[Consensus-Based Guidelines for Diagnosis, Prevention and Treatment of Tuberculosis in Children and Adolescents - A Guideline on Behalf of the German Society for Pediatric Infectious Diseases (DGPI)]. / S2k-Leitlinie zur Diagnostik, Prävention und Therapie der Tuberkulose im Kindes- und Jugendalter.

Recently, epidemiological data shows an increase of childhood tuberculosis in Germany. In addition to this, drug resistant tuberculosis becomes more frequent. Therefore, diagnosis, prevention and therapy in childhood and adolescence remain a challenge. Adult guidelines do not work for children, as there are age specific differences in manifestation, risk of progression and diagnostic as well as therapeutic pathways.The German Society for Pediatric Infectious Diseases (DGPI) has initiated a consensus-based (S2k) process and completed a paediatric guideline in order to improve and standardize care for children and adolescents with tuberculosis exposure, infection or disease.Updated dosage recommendations take age dependant pharmacokinetics in the treatment of drug sensitive but also drug resistant tuberculosis in account. In addition to this, there is a detailed chapter on perinatal exposure and disease as well as extrapulmonary manifestations.

Long-Term Respiratory Support for Children and Adolescents in Austria: A National Survey.

BACKGROUND: Population-based data on pediatric patients on long-term respiratory support (LTRS) in Austria are lacking. This study aimed to record the pediatric departments active in this field, as well as number and characteristics of patients on LTRS. METHODS: A national cross-sectional study was carried out by means of questionnaires sent to all pediatric departments in Austria. RESULTS: All departments answered to the questionnaires. On June 1st, 2013, the reference day for this study, 12 of the 41 pediatric departments in Austria were active in the field. At this time, these centers were caring for 143 patients, 111 (77.6%) of them under 18 years, which corresponds to a prevalence of 7.4 per 100 000. The patients suffered from neuromuscular disorders (44%), other neurological disorders (18.9%), disorders of respiratory drive (9.1%), obstructive sleep apnea (8.4%), thoracal and spinal diseases (8.4%), pulmonary disorders (4.9%) and other diseases (6.3%). Continuous positive airway pressure was used in 6.3%, non-invasive ventilation in 60.1% and invasive ventilation in 33.6% of the patients, respectively. LTRS was performed at home in 92.3%. CONCLUSION: LTRS represents a common management strategy in children and adolescents with a variety of disorders. Census reports such as this one provide the basis for appropriate planning of resource allocation. The age distribution of our patients shows the need for structured transition into adult care.

Fine-mapping of IgE-associated loci 1q23, 5q31, and 12q13 using 1000 Genomes Project data.

BACKGROUND: Genome-wide association studies (GWAS) repeatedly identified 1q23 (FCER1A), 5q31 (RAD50-IL13 and IL4), and 12q13 (STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine-mapping and re-genotyping of the three loci using 1000 Genomes Project datasets. METHODS: Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI-TOF-MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene-by-gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. RESULTS: Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single-nucleotide polymorphisms (SNPs) were associated with strongly elevated IgE levels. Gene-by-gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. CONCLUSION: This fine-mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation.

A role of FCER1A and FCER2 polymorphisms in IgE regulation.

BACKGROUND: Both FCER2 and FCER1A encode subunits of IgE receptors. Variants in FCER1A were previously identified as major determinants of IgE levels in genome-wide association studies. METHODS: Here we investigated in detail whether FCER2 polymorphisms affect IgE levels alone and/or by interaction with FCER1A polymorphisms. To cover the genetic information of FCER2, 21 single-nucleotide polymorphisms (SNPs) were genotyped by Illumina HumanHap300 BeadChip (5 SNPs) and the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS; 14 SNPs) in at least 1303 Caucasian children (651 asthmatics) (ISAAC II/ MAGICS population); genotypes of two SNPs were imputed. RESULTS: SNP rs3760687 showed the most consistent effect on total serum IgE levels (b [SE] = -0.38 [0.16]; P = 0.016), while FCER2 polymorphisms in general were predominantly associated with mildly-to-moderately increased IgE levels (50th and 66th percentiles). Gene-by-gene interaction analysis suggests that FCER2 polymorphism rs3760687 influences IgE levels mainly in individuals not homozygous for the risk allele of FCER1A polymorphism rs2427837, which belongs to the major IgE-determining tagging bin in the population. CONCLUSION: FCER2 polymorphism rs3760687 affects moderately elevated total serum IgE levels, especially in the absence of homozygosity for the risk allele of FCER1A SNP rs2427837.

Polymorphisms in the IRF-4 gene, asthma and recurrent bronchitis in children.

BACKGROUND: Interferon-regulatory factors (IRFs) play a crucial role in immunity, not only influencing interferon expression but also T cell differentiation. IRF-4 was only recently recognized as a further major player in T cell differentiation. OBJECTIVE: As IRF-1 polymorphisms were shown to be associated with atopy and allergy, we comprehensively investigated effects of IRF-4 variants on allergy, asthma and related phenotypes in German children. METHODS: Fifteen tagging single nucleotide polymorphisms (SNPs) in the IRF-4 gene were genotyped by MALDI-TOF MS in the cross-sectional ISAAC phase II study population from Munich and Dresden (age 9-11; N = 3099). Replication was performed in our previously established genome-wide association study (GWAS) data set (N = 1303) consisting of asthma cases from the Multicenter Asthma Genetic in Childhood (MAGIC) study and reference children from the ISAAC II study. RESULTS: SNPs were not significantly associated with asthma but with bronchial hyperresponsiveness, atopy and, most interestingly, with recurrent bronchitis in the first data set. The IRF-4 variant rs9378805 was associated with recurrent bronchitis in the ISAAC population and replicated in the GWAS data set where further SNPs showed associations with recurrent bronchitis and asthma. CONCLUSIONS: We found genetic associations in IRF-4 to be associated with recurrent bronchitis in our two study populations. Associated polymorphisms are localized in a putative regulatory element in the 3'UTR region of IRF-4. These findings suggest a putative role of IRF-4 in the development of bronchitis.

Lung transplantation in children following bone marrow transplantation: a multi-center experience.

Allogenic BMT has been successfully performed as a treatment for hematologic diseases with an expected long-term survival. This survival is truncated by respiratory complications including airway obstruction especially BO. Chronic GVHD has been reported to precede almost all cases reported. LTx has become a therapeutic life-saving option for patients with end-stage lung disease that maybe offered for the treatment of GVHD. We report a multi-center experience of pediatric LTx following BMT in 11 patients age- and gender-matched with 11 controls who received LTx for end-stage lung disease secondary to CF. Overall death was 36.4% over a follow-up period of 19 months (range 3-36 months) for the cases and 27.3% for the control group followed for 17 months (range 8-32 months). Median FEV1 one yr post-transplant for the cases was 78% predicted compared with 67.3% predicted for the controls. The median for episodes of infection was comparable at a median of one episode per patient through the entire follow-up period among both groups. Acute rejection episodes were significantly higher in the control group with a median of one episode per patient in the control group compared to none within the cases. Our data suggest that LTx may be a valuable therapeutic option for children with end-stage lung disease post-BMT with comparable survival outcome to that after LTx in children for other indications such as CF. Hospital stay was significantly longer in our case group. Infection rate was comparable between groups albeit type of infection varied. Significantly and of interest is that acute rejection episodes were non-existent in these cases.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

Impact of systemic immuno-suppression after solid organ transplantation on allergen-specific responses.

