A 58-year-old woman visited her primary physician with a chief complaint of exertional dyspnea that began 2 months before hospitalization. Chest radiography showed a reticulated pattern in both lower lung fields and bilateral hilar lymphadenopathy. The patient was referred to our hospital and admitted for further evaluation.
She was a current smoker with 60-pack-year smoking history. The findings on admission were as follows: New York Heart Association (NYHA) Class III, body temperature, 36C; blood pressure, 118/72 mmHg; pulse rate, 78/min; respiratory rate, 28/min; and SpO2, 88% (room air).
The laboratory tests on admission (Table 1) showed mild elevations in the patient's lactate dehydrogenase (LDH), surfactant protein-D (SP-D), carcinoembryonic antigen (CEA), and rheumatoid factor (RF) levels. The patient was negative for all connective tissue disease (CTD) markers. An arterial blood gas analysis showed hypoxemia and respiratory alkalemia. Pulmonary function tests showed a mild restrictive disorder (vital capacity, 76.9%), whereas the diffusing capacity of the lung for carbon monoxide (DLCO), as determined by the steady state method, was reduced to 33.5% of the predicted value. An electrocardiogram showed peaked p waves in leads II, aVF, and V1. Echocardiography showed that the left ventricular systolic function was maintained, while the right ventricular systolic pressure (RVSP) and tricuspid regurgitation pressure gradient (TRPG) were mildly elevated at 52.0 mmHg, 42.0 mmHg, respectively and the right ventricle was enlarged. We did not perform a 6-minute walk test. Chest radiography on admission (Fig. 1) showed a reticular pattern in both lower lung fields, bilateral hilar adenopathy, and right atrial enlargement. Chest computed tomography (CT) on admission (Fig. 2) showed bilateral hilar and mediastinal lymphadenopathy, ground glass opacities with lobular septal thickening, predominantly in both lower lung fields, and pulmonary artery enlargement.
Bronchoscopy was performed on hospital Day 5. TBLB of the right lower, middle, and upper lobes was performed. The histopathology was nonspecific, showing only alveolar septal fibrosis and small round cell infiltration, leading to a pathological diagnosis of chronic interstitial pneumonitis. The TBLB findings were again reviewed after the diagnosis was made. Although alveolar septal fibrosis and the fibrous obliteration of the small veins and venules were present (Fig. 3), these changes were slight and could not lead to the correct diagnosis. A thoracoscopic lung biopsy was contraindicated because of the high risk of morbidity and mortality. She was discharged from hospital on Day 17 with home oxygen therapy (1.5 L/min at rest and 3 L/min during exertion) to maintain SpO2 level of >90%. We continued the prescription of furosemide (20 mg/day) and enalapril (2.5 mg/day), which had been prescribed by her primary care doctor before admission.
However, the patient's symptoms did not improve. At approximately 6 months after her discharge from hospital, her dyspnea worsened due to a cold and she revisited our hospital. Since her SpO2 was 80-85% with 2 L/min of oxygen by cannula, the patient was readmitted to our hospital.
Laboratory tests showed an elevated LDH level, severe hypoxemia and the deterioration of her respiratory alkalemia (Table 2). An electrocardiogram showed peaked p waves in leads II, aVF, and V1, a deep S wave in lead I, and a negative T wave in lead III, all of which were consistent with right heart overload. Echocardiography showed a decreased left ventricular systolic function with an ejection fraction (EF) of 50%. Her RVSP and TRPG values were further elevated to 72.0 mmHg and 60.0 mmHg, respectively, and right ventricular enlargement and ventricular septal flattening were observed. In addition to a reticular pattern in both lower lung fields and bilateral hilar lymphadenopathy, chest radiography also showed right atrial enlargement and a right pleural effusion (Fig. 4). Chest CT revealed an increase in bilateral hilar and mediastinal lymphadenopathy, a small amount of right pleural effusion, a severely enlarged pulmonary artery, increased pulmonary vascular markings, and a reticular granular pattern, predominantly in the lower lung fields (Fig. 5). We could not perform pulmonary function tests or a 6-minute walk test.
Based on the marked hypoxemia, the imaging findings of a reticular pattern with lobular septal thickening, and the TBLB findings during her previous hospitalization, an acute exacerbation of interstitial pneumonitis was initially considered. Steroid pulse therapy (methylprednisolone [1 g for 3 days]) was started on admission. Her SpO2 was maintained at about 95% with an oxygen cannula (2 L/min), and there was a slight temporary improvement in her exertional dyspnea. However, on hospital Day 14, the patient's dyspnea and oxygenation worsened, and 12 L/min of 50% oxygen by venturi mask was required to achieve an SpO2 of 95%. Thus, a second course of steroid pulse therapy was administered. In addition, her brain natriuretic peptide (BNP) was elevated to 827 pg/mL, pleural effusion developed, and echocardiography showed an increase in TRPG to 62.1 mmHg (Fig. 6a). Diuretics were added to treat the patient's worsening right heart failure.
Her respiratory status improved with an SpO2 level of >=90% on 6 L/min of oxygen by cannula. However, the patient developed severe lower leg edema, and echocardiography on hospital Day 42 showed a further increase in TRPG to 72.9 mmHg (Fig. 6b). For the PH with right heart failure, beraprost sodium (120 mug/day) was started on hospital Day 43. On hospital Day 48, however, her respiratory status worsened again and required 8 L/min of oxygen by reservoir mask. Chest radiography showed an increased reticular pattern in both lungs, again suggesting an acute exacerbation of interstitial pneumonitis. A third course of steroid pulse therapy was given, and then prednisolone (30 mg) was initiated as an after-treatment. Nevertheless, the respiratory insufficiency progressed, and the patient died suddenly on hospital Day 59 (Diagram: Fig. 7).
Consent was obtained from the patient's family for an autopsy. The left lung weighed 485 g, and the right lung weighed 445 g. A histopathological examination showed hyaline fibrosis of the alveolar septa and fibrous obliteration and concentric intimal thickening of the venules (Fig. 8a and b). Heath-Edwards grade II medial hypertrophy of the pulmonary artery was present, but plexiform lesions were not observed (Fig. 8c). There were also dilated, multi-layered capillaries, hemorrhages in the alveolar spaces and alveolar septum, and areas of hemosiderosis (Fig. 8d). The mediastinal lymph nodes were enlarged to 40 mm x 35 mm x 15 mm, with enlarged lymph sinuses and histiocytic hemophagocytosis (Fig. 8e). A diagnosis of PVOD was made based on the clinical course and autopsy findings. We concluded that her cause of death was respiratory failure by progressive right heart failure.
a: Chest CT on initial admission (lung fields). Ground glass opacities with lobular septal thickening were predominant in both lower lobes.