Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients.

Patients with interstitial lung disease due to surfactant protein C (SFTPC) mutations are rare and not well characterised. We report on all subjects collected over a 15-year period in the kids-lung register with interstitial lung disease and a proven SFTPC mutation. We analysed clinical courses, interventions and outcomes, as well as histopathological and radiological interrelations. 17 patients (seven male) were followed over a median of 3 years (range 0.3-19). All patients were heterozygous carriers of autosomal dominant SFTPC mutations. Three mutations (p.L101P, p.E191 K and p.E191*) have not been described before in the context of surfactant protein C deficiency. Patients with alterations in the BRICHOS domain of the protein (amino acids 94-197) presented earlier. At follow-up, one patient was healthy (2 years), six patients were "sick-better" (2.8 years, range 0.8-19), seven patients were "sick-same" (6.5 years, 1.3-15.8) and three patients were "sick-worse" (0.3 years, 0.3-16.9). Radiological findings changed from ground-glass to increasing signs of fibrosis and cyst formation with increasing age. Empiric treatments had variable effects, also in patients with the same genotype. Prospective studies with randomised interventions are urgently needed and can best be performed in the framework of international registers.

Omega-3 polyunsaturated fatty acids and bronchial inflammation in grass pollen allergy after allergen challenge.

UNLABELLED: RATIO: Asthma is a major public health problem, with bronchial inflammation as the therapeutic target. The role of dietary fish oil derived polyunsaturated fatty acids (PUFAs) in allergic inflammation is controversial. Most asthmatics suffer from mild disease and non-pharmacologic interventions are attractive. This study investigates the anti-inflammatory potential of nutritional PUFAs in an experimentally induced bronchial inflammation. METHODS: We examined 38 grass pollen allergic asthmatics and 19 controls. History of dietary PUFA intake was compared with levels of PUFAs in erythrocyte membranes, and stratified according to low (25th quartile; Q25) and high (75th quartile; Q75) ratios of omega-3 (n-3) to omega-6 (n-6) PUFAs as a surrogate for anti-inflammatory (Q75) or proinflammatory (Q25) effects. Bronchial inflammation was simulated with one-step inhalation of grass pollen. Bronchial response (exhaled nitric monoxide, eNO as surrogate for inflammation, decrease of FEV(1)) was correlated with levels of PUFAs in erythrocyte membranes. RESULTS: Ratios of n-3/n-6 PUFA were significantly lower in asthmatics than in healthy controls. Levels of eNO were significantly higher in Q25 asthmatics than in Q75 asthmatics (p = 0.040). There was a trend of higher bronchial hyperreactivity in Q25 asthmatics (median PD(20) 0.27 vs. 0.14; n.s.), induced by specific bronchial challenge with grass pollen (FEV(1) decrease 16.7 vs. 23.1%; n.s.). CONCLUSION: When stratifying for erythrocyte membrane PUFA content as a surrogate for alimentary intake, we found mild effects on bronchial allergic inflammation. Future intervention studies with pharmacological PUFA doses appear suitable to clarify dietary PUFA role as an adjunctive intervention to the established treatment of asthma. ClinicalTrials.gov No. NCT00519740.

Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics.

OBJECTIVE: Respiratory infections are major triggers of exacerbations in preschool asthma. Many countries' guidelines recommend immunization against pneumococci for patients suffering from chronic airway disease. Beyond infancy, however, data on the immunogenicity and safety are scarce. Also, the interval between priming and booster is a matter of debate. PATIENTS AND METHODS: Seventy preschool asthmatics (2-5-year-old; mild to moderate asthma) underwent sequential immunization: one dose of seven-valent pneumococcal conjugate vaccine (PCV-7) followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23). We randomly assigned half of the vaccinees to receive PPV-23 eight weeks after PCV-7 (group A), and the rest to a 10-month interval (group B). Pneumococcal antibody concentrations to serotype 4, 5, 6B, 7, 9V, 14, 18c, 19F and 23F were determined initially, after two and 12 months after PCV-7. Local and systemic reactions to each vaccine were recorded. RESULTS: Initially, depending on the serotype, up to 79.4% (group A) or 80.4% (group B) individuals did not reach the protective antibody threshold of 0.35 microg/ml. Sequential pneumococcal immunization was immunogenic in preschool asthmatics, inducing protection in the majority of our children. Subjects boostered after eight weeks had significantly lower antibody levels than those boostered after 10 months. Local and systemic adverse events were mild in character and self-limiting. CONCLUSIONS: Although both sequential pneumococcal vaccine regimens were safe and immunogenic among preschool asthmatics, immunogenicity was higher when the booster was given after 10 months.

