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Objective: Evidence for the duration of perioperative antibiotic prophylaxis (PAP) after the correction of craniosynostosis in children is scarce. We evaluated the necessary duration of PAP to ensure a minimal rate of postoperative wound infections. Methods: In this monocentric, retrospective, and prospective pilot study, two PAP protocols were compared. From August 2017 to May 2018, treatment group 1 (TG 1) was treated using the standard PAP protocol with at least three doses of antibiotics. Between May 2018 and March 2019, a shortened PAP with a single-shot administration was given to treatment group 2 (TG 2a and b). Endpoints of this study were wound infection rate, colonization rate of wound drains, and the course of treatment reflected by clinical and laboratory data. Results: A cohort of 187 children underwent craniosynostosis correction: 167 were treated according to protocols--95 patients with at least three doses (TG 1) and 72 patients with a single-shot of cefuroxime (TG 2a). Baseline characteristics were similar for both groups. We could not detect significant differences, neither for wound infection rates (TG 1: 1.1%, TG 2a: 0.0%, p = 0.38) nor for colonization rates of wound drains (TG 1: 4.8%, TG 2a: 10.5%, p = 0.27). Conclusions: Single-shot PAP had no adverse effects on the wound infection rate or the colonization rate of the wound drains compared with prolonged perioperative antibiotic prophylaxis. As a result, single-shot preoperative PAP is now applied to the majority craniosynostosis patients undergoing surgical correction in our unit.

Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported. We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children. Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study. Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5–52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified. PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures.

Die in dieser Habilitationsschrift vorgestellten Arbeiten leisten einen Beitrag zur Verbesserung der Diagnostik angeborener Immundefekte. Diagnostik bei Verdacht auf Immundefekt basiert einerseits auf der korrekten Einschätzung der klinischen Situation und andererseits auf der raschen Verfügbarkeit notwendiger, preiswerter und robuster diagnostischer Methoden. Letzterem Ziel dient die Arbeit, die eine solche Methode für die Diagnostik von Defekten der Toll-like Rezeptoren vorstellt. Ersterem Ziel dienen die Arbeiten, die neue Krankheitsbilder bei bekannter genetischer Ätiologie beschreiben und die Arbeiten, die bekannten Infektionserkrankungen neue genetische und immunologische Ätiologien zuordnen. Vor allem letztere Arbeiten können sowohl den klinisch tätigen, als auch den forschenden Pädiater stimulieren bei lebensbedrohlichen und/oder seltenen Infektionserkrankungen nach einem Immundefekt zu suchen. Neben den in dieser Habilitationsschrift vorgestellten Erkrankungen mit Prädisposition zu invasiven bakteriellen Infektionen und der Herpesenzephalitis, könnten auch die Late-onset-sepsis des Neugeborenen, die Miliartuberkulose oder schwere Virusinfektionen innerhalb der ersten 12 Lebensmonate durch angeborene Immundefekte bedingt sein., The work presented her aims at improving diagnostics in primary immunodeficiencies. When primary immunodeficiencies are suspected diagnostic work up is based on correct judgment of the clinical situation and of access to necessary, robust and affordable diagnostic assays. Work discussed in this thesis established such a method for the diagnosis of defects in Toll-like- receptor signalling. The work on patients with chronic granulomatous disease (CGD) and on patients with Sever combined Immunodeficiency (SCID) aims at improving the clinical judgment of patients with a well-defined genotype who yet present with a variable clinical phenotype. The presented work on IRAK4-deficiency and on MyD88-deficiency discusses newly defined genotypes for well-known clinical phenotypes as invasive pneumococcal and staphylococcal disease. The later work may stimulate clinicians to suspect a primary immunodeficiency in any incident of so-called idiopathic life-threatening infection or infection caused by rare pathogens. Besides invasive pyogenic infections and encephalitis caused by Herpes Simplex Type 1, late-onset sepsis caused by Streptococcus agalacticae, dissiminated tuberculosis and severe viral infections in the first 12 months of life may be caused by primary immunodeficiencies. The classification of a life-threatening or rare infectious disease as warning sign for a primary immunodeficiency may help to initiate research in patients without yet well-defined primary immunodeficiency.�xxx

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. Disease severity depends on genotype and gene dose with most serious clinical courses observed in patients with M694V homozygosity. Neutrophils are thought to play an important role in the initiation and perpetuation of inflammatory processes in FMF, but little is known about the specific characteristics of these cells in FMF patients. To further characterize neutrophilic inflammatory responses in FMF and to delineate gene-dose effects on a cellular level, we analyzed cytokine production and activation levels of isolated neutrophils derived from patients and subjects with distinct MEFV genotypes, as well as healthy and disease controls. Serum levels of interleukin-18 (IL-18) (median 11,485 pg/ml), S100A12 (median 9,726 ng/ml), and caspase-1 (median 394 pg/ml) were significantly increased in patients with homozygous M694V mutations. Spontaneous release of S100A12, caspase-1, proteinase 3, and myeloperoxidase (MPO) was restricted to ex vivo cultured neutrophils derived from patients with two pathogenic MEFV mutations. IL-18 secretion was highest in patients with two mutations but also increased in neutrophils from healthy heterozygous MEFV mutation carriers, exhibiting an ex vivo gene-dose effect, which was formerly described by us in patients' serum. CD62L (l-selectin) was spontaneously shed from the surface of ex vivo cultured neutrophils [median of geometric mean fluorescence intensity (gMFI) after 5 h: 28.8% of the initial level]. While neutrophils derived from healthy heterozygous mutation carriers again showed a gene-dose effect (median gMFI: 67.1%), healthy and disease controls had significant lower shedding rates (median gMFI: 83.6 and 82.9%, respectively). Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.

Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous CD70 missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation.