Health-related quality scores in childhood interstitial lung disease: Good agreement between patient and caregiver reports.

INTRODUCTION: Childhood interstitial lung disease (chILD) is a heterogeneous group of mostly chronic respiratory disorders. Assessment of health-related quality of life (HrQoL) in chILD has become increasingly important in clinical care and research. The aim of this study was to assess differences between patient-reported (self) and caregiver-reported (proxy) HrQoL scores. METHODS: This study used data obtained from the chILD-EU Register. After inclusion (baseline), the patient's health status was followed up at predefined study visits. At each study visit, caregivers and patients were handed validated, age-specific HrQoL questionnaires. HrQoL data entered at baseline were used to compare self- and proxy-reported HrQoL scores. For the longitudinal analysis, we compared HrQoL scores between the baseline and the next follow-up visit. RESULTS: No differences between patient- and caregiver-reported HrQoL scores were found for school functioning, chILD-specific questionnaire score, and physical health summary score. Self-reported HrQoL scores were higher for the subscales emotional functioning (77.4 vs. 70.7; p < .001), social functioning (81.9 vs. 76.2; p < .001), as well as psycho-social summary score (76.5 vs. 71.8; p < .001) and total score (74.7 vs. 70.8; <.001). The longitudinal analysis showed that a significant change in a patient-reported HrQoL score resulted in a significant change in a caregiver-reported HrQoL score after a mean time of 11.0 months (SD 9.4). CONCLUSIONS: We found a good agreement between children- and caregiver-related HrQoL scores. In chILD, caregivers are able to sense changes in children's HrQoL scores over time and may be used as a proxy for children unable to complete HrQoL questionnaires.

A novel mutation in GAS8 gene associated with chronic rhinosinusitis with nasal polyposis in a case of primary ciliary dyskinesia: a case report.

Background: Primary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus. Case presentation: We report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8. Conclusion: Children with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.

Increased bronchiolitis burden and severity after the pandemic: a national multicentric study.

BACKGROUND: The coronavirus 2019 (COVID-19) related containment measures led to the disruption of all virus distribution. Bronchiolitis-related hospitalizations shrank during 2020-2021, rebounding to pre-pandemic numbers the following year. This study aims to describe the trend in bronchiolitis-related hospitalization this year, focusing on severity and viral epidemiology. METHODS: We conducted a retrospective investigation collecting clinical records data from all infants hospitalized for bronchiolitis during winter (1st September-31th March) from September 2018 to March 2023 in six Italian hospitals. No trial registration was necessary according to authorization no.9/2014 of the Italian law. RESULTS: Nine hundred fifty-three infants were hospitalized for bronchiolitis this last winter, 563 in 2021-2022, 34 in 2020-2021, 395 in 2019-2020 and 483 in 2018-2019. The mean length of stay was significantly longer this year compared to all previous years (mean 7.2 ± 6 days in 2022-2023), compared to 5.7 ± 4 in 2021-2022, 5.3 ± 4 in 2020-2021, 6.4 ± 5 in 2019-2020 and 5.5 ± 4 in 2018-2019 (p < 0.001), respectively. More patients required mechanical ventilation this winter 38 (4%), compared to 6 (1%) in 2021-2022, 0 in 2020-2021, 11 (2%) in 2019-2020 and 6 (1%) in 2018-2019 (p < 0.05), respectively. High-flow nasal cannula and non-invasive respiratory supports were statistically more common last winter (p = 0.001 or less). RSV prevalence and distribution did not differ this winter, but coinfections were more prevalent 307 (42%), 138 (31%) in 2021-2022, 1 (33%) in 2020-2021, 68 (23%) in 2019-2020, 61 (28%) in 2018-2019 (p = 0.001). CONCLUSIONS: This study shows a growth of nearly 70% in hospitalisations for bronchiolitis, and an increase in invasive respiratory support and coinfections, suggesting a more severe disease course this winter compared to the last five years.

Severe asthma guidelines in children and adolescents: A practical document for physicians.

Asthma is a common disease in childhood with a minority of affected children suffering from severe asthma. Patients with severe asthma require high dose inhaled glucocorticoids plus a second controller and/or systemic corticosteroids to be well-controlled or remain uncontrolled despite such treatment. Although only a small subset of children and adolescents falls in this category, the management of affected patients represents a major concern for pediatricians. Guidelines and recommendations have been designed to guide the management of this group of patients. Though the terms "recommendations" and "guidelines" are often used interchangeably, it should be noted that the first one should be used more narrowly to identify specific actions and the second one to broadly refer to the umbrella under which multiple recommendations for a specific condition are provided. Moreover, the availability of several and sometimes-conflicting documents on severe asthma management both in adult and pediatric age could generate confusion among health care professionals. The manuscript analyses seven papers addressing severe asthma, comparing any key aspects and differences. Finally, we tried to create a more practical document for physicians to simplify the interpretation of the several available documents on severe asthma management focusing the pediatric age.

