DSA - Chronic Dyspnea & Pulmonary Hypertension PDF

DSA - Chronic Dyspnea & Pulmonary Hypertension Collin O’Hara, MD [email protected] Reading Robbins Basic Pathology, 10th ed. Chapter 13 pp 498-506 & 517-518; Chapter 7 pp 250-254 1  CLASSIFICATION – PFT’s (pulmonary function tests) Obstr...

DSA - Chronic Dyspnea & Pulmonary Hypertension Collin O’Hara, MD [email protected] Reading Robbins Basic Pathology, 10th ed. Chapter 13 pp 498-506 & 517-518; Chapter 7 pp 250-254 1  CLASSIFICATION – PFT’s (pulmonary function tests) Obstructive disease/airway disease  Increase in resistance to expiratory airflow  Secondary to partial or complete obstruction at any level  Anatomic airway narrowing(asthma)  Loss of elastic recoil(emphysema) Restrictive disease  Reduced expansion of lung parenchyma  Decreased total lung capacity(TLC) 2  MAJOR DIFFUSE OBSTRUCTIVE DISORDERS Obstructive disorders include Emphysema Chronic bronchitis Bronchiectasis Asthma PFTs normal to slightly decreased FVC, decreased FEV1, and decreased FEV1/FVC 3 MAJOR DIFFUSE RESTRICTIVE DISORDERS Chest wall disorders in presence of normal lungs Severe obesity, pleural diseases, neuromuscular disorders (Guillain-Barré) affecting respiratory muscles. Acute or chronic interstitial diseases Acute=ARDS Chronic= pneumoconioses, idiopathic interstitial 4 fibrosis, infiltrative disorders(sarcoidosis, hypersensitivity pneumonitis) Chronic obstructive pulmonary disease COPD = emphysema + chronic bronchitis Clinical & anatomic grouping Overlapping features of damage; tend to coexist Acinar level/emphysema and bronchial level/bronchitis Small airway disease/chronic bronchiolitis contributes to obstruction in both- bronchioles Common extrinsic trigger cigarette smoking 5 35-50% of heavy smokers develop COPD & conversely 80% of COPD is d/t smoking. Overlap between chronic obstructive lung diseases Fig 13.4 Basic Pathology 6  EMPHYSEMA Irreversible abnormal permanent enlargement of airspaces Obstruction to airflow out of lungs Distal to the terminal bronchiole With destruction of bronchiolar walls Without obvious fibrosis Classified according to anatomic distribution within respiratory lobule 7 Types of emphysema A. Normal terminal bronchiole → proximal to respiratory bronchiole B. Centriacinar → with dilation → first affects respiratory bronchioles C. Panacinar → initial distention of peripheral structures(alveolar ducts & alveoli) D. Paraseptal E. Irregular Only B & C cause significant airflow obstruction (>95% of cases) 8  CENTRIACINAR/CENTRILOBULAR EMPHYSEMA Affects Central/proximal acinar parts(respiratory bronchiole) Distal alveolar ducts/alveoli spared Combination of both emphysematous and normal airspaces found in same acinus/lobule More common/more severe in upper lobes Especially apical segments In severe form, distal acinus may also be involved d/dx from panacinar difficult Mainly in heavy smokers Often associated with chronic bronchitis 9  CENTRILOBULAR EMPHYSEMA Central areas with marked N emphysematous damage (E) Surrounded by relatively normal regions (N) N N 10 Robbins PBD, 9th Ed., Figure 15-7 (A)  11 Anthracosis Note the (black dirty pigment) spaces from duesmoking to cig plus smokeemphysematous changes  Leeds Institute of Medical Emphysema Research, University of Leeds. © 2019 E E E Normal Emphysema 12  PANACINAR/PANLOBULAR EMPHYSEMA Acini are uniformly enlarged From level of respiratory bronchiole to terminal blind alveoli “Pan” = entire acinus/not the entire lung More common lower zones & anterior margins of the lung Most severe in bases Associated w/ 1- antitrypsin (1-AT) deficiency 13 PANACINAR EMPHYSEMA Involving the entire pulmonary lobule (panlobular) Acini uniformly enlarged From level of resp. bronchiole to terminal blind alveoli 14 Paraseptal (distal meddean.luc.edu