyelitis (BOM). A chart review of osteomyelitis patients from the departments of pediatrics, pediatric surgery, orthopedic surgery, and oral and maxillofacial surgery was conducted in a tertiary referral center, covering the years 2004-2014. Institutional incidences of CNO (n = 49) and BOM (n = 56) were comparable. Differentiation between CNO and BOM based on clinical or laboratory findings was mostly impossible. However, children with BOM more frequently presented with local inflammatory signs (47 vs. 68 %, p = 0.040), fever (12 vs. 38 %, p = 0.003), and abscesses (0 vs. 39 %, p < 0.001). Peripheral arthritis (14 vs. 0 %, p < 0.001), inflammatory bowel disease (10 vs. 2 %, p = ns), and hyperostosis (29 vs. 4 %, p = 0.001) were more common in CNO. Whole-body MRI was performed in 76 % of CNO patients, unveiling multifocal lesions in 80 % (CRMO). Though considered a rare disorder, institutional incidences of CNO were comparable to BOM, and the discrimination between CNO and BOM solely based on clinical aspects was mostly impossible. This is of special interest, since a correct and timely diagnosis is of utmost importance for long-term outcomes in both disorders. Whole-body MRIs should be considered in chronic osteomyelitis to (1) detect clinically inapparent lesions in CNO and (2) indirectly exclude (usually unifocal) chronic bacterial infections. Prospective studies are warranted to establish evidence-based diagnostic and therapeutic approaches to CNO.

Detection of opsonic antibodies against Enterococcus faecalis cell wall carbohydrates in immune globulin preparations.

Three different commercially available polyvalent immune globulins (IG) were investigated for the existence of antibodies against cell wall carbohydrates of four different E. faecalis serotypes (using a cell wall carbohydrate-enzyme-linked immunosorbent assay), and whether these antibodies mediated opsonic killing (using an opsonic-killing assay). All three IG preparations contained antibodies against all four serotypes (CPS-A to CPS-D). However, only one of the three IG preparations showed opsonic killing against all four serotypes. Average killing was higher against serotypes A and B (72 and 79 %, respectively) than against serotypes C and D (30 and 37 %, respectively). Such IG preparations could play a role as an adjuvant therapeutic option in life-threatening infections with E. faecalis, particularly when resistant strains are involved.

Refining the hospitalization rate: A mixed methods approach to differentiate primary COVID-19 from incidental cases.

Purpose: Until now, the Hospitalization Rate (HR) served as an indicator (among others) for the COVID-19 associated healthcare burden. To ensure that the HR accomplishes its full potential, hospitalizations caused by COVID-19 (primary cases) and hospitalizations of patients with incidental positive SARS-CoV-2 test results (incidental cases) must be differentiated. The aim of this study was to synthesize the existing evidence on differentiation criteria between hospitalizations of primary cases and incidental cases. Methods: An online survey of the members of the German Network University Medicine (NUM) was conducted. Additionally, senior clinicians with expertise in COVID-19 care were invited for qualitative, semi-structured interviews. Furthermore, a rapid literature review was undertaken on publications between 03/2020 and 12/2022. Results: In the online survey (n=30, response rate 56%), pneumonia and acute upper respiratory tract infections were the most indicative diagnoses for a primary case. In contrast, malignant neoplasms and acute myocardial infarctions were most likely to be associated with incidental cases. According to the experts (n=6), the diagnosis, ward, and type of admission (emergency or elective), low oxygen saturation, need for supplemental oxygen, and initiation of COVID-19 therapy point to a primary case. The literature review found that respiratory syndromes and symptoms, oxygen support, and elevated levels of inflammatory markers were associated with primary cases. Conclusion: There are parameters for the differentiation of primary from incidental cases to improve the objective of the HR. Ultimately, an updated HR has the potential to serve as a more accurate indicator of the COVID-19 associated healthcare burden.

Impact of technical training on rapid antigen detection tests (RADT) in group A streptococcal tonsillopharyngitis.

Rapid antigen detection tests (RADT) are widely used for the rapid diagnosis of group A streptococcal (GAS) tonsillopharyngitis. In a prospective 3-year study, the reliability of two different RADT methods was compared, as performed by lab technicians versus physicians. Sensitivity and specificity, as well as positive and negative predictive values, were calculated. When performed by physicians, the results (44.4 %, 8.3 %, 26.7 % and 16.7 %) of a latex agglutination test (LAT) were unacceptably low. However, after switching to a lateral-flow immunoassay (LFIT) and implementing additional hands-on training, the performance improved dramatically (100 %, 92.6 %, 84.6 % and 100 %). In conclusion, technical errors, along with a lack of experience and expertise, negatively impact RADT accuracy.

