Eosinophilic granulomatosis with polyangiitis in children: Data from the French RespiRare® cohort.

OBJECTIVES: To describe the characteristics of pediatric cases of eosinophilic granulomatosis with polyangiitis (EGPA), a systemic necrotizing vasculitis rarely diagnosed in children, retrieved from the French Reference Center for rare pediatric lung diseases and compared with adult cases included in the French Vasculitis Study Group cohort. METHODS: We collected information on pediatric EGPA disease presentation, management, and outcome. Cases met the Lanham criteria and/or American College of Rheumatology classification criteria. RESULTS: Fourteen cases of pediatric EGPA were included, from 1980 to 2012, with a median follow-up of 58.5 months. Median age at diagnosis was 12.3 years. All cases had respiratory involvement. The organ systems most frequently involved were the upper airway (85%), skin (71%), digestive tract (64%), and heart (57%). Neurological and renal involvement were rare. Four of the fourteen children were positive for ANCA (30.7%). During follow-up, three children required intensive care and one child died. The relapse rate was 64%. In comparison with an adult cohort, we found more ENT, heart, and digestive-tract involvement, and fewer neurological manifestations. In children, the delay between asthma onset and diagnosis was shorter, and biopsies showed fewer features of vasculitis. CONCLUSION: This French cohort is the biggest pediatric EGPA series described to date, with a long follow-up period. The findings confirm that pediatric EGPA has specific clinical, radiological, and histological characteristics that differ from adult EGPA. Development of systemic symptoms, and consequently diagnosis, occur with a shorter delay in children, mainly during the eosinophilic phase and leading to a specific presentation.

Frey Syndrome.

OBJECTIVE: To describe the features of Frey syndrome (auriculotemporal nerve dysfunction with gustatory flushing) in childhood. STUDY DESIGN: A multicenter, retrospective, descriptive observational national case series study was conducted with the help of French academic societies. Diagnostic criteria were based on clinical history, and sometimes also on photographs or provocation tests. RESULTS: Forty-eight cases were identified, with 2 subtypes: 35 unilateral and 13 bilateral. Associated sweating was reported in only 10% of cases. Diagnosis was made in only 20% of children at the first consultation and inappropriate dietary restriction was prescribed for 21%. Instrumented vaginal delivery was significantly associated with unilateral forms (OR [unilateral vs bilateral] = 29; 95% CI 3.99-311.58; P < .001). The outcome was favorable overall with 57% regression, 20% recovery, and only 23% persistence of initial symptoms. Regression was more frequent in unilateral forms (OR = 6.60; 95% CI 1.23-44.04; P = .016), observed in 69% of unilateral forms at a median age of 27 (24-48) months. Recovery predominated in bilateral forms (OR = 0.05; 95% CI 0-0.38; P = .001), observed in 58% of bilateral cases at a median age of 8 (7-9) months. CONCLUSIONS: Frey syndrome in childhood is a rare but benign condition with mild symptoms and a favorable outcome in most cases. Unilateral forms are mostly associated with instrumented delivery. Pediatricians should be familiar with this disorder in order to avoid misdiagnosis, mainly as food allergy, and unnecessary referrals and tests.

Eosinophilic pneumonias in children: A review of the epidemiology, diagnosis, and treatment.

Pediatric eosinophilic pneumonias (EPs) are characterized by a significant infiltration of the alveolar spaces and lung interstitium by eosinophils, with conservation of the lung structure. In developed countries, EPs constitute exceptional entities in pediatric care. Clinical symptoms may be transient (Löffler syndrome), acute (<1 month and mostly <7 days), or chronic (>1 month). Diagnosis relies on demonstration of alveolar eosinophilia on bronchoalveolar lavage, whether or not associated with blood eosinophilia. EPs are a heterogeneous group of disorders divided into: (i) secondary forms (seen mainly in parasitic infections, allergic bronchopulmonary aspergillosis, and drug reactions); and (ii) primary forms (eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, idiopathic chronic eosinophilic pneumonia, and idiopathic acute eosinophilic pneumonia). Despite their rarity, the etiological approach to EP must be well-defined as some causes can be rapidly life-threatening without initiation of the proper treatment. This approach (i) eliminates secondary forms, with comprehensive history taking and minimal biological assessment, (ii) is oriented in primary forms by the acute or chronic setting, and the existence of extrapulmonary symptoms. Treatment of primary forms has traditionally relied on corticosteroids, usually with a dramatic response. Specific treatments or the adjunction of corticosteroid-sparing treatment or immunosuppressors are currently being evaluated in order to improve the prognosis and the side effects associated with corticosteroid treatment in a pediatric setting.

