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Division of Pulmonary and Critical Care Medicine, Providence VA Medical Center, Providence, RIDivision of Pulmonary, Critical Care and Sleep Medicine, Alpert Medical School of Brown University, Providence, RI
A 64-year-old man with a past medical history of alcoholic cirrhosis with resultant hepatorenal syndrome requiring kidney and liver transplantation 10 years previously sought treatment at the ED with progressive lower-extremity edema and dyspnea. After noting worsening shortness of breath and cough as an outpatient, he had been referred to a pulmonary clinic and was undergoing a workup for interstitial lung disease (ILD). He had been started on prednisone 40 mg/d after a lung biopsy 4 months before admission. He was also receiving chronic immunosuppression with tacrolimus and mycophenolate mofetil. He had noted worsening of edema since starting prednisone.
He had an additional past medical history of coronary artery disease requiring coronary artery bypass grafting 8 years earlier, carotid stenosis, hypertension, and hyperlipidemia. He was last seen 1 year earlier in the cardiology department with no reported evidence of pulmonary hypertension (pHTN) or heart failure at that time. He had a 20 pack-year smoking history and had quit 30 years earlier. He had no pets or animal exposures. He had worked as an electrician and noted significant asbestos exposure.
His physical examination findings were remarkable for a oxygen saturation reading of 90% on 21 pm nasal cannula oxygen, jugular venous distention, bilateral fine crackles, and severe lower extremity edema. No skin tightening, rash, joint swelling, or telangiectasias was evident. Pulmonary function tests performed as an outpatient showed symmetrically reduced FEV1 and FVC with no bronchodilator response, with an FVC of 67% predicted, TLC of 70%, and Dlco of 46%. A serologic workup for ILD had been performed as an outpatient: anti-nuclear antibody, anti-cyclic citrullinated peptide, anti-ribonucleoprotein, anti-topoisomerase 1 (SCL70), anti-Smith, anti-Jo, anti-nuclear cytoplasmic antibodies screen, proteinase-3 antibody, and myeloperoxidase all showed negative results. His current laboratory studies were notable for a brain natriuretic peptide of 3039 pg/mL with normal liver and kidney function and albumin levels.
On hospital admission, an ECG showed sinus tachycardia, with a rate of 100 beats/min, and evidence of right ventricular (RV) hypertrophy. Echocardiography showed a small left ventricular cavity with flattened septum, a severely dilated RV with severely reduced function, and an estimated RV systolic pressure of > 60 mm Hg (vs 40-50 mm Hg on echocardiography 8 months earlier). A right heart catheterization was performed on 4 L/min supplemental oxygen and confirmed severe precapillary pHTN with right atrial mean pressure of 12 mm Hg, right ventricular pressure of 95 mm Hg/18 mm Hg, pulmonary arterial pressure of 93 mm Hg/39 mm Hg with a mean of 58 mm Hg, pulmonary artery wedge pressure of 12 mm Hg, cardiac output of 3.4 L/min via thermodilution, and pulmonary vascular resistance of 13.5 Wood units.
Chest radiography demonstrated prominent interstitial markings. A CT scan of the chest demonstrated subpleural reticulation, traction bronchiectasis, ground-glass opacities sparing the bases, and small ascites in the upper abdomen (Fig 1). Neither the chest radiograph nor the CT scan showed evidence of asbestos-related pleural disease. A V̇/Q̇ single-photon emission CT scan study for pulmonary embolism showed heterogeneous perfusion with no segmental or subsegmental defects; the pulmonary artery was noted to be enlarged (diameter, 40 mm). Lower extremity ultrasound studies showed negative results for deep venous thrombosis. An abdominal ultrasound showed normal blood flow and echotexture in the transplanted liver.
Because of extensive adhesions, only one biopsy sample (3.7 × 2.0 × 1.2 cm) was retrieved from the right upper-to-middle lobe (Fig 2A-C). On histologic analysis, the tissue demonstrated an overall preserved lung architecture, with no evidence of honeycombing. Mild to moderate interstitial thickening by a fibroinflammatory process with relatively prominent chronic inflammatory infiltration and occasional lymphoid aggregates was present, supportive of a cellular and fibrotic nonspecific interstitial pneumonia (NSIP) pattern (Fig 2A). Foci of organizing pneumonia were noted (Fig 2B). Also evidence was present of medial and intimal hypertrophy in the pulmonary arterial and arteriolar branches (Fig 2C) and of a moderate amount of alveolar hemosiderin-laden macrophages. No pulmonary vein remodeling was noted.
While hospitalized, the patient diuresed a total of 21 L and was started on oral sildenafil and IV epoprostenol (titrated to tolerance). Additional serologic studies were ordered.
What additional serologic studies should be ordered?
What is the diagnosis?
