17q21 variants modify the association between early respiratory infections and asthma.

Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset

[Exercise alveolar hypoventilation in long-term survivors of bronchopulmonary dysplasia]. / Hypoventilation alvéolaire à l'exercice chez des enfants avec dysplasie bronchopulmonaire.

BACKGROUND: We aimed to confirm that children who have survived bronchopulmonary dysplasia (BPD) display lower ventilation during exercise than healthy children, and to determine whether alveolar hypoventilation associated with exercise-induced hypoxemia occurred in these children. METHODS: Twenty children with BPD (birth weight 1441+/-523 g [mean +/- SD], gestational age 31+2.3 weeks), aged 7 to 14 years, and 18 matched healthy children, born at term, performed resting pulmonary function and cardiopulmonary incremental exercise tests. Arterialized capillary blood gases were measured at rest and at maximal exercise in the BPD group. RESULTS: The BPD group showed moderate expiratory airflow limitation and hyperinflation. Maximal oxygen uptake and ventilatory threshold were similar in the two groups. The BPD group displayed ventilatory limitation on exercise, with greater use of the ventilatory reserve (p<0.01), lower maximal ventilation (p<0.01), tidal volume (p=0.01). Changes in ventilation (p<0.0001) and tidal volume (p=0.003) during exercise were significantly smaller in the BPD group than in controls, at similar submaximal workloads. At peak exercise, we observed hypoxemia in 12 BPD children (60%). In the subgroup with hypoxemia, a significant increase in PaCO2 (p=0.01) was measured at peak exercise, showing alveolar hypoventilation sustained by the lower tidal volume. CONCLUSIONS: Despite normal maximal aerobic performance, BPD children showed ventilatory limitation on exercise, frequently with hypoxemia and alveolar hypoventilation. Despite an improvement in their pulmonary condition, continued follow-up by cardiopulmonary exercise testing, is strongly recommended.

Airway remodeling is correlated with obstruction in children with severe asthma.

BACKGROUND: Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. METHODS: Two groups of children with severe asthma and persistent symptoms, 5-14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV(1)) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). RESULTS: Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM-ASM was shorter in group O (P = 0.007). FEV(1) negatively correlated with ASM area (r = -0.6; P = 0.002), MLCK expression (r = -0.45; P = 0.02) and CD31 expression (r = -0.7; P = 0.0003), and positively correlated with the distance of RBM-ASM (r = 0.5; P = 0.007). CONCLUSIONS: Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.

Identification of a new natural Ara h 6 isoform and of its proteolytic product as major allergens in peanut.

Numerous food allergens of plant origin belong to the 2S albumin family, including peanut Ara h 2. In addition to Ara h 2, several other conglutins related to 2S albumins are present in peanut seeds. We evaluated the allergenicity of different peanut conglutins as compared with Ara h 2. Several conglutins were isolated from the kernel, i.e. Ara h 2, a new isoform of Ara h 6 and its derived product, which is likely to be naturally formed during seed processing. Enzyme allergosorbent tests performed on sera of peanut allergic patients showed that more than 94% of 47 analyzed patients had positive IgE responses to Ara h 6 isoform and to its degradation product. Skin prick tests with the new isoform of Ara h 6 led to a positive response in seven out of the eight tested patients. Both enzyme allergosorbent tests and skin prick tests showed that the reactivity of Ara h 6 was similar to, or even higher than, that of Ara h 2, suggesting that the present isoform of Ara h 6 is as allergenic as Ara h 2. In addition the IgE response to the plant processed (i.e., hydrolyzed) Ara h 6 new isoform is equivalent to the IgE response to the native isoform. The IgE immunoreactivity is mostly abrogated by chemical reduction and denaturation of Ara h 6 isoforms, which underlined the importance of tertiary structure in Ara h 6 immunoreactivity. These results, and particularly the high correlation between anti-Ara h 2 and anti-Ara h 6 IgE responses, emphasise the major role of 2S albumins in peanut allergenicity.

Incidence rate and factors related to post-bronchoalveolar lavage fever in children.

BACKGROUND: Post-bronchoscopy and bronchoalveolar lavage (BAL) fever in children has been described by several authors. OBJECTIVES: This study aimed at assessing the occurrence of fever after these examinations and associated risk factors. METHODS: The study was performed in the Bronchoscopy Unit of Hôpital Necker-Enfants Malades, Paris, France, from June 2004 to July 2005. 148 children who underwent fiberoptic bronchoscopy and BAL, and remained in the Unit for 24 h, were included. RESULTS: 37.8% of the patients presented post-BAL fever. In the multivariate analysis of the selected factors (age, immunodeficiency, general or local anesthesia, mucosal biopsy, inflammation and suppuration at the moment of the examination, abnormal bronchoalveolar fluid cellularity and infection), only age <2 years and presence of infection remained associated with fever. CONCLUSIONS: The occurrence of fever is a frequent event in children who underwent BAL. In order to reduce post-BAL fever, antibiotic strategies should be devised based on prospective studies assessing identification of predictive air-way infection criteria and/or rapid bacteriological result analysis.

