1. Pulmonary Complications of Sickle Cell Disease Kenneth I. Ataga, MD Comprehensive Sickle Cell Program University of North Carolina - Chapel Hill

2. Introduction Sickle hemoglobin (Hb S) occurs when the normal  6 glutamic acid residue is replaced by valine The polymerization of deoxygenated Hb S is the primary event in the molecular pathogenesis of SCD SCD is also characterized by increased adhesion of RBC and other cellular elements to endothelium

3. Sickle Cell Disease

4. Introduction SCD may be complicated by several pulmonary complications:  Acute chest syndrome  Airway hyperreactivity/Asthma  Pulmonary embolism  Nocturnal oxyhemoglobin desaturation  Pulmonary hypertension  Pulmonary fibrosis

5. Acute Chest Syndrome Case Presentation HPI: 30 year old black female presented with a 3 day history of fever & chest pain PMH: Homozygous SS. Multiple admits for painful VOCs. Occasional pRBCs. S/P Lap Cholecystectomy. G 2 P 2 Proteinuria - S/P Renal biopsy. Path - SS Nephropathy. Current Meds: Folic acid (1 mg/d)

6. Acute Chest Syndrome PE: BP = 124/62. P = 128. RR = 30. T = 38.5  Sclerae - icteric. Neck: few nodes. JVD at 30  Chest - rales bilaterally, dullness to percussion, especially in R mid lung field. CVS - Loud P 2. 3/6 SEM. No edema. Abd - Distended, non-tender. No masses or visceromegaly. Nl BS. Neurol - non-focal, lethargic but easily arousable. Oriented x 3.

7. Acute Chest Syndrome Adm Labs: H/H 6.4/20, WBC 23,100. Plat 270K LFTs - WNL. LDH - 2200. TBili - 13.4 CXR: Cardiomegaly. Pulm. venous congestion. Subsegmental atelectasis - RUL. Patchy density in the L costophrenic angle. EKG : Sinus tachycardia. RVH & LVH. RAD with evidence of right heart strain.

9. Acute Chest Syndrome Admission Orders: l Sputum/urine/blood cultures l Cefotaxime 1 gram IV Q8H l Azithromycin l IV fluids l O 2 - 2 Liters per minute via nasal cannula l IV narcotic analgesics

10. Acute Chest Syndrome 6 hours later l Decreased responsiveness, somnolent, difficult to arouse, and confused. l BP=100/52, P=156, RR=44, T38.8  C l Extremities - cool with thready pulses

11. Acute Chest Syndrome Repeat Laboratory Studies l Hematocrit = 14% l WBC = 31,300 l Platelets = 284K l PT = 20.6, PTT = 59.4, TCT = 11.1 l ABG (2L O 2 ): pH 7.11, PO 2 89, PCO 2 19 l Repeat CXR - extensive infiltrates/fluid with white out of right lung

13. Acute Chest Syndrome Patient intubated emergently and then transferred to the Intensive Care Unit

14. Acute Chest Syndrome Multiorgan Failure Hematologic Status pRBC (8 units) FFP Cryoprecipitate Coags normalized At D/C: PT 12.0, Hct 29% Renal Status Became oliguric in ICU Peak BUN/Cr = 110/4.6 Hemodialysis x 1 Urine output increased Renal function improved At D/C: BUN 17, Cr 1.5

15. Acute Chest Syndrome Respiratory System Extubated on day #5 Slow resolution of CXR All cultures negative ABG on day of D/C (RA) pH 7.53 PO 2 67 PCO 2 30 ABG (6 weeks later) pH 7.43 PO 2 79 PCO 2 38 PFTs (6 weeks later) FVC - 2.19 (63%) FEV1 1.99 (68%) DLCO c - 28% Cardiovascular System Pressor support on vent Echo (day #2)- severe TR Dilated RA & RV Mean PA pressure = 80 Repeat echo (day of D/C) mild TR with minimal pulmonary hypertension

