Continuing Education Activity

Acute chest syndrome occurs due to vaso-occlusion within the pulmonary vasculature of patients with sickle cell disease. This results in deoxygenation of hemoglobin and sickling of erythrocytes, which can cause further vaso-occlusion, ischemia, and endothelial injury. Acute chest syndrome can progress quickly and is the most common cause of death in patients with sickle cell disease. This activity reviews the etiology, pathophysiology, evaluation, and management of acute chest syndrome and highlights the role of interprofessional team members in caring for patients with this condition.

Objectives:

• Screen patients with sickle cell disease for early signs and symptoms of acute chest syndrome.
• Implement appropriate treatment interventions for acute chest syndrome based on the severity of the condition.
• Apply pharmacological interventions, such as analgesics, bronchodilators, and antibiotics, as indicated.
• Collaborate with hematologists, pulmonologists, respiratory therapists, and other specialists to manage acute chest syndrome.

Introduction

Acute chest syndrome is a dangerous complication of sickle cell disease characterized by a new radiodensity on chest imaging accompanied by respiratory symptoms and possibly fever.[1] Acute chest syndrome occurs when various factors in individuals with sickle cell disease trigger vaso-occlusion within the pulmonary vasculature.[2] While acute chest syndrome can occur in any sickle cell disease phenotype, it is most prevalent in HbSS.[3]This syndrome can progress quickly and represents the leading cause of death in patients with sickle cell disease.[4] Therefore, early diagnosis and prompt initiation of treatment are crucial to improve patient outcomes.

Etiology

Acute chest syndrome can be attributed to various inciting factors. While the distinct etiology of most cases remains unclear, fat or bone marrow emboli are suspected of causing most adult patients.[5] Postmortem analysis of bronchoalveolar lavage in individuals who succumbed to sickle cell disease often reveals the presence of alveolar macrophages containing fat. Vaso-occlusive crises, characterized by bone marrow ischemia and necrosis, can release bone marrow and fat into the venous circulation. These particles can subsequently travel to the lungs, triggering vaso-occlusion and ultimately causing acute chest syndrome.

Other causes of acute chest syndrome include infection, asthma, hypoxemia, oversedation, and postoperative complications. Infection is often a common inciting event in children. Asthma-related bronchospasm can lead to hypoxia, which leads to sickling. Patients with sickle cell disease and asthma are 2 to 4 times more prone to developing acute chest syndrome than those with sickle cell disease alone.[6] 

Chronic hypoxemia is commonly observed in individuals with concurrent sickle cell disease and asthma, particularly in children overnight. Notably, these patients may exhibit normal oxygen saturation during the day but develop hypoxia at night, which can contribute to sickling. Postoperative patients may experience hypoventilation due to pain or sedating medications, which can provoke sickling in the pulmonary circulation and result in acute chest syndrome.

It is worth mentioning that patients with sickle cell disease are more inclined to develop in situ thrombi in the pulmonary circulation rather than a pulmonary embolism.[5] Nevertheless, the possibility of pulmonary embolism should still be considered if the patient has signs of deep venous thrombosis in the extremities or clinical manifestations suggestive of pulmonary embolism.

Epidemiology

Acute chest syndrome is the most prevalent acute pulmonary disorder in individuals with sickle cell disease.[5] Approximately 50% of patients with sickle cell disease will experience more than 1 episode of acute chest syndrome. The peak incidence of acute chest syndrome is observed in pediatric patients between 2 and 4 years old. Among adults, 78% of acute chest syndrome episodes are secondary to vaso-occlusive pain episodes. Acute chest syndrome is the most common cause of death in individuals with sickle cell disease, accounting for nearly 25% of all deaths. The mortality rates associated with acute chest syndrome are 4.3% in adults and 1.1% in children.

Pathophysiology

Approximately 40% of acute chest syndrome cases in children can be attributed to a specific cause. Among those cases with identifiable causes, about 40% are associated with infections. Viral infections, mycoplasma pneumonia, and chlamydia pneumonia are the most frequently encountered infectious causes.[5] Pulmonary infarction and fat embolism are also significant contributors to acute chest syndrome in children.

