Dr Tom Gilmartin, reviewed by Dr Kirstin Lund, Paediatric Haematology consultant

A 4-year-old boy presents to the emergency department with a cough. Probably just a viral illness, right? Young children seem as though they always have a cold. When you start talking with the family, you soon discover that he has also been complaining of chest pain. You remember learning about cardiac causes of chest pain and are relieved that he does not have any red flag symptoms that may suggest he has a serious cardiac issue. Great! Maybe just a little costochondritis from coughing? You gather a complete history and learn that your patient has sickle cell disease. Does this change anything? Hmm, there was something about sickle cell disease… chest pain…respiratory symptoms…what was it… Acute Chest Syndrome!

What is Acute Chest Syndrome (Sickle Chest)?

Acute chest syndrome (ACS) is a syndrome of acute pulmonary disease in an individual with a sickling disorder. After sickle pain crises, ACS is the second most common complication in children with sickle cell disease and the leading cause of death. More than half of all patients with homozygous sickle cell disease (HbSS) will have at least one episode of ACS during their first decade of life. ACS is more likely to occur in individuals with HbSS or Sβ0 thalassemia, though it can be seen in milder sickling diseases.  

ACS can be thought of as: presence of radiological changes + respiratory symptoms/signs in the presence of a sickling disorder.

Acute Chest Syndrome is defined as:

• A new pulmonary infiltrate on chest x-ray that involves at least one lung segment that is not consistent with atelectasis.

And

• Any of the following symptoms: fever, hypoxemia, increased work of breathing, tachypnea, cough, wheezing, or chest pain in an individual with a sickling disorder.

Pathophysiology

The pathophysiology of ACS is complex and centers around vaso-occlusion from the sickling of red blood cells within the pulmonary microvasculature. Many factors can contribute to this process and lead to a vicious cycle of worsening pulmonary disease. The inciting event of an episode, however, is not always apparent. Nearly half of all cases do not have an identifiable cause. The most common identified causes are:

• Infection: This can be viral pneumonia, bacterial pneumonia or a systemic infection. Common pathogens include Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory syncytial virus (RSV), Staphylococcus aureus, and Haemophilus influenzae.
• Fat embolism: Vaso-occlusion can cause bone marrow infarction leading to the release of fat droplets that can embolize to the lungs.
• Pulmonary infarction: Primary vaso-occlusion in the pulmonary vasculature that causes ventilation-perfusion mismatch.

Regardless of the cause initiating the process, patients are at risk for a cycle of events that can lead to a spiral of clinical decline. This process is depicted in the diagram above where vaso-occlusion can lead to infarction of bone marrow, pain, hypoventilation, atelectasis, hypoxemia, and further sickling. For this reason, prompt intervention is necessary to prevent clinical deterioration.

How does Acute Chest present?

Patients may present with classic symptoms that include: Chest pain, dyspnea, fever, or cough. Clinicians should also consider ACS if a patient complains of back, shoulder, or abdominal pain, particularly in young children who may have difficulties localising their pain. Signs include tachypnea, tachycardia, and hypoxia. Sometimes these signs may be present, even while the patient does not appear overtly ill. About half of patients diagnosed with ACS are actually admitted with a different diagnosis such as a vaso-occlusive pain crisis before developing ACS. It is not uncommon for a patient to be admitted for a pain crisis, then develop ACS on day two or three of hospitalization. Other common scenarios include developing ACS during post operative recovery or in the setting of an acute asthma exacerbation. For this reason, it is important to be vigilant in monitoring for signs and symptoms of ACS in all patients with sickle cell disease.

Also consider ACS if a patient complains of back, shoulder, or abdominal pain, particularly in young children who may have difficulties localising their pain.

Diagnostic Evaluation

Complete Blood Count (CBC)	White blood cell count can provide information to suggest an infectious process, though white count is often raised in sickle crisis even in the absence of infection. Haemoglobin/Haematocrit will provide information as to whether the patient is anaemic and may require blood transfusion. Access to previous results is useful to provide information about a patient’s baseline blood counts.
Reticulocyte count, lactate dehydrogenase, and bilirubin	These all may be elevated in ACS as a result of increased sickling and haemolysis.
C-Reactive Protein (CRP)	Though non specific, will likely be elevated in patients with ACS.
Septic screen including sputum culture and viral studies	Cultures and viral studies including PCR tests may help identify a causative pathogen.
Blood gas	Will help identify any acid/base disorder in critically ill patients.
Blood group and crossmatch	Preparation for possible transfusion.
Chest X-Ray	Imaging is necessary for the diagnosis of acute chest. It is important to obtain a chest x-ray in patients with chest pain or lower respiratory tract symptoms. One study showed that more than half of ACS cases were not suspected prior to the confirmation of diagnosis on chest imaging.

