ERS International Congress 2021: highlights from the Paediatric Assembly.

In this review, Early Career Members of the European Respiratory Society (ERS) and the Chairs of the ERS Assembly 7: Paediatrics present the highlights in paediatric respiratory medicine from the ERS International Congress 2021. The eight scientific Groups of this Assembly cover respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology, bronchology, and lung and airway development. We here describe new developments in lung function testing and sleep-disordered breathing diagnosis, early life exposures affecting pulmonary function in children and effect of COVID-19 on sleep and lung function. In paediatric asthma, we present the important role of the exposome in asthma development, and how biologics can provide better outcomes. We discuss new methods to assess distal airways in children with CF, as some details remain blind when using the lung clearance index. Moreover, we summarise the new ERS guidelines for bronchiectasis management in children and adolescents. We present interventions to reduce morbidity and monitor pulmonary function in newborns at risk of bronchopulmonary dysplasia and long-term chronic respiratory morbidity of this disease. In respiratory epidemiology, we characterise primary ciliary dyskinesia, identify early life determinants of respiratory health and describe the effect of COVID-19 preventive measures on respiratory symptoms. Also, we describe the epidemiology of interstitial lung diseases, possible consequences of tracheomalacia and a classification of diffuse alveolar haemorrhage in children. Finally, we highlight that the characterisation of genes and pathways involved in the development of a disease is essential to identify new biomarkers and therapeutic targets.

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020.

BACKGROUND: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). METHODS: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. RESULTS: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). CONCLUSIONS: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.

Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. METHODS: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. RESULTS: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). CONCLUSION: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

Protein-energy malnutrition as the first manifestation of cystic fibrosis in infancy.

BACKGROUND: The protein-energy malnutrition (PEM) that is characterized by hypoproteinemia, edema, and anemia has been reported in 5-13% of infants with cystic fibrosis (CF). Due to the surprising higher incidence of PEM as the first presenting manifestation of CF in Macedonia, the aim of the present study was to evaluate the possible risk factors in its development. METHODS: Clinical and laboratory profiles (hemoglobin, red blood cell count, total serum protein, serum albumin and liver enzyme levels) and genotype data were analyzed in 115 newly diagnosed infants with CF, during the period 1990-2006. RESULTS: PEM manifested in 39 CF infants (33%), usually within the first 5 months of life and in breast-fed infants. Mean hemoglobin, red blood cell count, total serum protein and serum albumin values in the PEM subgroup were, respectively, 76.0 g/L, 2.4 x 10(12)/L, 38.0 g/L and 16.6 g/L. Clinically significant liver involvement was found in 22 patients (56.4%) with PEM. Concerning the molecular basis of CF in these patients, PEM was always associated with triangle upF508, G542X, N1303K and other severe mutations. CONCLUSION: PEM is a common manifestation of CF in infancy. Early infant age, breast-feeding, impaired liver function and the presence of severe cystic fibrosis transmembrane conductance regulator mutations are predisposing factors for the development of PEM.

Coping with Cystic Fibrosis in the Republic of Macedonia-Parent Perspective.

INTRODUCTION: Cystic fibrosis (CF) is a progressive, life-threatening, genetic disease which mainly damages the lungs and the digestive system. It's a complex medical condition, with several individual forms and variation in the symptoms severity. Few factors such as age of establishing the diagnosis, the number and the type of infections and their management, best treatment options, comorbid conditions etc. can influence the patient's overall health, disease progression and quality of life. Many CF patients will reach adulthood, so coping with the chronic disease is very important for the overall health and everyday living. AIM OF THE STUDY: To screen the quality of life in CF patients in the Republic of Macedonia, from the parent perspective. SUBJECTS AND METHODS: In the study we have included 55 parents of CF patients. We have created a questionnaire, specially designed for this survey, with questions related to their everyday coping with CF and quality of life. RESULTS: The majority of the parents refer to the overall typical social and emotional life of their children, addressing some difficulties concerning the financial aspect of the disease and still significantly having fear from the stigma in the society. CONCLUSION: CF patients and their families in the Republic of Macedonia must overcome many obstacles on daily basis. Despite that, they can still have full and meaningful lives.

Screening for liver disease in cystic fibrosis: analysis of clinical and genetic risk factors for its development.

This study analyzes the prevalence and the role of possible clinical and genetic risk factors for the development of cystic fibrosis (CF)-related liver disease (LD) in a Macedonian CF population. All patients older than three years (n=52) were screened for LD. LD was defined by the finding of hepatomegaly and/or splenomegaly, significant and persistent increase of at least two serum liver enzyme levels, suggestive ultrasonographic abnormalities (score >4), and morphologic or functional scintigraphic abnormalities. According to predefined criteria, 18 patients (34.6%) were classified as having LD, three of them with portal hypertension. A male predominance was found in the group with LD (72%). There was no significant difference in the pulmonary function, nutritional status, and in the prevalence of meconium ileus. Genetic analysis showed higher frequency of DeltaF508 mutation in the LD group (77.8%) vs. the no LD group (66.2%). All patients with LD had severe mutations: DeltaF508, G542X, N1303K, CFTRdel.21Kb, 1811+1G-->C, and Y1092X.

