Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.

[Secondary surgeries in craniosynostosis and faciocraniosynostosis]. / Chirurgie secondaire des craniosténoses et faciocraniosténoses.

Secondary surgeries for single craniosynostosis surgeries are mainly esthetic refinements rather than functional indications. However, cranioplasties for bone defects correction or insufficient corrections may be undertaken. Management of syndromic craniosynostoses usually requires multiple surgical interventions, the sequence of which might vary per the genetic mutation. It is commonplace to start with posterior vault expansion before age 6 months, then treat cerebellar tonsillar herniation by the age of twelve months, and delay fronto-facial monobloc advancement until at least 18-24 months of age. Ventricular shunting is preferably avoided or delayed. Failure to respect these guidelines can significantly complicate the subsequent management. Primary fronto-orbital advancement or early facial osteotomy type Le Fort3, may compromise the subsequent fronto-facial monobloc advancement. However, this salvage secondary monobloc may be undertaken in some instances despite previous anterior osteotomies with a higher morbidity.

[Craniofacial strategy for syndromic craniosynostosis]. / Stratégie craniofaciale pour les faciocraniosténoses.

The complexity of treatment of faciocraniosynostosis justifies the treatment in a reference center for rare diseases. The growth disturbances in the skull and face being variable according to the type of mutation in the FGFr (Crouzon, Pfeiffer, Apert), the strategy is adapted to the phenotype according to the following principles: posterior expansion with or without distraction around 6 months to limit the descent of the cerebellum tonsils and to prevent the turricephalic development; fronto-facial monobloc advancement with internal distraction around the age of 18 months in case of severe exorbitism or breathing impairment. The dissociated strategy (fronto-orbital advancement first, followed by facial osteotomy of Le Fort 3 type). The growing evolution dictates the sequence of subsequent surgeries according to the monitoring of intracranial pressure by fundus examination and of the respiration by polysomnography. Le Fort 3 and transversal maxillary distraction may be repeated if necessary. Orthognathic surgery is almost always compulsory after the age of 14, before the aesthetic refinements which can be undertaken ultimately (rhinoplasty, genioplasty, canthopexies, fat grafting…).

Respiratory morbidity of preterm infants of less than 33 weeks gestation without bronchopulmonary dysplasia: a 12-month follow-up of the CASTOR study cohort.

The aim of this study was to describe the incidence and risk factors for respiratory morbidity during the 12-month period following the first respiratory syncytial virus (RSV) season in 242 preterm infants [<33 weeks gestational age (GA)] without bronchopulmonary dysplasia and 201 full-term infants (39-41 weeks GA) from the French CASTOR study cohort. Preterm infants had increased respiratory morbidity during the follow-up period compared to full-terms; they were more likely to have wheezing (21% vs. 11%, P = 0·007) and recurrent wheezing episodes (4% vs. 1%, P = 0·049). The 17 infants (14 preterms, three full-terms) who had been hospitalized for RSV-confirmed bronchiolitis during their first RSV season had significantly more wheezing episodes during the follow-up period than subjects who had not been hospitalized for RSV-confirmed bronchiolitis (odds ratio 4·72, 95% confidence interval 1·71-13·08, P = 0·003). Male gender, birth weight <3330 g and hospitalization for RSV bronchiolitis during the infant's first RSV season were independent risk factors for the development of wheezing episodes during the subsequent 12-month follow-up period.

Weaning from noninvasive ventilatory support in infants with severe bronchiolitis: An observational study.

BACKGROUND: The aim of the study was to analyze the weaning success, the type of weaning procedures, and weaning duration in consecutive infants hospitalized in a pediatric intensive care unit over a winter season. METHODS: A retrospective observational study was conducted in a pediatric intensive care unit in a tertiary center. Infants hospitalized for severe bronchiolitis were included and the weaning procedure from continuous positive airway pressure (CPAP), noninvasive ventilation (NIV), or high-flow nasal cannula (HFNC) was analyzed. RESULTS: Data from 95 infants (median age, 47 days) were analyzed. On admission, 26 (27%), 46 (49%), and 23 (24%) infants were supported with CPAP, NIV, and HFNC, respectively. Weaning failed in one (4%), nine (20%), and one (4%) infants while supported with CPAP, NIV, or HFNC, respectively (p = 0.1). In infants supported with CPAP, CPAP was stopped directly in five patients (19%) while HFNC was used as an intermediate ventilatory support in 21 (81%). The duration of weaning was shorter for HFNC (17 h, [IQR: 0-26]) than for CPAP (24 h, [14-40]) and NIV (28 h, [19-49]) (p < 0.01). CONCLUSIONS: The weaning phase corresponds to a large proportion of noninvasive ventilatory support duration in infants with bronchiolitis. The weaning procedure following a "step-down" strategy may lead to an increase in the duration of weaning.

