Pulmonary Complications of Sickle Cell Disease Aneesa Vanker Respiratory Meeting Tygerberg Children`s Hospital

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.

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.

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

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

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.

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.

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

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.

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

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

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

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)

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.

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.

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.

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

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

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.

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.