acinar/localized) Characteristic findings multiple continuous enlarged airspaces at distal acinus Proximal acinus is normal Adjacent to pleura, along lobular connective tissue septa & at lobule margins. Air space size ranges from < 0.5 mm to > 2.0 cm Can coalesce and form bullae Bullous emphysema Most likely assoc w/ spontaneous 15 pneumothorax in young adults d/t rupture of bullaevaping https://thoracickey.com BULLOUS EMPHYSEMA Seen in advanced of disease Very large abnormal airspaces Formation of blebs/bullae Subpleural bullae seen Spaces > 1 cm in diameter/in distended state Apical is most common 16  Irregular emphysema Airspace enlargement with Meddean.luc.edu fibrosis Acinus irregularly involved Almost invariably associated with scarring May be most common form Asymptomatic & clinically insignificant Usually incidental finding at autopsy 17 PATHOGENESIS – emphysema/COPD Inhaled cigarette smoke & other noxious particles lead to lung damage & inflammation Results in parenchymal destruction (emphysema) and airway disease (bronchiolitis & chronic bronchitis) Shows increased macrophages, CD 4+ & CD8+ T lymphocytes, neutrophils Nicotine chemotactic for neutrophils Activated inflammatory cells release mediators LTB4, IL-8, TNF damage lung structures, maintain neutrophilic inflammation 18 Protease- antiprotease imbalance Inflammatory & epithelial cells release proteases Alveolar wall destruction occurs due to imbalance between proteases (mainly elastase) and protective antiproteases in emphysema patients Other factors include Oxidative stress d/t reactive oxygen species produced by cig smoke & inflammatory cells Inhibition of alpha1 anti-Trypsin (AAT normally inhibits proteases) Low levels AAT allow elastase activity to go unchecked as in panacinar emphysema 19 Airway infections causes acute exacerbations but may not be involved in tissue destruction PATHOGENESIS OF EMPHYSEMA SCHEMATIC Protease- antiprotease imbalance & oxidant-antioxidant imbalance are 20 additive and both contribute to tissue damage  Genetic 1-AT deficiency Why are proteases important? In a Homozygous patient:  Genetic deficiency of the protease inhibitor 1-AT tendency for emphysema will be compounded by smoking  1-AT  synthesized in liver; present in serum, tissue fluids & macrophages, inhibits proteases Normal 1-AT phenotype = PiM or PiMM have normal levels PiZZ = most serious type assoc w/ emphysema 0.012% of populace >80% of latter develop symptomatic disease 21  Alpha 1-antitrypsinase(AAT) PiZZ homozygotes have only 10-15% of normal plasma concentration These pts have abnormal protein poorly secreted by liver At risk for developing cirrhosis of liver and panacinar emphysema Majority of persons diagnosed with emphysema below age 40 Without smoking; develop around age 45-50 With smoking; develop at about 35 22  AAT deficiency histology Panacinar emphysema & liver cirrhosis © University of Alabama at Birmingham, Department of Pathology 23  AAT deficiency Liver PAS positive granules from case of liver cirrhosis due to AAT deficiency © University of Alabama at Birmingham, Department of 24 Pathology Role of smoke particles in emphysema Postulated that small bronchi and bronchioles become impacted with smoke particles Paralyzes the cilia lining bronchi & bronchioles causing the particles to become permanently entrapped Causes influx of neutrophils and macrophages within this area resulting in centrilobular emphysema 25  Emphysema- Clinical Symptoms appear when at least 1/3 functional lung affected Usu > 60yrs Insidious but progressive disease Dyspnea – first symptom Coughing or wheezing w/ assoc chronic bronchitis/asthma “Pink puffer” Prominent dyspnea Adequate oxygenation of hemoglobin Cause of death- respiratory failure or right sided heart failure (cor pulmonale) 26  CHRONIC BRONCHITIS  Definition: presence of persistent cough with mucoid sputum production for at least 3 months in at least 2 consecutive years  Common in cig smokers & urban dwellers of smoggy cities  Most cases in smokers  “Blue Bloater” Less prominent dyspnea More assoc w obesity Retention of carbon dioxide Appear hypoxic & cyanotic  Cause of death- variable; range from infections, right cardiac failure (cor pulmonale) to respiratory failure. 