Mild Lung Disease Research Articles

Cytokines Measured in Nasal Lavage Compared to Induced Sputum in Patients with Mild Cystic Fibrosis

The measurement of cytokines in induced sputum and nasal lavage (NL) samples has been performed for years in people with cystic fibrosis (CF). The aim of this study was to directly compare sputum and NL samples and interpret results based on disease severity in patients who were categorized as having mild or severe lung disease. The categorization was based primarily on structural abnormalities detected on lung computed tomography and secondarily on lung function. The serum inflammatory markers neutrophil elastase (NE), IL-1β, 2, 6, 8, 10 and 17a were measured in each sputum and NL sample. Thirty-two sample pairs from 29 patients were included in this study (13 mild, 19 severe). In the patients classified as severe, many systemic inflammatory markers as well as sputum cytokines were significantly higher compared to those in the mild patients. However, all the markers measured in the NL were higher in the mild patients (p =< 0.05 for NE, IL-6 and IL-8). In addition, many cytokines in the NL correlated negatively with those in the sputum samples. Major differences in the cytokine levels were shown although the samples were obtained at the same time in the same patient. Advanced structural lung disease was closely related to systemic and lower airway inflammation, whereas preserved lung function was associated with higher levels in the NL. We hypothesize that the main part of the immune response takes place in the nasal mucosa in patients with minor pulmonary changes. Our results suggest that inflammation must be interpreted individually depending on the compartment in which it is measured. Further research is needed to accurately understand inflammatory markers measured in NL.

Teatime: epigallocatechin gallate targets fibroblast-epithelial cell crosstalk to combat lung fibrosis.

Epigallocatechin gallate (EGCG) is a polyphenol plant metabolite abundant in tea that has demonstrated antifibrotic properties in the lung. In this issue of the JCI, Cohen, Brumwell, and colleagues interrogated the mechanistic action of EGCG by investigating lung biopsies of patients with mild interstitial lung disease (ILD) who had undergone EGCG treatment. EGCG targeted the WNT inhibitor SFRP2, which was enriched in fibrotic fibroblasts and acted as a TGF-β target, with paracrine effects leading to pathologic basal metaplasia of alveolar epithelial type 2 cells. This study emphasizes the epithelial-mesenchymal trophic unit as a central signaling hub in lung fibrosis. Understanding and simultaneous targeting of interlinked signaling pathways, such as TGF-β and WNT, paves the road for future treatment options for pulmonary fibrosis.

P193 Cytokine values in nasal lavage samples of patients with cystic fibrosis indicate a primary mucosal immune response in patients with mild lung disease

P193 Cytokine values in nasal lavage samples of patients with cystic fibrosis indicate a primary mucosal immune response in patients with mild lung disease

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening – A nationwide observational study

BackgroundNon-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. MethodsLung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 – 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. ResultsLCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. ConclusionsThe LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.

Lung T1 MRI assessments in children with mild cystic fibrosis lung disease.

Lung T1 MRI is a potential method to assess cystic fibrosis (CF)lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease. Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease. We performed T1 MRI, multiple breath washout (MBW),chest computed tomography (CT),and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age). Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI)measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP)measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores. T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLPfrom T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease.

Mild elevation of pulmonary vascular resistance predicts mortality regardless of mean pulmonary artery pressure in mild interstitial lung disease

BackgroundPulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients...

119 Interim results of test reliability of 19F MRI in mild cystic fibrosis lung disease

119 Interim results of test reliability of 19F MRI in mild cystic fibrosis lung disease

A prognostic model for systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study

BackgroundPulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension.Research questionTo develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension.MethodsA prognostic model was developed from a multicenter, longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. The study was conducted between November 2006 and February 2020. All-cause death was defined as the endpoint. Cox regression and least absolute shrinkage and selection operators were used to fit the model. Internal validation of the model was assessed by discrimination and calibration using bootstrapping.ResultsOf 310 patients included in the study, 81 (26.1%) died within a median follow-up of 5.94 years (interquartile range 4.67–7.46). The final prognostic model included eight variables: modified World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, estimated glomerular filtration rate, thrombocytopenia, mild interstitial lung disease, N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level, and direct bilirubin level. A 5-year death probability predictive algorithm was established and validated using the C-index (0.77) and a satisfactory calibration curve. Risk stratification was performed based on the predicted probability to improve clinical decision-making.ConclusionsThis new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors. External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.

