Pulmonary Complications of Sickle Cell Disease

Liz Klings, MD

The Pulmonary Center

Boston University School of Medicine

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)

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

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?

Acute Chest Syndrome

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

ACS – Diagnostic Work-Up

CXR/Labs – WBC, markers of hemolysis, ABG

V/Q scan

Bronchoscopy/Induced Sputum

Hb S levels

Secretory phospholipase A2/CRP

ACS – CXR Findings

Vichinsky EP, et al. Blood 1997

ACS – Etiology

Vichinsky EP, et al NEJM 2000

Vichinsky EP 2000

Predictors of Respiratory Failure in ACS

Multi-lobar disease (>4 lobes highest risk)

History of cardiac disease

Thrombocytopenia

Pre-existent pulmonary hypertension

ACS - Etiology

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

Pulmonary HTN in SCDWas 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.

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.

But an Elevated TRV is Not PH

Echo- 25% positive predictive value for PH73% false positive rate

PH prevalence – 6%

Parent F, et al. NEJM 2011; 365:44-53.

  PH (n=56) No PH (n=30) p value

CVP (mmHg) 10± 5 6± 3 <0.001mPAP (mmHg) 36± 9 19 ± 4 <0.001PCWP (mmHg) 16 ± 5 12± 3 <0.001CO (L/min) 8 ± 3 9± 2 0.14CI (L/min/m2) 5± 1 5± 1 0.063PVR (dyne.sec/cm5) 229± 149 74± 38 <0.001

  PH (n=24) No PH (n=72) p valueCVP (mmHg) 10 ± 6 7 ± 2 <0.001

mPAP (mmHg) 30 ± 6 19 ± 3 <0.001

PCWP (mmHg) 16 ± 7 11 ± 3 <0.001

CO (L/min) 8.7 ± 1.9 8.4 ±2.1 0.60

PVR(dyne.sec/cm5) 138 ± 58 72 ± 26 <0.001

  PH (n=8) No PH (n=18) p value

mPAP (mmHg) 33.1 ± 8.9 18.7 ± 2.8 <0.001

PCWP (mmHg) 16.0 ± 5.7 13.3 ± 2 0.07

CI (L/min/m2) 5 ± 1.36 4.9 ± 1.7 0.85

PVR (dyne.sec/cm5) 179 ± 120 64 ± 48 0.002

NIH

Brazil

French

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

Differences from IPAH

Often a paucity of symptoms

PA pressures/PVR tend to be lower

Preservation of cardiac output

Increased PCWP in some patients

Survival in PH of SCD

Mehari A, et al. JAMA 2012; 307:1254-1256.

Associated Findings in PH of SCD

Parent F et al. N Engl J Med 2011;365:44-53.

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; 307:1254-1256Fonseca GH, et al. Eur Respir J 2012;39(1):112-8.Klings ES, et al. AJRCCM March 1, 2014 (in press)

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

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

Histopathology of PH in SCD

Gladwin MT and Vichinsky EP NEJM 2008

Hemolysis-related PH

PH associated with other hemolytic diseases:

1) Post-splenectomy2) β-thalassemia3) Hereditary spherocytosis4) Pyruvate kinase deficiency

May be a mechanism of decreased NO bioavailability

Decreased NO Bioavailability

Decreased NO production

Increased NO consumption

a) Scavenging by free Hb

b) Oxidant consumption

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

Treatment of PH in SCD

Treatment Issues Specific to SCD

Multiple co-morbiditiesAnemia produces an elevated CO and symptoms can be delayedIncreased risk of bleeding and possibly infectionNot all PH in SCD is PAHNo randomized trials completed in this populationRecommend referral to PH center with expertise in SCD

SCD Specific Therapies and Co-Morbidities

• Hydroxyurea

• Chronic Transfusions

• Treatment of associated conditions: OSA, VTE, hypoxemia

HydroxyureaOnly 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.

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

The Link Between VTE and PH

2-4% of patients with PE will develop CTEPHAutopsy studies of IPAH patients – in situ thrombosisSCD is a hyper-coagulable statePatients with PH of SCD – thrombotic arteriopathy of small PA’sBut 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.

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 2004-2010Enrolled all SCD patients > 12 yrsAll subjects underwent a screening questionnaire, echocardiogram and procurement of a blood sample

VTE in SCD Patients with an Elevated TRV

Patients with DVT

Patients with PE

Patients with DVT + PE

Total VTE Events

TRV<2.5 m/sec

(N = 53) 1 2 2 5

TRV > 2.5 m/sec

(N=44) 3 10 0 13

Increased Risk of VTE in SCD Patients with an Elevated TRV

18.5% of SCD patients had a history of VTE5/53 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).

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

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.

Acute and Long-Term Effects of Sildenafil in PH/SCD

Machado RF, Br J Hematol 2005;130:445-453.

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.

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

But wait, there’s more

WHO/NYHA ClassHb-SS

Hb-SC

60%18%

22% 0%

I

II

III

IV

49%37%

13% 1%

I

II

III

IV

Klings ES, et al. Am J Hematology 2008

PFT Classifications

Adult

Pediatric

Klings ES AJRCCM 2006

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 hyperplasiaAdenoidectomy/tonsillectomy- curative in some, but impact on cardiopulmonary outcomes unclearMay be associated with daytime hypoxemia Risk for adults - unknown

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?

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

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