Acute Chest Syndrome Diagnosis: A Comprehensive Guide

Introduction

Acute Chest Syndrome (ACS) is a serious complication of sickle cell disease (SCD), marked by a new opacity on a chest X-ray, accompanied by respiratory symptoms and often fever.[1] This syndrome arises from vaso-occlusion in the pulmonary blood vessels of individuals with SCD.[2] ACS can affect anyone with sickle cell disease, but it is most frequently observed in those with HbSS.[3] It’s a rapidly progressing condition and the primary cause of mortality among sickle cell disease patients.[4] Therefore, a swift and accurate Acute Chest Syndrome Diagnosis is critical, followed by immediate treatment, to significantly improve patient outcomes.

Etiology of Acute Chest Syndrome

Several factors can trigger acute chest syndrome. In many cases, the precise cause remains unidentified. However, fat or bone marrow emboli are considered the leading causes, particularly in adults.[5] Postmortem examinations of bronchoalveolar lavage fluid from SCD patients who died from ACS frequently reveal fat-containing alveolar macrophages. Vaso-occlusive crises, which involve bone marrow ischemia and necrosis, can release fat and bone marrow into the bloodstream. These particles can then travel to the lungs, causing vaso-occlusion and initiating acute chest syndrome.

Other contributing factors to acute chest syndrome include infections, asthma, hypoxemia, oversedation, and postoperative complications. Infections are more commonly implicated in children. Asthma-related bronchospasm can induce hypoxia, leading to erythrocyte sickling. Individuals with both sickle cell disease and asthma have a 2 to 4 times higher risk of developing acute chest syndrome compared to those with sickle cell disease alone.[6]

Chronic hypoxemia is often seen in patients with both sickle cell disease and asthma, especially children during sleep. They might have normal oxygen saturation levels during the day but experience nocturnal hypoxia, which can promote sickling. Postoperative patients are susceptible to hypoventilation due to pain or sedative medications, potentially causing sickling in the pulmonary circulation and resulting in acute chest syndrome.

It’s important to note that individuals with sickle cell disease are more prone to developing in situ thrombi in the pulmonary circulation, rather than experiencing a pulmonary embolism.[5] Nevertheless, pulmonary embolism should still be considered, especially if the patient shows signs of deep vein thrombosis in the limbs or clinical symptoms suggestive of pulmonary embolism.

Epidemiology of Acute Chest Syndrome

Acute chest syndrome is the most frequent acute pulmonary complication in sickle cell disease patients.[5] Approximately half of all individuals with sickle cell disease will experience at least one episode of acute chest syndrome. The highest incidence is observed in children aged 2 to 4 years. In adults, about 78% of acute chest syndrome episodes occur in conjunction with vaso-occlusive pain crises. ACS is the leading cause of death in sickle cell disease, accounting for approximately 25% of all deaths. Mortality rates associated with ACS are around 4.3% in adults and 1.1% in children.

Pathophysiology of Acute Chest Syndrome

In about 40% of pediatric acute chest syndrome cases, a specific cause can be identified. Of these, infections account for roughly 40%. Viral infections, mycoplasma pneumonia, and chlamydia pneumonia are the most common infectious agents.[5] Pulmonary infarction and fat embolism are also significant factors in children.

In adult patients, approximately half of those who develop acute chest syndrome are initially hospitalized for other reasons, often vaso-occlusive crises. As mentioned, vaso-occlusive crises can release bone marrow or fat emboli into the pulmonary circulation, which are primary triggers for acute chest syndrome. Vaso-occlusive crises affecting the spine, ribs, and abdomen pose an elevated risk. In these areas, pain from vaso-occlusive crises and the use of opioids for pain relief can lead to hypoventilation, subsequently causing hypoxemia and alveolar hypoxia. This, in turn, lowers arterial oxygen tension and promotes sickling, leading to the development of acute chest syndrome.