Primary ciliary dyskinesia: A multicenter survey on clinical practice and patient management in Italy.

INTRODUCTION: There are no recent data on primary ciliary dyskinesia (PCD) distribution, diagnosis and treatment in Italy. METHODS: A descriptive study based on a survey questionnaire. It consisted of three sections (patients, diagnosis, and treatment), and sent to all the Italian PCD Centers. RESULTS: Questionnaires obtained from 20/22 centers in 12/20 regions showed that the total number of PCD patients treated at the participating centers was of 416. Out of all centers, 55% follow <20 patients, two centers have >40 patients, and 75% follow both pediatric and adults. Age at diagnosis was between 4 and 8 years in 45% of the centers, <3 years in three centers. Nasal nitric oxide, transmission electron microscopy and ciliary high-speed video microscopy are performed in 75%, 90%, and 40% of centers, respectively. Immunofluorescence is available in five centers. Genetic analysis is offered in 55% of the centers, and in seven centers >50% of the patients have a known genetic profile. Patients treated at all centers receive inhaled saline solutions, corticosteroids and chest physiotherapy. Prophylactic antibiotics and mucolytics are prescribed in 95% and 50% of the centers, respectively. Pseudomonas infection is treated with oral or inhaled antibiotics. CONCLUSIONS: Many Italian centers care for a small number of pediatric and adult patients, and diagnosis is often delayed. We found a great variability in the available diagnostic procedures, as well in the prescribed therapies. Our study will help to uniform diagnostic algorithm and share treatments protocols for PCD in Italy and allowed to set specific national goals.

Comparison of mental health in individuals with primary ciliary dyskinesia, cystic fibrosis, and parent caregivers.

INTRODUCTION: Individuals with chronic respiratory diseases and caregivers are at higher risk for depression and anxiety. Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both rare genetic diseases, characterized by recurrent respiratory infections. This study compared depression and anxiety in people with PCD (pwPCD) and CF (pwCF), and caregivers, using the screening tools recommended in the CF guidelines. METHODS: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) were administered to a PCD and CF sample. Given that PCD is extremely rare, they were matched on age and sex to pwCF at a 1:2 ratio. Similar procedures were performed with parents. RESULTS: A total of 63 patients and 129 caregivers participated: 21 pwPCD and 42 pwCF (ages 12-34 years) plus 43 caregivers of pwPCD and 86 caregivers of pwCF. A high percentage of patients scored above the cut-off for depression (PCD: 33%; CF: 43%) and anxiety (PCD and CF both: 43%), mostly mild. Similarly, a high percentage of caregivers scored above the cut-off for depression (PCD: 42-54%; CF: 45-46%) and anxiety (PCD: 47-54%; CF: 39-56%). Suicidal ideation was endorsed by 9.5% of pwPCD, 20% of mothers and 10% of fathers and 5% of pwCF, 3% of mothers, but no fathers. CONCLUSION: A large percentage of patients and caregivers reported elevated psychological distress and suicidal ideation. Addressing psychological symptoms is critical given they are associated with poor adherence, missed clinic visits, increased inflammation and worse quality of life. Mental health screening and treatment should be integrated into PCD care.

Long-Term Ventilation in Children with Medical Complexity: A Challenging Issue.

Children with medical complexity (CMCs) represent a subgroup of children who may have congenital or acquired multisystemic disease. CMCs are frequently predisposed to respiratory problems and often require long-term mechanical ventilation (LTMV). The indications for LTMV in CMCs are increasing, but gathering evidence about indications, titration, and monitoring is currently the most difficult challenge due to the absence of validated data. The aim of this review was to examine the clinical indications and ethical considerations for the initiation, continuation, or withdrawal of LTMV among CMCs. The decision to initiate long-term ventilation should always be based on clinical and ethical considerations and should be shared with the parents.

Increased use of high-flow nasal cannulas after the pandemic in bronchiolitis: a more severe disease or a changed physician's attitude?