Antibiotic susceptibility profiles of neonatal invasive isolates of Escherichia coli from a 2-year nationwide surveillance study in Germany, 2009-2010.

A nationwide 2-year surveillance study on invasive neonatal Escherichia coli infections in Germany was conducted. A total of 158 isolates were tested for antibiotic susceptibility. The empirical treatment regimen of ampicillin plus gentamicin for neonatal sepsis appears to remain effective, but emerging resistance needs to be closely monitored.

Accidental clozapine intoxication in a toddler: clinical and pharmacokinetic lessons learnt.

WHAT IS KNOWN AND OBJECTIVE: Clozapine, a second generation antipsychotic which is relatively safe in overdose, has been used as an effective treatment alternative to traditional antipsychotics. The therapeutic use in children remains controversial. However, in accordance with the increasing prescription in adults, the accidental ingestion in childhood becomes more frequent. We report the youngest case of accidental clozapine ingestion. CASE SUMMARY: A 13-month-old girl presented with acute respiratory insufficiency and coma of unknown origin. The medical history, laboratory and radiological assessment did not link to aetiology until an almost spontaneous arousal after 22 h pointed towards intoxication. The initial standard drug screening using immunoassay had been negative. Hence, liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) was performed, and clozapine was detected with a serum concentration of 736 ng/mL. WHAT IS NEW AND CONCLUSION: This case illustrates the diagnostic and forensic pitfalls in a coma of unknown origin due to the limits of toxicological screening immunoassays. LC-MS/MS analysis by an established method showed clozapine metabolites (norclozapine and clozapine-N-oxide) are detectable for longer period, especially in urine, when compared with clozapine. The clinical course is presented in unique correlation with plasma and urine concentrations of clozapine and its metabolites. The elimination pattern of clozapine in toddlers is similar to adults, and the toxic dose was found to be lower when compared with school-age children and adults.

[Surveillance of antibiotic consumption : clarification of the "definition of data on the nature and extent of antibiotic consumption in hospitals according to § 23 paragraph 4 sentence 2 of the IfSG"]. / Antibiotika-Verbrauchs-Surveillance : Ausführungen und Erläuterungen zur Bekanntmachung "Festlegung der Daten zu Art und Umfang des Antibiotika-Verbrauchs in Krankenhäusern nach § 23 Abs. 4 Satz 2 IfSG"

According to § 23 paragraph 4 of the German Infection Prevention Act (IfSG; July 2011), hospitals and clinics for ambulatory surgery are obliged to establish a continuous monitoring system of antibiotic consumption. This is aimed at contributing to an optimization of antibiotic prescription practices in order to confine the development and spread of resistant pathogens. The general requirements (restricted to hospitals) on the method and extent of data collection are provided by the national public health institution after discussion with representatives of various professional societies (Robert Koch-Institut, Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 59, 2013). The article aims to clarify these specifications and to provide background details. In agreement with national and European surveillance systems, the Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) classification system recommended by the WHO should be used as reference standard. Antibiotic consumption should be expressed as the number of DDDs per 100 patient days and per 100 admissions. The categories of antimicrobials and hospital organizational units to be monitored and the time intervals in which analyses should be conducted are determined. Furthermore, various approaches of data assessment are described.

Significant decline in the erythromycin resistance of group A streptococcus isolates at a German paediatric tertiary care centre.

Group A streptococcus (GAS) is considered to be a major pathogen of bacterial tonsillopharyngitis in children. Although GAS is generally susceptible to penicillin, macrolides are often used as the second-line treatment. Over the last several decades, the rising macrolide resistance of GAS has been detected in several countries. With the current study, we aimed to determine the development of macrolide resistance at our paediatric centre. From March 2006 to May 2009, 350 GAS isolates were tested for susceptibility to erythromycin, azithromycin, clindamycin, penicillin and cefotaxime. Macrolide-resistant isolates were screened for the presence of genes related to macrolide resistance (mefA, ermB, ermTR, prtF1). In comparison to a prior study at our hospital, the erythromycin resistance rate decreased significantly from 13.6 to 2.6%. This effect may be attributable to a more restrictive use of macrolides in children in our region.

Performance of a novel microarray multiplex PCR for the detection of 23 respiratory pathogens (SYMP-ARI study).

