Pulmonary Complications of Sickle Cell Disease

1. Pulmonary Complications of Sickle Cell Disease Aneesa Vanker Respiratory Meeting 17-03-2009 Tygerberg Children`s Hospital

2. Sickle Cell Disease(SCD) • Caused by the inheritance of 2 copies of a mutant beta-globin gene – 1 from each parent. • Mutation = GAG GTG at position 6 in beta-globin chain of HbA  HbS • One of the most common inherited autosomal recessive disorders in the world. • Certain areas in sub-Saharan Africa – 40-60% of population heterozygote  1-4% of babies born have disease.

3. HbS polymerises on deoxygenation  rigidity of erythrocyte, distorts its shape & causes structural damage in red cell membrane. • Altered rheologic properties of cell impairs blood flow through microvasculature  haemolysis &vaso-occlusive episodes.

4. Pulmonary Complications • Pulmonary complications of SCD in children remain leading cause of morbidity and mortality.

5. What does the literature say? • 2 recent articles on Pulmonary complications of (SCD)

7. Vaso-occlusive crises • Recurrent episodes of severe pain in SCD • Caused by microvascular entrapment of RBC & WBC  obstruction in blood flow & organ ischaemia • Microvascular events  episodes of explosive pain & inflammation. • May be accompanied by fever & leukocytosis +/- bone marrow necrosis with pulmonary emboli.

9. The Acute Chest Syndrome (ACS) • Common form of lung injury in SCD • When severe analogous to acute respiratory distress syndrome. • Defined by development of new pulmonary infiltrates consistent with alveolar consolidation but not atelectasis involving at least one segment. • Radiographic abnormality accompanied by chest pain, fever, tachypnoea, wheezing or cough.

10. Causes of Acute Chest Syndrome • 3 major causes proposed: 1. pulmonary infection 2. embolisation of bone marrow fat – ffg vaso-occlusive crisis 3. intravascular pulmonary sequestration of sickled erythrocytes lung injury & infarction

12. Clinical aspects of ACS • Associated with marked systemic inflammation, fever, leukocytosis , abrupt drop in Hb and thrombocytopaenia. • May require ventilatory support • Rapid simple or exchange blood transfusion, removes sickled erythrocytes  rapid recovery.

13. Pulmonary Complications of SCD in children • Acute chest syndrome • Asthma (airway hyperreactivity) • Chronic sickle lung disease • Pulmonary hypertension • Sleep disordered breathing

14. Asthma • Significant comorbidity in children with SCD • Chronic lung dx can also occur – probably result of recurrent episodes of ACS • High incidence of airway hyperreactivity in several studies • However, low prevelance of asthma – may be underdiagnosed

16. Children with SCD and asthma have nearly twice as many episodes of ACS. • Several theories: VQ mismatch local tissue hypoxia and increased sickling of RBC, increase release of inflammatory markers may cause increase airway hyperreactivity. • Further studies warranted to determine if aggressive Rx of asthma reduces risk of ACS and possibly morbidity & mortality of ACS in SCD

18. Pulmonary Hypertension • Prevalence of pulmonary hypertension in children with SCD similar to that in adults (+/- 33%) • Defined as pulmonary artery systolic pressure: greater than 35mmHg (mild) greater than 45mmHg (mod- severe) OR • Tricuspid regurgitation velocity jet over 2.5m/s(mild) or 3.5m/s (mod-severe)

19. Calculating pulmonary artery pressure • Pulmonary artery pressure assumed to = right ventricular(RV) systolic pressure. • RV systolic pressure estimated from Bernoulli principle = as a fluid jet increases velocity, its lateral pressure is reduced.

22. Pathophysiology of pulmonary hypertension • Mulitiple mechanisms: - Left ventricular dysfunction from chronic anaemia - Lung damaging infarctions - Recurrent pneumonia & ACS - Recent interest – role of nitric oxide, decreased NO bioavailability  pulmonary vasoconstriction.

23. Rx of Pulmonary HPT • Information on Rx remains anecdotal. • Sildenafil use studied. • Arginine – substrate of NO shown to reduce pulmonary artery pressure in SCD • Other agents: prostacycline, bosentan (endothelin receptor blocker) • Blood transfusion – lowers plasma Hb by reducing hemolysis & suppressing hematopoesis of Hb sickle cells  lower pulmonary artery pressures.

24. Sleep disordered breathing(SDB) • Children with SCD have increased risk of SDB and abnormal ventilation during sleep. • 36% of children with SCD have SDB

25. Postulated reasons • Poor sleep quality associated with pain and VOC as well as nocturnal oxyhaemoglobin desaturations. • Upper airway obstruction – increased risk of obstructive sleep apnoea – thought to be due to compensatory lymphoid hyperplasia of tonsil and adenoids following splenic infarction. Significant reduction in symptoms ffg adenotonsillectomy

26. Postulated reasons cont.. • Correlation between SDB and elevated cerebral blood flow velocity (CBFV) in children with SCD. • Measured with transcranial doppler ultrasound. • Related to cerebral artery stenosis, severe anaemia & tissue hypoxia. • Association between elevated CBFV & UAO. Adenotonsillectomy can normalisation of CBFV and prevention of adverse neurological events.

28. Conclusion • Pulmonary dx remains an important cause of morbidity & mortality in children with SCD. • Pulmonary complications can interact with each other amplifying the adverse effects. • Further research needed to evaluate these relationships.