Reply to Jha

From the Authors:

We thank the author for their interest in our recent article on the French prospective cohort of coronavirus disease (COVID-19) in patients with pulmonary hypertension (PH) (1). First of all, the author wondered if all patients in our study truly had precapillary PH. As stated in the methods, all patients’ data were extracted from the French registry, which includes well-phenotyped patients with PH, all having undergone complete hemodynamic evaluation, and has led to many publications in recent decades (2, 3). All patients included in this analysis had precapillary PH at the time of diagnosis, in accordance with the current definition during the inclusion period (i.e., a mean pulmonary arterial pressure of ⩽25 mm Hg, a normal pulmonary arterial wedge pressure [PAWP] of ⩽15 mm Hg, and pulmonary vascular resistance of >3 Woods units) (4). According to international definitions, this excluded the presence of PH due to left heart diseases (group 2 PH) as the main cause of PH in this population. The most recent right heart catheterization data for these patients yielded a median PAWP of 10 (interquartile range, 7–13) mm Hg. At the last hemodynamic evaluation before COVID-19, a small subgroup of 14 patients (6.6% of the overall 213 patients) had combined pre- and postcapillary PH with PAWP >15 mm Hg, which is in accordance with the age and comorbidities reported in this population as well as the possibility of ventricular interdependence. The etiologies of PH among these patients were PH associated with chronic respiratory diseases (n = 6), idiopathic pulmonary arterial hypertension (PAH) (n = 4), anorexigen-associated PAH (n = 2), and chronic thromboembolic PH (n = 2). We disagree with the assumption that the high prevalence of comorbidities is, on its own, indicative of postcapillary PH and also wish to correct the author’s statement that all patients were >60 years of age, as the interquartile ranges for age in the groups presented in our Table 1 include patients in their 40s and 50s. Recent national registries highlight frequent pulmonary and cardiovascular comorbidities in patients with PAH (3, 5, 6). In the French PH Registry, systemic hypertension, obesity, diabetes, coronary heart disease, and atrial fibrillation were recorded in 50%, 32%, 25%, 14%, and 11%, respectively, in a large population (n = 1,611) of subjects with idiopathic, heritable and anorexigen-associated PAH (3). The prevalence of comorbidities was broadly similar in the present study, especially if we put in perspective that our cohort included patients with groups 3 and 4 PH, classically associated with older age and more frequent comorbidities. Indeed, the assumption that normal right atrial pressure in the presence of high brain natriuretic peptide or N-terminal pro–brain natriuretic peptide indicates left ventricular failure with normal right ventricular function has no meaning in a population with precapillary PH confirmed by cardiac catheterization with increased pulmonary vascular resistance and decreased cardiac index (1). Of the 14 patients with precapillary PH with increased PAWP diagnosed during hemodynamic follow-up, 3 patients died during hospitalization for COVID-19, representing a mortality rate of 21.4% that is in accordance with the overall mortality of the entire cohort (24.6%; 95% confidence interval, 18.8–30.5%). It is likely that some patients with precapillary PH had associated heart failure with preserved ejection fraction (HFpEF), as evidenced by the occurrence of increased PAWP in a subset of patients undergoing hemodynamic monitoring. However, the increase in PAWP in patients with precapillary PH was not associated with excess mortality in our cohort. It is nevertheless likely that HFpEF was probably underestimated in patients with precapillary PH, as fluid challenge was not systematically performed during right cardiac catheterization to diagnose HFpEF.

Similarly, the Dl_CO of 53.5% (95% confidence interval, 35–66%) reported in our cohort is in accordance with the etiologies of precapillary PH, including mainly PAH and chronic thromboembolic PH but also pulmonary venoocclusive disease and chronic respiratory disease–associated PH, which are all typically associated with major decreases in Dl_CO. Indeed, Hoeper and colleagues recently reported that low Dl_CO (<45%) was frequently observed in patients with diagnoses of idiopathic PAH, and this may represent a specific phenotype close to group 3 PH (6). In our cohort, we observed an increased risk of mortality in patients with chronic respiratory diseases, giving an obvious explanation for the lower Dl_CO in deceased patients. The recent 2022 European Society of Cardiology/European Respiratory Society guidelines highlight that comorbidities, including decrease in Dl_CO, were associated with worse response to PAH-approved drugs in patients with PAH (7).

In conclusion, the prevalence of cardiovascular and pulmonary comorbidities reported in our cohort is in accordance with the epidemiology of patients with precapillary PH in large national registries. Although it is possible that some patients had occult HFpEF, a small number had elevated PAWP during follow-up, and this was not associated with outcomes. Univariate and multivariate models demonstrated significant associations between chronic respiratory and cardiovascular diseases and the risk of in-hospital mortality in patients with precapillary PH. This is not surprising given that cardiopulmonary comorbidities are considered poor prognostic factors for PH and COVID-19.