Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

Inefficient antiviral response in reconstituted small-airway epithelium from chronic obstructive pulmonary disease patients following human parainfluenza virus type 3 infection.

Chronic obstructive pulmonary disease (COPD) affects over 250 million individuals globally and stands as the third leading cause of mortality. Respiratory viral infections serve as the primary drivers of acute exacerbations, hastening the decline in lung function and worsening the prognosis. Notably, Human Parainfluenza Virus type 3 (HPIV-3) is responsible for COPD exacerbations with a frequency comparable to that of Respiratory Syncytial Virus and Influenza viruses. However, the impact of HPIV-3 on respiratory epithelium within the context of COPD remains uncharacterized.In this study, we employed in vitro reconstitution of lower airway epithelia from lung tissues sourced from healthy donors (n = 4) and COPD patients (n = 5), maintained under air-liquid interface conditions. Through a next-generation sequencing-based transcriptome analysis, we compared the cellular response to HPIV-3 infection.Prior to infection, COPD respiratory epithelia exhibited a pro-inflammatory profile, notably enriched in canonical pathways linked to antiviral response, B cell signaling, IL-17 signaling, and epithelial-mesenchymal transition, in contrast to non-COPD epithelia. Intriguingly, post HPIV-3 infection, only non-COPD epithelia exhibited significant enrichment in interferon signaling, pattern recognition receptors of viruses and bacteria, and other pathways involved in antiviral responses. This deficiency could potentially hinder immune cell recruitment essential for controlling viral infections, thus fostering prolonged viral presence and persistent inflammation.

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

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.

Cumulative Incidence and Risk Factors for Severe Coronavirus Disease 2019 in French People With Cystic Fibrosis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), especially severe cases. Previous studies used hospitalization rates as proxy for severity. METHODS: We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF over the first pandemic year. Objective criteria were applied for defining severity (eg, respiratory failure and/or death). Data were compared to all French pwCF using the National Registry. RESULTS: As of 30 April 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (odds ratio [OR], 2.52 [95% confidence interval {CI}, 1.82-3.48]) and transplant recipients (OR, 2.68 [95% CI, 1.98-3.63]). Sixty (26.9%) patients were hospitalized, with increased risk in transplant recipients (OR, 4.74 [95% CI, 2.49-9.02]). In 34 (15%) cases, COVID-19 was considered severe; 28 (46.7%) hospitalizations occurred without objective criteria of severity. Severe cases occurred mostly in adult (85.3%) and posttransplant pwCF (61.8%; OR, 6.02 [95% CI, 2.77-13.06]). In nontransplanted pwCF, risk factors for severity included low lung function (median percentage of predicted forced expiratory volume in 1 second, 54.6% vs 75.1%; OR, 1.04 [95% CI, 1.01-1.08]) and CF-related diabetes (OR, 3.26 [95% CI, 1.02-10.4]). While 204 cases fully recovered, 16 were followed for possible sequelae, and 3 posttransplant females died. CONCLUSIONS: Severe COVID-19 occurred infrequently during the first pandemic year in French pwCF. Nontransplanted adults with severe respiratory disease or diabetes and posttransplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

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.

Small airway dysfunction is an independent dimension of wheezing disease in preschool children.

BACKGROUND: Whether small airway dysfunction (SAD), which is prevalent in asthma, helps to characterize wheezing phenotypes is undetermined. The objective was to assess whether SAD parameters obtained from impedance measurement and asthma probability are linked. METHODS: One hundred and thirty-nine preschool children (mean age 4.7 years, 68% boys) suffering from recurrent wheezing underwent impulse oscillometry that allowed calculating peripheral resistance and compliance of the respiratory system (markers of SAD) using the extended RIC model (central and peripheral resistance, inertance, and peripheral compliance). Children were classified using the probability-based approach of GINA guidelines (few, some, and most having asthma). A principal component analysis (PCA) that determined the dimensions of wheezing disease evaluated the links between SAD and asthma probability. RESULTS: Forty-seven children belonged to the few, 28 to the some, and 64 to the most having asthma groups. Whereas their anthropometrics and measured parameters were similar, the most having asthma group exhibited the lowest mean value of airway inertance after bronchodilator probably due to airway inhomogeneities. PCA characterized four independent dimensions including a peripheral resistance (constituted by baseline peripheral compliance, Frs, R5Hz, R5-20Hz, X5Hz, and AX), a central resistance (baseline central resistance, R20Hz), anthropometrics (age and height), and asthma probability (wheezing patterns and therapeutic steps). Thus, PCA showed that the SAD markers were independent from clinical dimensions and were unable to differentiate wheezing phenotypes. CONCLUSIONS: Lung function parameters obtained from impulse oscillometry and asthma probability were belonging to independent dimensions of the wheezing disease.

