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Refractory and Difficult to Control Asthma Abubakr A Bajwa MD FCCP Objectives • To define difficult to control asthma and refractory asthma • Understand factors related to refractory asthma • Understand different options for management Idiopathic Interstitial Pneumonias(IIPs) Diffuse Parenchymal Lung Diseases (DPLDs) Abubakr A Bajwa MD Pulmonary , Critical Care and Sleep Medicine CASE Mild DOE - slowly progressing over past year Nonproductive cough Chest x-ray… Restrictive PFTs Dry crackles on chest exam The DPLDs BIP GIP BOOP COP NSIP RB-ILD Pulmonary Fibrosis UIP LIP ILD AIP DIP DAD HX,EG,PLCH IPF BO OB Asbestosis HP EP CVD Radiation Metals Silicosis etc. Diagnoses of ILD Others = sarcoid, malignancies, LAM, HX, EP AIP/DAD BOOP LIP CVD NSIP “CFA”/IPF/UIP Extrinsic = radiation, drugs, hard metals, occupational CHP Others RBILD/DIP Extrinsic Diagnoses of ILD – The Goal AIP/DAD BOOP LIP CVD NSIP “CFA”/IPF/UIP CHP Extrinsic Others RBILD/DIP Bjoraker et al. (AJRCCM 1998) Diagnoses (102) 0.14 0.08 0.04 0.04 0.17 0.62 0.02 0.01 0.01 0.02 0.03 UIP NSIP DIP Bronchiolitis BOOP RB-ILD CEP HP AIP Other ATS/ERS International Multidisciplinary Consensus Classification of the IIP Diffuse Parenchymal Lung Disease Idiopathic Interstitial Pneumonias Idiopathic Pulmonary Fibrosis Known cause or associations Granulomatous Others: LAM, HX, EP Others than IPF DIP RB-ILD AIP COP NSIP LIP AJRCCM 2002 Major idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitis–interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Rare idiopathic interstitial pneumonias Idiopathic lymphoid interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis Unclassifiable idiopathic interstitial pneumonias* Potential Causes of ILD Inhaled Agents Inorganic: Silica, Asbestos, Beryllium Organic: (HP), Animals, Birds, Farm antigens Antibiotics, Antiarrhythmics, Anti-inflammatories, Chemotherapeutics, Antidepressants, Radiation, Oxygen Sarcoidosis, PCLH/EG/HX, BOOP, LAM, UIP, NSIP, DIP, RB-ILD, AIP, CEP Malignant Scleroderma, PM/DM, SLE, RA, MCTD, Ankylosing spondylitis, Sjögren's, Behçet's Atypical pneumonias, PCP, TB, CVID Idiopathic Connective Tissue Disease Infectious Drug-Induced Lymphangitic carcinomatosis, BAC Others MPA, IPH Adapted from: Flaherty, PCCU Vol 18, Lesson 3 (Chestnet.org) IPF Definition of IPF Major Criteria Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1/FVC ratio) and impaired gas exchange [increased AaPO2 with rest or exercise or decreased DLCO] Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis Minor Criteria Age > 50 yr Insidious onset of otherwise unexplained dyspnea on exertion Duration of illness > 3 mo Bibasilar, inspiratory crackles (dry or "Velcro" type in quality) IPF Survival Bjoraker et al. (AJRCCM 1998) History and Physical Exposures Drugs Birds, farmer, etc. Radiation Hx of malignancy Rheumatologic symptoms Constitutional features GERD Recurrent infections Family history Velcro crackles Clubbing Desaturation ? RHF or PAH ? Old films “ATS International Multidisciplinary Consensus Classification of the IIP” (AJRCCM 2002) Typical Clinical Features Clubbing (25-50%), Velcro crackles, insidious onset of dyspnea, dry cough, progressive course Atypical Clinical Features Young age (<50), absence of restriction, inconclusive exposure history, absence of dyspnea, lymphocytosis on BAL, significant constitutional symptoms At risk Occupations for IPF Multicenter, case-control study farming: OR 1.6 livestock: OR 2.7 hairdressing: OR 4.4 metal dust work: OR 2.0 raising birds: OR 4.7 stone cutting/polishing: [1.0, 2.5] [1.3, 5.5] [1.2, 16.3] [1.0, 4.0] [1.6, 14.1] OR 3.9 [1.2, 12.7] vegetable dust/animal dust exposure: OR, 4.7 [2.1, 10.4] Baumgartner (A J Epid 2000) Diagnosis- PFT Restrictive Reduced TLC, VC, FVC Increased FEV1/FVC ratio Reduced diffusing capacity Desaturation with exertion Prognosis… UIP/IPF CT Images CT Images Images from ATS Statement 2002 Attempted therapies Interferon gamma - negative Acetylcysteine – some positive effects ERAs – Bosentan negative, ambrisentan on going Steroids - negative Steroids plus Imuran - negative Steroids plus Imuran plus Acetylcysteine – on going Zileuton – animal studies Sildenafil – QOL improved but negative Anticoagulation with warfarin Pirfenidone – promising Nintedanib - promising NSIP Can’t know NSIP without knowing UIP NSIP Histopathologically does not meet any of the other IIP’s Mimic IPF Ill-defined from clinical standpoint Frequently NSIP-like areas seen in IPF Prevalent ground glass attenuation HRCT