In adult patients, approximately half of those who develop acute chest syndrome are initially admitted for other reasons, frequently vaso-occlusive crises. As previously discussed, vaso-occlusive crises can lead to the release of bone marrow or fat emboli to the pulmonary circulation, which are the primary causes of acute chest syndrome. Vaso-occlusive crises of the spine, ribs, and abdomen carry additional risk. In these regions, vaso-occlusive crises can lead to hypoventilation due to both pain and the use of opioids, subsequently triggering hypoxemia and alveolar hypoxia. This, in turn, results in low arterial oxygen tension and promotes sickling, leading to the development of acute chest syndrome.

The pathophysiology of acute chest syndrome is based on vaso-occlusion within the pulmonary microvasculature. Regardless of the inciting event, the process starts with the deoxygenation of hemoglobin, leading to polymerization and sickling of erythrocytes. Sickled erythrocytes further contribute to vaso-occlusion, causing ischemia and injury to the endothelial cells.

Fat emboli can induce the release of free fatty acids within the pulmonary vasculature through the action of phospholipase A2. These free fatty acids have pro-inflammatory properties, which can trigger pulmonary injury with resultant hypoxemia.[7]

History and Physical

The presentation of acute chest syndrome differs between pediatric and adult patients. In pediatric patients, who are more prone to infectious causes, symptoms such as wheezing, coughing, increased work of breathing, and fevers are commonly observed.[8] On the other hand, adult patients often present with chest pain, pain in the extremities, dyspnea, or may exhibit signs of vaso-occlusive crises in other parts of the body (eg, priapism).[1]

Evaluation

Diagnosing acute chest syndrome depends on radiographic evidence and clinical symptoms. To be diagnosed with acute chest syndrome, a patient must meet the following criteria:[8][9]

• New pulmonary infiltrates on chest imaging (chest x-ray, CT) involving at least one lung segment; this cannot be due to atelectasis and must have one of the following symptoms:

  • Chest pain
  • Temperature more than 38.5 C
  • Tachypnea, wheezing, rales, coughing, the appearance of an increased work of breathing
  • Hypoxemia, relative to baseline (more than 2% decrease in SpO2 from steady state on room air, PaO2 less than 60 mmHg)

These criteria lack specificity and can also be diagnostic of pneumonia. Therefore, obtaining a chest radiograph for every patient presenting with respiratory symptoms and sickle cell disease is crucial, as acute chest syndrome can have an insidious start. Early initiation of treatment is essential in managing this condition effectively.

Risk Factors

• Low fetal hemoglobin (HbF)
• Young age
• Presence of asthma or other hyperreactive lung disorder
• Smoking
• Recent trauma or surgery

Treatment / Management

Clinicians should maintain a high suspicion for acute chest syndrome during a vaso-occlusive crisis. Early recognition and prompt initiation of treatment are associated with lower mortality rates, shorter hospital stays, decreased healthcare costs, and a reduced likelihood of recurrence.[10] Once initiated, the treatment of acute chest syndrome should be aggressive due to the potential rapid progression of the disease.[11][12]

Acute chest syndrome management involves several key components, including pain control, intravenous fluids, antibiotics, supplemental oxygen, and blood transfusions. Pain control in pediatric patients typically begins with using ketorolac, as it is a non-sedating medication and is less likely to cause hypoventilation than opioid pain medications. The risk of hypoventilation and subsequent complications can be minimized by effectively managing pain.

In adult patients, pain management can also begin with the use of ketorolac. In adult and pediatric patients, if ketorolac and acetaminophen do not provide sufficient pain relief, opioid pain medication may be required. These opioid medications are preferably administered through a patient-controlled analgesia (PCA) device. Achieving adequate pain control in acute chest syndrome is a delicate balance between ensuring proper analgesia to prevent atelectasis and avoiding oversedation, which can lead to hypoventilation and hypoxia.

Fluid management is necessary to manage acute chest syndrome, particularly in cases of dehydration, as hypovolemia can exacerbate sickling. However, current recommendations no longer support using large-volume intravenous hydration, as excessive fluid administration can contribute to pulmonary edema and further respiratory complications. Instead, fluid management should be guided by the patient's hydration status to restore and maintain adequate hydration without causing fluid overload. 

