An overview of two most important pulmonary compications of sickle cell disease

1. Pulmonary Complications of
Sickle Cell Disease
S A Saleemi MD
Section of Pulmonary Medicine
Department of Medicine
King Faisal Specialist Hospital & Research Center
Riyadh, Saudi Arabia

2. Hippocrates (460-377 B.C.E.)
“Another sickness of the spleen. It comes on
mainly in the springtime and is caused by the
blood. The spleen becomes engorged with
blood, which evacuates into the stomach.
Shooting pains in the spleen, the breast, the
clavicle, the shoulder, and beneath the
shoulder blade. The body’s coloration
resembles lead. Sores form on the leg and
become large ulcerations. The discharges with
the feces are bloody and bluish green. The belly
hardens and the spleen is like a stone. This one
is more murderous than the one before, and few
survive it.”

3.  Worldwide ~250,000 children are
born each year with SCD
 Areas of Prevalence
Sub-Saharan Africa
SCD frequency ~ 2%
Sickle Cell Disease
~ 30 million people living with SCD worldwide
80,000 patients with SCD in USA
Median age at death - Male 42 yrs, Female 48 yrs
The History and Geography of Human Genes . Princeton University Press ; 1994
N Engl J Med 1994;330:1639-44

4. Epidemiology of sickle cell disease in
Saudi Arabia
2011 May-Jun; 31(3): 289–2932011 May-Jun; 31(3): 289–293
 Saudi Arabia’s population 23.98 million
 Sickle cell trait 2% to 21%
 SCD up to 2.6%
 Highest incidence in Eastern province
The Saudi Premarital Screening Program:
Sickle-cell trait 17%
SCD 1.2%
Newborn screening for SCD over a 9-year period:
Sickle-cell trait 21%
SCD 2.6%
Up to 21% pediatric and adult medical
admissions in Eastern province were SCD related
(saudi medical journal 26, 2006)

5. Pulmonary Complications of SCD
Acute & chronic
VTE
PFT
Abnormalities
Chronic
Dyspnea
Pulmonary
Hypertension
Pulmonary
fibrosis
Asthma
Sleep
Disorders
Acute Chest
Syndrome
Sickle
Cell
Disease
Am J Med. 2006;119(10):897.e7
AJRCCM. 2011;184(9):1022
AJRCCM. 2006;173(11):1264
Lung. 2010 ;188(6):499-504.
Am J Hematol. 2008.83(7):547-53
J Clin Sleep Med. 2015;11(3):219. Epub 2015 Mar 15.
Blood. 2006;108(9):2923
N Engl J Med. 2008;359(21):2254.
Chest. 2010;138(4):973

6. ACS and PH
are the two most serious complications
of SCD with high morbidity and mortality

7. Clinical Phenotypes of SCD
Pulmonary Hypertension
Leg ulcers
Priapism
Stroke
Pain crisis
ACS
Osteonecrosis
Decreased NO
bioavailability
Increased
Vaso-occlusion
Hemolysis
Endothelial dysfunction
Viscosity
Vaso-occlusion
Gladwin M and Vichinsky E, N Engl J Med 2008;359:2254

8.  ACS is the 2nd most common cause of hospitalization after VOC
 Cooperative Study of Sickle Cell Disease (3,751 subjects) -
29% incidence of ACS over 2-year period
12.8 episodes per 100 patient-years for HbSS disease
 Occurs in up to 45% of SCD patients; recurrent in up to 80%
 ADULTS - 1 to 3 days after admission for vaso-occlusive crisis
 CHILDREN - admitting diagnosis.
Acute Chest Syndrome (ACS)
N Engl J Med 1994;330:1639–1644.
Blood 1997;89:1787–1792.
N Engl J Med 2000;342:1855–1865.
N Engl J Med 2004;350:886–895.

