INTRODUCTION
Sickle Cell Disease (SCD) affects about one in every 400 African-Americans in the United States1 with significant complications including recurrent severe pain episodes2 and acute chest syndrome (ACS)3for which each episode carries a 4% chance of death4. Pulmonary complications are the cause of death in over 50% of autopsies in SCD patients yet reliable and sensitive tests to detect early lung disease are not available. An estimated 30-70% of children with SCD have wheezing and airway hyper-reactivity (AHR) and air trapping5-11 and those with asthma have higher rates of pain and ACS as well as premature death12-17. Ultimately, patients with multiple episodes of ACS and wheezing develop Sickle Cell Lung Disease (SCLD), which is a restrictive lung disorder18, often associated with pulmonary hypertension.
Diagnosis of early lung disease in SCD is delayed as spirometry and plethysmography, measures of obstructive or restrictive lung disease, cannot often be reliably performed in children under the age of 5 years. Additionally, spirometry is relatively insensitive in identifying and assessing early lung disease in the smaller, more distal airways until significant disease has developed19,20. The multiple breath washout (MBW) technique, which measures the Lung Clearance Index (LCI), is a novel noninvasive measurement of ventilation inhomogeneity that is simple, involves no risk or hazardous exposures and can be used in children, including preschoolers. LCI has been shown to be a sensitive tool in detecting lung disease in cystic fibrosis and asthma before any changes are apparent on spirometry21,22and has been demonstrated to be abnormal in patients with normal lung function on spirometry23,24.
To date, MBW has not been studied in children with SCD. One study explored the potential relationship between nitrogen single-breath washout (N2SBW) and exercise intolerance in 38 adults with SCD (median age of 28 years) 25. Results suggested that phase III slope (SIIIN2) values correlated with hemoglobin level, forced vital capacity (FVC), diffusing capacity and SpO2 after exercise. Given this, assessing the ability of MBW to detect potential ventilation inhomogeneity may prove beneficial and allow for earlier intervention in patients where the disease may go unrecognized. Since pulmonary complications such as ACS, wheezing and airway hyper-reactivity (AHR) often start early in SCD11,26we hypothesized that children with SCD (with or without asthma) would have an abnormal and elevated LCI compared to healthy controls. Findings of abnormal LCI in children with SCD during which time spirometry may be normal would be useful in initiating early intervention and more in-depth diagnostic screening.