[Environmental factors for asthma severity and allergy: results from the EGEA study]. / Facteurs environnementaux de l'asthme sévère et de l'allergie: résultats de l'étude EGEA.

INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

[Severe asthma in children: identification and investigation]. / Asthme difficile à traiter de l'enfant, identification et explorations.

Severe asthma in children is characterized by the persistence of symptoms or bronchial obstruction in spite of adequate treatment. Side effects of high dose inhaled or repeated courses of systemic corticosteroids must be considered. Therefore, an exact assessment is necessary. First, the observation of the child has to be secured and risk factors eliminated by interrogation and examination (smoking, ENT affection, allergy with persistence of high exposure, gastro-esophageal reflux). An initial thorax-X-ray is essential. After exclusion of differential diagnoses and confirmation of severe asthma, the child must be referred to a specialized department for a diagnostic work-up including a thoracic CT and bronchoscopy. Patient education including treatment can be realized in asthma schools and consultation intervals must be shortened.

[Streptococcus pneumoniae purulent pleurisy and hemolytic uremic syndrome. A case report]. / Pleurésie purulente à Streptococcus pneumoniae et syndrome hémolytique et urémique. A propos d'un cas.

A 22-month-old infant developed purulent pleurisy caused by Streptococcus pneumoniae and a hemolytic uremic syndrome. The diagnosis was suggested by the classical triad: hemolytic anemia, renal failure and thrombocytemia confirmed by renal biopsy which demonstrated extensive cortical necrosis. Renal involvement was severe, justifying an indication for renal transplantation.

[Latex allergy in children]. / Allergie au latex chez l'enfant.

UNLABELLED: The aim of our study was to determine the prevalence of latex allergy and the clinical features of children with latex allergy. PATIENTS AND METHODS: We prospectively investigated 243 children consulting in our allergy out-patients unit during 1 year. Parents answered a questionnaire, and children underwent skin prick tests with common allergens and latex. Latex-specific serum immunoglobulin E was determined by CAP test in children with latex sensitization. The results were compared in children with and without latex allergy. RESULTS: The prevalence of latex allergy was 1.3%. A family history of atopy (75%) and a personal history of previous surgery was associated with latex allergy (P < 0.0001). In children with latex allergy, the frequency of sensitization to inhaled and food allergens, atopic dermatitis, rhinitis and conjunctivitis was higher than in children without latex allergy (P < 0.05). Avocado allergy was the food allergy most commonly associated with clinical symptoms. Balloon was the most common latex product causing symptoms (60%). CONCLUSIONS: Due to its potential severe consequences, latex allergy should be investigated in children who had undergone multiple surgical procedures and in the children with pollen-food allergy syndrome. Avoidance of latex is an important preventive measure.

[Prevention of asthma and allergic diseases in children]. / La prévention de l'asthme et des maladies allergiques.

Allergic diseases have become a major public health problem in industrialized countries, justifying the development of prevention programs. A review of the literature on allergens and atopic symptoms, age of primary sensitization and other factors associated with allergic diseases development is presented and is followed by a discussion on prevention measures. The most recent physiopathological and immunological data indicate that persistent asthma and allergic diseases in adults may be associated with events in early childhood. The parallel increase in autoimmune and allergic diseases has been correlated with regulatory mechanism defects, contradicting the previous theory that involved a predominantly Th1 or Th2 pathway. The primary prevention of asthma and allergic diseases thus appear to be somewhat utopian. Indeed based on recent results, the risk of developing allergies appears to be related to modern "clean" lyfestyles. Secondary prevention is probably necessary, possibly through specific immunotherapy. Tertiary prevention must also be considered. Passive smoking must be prevented as it can alter the development of the respiratory system and promote allergen sensitization. Randomized, controlled, prospective studies are needed to evaluate the efficacy of the preventive measures.

Complications of flexible bronchoscopy in children: prospective study of 1,328 procedures.

