Acute chest syndrome (ACS) is the result of various inciting events causing vaso-occlusion within the pulmonary vasculature of patients with sickle cell disease (SCD). ACS can occur in any SCD phenotype. However, it is most common in HbSS. ACS can progress quickly and is the most common cause of death in patients with SCD. Therefore, it is important to make the diagnosis and begin treatment as soon as possible. 
Bone marrow or fat emboli have been suspected to cause the majority of adult cases of ACS. Analysis of postmortem bronchoalveolar lavage in patients who died of SCD frequently reveals fat containing alveolar macrophages. Bone marrow ischemia and necrosis are characteristic of vaso-occlusive crises, which can result in the release of bone marrow and fat into the venous circulation. These particles can then travel to the lungs triggering vaso-occlusion and ACS.
Other causes of ACS include infection, asthma, hypoxemia, oversedation, and post-operative complications. In children, infection is often a common inciting event. Asthma exacerbated bronchospasms can lead to hypoxia, which leads to sickling. Patients with SCD and asthma are two to four times more likely to get ACS than patients with SCD alone. Chronic hypoxemia is seen in many patients, especially in children overnight. Of note, these patients can have normal oxygen saturation during the day but develop hypoxia at night, leading to sickling. Postoperative patients can have hypoventilation due to pain or medications that can cause sedation. Hypoventilation in these settings may precipitate sickling in the pulmonary circulation resulting in ACS. Patients with sickle cell disease are more likely to develop in situ thrombi in the pulmonary circulation rather than a pulmonary embolism. However, pulmonary embolism should still be considered if the patient has signs of an extremity deep venous thrombosis or a clinical picture suggestive of pulmonary embolism. 
Acute chest syndrome is the most common acute pulmonary disorder in patients with sickle cell disease. Fifty percent of patients with SCD will have one episode of ACS. The peak incidence of ACS is in pediatric patients age 2 to 4 years. Within the adult population, 78% of ACS episodes are secondary to vaso-occlusive pain episodes. ACS is the most common cause of death among patients with SCD accounting for close to 25% of deaths. Adults with ACS have a 4.3% death rate, while children have a 1.1% death rate. 
A specific cause for ACS in children is found in approximately 40% of cases. Within this 40%, most are due to infections, with the next common causes being pulmonary infarction and fat embolism. Infectious causes most commonly are viral, mycoplasma pneumonia, or chlamydia pneumonia.
In adult patients, half of the patients who develop ACS are initially admitted for other reasons, frequently vaso-occlusive crises (VOC). VOC, as discussed earlier, can result in bone marrow or fat emboli to the pulmonary circulation, the most common causes of ACS. VOC of the spine, ribs, and abdomen, have an additional risk. VOC in these body regions can lead to hypoventilation secondary to both pain and opioids, which then triggers hypoxemia/alveolar hypoxia and low arterial oxygen tension, resulting in sickling and ACS.
The pathophysiology of ACS is based on vaso-occlusion within the pulmonary microvasculature. Whatever the inciting event, deoxygenation of hemoglobin is the common next step in SCD leading to polymerization and sickling of erythrocytes. These sickled erythrocytes then cause further vaso-occlusion, ischemia, and endothelial injury.
Fat emboli are known to cause the release of free fatty acids (FFA) within the pulmonary vasculature due to phospholipase A2. FFA is very pro-inflammatory, which leads to pulmonary injury with resultant hypoxemia.
The presentation of ACS varies between pediatric and adult patients. Pediatric patients are more likely to have an infectious cause and will therefore present with symptoms such as wheezing, cough, increased work of breathing, and fever. Adult patients are more likely to present with chest pain, pain in the arms and legs, shortness of breath, or a vaso-occlusive crisis elsewhere in the body (e.g., priapism).
This algorithm lacks some specificity, and can also be diagnostic of pneumonia. It is very important to get a chest radiograph on every SCD patient with any respiratory symptoms since ACS can start insidiously, and it is important to start treatment early.
Clinicians must have a high suspicion for ACS during a VOC. Early treatment leads to lower mortality, shorter length of stay, reduced cost and less chance of recurrence. Once initiated, treatment of ACS must be aggressive since the disease process can escalate quickly. 
Acute management of ACS includes pain control, intravenous (IV) fluids, antibiotics, supplemental oxygen, and blood transfusions. Pain control for children normally starts with ketorolac, since it is nonsedating and less likely to cause hypoventilation than opioid pain medication. Adult pain management can also begin with ketorolac. Both pediatric and adult patients whose pain is not adequately controlled with ketorolac and acetaminophen will require opioid pain medication best delivered by a PCA (patient controlled anesthesia) device. Pain control in ACS is a balance between analgesia to prevent atelectasis and oversedation which can lead to hypoventilation and hypoxia. Fluid management is necessary in cases of dehydration since hypovolemia can cause additional sickling. Recommendations no longer advise large volume IV hydration, since overhydration can lead to pulmonary edema, which again leads to more respiratory complications. Fluid management should be directed by the patient’s hydration status.