INTRODUCTION: The immunosuppressive therapy in solid organ transplantation targets mainly the T- and B-cell-mediated immune response. However, there is evidence that it neither suppresses sensitization nor clinical manifestation of allergic diseases in organ-transplanted patients. OBJECTIVE: This study addresses the question whether allergen-specific responses are altered by systemic immunosuppression via negative effects on the T-regulatory cell compartment and a more pronounced suppression on Th1-type T-cell responses. MATERIAL AND METHODS: Peripheral blood mononuclear cells from 65 solid organ-transplanted (kidney, liver, lung) children, adolescents, and young adults and 18 healthy, matched controls were included, and their clinical and sensitization status assessed. Allergen-specific proliferation, intracellular cytokine production, frequency of forkhead box P3 (FOXP3)+ CD3+ CD4+ CD25(high) cells, mRNA expression of IL-10, transforming growth factor (TGF)-ß and FOXP3 (real-time RT-PCR) of peripheral blood mononuclear cells or bronchoalveolar lavage fluid (BAL)-derived cells, and the inhibitory capacity of T-reg cells were investigated. RESULTS: Immunosuppression led to a significantly altered regulatory marker profile expressed by enhanced TGF-ß mRNA production and a reduced frequency of FOXP3+ CD4+ CD3+ cells in solid organ transplanted individuals. FOXP3 expression in BAL cells of lung-transplanted patients was significantly decreased. Allergen-specific proliferation was not significantly altered despite long-term immunosuppression. However, suppression of allergen-specific responses via the T-regulatory cell fraction was deficient in immunosuppressed individuals. CONCLUSION: The results suggest an insufficient control of allergen-specific responses via the Treg-cell compartment under systemic immunosuppression.

Factors influencing age at diagnosis of primary ciliary dyskinesia in European children.

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children.

Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage. This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report.

Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guidelines have focused exclusively on pediatric asthma. As a result, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America. This consensus report recommends strategies that include pharmacological treatment, allergen and trigger avoidance and asthma education. The report is part of the PRACTALL initiative, which is endorsed by both academies.

Mass spectrometrical analysis of the processed metastasis-inducing anterior gradient protein 2 homolog reveals 100% sequence coverage.

Anterior gradient protein 2 homolog is a metastasis-inducing protein in a rat model of rat breast cancer and prognostic for outcome in hormonally treated breast cancer patients. Carrying out protein profiling in several mammalian cells and tissues, we detected this protein (synonym: secreted cement gland protein XAG-2 homolog) that was originally described in toad skin, in human bronchial epithelia. Tissues obtained from biopsies were homogenised and extracted proteins were run on two-dimensional gel electrophoresis. Following in-gel digestion with proteases trypsin, AspN, LysC and chymotrypsin, mass spectrometrical analysis was carried out by MALDI-TOF/TOF. The use of MS following multi-enzyme digestion of the protein resulted into 100% sequence coverage. MS/MS analysis enabled sequencing of 87% of the protein structure. This percentage does not include the signal peptide that was not observed in our protein due to processing. No posttranslational modifications were detectable and no sequence conflicts were observed. Complete analysis, unambiguous identification and characterisation of this biologically important protein could be shown, which is relevant for the definition of a marker protein that has been described so far by immunochemical methods only. Complete analysis is of importance as it forms the basis for all future work on this protein and, moreover, may serve as an analytical tool for further studies.

Aromatic hydroxylation in nasal lavage fluid following ambient ozone exposure.

Ozone at ambient concentrations affects lung function and initiates an inflammatory response of the airways. However, the underlying mechanisms are poorly understood. In vitro studies have shown that ozone reacts with water to give reactive hydroxyl radicals capable of oxidizing a wide range of biomolecules. We conducted a study to determine if in vivo hydroxyl radical attack on human airways occurs under natural exposure to ozone. The relation of orthotyrosine to para-tyrosine as a measure of hydroxyl radical attack was analyzed in nasal lavage samples of 44 primary school children in an epidemiologic study. Repeated nasal lavages were performed between May and October 1991 both following "low" (daily half-hour maximum < 140 micrograms/m3, approximately 70 ppb) and "high" (daily half-hour maximum > 180 micrograms/m3, approximately 90 ppb) ozone exposure. Concomitantly, lung function tests were performed. On average, 11.6 (6-16) nasal lavages were performed for each of 24 study days (10 days following "low" ozone exposure and 14 days following "high" ozone exposure). Average ortho-tyrosine (median; 5-95% percentile) for each child was 0.037 mumol/L (0.016-0.064 mumol/L) and average para-tyrosine was 15.7 mumol/L (9.8-24.1 mumol/L). Ortho-tyrosine (as percentage of tyrosine) was significantly higher following days with "high" ozone exposure (0.18%) vs. days following "low" ozone exposure (0.02%; p = .0001). Ortho-tyrosine showed an inverse relationship with forced vital capacity (p = .01) but was not related to inflammation of the upper airways as assessed by cell counts of polymorphonuclear neutrophils. Hydroxyl radical attack subsequent to ambient ozone occurs in the upper airways of healthy children and is related to lung function decrements.