LPS inhalation challenge: a new tool to characterize the inflammatory response in humans.

Inhaling bacterial endotoxin and its derivative LPS can induce a distinct inflammatory response, varying among hosts. Experimental LPS-inhalation is an established procedure in inflammation research. We evaluated experimental LPS-inhalation in 20 young healthy volunteers to determine the safety and the reproducibility of markers of inflammation and clinical findings (symptoms, lung function, exhalative NO, and body temperature). LPS was increased every 30 min up to cumulative 100 microg, the protocol was repeated after 2, 4, and 6 weeks. During 71 provocations, 13 episodes of clinical complaints were observed in 10 subjects. Those were a total of 11 local reactions (15.5%, e.g., cough), and six systemic reactions (8.5%, e.g., fatigue). All adverse events resolved spontaneously within 10 h. Changes of FEV(1) and eNO showed no significant differences between the four visits. In the majority of our subjects (88.2% on visit 1-3, 76.5% on visit 4), a rise in body temperature (>0.5 degrees C) was recorded and normalised latest after 24 h. On the first and the last visit, serum concentrations of CrP and LBP increased significantly and correlated well with each other (r=0.71; P<0.001). LPS-challenge is a safe and tolerable tool to investigate inflammatory response in humans and could lead to better characterization of patients with chronic inflammatory disease.

Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease.

INTRODUCTION: Gastroesophageal reflux has been suggested as an underlying cause of chronic lung disease. The aim of this study was to assess the value of pepsin and bile acids, both components of GI secretions, in the lungs of children with chronic lung diseases as possible markers for gastroesophageal reflux disease and their relation to oxidation and inflammation. MATERIALS AND METHODS: BAL was performed in 96 children with different chronic lung diseases. Gastroesophageal reflux was analyzed by two-channel, 24-h esophageal pH measurements. Lung pepsin and bile acids were measured in BAL enzymatically, interleukin (IL)-8 by enzyme-linked immunosorbent assay, and protein carbonyls by slot blot immunoassay. RESULTS: Sixty-five of the 96 children (68%) had an extensive proximal acidic reflux index. Children with reflux had higher pepsin concentrations in their BAL fluid (BALF), compared to children without reflux despite low specificity. No differences were observed for bile acids. Percentages of neutrophils, levels of protein carbonyls, and levels of IL-8 in BALF correlated with the number of proximal reflux events. CONCLUSIONS: Pulmonary microaspiration as demonstrated by pepsin detection in BALF is common in children with chronic lung diseases, suggesting that gastroesophageal reflux may contribute significantly to the disease pathogenesis. BALF pepsin concentration correlates positively with the number of proximal reflux events. Protein oxidation in BALF is higher in children with extensive proximal acidic reflux, suggesting that pulmonary microaspirations contribute to lung damage.

Influence of low-dose polyunsaturated fatty acids supplementation on the inflammatory response of healthy adults.