Broad-spectrum antibiotics should to given to every ACS patient. Infection is more likely in the pediatric population than in adult patients. However, in both groups, it is difficult to differentiate between ACS and pneumonia. Patients should be started on a third-generation cephalosporin (cefotaxime or ceftriaxone) for routine bacterial coverage and a macrolide (azithromycin or erythromycin) for atypical coverage. If there is a concern for MRSA, vancomycin should be added. Treatment should last 7 to 10 days. Incentive spirometry should be done every 2 hours while awake to prevent atelectasis.
Supplemental oxygen should be given to correct a low SpO2 or PaO2. However, it is reasonable to give supplemental oxygen to any ACS patient because an appropriate oxygen saturation can mask possible focal hypoxemia. Co-oximetry is the most reliable way to monitor oxygen levels in SCD because patients have an oxyhemoglobin dissociation curve that is shifted to the right. Pulse oximetry can underestimate a patient’s oxygen pressure, and ABG can overestimate it. SpO2 should be kept above 92%, and PaO2 above 70 mmHg or no less than 3% below baseline. Of course, if supplemental oxygen is insufficient to correct hypoxemia, treatment can be escalated with BiPap, intubation, or ECMO as required.
Packed red blood cells (PRBC) transfusions have demonstrated some efficacy in case series. Unfortunately, no randomized controlled trials are evaluating PRBC transfusions versus supportive therapy for the management of ACS. Transfusions are given to improve oxygenation in ACS and have been shown to increase both SpO2 and PaO2. Blood transfusions are indicated when hemoglobin is 10% to 20% below baseline, less than 5 gm, a down trending hematocrit, if there is a worsening of radiographic signs, worsening symptoms, or if exchange transfusion is delayed. The goal of PRBC transfusion is to increase hematocrit to 30%, or Hg to 11. Exchange transfusions are used in severe cases of ACS. Indications would include severe hypoxemia, multilobar disease on chest radiographs, or failure of blood transfusion.The goal of exchange transfusion is to increase hemoglobin to 10 and decrease HbS to less than 30%. Exchange transfusion allows hemoglobin to increase while avoiding hyperviscosity. When considering transfusion/exchange transfusion, consult with a hematologist.
Bronchodilators are indicated when there is underlying asthma. However, they can be administered in any case in which bronchospasm is identified or suspected. Steroids have been shown to shorten the length of stay but carry the risk of a higher rate of rebound VOC and increased risk of re-admission and increased risk of fat emboli. Bronchoscopy/BAL is only indicated if ACS is refractory to conventional treatment.
Long-term management of ACS includes hydroxyurea, PRBC transfusions, and hematopoietic cell transplants. Hydroxyurea decreases the frequency of ACS by 50% in adults and 30% in kids. Hydroxyurea increases the concentration of HbF and is the only medication shown to decrease the incidence of ACS. Chronic transfusions can be used during the transition to hydroxyurea, in high-risk periods (winter), if hydroxyurea is inadequate, or if the patient is recovering from a life-threatening ACS. Risks of chronic transfusions include infection, iron overload, and allosensitization. Hematopoietic cell transplant has > 80% success and is indicated when the patient has had multiple episodes of ACS. This requires an HLA-matched sibling donor and carries all the risks associated with myeloablative regimens.
Long-term complications of repeated ACS include interstitial lung disease and pulmonary hypertension, however, the causation of this association is not well proven.
New research for ACS is focused on both diagnosis and treatment. Serum phospholipase A2 converts neutral fats to FFA and has been shown to increase hours before the onset of ACS. This may be able to predict an ACS episode. Inhaled nitric oxide has a current ongoing randomized controlled trial regarding its efficacy. Inhaled NO is a pulmonary vasodilator, which should improve V/Q mismatching and decrease pulmonary hypertension. It may also increase the oxygen affinity of HbS, leading to less sickling of erythrocytes.
ACS is a serious complication of sickle cell anemia with high morbidity and mortality. Many of these individuals have repeated episodes of sickle cell crises, and thus it is important to prevent them with education. Besides the physician, the nurse and the pharmacist need to educate the patient on the importance of vaccination against pneumococcus. Patients admitted with ACS should be encouraged to use the incentive spirometer to prevent lung collapse. A pain consultant is often necessary for pain relief and reduces respiratory splinting, but the dose has to be titrated to avoid causing sedation. The hematologist should be consulted to assess the need for blood transfusions and plasma exchange. The pulmonologist should be consulted if the patient has asthma, COPD or restrictive lung disease as these disorders are associated with high morbidity in ACS. Even after a single episode of ACS, the patient and family should be educated about the importance of hydroxyurea, which is a potent inducer of HbF. The drug has been shown to lower the risk of sickle cell crises. Finally, the patient should be educated at discharge to return to the hospital is the symptoms worsen because the earlier the disorder is treated, the better is the outlook. (Level V)
ACS is a severe complication of sickle cell anemia and usually required admission. There are no randomized clinical trials on the treatment of ACS and outcomes. Anecdotal reports indicate fair to a good outcome in the short term, but repeated admissions are common. In addition, the syndrome is also associated with a high morbidity and mortality. Without aggressive treatment, poor outcomes are common. Patients must be started on hydroxyurea to prevent future episodes. (Level V)