Management of obstructive sleep apnea syndrome type 1 in children and adolescents - A French consensus.

This document is the outcome of a group of experts brought together at the request of the French Society of Sleep Research and Medicine to provide recommendations for the management of obstructive sleep apnea syndrome type 1 (OSA1) in children. The recommendations are based on shared experience and published literature. OSA1 is suspected when several nighttime respiratory symptoms related to upper airway obstruction are identified on clinical history taking. A specialist otolaryngologist examination, including nasofibroscopy, is essential during diagnosis. A sleep study for OSA1 is not mandatory when at least two nighttime symptoms (including snoring) are noted. Therapeutic management must be individualized according to the location of the obstruction. Ear, nose, and throat (ENT) surgery is often required, as hypertrophy of the lymphoid tissues is the main cause of OSA1 in children. According to clinical findings, orthodontic treatment generally associated with specialized orofacial-myofunctional therapy might also be indicated. Whatever treatment is chosen, follow-up must be continuous and multidisciplinary, in a network of trained specialists.

Effect of manufacturer-inserted mask leaks on ventilator performance.

Most pressure-support devices use a single circuit with an exhalation port integrated in the mask. The aim of the current study was to compare the effects of masks having different manufacturer-inserted leaks on ventilator performance. We simulated chronic obstructive pulmonary disease and restrictive disease. Four ventilators (VENTImotion (Weinmann, Hamburg, Germany), VPAP III STA (ResMed, Saint Priest, France), Synchrony 2 (Respironics, Nantes, France) and Vivo 40 (Breas, Saint Priest)) were tested with the recommended masks and with the masks having the largest and smallest leaks. Tests were performed with pressure support levels of 10, 15 and 20 cmH(2)O. The in vivo evaluation compared two ventilators using recommended masks opposed in terms of exhaled port resistance. The ventilators were tested with their recommended mask, and after mask exchange. The mask with the largest leak induced auto-triggering and/or increased inspiratory-trigger sensitivity was the VENTImotion under both simulated conditions and VPAP III STA under the simulated obstructive-disease condition. The mask with the smallest leak-increased inspiratory-trigger delay was Synchrony 2 in the simulated obstructive-disease condition and increased rebreathing. The in vivo study confirmed the bench results. When switching to a mask that has a different leak, evaluation is needed to adjust trigger sensitivity and pressurisation level and to check the absence of rebreathing.

Respiratory medicines for children: current evidence, unlicensed use and research priorities.

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

Respiratory management of children with spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) causes a predominantly bilateral proximal muscle weakness and atrophy. The respiratory muscles are also involved with a weakness of the intercostal muscles and a relatively spared diaphragm. This respiratory muscle weakness translates into a cough impairment, resulting in poor clearance of airway secretions and recurrent pulmonary infections, restrictive lung disease due to a poor or insufficient chest wall and lung growth, nocturnal hypoventilation and, finally, respiratory failure. Systematic and regular monitoring of respiratory muscle performance is necessary in children with SMA in order to anticipate respiratory complications, such as acute and chronic respiratory failure, and guide clinical care. This monitoring is based in clinical practice on volitional and noninvasive tests, such as vital capacity, sniff nasal inspiratory pressure, maximal static pressures, peak expiratory flow and peak cough flow because of their simplicity, availability and ease. In young children, those with poor cooperation or severe respiratory muscle weakness, other, mostly invasive, tests may be required to evaluate respiratory muscle performance. A sleep study, or at least overnight monitoring of nocturnal gas exchange is mandatory for detecting nocturnal alveolar hypoventilation. Training for patients and caregivers in cough-assisted techniques is recommended when respiratory muscle strength falls below 50% of predicted or in case of recurrent or severe respiratory infections. Noninvasive ventilation (NIV) should be initiated in case of isolated nocturnal hypoventilation and followed by a pediatric respiratory team with expertise in NIV. Multidisciplinary (neurology and respiratory) pediatric management is crucial for optimal care of children with SMA. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Sniff nasal inspiratory pressure in children with muscular, chest wall or lung disease.

Sniff nasal inspiratory pressure is proposed as a noninvasive test of inspiratory muscle strength. During this manoeuvre, the nasal pressure is supposed to reflect oesophageal pressure. The aim of the present study was to compare the nasal pressure with the oesophageal pressure during a maximal sniff in children with neuromuscular disease (NM, n = 78), thoracic scoliosis (n = 12) and cystic fibrosis (CF, n = 23). A significant correlation was observed between the sniff nasal and oesophageal pressure. The ratio of the sniff nasal/oesophageal pressure was lower in patients with CF (0.72+/-0.13) than in NM patients (0.83+/-0.17) or patients with thoracic scoliosis (0.86+/-0.10). In patients with CF and NM disease, this ratio was not correlated to age or spirometric data. The difference between the sniff oesophageal and nasal pressure exceeded 15 cm H(2)O in 17, 33 and 87% of the NM, thoracic scoliosis and CF patients, respectively. Sniff nasal pressure often underestimates the strength of inspiratory muscles in cystic fibrosis. Such an underestimation occurs more rarely in neuromuscular disease disorders and thoracic scoliosis. A normal value excludes inspiratory muscle weakness but a low value requires the measurement of the oesophageal pressure.

