Pulmonary Complications of Sickle Cell Disease

1. Pulmonary Complications of Sickle Cell Disease Liz Klings, MD The Pulmonary Center Boston University School of Medicine

2. Why care about a hemoglobinopathy? • 0.15% of African Americans are HbSS (250,000 births per year worldwide) • 8% have sickle cell trait • Median age at death 42 (males) and 48 (females) • Pulmonary complications – major cause of mortality (20-30% of deaths)

3. Shortcomings in this Field • SCD is rare, hard to do large population-based studies • Difficult patient population to study • Lack of placebo-controlled randomized trials and outcomes studies

4. Important Unanswered Questions • Does screening for PH alter outcomes? • Does PAH of SCD respond to traditional PAH therapies? • Why do SCD patients develop diastolic dysfunction and how should we treat this? • What role does VTE play in disease modulation of SCD? • What is the contribution of airways disease, OSA and hypoxemia to chronic pulmonary disease?

5. Acute Chest Syndrome • Occurs in up to 45% of SCD patients; recurrent in up to 80% • Clinical presentation differs in kids vs. adults • Increased incidence in pediatric asthmatics (DeBaun 2006) • Defined as a new infiltrate + CP/fever/tachypnea/wheezing/cough

6. ACS – Diagnostic Work-Up • CXR/Labs – WBC, markers of hemolysis, ABG • V/Q scan • Bronchoscopy/Induced Sputum • Hb S levels • Secretory phospholipase A2/CRP

7. ACS – CXR Findings Vichinsky EP, et al. Blood 1997

8. ACS – Etiology Vichinsky EP, et al NEJM 2000

9. Vichinsky EP 2000

10. Predictors of Respiratory Failure in ACS • Multi-lobar disease (>4 lobes highest risk) • History of cardiac disease • Thrombocytopenia • Pre-existent pulmonary hypertension

11. ACS - Etiology

12. ACS – Treatment Strategies • Pain control/incentive spirometry • Bronchodilators • Antibiotics • Transfusion- Simple or exchange • Anti-coagulation if VTE confirmed • Other agents – inhaled NO, anti-adhesive agents, steroids

13. Pulmonary HTN in SCD • Was for many yrs thought to be part of “Chronic sickle cell lung disease” • Originally defined by a TRV > 2.5 m/sec • Observed in 1/3 of HbSS and 10-25% of HbSC adults • 10-22% of HbSS children and adolescents • Overlap in some with LV diastolic dysfunction Gladwin MT, et al. NEJM 2004; 350:886-95. Castro O, et al. Blood 2003; 4:1257-1261. Kato GJ, et al. Blood Rev 2007; 21:37-47. Klings ES, et al. Am J Hematol 2008; 83 (7):547-553.

14. An Elevated TRV Predicts Mortality in SCD Adults Gladwin MT, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. NEJM 2004.

15. But an Elevated TRV is Not PH Echo- 25% positive predictive value for PH 73% false positive rate PH prevalence – 6% Parent F, et al. NEJM 2011; 365:44-53.

16. NIH Brazil French Parent F, et al. NEJM 2011; 365:44-53. Mehari A, et al. JAMA 2012; 307:1254-1256 Fonseca GH, et al. Eur Respir J 2012;39(1):112-8.

17. Differences from IPAH • Often a paucity of symptoms • PA pressures/PVR tend to be lower • Preservation of cardiac output • Increased PCWP in some patients

18. Survival in PH of SCD Mehari A, et al. JAMA 2012; 307:1254-1256.

19. Associated Findings in PH of SCD Parent F et al. N Engl J Med 2011;365:44-53.

20. Summary of Hemodynamic Data in PH of SCD • 6-10.5% of HbSS adults have PH • Prevalence of PVH – 44-63% of PH patients • Prevalence of PAH in SCD 2.5-5.8% • PA pressures and PVR characteristically lower than IPAH Parent F, et al. NEJM 2011; 365:44-53. Mehari A, et al. JAMA 2012; 307:1254-1256 Fonseca GH, et al. Eur Respir J 2012;39(1):112-8. Klings ES, et al. AJRCCM March 1, 2014 (in press)

21. Is Screening for PH in SCD Necessary? • Evidence is stronger in adults • Pediatric population – No associated mortality, may be reversible, and may predict worse exercise capacity • No outcomes studies to predict benefit • But, this may be the only way to identify PH patients early in disease course

22. Etiology of PH in SCD • Unknown, likely multi-factorial • Historically, related to recurrent episodes of ACS, but this is not true • Endothelial dysfunction- pro-constrictive and pro-adhesive • Oxidant stress and decreased NO bioavailability

23. Histopathology of PH in SCD

24. Gladwin MT and Vichinsky EP NEJM 2008

25. Hemolysis-related PH • PH associated with other hemolytic diseases: • Post-splenectomy • β-thalassemia • Hereditary spherocytosis • Pyruvate kinase deficiency • May be a mechanism of decreased NO bioavailability

26. Decreased NO Bioavailability • Decreased NO production • Increased NO consumption • Scavenging by free Hb • Oxidant consumption