Broad-spectrum antibiotics should be administered to every patient with acute chest syndrome. The risk of infection is higher in the pediatric population, but it is still significant in adult patients. Distinguishing between acute chest syndrome and pneumonia can be challenging. While there is a lack of randomized clinical trials assessing the efficacy and potential harm of antibiotics in acute chest syndrome, it is recommended to initiate antibiotics.

A third-generation cephalosporin such as cefotaxime or ceftriaxone is commonly prescribed for routine bacterial coverage. A macrolide such as azithromycin or erythromycin is recommended for atypical coverage. Alternatively, a respiratory fluoroquinolone such as levofloxacin or moxifloxacin can be used as a monotherapy.[1][13] If there is a concern for methicillin-resistant Staphylococcus aureus (MRSA) infection, vancomycin should be added to the antibiotic regimen. The duration of treatment is typically 7 to 10 days.

To prevent atelectasis, incentive spirometry should be performed every 2 hours while the patient is awake. This helps promote deep breathing and lung expansion, reducing the risk of complications associated with atelectasis.

Supplemental oxygen should be administered to correct a low oxygen saturation (SpO₂) or arterial partial pressure of oxygen (PaO₂) in patients with acute chest syndrome. However, providing supplemental oxygen to all acute chest syndrome patients is reasonable, even if their oxygen saturation appears normal. This is recommended because a normal oxygen saturation can mask focal areas of hypoxemia. Some evidence suggests that early administration of supplemental oxygen may reduce the need for blood transfusions and is well tolerated.[12] 

Co-oximetry is the most reliable method for monitoring oxygen levels in individuals with sickle cell disease due to their characteristic shift in the oxyhemoglobin dissociation curve to the right. This shift can lead to underestimating a patient's oxygen pressure when using pulse oximetry and overestimating arterial blood gas measurements.

In sickle cell disease, it is recommended to maintain the SpO₂ above 92% and PaO2 above 70 mm Hg or no less than 3% below the individual's baseline. If supplemental oxygen is insufficient to correct hypoxemia, treatment should be escalated. In severe cases, this may involve interventions such as bi-level positive airway pressure (BiPAP) ventilation, intubation, or even extracorporeal membrane oxygenation (ECMO).[13][14]

Packed red blood cell transfusions have demonstrated some effectiveness in case series for managing acute chest syndrome. However, there is a lack of randomized controlled trials evaluating the use of packed red blood cell transfusions versus supportive therapy for managing acute chest syndrome.

Transfusions are administered to improve oxygenation in acute chest syndrome and have been observed to increase both SpO₂ and PaO₂. Blood transfusions are indicated when the hemoglobin level is 10% to 20% below baseline, the hemoglobin is less than 7 g/dL,  a decreasing hematocrit trend is seen, worsening radiographic signs or worsening symptoms are present, or a delay in performing an exchange transfusion occurs.[1] 

Packed red blood cell transfusion aims to increase the hematocrit to 30% or hemoglobin to 10 g/dL. In severe cases of acute chest syndrome, exchange transfusions may be warranted. Indications for exchange transfusions include severe hypoxemia, the presence of multilobar disease on chest radiographs, or failure of improvement with blood transfusion. An exchange transfusion aims to increase hemoglobin to 10 g/dL and reduce the percentage of sickle hemoglobin (HbS) to less than 30%. Exchange transfusion allows for an increase in hemoglobin while avoiding the risk of hyperviscosity.

When considering the need for transfusion or exchange transfusion, it is advisable to consult a hematologist experienced in managing sickle cell disease and its complications.

Bronchodilators are indicated only in cases with evidence of underlying asthma or a bronchospastic component contributing to the presentation. However, routine use of bronchodilators has not shown any measurable benefits in treating acute chest syndrome.[15] 

Steroids have shown efficacy in reducing the length of hospital stay in patients with acute chest syndrome. However, their use is associated with a higher rate of rebound vaso-occlusive crises, an increased risk of readmission, and an increased risk of fat emboli.

