Gupta, Nishant

Abstract Rationale: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary condition characterised by neuroendocrine cell proliferation along respiratory bronchioles resulting in tumourlet formation which may progress to pulmonary carcinoid. DIPNECH is a rare and under-recognised condition that predominantly affects females, with an estimated worldwide incidence of 5-6 people per million population. Given it's rarity and the poor understanding around the pathogenesis and treatment of this condition, we undertook the largest international case series to date of DIPNECH patients. We aim to further characterise this patient cohort to better understand the clinical features, identify common pulmonary function test (PFT) patterns and radiographic findings and describe current treatment practices. Methods: We collated data from 17 centres across 8 different countries comprising a total of 258 patients. Data collected included patient demographics, smoking history, symptoms, co-morbidities, pathological diagnosis, imaging findings, PFT pattern and therapies. Results: In total 258 patients were identified. The median age was 65 (SD+/- 10.6). 241 (93%) were female. 39% (n= 94/243) were ex-smokers. 79% (n=186/234) of patients reported pulmonary symptoms with cough being the most common symptom reported in 81% (n=151/186) of patients. Many patients were polysymptomatic, with cough and dyspnoea being the most common combination of symptoms described. (50.54%; n=94/186). Complete spirometry pattern was documented for 180 patients (69.78%) with an obstructive pattern being the most commonly observed (n=76/180; 42%). 27.5% (n=41/139) had clinically significant FEV1 reversibility post bronchodilator administration. Pathology specimens were available in 219 cases. Most common pathological features were neuroendocrine hyperplasia which was observed in 75% (n=165/219) and tumourlets in 74% (n=162/219) of cases. Carcinoid, either typical or atypical, was observed in 64% (n=141/219) of samples. 252 patients had computed tomography (CT) imaging performed. Pulmonary nodules were the most common feature identified in 99.60% of cases (248/250). Mosaic attenuation (69.30%; n=50/173) and airway dilatation (28.90%; n=50/173) were also frequently reported. There was no significant correlation between symptoms (cough, dyspnoea, wheeze) and airway dilatation (p=0.496), mosaic attenuation (p=0.496) and PFT pattern (p=0.837). There was a significant association between presence of symptoms and mosaic attenuation on CT (p=0.003). Conclusions: DIPNECH, while a rare disorder, is understudied. This international case series is the largest performed to date and highlights the complexity in management of these patients.

Abstract Background: Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm that can lead to progressive diffuse cystic lung disease. Pregnancy has been associated with accelerated disease progression and increased risk of spontaneous pneumothoraces in women with LAM. Sirolimus is the current first line treatment for LAM and has demonstrated benefit in stabilizing lung function decline and reducing the risk of spontaneous pneumothoraces; however, there is unclear evidence regarding the risk benefit ratio of the use of sirolimus during pregnancy. Methods: We queried physicians across the LAM Clinic Network and obtained information regarding demographics, baseline characteristics, LAM related complications, lung function, sirolimus dosing, and pregnancy outcomes in women with LAM who took sirolimus during pregnancy. Results: We identified 9 women with LAM who had used sirolimus during pregnancy for a total of 12 pregnancies. All women had sporadic LAM with moderate lung function impairment prior to pregnancy: median FEV1 56% predicted, median DLCO 43% predicted, and 2 patients on supplemental oxygen. Sirolimus was used throughout pregnancy in most instances (10/12 (83.3%)). Sirolimus was held prior to pregnancy in 2 patients; both these patients experienced a spontaneous pneumothorax in the first trimester and resumed sirolimus in the second trimester with no further pneumothoraces during the rest of the pregnancy. The median sirolimus dose during pregnancy was 1 (range 1-2) mg daily with a median trough level of 2.95 (range: 1 – 6.7) ng/ml. Ten pregnancies (83.3%) resulted in live births, 1 pregnancy was terminated due to molar pregnancy, and 1 pregnancy resulted in miscarriage. Spirometry and DLCO were available in 8 pregnancies and tended to be stable (Figure 1). None of the 10 pregnancies that resulted in live births reported any fetal health issues. Seven out of these 10 children (70%) were breastfed with continued sirolimus use. At the time of submission of this report, the median age of these children is 3.5 years (range: 1 – 6.5 years) with no reported adverse health outcomes from sirolimus exposure during pregnancy. Conclusions: The use of sirolimus during pregnancy in women with LAM appears to be safe for both mother and fetus and might help reduce the pregnancy associated risks of accelerated lung function decline and spontaneous pneumothoraces.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Abstract The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. Although lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in the clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light-chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies, and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutations, or aberrant lung development and provide an approach to aid in their diagnosis and management.