18th February 2025

Pulmonary complications of sickle cell disease

Overview of pulmonary complications of sickle cell disease

Sickle cell disease (SCD) refers to a group of haemoglobinopathies where the sickle mutation is co-inherited with another mutation affecting the other beta globin subunit in haemoglobin (Hb), causing reduced or absent normal beta globin production. Sickle cell anaemia (SCA) is the term used when someone is homozygous for the sickle mutation, resulting in the formation of the HbS (sickle haemoglobin) molecule. The HbS molecule is much less soluble than normal HbA when deoxygenated, causing red cells to deform (sickle). The complications seen in SCD occur as a result of this sickling, such as vaso-occlusive events, haemolysis and pulmonary complications such as acute chest syndrome and pulmonary hypertension (PH).

The pulmonary complications of SCD are particularly important because they are a major cause of morbidity and mortality, with acute chest syndrome and pulmonary hypertension having the highest associated mortality in these populations.

There are numerous pulmonary complications seen in SCD:

• Acute chest syndrome (discussed in detail later)
• Asthma – asthma is much more common in people with SCD, with up to 70% of children with SCD having airway hypersensitivity. Asthma is more common in children with a history of acute chest syndrome and children with asthma have a higher incidence of acute chest syndrome.
• Sleep disordered breathing – increased incidence in people with SCD, and is commonly due to obstructive sleep apnoea, associated with nocturnal hypoxaemia. These are linked with increased risk of vaso-occlusive events, cardiovascular complications and neurological disease.
• Pneumonia – more common in people with SCD. Common causative organisms include Chlamydophila pneumoniae and Mycoplasma pneumoniae. They’re also at increased risk of infection from encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae as they are functionally asplenic.
• Pulmonary venous thromboembolism – SCD is a hypercoagulable state, leading to increased risk of thromboembolisms
• Pulmonary hypertension – occurs in 6-11% of people with SCD and is an independent risk factor for mortality
• Chronic dyspnoea – likely multifactorial and often results in a reduction in exercise capacity in early to late adolescence; contributing factors include the pulmonary complications listed above, anaemia and myocardial dysfunction
• Pulmonary fibrosis – occasionally seen in people with recurrent acute chest syndrome episodes

Acute chest syndrome

Overview of acute chest syndrome

Acute chest syndrome is defined as a new pulmonary infiltrate on chest imaging associated with fever and/or respiratory symptoms in someone with SCD. Acute chest syndrome is the second most common cause of hospitalisation in people with SCD after vaso-occlusive events and is a leading cause of morbidity and mortality with a lifetime incidence of around 50% in those with SCD.

Clinically, acute chest syndrome is indistinguishable from pneumonia, but acute management of both is generally the same.

Increased incidence of acute chest syndrome occurs with:

• More severe genotypes of SCD, e.g. HbS or HbS-beta0-thalassaemia
• Lower HbF (foetal haemoglobin) concentrations
• Acute pain (vaso-occlusive events)
• Other respiratory problems: asthma, chronic hypoxaemia
• Environmental factors: active smoking, environmental smoke exposure, winter months

Common triggers for acute episodes of acute chest syndrome include:

• Respiratory infection or asthma
• Pulmonary infarction
• Fat embolism
• Vaso-occlusive pain

Multiple triggers may coexist in the same person, whereas in some cases, an acute trigger is not identified. Infection and asthma are more common triggers in children, while vaso-occlusive pain and fat embolism are more common causes in adults.

Clinical features and investigation of acute chest syndrome

The presentation and severity is variable. Some people present with an acute chest syndrome while others will develop it a few days into admission for another reason, mainly vaso-occlusive events. The most frequent presenting symptoms include:

• Fever
• Cough
• Chest pain
• Shortness of breath
• Pain preceding the acute chest syndrome episode (pain in arms, legs, rib and sternal pain)

Acute chest syndrome can be very severe, with around 10% of cases having respiratory failure so severe they require invasive mechanical ventilation.