17. Acute Chest Syndrome - Objectives Incidence Risk Factors Clinical Presentation Etiology Mortality Pathophysiology Treatment

18. Acute Chest Syndrome Definition? Charache suggested this name in 1979 for what he felt was a poorly understood process A new pulmonary infiltrate in a clinically ill patient with sickle cell disease Fever, cough, chest pain, tachypnea, wheezing, rales on exam

19. Acute Chest Syndrome - Sources of Data The Cooperative Study of Sickle Cell Disease (CSSCD) The National Acute Chest Syndrome Study Group (NACSSG)

20. Acute Chest Syndrome - CSSCD & NACSSG ACS: Incidence and Risk Factors; Clinical Presentation and Course (Castro et al., Blood, 1994 & Vichinsky et al., Blood, 1997) l Data from 3751 patients with 19,867 pt-years of follow-up Causes & Outcomes of ACS in SCD (Vichinsky et al., NEJM, 2000) l Data from 538 patients with 671 episodes of ACS

21. Acute Chest Syndrome - Incidence ACS incidence is higher in SS patients (12.8/100 pt-yrs) and S  0 thal patients (9.4/100 pt-yrs) ACS incidence in SC patients was 5.5/100 pt-yrs and in S  + thal patients was 3.9/100 pt-yrs Within each Hb type, incidence of ACS was strongly, but inversely associated with age

22. Acute Chest Syndrome - Incidence (SS) Age Group (yrs) Episodes of ACS (per 100 patient years) < 2 20.8 2-525.3 5-1015.6 10-20 9.3 > 20 8.8 from Castro et al. Blood, 1994

23. Acute Chest Syndrome - Incidence (SC) Age Group (yrs) Episodes of ACS (per 100 patient years) < 2 10.3 2-510.1 5-10 4.3 10-20 4.0 > 20 3.3 from Castro et al. Blood, 1994

24. from Castro et al., Blood, 1994 Acute Chest Syndrome - Risk factors Significant in multivariable analysis l Young age l Low fetal hemoglobin level l High hemoglobin level in steady state l High WBC in steady state

25. from Castro, et al., Blood, 1994. Acute Chest Syndrome - Effect of Hgb F Level on Risk Relationship between Hb F and ACS for the age groups shown

26. from Castro, et al., Blood, 1994. Acute Chest Syndrome - Effect of Steady State Hgb Level Relationship between total hemoglobin and rate of ACS in 3 age groups

27. Acute Chest Syndrome - Clinical Presentation Frequency of presenting symptoms in ACS is age-dependent Young children (2 – 4 yrs) present commonly with fever, cough, wheezing and rarely have pain Adults are often afebrile, have SOB, and severe pain in arms and legs

28. Acute Chest Syndrome Clinical Presentation On x-ray, upper lobe disease is predominant in children, while multilobe/lower lobe disease is more common in adults Children require less blood transfusions than adult patients Duration of hospitalization is ~ 5.4 days in children compared to ~ 9 days in adults

29. from Castro, et al., Blood, 1994 Acute Chest Syndrome Effect on Mortality l ACS during initial 2 yrs of f/u and those who did not. l Survival difference esp after age of 20 l Adults with ↑ ACS rate have a higher mortality than those with low rates

30. Acute Chest Syndrome Mortality (CSSCD) Overall death rate: 1.8% (32 / 1741) l In patients < 20 years, death rate = 1.1% (14 of 695 pts/1,322 events) n 9/14 were < 3 yrs l In patients > 20 years, death rate = 4.3% (18 of 271 pts/419 events)

31. Etiology of Acute Chest Syndrome (NACSSG ) (Total # of episodes = 671 in 538 pts) A specific cause was identified in 256 (38%) After excluding cases with incomplete data, a specific cause was found in 70% of cases Pulmonary infarction was presumed to be the cause in 16% of episodes with complete data but no identified etiology

