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.