Pulmonary Complications of Sickle Cell Disease
Kenneth I. Ataga, MD
Comprehensive Sickle Cell Program
University of North Carolina -
Chapel Hill
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
Sickle Cell Disease
Introduction
• SCD may be complicated by several pulmonary complications: Acute chest syndrome Airway hyperreactivity/Asthma Pulmonary embolism Nocturnal oxyhemoglobin desaturation Pulmonary hypertension Pulmonary fibrosis
Acute Chest SyndromeCase 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. G2P2
Proteinuria - S/P Renal biopsy. Path - SS Nephropathy.Current Meds: Folic acid (1 mg/d)
Acute Chest SyndromePE: 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 P2. 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.
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.
Acute Chest Syndrome
Admission Orders:
Sputum/urine/blood cultures Cefotaxime 1 gram IV Q8H Azithromycin IV fluids O2 - 2 Liters per minute via nasal cannula IV narcotic analgesics
Acute Chest Syndrome
6 hours later
Decreased responsiveness, somnolent, difficult to arouse, and confused.
BP=100/52, P=156, RR=44, T38.8 C
Extremities - cool with thready pulses
Acute Chest SyndromeRepeat Laboratory Studies
Hematocrit = 14% WBC = 31,300 Platelets = 284K PT = 20.6, PTT = 59.4, TCT = 11.1 ABG (2L O2): pH 7.11, PO2 89, PCO2 19 Repeat CXR - extensive infiltrates/fluid with white out of
right lung
Acute Chest Syndrome
Patient intubated emergently and then
transferred to the Intensive Care Unit
Acute Chest SyndromeMultiorgan 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 improvedAt D/C: BUN 17, Cr 1.5
Acute Chest SyndromeRespiratory System• Extubated on day #5
• Slow resolution of CXR
• All cultures negative
• ABG on day of D/C (RA) pH 7.53 PO2 67 PCO2 30
• ABG (6 weeks later) pH 7.43 PO2 79 PCO2 38
• PFTs (6 weeks later) FVC - 2.19 (63%)FEV1 1.99 (68%)DLCOc - 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
Acute Chest Syndrome - Objectives
• Incidence
• Risk Factors
• Clinical Presentation
• Etiology
• Mortality
• Pathophysiology
• Treatment
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
Acute Chest Syndrome - Sources of Data
• The Cooperative Study of Sickle Cell Disease (CSSCD)
• The National Acute Chest Syndrome Study Group (NACSSG)
Acute Chest Syndrome- CSSCD & NACSSG
ACS: Incidence and Risk Factors; Clinical Presentation and Course
(Castro et al., Blood, 1994 & Vichinsky et al., Blood, 1997) Data from 3751 patients with 19,867 pt-years of
follow-up
Causes & Outcomes of ACS in SCD(Vichinsky et al., NEJM, 2000)
Data from 538 patients with 671 episodes of ACS
Acute Chest Syndrome - Incidence
• ACS incidence is higher in SS patients (12.8/100 pt-yrs) and S0 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
Acute Chest Syndrome - Incidence (SS)
Age Group (yrs) Episodes of ACS (per 100
patient years)
< 2 20.82-5 25.35-10 15.610-20 9.3> 20 8.8
from Castro et al. Blood, 1994
Acute Chest Syndrome - Incidence (SC)
Age Group (yrs) Episodes of ACS
(per 100 patient years)
< 2 10.3
2-5 10.1
5-10 4.3
10-20 4.0
> 20 3.3
from Castro et al. Blood, 1994
from Castro et al., Blood, 1994
Acute Chest Syndrome - Risk factors
Significant in multivariable analysis
Young age Low fetal hemoglobin level High hemoglobin level in steady state High WBC in steady state
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
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
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
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
from Castro, et al., Blood, 1994
Acute Chest Syndrome Effect on Mortality
ACS during initial 2 yrs of f/u and those who did not.
Survival difference esp after age of 20
Adults with ↑ ACS rate have a higher mortality than those with low rates
Acute Chest Syndrome Mortality (CSSCD)
Overall death rate: 1.8% (32 / 1741) In patients < 20 years, death rate =
1.1% (14 of 695 pts/1,322 events) 9/14 were < 3 yrs
In patients > 20 years, death rate = 4.3% (18 of 271 pts/419 events)
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
Acute Chest Syndrome – Etiology
Acute Chest Syndrome Isolated Pathogens (NACSSG )
(Infectious pathogens were identified in 249 of 671 episodes of ACS)
• Chlamydia 71
• Mycoplasma 61
• RSV 26
• Staph Aureus 12
• S. Pneumoniae 11
• Parvovirus 10
• Rhinovirus 8
• Parainfluenza 6
• H. flu 5
• CMV 4
• Influenza A 4
• Legionella 4
• E. Coli 3
• EBV 3
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
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
Pathogenesis(Plasma levels of sVCAM-1 and NO from control and SCD patients – Stuart and
Setty, Blood, 1999)
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
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
Acute Chest Syndrome Treatment
• Hydroxyurea – known to decrease the frequency of acute chest syndrome
• Experimental treatments Steroids
Varespladib
Inhaled nitric oxide
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
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
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
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
Acute Chest Syndrome Next Steps
More research is needed! Further elucidate the pathophysiology of acute
chest syndrome
Analyze the pathophysiology of lung damage from PFE
Treatment and prevention trials
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)