ERS statement on transition of care in childhood interstitial lung diseases.

Interstitial lung diseases (ILD) are a heterogeneous group of rare diffuse diseases affecting the lung parenchyma in children and adults. Childhood interstitial lung diseases (chILD) are often diagnosed at very young age, affect the developing lung, and can have different presentations and prognosis compared to adult forms of these diseases. Also, chILD in many cases may apparently remit, and have a better response to therapy and better prognosis than adult ILD. Many affected children will reach adulthood with minimal activity or clinical remission of the disease. They need continuing care and follow-up from childhood to adulthood if the disease persists and progresses over time but also if they are asymptomatic and in full remission. Therefore, for every chILD patient an active transition process from paediatric to adult care should be guaranteed. This ERS statement provides a review of the literature and current practice concerning transition of care in chILD. It draws on work in existing transition care programs in other chronic respiratory diseases, disease-overarching transition of care programs, evidence on the impact of these programs on clinical outcomes, current evidence regarding long-term remission of chILD as well as the lack of harmonisation between the current adult ILD and chILD classifications impacting on transition of care. While the transition system is well established in several chronic diseases, such as cystic fibrosis or diabetes mellitus, we could not find sufficient published evidence on transition systems in chILD. This statement summarises current knowledge but cannot yet provide evidence-based recommendations for clinical practice.

High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Long-term evolution of neuroendocrine cell hyperplasia of infancy: the FRENCHI findings.

Only few studies report long-term evolution of patients with neuroendocrine cell hyperplasia of infancy (NEHI). We report data from a 54-patient cohort followed up in the French network for rare respiratory diseases (RespiRare). Demographic characteristics and respiratory and nutritional evolution were collected at the time of the patient's last scheduled visit. The mean duration of follow-up was 68 months (5 months to 18 years). Fifteen patients (27.8%) were considered clinically cured. During follow-up, hospitalizations for wheezy exacerbations were reported in 35 patients (55%), and asthma diagnosed in 20 (37%). Chest CT scan improvement was noted in 25/44 (56.8%). Spirometry showed a persistent obstructive syndrome in 8/27 (29.6%). A sleep disorder was rare (2/36, 5.5%). Oxygen weaning occurred in 28 of the 45 patients initially treated (62.2%) and was age-dependent (35.7% under 2 years, 70.5% between 2 and 6 years, and 100% after 7 years). Oxygen duration was linked to a biopsy-proven diagnosis (p = 0.02) and to the use of a nutritional support (p = 0.003). Corticosteroids were largely prescribed at diagnosis, with no evident respiratory or nutritional effect during follow-up. Among 23 patients with an initial failure to thrive, 12 (52.2%) had no weight recovery. Initial enteral feeding (17/54, 31.5%) was stopped at a mean age of 43 months (3 to 120), with no effect on cure and oxygen liberation at the last visit.  Conclusion: Our results show that NEHI has a globally positive, but unequal, improvement over time. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI. What is Known: • Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose long-term outcome is considered positive from very few studies including heterogeneous populations. What is New: • The 68-month follow-up of our 54-patient cohort showed respiratory/nutritional symptom persistence in 72.2%, oxygen requiring in 34%, and asthma in 37%. When controlled, radiological or functional improvement was noted in 56.8 and 40.7%. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI.

Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study.

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

French national cohort of neuroendocrine cell hyperplasia of infancy (FRENCHI) study: diagnosis and initial management.

Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%). CONCLUSION: This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs. WHAT IS KNOWN: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy. WHAT IS NEW: •In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.

Methylprednisolone pulse treatment improves ProSP-C trafficking in twins with SFTPC mutation: An isoform story?