9. Diagnostic criteria for ACS
●Temperature ≥38.5°C
●>2 percent decrease in SpO2 from baseline in steady state
●PaO2 <60 mmHg
●Tachypnea
●Signs of respiratory distress (Intercostal retractions, nasal
flaring, or use of accessory muscles of respiration)
●Chest pain
●Cough
●Wheezing
●Râles
Radiographic evidence of
consolidation
(at least one segment)
AND
at least one of the following:

10. Risk factors for increased ACS
Blood 2006;108:2923–2927.
Blood 2010;115:3852–3854.
Pediatr Blood Cancer 2011;57:289–293.
Higher
Hb level
Low
HbF level
Higher
Leukocyte
count History
Of Asthma
Smoking
HbSS
Winter
months
Younger
age
ACS

11. Etiology of ACS
The National ACS Study Group
(671 ACS episodes in 538 patients)
Atypical bacteria or viruses in 54% of
ACS admissions
.
ACS
Pulmonary infarction
due to vaso-occlusion
Fat embolism
pulmonary or
Systemic infection
National Acute Chest Syndrome Study Group. N Engl J Med 2000;342:1855–1865

12. Pathopysiology of ACS
(Vascular cell adhesion molecule)
Gladwin M and Vichinsky E. N Engl J Med 2008;359:2254

13. ADULTS CHILDREN
Incidence Lower Higher
Severity Greater less
mortality Higher (9%) Lower (1%)
Rate of death per ACS
episode
4.3 % 1.1%
Main etiology Marrow infarction
and fat emboli
infections
Onset Usually after
admission with VOC
Usually admission
diagnosis
Lung infiltrates delayed From onset
Mechanical ventilation 22% 10%
Prolonged hospital stay 13 days 10 days
DIFFERENCES BETWEEN ACS IN CHILDREN AND ADULTS
National Acute Chest Syndrome Study Group [NACSSG]
538 adults and children with SCD and 671 episodes of ACS
CLINICAL PRESENTATION

14. ADULTS CHILDREN
Chest pain 84% 41%
Extremity pain 47% 20%
SOB 58% 36%
Neurological symptoms 22% 8%
Pain preceding ACS 50% 11%
Fever 64% 85%
Rapidly progressive ACS Up to 1/5th Rare
DIFFERENCES BETWEEN ACS IN CHILDREN AND ADULTS
Cooperative Study of Sickle Cell Disease (CSCCD)
939 children and adults with SCD who had 1722 episodes of ACS
CLINICAL PRESENTATION

15. Severity of ACS
Mild Moderate Severe Very Severe Rapidly
Progressive
●SpO2 >90 %
on room air
●Only one lobe
involved
.
●SpO2 ≥85 %
on room air
●No more than
2 lobes invloved
●Respiratory
failure
●Mechanical
ventilator
support required
● ●involvement
of ≥3 lobes
●ARDS ●ARDS
●Multi-organ
failure

16. Diagnostic Work-Up
 CXR
 Labs – CBC, markers of hemolysis, Blood group
 ABG
 Induced Sputum for culture and multiplex
 Hb S levels
 Secretory phospholipase A2
 CRP
 CTPA or V/Q scan if indicated
 Bronchoscopy if indicated

17. ACS with Bilateral consolidation of lower lobes
Armand Mekontso Dessap et al. Thorax doi:10.1136/thoraxjnl-2013-203775

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

19. Distribution of lung opacities on CT according to
lung segmentation during ACS episodes
Armand Mekontso Dessap et al. Thorax doi:10.1136/thoraxjnl-2013-203775

20. Poor Prognostic indicators in ACS
 Multi-lobar disease (>4 lobes highest risk)
 History of cardiac disease
 Thrombocytopenia
 Pre-existent pulmonary hypertension
 Altered mental status and other neurological symptoms
 Persistent tachycardia >125/min
 Persistent respiratory rate >30/min or increased work of breathing
(nasal flaring, use of accessory muscles, sternal retractions)
 Temperature >40°C
 Hypotension compared with baseline
 Arterial pH <7.35
 Arterial oxygen saturation persistently <88%, despite aggressive
ventilatory support
 Serial decline in pulse oximetry or increasing A-a gradient
 Hemoglobin concentration fall by 2 g/dL or more
 Evidence for multi-organ failure
 Pleural effusion
Vichinsky 2000, Johnson 1988, Fine 1997

21. Management of ACS
Pain control
Fluid management
Oxygen
Incentive spirometry
Antibiotics
VTE prophylaxis
3rd generation
cephalosporin + macrolide,
or
fourth generation
fluoroquinolone
Bronchodilators
For mild to mod episodes -
simple transfusion
target HbS <30%
For severe ACS -
exchange transfusion
Final target Hb should be
no higher than 10 g/dL.
Supportive therapy Specific Therapy
Blood Transfusion