Familial cryptic translocation with del 4q34-->qter and dup 12pter-->p13 in sibs with tracheal stenosis: clinical, classical and molecular cytogenetic studies and CGH analyses from archival placental tissues evidencing tertiary trisomy 4 in one abortion specimen.

We report on two retarded half-sibs of different sex and seemingly normal karyotype who had the same syndrome of minor anomalies, heart defect and a distal tracheal stenosis, and who shared a healthy mother. These findings raised suspicions of a cryptic chromosome translocation. A translocation t(4;12)(q34;p13), balanced in the mother and unbalanced in the sibs with loss of terminal 4q and gain of terminal 12p regions, was verified by FISH using whole chromosome painting, subtelomeric and YAC probes. Clinical features could be explained by partial monosomy 4q and partial trisomy 12p. Tracheal stenosis was interpreted as a consequence of the same developmental disturbance leading to esophageal atresia and tracheo-esophageal fistula. It was attributed to the 4q deletion in which esophageal atresia as also respiratory difficulties and airway obstructions had been described. Paraffin-embedded placental tissues were available from three of the five abortions of the mother allowing DNA extraction and comparative genome hybridization (CGH). Two of the abortion specimens had the same der(4)t(4;12)(q34;p13) unbalanced translocation as identified in the sibs. In the third abortion specimen, suspicious of triploidy because of partial hydatidiform mole, CGH uncovered a tertiary trisomy 4 resulting from a 3:1 segregation of the translocation chromosomes and their homologs during maternal meiosis I. Differences in CGH results using DNA generated directly or after DOP-PCR were explained by DNA fragmentation in paraffin-embedded tissues and unequal amplification. Am. J. Med. Genet. 94:271-280, 2000.

Assessing the effect of time-varying covariates in cross-sectional studies.

In cross-sectional studies exposure and disease status of individuals are assessed at the same point in time, but sometimes information on prior exposure status is also gathered. Under such circumstances one approach to assessing the relationship between disease and exposure is using linear or logistic regression analysis, adjusting for exposure status at different points in time. It is shown that estimates for the effect of exposure at a certain point in time, adjusted for exposure at another point in time, are obtained from comparisons between groups with different patterns of exposure. Careful interpretation of the resulting estimates is necessary, taking into account a detailed consideration of possible exposure patterns. In addition, if changes in exposure are caused by the occurrence of the disease, then adjusting for multiple measurements of exposure can give misleading results. A regression analysis on dummy variables describing possible patterns of changes in exposure is proposed as an alternative approach. This approach facilitates interpretation of the resulting estimates. Furthermore, it can serve as a diagnostic tool to check for disease related changes in exposure. For this case transferring exposure change rates of healthy subjects to diseased subjects is suggested as an ad hoc method for assessing the hypothetical current relationship between exposure and disease.

Determinants of airway response to challenge with distilled water in a population sample of children aged 7 to 10 years old.

We challenged 446 schoolchildren and measured the percent decrease in FEV1 following 10 min of tidal inhalation of UNDW. Assessment tools for respiratory symptoms and atopy were questionnaire and skin testing, respectively. A previous diagnosis of asthma was most strongly associated with a positive airway response (defined as a fall in FEV1 greater than or equal to 10 percent. A positive response was also associated with atopy, presence of cough, cough during night, or any respiratory symptom. A child's age and the prechallenge FEF75% also explained response to distilled water indicating less responsiveness for older children and those with relative greater airway diameter. For the previous diagnosis of asthma, a positive distilled water challenge test had a sensitivity of 36 percent and a specificity of 92 percent. We conclude that a significant relationship between airway response to distilled water, asthma and symptoms suggestive for asthma exists for a childhood population sample.