27 Chronic bronchitis types Simple chronic bronchitis productive cough but no physiologic evidence of airflow obstruction Chronic asthmatic bronchitis hyperreactive airways with intermittent bronchospasm and wheezing Obstructive chronic bronchitis develop chronic airflow obstruction usually have associated emphysema 28  Pathogenesis of chronic bronchitis Hallmark is hypersecretion of mucus beginning in large airways  Most important cause is cig smoking, followed by other environmental pollutants  Histologic findings of: Mucus gland hyperplasia- increased size of glands Reid index= ratio of thickness of mucous gland layer to thickness of wall between the epithelium and the cartilage (NL=0.4) Goblet cell metaplasia often seen Inflammatory infiltration of bronchiolar walls (lymphs, macrophages, neutrophils, no eos) Fibrosis of the bronchiolar wall (older patients) 29 May see squamous metaplasia or dysplasia (esp w/ smoking) EVOLUTION OF CHRONIC BRONCHITIS AND EMPHYSEMA Although both pathways can culminate in chronic bronchitis and emphysema → pathways are different Either one can predominate Dashed arrows on the left → indicate the natural history of chronic bronchitis 30 CHRONIC BRONCHITIS- histopathology Chronic inflammation 31  Reid index Ratio of thickness of submucosal mucus gland layer to thickness of bronchial wall between epithelium and cartilage Normally = 0.4 or less Increased(>0.5) in chronic bronchitis proportionally to duration and severity of disease 32  ASTHMA a chronic disorder of the airways Usually an immunologic reaction marked by: 1) episodic bronchoconstriction d/t increased airway sensitivity to varied stimuli 2) inflammation of bronchial walls 3) increased mucus secretion Presents w/ recurrent episodes of wheezing, breathlessness, chest tightness and cough esp at night and/or in early morning Symptoms are usually assoc. w/ widespread/variable bronchoconstriction and airflow restriction that are at least partly reversible (spontaneously or with treatment) 33  ASTHMA - CATEGORIES Atopic Type I hypersensitivity reaction--IgE mediated induced by exposure to an extrinsic antigen Diagnosis High total serum IgE or serum radioallergosorbent tests(RAST) for antibodies specific for certain allergens Skin tests- positive wheal & flare rxn Non-Atopic Initiated by diverse, nonimmune mechanisms ASA (aspirin), pulmonary infections (viral), cold Inhaled irritants, stress, exercise 34 Skin Tests- negative Special types of asthma Aspirin sensitivity asthma Associated with recurrent rhinitis, nasal polyps, urticaria, & bronchospasm Pathogenesis- abnormal prostaglandin metabolism d/t inhibition of cyclooxygenase by ASA Occupational – after repeated exposure Fumes-epoxy resins, plastics Organic/chemical dusts-wood, cotton, platinum Gases-toluene Other chemicals 35  Pathogenesis of asthma Genetic predisposition to type I hypersensitivity (“atopy”) TH2 and IgE response to environmental allergens Acute and chronic airway inflammation Inflammation involves many cell types including eosinophils Bronchial hyperresponsiveness Precise relationship of specific inflammatory cells and 36 mediators not fully understood MODEL FOR ATOPIC ASTHMA Inhaled allergens/Ag elicit a TH2-dominated response Favors IgE produc- tion and eosinophil recruitment (priming or sensitization) followed by series of events