Mutations in the gene encoding surfactant protein C (SP-C) cause interstitial lung disease (ILD), and glucocorticosteroid (GC) treatment is the most recognized therapy in children. We aimed to decipher the mechanisms behind successful GC treatment in twins carrying a BRICHOS c.566G > A (p.Cys189Tyr) mutation in the SP-C gene (SFTPC). METHODS: The twins underwent bronchoscopy before and after GC treatment and immunoblotting analysis of SP-C proprotein (proSP-C) and SP-C mature in bronchoalveolar fluid (BALF). Total RNA was extracted and analysed using quantitative real-time PCR assays. In A549 cells, the processing of mutated protein C189Y was studied by immunofluorescence and immunoblotting after heterologous expression of eukaryotic vectors containing wild type or C189Y mutant cDNA. RESULTS: Before treatment, BALF analysis identified an alteration of the proSP-C maturation process. Functional study of C189Y mutation in alveolar A549 cells showed that pro-SP-CC189Y was retained within the endoplasmic reticulum together with ABCA3. After 5 months of GC treatment with clinical benefit, the BALF analysis showed an improvement of proSP-C processing. SFTPC mRNA analysis in twins revealed a decrease in the expression of total SFTPC mRNA and a change in its splicing, leading to the expression of a second shorter proSP-C isoform. In A549 cells, the processing and the stability of this shorter wild-type proSP-C isoform was similar to that of the longer isoform, but the half-life of the mutated shorter isoform was decreased. These results suggest a direct effect of GC on proSP-C metabolism through reducing the SFTPC mRNA level and favouring the expression of a less stable protein isoform.

Targeting p16INK4a Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury.

Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4aATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.

[Improving pain assessment of infants in paediatric emergency departments]. / Améliorer l'évaluation de la douleur des nourrissons aux urgences pédiatriques.

Not having access to language, the infant is deprived of an essential means of communicating its painful experience. The assessment of their pain in the emergency room is therefore quite complex. A study carried out in the paediatric emergency department of the Centre hospitalier intercommunal de Créteil shows that it is possible to improve this aspect thanks, among other things, to continuous training and the presence of experts in children's pain within the team.

A randomised trial of high-flow nasal cannula in infants with moderate bronchiolitis.

BACKGROUND: The objective was to determine whether high-flow nasal cannula (HFNC), a promising respiratory support in infant bronchiolitis, could reduce the proportion of treatment failure requiring escalation of care. METHODS: In this randomised controlled trial, we assigned infants aged <6 months who had moderate bronchiolitis to receive either HFNC at 3 L·kg-1·min-1 or standard oxygen therapy. Crossover was not allowed. The primary outcome was the proportion of patients in treatment failure requiring escalation of care (mostly noninvasive ventilation) within 7 days following randomisation. Secondary outcomes included rates of transfer to the paediatric intensive care unit (PICU), oxygen, number of artificial nutritional support-free days and adverse events. RESULTS: The analyses included 268 patients among the 2621 infants assessed for inclusion during two consecutive seasons in 17 French paediatric emergency departments. The percentage of infants in treatment failure was 14% (19 out of 133) in the study group, compared to 20% (27 out of 135) in the control group (OR 0.66, 95% CI 0.35-1.26; p=0.21). HFNC did not reduce the risk of admission to PICU (21 (15%) out of 133 in the study group versus 26 (19%) out of 135 in the control group) (OR 0.78, 95% CI 0.41-1.41; p=0.45). The main reason for treatment failure was the worsening of modified Wood clinical asthma score (m-WCAS). Short-term assessment of respiratory status showed a significant difference for m-WCAS and respiratory rate in favour of HFNC. Three pneumothoraces were reported in the study group. CONCLUSIONS: In patients with moderate bronchiolitis, there was no evidence of lower rate of escalating respiratory support among those receiving HFNC therapy.

International management platform for children's interstitial lung disease (chILD-EU).

BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.

Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities.

Stroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P< .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 10(9)/L (P< .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion.

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia.

Early transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI.

Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects.

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns-cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency-in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans.

Ultrasonography and Computed Tomographic Manifestations of Abdominal Sarcoidosis in Children.