is neither sensitive or specific for NSIP Better prognosis, better response to Tx Consider CVD/CTD, Drugs, Infection, immune-deficiency (HIV), Hypersensitivity Pneumonitis Semantics… By definition, there is a variable and no specific clinical profile of a patient with NSIP. Avoid giving patients diagnosis of NSIP as a clinical diagnosis, but consider “IIP-NSIP pattern”. Task One in NSIP : H&P Look for related conditions to make a primary diagnosis CTD/CVD (can present after ILD) HP Occupational exposures?, drugs? Immunodeficiency / HIV If none identified clinical diagnosis of idiopathic NSIP to account for the NSIP “pattern” Clinical features Younger than patients with IPF Gradual to subacute presentation 6 months – 3 years of symptoms to Dx Dyspnea, cough, fatigue, weight loss Onset around 40-50yo Can occur in children Clubbing less frequent than IPF (~10-35%) Crackles, sometimes insp. Squeaks Restrictive physiololgy Desaturation with exercise NSIP NSIP NSIP Images Images from ATS Statement 2002 Treatment - NSIP Favorable responsiveness to corticosteroids Look for primary or alternative diagnoses that can have an NSIP pattern Hypersensitivity, drugs, exposures, CVD Prognosis NSIP > UIP 5-year survival of up to 70% for NSIP Cellular NSIP > Fibrotic NSIP 10 year survival: 100% vs 35-90% Prognosis Bjoraker. AJRCCM 1998. 101 IIP: 22 Fibrotic vs 7 Cellular NSIP Travis WD. AJSP 2000; 24(1):19-33. COP The great mimicker COP Formerly BOOP “Organizing pneumonia” ≠ COP Injury pattern seen in many conditions from drug reactions, infections, CVD, IBD, Inhalational injuries, etc. More acute to subacute presentation More constitutional features Restrictive PFTs Patchy areas of consolidation & GGO, Subpleural, Lower zones, can present as nodule(s) or masses Histologic DDx: DAD, NSIP, DIP, UIP Responsive to steroids COP ATS Statement, AJRCCM 2002 AIP Could be ALI/ARDS AIP Acute to fulminant presentation Clinical criteria for ARDS (idiopathic) Patchy alveolar infiltrates and GGO diffuse consolidation Histopath: Organizing DAD No proven treatment Including corticosteroids Mortality > 50% Smoking related ILDs RB --- RB-ILD --- DIP RB --- RB-ILD --- DIP RB is a histopathologic feature found in most smokers RB-ILD Intraluminal pigmented (golden brown) macrophages Clinical features of ILD with RB findings DIP More advanced ILD with pigmented macrophages filling alveoli more diffusely in larger segments of lung RB-ILD RB-ILD --- Milder symptoms overlap with symptoms attributable to emphysema GGO, centrilobular nodules, thickened bronchial/bronchiolar walls Radiographic DDx: NSIP, DIP, HP RB with bronchiolocentric distribution More advanced features of ILD Diffuse GGO Lower zone, subpleural More reticular lines and some honeycombing Numerous macrophage accumulation more diffusely DIP Lacks bronchiolocentric distribution of RB-ILD With Tx, GGO resolves DIP LIP LIP Controversy as to whether it should be considered an IIP Slow, insidious onset Lymphoma (bronchial MALT) vs Reactive lymphoid hyperplasia Some LIP were probably (now) cellular NSIP or lymphoma,... Hypogammaglobulinemia; Polyclonal, or Monoclonal (75%) gammopathy Consider autoimmune, CVD, infections: SLE, RA, Sjogren’s, Chronic active hepatitis, Pernicious anemia, Hashimoto’s, immunodeficiency (HIV), PBC, MG, AIHA, Castleman’s, PCP, HepB, EBV, drugs/inhalational LIP Mostly GGO >> perivascular cysts/HC, reticulation 50%, nodules/consolidation Histopath: Immunohistochemistry and gene-rearrangement studies Tx with steroids typically 1/3 progresses to diffuse fibrosis Dense interstitial lymphoid infiltrates with DDX of NSIP & HP; non-necrotrizing granulomas Acute Fibrinous and Organizing Pneumonia The dominant histologic pattern is intraalveolar fibrin deposition and associated organizing pneumonia Abubakr A Bajwa MD FCCP Pulmonary Critical Care and Sleep Medicine University of Florida College of Medicine/Jacksonville CONDITIONS PREVALENCE* PAH 15 per million IPAH 5.9 per million FPAH† 28−100 U.S. families APAH-scleroderma Portopulmonary hypertension HIV Sickle cell disease Schistosomiasis 8−26.7% 1−6% 0.5% estimate 32% 11.8−80% * Prevalence varies substantially depending on the type, etiology, and underlying condition † Reported estimates are based on personal communications Note: Numbers may also reflect differences in diagnostic criteria (e.g., ECHO vs right heart catheterization) and study design (e.g., retrospective vs prospective) Cystic Fibrosis Introduction Autosomal recessive Most fatal 1 in 2000 – 3000 live births Genetics Single large gene mutation that