Chronic Pulmonary Complications HEMO 2016 Florianopolis, November 12, 2016
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1 Chronic Pulmonary Complications HEMO 2016 Florianopolis, November 12, 2016 Samir K. Ballas, MD, FACP, FASCP, DABPM, FAAPM Emeritus Professor of Medicine and Pediatrics Cardeza Foundation for Hematologic Research Thomas Jefferson University Philadelphia, PA USA
2 Conflict of Interest Disclosure Samir K. Ballas I hereby declare the following potential conflicts of interest concerning my presentation: Consultancy: Health Advances LLC, CERUS Corporation, Global Blood Therapeutics (GBT), Prolong Pharamtheuticals Research Funding: Sickle Cell Program of the Commonwealth of PA Honoraria: Novartis Patents and Royalties: IASP (International Association for the Study of Pain) Membership on an Entity s Board of Directors or Advisory Committees: Quintiles, Alexion Pharmaceuticals, Novartis Discussion of off-label drug use: None will be discussed
3 Pulmonary Complications of Sickle Cell Disease Pulmonary complications constitute a major cause of mortality in patients with SCD In CSSCD 20% of adults had fatal pulmonary complications In the long-term follow up study of MSH 28% of all deaths were due to lung disease Acute pulmonary complications of SCD are better studied than the chronic complications
4 Screening for Pulmonary Disease NIH Guidelines Recommendations In children and adults with SCD, assess for signs and symptoms of respiratory problems (such as asthma, COPD, restrictive lung disease, or obstructive sleep apnea) by history and physical examination. (Consensus Panel Expertise) In children and adults with SCD found to have signs or symptoms of respiratory problems by history and/or physical examination, further assessment, which includes pulmonary function tests, is recommended to determine the cause and develop a plan to address the problem. (Consensus Panel Expertise) Do not screen asymptomatic children and adults with pulmonary function tests. (Moderate Recommendation, Low-Quality Evidence)
5 Chronic Pulmonary Complications of Sickle Cell Disease Asthma Chronic Obstructive Lung Disease Airway Hyper-reactivity/Asthma Chronic Restrictive Lung Disease (Pulmonary Fibrosis) Obstructive Sleep Apnea Pulmonary Hypertension
6 Hypoxia and Hypoxemia Hypoxia: Decreased oxygen supply to a specific organ (tissue hypoxia) or to the whole body Hypoxemia: Abnormally low partial oxygen tension (low level of oxygen in the blood) Mechanism: Ventilation Perfusion (V/Q) mismatch
7 Hypoxia and Hypoxemia The Hypoxia Response Pathway Hypoxia Generates HIF-α (Hypoxia induced factor) A series of biochemical reactions ensues Hypoxia-induced factors translocate to the nucleus HIF-α activates the transcription of genes that increase Metabolism, Angiogenesis, Cell migration & Invasion, Cell Proliferation and Inflammation NEJM 375:17 October 12, 2016
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9 Asthma and Sickle Cell Disease Asthma is a chronic inflammatory disorder Characterized by repeated attacks of airway obstruction and symptoms of increased airway responsiveness Improves symptomatically in children and young adults but most often it persists in adults and worsens with age More common in African Americans More common among children (20 70%) than adults (20-30%) Diagnosis based on clinical picture and spirometry NIH Publication
10 Chronic Obstructive Pulmonary Disease (COPD) Characterized by airflow limitation that is not fully reversible Airflow limitation is usually progressive Associated with an abnormal inflammatory response to noxious particles or gases Diagnosis: Post-bronchodilator spirometry showing a reduction in the ratio of FEV1/FVC (< 0.70)
11 Comorbidities in COPD Patients A retrospective Egyptian study of 400 patients with COPD (mean age 62 y, 69% M and 36% smokers) reported the following comorbidities: CV 85%, DM2 35%, Dyslipidemia 23% Anemia 10%, Pneumonia 7%, Osteoporosis 6% GERD 2% and lung cancer 2% Mohammadien H Presentation at the 2016 Meeting of the ACCP
12 Chronic Restrictive Lung Disease Characterized by persistent reduction in total lung capacity (TLC) with or without interstitial lung disease. Accompanied by a reduction in vital capacity (VC) and functional residual capacity, but little change in residual volume. Diagnosis: VC <80% of predicted OR TLC <90% of predicted.