upon post re-exposure to antigen 37 BRONCHIAL ASTHMA HISTOLOGY Airway remodeling Airway wall thickening (blue arrow) Basement membrane thickened (black arrow) Submucosa widened by smooth muscle hypertrophy & inflammation with eosinophils (yellow arrow) Bronchial lumen with mucus and goblet cell hyperplasia 38 (green arrow) MUCOUS PLUG – INSPISSATED MUCUS Cast of the bronchial tree → formed by inspissated mucus Coughed up during an asthmatic attack(status asthmaticus) Outpouring of mucus, bronchoconstriction, dehydation 39 CURSCHMANN SPIRAL Mucous plug with whorls of shed epithelium Found in sputum or bronchioalveolar lavage fluid of asthmatic pt. Papanicolaou stain – reddish core with a fuzzy margin Cells attached secondarily Arrow points at a macrophage 40  CHARCOT-LEYDEN CRYSTALS eosinophils 41  BRONCHIECTASIS Characterized by permanent dilation of bronchi and bronchioles Caused by destruction of smooth muscle and supporting elastic tissue Resulting from or associated with chronic necrotizing infections Not a primary disorder 42  Conditions predisposing to bronchiectasis 1. Congenital or hereditary conditions Cystic fibrosis, 1 ciliary dyskinesia (immotile cilia syndrome/Kartagener syndrome). Immunodeficiency states assoc. w/ recurrent bacterial infections, i.e. immunoglobulin deficiencies 2. Postinfectious conditions Necrotizing bacterial pneumonias, esp with Staph aureus, Klebsiella, or TB in endemic regions 3. Bronchial obstruction due to tumor, foreign bodies 4. Other conditions such as Rheumatoid arthritis, SLE, IBD, 43 chronic GVHD  PATHOGENESIS OF BRONCHIECTASIS Cases due to nonspecific obstruction & infection Both necessary for full-blown lesions Either may be initiating factor Normal clearing mechanisms are impaired Most readily apparent in cystic fibrosis Thick viscid mucus obstructs airways & predisposes to infections Primary ciliary dyskinesia (immotile cilia syndrome) Autosomal recessive/variable penetrance Defects in ciliary motor proteins( dynein arm mutations) Kartagener syndrome- situs inversus, bronchiectasis, sinusitis Bronchiectasis Sterility in males- sperm dysmotility 44  Poorly functioning cilia retention of secretions recurrent infections bronchiectasis Immotile cilia syndrome Normal dynein arms Immotile cilia syndrome 45  46 Most common ©Medlibes.com BRONCHIECTASIS CT scan & gross specimen CT- dilated airways in longitudinal section (arrowhead) and cross section (arrow) Cut surface of lung with distended peripheral bronchi filled with mucopurulent secretions (white arrow) in cystic fibrosis  Bronchiectasis- gross Bronchiectasis tends to be localized with disease processes Widespread is typical in patients with cystic fibrosis as seen here in gross image of freshly explanted lung. 48 ©University of Alabama at Birmingham  Bronchiectasis- histology Desquamation of surface epithelium with ulceration Destruction of cartilage and smooth muscle Dilatation of airways Chronic inflammation and fibrosis of wall Intraluminal purulent material 49  Cystic fibrosis pathogenesis disorder of epithelial ion transport affecting fluid secretion in exocrine glands & epithelial linings of respiratory tract, GI tract, & reproductive tract Abnormally viscid mucous secretions  airway and the pancreatic duct blockages Leading to recurrent and chronic pulmonary infections and pancreatic insufficiency Most common (incidence 1:2500 live births) lethal genetic disease in whites (carrier freq 1:20) Classic biochemical abnormality – high sodium chloride level in sweat (sweat chloride test) Primary defect is reduced production(or abn fxn) of an epithelial chloride channel protein encoded by the CF transmembrane conductance regulator (CFTR) gene In sweat duct, result is increased sodium & chloride in sweat 50 In epithelium of resp & GI tract, decreased chloride secretion w/increased sodium & water reabsorption in airways results in dehydrated mucus layer, defective mucociliary action, & mucous plugging.  