Exhaled nitric oxide in cystic fibrosis: relationships with airway and lung vascular impairments.

A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.

Medicines used in respiratory diseases only seen in children.

Detailed literature searches were carried out in seven respiratory disease areas. Therapeutic evidence for efficacy of medicinal products was assessed using the Grades of Recommendation, Assessment and Evaluation (GRADE) methodology, as well as an assessment of safety and side-effects. Systemic corticosteroids may reduce the development of bronchopulmonary dysplasia but have serious side-effects. Antioxidants need further study to demonstrate whether they have long-term benefits. Treatments for acute bronchiolitis have shown little benefit but new antiviral and monoclonal antibodies need further assessment. Well-constructed studies are needed to confirm the value of inhaled corticosteroids and/or montelukast in the management of viral-induced wheeze. Corticosteroids are the treatment of choice in croup. Minimal or no information is available for the treatment of congenital lung abnormalities, bronchiolitis obliterans and interstitial lung disease.

[Sleep-disordered breathing in children]. / Les troubles respiratoires du sommeil chez l'enfant.

Sleep-disordered breathing (SDB) in children comprises a wide spectrum of symptoms ranging from primary snoring to obstructive sleep apnea (OSA). Twelve percent of children present primary snoring and 1-2% OSA. Polysomnography is the gold standard for diagnosis of SDB allowing the analysis of sleep stages, respiratory movements, airflow, and gas exchange. However, this test remains highly technical, expensive, and difficult to conduct; other simpler diagnostic methods are under evaluation. Recent studies highlight the frequency and importance of cognitive and behavioral disorders in children with SDB; both the age and the severity of the SDB seem to modulate in the expression of neurocognitive consequences. Local and systemic inflammation plays a key role in the physiopathology of SDB and its complications: OSA is a cardiovascular risk factor in childhood that could favor atheromatous complications later in life. Adenoidotonsillectomy is the treatment of choice, but anti-inflammatory therapies such as leukotriene receptor antagonists or nasal corticoids may be beneficial in mild SDB or in residual OSA after adenotonsillectomy. In case of failure, noninvasive ventilation by means of nasal continuous positive pressure will be necessary, aided by specialists. SDB and OSA are a public health problem, underlining the pivotal role of the pediatrician in preventing, diagnosing, and treating these frequent disorders.

Contribution of a better maxillofacial phenotype in Silver-Russell syndrome to define a better orthodontics and surgical management.

INTRODUCTION: Maxillofacial phenotype for SRS is incompletely described in literature. The aim of this study was to describe a maxillofacial phenotype for SRS, to determine a better treatment. MATERIALS AND METHODS: A retrospective study was conducted including 37 patients with SRS. 24-control patients had been included and appareled. The subjective clinical examination included analyzes of SRS defined criteria. Frontal and lateral photographs had been reviewed, according to Farkas analysis; dental photographs had been examined for the deep-bite and the crowding severity. Radiologic cephalometric analysis had been reviewed. RESULTS: Maxillofacial examination showed protruding forehead (55%), anteverted ears (55%) and low-set ears (16%), small triangular face (48%); retrognatia (29%) and micrognathia (13%). SSR patients presented a lower forehead transverse growth, forehead height, and higher sagittal and transverse mandibular growth than control patients. Deep-bite was present in 21 patients of patient, and crowding in 17 patients. Cephalometric analysis showed 18 patients with the skeletal class II. We did not note a correlation between sleep apnea and retrognatia, neither between genetic anomalies and craniofacial phenotype. CONCLUSION: In this study, we showed new SRS characteristics: small forehead, small mandible, skeletal class II and a dental phenotype, leading to a specific maxillofacial and orthopedic management.

Measuring inspiratory muscle strength in neuromuscular disease: one test or two?

