Introduction:
Sickle cell disease (SCD) is a hemoglobinopathy that leads to a chronic inflammatory state resulting in vasculitis, pulmonary fibrosis, and pulmonary hypertension1. Children with SCD (C-SCD) often suffer from impaired gas exchange, primarily due to hemoglobinopathy and related inflammatory pathology2. If untreated, gas exchange abnormalities in SCD may result in chronic hypoxemia, cardiopulmonary morbidity, and poor disease outcomes3. Chronic hypoxemia in SCD can contribute to the pathophysiology of vaso-occlusive crises (VOC) and acute chest syndrome (ACS)4, and it may also lead to pulmonary hypertension, which can impact life expectancy in this vulnerable population5,6. Quantifying the underlying pathophysiologic changes is not feasible in routine clinical practice, and thus gas exchange impairment could be used as a prognostic indicator of disease severity in SCD7.
The single-breath technique for estimating carbon monoxide uptake, also known as DLCO, is a widely used gas exchange measurement technique8. Chronic airway inflammation in SCD can lead to worsening diffusion capacity2; DLCO impairment also depends on the presence of hypoventilation9, as well as the degree of anemia10. Despite the importance of DLCO in C-SCD, very few studies have been published on diffusion impairment in C-SCD, and there is no available data on the determinants of DLCO in C-SCD other than anemia. Addressing that knowledge gap could help gain further insight into its origins and prevent morbidities related to impaired gas exchange.
Both DLCO and lung volumes have a faster rate of decline in SCD than healthy subjects. While the relationship is likely complex, it could have prognostic significance; however, it has never been studied before. In the non-SCD population, relationships between DLCO and FVC have been used to stratify mortality risk in pulmonary hypertension11,12. Since SCD can lead to pulmonary parenchymal disease and be complicated by pulmonary hypertension, the above-mentioned example underscores the importance of studying the predictors of DLCO and their complex interaction.
Anemia is a primary determinant of DLCO in SCD13,14. Subjects with low hemoglobin typically have under-estimated DLCO. Therefore, for precise interpretation, DLCO should be adjusted for hemoglobin in C-SCD. Alveolar ventilation (VA) is also a strong determinant of DLCO, and previous studies have shown an association between airflow obstruction and diffusion impairment in adults15. However, there have been no similar studies in C-SCD. We previously demonstrated the utility of impulse oscillometry (IOS) to measure obstructive airway disease in C-SCD16, but it is still unknown whether airway resistance or reactance is associated with or predicts gas exchange in C-SCD. Thus, the association between DLCO and measures of airflow obstruction including FEV1, FEV1/FVC, FVC25-75%, and IOS estimates (R5, X5), is a clinically relevant yet relatively unexplored domain. Unlike obstructive airway disease, restrictive lung disease can be a late manifestation in C-SCD17, and thus measures like total lung capacity (TLC) and vital capacity (VC) could be significant predictors of declining DLCO –which is more evident with advancing age in C-SCD18.
In this study, we aim to better understand the predictors of DLCO and their relative importance. Our primary objective was to identify PFT indices and biomarkers that are associated with and predict DLCO in these patients and assess their predictive accuracy. Our secondary objective was to determine if estimated DLCO (eDLCO) is associated with clinical outcomes in C-SCD, which would further emphasize the clinical relevance of DLCO.