These are pertinent investigations to perform in a person with suspected acute chest syndrome:

• Full blood count including reticulocytes
• Haemoglobinopathy screen with HbS percentage – HbS percentage needs to be monitored before and after transfusions (simple or exchange)
• Group and save
• Metabolic profile – acute chest syndrome can be associated with acute multiorgan failure syndrome
  • Renal profile
  • Liver function tests
• Cultures: blood and sputum
• Respiratory viral screen and atypical pneumonia screen
• Arterial blood gas – not routine unless there is significant respiratory compromise
• Chest x-ray – to identify if there are any new pulmonary infiltrates
• CT pulmonary angiogram – if a pulmonary embolism is suspected

Management of acute chest syndrome

The main aims of treatment are early intervention to prevent deterioration and early escalation if required.

Acute interventions include:

• Analgesia – to reduce hypoventilation and atelectasis
• Incentive spirometry and chest physiotherapy – to reduce atelectasis
• Empirical broad-spectrum antibiotics – as per local protocols covering for community-acquired pneumonia
• IV fluids – care should be taken to avoid hypervolaemia as this can precipitate pulmonary oedema
• Bronchodilators – if wheezing is present or there is a history of asthma
• Venous thromboembolism prophylaxis
• Respiratory support – supplementary oxygen should be given to maintain saturations ≥95% or at their baseline; may require continuous positive airway pressure, non-invasive ventilation or invasive ventilation
• Simple or exchange transfusion – prompt transfusion decreases progression of disease; the aim of simple transfusion is to increase haematocrit to ≥30% or Hb >100 g/L and the aim of exchange transfusion is to reduce HbS to <30%; Hb should not rise above 110 g/L due to risks of hyperviscosity.

Table 6 Indications for simple versus exchange transfusion in acute chest syndrome

Exchange transfusion allows for large transfusion volumes (6-8 units) whilst not risking hyperviscosity.

There are also numerous preventative measures that can be put in place to reduce the incidence of acute chest syndrome:

• Regular incentive spirometry if admitted to hospital for other reasons such as vaso-occlusive events
  • Prevent infections: prophylactic penicillin and up-to-date vaccinations
• Optimise underlying lung conditions, e.g. asthma
• Reduce vaso-occlusive events
  • Hydroxyurea – increases HbF concentration
  • Chronic transfusions or exchange transfusion programme (generally for patients with severe disease and recurrent episodes)

References

• Chapman S, Robinson G, Shrimanker R, Turnbull C, Wrightson J (eds.). Oxford Handbook of Respiratory Medicine. 4th ed. Oxford: Oxford University Press; 2021
• Machado RF, Gladwin MT. Pulmonary Complications of Hematological Diseases. In: Broaddus C, Mason RJ, Ernst JD, King Jr. TE, Lazarus SC, Murray JF (eds.) et al. Murray & Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia: Saunders; 2016. p. 1653-1670
• Klings ES, Willen S. Overview of the pulmonary complications of sickle cell disease [Internet]. Mandel J, Vichinsky EP, Dieffenback P, Tirnauer JS, editors. UpToDate. 2022 [cited 2023 May 9]. Available from: https://www.uptodate.com/contents/overview-of-the-pulmonary-complications-of-sickle-cell-disease
• Miller AC, Gladwin MT. Pulmonary Complications of Sickle Cell Disease. American Journal of Respiratory and Critical Care Medicine. 2012;185(11); 1154-1165. Available from: doi: 10.1164/rccm.201111-2082CI
• Vichinsky EP. Overview of the clinical manifestations of sickle cell disease. DeBaun MR, Tirnauer JS, editors. UpToDate. 2023 [cited 2023 May 13]. Available from: https://www.uptodate.com/contents/overview-of-the-clinical-manifestations-of-sickle-cell-disease
• Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbae M, Davis B. Guidelines on the management of acute chest syndrome in sickle cell disease. British Journal of Haematology. 2015;169(4); 492-505. Available from: doi: 10.1111/bjh.13348