Abstract

Introduction: Pulmonary hypertension (PHT), a common complication in patients with sickle cell disease (SCD), is associated with an increased risk of mortality. Patients with SCD are typically screened for the presence of PHT using Doppler echocardiography, with the diagnosis confirmed by right-sided heart catheterization. Validated biomarkers could provide additional diagnostic and prognostic information in these patients. The purpose of this study is to determine the relationship between a variety of biomarkers and the presence of PHT in SCD patients.

Methods: Selected biomarkers were obtained from a cohort of 76 SCD patients evaluated for PHT. The pulmonary artery systolic pressure (PASP) was determined by Doppler echocardiography and PHT was then defined using an age-, sex- and BMI-adjusted reference range. Receiver-operating characteristic curves, sensitivities, specificities, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive values (NPV) of each of these biomarkers was then used to assess its relationship to PHT.

Results: Elevated levels of lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, total bilirubin (T Bili), N-terminal pro-brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1 (sVCAM) are associated with PHT, while decreased levels of fetal hemoglobin (Hgb F) are associated with PHT. LDH and sVCAM are the most predictive biomarkers for the presence of PHT. An LDH level of 927 U/L (AUC 0.759, P = 0.0004) provides a sensitivity of 73%, a specificity of 72%, a LR+ of 2.61, a PPV of 59% and a NPV of 83%, while a sVCAM level of 865 ng/mL (AUC 0.712, P = 0.0026) provides a sensitivity of 63%, a specificity of 72%, a LR+ of 2.25, a PPV of 54% and a NPV of 79% The AUC, cut-off level, sensitivity, specificity, likelihood ratio, and PPV and NPV for each biomarker is shown in the table below.

Conclusion: Multiple biomarkers have different predictive capabilities for PHT in patients with SCD. Despite the small likelihood ratios, LDH appears to provide greater prediction for PHT than other measured biomarkers including NT-proBNP that has previously been reported to be independently associated with increased mortality in these patients. More studies are required to evaluate the predictability of combinations of biomarkers for PHT and to assess the relationship of biomarkers with mortality in this patient population.

Table 1
VariableAUCCutpoint based on Youden indexP valueSens (%)Spec (%)Likelihood Ratio (+)/(−)PPV/NPV (%)
LDH 0.759 927 U/L 0.0004 73 72 2.61/0.38 59/83 
BUN 0.665 14 mg/dL 0.015 50 84 3.13/0.60 62/76 
Creatinine 0.622 1.3 mg/dL 0.01 38 94 6.33/0.66 77/75 
Hgb F 0.669 4.3% 0.04 65 72 2.32/0.49 55/80 
T Bili 0.685 2.6 mg/dL 0.017 54 80 2.7/0.58 58/77 
NT-proBNP 0.66 103 pg/mL 0.06 65 60 1.63/0.58 47/76 
sVCAM 0.712 865 ng/mL 0.0026 63 72 2.25/0.51 54/79 
VariableAUCCutpoint based on Youden indexP valueSens (%)Spec (%)Likelihood Ratio (+)/(−)PPV/NPV (%)
LDH 0.759 927 U/L 0.0004 73 72 2.61/0.38 59/83 
BUN 0.665 14 mg/dL 0.015 50 84 3.13/0.60 62/76 
Creatinine 0.622 1.3 mg/dL 0.01 38 94 6.33/0.66 77/75 
Hgb F 0.669 4.3% 0.04 65 72 2.32/0.49 55/80 
T Bili 0.685 2.6 mg/dL 0.017 54 80 2.7/0.58 58/77 
NT-proBNP 0.66 103 pg/mL 0.06 65 60 1.63/0.58 47/76 
sVCAM 0.712 865 ng/mL 0.0026 63 72 2.25/0.51 54/79 

Author notes

Disclosure: No relevant conflicts of interest to declare.