J. M. Kay

Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry.

Qualitative and quantitative studies were performed on pulmonary blood vessels in lung tissue obtained by biopsy, pneumonectomy, or autopsy from 58 patients in the Registry of Primary Pulmonary Hypertension sponsored by the Heart, Lung, and Blood Institute of the National Institutes of Health. In 49 patients (84%), the hypertensive vascular disease involved predominantly or exclusively muscular pulmonary arteries and arterioles. In each of these 49 patients, pulmonary artery medial hypertrophy was observed, and in 48 patients, it was also associated with intimal or luminal lesions. On the basis of the predominant histopathologic features, 25 of the 48 patients were classified as having pulmonary arteriopathy with plexiform lesions characterized by a combination of concentric laminar intimal fibrosis, eccentric intimal fibrosis, and plexiform lesions; in nine of these 25, recanalized thrombi were also present. Pulmonary arteriopathy with thrombotic lesions, defined by the presence of both eccentric intimal fibrosis and recanalized thrombi but without plexiform lesions, was observed in 19 patients. Intimal fibrosis, either concentric or eccentric, without plexiform or thrombotic lesions was found in four patients. Among the remaining nine patients in the Registry, pulmonary veno-occlusive disease was present in seven and chronic pulmonary venous hypertension in one. Pulmonary blood vessels were microscopically normal in a lung biopsy specimen from another patient. In general, patients with plexiform lesions and those with veno-occlusive disease had a much poorer prognosis than patients with thrombotic lesions. The present study shows the existence of several distinct histopathologic patterns of pulmonary vascular disease in individuals with primary pulmonary hypertension diagnosed by standardized clinical and laboratory criteria.

Aminorex and the pulmonary circulation

Aminorex (2-amino-5-phenyl-2-oxazoline) is an appetite-suppressing drug which was available in Switzerland from November 1965 to October 1968. In 1967 a sudden 20-fold increase in the incidence of primary pulmonary hypertension was observed in a Swiss medical clinic. It was noticed that a considerable number of these patients had taken aminorex to reduce weight. A similar increase in the incidence of primary pulmonary hypertension was encountered in other clinics in Switzerland, and also in Austria and Germany, where aminorex was available. An increased incidence of the disease has not been reported in countries where this drug was not available. A decline in the incidence of primary pulmonary hypertension has occurred in Switzerland since the withdrawal of aminorex. We have administered a high oral dose of aminorex to rats for up to 43 weeks and to dogs for 20 weeks. A detailed quantitative pathological examination of the heart and pulmonary vasculature in these animals has failed to reveal any evidence of hypertensive pulmonary vascular disease. Although there is statistical evidence linking aminorex with pulmonary hypertension, there is no proof that aminorex causes hypertensive pulmonary vascular disease in man. It is nevertheless important to enquire into the diet and history of drug ingestion in any patient with unexplained pulmonary hypertension.

A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease

BACKGROUND Lung biopsies are frequently needed to diagnose diffuse interstitial lung diseases. A prospective randomized, controlled trial comparing limited thoracotomy (open lung biopsy) and thoracoscopy for lung biopsy was done. METHODS Ambulatory patients with a clinical diagnosis of diffuse interstitial lung disease were randomized to thoracoscopy or limited thoracotomy. Data on postoperative pain, narcotic requirements, operating room time, adequacy of biopsy, duration of chest tube drainage, length of hospital stay, spirometry, and complications were collected. RESULTS A total of 42 randomized patients underwent lung biopsy (thoracoscopy 20, thoracotomy 22). The two study groups were comparable with respect to age, gender, corticosteroid use, and preoperative spirometry. Visual analog scale pain scores were nearly identical in the two groups (p = 0.397). Total morphine dose was 50.8 +/- 27.3 mg in the thoracoscopy group and 52.5 +/- 25.6 mg in the thoracotomy group (p = 0.86). Spirometry (FEV1) values in the two groups were not significantly different on postoperative days 1, 2, 14, and 28 (p = 0.665). Duration of operation was similar in both groups (thoracoscopy 40 +/- 30 minutes, thoracotomy 37 +/- 15 minutes; p = 0.67). The thoracoscopy and thoracotomy groups had equivalent duration of chest tube drainage (thoracoscopy 38 +/- 28 hours, thoracotomy 31 +/- 26 hours; p = 0.47) and length of hospital stay (thoracoscopy 77 +/- 82 hours, thoracotomy 69 +/- 55 hours; p = 0.72). Definitive pathologic diagnoses were made in all patients. CONCLUSIONS There is no clinical or statistical difference in outcomes for thoracoscopic and thoracotomy approaches. Both thoracoscopy and thoracotomy are acceptable procedures for diagnostic lung biopsy in diffuse interstitial lung disease.