After the SARS-CoV-2 pandemic, we noticed a marked increase in high-flow nasal cannula use for bronchiolitis. This study aims to report the percentage of children treated with high-flow nasal cannula (HFNC) in various seasons. The secondary outcomes were admissions for bronchiolitis, virological results, hospital burden, and NICU/PICU need. We conducted a retrospective study in four Italian hospitals, examining the medical records of all infants (< 12 months) hospitalized for bronchiolitis in the last four winter seasons (1 September-31 March 2018-2022). In the 2021-2022 winter season, 66% of admitted children received HFNC versus 23%, 38%, and 35% in the previous 3 years. A total of 876 patients were hospitalized in the study periods. In 2021-2022, 300 infants were hospitalized for bronchiolitis, 22 in 2020-2021, 259 in 2019-2020, and 295 in 2018-2019. The percentage of patients needing intensive care varied from 28.7% to 18%, 22%, and 15% in each of the four considered periods (p < 0.05). Seventy-seven percent of children received oxygen in the 2021-2022 winter; vs 50%, 63%, and 55% (p < 0.01) in the previous 3 years. NIV/CPAP was used in 23%, 9%, 16%, and 12%, respectively. In 2021-2020, 2% of patients were intubated; 0 in 2020-2021, 3% in 2019-2020, and 1% in 2018-2019. CONCLUSION: This study shows a marked increase in respiratory support and intensive care admissions this last winter. While these severity indexes were all driven by medical choices, more reliable indexes such as intubation rate and length of stay did not change. Therefore, we suggest that there is a more aggressive treatment attitude rather than a more severe disease. WHAT IS KNOWN: • COVID-19 pandemic deeply impacted bronchiolitis epidemiology, reducing hospitalizations to onetenth. In the 2021-2022 winter, bronchiolitis resurged to pre-pandemic numbers in Europe. WHAT IS NEW: • Bronchiolitis hospitalization rose much faster in the 2021-2022 winter period, peaking at a higher level. Respiratory supports and high-flow nasal cannula increased significantly compared to the pre-pandemic era.

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

Severe Pediatric Asthma Therapy: Mepolizumab.

There is a growing need for advanced treatment in children with persistent and severe asthma symptoms. As a matter of fact, between 2 and 5% of asthmatic children experience repeated hospitalizations and poor quality of life despite optimized treatment with inhaled glucocorticoid plus a second controller. In this scenario, mepolizumab, a humanized monoclonal antibody, has proven to be effective in controlling eosinophil proliferation by targeting interleukin-5 (IL-5), a key mediator of eosinophil activation pathways. Mepolizumab is approved since 2015 for adults at a monthly dose of 100 mg subcutaneously and it has been approved for patients ≥ 6 years of age in 2019. Especially in children aged 6 to 11 years, mepolizumab showed a greater bioavailability, with comparable pharmacodynamics parameters as in the adult population. The recommended dose of 40 mg every 4 weeks for children aged 6 through 11 years, and 100 mg for patients ≥ 12 years provides appropriate concentration and proved similar therapeutic effects as in the adult study group. A marked reduction in eosinophil counts clinically reflects a significant improvement in asthma control as demonstrated by validated questionnaires, reduction of exacerbation rates, and the number of hospitalizations. Finally, mepolizumab provides a safety and tolerability profile similar to that observed in adults with adverse events mostly of mild or moderate severity. The most common adverse events were headache and injection-site reaction. In conclusion, mepolizumab can be considered a safe and targeted step-up therapy for severe asthma with an eosinophilic phenotype in children and adolescents.

Biological Treatments and Target Therapies for Pediatric Respiratory Medicine: Not Only Asthma.

We present a description of pediatric pneumology biological medications and other target therapies. The article aims at introducing the importance of a molecular approach to improve treatments. The first item treated was T2-High asthma and its current biological treatment and prescribing indications to propose a flow-chart to guide the clinical choice. Molecular rationales of such treatments are used to introduce a more general description of the biological and molecular approach to target therapies application. We introduce a general interpretation approach to neutrophilic asthma using the molecular plausibility one in order to propose possible future treatments mainly targeting interleukin-1 (IL-1), IL-17, IL-12, and IL-23. Indeed, cytokines can be excellent targets for several biological treatments. Downregulation of specific cytokines can be crucial in treating autoinflammatory and rheumatological diseases with a pulmonary involvement. Such conditions, although rare, should be early recognized as they can involve significant improvement with a properly targeted therapy. We face these conditions in a cherry-picking fashion picturing SAVI (STING-associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), and COPA (coat proteins alpha syndrome) syndrome pulmonary involvement. Such examples are functional to introduce molecular-based approach for patients with rare conditions. Molecular plausibility can be highly valuable in treating patients with not-approved but possibly highly effective therapies. Due to the rarity of these conditions, we stress the concept of basket trials using the example of cytokinin-directed immunosuppressive treatment. Lastly, we provide an example of augmentative therapy using the alpha1 antitrypsin deficiency as a model. In summary, the article presents a collection of the most recent achievements and some possible future developments of target therapies for pediatric pulmonary conditions.