22. Steroids not a standard
practice – risk of rebound
vaso-occlusion
Bronchoscopy – only in
atypical or refractory cases
Inhaled Nitric Oxide – may
improve oxygenation in
severe ACS
Role in affecting mortality or
ventilator free days unclear
Role of IV arginine,
glutamate and secretory
phospholipase A2 is not
clear
Management of ACS

23.  Hydroxyurea - initial therapy
 Chronic transfusion therapy - when the response to
hydroxyurea is inadequate
 Patients recovering from life threatening ACS -
Six-month transfusion regimen with transition to
hydroxyurea.
Prevention of ACS
Hydroxyurea Chronic transfusion

24. PH in SCD

25. Prevalence of PH in SCD
 20-30% of patients with SCD have PH (echo)
 30 million people worldwide with SCD
 6-9 million people with SCD associated PH !!
Hematol Oncol Clin North Am 1996;10
Am J Cardiol 1994;74
Autopsy study
20 patients with SCD
75% had histological evidence of PH
Haque AK, Hum Pathol. 2002 Oct;33(10):1037-1043.

26. Prevalence of PH in SCD in Saudi Arabia
 Echocardiography in 65 patients with SCD
 38% patients had PH
 76% had mild PH with sPAP <45 mm Hg Saudi Med J 2007; Vol 28 (7)
King Saud University, Riyadh
PULMONARY HYPERTENSION IN PATIENTS WITH SICKLE CELL DISEASE IN
EASTERN PROVINCE OF SAUDI ARABIA
?>300 patients retrospective record
30 had PHT
22 Mild PHT (sPAP 35-44)
6 Moderate PHT (sPAP 45-74)
2 Severe PHT (sPAP >75) Presented as poster at ESICM meeting Berling 2001

27. Prevalence of PH in SCD based on TRV
TRV
m/s
Gladwin M, et al.. N Engl J Med. 2004;350(9):886–895

28. SCD-PH
A Coat of Many Colors
PVH
CTEPH
Hypoxemic PH
PAH
PH of hyperdynamic state
mPAP ≥ 25 mm Hg
PVR ≥ 160 dyne/s/cm5
PCWP ≤15 mm Hg
mPAP ≥ 25 mm Hg
PVR ≥ 160 dyne/s/cm5
PCWP ≥ 15 mm Hg
mPAP ≥ 25 mm Hg
PVR ≤ 160 dyne/s/cm5
PCWP ≤15 mm Hg
Vallerie V. McLaughlin, AJRCCM, 2007

29. 403
SCD
96
TRV ≥ 2.5
RHC
72 (75%)
Normal PAP
24 (25%)
↑ PAP
(6% of 403)
13
PCWP ≥ 15
5
Hyperkinesis
6
True PAH
334
TRV<2.5
Correlation of PAP measured by Echo and RHC
in SCD-PH
Bachir et al in France, prospective multicenter survey
Blood (ASH Annual Meeting Abstracts). 2009;114(11, Abstract 572.

30. Pathophysiology
Asplenia
(↑ Plt-thrombosis)
ACS –ILD
( parenchymal &
Vascular injury)
SCD
vasculopathy
oxidant burden
(free iron and heme)
↑endothelin-1
Chronic
Hypoxemia
↑ Shear stress
(Hyperkinesis)
Klings ES, Respir Res. 2001;2:280 –5.
Rybicki AC, Blood. 1998;92:2594–6
Machado et al, British J Haematol, 2005, 129(4):449-64)
Hemolysis- free Hb
↓NO
↑Arginase

31. Independent risk factors for development of
PH in SCD
Low
hemoglobin
CVS and Renal
disease
Systemic
hypertension
Proteinuria
High
Ferritin level
Low Transferrin
level
Elevated
LDH
PH
Klings ES, Respir Res. 2001;2:280 –5.
Rybicki AC, Blood. 1998;92:2594–6
Machado et al, British J Haematol, 2005, 129(4):449-64)
Leg
ulcers