encodes CFTR protein Most common Δ F508 Types of defects Pathogenesis Abnormal secretions Defective Cl sceretion from epithelium Increased Na absorption Increased Cl secretion in sweat Chronic infection Chronic airway obstruction Bacterial colonization Nonmotile mucoid phenotype acquisistion Altered rheology and bacterial killing Psuedomonas infection Radiological Appearence Diagnosis A sweat chloride value greater than 60 meq/L Normal sweat chloride concentration may be observed in approximately 1 percent of patients with CF Diagnosis Molecular diagnosis Nasal potential difference measurements: Abnormalities in epithelial chloride secretion nasal transepithelial potential difference in the basal state, after nasal perfusion with amiloride, and after nasal perfusion with a chloride-free solution Newborn screening — Most infants with CF have elevated blood levels of immunoreactive trypsin (IRT), Management Usually in hospital: IV antibiotics Nutrition Physiotherapy Rest Home management: More cost effective Tailored Ensure all components of in hospital care can be provided Alpha one anti-trypsin deficiency History 1963 by Laurel and Eriksson Missing band for 1 antotrypsin Epidemiology Common and under-recognized 3.1 million americans - emphysema In COPD population 1.9% had deficiency So about 59,000 - 66,000 have symptomatic COPD due to deficiency 3.4 million worldwide with zz, sz, ss phenotypet Fewer than 10,000 are receiving specific therapy Survey shows that there is a mean delay of about 7.2 yrs bw symtoms and diagnosis Genetics Autosomal co-dominant > 100 alleles SERPINA1 gene ch 14 MM homozygous for normal M allele ZZ homozygous for Z allele - severe deficiency Normal concentration 80-220 mg/dl Pathophysiology Serine protease inhibitors (serpin) Major role in inactivating neutrophil elastatses Retention of polymerized aggregates in hepatocytes - liver disease Loss of natural antiprotease screen - emphysema Mechanism of Emphysema Polymerisation and retention of polymers in liver cells Decrease amount available in lung Proteolytic activity by neutrophil elastase unchecked Smoking - increases elastases Z- phenotype functionally less active Z-type antitrypsin polymers - chemoattractants for neutrophils Anti-inflammatory Properties Block human neutrophil peptides Regulated pro-inflammatory cytokines such as TNF, IL8, IL1 Clinical Manifestations Lung disease: Emphysema Early onset (4th-5th decade) Mean FEV1 from NHLBI registry was 43% (mean age 46) Panacinar Disproportionate disease in lung bases(15% may have normal chest xrays, 36% may have apical emphysema on CT chest) Clinical Manifestations Lung Disease: Bronchiectasis: Originally Larsson 1978 showed 11.3% of ZZ had bronchiectasis From NHLBI only 2% Recommendation: unknown bronchiectasis - check levels As levels fall below 11mol/L or about 80mg/dl. Role of CPET Cardiopulmonary exercise testing • Cardiopulmonary exercise testing (CPET), also known as cardiopulmonary exercise stress testing, is a non-invasive tool that provides a comprehensive evaluation of exercise responses involving the cardiovascular, pulmonary, hematopoietic, neuropsychological, and musculoskeletal systems. Role of CPET • Cardiopulmonary exercise testing entails measurements of: – – – – • Oxygen uptake (VO2) Carbon dioxide output (VCO2) Minute ventilation (VE) 12-lead electrocardiography (ECG), blood pressure (BP) monitoring and pulse oximetry. These data are gathered during a maximal symptom-limited incremental exercise test. In certain circumstances, an additional measurement of arterial blood gases may be used to assess pulmonary gas exchange. Indication Recommendation grade Detection of exercise-induced bronchoconstriction A Detection of exercise-induced arterial oxygen desaturation B Functional evaluation of subjects with unexplained exertional dyspnea and/or exercise intolerance and normal resting lung and heart function D To recognize specific disease exercise response patterns that may help in the differential diagnosis of ventilatory versus circulatory causes of exercise limitation C Functional and prognostic evaluation of patients with COPD B, C Functional and prognostic evaluation of patients with ILD B, B Functional and prognostic evaluation of patients with CF C, C Functional and prognostic evaluation of patients with PPH B, B Functional and prognostic evaluation of patients with CHF B, B Evaluation of interventions (Maximal incremental test) C Evaluation of interventions (High-intensity constant work-rate ‘‘endurance’’ tests) B Prescription of exercise training B