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.

Beneficial short-term effect of autogenic drainage on peripheral resistance in childhood cystic fibrosis disease.

BACKGROUND: Airway clearance techniques are supposed to be a necessary adjunct for the enhancement of impaired peripheral clearance in cystic fibrosis (CF). The objective was to assess the effect of one physiotherapy session (autogenic drainage: AD) on mucus clearance (sputum wet weight) and impulse oscillometry system (IOS) indices, including those obtained from extended Resistance-Inertance-Compliance (eRIC) modelling, considering the degree of bronchial congestion. METHODS: Thirty children with CF (median age: 12.7 years) in a stable condition prospectively underwent IOS measurements at baseline and after AD. They were divided in two groups: with (visual analog scale of bronchial congestion by the physiotherapist ≥ 5/10) and without (scale < 5/10) bronchial congestion. Paired-comparison of the effects of AD on airway resistance measurements was done with Wilcoxon test. RESULTS: The congestion scale correlated with the wet weight of sputum production during the session (Pearson test: p < 0.0001, R = 0.66). Ten children had bronchial congestion and 20 were without congestion. In the whole group, R5-20 Hz significantly decreased after AD (P = 0.049), which was related to a decrease in the children with congestion (P = 0.025), whereas it was not significantly modified in the children without congestion (P = 0.327). The eRIC model allowed the calculation of the peripheral resistance of the respiratory system, which also decreased in the children with congestion (P = 0.037), however, not modified in the children without congestion (P = 0.390). CONCLUSION: One session of autogenic drainage has the ability to decrease peripheral resistance obtained from IOS measurements, more specifically in children with CF with moderate to severe bronchial congestion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04094441.

Frequent lower respiratory tract disease in hematological patients with parainfluenza virus type 3 infection.

Human parainfluenza virus type 3 (HPIV-3) may cause lower respiratory tract infection disease (LRTI-D) after hematopoietic stem cell transplantation (HSCT). Most previous have studies focused on recipients of HSCT whereas data on characteristics and outcomes in patients with hematological malignancies (HMs) compared to non-hematological patients are limited. The prognostic value of viral load in respiratory specimens remains elusive. In a 2-year retrospective study, we determined the frequencies of LRTI-D in HM, HSCT, and in non-hematological patients, and HPIV-3 levels in respiratory tract secretions. Among 98 patients with HPIV-3 infection, including 31 HSCT and 40 HM, 36 had a diagnosis of LRTI-D. LRTI-D was significantly more frequent in patients with HM or HSCT (n = 32, 45.1%) than in non-hematological patients (n = 4, 14.8%) (p = 0.006). The median HPIV-3 loads were high in upper respiratory tract secretions regardless of the presence or absence of LRTI-D (8.3 log10 vs. 7.6 log10 TCID50 /106 cells). HPIV-3 loads in respiratory tract samples in HM were not significantly higher than those found in HSCT but significantly higher than in non-hematological patients (p = 0.007). In conclusion, LRTI-D was frequent in HM patients who were diagnosed with HPIV-3 infection.

Cross-sectional phenotyping of small airway dysfunction in preschool asthma using the impulse oscillometry system.