New insights into the treatment of severe asthma in children.

Severe asthma accounts for 0.5% of the general paediatric population and 4.5% of children with asthma, representing the major burden of asthma-health-care-associated costs. After ensuring a diagnosis of asthma and excluding difficult-to-treat patients with co-morbidities and non-adherence profiles, there remains children with real therapy-resistant asthma for whom the recommendations are to treat beyond guidelines. We describe new insights into the treatment of severe asthma in children, regarding both "classic drugs" (corticosteroids, bronchodilators) and innovative biological therapies targeting airway inflammation and impaired innate immunity. All of these new avenues remain to be studied and validated in children and will require fine clinical and biological phenotyping.

Idiopathic eosinophilic pneumonia in children: the French experience.

BACKGROUND: Idiopathic eosinophilic pneumonia is extremely rare in children and adults. We present herein the first series describing the specificities of idiopathic chronic (ICEP) and acute (IAEP) eosinophilic pneumonia in children. METHODS: We retrospectively analyzed all cases of ICEP and IAEP in children that were retrieved from French Reference Centers for rare pediatric lung diseases. RESULTS: Five cases of pediatric ICEP were identified. Corticosteroid or immunosuppressive therapy dramatically improved the outcome in three cases. The remaining two cases had a persistent interstitial pattern with progressive development of cystic airspace lesions. Three cases of IAEP in adolescents were reported, with one requiring four days of extracorporeal membrane oxygenation. CONCLUSION: ICEP is a rare disease with a polymorphic clinical presentation in children. We identified patients with persistent interstitial patterns progressing to cystic airspace regions, for which the boundaries with idiopathic interstitial pneumonias are difficult to establish. We therefore propose a specific pediatric definition and classification algorithm. IAEP in children remains an inflammatory reaction of the lung to an acute toxic exposure, mainly tobacco, as in adults. International studies are required to comprehensively assess the various clinical forms of the disease as well as the appropriate therapeutic regimens.

Chronic eosinophilic pneumonia with persistent decreased diffusing capacity for carbon monoxide.

We report a 15-year-old girl presenting with dry cough, exertional dyspnoea, weight loss, fever and night sweats for over 1 month. Blood tests revealed hypereosinophilia, high IgE and antinuclear antibodies levels. Chest x-rays showed bilateral peripheral infiltrates mostly in the right upper lobe which was confirmed by a chest CT. Bronchoalveolar lavage showed hypercellularity with 28% of eosinophils. Idiopathic chronic eosinophilic pneumonia was confirmed after exclusion of other causes of eosinophilic pneumonia and systemic disease. The patient responded dramatically to oral corticosteroids. Oral corticotherapy was stopped after 4 months. At 8 months of follow-up, diffusing capacity for carbon monoxide (DLCO) remained moderately low (58%) with persistent mild exertional dyspnoea. Cardiopulmonary exercise testing showed muscular peripheral limitation. Even if in our patient, mild exertional dyspnoea can be partly correlated to peripheral deconditioning, DLCO should be systematically evaluated to determine follow-up studies standards, to correlate with subclinical disease, relapse risk and to codify therapeutic options.

Distinct epithelial gene expression phenotypes in childhood respiratory allergy.