E35 Achondroplasia: delayed diagnosis of a severe, complicated form

Abstract Introduction Achondroplasia is the most common form of chondrodysplasia. It manifests by marked rhizomelia, hyperlordosis, brachydactyly and macrocephaly with large, prominent forehead and mid-face hypoplasia. Objective To describe a case of achondroplasia with delayed diagnosis and severe extra-skeletal complications. Result An eight-year-old girl, diagnosed with a bilateral pulmonary ecchinococcosis, was referred for thoracic surgery and a pediatric opinion was required. Physical examination revealed a severe juvenile form of achondroplasia with marked restriction of opening of the mouth and sleep apnea. Pulmonary function tests showed a mild restrictive lung disease. Her skeletal radiological survey showed the classic signs of achondroplasia and a bilateral coxa vara. Thoracic surgery was successfully scheduled with a multidisciplinary team encompassing pediatric surgeons, pediatricians, anesthesiologists and specialized nurses. A dedicated ENT and pulmonology team managed her sleep apnea and respiratory disorder respectively, while pediatric orthopedic team managed the hips. Discussion Achondroplasia is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene encoding a transmembrane receptor important among other things in the regulation of linear growth of long bones. Diagnosis is mainly based on the presence of specific clinical and radiological features. Strict adherence to recommendations for perioperative and surgical care are essential. Conclusion The management of achondroplasia is multidisciplinary, and supportive measures are more than crucial; especially in particular situations, such as anesthesia and surgery, that require additional precautions with prudent perioperative management and prolonged postoperative care. Evidently, long term follow-up of the respiratory and musculoskeletal systems is essential. The life expectancy of such patients is close to that of the general population, but patient’s and family’s quality of life is highly impacted. Ethics Parental consent taken before case reporting.

E36 Juvenile scleroderma in rheumatology unit Tripoli children hospital

Abstract Introduction Juvenile scleroderma is a rare chronic systemic connective tissue disease. It is classified into two main forms: localized scleroderma and systemic sclerosis. Since it is rare in children, many aspects of the disease remain undiscussed. Aim To study the clinical and demographic characteristics of patients diagnosed with various types of scleroderma who presented at the pediatric rheumatology unit in Tripoli Children hospital from the year 2000–2022 Materials and methods This is a retrospective case series conducted by reviewing the files of patients with scleroderma diagnosed and followed up in pediatric rheumatology unit from year 2000–2022 and collecting the data regarding patients’ demographics, time of diagnosis, clinical features, and laboratory results. Results Seven patients who met preliminary classification criteria for JSS were included. 2 males and 5 females. 1 patient with systemic sclerosis, 1 patient with linear morphea, 2 patients with generalized morphea, 1 patient with Parry Romberg syndrome, 1 patient with CREST syndrome, and 1 patient with deep morphea. The mean age at diagnosis was 8.2 ± 4.5 years. The first symptom attributable to JSS was hyperpigmented skin patches in 5 cases, no one presented with Raynaud's phenomenon. Respiratory involvement occurred in one patient, and it manifested as dyspnea as well as abnormal imaging and/or pulmonary function tests showed mild restrictive lung disease. Dysphagia was the commonest gastrointestinal symptom (4 patients, 57%). The most frequent musculoskeletal symptom was arthritis found in in 4 (57.1%) patients. Uveitis in 1 (14.3%), ANA was positive in 4 (57%) children: RF positive in 2 (28.6%) patients, ENA negative in the 7 (100%) patients. Skin biopsy was done in 2 patients and was consistent with scleroderma. Regarding treatment, six patients received MTX, one patient received prednisolone and one patient received MMF. Conclusion This report is the first describing Libyan patients with scleroderma. As reported in the literature, localized forms are more common than systemic sclerosis. Also a rare form of scleroderma (Parry Romberg syndrome) was present. Data about the disease mainly based on studies on adults and we need more studies on pediatric patients. Ethics Our study was approved by local ethical committee of pediatric department at Tripoli children hospital.