32. Classification of Pulmonary Hypertension
(Dana Point, 2008)
Group 1

33. Current Classification of Pulmonary
Hypertension
Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-4

35. Mortality in patients with SCD and PH

36. Prevalence and mortality of PH in SCD
Gladwin et al De Castro et al Ataga et al Machado et al
N 195 124 76 121
Prevalence of PH
(%)
32 32 34 30
Mortality in PH
patients
40% at
45 months
17% at
24 months
10% at
26 months
50% at
60 months
Mortality in
patients
without PH
2% at
45 months
2% at
24 months
1% at
26 months
15% at
60 months
Mortality in patients with SCD and PH

37. Screening Echocardiography
TRV < 2.5 m/s
Routine Screening
optimize SCD
specific therapy
Increased
frequency of screening
Right heart catheterization
TRV >3 m/sTRV 2.5-2.9 m/s
PH symptoms
Decreased 6MWD
Elevated pro-BNP
PRE-CAPILLARY PH
mPAP >25 mmHg
PCWP <15 mmHg
PVR>160 dynes/s/cm5
POST-CAPILLARY PH
mPAP >25 mmHg
PCWP >15 mmHg
PVR<160 dynes/s/cm5
mPAP <25 mmHg
NO PH
Increased
Frequency
of screening
Consider PAH
Specific therapy
ANA, HIV, LFT, CXR, EKG
PFT,VQ scan, Sleep study
Refer to PH/SCD center
Evaluation of PH in SCD
Klings ES, Machado RF, Barst RJ, et al, 2014..clinical practice guideline: diagnosis, risk stratification, and management of pulmonary
hypertension of sickle cell disease. American journal of respiratory and critical care medicine; 189:727

38. Standard Treatment
Hemolysis is the main trigger for development of PH in SCD
AIM of treatment of SCD
Hb level of ≥8 g/dl
HbS level of <40%.
?progression of PAH can be prevented
Br J Haematol. 2005; 129: 449-464.

39. Standard treatment
Hydroxyurea
↓ Hemolysis
↑ Hemoglobin levels
↓ Transfusion requirements
↓ Painful crisis
↓ Incidence of ACS
↓ Overall mortality by 40%
N Engl J Med . 1995 ; 332 ( 20 ): 1317 – 1322
JAMA . 2003 ; 289 ( 13 ): 1645 - 1651
Blood transfusion
↓ Synthesis of sickle cells
↓ Risk of SCD complications
↓ Risk of pulmonary events
↓CNS vasculopathy
N Engl J Med . 1998 ; 339 ( 1 ): 5 - 11
J Pediatr . 1995 ; 126 ( 6 ): 896 - 899
??Role in prevention of pulmonary hypertension in SCD

40.  Hydroxyuria use ↓ TRV in patients with SCD-PH
Open labeled study – 10 patients Br J Haematol 2009; 144:73
Case Series – 5 patients Am J Hematol. 2009, 84(8): 530–532
 Chronic Transfusion
Retrospective
55 non-transfused and 20 transfused pediatric SCD patients
significantly lower TRV in the transfused population
Joyce K et al. Blood 2006, 108:356a
Standard treatment

41.  Anticoagulation
 indefinite anticoagulant therapy for patients with RHC-
confirmed PH plus VTE, and no additional risk factors
for bleeding.
 Reduction in recurrent VTE (3.5 vs. 17.3%)
 and trend towards lower mortality (2.8 vs. 5.0%)
 Increase in major bleeding (3.3 vs. 0.9%)
Standard treatment
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines (8th edition) Chest 2008

42. <1995 1995 2001 2002 2004 2005 2007 2009 2013 2015
CCB
Anticoagulation
Digitalis
Diuretics
IV Epoprostenol
Bosentan
SC Treprostenol
IV Treprostenol
Inhaled
Iloprost
Sildenafil
Ambrisartan
Tadalafil
Inhaled
Treprostinil
Macitentan
Riociguat
Pulmonary Hypertension Treatment Timeline
IV Sildenafil
Oral
Treprostinil
Selexipag
BREATHE
SUPER
ARIES
PHIRST
AIR
SERAPHIN
PATENT
CHEST
GRIPHON
FREEDOM
TIMELINE for PAH targeted therapy

