Progressive Airflow Obstruction: Bronchiolitis Obliterans in DIPNECH with Pulmonary Carcinoid – A Longitudinal Case Report

Progressive Airflow Obstruction: Bronchiolitis Obliterans in DIPNECH with Pulmonary Carcinoid – A Longitudinal Case Report Elkhidir(Babikir¹,(Liam(Cormican²! ¹!Registrar!in!Respiratory!Medicine,!Respiratory!Department,!Conley!Hospital,!Dublin,! Ireland! ²!Consultant!in!Respiratory!Medicine,!Respiratory!Department,!Conley!Hospital,!Dublin,! Ireland! Correspondence(to:! Dr!Elkhidir!Babikir!—!Registrar!in!Respiratory!Medicine,!Respiratory!Department,!Conley! Hospital,!Dublin,!Ireland! Email:[email protected]! Abstract Diffuse!idiopathic!pulmonary!neuroendocrine!cell!hyperplasia!(DIPNECH)!is!a!rare! pulmonary!condition!that!can!progress!to!carcinoid!tumours!and!small!airway!obstruction.! We!report!a!48-year-old!woman!with!biopsy-confirmed!DIPNECH!and!a!typical!carcinoid! tumour!who!developed!progressive!fixed!airflow!obstruction!consistent!with!bronchiolitis! obliterans.!Despite!multiple!comorbidities,!including!thyroid!carcinoma!and!adrenal! insufficiency,!her!condition!stabilised!with!inhaled!therapy,!macrolide!prophylaxis,!and! pulmonary!rehabilitation.!This!case!highlights!the!diagnostic!challenge!of!DIPNECH,!often! mislabelled!as!asthma!or!COPD,!and!the!importance!of!multidisciplinary,!long-term!followup!focusing!on!functional!outcomes!and!quality!of!life.! Background Diffuse!idiopathic!pulmonary!neuroendocrine!cell!hyperplasia!(DIPNECH)!is!a!rare!and! under-recognised!pulmonary!disorder,!primarily!affecting!middle-aged,!non-smoking! women.!It!is!characterised!by!diffuse!proliferation!of!neuroendocrine!cells!within!the! bronchial!epithelium,!which!may!manifest!as!tumourlets!or!carcinoid!tumours.!Patients! often!present!with!chronic!cough!and!dyspnoea!and!are!frequently!misdiagnosed!with! obstructive!airway!diseases!such!as!asthma!or!chronic!obstructive!pulmonary!disease! (COPD).!The!disease!course!is!variable,!ranging!from!stable!indolent!disease!to!progressive! small!airway!obstruction!and!bronchiolitis!obliterans.!Optimal!management!remains! uncertain,!though!options!include!somatostatin!analogues,!inhaled!therapy,!and!supportive! measures.! Case Presentation A!48-year-old!woman!presented!with!a!decade-long!history!of!persistent!cough!and! exertional!dyspnoea.!She!was!a!lifelong!non-smoker!with!no!relevant!environmental!or! occupational!exposures.!Initial!diagnoses!of!asthma!and!later!COPD!were!made!in!the! community,!but!she!showed!minimal!response!to!standard!inhaled!therapy.!A!videoassisted!thoracoscopic!biopsy!was!performed!in!2016!due!to!progressive!symptoms!and! multiple!bilateral!nodules!on!CT,!confirming!DIPNECH!with!a!background!typical!carcinoid! tumour!and!associated!neuroendocrine!cell!hyperplasia.! Investigations Serial!pulmonary!function!tests!demonstrated!progressive,!fixed!airflow!obstruction,!with! FEV₁!declining!from!2.1!L!(70%!predicted)!to!1.2!L!(40%!predicted)!over!five!years,!despite! a!preserved!diffusion!capacity!(DLCO!85%!predicted).!High-resolution!CT!scans!revealed! bilateral!pulmonary!nodules!(2–6!mm),!mosaic!attenuation,!and!air!trapping,!consistent! with!bronchiolitis!obliterans.!There!was!no!evidence!of!metastatic!disease.!Comorbidities! identified!during!follow-up!included!papillary!thyroid!carcinoma,!adrenal!adenoma,! secondary!adrenal!insufficiency,!burning!mouth!syndrome,!and!chronic!upper!airway! disease.! Differential Diagnosis •!Obstructive!airway!disease!(asthma/COPD)! •!Bronchiolitis!obliterans!(post-infectious!or!autoimmune)! •!Hypersensitivity!pneumonitis! •!Diffuse!idiopathic!pulmonary!neuroendocrine!cell!hyperplasia!