P052 Efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with normal/near normal FEV1 (≥70%)

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated high efficacy in clinical trials that included people with CF (pwCF) with FEV1 between 40–90% and later with less than 40%. It is unclear if pwCF with mild lung disease can have measurable effect of ETI.

A Pilot Study of Lung Clearance Index as a Useful Outcome Marker in the Follow-Up of Pediatric Patients with Non-Cystic Fibrosis Bronchiectasis?

The forced expiratory volume in one second (FEV1) is regularly used for the follow-up of patients with non-cystic fibrosis bronchiectasis (nCF-BE). The lung clearance index (LCI), measured by the multiple breath washout test, has been recently proposed as a lung function measure and a potential tool more sensitive than the FEV1 measured by spirometry in assessing airway changes seen on imaging. While several data have been endorsed as a useful endpoint in clinical trials of patients with early or mild CF lung disease and as the main outcome measure in clinical trials with CFTR modulators in children and adolescents with CF, few data are available in the context of non-CF bronchiectasis. The aim of this pilot study was to compare the LCI with the FEV1 as well as the forced vital capacity (FVC), the forced expiratory flow at 25-75% of the FVC (FEF 25-75%), and chest imaging based on the modified Reiff score in patients with primary ciliary dyskinesia (PCD) and non-CF, non-PCD bronchiectasis (PCD-BE and nCFnPCD-BE). Additionally, we compared each test's duration and the preferred technique. Twenty children were included; nine had PCD-BE and eleven had nCFnPCD-BE. The median age was twelve years (ages ranging between five and eighteen years). The median LCI was seven while the median z-scores of the FEV1, FVC, and FEF 25-75% were -0.6, 0, and -0.9, respectively. No significant associations or correlations were observed between LCI, spirometric parameters, or the modified Reiff score. However, nearly half of the population (n = 9) had an abnormal LCI, while only 10% had an abnormal FEV1. A total of 75% of children preferred MBW, despite it lasting five times longer than spirometry. In this paper, the authors suggest that LCI might be useful in a cohort of pediatric patients with PCD-BE and nCFnPCD-BE for detecting early lung function changes during their follow-up. Additionally, MBW seems to be preferred by patients. These data may encourage further studies on this topic.

Physiological underpinnings of exertional dyspnoea in mild fibrosing interstitial lung disease

The functional disturbances driving “out-of-proportion” dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients’ lower exercise tolerance was associated with higher ventilation (V̇E)/carbon dioxide (V̇CO2) compared with controls (V̇E/V̇CO2 nadir=35 ± 3 versus 29 ± 2; p < 0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇E. Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇E/V̇CO2, and lower peak O2 uptake (p < 0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and “static” lung volumes at rest.

MDCT-based longitudinal automated airway and air trapping analysis in school-age children with mild cystic fibrosis lung disease.

Quantitative computed tomography (QCT) offers some promising markers to quantify cystic fibrosis (CF)-lung disease. Air trapping may precede irreversible bronchiectasis; therefore, the temporal interdependencies of functional and structural lung disease need to be further investigated. We aim to quantify airway dimensions and air trapping on chest CT of school-age children with mild CF-lung disease over two years. Fully-automatic software analyzed 144 serial spirometer-controlled chest CT scans of 36 children (median 12.1 (10.2-13.8) years) with mild CF-lung disease (median ppFEV1 98.5 (90.8-103.3) %) at baseline, 3, 12 and 24 months. The airway wall percentage (WP5-10), bronchiectasis index (BEI), as well as severe air trapping (A3) were calculated for the total lung and separately for all lobes. Mixed linear models were calculated, considering the lobar distribution of WP5-10, BEI and A3 cross-sectionally and longitudinally. WP5-10 remained stable (P = 0.248), and BEI changed from 0.41 (0.28-0.7) to 0.54 (0.36-0.88) (P = 0.156) and A3 from 2.26% to 4.35% (P = 0.086) showing variability over two years. ppFEV1 was also stable (P = 0.276). A robust mixed linear model showed a cross-sectional, regional association between WP5-10 and A3 at each timepoint (P < 0.001). Further, BEI showed no cross-sectional, but another mixed model showed short-term longitudinal interdependencies with air trapping (P = 0.003). Robust linear/beta mixed models can still reveal interdependencies in medical data with high variability that remain hidden with simpler statistical methods. We could demonstrate cross-sectional, regional interdependencies between wall thickening and air trapping. Further, we show short-term regional interdependencies between air trapping and an increase in bronchiectasis. The data indicate that regional air trapping may precede the development of bronchiectasis. Quantitative CT may capture subtle disease progression and identify regional and temporal interdependencies of distinct manifestations of CF-lung disease.

