Pulmonary Hypertension in Pulmonary Langerhans Cell Granulomatosis

Introduction. Pulmonary Langerhans cell granulomatosis is a rare disease with a variable course. In pulmonary Langerhans cell granulomatosis pulmonary hypertension is frequent and has an independent prognostic impact. A vasculopathy which ist not related to ventilatory disturbance and fibrosis has been identified. An arteriopathy and even a venulopathy have been described. Due to this possible venulopathy vasodilators carry a significant risk for pulmonary congestion and edema. No drugs have been approved until now. Case Presentation. One female with PLCG developed severe PH four years after primary diagnosis of pulmonary Langerhans cell granulomatosis. Retrospective analysis of lung biopsies revealed an arterial vasculopathy at the time of primary diagnosis without clinical signs of PH at this time. Sildenafil led to a sustained improvement of hemodynamic features and exercise capacity. Conclusion. This paper underlines that patients with PLCG with an arterial vasculopathy-related PH might improve under sildenafil. Further trials addressing treatment of PH and vasculopathy are needed.


Introduction
The course of adult pulmonary Langerhans cell granulomatosis (PLCG) is variable: in 25% the disease is spontaneously regressive, in 50% it remains stable, and in 25% there is a severe disease progression [1,2]. In severe PLCG pulmonary hypertension (PH) is a common complication. In patients waiting for lung transplantation PH was found in 90% [3].
Crausman and Keogh showed that in patients with severe PLCG abnormalities of ventilatory function are common but not exercise-limiting. The impairment of exercise capacity is due to pulmonary vascular dysfunction [4,5].
PH is often severe and not related to the ventilatory disorder or hypoxemia [3,6,7]. Different forms of a pulmonary vasculopathy affecting pulmonary arteries and pulmonary veins are described [6]. A progression of the vasculopathy in patients with no change of histopathological findings of lung parenchyma and a stable ventilatory disorder was reported [6]. The pathogenesis of this vasculopathy remains unclear: cytokines and growth factors may play an important role [8,9].
Modern vasoactive drugs that are approved for pulmonary arterial hypertension (PAH) seem to be an attractive tool for treating PH caused by a pulmonary vasculopathy in PLCG, but data of randomized controlled trials are missing. A single experience of Bosentan was reported [10].
Side effects of a vasoactive therapy leading to pulmonary edema might be a possible complication in patients with a predominant venous vasculopathy [6].

Case Presentation
We report successful treatment of PH with sildenafil in a female patient with adult PLCG.
A 51-year-old female was first admitted to our PH outpatient clinic in March 2010. In 2005 a PLCG was diagnosed and proven by histopathological findings. In 2005 the patient was treated with corticosteroids. In 2010 the patient reported worsening of exercise tolerance and exertional dyspnea over the last months. Echocardiography showed elevated pulmonary artery pressure and dilated right atrium and right ventricle (Figure 1(a)). Pulmonary function test revealed  moderate airflow obstruction and reduced transfer factor for carbon-monoxide ( Figure 2). The computed tomography showed fibrosis, cysts, and bronchiectasis but no active lesions as noduli or ground glass opacities ( Figure 3). We performed an RHC and so confirmed a severe precapillary PH (Table 1). Under exercise conditions the patient showed hypoxemia (Table 1). Retrospectively we analysed tissue samples of the year 2005 in which the PLCG was diagnosed: there were no clinical signs of PH, but tissue samples showed signs of a pulmonary vasculopathy (Figures 4(a)-4(e)).
In March 2010 we first started prednisolone with 0.5 mg/kg. There was no effect on exercise capacity, lung function, oxygen partial pressure, radiological findings, or pulmonary artery pressure. After the start of sildenafil (20 mg three times a day) dramatic hemodynamic and clinical improvements were seen. Table 1 shows the results from RHC, 6-minute walking test, cardiopulmonary exercise testing, and echocardiography before and after initiation of sildenafil. Oxygen tension remained stable, and no pulmonary congestion was seen. In the following 12 months  the patient remained stable, a rehabilitation was initiated, and listing for lung transplantation was considered.

Discussion
Not surprisingly there was no effect of a second course of corticosteroids in 2010 because CT scans showed endstage pulmonary Langerhans' cell granulomatosis with bronchiectasis and fibrosis without signs of activity as nodules.
The noted improvement under sildenafil is attributed to an effect on a pulmonary vasculopathy [6]. Surprisingly histopathological features of a vasculopathy had been already found in our patient 5 years ago, when she presented the first time with pulmonary Langerhans cell granulomatosis but without clinical signs of PH. As mentioned above foregoing studies reported arterial and venous vasculopathy. So a treatment with pulmonary vasodilators influencing the arterial vasculopathy was taken into account. On the other hand in patients with predominant venous vasculopathy side effects as pulmonary congestion caused by a vasodilatation of pulmonary arteries might appear and just have been described [6]. Such side effects did not appear under treatment with sildenafil in the patient reported here because the patient had a predominant arterial vasculopathy. Gas exchange was stable, and therapy was save. The ventilatory disturbance and fibrosis and the underlying PLCG are not influenced by sildenafil, so that it is not surprising that the patient did not experience complete normalization of exercise capacity. For further management a rehabilitation was initiated and listing for lung transplantation was planned.

Conclusion
In PLCG and severe PH sildenafil is a promising option and should be considered for bridging to lung transplantation. Sildenafil should not be used uncritically and patients should be controlled carefully, because, under special circumstances, especially a predominant pulmonary venous vasculopathy side effects as pulmonary edema might appear.
PH due to PLCG belongs to group 5 of the Dana Point classification, no drugs are approved for this kind of PH. There is a need for further studies addressing treatment of PH and vasculopathy. Millimeter mercury mPAP:

Abbreviations
Mean pulmonary artery pressure nT-pro-BNP: N-terminal-pro-brain natriuretic peptide pg: Picogram PAH: Pulmonary arterial hypertension PH: Pulmonary hypertension pCO 2 : Partial pressure of carbon dioxide PCWP: Pulmonary capillary wedge pressure pO 2 : Partial pressure of oxygen PVR: Pulmonary vascular resistance RA area: Right atrial area RAP: Right atrial pressure RHC: Right heart catheterization RVSP: Right ventricular systolic pressure PHLCG: Pulmonary Langerhans cell granulomatosis sec: Second SO 2 : Oxygen saturation 6-MWD: Six-minute walking distance TAPSE: Tricuspid plane systolic excursion TLC: Total lung capacity TLCO-VA: Transfer factor carbon monoxide per alveolar volume VE/VCO 2 : VE/VCO 2 slope W: Watt WHO: World Health Organization WHO-FC: World Health Organization functional class % pred: % predicted.