Influence of maternal smoking on variability of peak expiratory flow rate in school children.

Diurnal variability of peak expiratory flow rates (PEFRs) was assessed in 1,237 children. The PEFR was measured twice daily over a 1-week period. As an index of variability, the log of a week's mean of daily amplitude was calculated. Linear regression analyses revealed a significant positive association between maternal smoking and the variability of PEFR for nonasthmatic children. For these children, exposure to maternal smoking was associated with a 13.7 percent increase (confidence interval [CI], 3.8 to 24.7 percent) in PEFR variability. For asthmatic children an effect was found for nonatopic (54.7 percent increase; CI, 5.5 to 226.8 percent) but not for atopic children (-8.5 percent change; CI, -41.2 to 42.3 percent). In the latter group, there was evidence that mothers changed their smoking habits subsequent to the development of disease in their children. We conclude that exposure to maternal smoking can increase the variability of PEFR and thus might contribute to the development of asthma.

Determinants of reproducibility of lung function tests in children aged 7 to 10 years.

Lung function (LF) tests are part of many investigations in childhood lung disease. However, individual reproducibility of LF will confound between-subject differences. At the same time, increased LF variability has been linked to respiratory disease. In a sample of 598 children, two LF tests, separated by a 5-min interval, were recorded, and reliability (Rel) of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and maximal expiratory flow at 50% of FVC (MEF50) was determined. Rel was also assessed in children trained and untrained in the performance of LF. To investigate determinants of reproducibility for FEV1, the absolute difference between two repeated tests was calculated. Whenever this difference was > 120 ml, a child was considered to demonstrate excessive variability (poor reproducibility) in FEV1. For volume parameters coefficients of reliability (Crel) were found to be better than for MEF50 (FEV1: 0.96; FVC: 0.94, MEF50: 0.91). In untrained children Crel for FEV1 was only 0.91, but it was increased in subsequent visits (0.98, 0.97, and 0.97 at the second, third, and fourth tests, respectively). Excessive variability in FEV1 was observed in 10% of children and was related to the presence of wheeze [odds ratio (OR) 6.31; 95% confidence interval (CI) 1.78-22.4), shortness of breath (OR 3.14; 95% CI 1.00-9.93), a diagnosis of asthma (OR 6.25; 95% CI 1.76-22.1), and bronchial hyperresponsiveness (OR 4.30; 95% CI 2.07-8.94). We conclude that increased variability of LF is likely to be present in young children not accustomed to the testing procedure and in children with respiratory symptoms. Therefore, before guidelines for LF testing are applied, children should be trained to perform the tests and we should be cautious in the interpretation of test results in children who present with symptoms.

Relationship between atopy and frequent bronchial response to exercise in school children.

The natural history of a bronchial response to exercise (BRE) was studied in a cohort of primary-school children, who were followed over a 2-year period. In 1,094 children, three free-running tests were performed in 1-year intervals. Children who responded in one of the tests were designated as "infrequent" responders (20.5%), whereas those responding at two or all three occasions were designated as "frequent" responders (7.4%). A frequent positive BRE was closely associated with atopy (defined as skin test positivity to 1 of 7 common aeroallergens) and respiratory symptom status. Compared to atopics without respiratory symptoms, an increased risk for a frequent positive BRE was seen for atopic children who were symptomatic during the whole study period [odds ratio (OR) 25.4; confidence interval (CI) 6.9-94.0], who had gained symptoms (OR, 11.0; CI, 2.8-43.2) or who had symptoms at the beginning of the study but had lost them during follow-up (OR, 4.6; CI, 1.0-20.6). A sensitization to dust mites (OR, 8.0; CI, 4.3-15.0) but not to animal dander (OR, 2.3; CI, 1.0-5.2) or pollen (OR, 0.7; CI, 0.3-1.6) was significantly related to a frequent positive BRE. Our findings support the notion that while "children grow out of asthma," they might maintain their bronchial hyperresponsiveness. Regarding specific sensitization, mite allergy seems to play the predominant role.