Lung Function in Children with Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance that results in accumulation of mucus and bacteria in the airways. Lower respiratory tract infections lead to airway remodeling and lung function impairment. The aim of our narrative review is to discuss available data on lung function in PCD children, focusing on risk factors for lung function impairment. Relevant published studies searching MEDLINE/Pubmed are included in this narrative review, using these terms: "primary ciliary dyskinesia" and "pulmonary function test" or "spirometry" or "lung function". Filters were language (English) and age of study subjects (0-18 years). The majority of recent published studies showed normal spirometric values in PCD children, even if some authors described a pulmonary impairment. Together with spirometry, Lung Clearance Index has been applied for detecting peripheral airway disease, and it might have a role in early mild lung disease assessment. Studies on lung function trajectories after PCD diagnosis showed a significant heterogeneity, with some patients maintaining reasonably good lung function, whereas others showing a decline. Further studies are needed to analyze lung function prospectively from childhood into adulthood, and to evaluate whether lung function trajectories are affected by PCD clinical phenotype, ultrastructural ciliary defect or genetic background.

Dynamic Perfluorinated Gas MRI Shows Improved Lung Ventilation in People with Cystic Fibrosis after Elexacaftor/Tezacaftor/Ivacaftor: An Observational Study.

The availability of highly effective CFTR modulators is revolutionizing the treatment of cystic fibrosis (CF) and drastically improving outcomes. MRI-based imaging modalities are now emerging as highly sensitive endpoints, particularly in the setting of mild lung disease. Adult CF patients were recruited from a single center prior to starting treatment with E/T/I. The following studies were obtained before and after one month on treatment: spirometry, multiple breath nitrogen washout (MBW), 1H UTE MRI (structural images) and 19F MRI (ventilation images). Changes between visits were calculated, as were correlations between FEV1, lung clearance index (LCI), MRI structural scores, and MRI-based ventilation descriptors. Eight subjects had complete datasets for evaluation. Consistent with prior clinical trials, FEV1 and LCI improved after 28 days of E/T/I use. 1H UTE MRI detected improvements in bronchiectasis/airway wall thickening score and mucus plugging score after 28 days of therapy. 19F MRI demonstrated improvements in fractional lung volume with slow gas washout time (FLV↑tau2) and ventilation defect percentage (VDP). Improvements in FLV↑tau2 and VDP correlated with improvement in FEV1 (r = 0.81 and 0.86, respectively, p < 0.05). This observational study establishes the ability of 19F MRI and 1H UTE MRI to detect improvements in lung structure and function after E/T/I treatment. This study supports further development of 19F MRI and 1H UTE MRI as outcome measures for cystic fibrosis research and drug development.