The underlying mechanism of acute chest syndrome is vaso-occlusion within the pulmonary microvasculature. Regardless of the initiating factor, the process begins with hemoglobin deoxygenation, resulting in polymerization and sickling of red blood cells. Sickled erythrocytes further exacerbate vaso-occlusion, causing ischemia and damage to the endothelial cells.

Fat emboli can induce the release of pro-inflammatory free fatty acids within the pulmonary vasculature through the action of phospholipase A2. These free fatty acids contribute to pulmonary injury and subsequent hypoxemia.[7]

History and Physical Examination in Acute Chest Syndrome

The clinical presentation of acute chest syndrome varies between children and adults. Pediatric patients, who are more susceptible to infection-related ACS, commonly exhibit symptoms such as wheezing, cough, increased breathing effort, and fever.[8] Adults, on the other hand, often present with chest pain, extremity pain, dyspnea, or signs of vaso-occlusive crises in other parts of the body, such as priapism.[1]

Evaluation and Acute Chest Syndrome Diagnosis

Acute chest syndrome diagnosis relies on both radiographic findings and clinical symptoms. To be diagnosed with ACS, a patient must meet specific criteria:[8, 9]

• New pulmonary infiltrate on chest imaging (chest X-ray or CT scan) involving at least one lung segment. This infiltrate must not be due to atelectasis.
• Presence of at least one of the following symptoms:
  • Chest pain
  • Fever greater than 38.5°C (101.3°F)
  • Tachypnea, wheezing, rales, cough, or increased work of breathing
  • Hypoxemia, relative to baseline (more than a 2% decrease in SpO2 from steady state on room air, or PaO2 less than 60 mmHg)

These diagnostic criteria are not highly specific and can overlap with pneumonia. Therefore, it is crucial to perform a chest radiograph on any sickle cell disease patient presenting with respiratory symptoms, as acute chest syndrome can have a subtle onset. Early acute chest syndrome diagnosis and prompt treatment initiation are essential for effective management.

Image: Chest X-ray demonstrating pulmonary infiltrates, a key diagnostic feature in acute chest syndrome.

Risk Factors for Acute Chest Syndrome:

• Low fetal hemoglobin (HbF) levels
• Young age
• Asthma or other hyperreactive airway diseases
• Smoking
• Recent trauma or surgery

Treatment and Management of Acute Chest Syndrome

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

Management of acute chest syndrome involves several key components:

1. Pain Control: Effective pain management is crucial. In children, ketorolac is often used initially as it is non-sedating and less likely to cause hypoventilation compared to opioids. In adults, ketorolac may also be used initially. If pain is not adequately controlled with ketorolac and acetaminophen, opioid pain medication may be necessary in both adults and children, preferably administered via a patient-controlled analgesia (PCA) device. Balancing pain relief to prevent atelectasis with avoiding oversedation and hypoventilation is critical.

2. Intravenous Fluids: Fluid management is important, especially in cases of dehydration, as hypovolemia can worsen sickling. However, current guidelines advise against large-volume intravenous hydration due to the risk of pulmonary edema and respiratory complications. Fluid administration should be guided by the patient’s hydration status to maintain adequate hydration without fluid overload.

3. Broad-spectrum Antibiotics: Antibiotics should be started in all patients with acute chest syndrome. While infection risk is higher in children, it remains significant in adults. Distinguishing between ACS and pneumonia can be challenging. Although randomized clinical trials evaluating antibiotic efficacy in ACS are lacking, initiating antibiotics is generally recommended.

   • Common antibiotic regimens include a third-generation cephalosporin like cefotaxime or ceftriaxone for general bacterial coverage, plus a macrolide such as azithromycin or erythromycin for atypical organisms.
   • Alternatively, a respiratory fluoroquinolone like levofloxacin or moxifloxacin can be used as monotherapy.[1, 13]
   • If methicillin-resistant Staphylococcus aureus (MRSA) is suspected, vancomycin should be added. Treatment duration is typically 7 to 10 days.

4. Incentive Spirometry: To prevent atelectasis, incentive spirometry should be performed every 2 hours while awake. This promotes deep breathing and lung expansion.