Electron microscopy of Crotalaria pulmonary hypertension

The lungs of 11 rats fed on Crotalaria spectabilis seeds for periods ranging from 12 to 61 days were examined by both light and electron microscopy. The findings were compared with those obtained from nine control rats given a normal diet. Eight of the 11 test rats showed morphological evidence of pulmonary arterial hypertension in the form of right ventricular hypertrophy; the exceptions were rats killed after receiving the Crotalaria diet for 12, 22, and 29 days respectively. On light microscopy, all the test rats showed exudative lesions in the lungs consisting of eosinophilic alveolar coagulum, intra-alveolar haemorrhage, interstitial fibrosis, and a proliferation of mast cells. Enlarged and proliferated cells were seen to line the alveolar walls or lie free within the alveolar spaces. Electron microscopy showed these cells to be enlarged granular pneumocytes containing enlarged, electron-dense, lamellar secretory inclusions. Scanty macrophages were also seen in the alveolar spaces, in which excessive numbers of myelin figures and lattices were seen: these structures resembled phospholipid membranes and were probably related to pulmonary surfactant. We think that proliferation of granular pneumocytes is a non-specific reaction of the alveolar walls to injury. The alveolar-capillary wall showed interstitial oedema with the formation of intraluminal endothelial vesicles, probably representing the early ultrastructural phase of pulmonary oedema, and more likely to be an effect of the pulmonary hypertension than its cause.

Fulvine and the pulmonary circulation

The pyrrolizidine alkaloid, fulvine, is now accepted as a major cause of veno-occlusive disease of the liver in the West Indies, where it is ingested as a decoction of the plant Crotalaria fulva in bush tea. Fulvine is similar in chemical structure to monocrotaline, which is known to cause pulmonary hypertension in rats. Thirty young female rats were given a single dose of fulvine either by intraperitoneal injection (50 mg/kg body weight) or by stomach tube (80 mg/kg body weight). Eleven of these rats died of acute haemorrhagic centrilobular necrosis of the liver, and two of pneumonia, within 23 days of receiving fulvine. These 13 showed no evidence of hypertensive pulmonary vascular disease. The remaining 17 rats (which survived from 24 to 37 days) developed hypertensive pulmonary vascular disease with right ventricular hypertrophy together with medial thickening of the pulmonary trunk and muscular pulmonary arteries. The pulmonary arterioles showed hypertensive changes and some contained thrombi. In four animals an acute necrotizing arteritis also occurred. We have shown that fulvine resembles monocrotaline in its ability to produce pulmonary hypertension in rats. We suggest that, in any patient presenting with unexplained pulmonary hypertension, a careful enquiry should be made to elicit the possibility of recent ingestion of drugs or plant extracts that may have caused a rise in the pulmonary arterial pressure.

Pulmonary Vasculopathy in Idiopathic Spontaneous Pneumothorax in Young Subjects

BACKGROUND We have encountered instances where young subjects with idiopathic spontaneous pneumothorax have been needlessly referred for investigation of pulmonary hypertension because surgical pathologists have misinterpreted the significance of medial hypertrophy and intimal fibrosis of muscular pulmonary arteries in lung resection specimens. METHODS We reviewed 20 cases of idiopathic spontaneous pneumothorax and determined the prevalence and severity of medial and intimal lesions in the pulmonary arteries and pulmonary veins. We correlated the vascular changes with inflammation and fibrosis in the lung. RESULTS Pulmonary artery medial hypertrophy was seen in 15% of cases, pulmonary artery intimal fibrosis in 90% of cases, and pulmonary vein intimal fibrosis in 80% of cases. In 95% of cases, the lung showed some fibrosis and chronic inflammation. There was a significant positive correlation between pulmonary artery medial thickness and lung fibrosis and inflammation scores. CONCLUSIONS Pulmonary artery medial hypertrophy and intimal fibrosis of pulmonary arteries and pulmonary veins are commonly seen in resected lung tissue from patients with idiopathic spontaneous pneumothorax. The vascular lesions are probably secondary to chronic inflammation and fibrosis in the adjacent lung. They are not clinically significant and do not represent hypertensive pulmonary vascular disease.