80 Case series of juvenile scleroderma at Aga Khan University Hospital, Nairobi

BackgroundJuvenile scleroderma includes a range of conditions presenting with skin fibrosis. It’s classified into two major categories, localized and systemic. Juvenile localized scleroderma (morphea) is limited to the skin and forms majority of pediatric presentations (>95%). Though rare, juvenile systemic sclerosis involves the skin and other internal organs and is associated with a poorer prognosis.ObjectiveTo characterize the clinical profile of two cases of scleroderma at Aga Khan university hospital, Nairobi.MethodsRetrospective review of medical records of two patients with Juvenile scleroderma managed at Aga Khan university hospital, Nairobi.ResultsThe first patient was a 7-year-old boy presenting with joint pains for 2 months, restricted activities and limping. He also had a non-itchy lesion on the right thigh for about 6 years. On examination, there was an 8 by 18 cm, flat, shiny skin lesion with ill-defined margins and skin thickening around it. There were 2 punched out scars from previous skin biopsy sites with latest biopsy showing atrophic epidermis, dermal collagen homogenization with thick sclerosed fibers in keeping with morphea. Pulmonary function tests revealed mild restrictive lung disease. There were no other systems involved on further evaluation. He was started on weekly methotrexate, daily prednisone, daily folic acid and omeprazole to be followed up in clinic.The second case is a 5-year-old girl who presented with 3-year history of inability to walk. Physical examination revealed areas of skin hypopigmentation and hyperpigmentation on the neck and back with active lesions on the left flank and posterior right leg. She had left lower limb atrophy and extreme wasting of thigh and calf muscles, a contracture of the left knee, ankle and limb length discrepancy. Her investigations revealed positive rheumatoid factor, positive antinuclear antibody (ANA), microcytic hypochromic anaemia and skin biopsy with features of morphea. She received six courses of high dose methyl prednisone over six months, weekly methotrexate, daily folic acid, daily prednisone that was tapered off gradually, calcium supplementation and iron supplementation. In addition, she received isoniazid for tuberculosis prophylaxis with pyridoxine. Her management was multidisciplinary involving orthopedics, physiotherapy, occupational therapy, and dieticians. She developed a new skin lesion on the left forearm about five months after initiation of treatment but no worsening of symptoms or other new lesions thereafter.ConclusionJuvenile scleroderma though rare has a high risk of misdiagnosis with delay in initiation of treatment. It is associated with significant morbidity and early diagnosis, treatment and follow up is imperative for good outcomes.

INTRAMEDULLARY GAS: A NEW FEATURE THAT PORTENDS A POOR PROGNOSIS IN COVID-19?

INTRAMEDULLARY GAS: A NEW FEATURE THAT PORTENDS A POOR PROGNOSIS IN COVID-19?

116 Associations between lung T1 magnetic resonance imaging, chest computed tomography, and multiple-breath washout in young children with mild cystic fibrosis lung disease

116 Associations between lung T1 magnetic resonance imaging, chest computed tomography, and multiple-breath washout in young children with mild cystic fibrosis lung disease

Anesthetic Management of Achondroplastic Dwarf with Bronchial Asthma and Hypothyroidism Posted for Abdominal Hysterectomy

Introduction: Achondroplasia is most common cause of dwarfism caused by FGFR-3 gene mutation. It possess anesthetic challenges due to multiorgan system involvement, spine abnormality, difficulty in mask ventilation and endotracheal intubation. Case Report: A 38yr old, female, case of achondroplastic dwarfism with history of bronchial asthma and hypothyroidism was posted for abdominal hysterectomy. She weighed 30 kgs and 43 cm in height. Spine examination showed thoracolumbar kyphoscoliosis. Airway assessment revealed large tongue, receding mandible, Mallampatti class IV. Pulmonary function test suggested mild restrictive disease. Difficult intubation trolley was kept ready. Routine monitoring, radial artery cannulation done for invasive blood pressure monitoring. Patient was given general anesthesia. On laryngoscopy, CL grade III view was obtained, with the aid of bougie endotracheal tube was placed. Delayed recovery time from general anesthesia was encountered, neuromuscular monitoring was doneandreversed and extubated uneventfully. Conclusion: we present a successful anesthetic management of a dwarf patient with bronchial asthma and hypothyroidism who underwent hysterectomy. We emphasize the risk of neurological injury while extending the neck during laryngoscopy for tracheal intubation due to anatomical abnormalities in these patients. A detailed pre anesthetic evaluation evaluation and planning is utmost important and the anesthetic technique has to be individualized based on the patients anatomical characterstics and associated co-morbidities. Keywords: Dwarf, Asthma, Hypothyroidism. Key Messages: A 38 yrs old female patient with achondroplastic dwarfism (43cm tall) with associated comorbidities like bronchial asthma and hypothyroidism, thoracolumbar kyphoscoliosis and mild restrictive lung disease posted for abdominal hysterectomy possesses various anesthetic challenges. Since multiple systems are involved preanesthetic evaluation, preoperative optimization of the patient and planning of anesthesia is important. As the spread of drug in regional anesthesia is unpredictable, we planned general anesthesia. A successful management of major abdominal surgery in such patients, with anesthetic challenges and implications in these patients are reviewed in this case report.