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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

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pulmonary complications of sickle cell disease
Pulmonary Complications of Sickle Cell Disease

Kenneth I. Ataga, MD

Comprehensive Sickle Cell Program

University of North Carolina -

Chapel Hill

  • 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
  • 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 syndrome case presentation
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 syndrome
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 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 syndrome7
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 syndrome9
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 syndrome10
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 syndrome11
Acute Chest Syndrome

Repeat 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 syndrome13
Acute Chest Syndrome

Patient intubated emergently and then transferred to the Intensive Care Unit

acute chest syndrome multiorgan failure
Hematologic Status

pRBC (8 units)



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

Acute Chest SyndromeMultiorgan Failure
acute chest syndrome15
Respiratory 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
acute chest syndrome objectives
Acute Chest Syndrome -Objectives
  • Incidence
  • Risk Factors
  • Clinical Presentation
  • Etiology
  • Mortality
  • Pathophysiology
  • Treatment
acute chest syndrome definition
Acute Chest SyndromeDefinition?
  • 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
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
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
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
acute chest syndrome incidence ss
Acute Chest Syndrome - Incidence (SS)

Age Group (yrs) Episodes of ACS

(per 100 patient years)

< 2 20.8

2-5 25.3

5-10 15.6

10-20 9.3

> 20 8.8

from Castro et al. Blood, 1994

acute chest syndrome incidence sc
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

acute chest syndrome risk factors
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
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
Acute Chest Syndrome - Effect of Steady State Hgb Level

Relationship between total hemoglobin and rate of ACS in 3 age groups

from Castro, et al., Blood, 1994.

acute chest syndrome clinical presentation
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 presentation28
Acute Chest SyndromeClinical 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
acute chest syndrome effect on mortality
Acute Chest SyndromeEffect 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

from Castro, et al., Blood, 1994

acute chest syndrome mortality csscd
Acute Chest SyndromeMortality (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
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
Chlamydia 71

Mycoplasma 61

RSV 26

Staph Aureus 12

S. Pneumoniae 11

Parvovirus 10

Rhinovirus 8

Parainfluenza 6

H. flu 5


Influenza A 4

Legionella 4

E. Coli 3


Acute Chest SyndromeIsolated Pathogens (NACSSG)(Infectious pathogens were identified in 249 of 671 episodes of ACS)
acute chest syndrome pathogenesis
Acute Chest SyndromePathogenesis
  • 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 pathogenesis35
Acute Chest SyndromePathogenesis
  • 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 pathogenesis37
Acute Chest SyndromePathogenesis
  • 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
Acute Chest SyndromeTreatment
  • 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 treatment39
Acute Chest SyndromeTreatment
  • Hydroxyurea – known to decrease the frequency of acute chest syndrome
  • Experimental treatments
    • Steroids
    • Varespladib
    • Inhaled nitric oxide
acute chest syndrome prevention
Acute Chest SyndromePrevention
  • 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 prevention41
Acute Chest SyndromePrevention
  • 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 prevention42
Acute Chest SyndromePrevention
  • 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
Acute Chest SyndromeSummary
  • 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
Acute Chest SyndromeNext 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
Acute Chest SyndromeCurrent 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)