Objective. Asthma is a chronic inflammatory airway disorder known to induce small airways dysfunction (SAD). It is important to develop tools to assess the presence and extent of SAD in daily clinical practice. An Impulse Oscillometry System (IOS) might detect SAD, but the validity of the underlying model (serial Resistive airway and Compliant tissue model: RC model) in diseased lungs remains questionable.Methods. Our objective was to evaluate the usefulness of parameters obtained from six electrical circuit models that were fitted to the measurements of impedance obtained with IOS in asthmatic children characterized by an abnormal lung function defined by an increased baseline interrupter resistance (Rint, z-score > +1.645).Results. The six models were tested in 102 asthmatic children (median age: 5.5 years). Two models allowed the description of 92/102 (90%) children: 74 by the extended RIC model (central and peripheral Resistance, Inertance and peripheral airway Compliance) and 18 by the Mead1969 model (extended RIC plus lung compliance). Thus, peripheral airway compliance and resistance were essential to describe lung function abnormalities of these asthmatic children. Parenchyma impairment (increased lung compliance) which was responsive to salbutamol was present in 18% of asthmatic children. After salbutamol, peripheral airway resistance decreased while peripheral airway compliance increased, arguing for asthma-related SAD. R5-20Hz independently correlated with the two latter parameters but was increased in two thirds of children with increased Rint only.Conclusion. Additional modeling of IOS results can be a reliable tool to assess the presence and extent of SAD in young asthmatic children.

Lung evaluation in 10 year survivors of pediatric allogeneic hematopoietic stem cell transplantation.

There is little data on the long-term respiratory development of children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We describe the respiratory assessment 10 years after allo-HSCT of 35 children transplanted between 2000 and 2004. During this period, 90 children were transplanted at our center. Twenty-five children died, thirty were lost to follow-up, and thirty-five came to have a pulmonary investigation. The thirty-five participants answered a questionnaire asking if they had pulmonary symptoms, and pulmonary function tests (PFTs) were performed. The median age of these children 10 years after the transplant was 16 years old. Just over a third of them had pulmonary symptoms. Among them, 5/13 (38%) had bronchiolitis obliterans syndrome (BOS). The majority of children (62.8%) did not have respiratory symptoms. PFTs were abnormal in one-third of asymptomatic children, revealing restrictive lung disease that was always mild to moderate (p = 0.02).Conclusion: In the long term, research at the time of the medical examination for the presence of chronic cough, shortness of breath on exertion, or wheezing helps to guide the clinician as to the need for further lung exploration. Similarly, informing patients and their families about these symptoms, which can be underestimated, should allow for more specific management.What is Known:• Pulmonary complications are a major cause of hematopoietic stem cell transplantation (HSCT) morbidity and mortality.• A long time after allogeneic HSCT, pulmonary function tests abnormalities may occur in children, but it is not always related to symptoms.What is New:• The occurrence of respiratory symptoms: cough, dyspnea on exertion, chronic bronchitis, and wheezing should be systematically investigated in the follow-up of allografted patients, even at a distance.• The presence of respiratory symptoms should lead to a respiratory functional investigation to detect the presence of an obstructive syndrome.

Association Between Migraine and Atopic Diseases in Childhood: A Potential Protective Role of Anti-Allergic Drugs.

BACKGROUND: Migraine is a common cause of headache in childhood. Several studies have investigated the association between migraine and atopic diseases, mostly in the adult population. OBJECTIVE: This study aimed to investigate this association in children. METHODS: A case-control study was conducted across 3 European tertiary care hospitals between June 2014 and August 2014. Cases (n = 229) were children aged 6-18 years consulting for a migraine episode. Controls in the same age range (n = 406) were consulting for a minor injury and did not have a history of recurrent headache. Logistic regression analyses tested the effect of atopic diseases and anti-allergic therapies on occurrence of migraine. RESULTS: Children with migraine were more likely to have persistent asthma compared to absence of asthma (odds ratio [OR]: 4.57, 95% confidence interval [CI]: 2.04-10.24) and less likely to have been treated by inhaled or nasal corticosteroid (OR: 0.34, 95% CI: 0.15-0.76) or antihistamine therapy (OR: 0.33, 95% CI: 0.18-0.60). The median number of monthly migraine episodes was higher in children with persistent asthma (3; interquartile [IQR]: 1-4; range: 0.5-10) compared to children with intermittent asthma (2; IQR: 1-3; range: 0.1-4) or non-asthmatic children (2; IQR: 1-3; range: 0.1-12) (P < .01). CONCLUSION: Persistent childhood asthma was associated with increased risk of migraine and higher frequency of migraine attacks. History of anti-asthmatic or anti-allergic therapies was associated with decreased risk of migraine in children and adolescents. The role of these therapies on the pathogenesis and occurrence of migraine needs to be further elucidated because of the huge potential impact in terms of public health.