Bronchoscopy with bronchoalveolar lavage (BAL) is indicated only in cases where acute chest syndrome is refractory to conventional treatment.[16]

Differential Diagnosis

When evaluating a patient with symptoms of acute chest syndrome, it is important to consider a broad range of potential causes. The following is a list of differential diagnoses with a description of their symptoms that should be considered:

• Acute coronary syndrome: conditions such as unstable angina and myocardial infarction, chest pain, shortness of breath, and other cardiac symptoms
• Pulmonary embolism: sudden-onset chest pain, shortness of breath, and potentially life-threatening symptoms.
• Pneumothorax: sudden-onset sharp chest pain and difficulty breathing
• Pneumonia: productive cough, fever, chest pain, and difficulty breathing
• Pleural effusion: chest pain, shortness of breath, and reduced breath sounds on examination
• Empyema: chest pain, fever, productive cough, and difficulty breathing
• Aortic dissection: severe chest pain radiating to the back
• Acute respiratory distress syndrome (ARDS): difficulty breathing, low oxygen levels, and chest X-ray abnormalities

Prognosis

Acute chest syndrome is a common and potentially severe complication in individuals with sickle cell disease, with approximately 50% of patients experiencing an episode at some point.[1] Acute chest syndrome significantly contributes to mortality in sickle cell disease, accounting for about 25% of deaths. In adults, the mortality rate can be as high as 9% per episode of acute chest syndrome.

When considering the pediatric population, acute chest syndrome is more likely to recur in younger children, particularly those younger than 4.[17] Several factors have been identified as predictors of repeat hospitalization in children, including a history of asthma, shortness of breath, and longer initial length of stays upon presentation and hospitalization with acute chest syndrome. 

Long-term complications of acute chest syndrome may include recurrent episodes of acute chest syndrome, interstitial lung disease, and pulmonary hypertension.

Complications

Acute chest syndrome can lead to various complications, including those listed below.

• ARDS can result from severe lung inflammation and fluid accumulation. This condition impairs oxygenation and can lead to respiratory failure.
• Respiratory failure occurs due to significant impairment in lung function, characterized by inadequate oxygenation and ventilation.
• Pulmonary infarction occurs when a blood clot lodges in a pulmonary artery, leading to tissue damage and impaired lung function.
• Pulmonary fibrosis can result from recurrent episodes of acute chest syndrome. Pulmonary fibrosis involves the scarring and thickening of lung tissue, leading to impaired lung function and long-term respiratory compromise.
• Pulmonary hypertension is due to chronic lung damage from acute chest syndrome. This condition can also lead to heart strain and impaired cardiac function.
• Severe pain
• Death

Deterrence and Patient Education

Long-term management strategies for acute chest syndrome include hydroxyurea, packed red blood cell transfusions, and hematopoietic cell transplants.

Hydroxyurea is a medication shown to decrease the frequency of acute chest syndrome by 50% in adults and 30% in children.[17] Hydroxyurea works by increasing the concentration of HbF in red blood cells. It is the only medication shown to decrease the incidence of acute chest syndrome.

Chronic red blood cell transfusions can be utilized during the transition to hydroxyurea in high-risk periods (such as winter) if hydroxyurea is ineffective or if the patient is recovering from a life-threatening episode of acute chest syndrome. It's important to note that chronic transfusions carry risks, including the potential for infections, iron overload, and allosensitization.

A hematopoietic cell transplant is an option for patients with sickle cell disease who have experienced multiple episodes of acute chest syndrome. This procedure requires an HLA-matched sibling donor and involves myeloablative regiments with associated risks. However, hematopoietic cell transplant has shown a success rate of over 80% in treating sickle cell disease.

Pearls and Other Issues

Recent research in acute chest syndrome has focused on enhancing diagnosis, understanding the disease characteristics, and improving treatment strategies. Two areas of interest in current research include bedside ultrasound for diagnosis and evaluating biomarkers for early detection.

Bedside ultrasound has emerged as a promising method for detecting acute chest syndrome. It has shown potential for higher sensitivity compared to traditional imaging methods like X-rays. Ultrasound findings such as b-lines, pleural effusions, and consolidations have demonstrated greater sensitivity in predicting the progression to acute chest syndrome in individuals evaluated for a pain crisis.[8] 

In addition to imaging techniques, researchers are exploring using biomarkers to aid in the early detection of acute chest syndrome. One biomarker under study is serum phospholipase A2, which converts neutral fats to free fatty acids. Studies have shown that levels of free fatty acids increase hours before the onset of acute chest syndrome.[18] This indicates that measuring free fatty acid levels in the future could be a predictive tool for identifying individuals at risk of developing acute chest syndrome.