Prevalence of low bone mass and vitamin D deficiency in pediatric and adult patients with cystic fibrosis in Republic of Macedonia.

UNLABELLED: Bone disease in cystic fibrosis (CF) has become a topic of widespread interest and impact in the CF community. Recently, some biochemical markers have been proposed to provide information about the dynamics of bone turnover. Only limited information is available for young patients. Imbalance between bone formation and degradation in CF especially in puberty has become an important issue for developing osteopenia. Influence of vitamin D receptor alleles on BMD suggests that these polymorphisms have a greater influence on BMD in childhood. The aim of our study was to assess prevalence of vitamin D deficiency and osteopenia in pediatric and adult CF patients. METHODS: The study included 77 clinically stable CF patients (range 5-36 y), who regularly attended CF center at the Pediatric Clinic in Skopje, Macedonia. Serum osteocalcin (OC), ßcrosslaps, 25OHD and PTH were determined by electrohemiluminiscent method. BMD was measured via dual energy-ray absorptiometry (DXA) scans with spinal scores recorded. RESULTS: 50% of the CF patients with PI had serum vitamin D>20 ng (range 10-44 ng/ml) with no difference of age. Osteopenia was determined in 35% of patients. High plasma ßcrosslaps values reflect raised osteoclast activity in 50% of patients with osteopenia. We found one CF patient homozygote for Taq1 and Bsm1, one for Taq1 and one for Fok1. These patients have vitamin D deficiency and osteopenia. CONCLUSIONS: Bone remodeling in CF patients is impaired. Further investigations are needed to find underlying pathogenesis of low bone mass and vitamin D deficiency.

Liver cirrhosis and portal hypertension in cystic fibrosis.

INTRODUCTION: As the expected survival improves in individuals with the cystic fibrosis (CF), so they may be faced with a number of medical complications. OBJECTIVE: The aim of this study was to analyze the prevalence of liver cirrhosis in our CF population as well as the clinical and genetic characteristics of these patients. METHODS: All patients older than 2 years (n = 96) were screened for liver disease. Liver cirrhosis was defined by ultrasonographic findings of distinct heterogeneity of liver parenchyma and nodular liver surface and/or by liver biopsy findings. Enlarged spleen, distended portal vein and abnormal portal venous flow indicated portal hypertension. Clinical and genotype data were analyzed. RESULTS: Sixteen patients were found to have liver cirrhosis, three of them with portal hypertension. All patients had pancreatic insufficiency. Nutritional status expressed as standard deviation score (Z score) for weight, height, and body mass index was as follows: zW = -0.40 +/- 1.24, zH = -0.83 +/- 1.02, and BMI = 20.1 +/- 2.3. CF patients with liver cirrhosis generally had mild-to-moderate lung disease, with average FVC and FEV1 values of 97.1 +/- 16.5% of predicted and 87.9 +/- 23.5% of predicted, respectively. Genetic analysis showed high frequency of F508del mutation in the group with cirrhosis (90.6%). CONCLUSION: The prevalence of liver cirrhosis in our CF population older than 2 years was 16.6%. Patients with pancreatic insufficiency and severe CFTR mutations, especially F508del, were exposed to higher risk of developing liver cirrhosis. Liver cirrhosis has no significant impact on the pulmonary function and the nutritional status, until the end-stage liver disease.

Metabolic alkalosis with hypoelectrolytemia in infants with cystic fibrosis.

BACKGROUND: Infants with cystic fibrosis (CF) can develop episodes of hyponatremic hypochloremic dehydration with metabolic alkalosis when they sweat excessively, which is not caused by sweating in normal infants. We investigated the incidence of the metabolic alkalosis with hypoelectrolytemia in CF infants, the possible risk factors for its occurrence and the importance of the manifestation in the diagnosis of CF. METHODS: In order to evaluate the incidence and the risk factors for the development of this sweat-related metabolic disorder in CF, we reviewed the records of all children diagnosed as having CF before the age of 12 months in a 10-year period. Data analysis included medical history data, clinical features, biochemical parameters (blood pH, serum bicarbonate, sodium, chloride and potassium levels), sweat chloride test values, as well as genetic analysis data. RESULTS: The prevalence of metabolic alkalosis in association with low serum electrolyte concentrations (hyponatremia, hypochloremia, and hypokalemia) in infant CF population in our region was 16.5%. We found no season predilection in its occurrence. Early infant age, breast-feeding, delayed CF diagnosis, heat exhaustion and the presence of severe CF transmembrane conductance regulator mutations are predisposed factors for the development of metabolic alkalosis with hypoelectrolytemia. CONCLUSIONS: The results from our study suggest that metabolic alkalosis with hypoelectrolytemia is a relatively common manifestation of CF in infancy. The possibility of CF should be seriously considered in any infant with this metabolic disorder.