Cystic fibrosis affects several organs Pancreas- mild to most severe Exocrine gland atrophy & fibrosis Impaired fat absorption Vit A deficiency Small intestine- mucous plugs meconium ileus Pulmonary Thick viscid mucous of submucosal glands sinusitis, mucous plugging of bronchioles bronchiectasis abscesses Staph aureus, Hemophilus influenzae & Pseudomonas aeruginosa MC w/ Burkholderia cepacia (formerly Pseudomonas cepacia) increasing. Liver Bile canaliculi mucus plugging, followed by ductular proliferation & portal inflammation, hepatic steatosis(fatty liver) cirrhosis Reproductive- infertility males Azoospermia, bilateral absence of vas deferens Most common causes of death in CF are cardiopulmonary 51 Lung infections w/resistant Pseudomonas spp Bronchiectasis leading to right heart failure Pulmonary Hypertension defined as pressures of 25 mm Hg or more at rest Causes decrease in the cross-sectional area of the pulmonary vascular bed less commonly, increased pulmonary vascular blood flow Normal pulmonary blood pressure- low resistance & 1/8th of systemic pressure Clinical presentation is dyspnea & fatigue progressing to cyanosis, resp. distress, RVH, and then to decompensated cor pulmonale & death 52  Five groups of pulmonary hypertension (WHO classification) 1. Pulmonary arterial hypertension Diverse causes Autoimmune diseases and/or systemic sclerosis causing increased vascular resistance Diseases affecting small pulmonary muscular arterioles 2. Pulmonary hypertension d/t left-sided heart disease Systolic & diastolic dysfxn Valvular disease- mitral stenosis 3. Pulmonary hypertension d/t lung diseases &/or hypoxia COPD obliterates alveolar capillaries, thus increasing pulmonary resistance to blood flow and, secondarily, pulmonary blood pressure. Interstitial lung disease and obesity with obstructive sleep apnea also 4. Chronic thromboembolic pulmonary hypertension Disorders such as lupus anticoagulant, antiphospholipid syndrome, deficiencies of antithrombin, Protein C or S reduce functional cross-sectional area of pulmonary vascular bed with constant 53 micoremboli  increase in pulmonary vascular resistance 5. Pulmonary hypertension w/ unclear or multifactorial mechanisms Idiopathic Pulmonary Hypertension AKA Primary pulmonary hypertension All known causes excluded, not attributable to any other disease process Up to 80% Genetic- AD, incomplete penetrance(only 10-20% develop disease) Role of Bone morphogenetic protein(BMP)- signaling pathway Inactivating germ line mutations of gene encoding bone morphogenetic protein receptor 2 (BMPR2) found in 75% familial cases of pulmonary hypertension & 25% sporadic cases defects in BMPR2 signaling possibly lead to dysfunction of endothelium and proliferation of vascular smooth muscle cells in the pulmonary vasculature. 54 Morphology of pulmonary HTN medial hypertrophy of the pulmonary muscular and elastic arteries, pulmonary arterial atherosclerosis, and right ventricular hypertrophy Gross Severe cases atheroma formation in pulmonary arterial vasculature( atherosclerosis) Right ventricular hypertrophy Many pulmonary emboli- organizing or recanalizing Microscopic Arterioles & small arteries medial hypertrophy & intimal fibrosis Uncommonly plexiform lesions (complex vascular formations originating from remodeled pulmonary arteries) ulm HTN gross and micro L R ht ventricular hypertrophy d/t pulm hypertension Lung blood vessel with medial hypertrophy in 4 y.o. w/ primary pulm HTN Very thick right ventricle ©University of Alabama at Birmingham, Dept. of Pathology  Pulm HTN Plexiform lesion on histology RB Think of this plexiform lesion