The severity of acute chest syndrome can vary among individuals. Within the broader group of patients who develop this condition, a subset experiences a rapidly progressive course.[19] This subgroup tends to have poorer outcomes than the larger group of patients with acute chest syndrome. In particular, low platelet counts in adults have been identified as a risk factor for a more rapid disease progression and generally worse outcomes.

Evidence-based interventions for acute chest syndrome are limited. In the case of inhaled nitric oxide, a randomized controlled trial did not find a difference in outcomes for treating acute chest syndrome.[20] However, there was some evidence that a subgroup with more severe hypoxemia in the trial could have experienced a modest benefit. Inhaled nitric oxide is a pulmonary vasodilator, which should improve ventilation-perfusion mismatching and decrease pulmonary hypertension. It may also increase the oxygen affinity of hemoglobin S (HbS), leading to less sickling of erythrocytes. 

Current practice for managing acute chest syndrome often includes regular packed red blood cell transfusions and consideration of exchange transfusion in severe cases. However, evidence suggests that the length of hospital stay is unchanged between groups with acute chest syndrome who received an exchange transfusion and those who did not.[21] Decreased length of hospital stay was found in subgroups that targeted transfusion goals to hemoglobin >8.0 g/dL.

Enhancing Healthcare Team Outcomes

Acute chest syndrome is a serious complication of sickle cell anemia with high morbidity and mortality. Many individuals diagnosed with acute chest syndrome have repeated episodes of sickle cell pain crises or recurrence of acute chest syndrome. It is essential to attempt to minimize the risk of recurrence with education and a multidisciplinary coordinated care approach. Studies have shown that implementing a coordinated care team can decrease the incidence of acute chest syndrome, decrease the number of ICU admissions, and decrease the length of stay for vaso-occlusive crises.[22]

A collaborative and multidisciplinary approach involving various healthcare professionals is crucial in managing acute chest syndrome. The following key points should be emphasized and organized:

1. Incentive spirometer and respiratory therapy: The nursing and respiratory therapy teams should encourage patients admitted with acute chest syndrome to utilize the incentive spirometer. This helps prevent lung collapse and improves lung function.
2. Patient-reported pain score: A patient-reported pain score is essential for assessing and treating pain crises and acute chest syndrome. It remains the gold standard for detecting pain in sickle cell disease. No other sign, symptom, or lab value is more accurate in detecting pain. In challenging cases, a pain consultant may be necessary to optimize pain control while avoiding over-sedation and hypoventilation.
3. Consulting with specialists:

   • Hematologist: Consultation with a hematologist is essential to assess the need for blood transfusions and plasma exchange to manage acute chest syndrome.
   • Pulmonologist: If the patient has asthma, chronic obstructive pulmonary disease (COPD), or restrictive lung disease, consulting a pulmonologist is crucial as these conditions are associated with high morbidity in acute chest syndrome.
4. Importance of hydroxyurea: Even after a single episode of acute chest syndrome, patients and their families should be educated about the importance of hydroxyurea. Hydroxyurea is a potent inducer of HbF and has been shown to lower the risk of sickle cell crises.
5. Vaccination against pneumococcus: Besides the physician, the nurse and pharmacist play a vital role in educating patients about the importance of pneumococcal vaccination. Studies have shown that implementing vaccination has led to a significant decline in the incidence of acute chest syndrome in specific populations.[23] 
6. Extensive patient education and return precautions: Patients should receive comprehensive education about acute chest syndrome and its management. Strict return precautions should be emphasized to ensure early initiation of treatment, as prognosis improves with timely intervention. 

Outcomes

Acute chest syndrome is a severe complication of sickle cell anemia that necessitates hospital admission. No randomized clinical trials are available that compare standardized treatments for acute chest syndrome. While some studies indicate a fair-to-good outcome in the short term when acute chest syndrome is treated early and aggressively, other evidence suggests high morbidity and mortality without aggressive treatment.[13][24] 

Patients must be started on hydroxyurea to prevent future episodes. [Level 5] In severe and recurrent cases, hematopoietic cell transplant should be considered.

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Disclosure: Amanda Friend declares no relevant financial relationships with ineligible companies.

Disclosure: Teagan Settelmeyer declares no relevant financial relationships with ineligible companies.

Disclosure: Daniel Girzadas declares no relevant financial relationships with ineligible companies.