What is acute chest syndrome in patients with sickle cell disease?

Acute Chest Syndrome in Sickle Cell Disease

Acute chest syndrome (ACS) is a life-threatening pulmonary complication of sickle cell disease defined by a new segmental infiltrate on chest radiograph accompanied by lower respiratory tract symptoms (fever, cough, chest pain, dyspnea, or hypoxemia), and it represents the leading cause of death in this patient population with mortality rates up to 13%. 1, 2

Definition and Diagnostic Criteria

ACS requires both of the following components 1:

• New segmental pulmonary infiltrate on chest imaging (chest X-ray is first-line, though lung ultrasound shows promise) 3
• At least one respiratory symptom: fever, cough, chest pain, dyspnea, or hypoxemia 1, 3

The syndrome can present acutely or develop during hospitalization for other complications, particularly vaso-occlusive pain crises—nearly half of ACS cases initially present for pain rather than respiratory symptoms 4, 5

Pathophysiology

ACS arises from multiple mechanisms that often coexist 6:

• Vaso-occlusion: Deoxygenated hemoglobin S polymerizes, causing rigid sickled red cells that obstruct pulmonary microvasculature and create tissue ischemia 6
• Pulmonary fat embolism: An underdiagnosed but clinically important trigger, especially in adults 6, 5
• Infection: The most common identifiable cause, particularly community-acquired pneumonia with 27 different pathogens identified in landmark studies 7, 5
• Hypoventilation and atelectasis: Inadequately treated thoraco-abdominal pain reduces inspiratory effort, worsening hypoxemia and promoting further sickling 6
• Hemolysis-mediated endothelial injury: Cell-free hemoglobin scavenges nitric oxide, depleting this vasodilator and causing endothelial dysfunction 6

Clinical Presentation and Risk Factors

High-Risk Features

Patients ≥20 years old have more severe disease courses than younger patients 5. Additional risk factors include 8:

• Severe genotypes (HbSS, HbSβ⁰-thalassemia) 4
• Reactive airway disease or asthma 4, 6
• Higher steady-state hemoglobin and white blood cell counts 8
• Lower fetal hemoglobin concentrations 8

Clinical Course

• Respiratory failure requiring mechanical ventilation occurs in 20% of adults and 13% overall 3, 5
• Neurologic events complicate 11% of cases, with 46% of these patients developing respiratory failure 5
• Mean hospitalization length is 10.5 days 5
• Mortality rate is 3% overall, with ACS accounting for 25% of all sickle cell disease deaths 9, 5

Management Algorithm

Immediate Actions (Within 30 Minutes)

Emergency transfer to acute care setting with rapid triage is mandatory 2. Upon arrival 1, 2:

• Administer first analgesic dose within 30 minutes using parenteral opioids with scheduled around-the-clock dosing or patient-controlled analgesia (never as-needed dosing) 1, 2
• Obtain baseline oxygen saturation and initiate continuous pulse oximetry 2
• Administer supplemental oxygen to maintain SpO₂ at baseline or ≥96% (whichever is higher) 1, 2
• Initiate incentive spirometry every 2 hours immediately for all patients, especially those with chest pain, as this significantly reduces ACS development 1, 2

Mandatory Initial Workup

Order immediately 2:

• Complete blood count with reticulocyte count
• Comprehensive metabolic panel
• Blood type and crossmatch
• Blood cultures if temperature ≥38.0°C or any signs of sepsis 1
• 12-lead ECG and troponin to exclude acute coronary syndrome (AMI occurs at early age in sickle cell disease without traditional risk factors) 2

Treatment Protocol

Respiratory Support

• Maintain SpO₂ above baseline or ≥96% with supplemental oxygen 1
• Incentive spirometry every 2 hours to prevent atelectasis 1
• Escalate to continuous positive airway pressure, high-flow nasal oxygen, or nasopharyngeal airway for increasing respiratory distress 1

Antimicrobial Therapy

• Initiate antibiotics if temperature ≥38.0°C or signs of sepsis, covering atypical pathogens 1, 3

Pain Management

• Aggressive pain control with parenteral opioids using scheduled dosing or PCA 1
• Avoid opiate overdose causing hypoventilation, which can trigger ACS 8

Hydration

• Aggressive hydration with careful fluid balance monitoring to prevent pulmonary edema 1
• Prefer oral hydration when possible; use IV fluids if oral intake inadequate 1

Bronchodilators

• Consider bronchodilators if history of asthma or acute bronchospasm present (20% of patients show clinical improvement) 1, 5

Temperature Management

• Maintain normothermia as hypothermia causes shivering and peripheral stasis, increasing sickling 1

Transfusion Strategy

The decision between simple transfusion versus exchange transfusion depends on disease severity 1:

For Severe ACS (Bilateral Infiltrates or Rapidly Progressive Disease):

Automated or manual red cell exchange transfusion is the definitive treatment 1. This approach:

• Rapidly reduces HbS to <30% (ideally <20%) 1
• Avoids increasing hematocrit excessively, preventing hyperviscosity 1
• Is preferred over simple transfusion because it reduces HbS levels more rapidly 1

For Moderate ACS:

Either automated RCE, manual RCE, or simple transfusions may be used, but escalate to exchange transfusion if the patient develops rapidly progressive disease or fails to respond to initial simple transfusion 1

Transfusion Considerations:

• Discuss all transfusion decisions with a hematologist given 7-30% risk of alloimmunization 1
• Use phenotypically matched transfusions (1% alloimmunization rate with matching) 5
• Do not use simple transfusion if baseline hemoglobin is high, as this increases viscosity and worsens vaso-occlusion 1
• If acute hemolytic reaction suspected, do not resume transfusion until transfusion medicine specialist consultation obtained 1

ICU Admission Criteria

Maintain a low threshold for ICU or high-dependency unit admission for 1, 2:

• Rapidly progressive disease despite initial interventions
• Respiratory distress or increasing oxygen requirements
• Consideration for exchange transfusion
• Comorbidities or signs of clinical deterioration

Monitoring and Prevention

• Regular oxygen saturation monitoring provides early warning of worsening ACS 1
• Thromboprophylaxis for post-pubertal patients due to increased deep vein thrombosis risk 1
• Early mobilization when appropriate, or chest physiotherapy if unable to mobilize 1
• Daily hematology specialist assessment 1

Critical Pitfalls to Avoid

• Do not delay exchange transfusion in severe disease with bilateral infiltrates while waiting for simple transfusion to work—this can lead to respiratory failure 1
• Do not use simple transfusion alone if baseline hemoglobin is high—this increases blood viscosity and worsens vaso-occlusion 1
• Do not delay pain management—delays are associated with worse morbidity and can trigger hypoventilation leading to ACS 2, 6
• Avoid overhydration—this can lead to pulmonary edema 1
• Do not miss acute coronary syndrome—obtain ECG and troponin as AMI occurs at early age in sickle cell disease 2
• Monitor for transfusion reactions including delayed hemolytic transfusion reactions 1

Long-Term Prevention

Treatment with hydroxyurea should be considered for prevention of recurrent episodes, as it raises fetal hemoglobin levels and reduces sickling 4, 8