Acute Chest Syndrome in Sickle Cell Disease

1. Sickle cell anemia is also known as sickle cell disease, but is different from sickle cell trait. It is an autosomal recessive hemoglobinopathy where amino acid 6 on beta globin gene changes from glutamic acid to valine (missense mutation). This results in hemoglobin S, which sickles and causes hemolysis under hypoxic conditions.
2. HbSS, HbSC, and HbSBeta thalassemia can all cause sickle cell disease (SCD)
3. Sickle cell disease can affect every organ, and treatment begins in childhood and is multidisciplinary. Clinical manifestations include vaso-occlusive syndromes (e.g. dactylitis, acute pain syndrome, acute chest syndrome, priapism), visceral complications such as stroke, infections due to immunosuppresion from a functional asplenia, osteomyelitis, avascular necrosis of the femoral/humeral head, renal dysfunction, retinopathy, pulmonary arterial hypertension, skin ulcers, etc. Please refer to the review article below as a reference. 
4. Acute chest syndrome (ACS) is a respiratory complication of sickle cell disease that can be life-threatening. It is caused by vaso-occlusive disease in the pulmonary vasculature or is triggered by vaso-occlusive disease elsewhere in the body (e.g. fatty embolism from infarcted bone marrow)
5. ACS is more common in children than adults but more severe when in occurs in adults. It is also more common with HbSS disease than HbSC or HbSBeta thalassemia disease. The case mortality rate is usually between 1-10%. 
6. As per the Cooperative Study in Sickle Cell Disease (CSSCD), ACS will occur in roughly 50% of SCD patients. 
7. The diagnosis of ACS requires radiologic evidence of a pulmonary infiltrate as well as a fever or respiratory symptoms (e.g.. cough, increased work of breathing, hypoxia, tachypnea, PaO2<60mmHg) so it cannot diagnostically be distinguished from pneumonia. 
8. Triggers include pulmonary fatty embolism from infarcted bone marrow (45-75% of cases; a bronchoalveolar lavage can be performed to confirm this etiology but is invasive and usually not done), infection (mostly Chlamydiae pneumonia, Mycoplasma pneumonia, RSV, Streptococcus pneumonia), asthma, pain crisis (e.g. vaso-occlusive crisis in long bones), and hypoventilation.
9. Treatment is divided into acute and preventive therapies. Acute therapies include the following 5 pillars of management:

• Pain control (opioids usually effective, but must balance analgesic effects with risk of respiratory depression; NSAIDS should be avoided as they worsen vaso-occlusive disease)
• IV hydration to keep the patient euvolemic as dehydration increases sickling of RBCs
• Antibiotics: Should cover expected organisms above so usually a 3rd generation cephalosporin + a macrolide is chosen, or a 3rd/4th generation fluoroquinolone. 
• Supplemental oxygen, bronchodilators, and incentive spirometry (e.g. 10 deep breaths every 2 hours while awake)
• Blood transfusions to keep Hb between 90-100g/L. A Hb >100g/L can lead to increased viscosity which worsens vaso-occlusion. There have not been any RCTs to compare simple versus exchange tranfusions, but generally exchange transfusions are used in "severe" cases.

    10. Preventive measures include the following:

• Hydroxyurea: Indicated with 1 or more episodes of ACS and acts by increasing the level of HbF (fetal hemoglobin, composed of 2 alpha and 2 gamma chains). Increased HbF reduces the likelihood of HbS polymerization. There is an inverse correlation between HbF levels and the incidence of ACS, and in the MSH study the incidence of ACS decreased by 50% with the use of hydroxyurea. The dose is 30mg/kg per day divided BID. 
• Chronic transfusion if 2 or more episodes of ACS in the last 12 months. NB hyperhemolytic syndrome can occur 5-7 days post transfusion in SCD patients and can lead to an acute drop in hemoglobin. 
• HSCT (hematopoietic stem cell transplant) can be a curative therapy.
• Incentive spirometry. 

Reference Articles:

1. Management of sickle cell disease in the community by Valentine Brousse, Julie Makani, and David Rees

• BMJ 2014;348:g1765  

2. Acute chest syndrome: sickle cell disease by Rabindra Paul, Oswaldo Castro, Anita Aggarwal, and Patricia Oneal

• European Journal of Haematology 87 (191-207)

3. How I treat acute chest syndrome in children with sickle cell disease by Scott Miller

• Blood, 19 May 2011. Volume 117, Number 20