5. Supplemental Oxygen: Oxygen should be administered to correct hypoxemia (low SpO2 or PaO2). It is reasonable to provide supplemental oxygen even if oxygen saturation appears normal, as pulse oximetry can mask focal hypoxemia. Early oxygen administration may reduce the need for transfusions and is generally well-tolerated.[12]

   • Co-oximetry is the most accurate method for monitoring oxygen levels in SCD patients due to the rightward shift of the oxyhemoglobin dissociation curve. Pulse oximetry can underestimate oxygen pressure, while arterial blood gas measurements can overestimate it.
   • In SCD, aim to maintain SpO2 above 92% and PaO2 above 70 mm Hg, or no more than 3% below baseline.

6. Blood Transfusions: Packed red blood cell transfusions can be effective in managing ACS. Transfusions improve oxygenation, increasing both SpO2 and PaO2.

   • Indications for transfusion include hemoglobin 10% to 20% below baseline, hemoglobin less than 7 g/dL, decreasing hematocrit, worsening radiographic signs or symptoms, or delays in exchange transfusion.[1]
   • Packed red blood cell transfusion aims to increase hematocrit to 30% or hemoglobin to 10 g/dL.
   • In severe ACS, exchange transfusions may be necessary. Indications include severe hypoxemia, multilobar disease on chest radiographs, or failure to improve with simple transfusion. Exchange transfusion aims to increase hemoglobin to 10 g/dL and reduce sickle hemoglobin (HbS) to less than 30%, increasing hemoglobin while avoiding hyperviscosity.
   • Consult a hematologist experienced in SCD for transfusion decisions.

7. Bronchodilators: Bronchodilators are indicated only if there is evidence of underlying asthma or bronchospasm. Routine use in ACS has not shown benefit.[15]

8. Steroids: Steroids have been shown to shorten hospital stays in ACS, but are associated with higher rates of rebound vaso-occlusive crises, increased readmission risk, and increased risk of fat emboli.

9. Bronchoscopy with Bronchoalveolar Lavage (BAL): BAL is considered only in cases of ACS refractory to conventional treatment.[16]

Differential Diagnosis of Acute Chest Syndrome

When evaluating a patient with symptoms suggestive of acute chest syndrome, it is important to consider other potential diagnoses:

• Acute Coronary Syndrome: Conditions like unstable angina and myocardial infarction, presenting with chest pain, shortness of breath, and other cardiac symptoms.
• Pulmonary Embolism: Characterized by sudden chest pain, shortness of breath, and potentially life-threatening symptoms.
• Pneumothorax: Sudden onset of sharp chest pain and breathing difficulty.
• Pneumonia: Typically involves productive cough, fever, chest pain, and breathing difficulty.
• Pleural Effusion: Presents with 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): Characterized by severe breathing difficulty, low oxygen levels, and abnormal chest X-rays.

Prognosis of Acute Chest Syndrome

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

In children, ACS is more likely to recur, particularly in those younger than 4 years.[17] Risk factors for repeat hospitalization in children include a history of asthma, shortness of breath, and longer initial hospital stays for ACS.

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

Complications of Acute Chest Syndrome

Acute chest syndrome can lead to various serious complications:

• ARDS (Acute Respiratory Distress Syndrome): Resulting from severe lung inflammation and fluid buildup, impairing oxygenation and potentially leading to respiratory failure.
• Respiratory Failure: Due to significant lung function impairment, characterized by inadequate oxygenation and ventilation.
• Pulmonary Infarction: Occurs when a blood clot blocks a pulmonary artery, causing tissue damage and impaired lung function.
• Pulmonary Fibrosis: Can develop from repeated ACS episodes, involving lung tissue scarring and thickening, leading to chronic respiratory compromise.
• Pulmonary Hypertension: Due to chronic lung damage from ACS, potentially leading to heart strain and impaired cardiac function.
• Severe Pain
• Death

Deterrence and Patient Education for Acute Chest Syndrome

Long-term management strategies to reduce the risk of acute chest syndrome include:

• Hydroxyurea: This medication has been shown to reduce the frequency of ACS by 50% in adults and 30% in children.[17] It increases HbF levels in red blood cells and is the only medication proven to decrease ACS incidence.
• Chronic Red Blood Cell Transfusions: Can be used during the transition to hydroxyurea, in high-risk periods like winter, if hydroxyurea is ineffective, or during recovery from a severe ACS episode. Chronic transfusions carry risks such as infections, iron overload, and allosensitization.
• Hematopoietic Cell Transplant: An option for patients with multiple ACS episodes. Requires an HLA-matched sibling donor and involves myeloablative regimens with associated risks, but has a high success rate (over 80%) in treating SCD.

Pearls and Recent Advances in Acute Chest Syndrome

Current research is focused on improving acute chest syndrome diagnosis, understanding disease characteristics, and enhancing treatment strategies.

• Bedside Ultrasound: Emerging as a promising diagnostic tool, potentially more sensitive than chest X-rays. Ultrasound findings like b-lines, pleural effusions, and consolidations show promise in predicting ACS progression in patients presenting with pain crises.[8]
• Biomarkers: Researchers are exploring biomarkers for early detection. Serum phospholipase A2, which converts neutral fats to free fatty acids, is being studied. Elevated free fatty acid levels have been observed hours before ACS onset, suggesting they could serve as a predictive marker.[18]
• Rapidly Progressive ACS: A subset of patients experience a rapidly progressive form of ACS with poorer outcomes.[19] Low platelet counts in adults are a risk factor for rapid progression and worse outcomes.
• Inhaled Nitric Oxide: A randomized controlled trial showed no overall benefit of inhaled nitric oxide in ACS treatment.[20] However, a subgroup with severe hypoxemia may have experienced modest benefit. Nitric oxide is a pulmonary vasodilator that could improve ventilation-perfusion mismatch and reduce pulmonary hypertension.
• Transfusion Strategies: Evidence suggests that exchange transfusion does not change hospital length of stay compared to no exchange transfusion in ACS.[21] Shorter stays were observed in subgroups with transfusion goals targeting hemoglobin >8.0 g/dL.

Enhancing Healthcare Team Outcomes in Acute Chest Syndrome Management

Acute chest syndrome is a serious SCD complication with high morbidity and mortality. Many patients experience recurrent episodes. A multidisciplinary, coordinated care approach is crucial to minimize recurrence risk through education and comprehensive management. Studies show that coordinated care teams can reduce ACS incidence, ICU admissions, and length of stay for vaso-occlusive crises.[22]

Key elements for enhancing healthcare team outcomes:

1. Incentive Spirometry and Respiratory Therapy: Nursing and respiratory therapy teams should encourage incentive spirometry use to prevent lung collapse and improve function.
2. Patient-Reported Pain Score: Essential for assessing pain in SCD. It is the gold standard for pain detection. Pain consultants can optimize pain control while preventing oversedation.
3. Specialist Consultations:
   • Hematologist: For transfusion and exchange transfusion decisions.
   • Pulmonologist: For patients with asthma, COPD, or restrictive lung disease, as these conditions increase morbidity in ACS.
4. Hydroxyurea Education: Educate patients and families about the importance of hydroxyurea to reduce sickle cell crises.
5. Pneumococcal Vaccination Education: Nurses and pharmacists play a vital role in educating patients about pneumococcal vaccination, which has significantly reduced ACS incidence in specific populations.[23]
6. Comprehensive Patient Education and Return Precautions: Educate patients about ACS, its management, and emphasize strict return precautions for early treatment initiation, which improves prognosis.

Outcomes of Acute Chest Syndrome

Acute chest syndrome requires hospital admission and is a severe SCD complication. While early and aggressive treatment can lead to fair-to-good short-term outcomes, without aggressive treatment, morbidity and mortality are high.[13, 24]

Starting patients on hydroxyurea to prevent future episodes is crucial. [Level 5] In severe and recurrent cases, hematopoietic cell transplant should be considered.

Review Questions

(Note: Review questions are available in the original article link for further learning.)

References

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