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

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.


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


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


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


• 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)


• 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


• 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)



• 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


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)

Documents

Pulmonary Complications of Sickle Cell Disease