OBJECTIVE: The aim of the present study was to examine the immune-modulating effect of two different fat blends enriched with a low dose of anti- or proinflammatory polyunsaturated fatty acids on the fatty acid status and subsequently on the immune response of healthy volunteers. METHODS: Thirty healthy volunteers were randomly assigned to group A (anti-inflammatory blend rich in polyunsaturated fatty acids: alpha-linolenic acid, 240 mg/d; eicosapentaenoic acid, 120 mg/d; stearidonic acid, 49 mg/d; and gamma-linolenic acid, 73 mg/d) or group B (arachidonic acid, 40 mg/d; containing an inflammatory fat blend) for a 2-wk dietary supplementation period. Concentrations of interleukin-8, interleukin-10, tumor necrosis factor-alpha, prostaglandins E(1) and E(2), and leukotriene B(4) were investigated before, after 2 wk of supplementation, and 2 wk after stopping supplementation using a whole blood ex vivo lipopolysaccharide-stimulation assay. RESULTS: Plasma concentrations of alpha-linolenic acid and eicosapentaenoic acid were significantly increased in group A. In addition, dietary fat blends influenced eicosapentaenoic acid concentration in erythrocyte membranes. Supplementation of the fat blends resulted in contrasting effects on the expression of lipid mediators and cytokines after ex vivo lipopolysaccharide stimulation. Release of prostaglandin E(1) and leukotriene B(4) were significantly decreased in group A, whereas prostaglandin E(2) and interleukin-10 concentrations were significantly increased in group B. No effect on interleukin-8 or tumor necrosis factor-alpha release was found after supplementation with either fat blend. CONCLUSIONS: These results show an immune-modulating effect of a low-dose dietary polyunsaturated fatty acid supplementation. However, further studies regarding fat-blend composition and period of supplementation in patients with inflammatory conditions are required.

Impact of early dietary gamma-linolenic acid supplementation on atopic eczema in infancy.

Polyunsaturated fatty acids (PUFAs) are components of cell membranes and may play an immunomodulating role in the pathogenesis of atopic dermatitis (AD). The goal was to determine the impact of PUFAs on AD by dietary supplementation of infants. Based on the parents' decision on their babies' primary feeding, mothers and newborns were randomized to the supplementation with gamma-linolenic acid (GLA) or placebo for up to 6 months. Breastfed infants received GLA by supplementing their mothers. Formula diet was commercial whey hydrolysate unsupplemented with PUFAs. Of 131 eligible infants, 24 developed AD within the first year of life. Of these, nine belonged to the exclusively breastfed group (n = 58), 14 to the combined-fed group (n = 53), and one to the never breastfed group (n = 20). We could not find an influence of GLA on the development of AD. In subjects with AD, at 1 yr of age the serum-immunoglobulin E (IgE) was the lowest in the GLA-supplemented group A-subjects. In the GLA-supplemented group, GLA-levels in breast milk were similar in atopic and non-atopic infants. In the non-supplemented group the GLA-content of breast milk was 0.07% of total fatty acids in atopic infants vs. 0.17% in non-atopic infants (p < 0.01). Dietary GLA-supplementation could not prevent AD. Interestingly, the number of infants developing AD was the lowest in never breastfed children. In infants suffering from AD, GLA-supplementation seemed to reduce total IgE in the first year of life.

Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects.

BACKGROUND: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyperreactivity. OBJECTIVE: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. PATIENTS AND METHODS: A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 microg (2.5, 10.5, 42, 45 microg). After each provocation and up to 24 h later, FEV(1) was determined; the procedure was stopped when FEV(1) declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. RESULTS: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV(1) decrease and basal eNO levels. CONCLUSIONS: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.

Granular cell tumor of the trachea in a child.

Granular cell tumors are uncommon benign neoplasms. Their location is mostly in the head and neck region; appearance in other parts of the body is rare, but it has been reported. We present the case of a 14-year-old girl with a granular cell tumor of the trachea. The tumor was incidentally found at bronchoscopy performed to exclude suspected foreign body aspiration. It was located in the ventral part of the main carina. Biopsies revealed the histologic pattern of a benign granular cell tumor. The girl underwent resection of the main carina followed by reconstruction of a neo-carina with both main bronchi. She has not had any recurrence of the tumor during 3 years of follow-up.

Severe isolated pulmonary Langerhans cell histiocytosis in a 6-year-old girl.

UNLABELLED: Langerhans cell histiocytosis (LCH) usually affects different organs or bones. Isolated pulmonary disease is rare in childhood. We report about a 6-year-old girl with progressive pulmonary insufficiency, onset of clubbing at 4 years of age and honeycombing lung infiltrations on X-ray films. The radiological suspicion of primary pulmonary LCH was confirmed by the presence of CD1a positive cells in the bronchoalveolar lavage fluid. Other organs were not involved. The girl was treated according to the LCH-III International Study Protocol with a good response. Follow-up showed no reactivation of LCH but a reduced vital capacity and signs of interstitial pulmonary involvement on a CT scan. CONCLUSION: Langerhans cell histiocytosis should be considered in the aetiology of cystic lung diseases. Early responders to treatment have a high likelihood of becoming free of disease. However, pulmonary fibrosis is an important mechanism of lung remodelling in pulmonary Langerhans cell histiocytosis and the long-term prognosis is unclear.