27. Rother RR, JAMA 2005;293:1653-1662.

28. Treatment of PH in SCD

29. Treatment Issues Specific to SCD • Multiple co-morbidities • Anemia produces an elevated CO and symptoms can be delayed • Increased risk of bleeding and possibly infection • Not all PH in SCD is PAH • No randomized trials completed in this population • Recommend referral to PH center with expertise in SCD

30. SCD Specific Therapies and Co-Morbidities • Hydroxyurea • Chronic Transfusions • Treatment of associated conditions: OSA, VTE, hypoxemia

31. Hydroxyurea • Only FDA approved medication for SCD, under-utilized • Reduces VOC, ACS and need for transfusion in HbSS • Primary action – induction of HbF • Long-term studies – improved survival at 17.5 yrs • Benefits in PH of SCD theoretical, not studied Steinberg MH, et al. JAMA 2003;285;1645-1651. Steinberg MH, et al. Am J Hematol 2010; 85:403-408.

32. Chronic Transfusions • Best studied in pediatric patients for stroke prevention – STOP 1 and 2 • May reduce frequency of VOC/ACS • No effects on mortality • In a small case series, lowered PASP by echo • Risk of iron overload and allo-immunization Lee MT, et al. Blood 2006; 108:847-852. Wang WC, et al. J Pediatr 2005; 147:244-247

33. The Link Between VTE and PH • 2-4% of patients with PE will develop CTEPH • Autopsy studies of IPAH patients – in situ thrombosis • SCD is a hyper-coagulable state • Patients with PH of SCD – thrombotic arteriopathy of small PA’s • But the link between DVT/PE and PH in SCD is unclear Haque AK, et al.Hum Pathol 2002; 33(10):1037-1043. Graham JK, et al. Am J Forensic Med Pathol 2007; 28(2):168-172. van Beers EJ, et al. Haematologica 2008; 93(5):e42-e44. Ataga KI, et al. Haematologica 2008; 93(1):20-26. Wilkins H, et al. Int J Cardiol 2011; 154S1: S54-S60.

34. Risk of VTE in SCD Patients with an Elevated TRV • Used clinical data from patients recruited as part of the PH in SCD study at Boston University (n=162) • Prospective observational study conducted from 2004-2010 • Enrolled all SCD patients > 12 yrs • All subjects underwent a screening questionnaire, echocardiogram and procurement of a blood sample

35. VTE in SCD Patients with an Elevated TRV

36. Increased Risk of VTE in SCD Patients with an Elevated TRV • 18.5% of SCD patients had a history of VTE • 5/53 patients (9.4%) with a normal echo had a history of VTE, compared with 13/44 (29.5%) in the elevated TRV group. • SCD patients with an elevated TRV were four times more likely to have a history of VTE compared to those with a normal echo (OR: 4.03, 95% CI 1.31-12.41, p=0.01).

37. ASSET-1 and 2: Bosentan in PH of SCD • Randomized placebo controlled trials of bosentan in PAH or PVH of SCD • Industry sponsored • Difficulties with site initiation and enrollment led to sponsor withdrawal • 26 subjects enrolled, efficacy endpoints not analyzed Barst RJ, et al. Br J Haematol 2010;149(3):426-35

38. ERA’s in PH of SCD Open label study of 14 patients with RHC-confirmed PAH Six patients also on sildenafil Bosentan or ambrisentan used Minnitti CP, et al. Br J Haematol 2009; 147(5):737-43.

39. Acute and Long-Term Effects of Sildenafil in PH/SCD Machado RF, Br J Hematol 2005;130:445-453.

40. Walk-PHaSST – Sildenafil for PH of SCD • Used echo definition of PH (TRV > 2.7 m/sec) • Primary outcome: improved 6MWD • Planned to enroll 132 subjects • Study stopped prematurely after 74 were randomized • Increased SAE’s in sildenafil group – primarily VOC • Questions about efficacy Machado RF, et al. Blood 2011;118(4):855-64.

41. Klings ES, et al. ATS Guidelines for Diagnosis and Treatment of PH in SCD AJRCCM 2014 (in press)

42. But wait, there’s more

43. WHO/NYHA Class Hb-SS Hb-SC Klings ES, et al. Am J Hematology 2008

44. PFT Classifications Adult Pediatric Klings ES AJRCCM 2006

45. Sleep-Disordered Breathing and SCD • Multiple small studies in kids and adolescents – nocturnal desats in up to 79% • Prevalence of OSA – 10-20% • Upper airway obstruction related to lymphoid hyperplasia • Adenoidectomy/tonsillectomy- curative in some, but impact on cardiopulmonary outcomes unclear • May be associated with daytime hypoxemia • Risk for adults - unknown

46. Linking Adult And Pediatric SCD-Related Lung Disease • Link between asthma/ACS in pediatric patients and restrictive disease in adults • Changes in cardiopulmonary physiology in early adulthood • Can early intervention prevent PH in SCD?

47. Pulmonary Fibrosis and SCD • Thought to be part of the spectrum of chronic sickle cell lung disease • Mechanism unknown, may be long-term effect of recurrent episodes of ACS • CT scan – Ground glass infiltrates with mild fibrotic changes • May be associated with PH

48. Summary • Pulmonary disease is an important cause of morbidity and mortality in SCD • Dyspnea is very common in SCD population, not all of this is due to PH • All SCD adults should be screened annually for PH • Lots of work still needs to be done