Complications of flexible bronchoscopy (FB) were prospectively evaluated during 1,328 diagnostic procedures in children, not in intensive care units. A total 92.8% of the procedures were performed in conscious patients under sedation and 7.2% under deep sedation. Supplementary oxygen was provided in approximately 80% of cases via endoscopic face mask (n=783) or nasal prongs (n=290). At least one complication was recorded in 91 cases (6.9%). Minor complications (n=69; 5.2%) included moderate and transient episodes of desaturation (n=15), isolated excessive coughing (n=22), excessive nausea reflex with coughing (n=20), transient laryngospasm (n=6) and epistaxis (n=6). Major complications (n=22; 1.7%) included oxygen desaturation to <90%, either isolated (n=10) or associated with laryngospasm (n=6), coughing (n=4), bronchospasm (n=1), and pneumothorax (n=1). Major complications involving oxygen desaturation were associated with age <2 yrs (13 of 529 versus 8 of 778) and laryngotracheal abnormalities (7 of 85 versus 14 of 1,222). The overall frequency of complications was similar in conscious (6.7%) but sedated patients and patients under deep (7.3%) sedation. However, the frequency of transient desaturation was significantly higher in children undergoing FB under deep sedation. Transient fever after bronchoalveolar lavage was observed in 52 of 277 cases (18.8%). Flexible bronchoscopy is a safe procedure with <2% major complications. Careful analysis of indications and clinical status for each patient, and proper anaesthesia and monitoring during the examination ensure that the procedure is successful, with a minimum of complications.

Kinetics of plasma cytokine levels in children hyposensitized with wasp venom.

Specific immunotherapy shifts immune responses towards a Th0/Th1 response. Production of chemokines is also decreased early after the initiation of rush venom immunotherapy. We aimed to investigate in vivo whether cytokine plasma levels reflect the shift towards a Th0-Th1 pattern of immune response as seen in vitro in lymphocytes from patients undergoing venom immunotherapy. Therefore, we studied plasma levels of various cytokines before (day 1), during (day 2), and after (day 4) rush immunotherapy in nine wasp-allergic children. The levels of interleukin-5 and IFN-gamma were below the detection threshold. No variations were observed in levels of interleukin-4, interleukin-10, and TNF-alpha. In contrast, mean levels of RANTES transiently increased at day 2, and decreased below the pretreatment levels at day 4. Those alterations were significant in five children with high levels of RANTES at day 1, and reporting severe anaphylaxis. In the four other children, the levels of RANTES were not significantly increased at day 4. These results suggest that RANTES plasma levels are positively correlated with the severity of the reaction to hymenoptera venom, and that a significant decrease in the levels of RANTES occurs only in children with high pretreatment levels. However, the kinetics of RANTES plasma levels correlated neither with the results of allergological tests, nor with the outcome of venom immunotherapy.

[Epidemiological study of genetic and environmental factors in asthma, bronchial hyperresponsiveness and atopy. Protocol and potential selection bias]. / Etude épidémiologique des facteurs génétiques et environnementaux de l'asthme, l'hyperréactivité bronchique et l'atopie (EGEA). Protocole et biais de sélection potentiels.

BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.

Cardiopulmonary exercise testing in children: an individualized protocol for workload increase.

OBJECTIVES: To investigate the feasibility of individualized workload increments, as used in adults, for exercise testing in children; and to investigate whether this individualized protocol makes it possible to satisfy the usual criteria for maximal exercise (clinical exhaustion, predicted maximum heart rate [HRmax], oxygen uptake [O(2)] plateau, maximal respiratory exchange ratio > 1.1). DESIGN: Prospective clinical study. SETTING: Pediatric exercise testing laboratory. SUBJECTS: Ninety-two children aged 5 to 17 years with various cardiac and respiratory diseases (33 with asthma, 11 with bronchopulmonary dysplasia, 6 with cystic fibrosis, 10 with congenital heart disease, and 32 miscellaneous). INTERVENTIONS: Individualized maximal incremental exercise testing. The increase in workload was adapted to the individual and was calculated from predicted maximal oxygen uptake (O(2)max) for each child. The test lasted 10 to 12 min. RESULTS: The exercise test was well tolerated by all children and was maximal in all but seven patients. A total of 65.7% of children reached the predicted O(2)max and 68.4% satisfied the criteria for a O(2) plateau at peak exercise. The predicted HRmax was achieved in all but two children. The mean maximal respiratory exchange ratio was 1.06. CONCLUSION: The individualized protocol for increasing workload, based on O(2) rather than power, was well tolerated by children. In our view, the best two criteria for assessing the maximality of the tests were clinical exhaustion and HRmax, especially if the O(2) plateau was not reached. These results suggest that individualized protocols could be used instead of standardized tests for exercise testing in children.

Value of open lung biopsy in immunocompromised children.