as a big vascular tangle Plexiform lesion in blue bracket adjacent to respiratory bronchiole (RB) 57 ©University of Alabama at Birmingham, Dept. of  Practice questions A 45 y.o. male patient who does not smoke and has homozygous alpha 1 antitrypsin deficiency is most likely to develop which type of lung disease? a. Asthma b. Bullous emphysema c. Centrilobular emphysema d. Chronic bronchitis 58 e. Panacinar emphysema A 62 y.o. male presents with a long history of exertional dyspnea. He states that he has an occasional dry cough and has been losing some weight. He smells of cigarette smoke and admits to a 40 pack year cigarette history. On physical exam he has tachypnea with prolonged expiration phase. Chest x-ray reveals depressed diaphragms and long narrow heart shadow. Microscopic exam of upper lung wedge biopsy would most likely reveal a. Airspace enlargement & respiratory bronchiole destruction b. Normal histology c. Permanently dilated airways with destruction of smooth muscle and elastic tissue d. Mucous gland hyperplasia & hypersecretion e. Smooth muscle hyperplasia, eosinophils and excess mucus 59 production A 54 y.o. smoker complains of increasing dyspnea on exertion over the last week. He notes that he has had a persistent cough that is productive of large amounts of mucopurulent sputum for the last 2 years. Histologic examination of a bronchial biopsy would reveal which of the following? a. Abundant mucus with plugging of bronchioles b. Alveolar destruction and enlargement c. Interstitial fibrosis d. Non-caseating granulomas e. Masson bodies An 8-year-old female with known allergies to cats, and asthma, spends the night at her aunt’s house where 3 cats reside. She has forgotten her medications including her rescue inhaler. The girl presents to the emergency room with severe wheezing, breathlessness and cough. Physical exam reveals very little air movement, however inspiratory and expiratory wheezes can be heard. A sputum examination in this patient may show A. Many neutrophils B. Curschman spirals and Charcot-Leyden crystals C. Deposits of type I and III collagen D. Ferruginous bodies 61 E. Many hemosiderin laden macrophages A 32 year old male presents to his family practitioner with his third episode of pneumonia in the past 6 months. The first two episodes cleared with antibiotics, but due to the recurrent nature of his symptoms, a sputum culture is ordered and a mucoid Pseudomonas aeruginosa is isolated. A chest x-ray also shows bilateral vertical dilatation of the airways. It is likely the patient has an undiagnosed illness caused by a. A gene mutation that involves chloride ion secretion b. A foreign body lodged in the right middle lobe c. An allergic reaction to Aspergillus d. A tumor growing in the lumen of the right main stem bronchus e. An IgE mediated reaction 62 A 36 year old female with a BMI of 20 and a known Protein S deficiency presents to the emergency room with acute shortness of breath, hypoxemia and chest pain. This is her third presentation with similar symptoms in the past 2 years. Unfortunately, she does not survive this episode. A medical examiner identifies numerous pulmonary emboli, both acute and chronic as well as an enlarged heart at autopsy. Histologically pulmonary atherosclerosis is also present. The elevated mean pulmonary artery pressure identified before her death is most likely due to a. Acquired mitral stenosis b. Systemic sclerosis c. Recurrent thromboemboli d. Sleep apnea e. The BMPR2 mutation 63  Additional references Rubin’s Pathology, 7th ed, Chapter 18 The Respiratory System>The Lungs>Obstructive Pulmonary Disease, Pneumonconioses & Interstitial lung disease Harrison’s Principles of Internal Medicine, 20th Ed. Part 7 Disorders of Respiratory system, Chapters 281, 284, 285, & 286