OBJECTIVES: Sarcoidosis is a multisystem, granulomatous inflammatory disease affecting both pediatric and adult patients. So far in children, very few radiological descriptions of abdominal sarcoidosis manifestations have been reported. The present study describes the frequency and the appearance of abdominal radiologic manifestations in pediatric patients with histologically proven sarcoidosis. METHODS: We reviewed retrospectively all of the radiological examinations of 22 patients ages 1 to 15 years at diagnosis with proven sarcoidosis evaluated in a university pediatric hospital between 1994 and 2014. The locations of biopsies and the angiotensin-converting enzyme level were reported. The size, shape, and parenchymal homogeneity of the liver and spleen, the presence of abdominal lymph nodes, and abnormalities of the gastrointestinal tract were tabulated. RESULTS: The study included 22 children (mean age: 9.9 ±â€Š2.8 years). The liver was the most frequent location of biopsy (12/22), even without radiological involvement. Abdominal manifestations were present in 11 of 22 children with sarcoidosis. Hepatomegaly was the most frequent abnormality, reported in 8 of 11 cases either homogeneous (n = 7) or nodular (n = 1). Homogeneous lymph node enlargement was noted in 6 of 11 cases and splenomegaly in 4 of 11 cases. No calcification was observed. All patients with initial abdominal sarcoidosis had simultaneous thoracic involvement. CONCLUSIONS: Abdominal manifestations in children sarcoidosis are frequent but often nonspecific. Nodular hepatosplenomegaly is rare. All of our patients with abdominal abnormalities had a more specific associated thoracic involvement. Awareness of this association could assist the clinicians in assessing the initial diagnosis of abdominal sarcoidosis in children.

Lung sarcoidosis in children: update on disease expression and management.

BACKGROUND: Sarcoidosis is a rare lung disease in children. The aim of the present study was to provide update information on disease presentation and progression, patient management and prognosis factors in a cohort of children with lung sarcoidosis. METHODS: With the network of the French Reference Centre for Rare Lung Diseases (RespiRare), we collected information on a large cohort of paediatric thoracic sarcoidosis to provide information on disease presentation, management and outcome. RESULTS: Forty-one patients were included with a median age at diagnosis of 11.8  years (1.1-15.8), mostly from Afro-Caribbean and Sub-Saharan origin. At diagnosis, 85% presented with a multi-organic disease, and no major differences were found regarding disease severity between the patients diagnosed before or after 10 years old. Corticosteroids were the most used treatment, with more intravenous pulses in the youngest patients. The 18-month outcome showed that patients diagnosed before 10 years old were more likely to recover (50% vs 29%), and presented fewer relapses (29% vs 58%). At 4-5 years of follow-up, relapses were mostly observed for patients diagnosed after 10 years old. DISCUSSION: In the included children, mostly of Afro-Caribbean and Sub-Saharan origin, sarcoidosis seems severe, with multi-organic involvement and foreground general symptoms. Common prognosis factors are not suitable in paediatric patients, and a young age at diagnosis does not seem to be associated with a poorer prognosis. The study is ongoing to provide further information on the very-long-term follow-up of paediatric sarcoidosis.

European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

Interstitial lung disease in children (chILD) is rare, and most centres will only see a few cases/year. There are numerous possible underlying diagnoses, with specific and non-specific treatment possibilities. The chILD-EU collaboration has brought together centres from across Europe to advance understanding of these considerations, and as part of this process, has created standard operating procedures and protocols for the investigation of chILD. Where established consensus documents exist already, for example, for the performance of bronchoalveolar lavage and processing of lung biopsies, these have been adopted. This manuscript reports our proposals for a staged investigation of chILD, starting from when the condition is suspected to defining the diagnosis, using pathways dependent on the clinical condition and the degree of illness of the child. These include the performance of genetic testing, echocardiography, high-resolution CT, bronchoscopy when appropriate and the definitive investigation of lung biopsy, in order to establish a precise diagnosis. Since no randomised controlled trials of treatment have ever been performed, we also report a Delphi consensus process to try to harmonise treatment protocols such as the use of intravenous and oral corticosteroids, and add-on therapies such as hydroxychloroquine and azithromycin. The aim is not to dictate to clinicians when a therapeutic trial should be performed, but to offer the possibility to collaborators of having a unified approach when a decision to treat has been made.