Acute ethanol intoxication during pregnancy and consecutive fetal cardiac arrest: a case report.

Chronic alcohol exposure during pregnancy and the resulting toxic effects for the fetus has been the subject of many investigations. In contrast, acute alcohol intoxication during pregnancy is a rare event and less is known about the consequences for fetal life. We report a case of the acute ethanol intoxication of a pregnant woman at the 35th week of gestation and the consecutive cardiac arrest of the neonate. Despite the life threatening event, the newborn recovered after resuscitation and intensive care treatment and could be discharged from hospital in good physical condition. We suggest that acute alcoholized pregnant women should be transferred to Perinatal Centers to cater for the possible need for emergency cesarean section and resuscitation of the newborn.

Streptococcus pyogenes meningitis complicating varicella in a 3-month-old child.

Varicella is a common, usually self-limited infectious disease, and complications are believed to be rare. Despite the dramatic increase in invasive Streptococcus pyogenes infections associated with varicella zoster virus infections in recent years, post-varicella S. pyogenes meningitis occurs very rarely. The third case in the literature is described here.

Surgical treatment of tracheomalacia by bronchoscopic monitored aortopexy in infants and children.

BACKGROUND: Aortopexy has become an established surgical procedure for the treatment of severe tracheomalacia (TM) in infancy. However, postoperative outcome may be improved by intraoperative bronchoscopic control of the aortopexy. METHODS: Between 1992 and 2000, 16 infants and children (2 female, 14 male) with TM were treated by pexis of the aorta via a right (15 patients) or left (1 patient) anterior thoracotomy. Patients age ranged from 4 to 122 months (mean, 26 mon). Three infants had previous surgery for esophagus atresia and tracheoesophageal fistula. Another four patients were operated for gastroesophageal reflux. In all cases, the aortopexy was monitored intraoperatively by bronchoscopy. Respiratory function was verified for each patient by comparing pre- and postoperative tidal expiratory flow values (TEF 25% in ml/sec). RESULTS: Mean follow-up was 36 months (range, 2 to 60 mo). There was no intraoperative or postoperative mortality. 13 patients showed permanent relief of symptoms. Postoperative median TEF 25% increased significantly compared with preoperative values (81 ml/sec vs. 56 ml/sec; p = 0.016). In one patient repeat aortopexy was necessary. CONCLUSIONS: Aortopexy through a right anterior thoracotomy is an efficient and feasible method in the surgical treatment of TM in infancy and, therefore, can improve postoperative respiratory function. Intraoperative bronchoscopy is advantageous.

Surfactant proteins A and D in children with pulmonary disease due to gastroesophageal reflux.

Children with gastroesophageal reflux often suffer from chronic, severe lung damage and recurrent infections. The mechanisms may involve reflux induced lung injury with alterations of the surfactant proteins (SP) SP-A and SP-D, which bind specifically to various microbes and increase their elimination by granular leukocytes and macrophages. In 20 children with gastroesophageal reflux disease (GERD) the bronchoalveolar lavage content and macromolecular organization of SP-A and SP-D was determined by enzyme linked immunosorbent assay and gel chromatography. For comparison, lavages from 17 children without respiratory diseases were investigated. Both, SP-A and SP-D were significantly reduced in children with GERD-median (25, 75 percentiles) SP-A: 362 (169, 494) ng/ml versus 867 (656, 1,761) in control subjects and SP-D: 174 (73, 456) ng/ml versus 518 (295, 748) ng/ml in control subjects. The more active, higher molecular weight oligomers of SP-A and especially those of SP-D were diminished, whereas the smaller sized forms of SP-D were markedly increased. In children with GERD, significantly reduced amounts of SP-A and SP-D and an altered structural organization of the surfactant protein oligomers were demonstrated. Such impairments of central components of the innate host defense system may contribute to the pathogenesis of the chronic lung disease commonly observed in these children.