Diagnosis: Antisynthetase syndrome complicated by severe pulmonary arterial hypertension (PAH) and right heart failure. An extended myositis autoantibody panel showed positive results for PL-7 antibody, providing a diagnosis of antisynthetase syndrome 1 year after the initial symptom of a dry cough
The patient’s clinical presentation on hospitalization was consistent with right heart failure or cor pulmonale. The patient showed dyspnea, lower extremity edema, and elevated jugular venous pulse. Brain natriuretic peptide was severely elevated and electrocardiography and echocardiography suggested severe pHTN with decompensation in RV function. Although pHTN associated with lung disease usually manifests as mild to moderate pHTN, the combination of ILD and severe pHTN has been noted in patients with antisynthetase syndrome.
The incidence of pHTN in antisynthetase syndrome has not been established clearly. In one retrospective study, it was noted that 23% of patients with antisynthetase syndrome showed echocardiographic findings suggestive of pHTN, and of those, only half underwent right heart catheterization. This yielded a 7.9% prevalence of pHTN in patients with antisynthetase syndrome.
The present patient showed no overt manifestations of an inflammatory myopathy, making the potential diagnosis obscure. We speculate that the immunotherapy may have modulated his clinical presentation.
Antisynthetase syndrome should be considered in patients with ILD, with or without pHTN, because this is the most common presentation. ILD is reported in 80% to 90% of patients with antisynthetase syndrome. It has been suggested that myositis autoantibodies should be tested routinely in all patients with ILD.
The patient’s posttransplant state is notable; neither antisynthetase syndrome nor severe PAH are typical in this population. Although reports of onset or recurrence of porto-pHTN after liver transplantation exist, this patient had no prior history of porto-pHTN on liver ultrasound, and liver function tests showed normal results.
After discussion with the patient’s transplant team, the dose of mycophenolate mofetil was increased to provide more robust immunosuppression. Tacrolimus, prednisone, and trimethoprim-sulfamethoxazole were continued. He declined consideration of lung transplantation and continued combination therapy for PAH with improvement in estimated RV systolic pressure to 30 to 40 mm Hg, a decrease in RV dilation, and some improvement in RV dysfunction on follow-up echocardiography. At 7 months since hospital discharge, a 1-L decrease in FVC on pulmonary function tests without functional decline was observed. On 2 to 4 L/min supplemental oxygen at rest and 6 to 8 L/min on exertion, he is able to perform all instrumental activities of daily living independently.
High-resolution CT imaging is used to characterize the pattern and distribution of ILD in antisynthetase syndrome. Ground-glass opacities and reticulation are the most common findings, followed by traction bronchiectasis.
Findings on high-resolution CT imaging may vary. Common patterns include (1) diffuse patchy ground-glass opacification and peripheral reticulation with a lower lobe and subpleural predominance suggesting NSIP, (2) honeycombing and subpleural reticulation without ground-glass opacification suggesting usual interstitial pneumonia, (3) dense consolidation consistent with pneumonia or organizing pneumonia (OP), and (4) combined NSIP plus OP pattern.
This patient’s chest CT scan showed subpleural reticular opacities, scattered ground-glass or mosaic attenuation, traction bronchiectasis, and absence of honeycombing, more consistent with an underlying NSIP pattern. The enlarged pulmonary artery and possible mosaicism suggested pHTN.
Antisynthetase syndrome is a heterogeneous connective tissue disease characterized by the association of an ILD, inflammatory myositis with the presence of anti-aminoacyl-tRNA-synthetase antibodies, or both.
Anti-histidyl(J01)-tRNA-synthetase antibodies are the most common (20%). The other antibody specificities, including anti-alanyl (PL-12), anti-threonyl (PL-7), anti-isoleucyl (OJ), and anti-glycyl (EJ)-tRNA-synthetase antibodies, are found less commonly (each < 5%). The present patient showed an anti-PL-7 antibody despite taking multiple immunosuppressants when tested.
NSIP and OP are the most frequently reported lung histologic pattern in ILD associated with antisynthetase syndrome.
However, in a pathologic analysis of a series of patients with ILD and anti-PL-7 antibodies, usual interstitial pneumonia was present in four of eight patients, with OP seen in two of eight patients, lymphocytic interstitial pneumonia or diffuse lymphoid hyperplasia in one of eight patients, and NSIP in one of eight patients.
The current patient’s biopsy results showed mixed cellular and fibrotic NSIP with isolated foci of OP, consistent with the chest CT scan findings of reticulation and ground-glass opacities with an absence of dense consolidation or honeycombing. This patient’s biopsy results also showed pulmonary arteriolar remodeling consistent with the subsequent diagnosis of PAH. Pulmonary venoocclusive disease has been described in the setting of antisynthetase syndrome, but was not present in this patient.
The convergence of ILD and severe precapillary pHTN may be seen in antisynthetase syndrome. Lung imaging in antisynthetase syndrome ILD can show nonspecific ground-glass infiltrates, consolidation, and subpleural reticulation; evidence of pHTN on imaging or echocardiography merits further evaluation. Testing for anti-aminoacyl-tRNA synthetase antibodies should be considered in patients with ILD of unclear origin, especially when significant pHTN also is suspected or present.