A 58-year-old woman presented to the Coburg Clinic in February 2013 with dyspnea, loss of energy, slight edema of the lower extremities, and a 4 kg weight loss in the 4 weeks before presentation. A 3/6 systolic murmur with a left apical maximum point was noted on physical examination. Except for an appendectomy more than 30 years earlier, the patient had never been hospitalized or on any medication. She had never smoked. Family history was unremarkable, except for a sister who had experienced uncomplicated tuberculosis. She had worked as a seamstress until giving birth to a healthy daughter in 1973. From 1976 to 1980 and then again from 1985 to1997 she reported having worked in the ceramics industry, but her job was not associated with significant exposure to ceramic dust. During that time, living in the former German Democratic Republic, she had had annual chest X-rays without any abnormalities. During a second examination, she reported having felt dyspnea on exercise since 2003, but did not complain of loss of energy, and had been able to perform regular work. The electrocardiogram performed on admission showed sinus tachycardia at a rate of 109 beats per minute, incomplete right bundle branch block, and preterminal inverted T-waves in II, III, aVF, and V1-V6.
Body plethysmography showed slight restriction with forced expiratory volume in one second being 68% predicted, inspiratory vital capacity 70% predicted, and a Tiffeneau index of 101%. Her diffusion capacity was reduced at 60%. Her respiratory insufficiency was managed with oxygen substitution therapy (pO2 60 mmHg and pCO2 33 mmHg under oxygen 3 L per minute).
An initial transthoracic echocardiogram on February 1, 2013 demonstrated dilatation of the right ventricle to 38 mm and dilatation of the left atrium to 43 mm. Sclerosis of the aortic valve, minimal aortic insufficiency, first-degree mitral insufficiency, obvious tricuspid valve insufficiency with a diastolic gradient of 67 mmHg, and diastolic dysfunction of the left ventricle with a slightly pathological E/A ratio could also be visualized. Left ventricular ejection fraction was normal at 65%.
The woman presented for the first time to the pulmonary consultant late on a Friday afternoon with dyspnea and spontaneous oxygen saturation of 83% on the bronchoscopy table (pO2 38 mmHg, pCO2 31 mmHg). She complained of rapid deterioration in the previous 2 days in comparison with her status on admission. Her weight was 58 kg, but she complained a 19 kg weight loss in the previous 2 months. Her height was 158 cm (body mass index 23.1 kg/m2). At that time, only a standard chest X-ray taken on admission was available, and showed a prominent bihilar region with a suspicious mass in the left apex of the lung (Figure 1). Standard serum analysis showed slightly elevated lactate dehydrogenase and uric acid levels, with a mild anemia. On fluoroscopy, the right hilum appeared to be enlarged compared with the X-ray taken on admission. No result suspicious for a central tumor or other infiltrative disease was seen on bronchoscopy. Endobronchial ultrasound revealed enlarged pulmonary arteries containing multiple thrombi, a few enlarged lymph nodes, and abnormal mediastinal tissue anatomy suspicious for mediastinal infiltration of a malignant process. We did not perform transbronchial needle aspiration before the weekend due to her dyspnea. She was put on low-dose low molecular weight heparin. The decision was taken to start her on radiotherapy over the weekend due to the suspicion of rapid progression of small cell lung cancer or lymphoma in the mediastinum. Computed tomography planning was done in the radiotherapy department on the following day and she received radiation with 4 Gy to the mediastinum including both hila over the weekend (2 Gy per day).
After the weekend, we observed a mediastinal mass, abnormally enlarged central pulmonary arteries with tortuous peripheral branches, and a consolidation in the left upper lobe on the patient's computed tomography scan (Figures 2 and 3). At that point we stopped radiation therapy because it was clear that we were not dealing with a typical case of suspected small cell lung cancer or lymphoma. Repeat bronchoscopy and endobronchial ultrasound demonstrated partial compression of the central vessels by a mass located in the left mediastinum, and partial infiltration of the walls by this mass was suspected. Given that the lymph nodes in position 10 R (right) and 7 had a diameter of 15-20 mm, we took several biopsies from these sites in addition to biopsies of the mediastinal mass. Histologically, there was no suggestion of malignancy, but a strong suspicion for fibrosis was raised on evaluation of the magnetic resonance imaging (MRI) scans (Figure 4) but could not be proven.
Two weeks later, an endoesophageal ultrasound was performed with a thicker needle in lymph node position 7. Again there was only a hint of fibrosis. A transthoracic lung puncture of the mass in the left upper lobe revealed thickened pulmonary arterial walls, activated pneumocytes, and fibrosis (Figures 5-7). Several endoscopic ultrasound consultants and endobronchial ultrasound examinations reported massive "smoke" (indicating prethrombotic formations) in the central pulmonary arterial vessels. Tuberculosis was ruled out by a negative interferon gamma release assay, several negative bronchial specimens examined by microscopy, polymerase chain reaction, and cultures for tuberculosis collected by bronchoscopy. Nontuberculous mycobacteria was ruled out by negative polymerase chain reaction, microscopy, and culture results, as was sarcoidosis, given the patient's normal serum soluble interleukin-2 receptor and angiotensin-converting enzyme levels. We could not find any histological suggestion of histoplasmosis, but this diagnosis was not ruled out by serum analysis as the patient appeared to be immunocompetent with normal immunoelectrophoresis and a negative human immunodeficiency virus test result.
Cardiac MRI showed reduced right ventricular function, dilatation of the right ventricle and a hypertrophic wall, a flattened septum with paradoxical movement (Figure 4), and dilated pulmonary artery trunks. There was no suggestion of intravascular thrombus on pulmonary angiography during cardiac MRI. A sudden change in diameter of the pulmonary arteries could be seen in the peripheral regions. Small tortuous peripheral pulmonary arteries were seen on cardiac MRI and computed tomography (Figure 3). The aforementioned abnormal mediastinal mass and left upper lobe mass were also observed.