Epithelial cell contribution to the natural history of childhood allergic respiratory disease remains poorly understood. Our aims were to identify epithelial pathways that are dysregulated in different phenotypes of respiratory allergy. We established gene expression signatures of nasal brushings from children with dust mite-allergic rhinitis, associated or not associated with controlled or uncontrolled asthma. Supervised learning and unsupervised clustering were used to predict the different subgroups of patients and define altered signalling pathways. These profiles were compared with those of primary cultures of human nasal epithelial cells stimulated with either interleukin (IL)-4, IL-13, interferon (IFN)-α, IFN-ß or IFN-γ, or during in vitro differentiation. A supervised method discriminated children with allergic rhinitis from healthy controls (prediction accuracy 91%), based on 61 transcripts, including 21 T-helper cell (Th) type 2-responsive genes. This method was then applied to predict children with controlled or uncontrolled asthma (prediction accuracy 75%), based on 41 transcripts: nine of them, which were down-regulated in uncontrolled asthma, are directly linked to IFN. This group also included GSDML, which is genetically associated with asthma. Our data revealed a Th2-driven epithelial phenotype common to all children with dust mite allergic rhinitis. It highlights the influence of epithelially expressed molecules on the control of asthma, in association with atopy and impaired viral response.

Evaluation of impulse oscillometry during bronchial challenge testing in children.

BACKGROUND: The impulse oscillation system (IOS) allows easy measurement of respiratory system impedance (Zrs). The aim of this retrospective study was to evaluate the accuracy of IOS parameters obtained during methacholine challenge by comparison with "the gold standard" forced expiratory volume in the first second (FEV1). METHODS: Measurements of FEV1 and resistances at 5 and 20 Hz, reactance at 5 Hz, impedance at 5 Hz and resonant frequency were performed in 227 children with suspected asthma, before and during methacholine challenge. Data were analyzed in the overall population and in three subgroups according to the final diagnosis: asthma (n = 72), chronic cough and nonspecific respiratory symptoms (n = 122), allergic rhinitis (n = 33). RESULTS: All IOS parameters changed significantly during the tests but only changes in X5 were significantly different between responders and nonresponders. Moreover, changes in IOS parameters were not correlated with changes in FEV1 apart from a weak correlation for X5. The receiver operating characteristic (ROC) curve for changes in X5 (to predict a 20% decrease in FEV1 showed a best decision level for a 50% decrease in X5 with a sensitivity of 36% and a specificity of 85%. Results were not different in the asthma group. CONCLUSION: The accuracy of measurements by IOS during methacholine bronchial challenge in children was not suitable when compared with FEV1 . It could be assumed that spirometry and IOS, while both providing indirect indices of airway patency, are exploring different mechanisms, each with its own methodological potentials and limitations.

Relationship between impulse oscillometry and spirometric indices in cystic fibrosis children.

BACKGROUND: The aim of our retrospective study was to determine the relationship between impulse oscillometry (IOS) data and spirometric tests in cystic fibrosis (CF) children. methods: Thirty CF children aged 4-19 years have performed lung function tests (LFT). A subset of 15 patients repeated LFT on five separate occasions. IOS parameters were respiratory resistance (Rrs), reactance (Xrs) and impedance at 5 Hz (R5, X5, Zr) and the resonant frequency (Fres). Spirometry indices (SI) included forced expiratory volume in 1 sec (FEV(1)), forced expiratory flow during the middle half of FVC (FEF(25-75)) and forced vital capacity (FVC). RESULTS: An inverse relationship was observed between raw values of R5, Zr, Fres and SI respectively, and X5 correlated positively with SI. Although significant, these correlations were poor. Receiver operating characteristic curves (ROC) were constructed to identify cutoff points for IOS parameters to discriminate between children according to predefined FEV(1) thresholds (percent predicted), generally used to categorize the level of lung function impairment. No acceptable cutoff points can be found for IOS parameters. Trends analyses in the subgroup of 15 patients showed a significant decline of FEV(1) between the first and the fifth evaluation. None of the IOS indices demonstrated a consistent tendency, apart from a slight decrease of Fres. CONCLUSION: IOS measurements presented an insufficient sensitivity to detect and follow bronchial obstruction in CF patients.