Johannes G. Liese

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

BackgroundIn 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.MethodsData 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.ResultsVaricella 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.ConclusionsOverall, the results show increasing acceptance and a strong impact of the varicella vaccination program, even with still suboptimal vaccination coverage.

Pathogenic Fungi Regulate Immunity by Inducing Neutrophilic Myeloid-Derived Suppressor Cells

Summary Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.

Clinical Aspects of Hypophosphatasia: An Update

Hypophosphatasia (HPP) is a heterogeneous rare inborn error of bone and mineral metabolism caused by mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). These mutations result in a decreased level of TNAP activity and increased levels of its substrates, including inorganic pyrophosphate, pyridoxal-5′-phosphate and phosphoethanolamine. Clinical presentations are highly variable, ranging from stillbirth and absence of mineralization in severe disease to mild dental problems or osteopenia in adulthood. Further clinical symptoms include defective bone mineralization with bone deformities, recurrent fractures, chronic non-bacterial osteomyelitis, craniosynostosis, neonatal seizures, nephrocalcinosis, muscular hypotonia, failure to thrive and dental abnormalities with premature exfoliation of teeth and caries. Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease but patients with mild phenotypes (adult form or Odonto-HPP) usually do not have a limitation in their life expectancy. Although TNAP is a ubiquitous enzyme, mostly known for its crucial role during mineralization of bone and teeth, its exact biological role in different human organs is still unclear, and the pathophysiology of symptoms due to TNAP deficiency in HPP are not understood in detail. Since inflammation and tissue destruction of the musculoskeletal system may occur in HPP, TNAP may also play an important role in controlling inflammatory processes. Recent investigations provide evidence that TNAP is also essentially involved in the development of the central nervous system and might contribute to multiple functions of the human brain. HPP can be diagnosed on clinical, biochemical and radiological criteria, and genetic testing confirms the diagnosis and is useful for genetic counseling. Since clinical symptoms are highly variable, patients should be followed up by a multidisciplinary team having experience in HPP treatment. Up to now, no curative treatment of HPP is available. Therefore, symptomatic treatment in particular with regard to pain, seizures and other metabolic phenomena is most important. However, recently, enzyme replacement therapy with a bone-targeted recombinant human TNAP molecule has been reported to improve bone mineralization, respiratory function and physical activity in severely affected infants with HPP, and further clinical trials are ongoing. Hopefully, this and other new therapeutic strategies may improve the prognosis and quality of life of patients with HPP and may contribute to our understanding of bone metabolism in general.

Decline of varicella vaccination in German surveillance regions after recommendation of separate first-dose vaccination for varicella and measles-mumps-rubella.

BACKGROUNDnGermany introduced routine varicella (V) vaccination in 2004. Due to a slightly increased risk of febrile convulsions after first-dose application of combined measles-mumps-rubella-varicella (MMRV) vaccine separate first-dose vaccinations with MMR and monovalent V vaccine were recommended in September 2011.nnnMETHODSnWe compared V and MMR vaccinations in paediatric practices from two surveillance regions (Munich and Würzburg) one year before and after the change in the recommendation.nnnRESULTSnA total of 1405/326 monthly reports were provided by a monthly average of 79/14 practices participating in Munich/Würzburg. V first-dose vaccinations (monovalent V or MMRV vaccine) declined by 12% in Munich (from 10.1 to 8.9 vaccinations per month and practice; p<0.005) and by 4% in Würzburg (from 9.9 to 9.5; p=0.620), respectively. First-dose vaccinations for MMR (MMR or MMRV vaccine) did not change significantly in both regions.nnnCONCLUSIONnAcceptance of V vaccination depends in part on the use of combination vaccine.

Varicella vaccination coverage in Bavaria (Germany) after general vaccine recommendation in 2004.