Lung embolism was excluded using ventilation and perfusion scintigraphy. Combined ventilation and perfusion defects in the left upper and middle lobes were associated with the mediastinal mass.
Precapillary PAH with a PAR of 1,360 dyn   s   cm-5 and completely normal wedge pressure was seen on right heart Swan-Ganz catheterization, coronary angiography, and dextrography (Figure 8). There were no definite criteria for reactive PAH on inhalation of iloprost. The right ventricle was hypokinetic especially in its anterior portion (Figure 8C and D) with an enlarged wall which, on echocardiography, was 8 mm thick (ie, thickness of right ventricular anterior wall in end diastole). The median right atrial pressure was 8 mmHg and borderline for right heart decompensation. The pulmonary arteries were shown to be dilated on angiography, but there was no indication of peripheral obstruction or chronic thromboembolic pulmonary hypertension. The left marginal artery and diagonal branch showed an angiographic stenosis of 70% (Figure 8A and B), and left ventricular ejection fraction was 70%. There was endothelial dysfunction with low flow phenomenon in different coronary arteries, besides the partly abnormal coronary anatomy with dilated cardiomyopathy (Figure 8A and B). There was no suggestion of vasculitis, coagulopathy, a thyroid or hepatic disorder, or collagenosis on serum analysis. No other predominant cardiopulmonary disease directly involved in the initially highly elevated PAH hemodynamics was found after working through the algorithm for PAH recommended by the European Society of Cardiology.
A dobutamine MRI stress test was performed a week later without any suspicion for ischemia, so stenting of the abovementioned stenosis observed on angiography was not performed. Because thrombus was expected in the pulmonary arterial walls, transesophageal echocardiography was performed and supported the presumption of thrombus in the pulmonary arterial walls, including prethrombotic "smoke" in the central vessels. No shunt was observed. Phenprocoumon was started as oral anticoagulation therapy. Thoracic surgeons at the nearby Kutzenberg Hospital refused to do mediastinoscopy because of the diagnosis of PAH.
Positron emission tomography at the University of Erlangen showed no suspicion of tumor or lymphoma in the mediastinum or elsewhere, and mediastinal fibrosis was again diagnosed. Lymphoma was ruled out in an oncologic ambulatory setting via peripheral lymph node biopsies from the groin, serum electrophoresis, urinalysis, and bone marrow puncture. Serum beta2-microglobulin was negative.
At the end of April, the patient was presented for the first time at the National Pulmonary Hypertension Center of Excellence in Bad Nauheim/Giessen and a second time in May 2013 (Figure 9) with a differential diagnosis of idiopathic PAH. This was done because the referring cardiopulmonary consultant at Coburg Clinic, who is also an expert in the treatment of PAH and a member of the national guideline group, was surprised by this patient's abnormal anatomy and the massive extent of central smoke without any peripheral suggestion of embolism. Repeat pulmonary angiography showed no thrombus (Figure 9), and chronic thromboembolic pulmonary hypertension was excluded on ventilation/perfusion (V/Q) scintigraphy. Right heart catheterization revealed precapillary pulmonary hypertension with a PAR of 600 dyn   s   cm-5 and no reactive properties, which was quite striking given that our patient had not received any specific treatment in the preceding weeks. Cardiac MRI revealed the same pathologies in the pulmonary arterial walls as before, and functional and anatomic abnormalities of the right ventricle and mediastinal fibrosis were again reported. The diagnosis of idiopathic PAH was confirmed at several conferences with the team led by Ghofrani and Mayer (Professor Hossein A Ghofrani, Pulmonary Department, University Hospital Giessen, Giessen, Germany; and Professor Eckhard Mayer, Thoracic Surgery Department, Bad Nauheim, Germany). During discussion between the experts at both institutions, the question was raised as to whether a spontaneous dissection of the pulmonary arterial walls with secondary thrombus formation in the walls was possible, and a diagnosis of mediastinal fibrosis was accepted.
Four months after her first admission, the patient was electively rehospitalized to initiate specific treatment in June 2013. In view of her coronary artery disease without evidence of ischemia, the decision was made to start treatment with bosentan instead of sildenafil. On this admission, an echocardiogram showed no signs of pulmonary hypertension, and no enlargement of the right ventricle or paradoxical septal shift was detectable by an experienced examiner. The patient had not had any complaints for at least 2 months, and was started on bosentan without any problems.
The patient was evaluated 2 months later by Swan-Ganz catheterization of the right heart on full-dose bosentan 125 mg twice daily for 4 weeks. Again, precapillary pulmonary hypertension was reported and her PAR had dropped to 450 dyn   s   cm-5. Meanwhile, her spontaneous pO2 at rest had increased to 76 mmHg and her 6-minute walking distance was 360 m (Figure 10).
As a proof-of-concept of our hypotheses, we interrupted her full-dose bosentan therapy for 2 weeks and again obtained invasive hemodynamic measurements via Swan-Ganz catheterization of the right heart. The results seemed to be only slightly different and obvious precapillary pulmonary hypertension was again demonstrated but, interestingly, her PAR was 400 dyn   s   cm-5, and therefore not elevated compared with the last measurement taken when the patient was on bosentan 125 mg twice daily.
Seven and a half months after the initial diagnosis of idiopathic PAH with a PAR of 1,360 dyn   s   cm-5, we observed a reduction in PAR of at least two thirds without having established any specific treatment, except for low-dose radiation to the main stems of the pulmonary arteries (Figure 10).