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.

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.

Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study.

The primary objective of our multicenter prospective study was to describe the incidence of late-onset non-infectious pulmonary complications (LONIPCs) in children undergoing hematopoietic cell transplantation (HCT) using sensitive criteria for pulmonary function test (PFT) abnormalities including the non-specific pattern of airflow obstruction. Secondary objectives were to assess the factors associated with LONIPC occurrence and the sensitivity of the 2014 NIH-Consensus Criteria of bronchiolitis obliterans syndrome (BOS). PFT and clinical assessment were performed prior to HCT and at 6, 12, 24, and 36 months post-HCT. LONIPC diagnosis was validated by an Adjudication Committee. The study comprised 292 children from 12 centers. Thirty-two individuals (11%, 95% CI: 8-15%) experienced 35 LONIPCs: 25 BOS, 4 interstitial lung diseases, 4 organizing pneumonia and 2 pulmonary veno-occlusive diseases. PFT abnormalities were obstructive defects (FEV1/FVC z-score < -1.645; n = 12), restrictive defects (TLC < 80% predicted, FEV1 and FVC z-scores < -1.645; n = 7) and non-specific pattern (FEV1 and FVC z-score< -1.645, FEV1/FVC z-score > -1.645, and TLC > 80% predicted; n = 8). HCT for malignant disease was the only factor associated with LONIPC (P = 0.04). The 2014 NIH-Consensus Criteria would only diagnose 8/25 participants (32%) as having BOS. In conclusion, 11% of children experienced a LONIPC in a prospective design. Clinical Trials.gov identifier (NCT number): NCT02032381.

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

Diagnostic tests and subtypes of dysfunctional breathing in children with unexplained exertional dyspnea.

BACKGROUND: Inappropriate hyperventilation during exercise may be a specific subtype of dysfunctional breathing (DB). OBJECTIVE: To assess whether Nijmegen questionnaire and hyperventilation provocation test (HVPT) are able to differentiate inappropriate hyperventilation from other DB subtypes in children with unexplained exertional dyspnea, and normal spirometry and echocardiography. METHODS: The results were compared between a subgroup of 25 children with inappropriate hyperventilation (increased V'E/V'CO2 slope during a cardiopulmonary exercise test (CPET)) and an age and sex matched subgroup of 25 children with DB without hyperventilation (median age, 13.5 years; 36 girls). Anxiety was evaluated using State-Trait Anxiety Inventory for Children questionnaire. RESULTS: All children were normocapnic (at rest and peak exercise) and the children with hyperventilation had lower tidal volume/vital capacity on peak exercise (shallow breathing). The Nijmegen score correlated positively with dyspnea during the CPET and the HVPT (p = 0.001 and 0.010, respectively) and with anxiety score (p = 0.022). The proportion of children with a positive Nijmegen score (≥19) did not differ between hyperventilation (13/25) and no hyperventilation (14/25) groups (p = 0.777). Fractional end-tidal CO2 (FETCO2 ) at 5-min recovery of the HVPT was < 90% baseline in all children (25/25) of both subgroups. Likewise, there was no significant difference between the two subgroups for other indices of HVPT (FETCO2 at 3-min recovery and symptoms during the test). CONCLUSION: The validity of the Nijmegen questionnaire and the HVPT to discriminate specific subtypes of dysfunctional breathing, as well as the relevance of the inappropriate hyperventilation subtype itself may both be questioned.