Inspiratory muscle strength monitoring is crucial in patients with neuromuscular disorders. The sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (P(I,max)) are usually measured. The present study investigated whether the test yielding the best value at baseline continued to yield the best value during follow-up. The present study included 25 patients with Duchenne muscular dystrophy (DMD) and 61 with myotonic muscular dystrophy (MMD). SNIP and P(I,max) were measured at baseline and then annually. At baseline, SNIP was lower than P(I,max) in 20 (80%) DMD patients and 32 (52%) MMD patients. During follow-up in DMD patients, changes in the best method always occurred from SNIP to P(I,max). In MMD patients, when SNIP was better than P(I,max) at baseline, SNIP was usually (88%) better during follow-up, whereas a better P(I,max) than SNIP at baseline was frequently (50%) followed by a shift to SNIP. Maximal inspiratory pressure may be sufficient for monitoring inspiratory muscle function in Duchenne muscular dystrophy adults. In myotonic muscular dystrophy, the marked variability in the test yielding the best value at baseline indicates a need for performance of both tests at baseline. However, when sniff nasal inspiratory pressure measurement yields the best value at baseline, using sniff nasal inspiratory pressure alone during follow-up may be appropriate.

Performance of ventilators for noninvasive positive-pressure ventilation in children.

The aim of the present study was to evaluate the performance characteristics of all the ventilators proposed for home noninvasive positive-pressure ventilation in children in France. The ventilators (one volume-targeted, 12 pressure-targeted and four dual) were evaluated on a bench which simulated six different paediatric ventilatory patterns. For each ventilator, the quality of the inspiratory and expiratory trigger and the ability to reach and maintain the preset pressures and volumes were evaluated with the six patient profiles. The performance of the ventilators showed great variability, and depended upon the type of trigger (flow or pressure), type of circuit and patient profile. Differences were observed between the preset and measured airway pressure and between the tidal volume measured by the ventilator and on the bench. Leaks were associated with an inability to detect the patient's inspiratory effort or autotriggering. No single ventilator was able to adequately ventilate the six paediatric profiles. Only a few ventilators were able to ventilate the profiles simulating the youngest patients. A systematic paediatric bench evaluation is recommended for every ventilator proposed for home ventilation, in order to detect any dysfunction and guide the choice of the appropriate ventilator for a specific patient.

[Malnutrition in children with chronic bronchitis]. / Prévalence et conséquences de la dénutrition au cours de la bronchite chronique de l'enfant.

OBJECTIVE: To study nutritional status in children with chronic bronchitis (CB) in relation with lung function. METHODS: In this cohort of study, 46 patients aged 6.0 to 17.5 years (mean: 11.9 years) with chronic bronchitis were recruited. None had cystic fibrosis. Body weight, height, skinfold thicknesses, percentage of ideal body weight-for-height (percentage of IBW), body mass index (BMI), BMI Z-score, fat mass and fat-free mass were used to evaluate nutritional status. Arterial blood gases, vital capacity (VC), forced expiratory volume in one s (FEV1), functional residual capacity (FRC) and maximum inspiratory (Pi(max)) and expiratory (Pe(max)) pressures at the mouth were used to evaluate respiratory function. RESULTS: Thirteen children (28%) had malnutrition defined as percentage of IBW lower than 90%, with a predominant fat mass depletion. VC (65+/-13% versus 79+/-15%; p=0.006) and FEV1 (59+/-16% versus 69+/-14%; p=0.03) were significantly lower in children with malnutrition than in children without malnutrition, but no significant differences were observed with regard to the FEV1/VC ratio and blood gases. Pi(max) (56+/-11% versus 88+/-37%, p=0,02) and Pe(max) (46+/-12% versus 58+/-19%, p=0,3) were also lower in children with malnutrition as compared to than without malnutrition. CONCLUSION: Malnutrition can be observed in children with CB and is associated with significant lower lung function parameters. This could be explained by decrease in respiratory muscle strength.

[Pneumocystis jiroveci pneumonia during prolonged corticosteroid therapy in an immunocompetent infant]. / Pneumonie àPneumocystis jiroveci au cours d'une corticothérapie prolongée chez un nourrisson immunocompétent.

INTRODUCTION: Pneumocystis jiroveci (PJ) infection is rare in infants and is suggestive of primary or secondary immunodeficiency. We report on a case of severe PJ pneumonia in an immunocompetent infant after prolonged corticosteroid treatment. CASE REPORT: A 5 1/2 month-old girl presented with hypoxemic respiratory distress. Her medical record was remarkable only for a bulky parotid haemangioma, which was treated with prolonged oral corticosteroid therapy. The chest X-ray showed a mixed alveolar-interstitial pattern, and bronchoalveolar lavage revealed the presence of PJ. A favourable outcome was obtained after three weeks of intravenous trimethoprim-sulfamethoxazole treatment. CONCLUSION: PJ infection should be suspected in infants presenting with progressive respiratory distress associated with a mixed alveolar-interstitial pattern. Its potential seriousness justifies prophylactic therapy during prolonged immunosuppressive treatment (chemotherapy, corticosteroid treatment).