Since 2004, general varicella vaccination has been recommended for all children 11-14 months of age in Germany. The objective of this study was to examine vaccination coverage in children and factors associated with parental acceptance during the first years after recommendation. In a regional surveillance area, cross-sectional parent surveys were conducted in 2006, 2007 and 2008 in random samples (n=600) of children aged 18-36 months; data were obtained for 372, 364 and 352 children, respectively. Parents were questioned on their childs varicella disease history, and on varicella vaccination status as recorded in the childs vaccination booklet. Overall coverage increased from 38% in 2006 to 51% in 2007 and stagnated at 53% in 2008; in susceptible children (without previous varicella disease until vaccination or time of survey) coverage was 42%, 61% and 59%, respectively. Recommendation by the paediatrician as reported by the parents increased from 48% (2006) to 57% (2007) and 60% (2008), and was the main independent factor associated with parental acceptance. In 32-35% of unvaccinated children parents had not yet decided whether to vaccinate against varicella. Additional programmes targeting paediatricians and parents acceptance of varicella vaccination are needed to achieve the WHO-defined goal of at least 85% coverage.

Differences of IgG antibody avidity after an acellular pertussis (aP) booster in adolescents after a whole cell (wcP) or aP primary vaccination

Compared to whole cell pertussis (wcP) vaccines, acellular pertussis vaccines (aP) have a better safety profile with lower reactogenicity, although their short and long-term efficacy was found to be slightly lower. Up to now, no established serological parameter to predict long-term protection exists. IgG-anti-pertussis avidity possibly determines the effect of different pertussis vaccines and boosting intervals on long-term immunity. Thus, the avidity of a tetanus-diphtheria-aP booster at 10-14 years was tested in three groups of adolescents who had been previously immunized with either five doses of aP (5aP) at 2, 4, 6, 15-18 months and 5-6 years of age, four doses of aP (4aP) or four doses of wcP (4wcP) at 2, 4, 6 and 15-18 months of age. Relative avidity index (RAI) of IgG-anti-pertussis toxin (PT) and IgG-anti-filamentous-hemagglutinin (FHA) was assessed by an adapted ELISA. RAI of IgG-anti-PT and of IgG-anti-FHA correlated positively with antibody concentrations in the pre-vaccination and in the post-vaccination analysis and significantly increased after adolescent booster with aP in all groups. Pre- and post-vaccination, the proportion of participants with IgG-anti-PT RAI>40% (moderate to high avidity) was significantly lower in the 4wcP group (52.9% and 88.9%) compared to the 5aP group (89.5% and 100.0%). In conclusion, TdaP in adolescence induces an increase of antibody avidity and, thus, is able to enhance the binding-quality of antibodies against pertussis. The study suggests including antibody avidity into serological studies on the humoral response to provide information about the long-term efficacy of the vaccine.

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

BackgroundPrevious 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.MethodsWe conducted a prospective surveillance study in 24 PICUs in Bavaria (Germany) from October 2010 to September 2013. Influenza cases among children between 1xa0month and 16xa0years of age admitted to these PICUs with acute respiratory infection were confirmed by PCR analysis of respiratory secretions.ResultsA 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, 80xa0% had influenza A, including 65xa0% 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 4.8xa0years (IQR 1.6–11.0). The most frequent diagnoses were influenza-associated pneumonia (62xa0%), bronchitis/bronchiolitis (32xa0%), secondary bacterial pneumonia (26xa0%), and ARDS (21xa0%). Thirty-six patients (77xa0%) had underlying medical conditions. Median duration of PICU stay was 3xa0days (IQR 1–11). Forty-seven per cent of patients received mechanical ventilation, and one patient (2xa0%) extracorporeal membrane oxygenation; 19xa0% were treated with oseltamivir. Five children (11xa0%) had pulmonary sequelae. Five children (11xa0%) 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 (pu2009=u20090.020), were diagnosed more often with bronchitis/bronchiolitis (pu2009=u20090.004), and were admitted to a PICU later after the onset of influenza symptoms (pu2009=u20090.041).ConclusionsActive 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.

Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Northern Bavaria, Germany

BackgroundThe 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18u2009years of age. All hospitalized cases of children <18u2009years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications.ResultsBetween July 2009 and March 2010, 94 PIAH (62% males) occurred in children <18u2009years of age, with a median age of 7u2009years (IQR: 3–12u2009years). Underlying diseases and predisposing factors were documented in 40 (43%) children; obesity (nu2009=u200912, 30%), asthma (nu2009=u200910, 25%) and neurologic disorders (nu2009=u20098, 20%) were most frequently reported. Sixteen (17%) children received oxygen supplementation; three (3%) children required mechanical ventilation. Six (6%) children were admitted to an intensive care unit, four of them with underlying chronic diseases.ConclusionsMost PIAH demonstrated a benign course of disease. However, six children (6%) needed treatment at an intensive care unit for severe complications.

Therapy of 645 children with parapneumonic effusion and empyema—A german nationwide surveillance study

Objective: To evaluate the initial management of pediatric parapneumonic effusion or pleural empyema (PPE/PE) with regard to length of hospital stay (LOS). Methods: Collection of pediatric PPE/PE cases using a nationwide surveillance system (ESPED) from 10/2010 to 06/2013, in all German pediatric hospitals. Inclusion of PPE/PE patients <18 years of age requiring drainage or with a PPE/PE persistence >7 days. Staging of PPE/PE based on reported pleural sonographic imaging. Comparison of LOS after diagnosis between children treated with different forms of initial invasive procedures performed ≤3 days after PPE/PE diagnosis: pleural puncture, draining catheter, intrapleural fibrinolytic therapy, surgical procedures. Results: Inclusion of 645 children (median age 5 years); median total LOS 17 days. Initial therapy was non‐invasive in 282 (45%) cases and invasive in 347 (55%) cases (pleural puncture: 62 [10%], draining catheter: 153 [24%], intrapleural fibrinolytic therapy: 89 [14%], surgical procedures: 43 [7%]). LOS after diagnosis did not differ between children initially treated with different invasive procedures. Results remained unchanged when controlling for sonographic stage, preexisting diseases, and other potential confounders. Repeated use of invasive procedures was observed more often after initial non‐invasive treatment or pleural puncture alone than after initial pleural drainage, intrapleural fibrinolytic therapy or surgery. Conclusions: Initial treatment with intrapleural fibrinolytic therapy or surgical procedures did not result in shorter LOS than initial pleural puncture alone. Larger prospective studies are required to investigate which children benefit significantly from more intensive forms of initial invasive treatment. Pediatr Pulmonol. 2017;52:540–547.

Recombinant Enzyme Replacement Therapy in Hypophosphatasia

Hypophosphatasia (HPP) is a rare monogenetic and multisystemic disease with involvement of different organs, including bone, muscle, kidney, lung, gastrointestinal tract and the nervous system. The exact metabolic mechanisms of the effects of TNAP deficiency in different tissues are not understood in detail. There is no approved specific treatment for HPP; therefore symptomatic treatment in order to improve the clinical features is of major interest. Enzyme replacement therapy (ERT) is a relatively new type of treatment based on the principle of administering a medical treatment replacing a defective or absent enzyme. Recently ERT with a bone targeted recombinant human TNAP molecule has been reported to be efficient in ten severely affected patients and improved survival of life threatening forms. These results are very promising especially with regard to the skeletal phenotype but it is unclear whether ERT also has beneficial effects for craniosynostosis and in other affected tissues in HPP such as brain and kidney. Long-term data are not yet available and further systematic clinical trials are needed. It is also necessary to establish therapeutic approaches to help patients who are affected by less severe forms of HPP but also suffer from a significant reduction in quality of life. Further basic research on TNAP function and role in different tissues and on its physiological substrates is critical to gain a better insight in the pathogenesis in HPP. This and further experiences in new therapeutic strategies may improve the prognosis and quality of life of patients with all forms of HPP.