13 Pulmonary Fibrosis/Restrictive Lung Disease Recurrent ACS results in parenchymal damage leading to pulmonary fibrosis Patients with H/O ACS tend to have lower TLC consistent with pulmonary fibrosis/restrictive disease Restrictive lung disease is associated with increasing severity of SCD Powars et al Medicine 1998 Klings et al AJRCCM 2006
14 Obstructive Sleep Apnea Recurrent OFF (stopping) and ON (restarting) breathing during sleep Nocturnal Hypoxemia has been reported in children, adolescents and young adults Occurs when the muscles that support the soft tissues of the throat, such as the tongue and soft palate, temporarily relax and also when there is lymphoid proliferation When these muscles relax, the airway is narrowed or closed, and breathing is momentarily cut off Signs include snoring, morning headache, daytime sleepiness, etc. OSA is more common (about 4X) in children with SS than in controls Treatment: Continuous positive airway pressure (CPAP )machine
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16 Pulmonary Hypertension Definition: Increase of Blood Pressure in the Pulmonary Vasculature (Both Micro & Macro) Clinical Picture: Dyspnea, Palpitations, Pain (chest and Abdomen), Syncope, Cyanosis, Leg Edema, Fatigue, etc. First Described in 1891 by Ernst von Romberg
17 WHO Classification of Pulmonary Hypertension Group 1. Pulmonary Arterial Hypertension (PAH): Idiopathiic, Heritable (HHT), Drug-induced, Chronic Hemolytic anemia (SCD), Schistosomiasis, etc. Group 2. Pulmonary Venous Hypertension with left heart disease (PVH): Systolic Dysfunction, Diastolic Dysfunction, Valvular Heart Disease Group 3. Pulmonary Hypertension Associated with Lung Disease : COPD, Interstitial Lung Disease, Sleep Apnea, Chronic Exposure to High Altitude, Developmental Abnormalities Group 4. Pulmonary Hypertension due to Thrombotic Disorders: Chronic Thromboembolic Pulmonary Disease Group 5. Pulmonary Hypertension due to other disorders: Myeloproliferative disease, Splenectomy, Sarcoidosis, Gaucher Disease, etc.
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20 Pulmonary Hypertension Pathophysiology Normally, Nitric Oxide Synthase Produces NO from L- Arginine in the Presence of Oxygen In PAH Less NO & other Vasodilators are Produced and Replaced by more Vasoconstrictors Accordingly, in PAH there is constant Vasoconstriction For this Reason, NO and inhibitors of Vasoconstriction such as Sildenafil, Tadadafil, Bosentan, Ca Chanel blockers were considered possible therapies
21 Gaines S JAMA 2000; 384:3160
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23 Diagnosis of Pulmonary Hypertension in SCD (NIH GUIDELINES) Recommendations If people with SCD have symptoms or signs suggestive of PH, refer them for echocardiography. (Strong Recommendation; Moderate- Quality Evidence) For people with an elevated TRV 2.5 m/sec by echocardiography, consult a provider with expertise in pulmonary hypertension to guide further assessment and management, including right heart catheterization, and consideration of PH therapy. (Consensus Panel Expertise)
24 Prevalence of Pulmonary Hypertension (PAH) by Echocardiogram in 195 Unselected Adults with Sickle Cell Disease Percent 10 0 Normal: TRV <2.5 m/sec Mild PAH: TRV m/sec Severe PAH: TRV >2.9 m/sec Gladwin et al. N Engl J Med. 2004;350:886.
25 Risk Factors of Pulmonary Arterial Hypertension Age 32 years Worsening anemia: Decreasing Hb High levels of LDH High levels of reticulocyte count Worsening renal function with serum creatinine > 1.0 mg/dl
26 Interpretation of Tricuspid Valve Velocity (TRV) Normal TRV < 2.5 m/sec TRV > 2.5 m/sec is associated with poor prognosis and high mortality among patients with SS TRV > 2.5 m/sec is NOT diagnostic of pulmonary hypertension Diagnosis of pulmonary hypertension requires right heart catheterization
27 Diagnosis of Pulmonary Hypertension by Right Heart Catheterization (RHC) Mean Pulmonary Artery Pressure (MPAP) Normal < 25 mmhg < 15 mmhg Pulmonary Arterial Hypertension (PAH) Pulmonary Venous Hypertension (PVH) 25 mmhg 25 mmhg Mean Pulmonary Capillary Wedge Pressure 15 mmhg > 15 mmhg
28 Treatment of Pulmonary Hypertension Pulmonary Venous Hypertension (PVH) Treat The cardiovascular complications Pulmonary Arterial Hypertension (PAH) No specific treatment confirmed to date Anecdotal & Observation reports include Red Blood Cell Exchange transfusion Hydroxyurea Both Transfusion & HU
29 OBRIGADO
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