43. Baseline
N=8
IV Epo
N=8
mPAP (mmHg) 38 30
CO (L/min) 7.3 9.1
mPCWP (mmHg) 15 13
PVR (d/s/c-5) 271 170

44. Endothelin receptor antagonist in
SCD-PH
Minniti CP et al:.Br J Haematol 2009, 147:737-43.
14 patients
Open labeled study

45. Endothelin receptor antagonist in SCD-PH
ASSET 1 and ASSET 2 studies
double-blind, placebo-controlled, 16-week studies
 ASSET 1 for PAH in SCD
 ASSET 2 for PVH in SCD
Studies terminated early because of slow recruitment
(total patients recruited = 26)
 Bosentan was well tolerated
 Non-significant ↑ in CO
 Non-significant ↓ in PVR were observed with Bosentan
 Limited sample sizes - efficacy endpoints not analyzed

46. 12 Patients

47. Walk -Pulmonary Hypertension and Sickle Cell
Disease with Sildenafil Therapy
(walk-PHaSST)
 Multicenter randomized double blind trial
 Study terminated - July 7, 2009
 Safety issue - 38 % of treatment group had Sickle cell crisis
requiring hospitalization vs. 8 % in control group.
 Enrolled 74 patients with SCD and PH – age >19 yrs (m45)
 Randomly assigned to receive Sildenafil or placebo for 16 w
 After 16 weeks patients opted to open labeled use of Sildenafil and
follow up for 1 year

48.  33 patients completed the study
 23 with TRV > 3.0 underwent RHC
 iNO and Sildenafil 60 mg single dose given at the time of RHC
Acute change after single dose
↓ mean PAP (p=0.01)
↓ mean BP (p<0.01)
↓ RAP
↓ PCWP
No significant change in PVR
No significant change in SVO2
After 16 weeks of treatment
Change in TRV (p=0.7)
Change in 6MWD (P=0.47)
Walk -Pulmonary Hypertension and Sickle Cell
Disease with Sildenafil Therapy
(walk-PHaSST)

49. Phosphodiesterase-5 inhibitors should not be used
as first line agents for the treatment of SCD-PH !
Walk -Pulmonary Hypertension and Sickle Cell
Disease with Sildenafil Therapy
(walk-PHaSST)

50. L-arginine Therapy
Open-label phase II study
Oral L-arginine
 TRV (n = 11) – mean change 2.57 to 2.69 m⁄ s (P = NS)
 6 min walk (n = 9)-↑ from 494.3 to 511.0 m (P = NS)
Little J et al. Eur J Haematol.2009(4):315-321

51. PH specific therapy
PH specific therapy complications
Prostanoids High output cardiac failure
Line sepsis and thrombosis
Endothelin receptor
antagonists
hepatotoxicity
PDE5 inhibitors Priapism
Increased incidence of
vaso-occlusive crisis
NO Complicated gas delivery system
Arginine Large number of tablets
GI side effects

52. Recommendation:
For all patients with SCD who have elevated TRV alone, or elevated NT-pro-BNP
alone, and for most patients with SCD who have RHC-confirmed PH, we
recommend against targeted PAH therapy
(strong recommendation, moderate-quality evidence).
American journal of respiratory and critical care medicine; 2014. 89:727
For selected SCD patients with RHC-confirmed PAH and symptomatic, a trial with
either a prostacyclin agonist or an endothelin receptor antagonist.
(weak recommendation, low-quality evidence).
We recommend against PDE-5 inhibitor therapy as a first-line treatment
(strong recommendation, moderate-quality evidence).
use of targeted PAH therapy in SCD-PH patients is considered off-label

53. SUMMARY
 ACS and PH are the leading causes of death in patients with SCD
 ACS requires prompt management to prevent clinical deterioration and
death.
 Since pneumonia without ACS cannot be distinguished from pneumonia
with ACS on clinical grounds, empiric antibiotics including coverage for
atypical bacteria should be part of management of ACS.
 Management of ACS include supportive therapy and blood
transfusion/exchange transfusion depending upon the severity of ACS
 PH occurs in about one third of adults with SCD based on
Echocardiogram while incidence of true PAH on right heart cath is low
 Standard treatment of SCD i.e.; Hydroxyurea , blood transfusion and
supportive measures are the mainstay of management in most patients
 PH specific therapy may cautiously be tried in selected symptomatic
patient with PAH
 PDE5 inhibitors should NOT be used as as first line therapy