Symptoms of acute febrile respiratory tract infection are often unspecific, but the rapid identification of pathogens allows optimised patient management. The objective of this study was to evaluate a novel multiplex polymerase chain reaction (PCR) suspension microarray which detects 19 viral and four atypical bacterial targets. A comprehensive set of sensitive monoplex real-time PCR assays was used for each pathogen as the gold standard. A panel of archived as well as 300 prospectively collected clinical samples was analysed by both methods. At least one target was detected in 165/300 (55 %) samples by monoplex PCR and in 140/300 (46 %) samples by multiplex PCR, respectively. The positivity rate was significantly higher in paediatric patients compared to adults [126/154 (82 %) vs. 39/146 (27 %) by monoplex and 114/154 (74 %) vs. 26/146 (18 %) by multiplex PCR, respectively]. Among all samples, 17/300 (5.6 %) were positive for atypical bacteria by monoplex and 8/300 (2.6 %) by multiplex PCR, respectively. Multiple detections were recorded in 35/300 (11.6 %) samples by monoplex and 26/300 (8.7 %) by multiplex PCR. For the most common pathogens, the sensitivity ranged from 57 to 93 % and the specificity ranged from 95 to 100 %. The overall concordance between both methods was 77 % [95 % confidence interval (CI) 72-81 %]. False-negative results by multiplex PCR were mainly due to the low target concentration. Compared to monoplex PCR, the novel microarray assay proved its principle but displayed overall lower sensitivities, potentially restricting its use to paediatric patients. For some targets, only small numbers of positive samples were available, requiring larger studies to firmly assess the sensitivity and specificity.

Prevention of group B streptococcal neonatal disease revisited. The DEVANI European project.

The purpose of this paper was to present the current knowledge on the prevention of group B streptococcus (GBS) neonatal infections and the status of prevention policies in European countries and to present the DEVANI pan-European program, launched in 2008. The aim of this program was to assess the GBS neonatal infection burden in Europe, to design a new vaccine to immunize neonates against GBS infections, to improve the laboratory performance for the diagnosis of GBS colonization and infection, and to improve the methods for the typing of GBS strains. The current guidelines for GBS prevention in different countries were ascertained and a picture of the burden before and after the instauration of prevention policies has been drawn. After the issue of the Centers for Disease Control and Prevention (CDC) guidelines, many European countries have adopted universal screening for the GBS colonization of pregnant women and intrapartum prophylaxis to colonized mothers. Nevertheless, some European countries continue advocating the risk factor approach to GBS prevention. Most European countries have implemented policies to prevent GBS neonatal infections and the burden of the disease has decreased during the last several years. Nevertheless, further steps are necessary in order to develop new strategies of prevention, to improve microbiological techniques to detect GBS colonization and infection, and to coordinate the prevention policies in the EU.

Primary erythromelalgia in a 12-year-old boy: positive response to sodium channel blockers despite negative SCN9A mutations.

Erythromelalgia is a rare disorder characterized by recurrent pain attacks, swelling and redness in the distal extremities. The primary forms of the disorder are caused by mutations in voltage-gated sodium channels. Treatment is difficult and controlled therapeutic studies offer little to no guidance. We report on a 12-year-old boy and his first occurrence of primary erythromelalgia. Genetic findings for mutations in the SCN9A gene, which encodes for the α-subunit of sodium channel NaV1.7, were negative. Although initial treatment with sodium nitroprusside was ineffective, subsequent medication with lidocaine and mexiletine, in combination with gabapentin, was successful. Despite negative findings for mutations in the sodium channels, the use of sodium channel blockers should be considered in these patients.

Lower SARS-CoV-2 household transmission in children and adolescents compared to adults.

In the COVID-19 pandemic, children were considered to play a major role in SARS-CoV-2 transmission similar to influenza. Thus, mitigation measures have been focused on children, impacting their everyday life severely. Despite this, infectivity in this age group regarding SARS-CoV-2 is not yet clarified. We performed a serology study in households with confirmed SARS-CoV-2 infection to evaluate virus transmission with focus on children and adolescents. Between January and July 2021, 341 minors and 650 adults from 300 households with a confirmed index case participated in the FamilyCoviDD19-study including serological assessment for SARS-CoV-2 antibodies and a questionnaire on demographics, recent and ongoing symptoms, hygiene measures and comorbidities. 45 (16.3%) of all index cases were < 18 years old. Thereof, 55.6% reported COVID-19 associated symptoms, while nearly all adult index cases were symptomatic (94.8%). There was significantly less virus transmission by children and adolescents compared to adult index cases with a secondary attack rate of 0.29 vs. 0.54. With the caveat that the results do not necessarily apply to the Delta and Omicron variants, we conclude that children and adolescents are less susceptible for SARS-CoV-2 infection, more frequently show an asymptomatic course of disease and are less infective than adults.