(DIPNECH)! ! Asthma!and!COPD!were!excluded!due!to!lack!of!reversibility!and!normal!diffusion!capacity,! while!hypersensitivity!pneumonitis!was!ruled!out!by!negative!serology!and!absence!of! exposure!history.!The!presence!of!mosaic!attenuation,!small!nodules,!and!histological! evidence!of!neuroendocrine!cell!hyperplasia!confirmed!DIPNECH!complicated!by! bronchiolitis!obliterans.! Treatment The!patient!commenced!Lanreotide!(somatostatin!analogue)!but!discontinued!it!after! several!months!due!to!gastrointestinal!side!effects,!despite!initial!symptomatic! improvement!in!cough.!Ongoing!management!included!an!inhaled!corticosteroid!and!longacting!β₂-agonist!combination,!long-term!azithromycin!prophylaxis,!and!pulmonary! rehabilitation.!She!received!supportive!care!for!recurrent!respiratory!infections!and!two! episodes!of!COVID-19.!Her!treatment!was!coordinated!through!a!multidisciplinary!team,! involving!respiratory,!endocrinology,!and!ENT!specialists,!to!address!her!comorbidities!and! optimise!quality!of!life.! Outcome and Follow-Up Over!nine!years!of!follow-up,!the!patient!developed!progressive!airflow!limitation,!though! her!condition!has!stabilised!clinically!and!radiologically!in!recent!years.!FEV₁!has!remained! stable!at!1.2–1.3!L,!and!CT!scans!have!shown!no!new!nodules!or!progression.!She!reports! persistent!fatigue!and!functional!limitation!but!has!remained!free!of!major!exacerbations.! Discussion This!case!illustrates!the!slowly!progressive!yet!clinically!challenging!course!of!DIPNECH! complicated!by!a!carcinoid!tumour!and!bronchiolitis!obliterans.!Fixed!airflow!obstruction!in! DIPNECH!reflects!small!airway!fibrosis!rather!than!reversible!bronchospasm,!explaining!the! poor!response!to!bronchodilators.!Somatostatin!analogues!such!as!Lanreotide!or!Octreotide! may!reduce!cough!and!stabilise!radiological!progression!in!some!patients,!though! tolerability!and!efficacy!vary.!Macrolide!prophylaxis!and!pulmonary!rehabilitation!can!help! improve!symptoms!and!reduce!exacerbation!frequency.!Airway!obstruction!in!DIPNECH!is! believed!to!result!from!bronchiolar!wall!fibrosis!secondary!to!neuroendocrine!cell! proliferation!and!inflammation.!Trials!of!somatostatin!analogues!and!mTOR!inhibitors!are! ongoing,!but!evidence!remains!limited.!Clinicians!should!maintain!awareness!of!DIPNECH!as! a!potential!cause!of!unexplained!fixed!airflow!obstruction!in!non-smokers,!as!timely! diagnosis!can!prevent!unnecessary!corticosteroid!exposure!and!facilitate!appropriate! follow-up.! Learning Points 1.!Suspect!DIPNECH!in!middle-aged,!non-smoking!women!with!chronic!cough!and! unexplained!fixed!obstruction.! 2.!Histology!confirms!diagnosis!and!identifies!associated!carcinoid!tumours.! 3.!Bronchiolitis!obliterans!contributes!to!irreversible!airflow!limitation.! 4.!Somatostatin!analogues,!macrolide!prophylaxis,!and!rehabilitation!may!stabilise!disease! and!improve!quality!of!life.! Keywords DIPNECH,!carcinoid!tumour,!bronchiolitis!obliterans,!fixed!airflow!obstruction,! somatostatin!analogue! References 1.!Davies!SJ!et!al.!Diffuse!idiopathic!pulmonary!neuroendocrine!cell!hyperplasia:!A! systematic!review.!Eur!Respir!Rev!2020;29:190135.! 2.!Nassar!AA!et!al.!Diffuse!idiopathic!pulmonary!neuroendocrine!cell!hyperplasia!syndrome:! A!review.!Chest!2011;139(2):567–574.! 3.!Carr!LL,!Chung!JH,!Achcar!RD,!et!al.!The!clinical!course!of!diffuse!idiopathic!pulmonary! neuroendocrine!cell!hyperplasia.!Chest!2015;147(2):415–422.! 4.!Amin!R,!Matsui!H,!Gould!MK.!Somatostatin!analog!therapy!for!diffuse!idiopathic! pulmonary!neuroendocrine!cell!hyperplasia!(DIPNECH):!A!systematic!review.!Lung! 2021;199(2):143–151.! 5.!Gorshtein!A,!Gross!DJ,!Barak!D,!et!al.!Diffuse!idiopathic!pulmonary!neuroendocrine!cell! hyperplasia:!Clinical!characteristics!and!treatment!outcome!with!somatostatin!analogues.! Endocrine!2015;50(2):482–488.!