Healthcare resource utilisation and medical costs for children with interstitial lung diseases (chILD) in Europe.

BACKGROUND: No data on healthcare utilisation and associated costs for the many rare entities of children's interstitial lung diseases (chILD) exist. This paper portrays healthcare utilisation structures among individuals with chILD, provides a pan-European estimate of a 3-month interval per-capita costs and delineates crucial cost drivers. METHODS: Based on longitudinal healthcare resource utilisation pattern of 445 children included in the Kids Lung Register diagnosed with chILD across 10 European countries, we delineated direct medical and non-medical costs of care per 3-month interval. Country-specific utilisation patterns were assessed with a children-tailored modification of the validated FIMA questionnaire and valued by German unit costs. Costs of care and their drivers were subsequently identified via gamma-distributed generalised linear regression models. RESULTS: During the 3 months prior to inclusion into the registry (baseline), the rate of hospital admissions and inpatient days was high. Unadjusted direct medical per capita costs (€19 818) exceeded indirect (€1 907) and direct non-medical costs (€1 125) by far. Country-specific total costs ranged from €8 713 in Italy to €28 788 in Poland. Highest expenses were caused by the disease categories 'diffuse parenchymal lung disease (DPLD)-diffuse developmental disorders' (€45 536) and 'DPLD-unclear in the non-neonate' (€47 011). During a follow-up time of up to 5 years, direct medical costs dropped, whereas indirect costs and non-medical costs remained stable. CONCLUSIONS: This is the first prospective, longitudinal study analysing healthcare resource utilisation and costs for chILD across different European countries. Our results indicate that chILD is associated with high utilisation of healthcare services, placing a substantial economic burden on health systems.

Acute exacerbations in children's interstitial lung disease.

INTRODUCTION: Acute exacerbations (AEs) increase morbidity and mortality of patients with chronic pulmonary diseases. Little is known about the characteristics and impact of AEs on children's interstitial lung disease (chILD). METHODS: The Kids Lung Register collected data on AEs, the clinical course and quality of life (patient-reported outcomes - PRO) of rare paediatric lung diseases. Characteristics of AEs were obtained. RESULTS: Data of 2822 AEs and 2887 register visits of 719 patients with chILD were recorded. AEs were characterised by increased levels of dyspnoea (74.1%), increased respiratory rate (58.6%) and increased oxygen demand (57.4%). Mostly, infections (94.4%) were suspected causing an AE. AEs between two register visits revealed a decline in predicted FEV1 (median -1.6%, IQR -8.0 to 3.9; p=0.001), predicted FVC (median -1.8%, IQR -7.5 to 3.9; p=0.004), chILD-specific questionnaire (median -1.3%, IQR -3.6 to 4.5; p=0.034) and the physical health summary score (median -3.1%, IQR -15.6 to 4.3; p=0.005) compared with no AEs in between visits. During the median observational period of 2.5 years (IQR 1.2-4.6), 81 patients died. For 49 of these patients (60.5%), mortality was associated with an AE. CONCLUSION: This is the first comprehensive study analysing the characteristics and impact on the clinical course of AEs in chILD. AEs have a significant and deleterious effect on the clinical course and health-related quality of life in chILD.

All You Need Is Evidence: What We Know About Pneumonia in Children With Neuromuscular Diseases.

Neuromuscular diseases may involve all major respiratory muscles groups including inspiratory, expiratory, and bulbar muscles. Respiratory complications are the major cause of morbidity and mortality. Pneumonia represents a frequent cause of morbidity in children with neuromuscular disease. The aim of this review is to collect knowledge about pneumonia in children with neuromuscular diseases. Pneumonia usually follows viral respiratory infections of the upper respiratory tract, due to the combination of an increased amount of nasal and oral secretions and an impairment of the cough efficiency and of the clearance of secretions due to the muscle weakness, further compromised by the infection itself. The accumulation of bronchial secretions leads to atelectasis and promote bacterial infection. Moreover, dysfunction of swallowing mechanism exposes these children to the risk of developing aspiration pneumonia. However, etiology of viral and bacterial respiratory infection in these patients is still poorly studied.

Noncystic fibrosis bronchiectasis in children and adolescents: Follow-up over a decade.