32. Acute Chest Syndrome – Etiology

33. Acute Chest Syndrome Isolated Pathogens (NACSSG ) (Infectious pathogens were identified in 249 of 671 episodes of ACS) Chlamydia71 Mycoplasma61 RSV26 Staph Aureus12 S. Pneumoniae11 Parvovirus10 Rhinovirus 8 Parainfluenza 6 H. flu 5 CMV4 Influenza A4 Legionella4 E. Coli3 EBV3

34. Acute Chest Syndrome Pathogenesis ACS appears to be caused by hypoxia- enhanced RBC-pulmonary microvessel adhesion Factors that inhibit this interaction may be potentially beneficial in the treatment of this complication

35. Acute Chest Syndrome Pathogenesis Hypoxia enhances sRBC adherence to endothelial cells Hypoxia has been shown to decrease the production of NO, which inhibits VCAM-1 upregulation sRBC also inhibit NO production by  protein levels of constitutive NO synthase in endothelial cells From Stuart & Setty, Blood, 1999

36. Pathogenesis (Plasma levels of sVCAM-1 and NO from control and SCD patients – Stuart and Setty, Blood, 1999)

37. Acute Chest Syndrome Pathogenesis In-vitro studies show that in the presence of both hypoxia and oleic acid:  There is  expression of VCAM-1 in pulmonary endothelial cells  There is  adherence of sRBC to endothelial cell monolayers Administration of NO substrates reduce adhesion of sRBC to endothelial cells after exposure to hypoxia  expression of adhesion molecules by hypoxia, cytokines and fat embolization with  NO contributes to pathogenesis of ACS From Stuart & Setty, Blood, 1999

38. Acute Chest Syndrome Treatment Early diagnosis is important, but also crucial to recognize that VOC may be prodrome of ACS Broad spectrum antibiotics – cephalosporin + macrolide Bronchodilator, incentive spirometry  chest PT Early RBC transfusion (Simple vs Exchange)  Phenotypically matched RBC Gentle hydration

39. Acute Chest Syndrome Treatment Hydroxyurea – known to decrease the frequency of acute chest syndrome Experimental treatments  Steroids  Varespladib  Inhaled nitric oxide

40. Acute Chest Syndrome Prevention Styles et al evaluated whether RBC transfusion before ACS eliminates or lessens severity of ACS Patients admitted for pain crisis were followed with daily sPLA2 levels Patients with  sPLA2 (> 100 ng/mL), fevers & -ve CXR were enrolled Styles et al, Br J Haematol, 2007

41. Acute Chest Syndrome Prevention Patients randomized to transfusion to Hb of 10 g/dL or standard care 7 patients in Tx arm (mean sPLA2 = 303  275 ng/ml) and 8 in non-Tx arms (mean sPLA2 = 434  250 ng/ml, NS) 5/8 in non-Tx arm developed ACS in 48 Hrs 0/7 in Tx arm developed ACS (p =0.026, OR 23.6, CI: 1 to 557) Styles et al, Br J Haematol, 2007

42. Acute Chest Syndrome Prevention Length of hospitalization was 1 day shorter in the transfused group This pilot study shows that prevention of ACS is possible with transfusion using sPLA2 as a screening tool With side effects of transfusion, other interventions that reduce sPLA2 (e.g. varespladib) are now in clinical trials Styles et al, Br J Haematol, 2007

43. Acute Chest Syndrome Summary ACS is seen most commonly in the youngest patients with SCD The etiology of ACS is varied: even with extensive investigation, infection is found in only a minority of cases Acute pain episode appears to be a prodrome for acute chest syndrome

44. Acute Chest Syndrome Next Steps More research is needed! l Further elucidate the pathophysiology of acute chest syndrome l Analyze the pathophysiology of lung damage from PFE l Treatment and prevention trials

45. Acute Chest Syndrome Current Studies! Varespladib Infusion (A-001) for the Prevention of Acute Chest Syndrome in At-Risk Patients with SCD and Vaso- occlusive crisis Blood Transfusion for the Prevention of Acute Chest Syndrome in At-Risk Patients with SCD and Vaso-occlusive crisis (PROACTIVE)