Factors Associated with Pulmonary Hypertension and Overall Survival in Adult Patients with Sickle Cell Disease: A Single Centre Retrospective Study

Background

Pulmonary hypertension is associated with increased morbidity and mortality in the general population either related to the underlying factors predisposing to elevated pulmonary artery pressures or though the hemodynamic changes induced in the cardiopulmonary circuit. It is known that patients with Sickle cell disease have an even a greater incidence of pulmonary hypertension than the general population and presumably a similar association with poor outcome related to this.

Very little data is available regarding which adult patients with sickle cell disease would be at a higher risk for Pulmonary hypertension and as such benefit from screening. Many of the more commonly suggested clinical symptoms of pulmonary hypertension may be less specific in patients with SCD. The gold standard for diagnosis of PHT is Right heart catheterization, however for practical purposes echocardiographic variables such as Tricuspid Regurgitant velocity(TRV) and right ventricular systolic pressure(RVSP) are used in the general population. Several prior studies have focused on laboratory tests or historical risk factors associated with increased hemolysis.

We evaluated the association of several variables with the occurrence of PHT in a population of adult patients with SCD and assessed their association with overall survival(OS). The factors we focused on could be seen as having biological plausibility for causing PHT as they relate to factors that increase flow through the pulmonary circuit, such as occurrence of hemolysis, or affect microvascular flow such as episodes of acute chest syndrome(ACS).

Methods

We identified patients aged 18 years or older with sickle cell disease from our electronic database who had an echo performed between 2009- 2017. Primary outcome was to determine the factors associated with PHT and OS. PHT was defined as RVSP of >25 mm Hg or TRV of >250 cm/sec. Factors investigated included age, sex, sickle cell type, absolute reticulocyte count(ARC), ferritin, use of iron chelation agent, and episodes of acute chest. Chi square test was used to compare proportion of PHT among factors.

Results

We identified 300 patients with SCD from our clinic population, of whom 243 patients had echocardiographic data available. 52.7 % were females and 47.3 % were males. Out of the 234 patients who had TRV or RVSP measured, 63 patients met our criteria for PHT. 79 patients had TRV measured. 50.6 % had TRV <250 cm/sec, 29.1% had TRV 250-300 cm/sec and 20.2 % had TRV >300 cm/sec.

223 patients had data on sickle cell type. HbSS, Hb SC , HbSß⁺ Thal, HbSß°Thal occurred with a frequency of 64.3%, 17.9%,13% and 4.9 % respectively. There was no association between sickle cell type and presence of PHT or OS.

243 patients with Ferritin levels documented, of which 38.7% had Ferritin levels >1000 ng/ml. There was a strong correlation between an elevated ferritin level and PHT (p value =0.001) but not with OS. ARC was not associated with PHT (p value =0.87), but interestingly a normal ARC was strongly associated with worse OS (p value = 0.03)

234 patients had documentation of whether or not they had an episode of ACS. 50 patients had one or more episodes of acute chest. There was a trend towards association of acute chest episodes with PHT (p value =0.08) and OS (p value =0.11).

21 patients were deceased at the time of final analysis. Median overall survival was 3.8 years after TRV was initially documented. Median TRV was 248.8 cm/sec. There was a trend towards worse overall survival with a TRV of >300 cm/sec when compared to TRV of <250 cm/sec (p value =0.08).

Conclusion

Our study suggests that patients with elevated ferritin and ACS episodes should undergo screening for PHT. A normal ARC in this study while not being statistically associated with PHT was very strongly associated with worse OS. These findings are as observed in a small single center study and further evaluation of these clinical and laboratory factors should be pursued using a larger database in a prospective fashion.