BACKGROUND: Noncystic fibrosis bronchiectasis (NCFB) is still considered an "orphan disease" in pediatric age. OBJECTIVE: The study describes the clinical and functional features, the instrumental, and microbial findings of a large cohort of patients with NCFB, followed in a single tertiary level hospital. METHODS: Children and adolescents diagnosed with NCFB from January 1, 2010 to December 31, 2019 were included. Data from the diagnosis and during the years of follow-up were recorded retrospectively. RESULTS: One hundred and thirty-eight patients were enrolled. The most common cause of NCFB was postinfectious (33%), followed by primary ciliary dyskinesia (PCD) (30%), esophageal atresia (EA) (9.5%), and secondary immunodeficiency (9.5%). Chronic cough was the most frequent symptom. The median age of symptoms presentation was 3 years (interquartile age [IQR]: 12-84), with a precocious onset in PCD and EA groups. The median age of CT diagnosis was 9 years for all groups but PCD patients who were diagnosed at older age. Lingula, medium, upper, and lower lobes were more involved in PCD group, while diffuse distribution was observed in the postinfectious one. Microbial exams showed Pseudomonas aeruginosa colonization higher in PCD patients (22%). Despite microbial differences in airways colonization, no difference in respiratory exacerbation rate was recorded among groups. Lung function tests demonstrated the stability of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) over time, except for the secondary immunodeficiency group. CONCLUSIONS: The role of infections in developed countries should not be underestimated and a major effort to obtain an earlier identification of bronchiectasis should be taken. A prompt diagnosis of NFCB could help to reduce the frequency of exacerbations and improve the stability of lung function over time.

Effects of the COVID-19 pandemic and lockdown on symptom control in preschool children with recurrent wheezing.

INTRODUCTION: Preschool wheezers are at high risk of recurrent attacks triggered by respiratory viruses, sometimes exacerbated by exposure to allergens and pollution. Because of the COVID-19 infection, the lockdown was introduced, but the effects on preschool wheezers are unknown. We hypothesized that there would be an improvement in outcomes during the lockdown, and these would be lost when the lockdown was eased. MATERIALS AND METHODS: Patients underwent medical visits before and after the COVID-19 lockdown. We recorded the childhood Asthma Control Test (cACT) and a clinical questionnaire. Data on symptoms, the need for medications and the use of healthcare resources were recorded. We compared these data with retrospective reports from the preceding year and prospectively acquired questionnaires after lockdown. RESULTS: We studied 85 preschool wheezers, mean age 4.9 years. During the lockdown, cACT score was significantly higher (median 25 vs. 23); families reported a dramatic drop in wheezing episodes (51 vs. none), significant reductions in the day and nighttime symptoms, including episodes of shortness of breath (p < .0001); the use of salbutamol and oral corticosteroids (OCS) dropped significantly (p < .0001) and 79 (95%) patients needed no OCS bursts during the lockdown. Finally, patients had significantly fewer extra medical examinations, as well as fewer Emergency Room visits (p < .0001). All were improved compared with the same time period from the previous year, but outcomes worsened significantly again after lockdown (cACT median: 22). CONCLUSIONS: During the national lockdown, children with persistent preschool wheeze showed a significant clinical improvement with reduction of respiratory symptoms, medication use for exacerbations, and use of healthcare resources. This trend reversed when lockdown restrictions were eased.

Telemedicine in children with medical complexity on home ventilation during the COVID-19 pandemic.

Children with medical complexity (CMC) are patients with one or more complex chronic conditions dependent on medical technologies. In our unit (Pediatric Pulmonology and Respiratory Intermediate Care Unit, Department of Pediatrics, "Bambino Gesù" Children's Hospital and Research Institute), we regularly follow-up CMC patients, particularly children on long-term, invasive (IMV) or noninvasive (NIV), ventilation. Children suffering from chronic diseases and with medical complexity have lost the possibility to go to the hospital during the COVID-19 pandemic. The aim of this article is to describe our experience with telemedicine (teleconsultation [TC] and telemonitoring of ventilator [TM]) in CMC on ventilation. We presented 21 children on long-term ventilation (NIV or IMV) whose planned hospital admission was postponed due to lockdown. A total of 12 healthcare problems were detected during scheduled TCs. Only one problem was not solved by our remote intervention. Specifically, TM has allowed us to change the ventilator parameters and to monitor patients on ventilation remotely. In conclusion, the use of telemedicine in CMC ventilated patients resulted in a feasible tool to avoid in-person visits during the pandemic.