Management of acute chest crisis

Acute Management

• Respiratory support: Supplemental oxygen as needed. Typically a target O2 saturation of at least 92% is desired to prevent further oxygen dissociation and sickling of erythrocytes. Some institutions recommend target saturations up to 96%. Incentive spirometry/physiotherapy may also be used to help reduce atelectasis and hypoventilation. 
• Hydration: Start IV fluids if the patient is dehydrated and continue maintenance IV fluids if not meeting the requirements to stay euvolemic through oral intake. Care must be taken to maintain an appropriate fluid balance. Strict monitoring of intakes, outputs, and weights are important to avoid both fluid overload and dehydration. 
• Analgesia: Adequate pain control is important to stop the cycle as previously described. Thoracic pain can lead to hypoventilation atelectasis that can worsen the process. Analgesia is commonly provided with nonsteroidal anti-inflammatory medications and severe pain may be treated with opioids. A careful balance should be struck, as oversedation with opiates can lower respiratory drive also causing atelectasis and precipitate further sickling.
• Antibiotics: Broad spectrum antibiotics are typically given to cover community acquired pneumonia with a third generation cephalosporin such as ceftriaxone and atypical pneumonia with a macrolide such azithromycin.
• Consider transfusion:  A haematologist should be consulted for any individual with ACS to discuss transfusion. There is no consensus criteria for transfusion in ACS, but transfusion is often recommended if there is a 10-20g/L decrease in hemoglobin from baseline. The decision to escalate from simple transfusion to an exchange transfusion is often made based on the severity of disease or if a patient fails to improve with simple transfusion. Keep in mind that overly aggressive transfusion can lead to hyperviscosity and increased risk for the formation of thrombi.  

Thoracic pain can lead to hypoventilation atelectasis that can worsen the process.

Long term management mainly consists of infection prevention. Children with sickle cell disease are at increased risk of infection, particularly encapsulated bacteria due to functional asplenia (progressive splenic infarction leads dysfunction of the spleen). This can be managed through:

• Vaccinations: follow the recommended national vaccination schedule with attention to special considerations for children with functional asplenia. This may include altered vaccination schedules for pneumococcal, meningococcal, and Haemophilus influenzae type B (Hib) vaccines.
• Prophylactic penicillin: this is recommended for all patients with sickle cell disease.

Other long term management strategies include the use of hydroxyurea (hydroxycarbamide). Hydroxyurea is used to prevent sickling of erythrocytes by increasing fetal hemoglobin production, and has been shown to reduce incidence of ACS. It is recommended that all children over the age of 9 months and those under 9 months and symptomatic should be on daily hydroxyurea.

Summary

Acute chest syndrome is a common and deadly complication of sickle cell disease. During an episode, patients can quickly decompensate in a vicious cycle of vaso-occlusion and hypoxia. Clinicians should stay vigilant for signs and symptoms of acute chest syndrome and educate patients and their families to recognise these as well.

Key Learning Points:

• ACS is the leading cause of death in individuals with sickle cell disease.
• ACS is defined as a new infiltrate on CXR  + symptoms concerning for pulmonary disease in an individual with a sickling disorder.
• Initial treatment should address respiratory support, hydration, pain, and antibiotic therapy. 
• ACS often develops during hospitalizations for other diagnoses.

Further resources

• Crabtree et al. “Improving Care for Children With Sickle Cell Disease/Acute Chest Syndrome Pediatrics vol. 127
• Eisenbrown et al. “Which Febrile Children With Sickle Cell Disease Need a Chest X-Ray?” Academic Emergency Medicine
• Jain et al. Acute Chest Syndrome in Children with Sickle Cell Disease.” Pediatric Allergy, Immunology, and Pulmonology
• Morris et al. Clinician Assessment for Acute Chest Syndrome in Febrile Patients With Sickle Cell Disease: Is It Accurate Enough?
• NICE guidance on sickle cell disease

Tom Gilmartin is a PGY-3 paediatric resident at Dell Children’s Medical Center, Austin, Texas. Consultant reviewer for this article was by Kirstin Lund, Consultant Paediatric Haematologist at St Mary’s Hospital, London