OBJECTIVES: To determine the value of open lung biopsy (OLB) in terms of diagnosis, morbidity, mortality, and benefits in immunocompromised children with pulmonary involvement. STUDY DESIGN: We retrospectively reviewed 36 OLBs performed in 32 immunocompromised children between 1985 and 1998. Seventeen biopsies were performed in patients with primary immunodeficiency syndromes and 19 in patients with secondary immunodeficiency syndromes. Twenty-eight biopsies were performed because of a lack of response to ongoing antimicrobial treatments with negative or positive findings on bronchoalveolar lavage (BAL) and a deteriorating clinical or radiologic course, and 8 biopsies were performed because of persistent chest x-ray infiltrates. RESULTS: Diffuse pulmonary infiltrates were observed on chest x-ray in 28 cases, hyperinflation in 3 cases, and nodular infiltrates in 5 cases. A histopathologic diagnosis was possible for all 36 OLBs. Specific diagnosis was obtained in 22 (61%) (12 infectious agents, 6 tumors, 4 bronchiolitis obliterans) and non-specific diagnosis in 14 (39%). Fungi were the main infectious agents (8 of 12). For the diagnosed infections, BAL provided 4 true-positive, 3 false-positive, and 6 false-negative results. Specific treatment was changed in 77% of cases, providing real benefits in 12 (33%) cases. The morbidity and overall mortality rates were 31% and 33%, respectively. The mortality rate was significantly higher in the first 30 days after OLB in patients receiving ventilatory assistance (58%). CONCLUSIONS: OLB in immunocompromised children with deteriorating clinical or radiologic course is a sensitive diagnostic tool.

[Asthma and the child below 5 years of age: diagnosis and treatment]. / Asthme de l'enfant avant 5 ans: diagnostic et traitement.

Asthma is the most frequent chronic disease in pediatrics and the increase in its prevalence is a major public health problem. Diagnosis may be difficult in the young child, symptomatology most often occurring following a viral infection. It is important not to ignore a foreign body in the airways or fibrocystic disease and asthma remains, particularly in infants, a diagnosis of elimination. Misdiagnosis or insufficient treatment of asthma may risk the development of irreversible histological lesions and also could compromise pulmonary growth and the child's lung reserve. Spacer devices and nebulisers enable inhaled therapy to be administered to very young children. The value of early diagnosis is to institute appropriate treatment notably in severe asthma with inhaled corticosteroid therapy, the aim being to reduce remodelling lesions of the airways. The minimal effective dose should be defined to minimalise side-effects. The treatment of asthma is not restricted to pharmacotherapy: attempts should be made to reduce intercurrent viral infections, domestic pollution (including smoking) and allergenic concentrations. However, as for all chronic diseases, the clinician will encounter poor compliance. The work of education and support of health professionals is fundamental to the management of asthma.

Cytokine transcripts in pediatric tuberculosis: a study with bronchoalveolar cells.

Pediatric tuberculosis (TB) differs from adult TB in many features. To date, cytokine expression has not been studied in children with TB. The relative amounts of the various cytokines released at the site of infection may be important determinants of TB disease development and pathology. We determined cytokine transcripts in bronchoalveolar cells (BACs) recovered from 9 children presenting with TB and from 9 children with pulmonary diseases other than TB. An RT-PCR-based method was developed to quantify the mRNAs encoding six cytokines (IFN- gamma, IL-12, TNF- alpha, IL-10, IL-4, TGF- beta 1) known to play key roles in mycobacterial infections. Expression of mRNA encoding TGF- beta, TNF- alpha and IFN- gamma was statistically significantly higher in BACs from children with TB than in BACs from children with other pulmonary diseases; whereas the levels of mRNA transcription for TGF- beta is high, the levels of mRNA transcription for IFN- gamma and TNF- alpha remain low. All children had low levels of mRNA for IL-12(p40). IL-4 was barely detectable in all cases. Children with miliary TB had high levels of IL-10 transcripts and low levels of mRNA encoding TGF- beta. The immunosuppressive cytokines TGF- beta and IL-10, are overproduced in children with non-miliary TB and miliary TB respectively and are probably involved in the progression of the disease. These data suggest that Th1 responses are reduced in children with TB.

Early use of inhaled corticosteroids in infancy.

The inability to accurately predict the outcome of infants with recurrent wheezy bronchitis makes the early use of inhaled corticosteroids (ICS) controversial. Data from bronchoalveolar lavages and epidemiological surveys suggest a persistent inflammation of the airways in the more severe cases. Prospective studies, mostly with nebulized corticosteroids, have demonstrated clinical efficacy on daytime and nightime symptoms, reduced requirements for rescue bronchodilators and a real steroid sparing effect. In infants with episodic viral-associated wheeze with or without interval symptoms, ICS use carries the risk of overtreatment and of adverse effects. Long-term prospective studies are urgently required to assess the efficacy and safety of ICS and their possible effects on the natural history of infantile asthma.