Bridging knowledge gaps: A case report of pulmonary Veno-occlusive disease in systemic sclerosis

ABSTRACT

Pulmonary Veno-Occlusive Disease (PVOD) is a rare cause of pulmonary hypertension (PH) in patients with systemic sclerosis (SSc), posing significant diagnostic and therapeutic challenges. Here, we present a case of a patient with systemic sclerosis who presented with symptoms of progressive dyspnea for 1 year. Her chest radiogram was normal, and echocardiography was suggestive of severe PH. She was started on a combination of Ambrisentan and Tadalafil. However, she developed pulmonary edema after the initiation of pulmonary vasodilators. Diagnostic workup, including imaging studies, with clinical and radiological worsening with pulmonary vasodilators, confirmed PVOD in the setting of SSc. The patient gradually improved with diuretic therapy. This case emphasizes the importance of early clinical suspicion and multidisciplinary discussion in managing rare pulmonary complications associated with systemic sclerosis. Additionally, it highlights the urgent need for further research to delineate the underlying pathophysiological mechanisms and optimize therapeutic strategies for this challenging clinical entity.

INTRODUCTION

Pulmonary hypertension (PH) frequently complicates systemic sclerosis (SSc) and stands as a primary contributor to both morbidity and mortality in affected individuals.[1]

PH can be categorized into five distinct groups,[2] most of which have the potential to manifest in patients with SSc.[3,4] The development of PH in patients with SSc involves various mechanisms, highlighting the importance of comprehensive assessment because of its substantial impact on determining appropriate treatment strategies. Pulmonary Arterial Hypertension (PAH), classified as group 1, occurs in approximately 5–19% of cases of SSc, with an annual incidence of PAH development ranging from 0.7% to 1.5%.[5,6]

Pulmonary Veno-Occlusive Disease (PVOD) is a rare entity belonging to group 1 PAH, with an estimated prevalence of 0.1–0.2 cases per million people per year.[7] The clinical features of PVOD and PAH may be indistinguishable; however, patients with PVOD usually have a severe reduction of DLCO with severe hypoxemia and exertional desaturation.[7]

In this case, we present a case of SSc-associated PH who developed pulmonary edema after the initiation of pulmonary vasodilators. On subsequent evaluation, she was diagnosed with PVOD.

CASE PRESENTATION

A female in her early 60s with limited cutaneous systemic sclerosis of 2-year duration presented to the outpatient department with complaints of shortness of breath for 1 year, which progressed from Modified Medical Research Council (mMRC) Grade II to Grade III for the past month. She was a nonsmoker and did not give any history of other drug abuse. She did not have any history of respiratory or cardiac illness in the family. Her medical history was significant for hypothyroidism, controlled on levothyroxine. General examination showed presence of Raynaud’s phenomenon in both hands and skin induration on the face and distal to the wrist. Her vitals on the presentation were 128/72 mmHg blood pressure, 78 beats/min heart rate, 26 breaths/min respiratory rate, and 92% oxygen saturation on room air. Bilateral vesicular breath sounds were present on auscultation, with no adventitious breath sounds. Cardiac auscultation revealed splitting of the second heart sounds with loud P2 in the pulmonary area. Laboratory workup showed ANA positivity with - centromere pattern (titer of 1:320), ESR elevated with 67 mm/h CRP of: 22.79 mg/L. ENA profile revealed antibodies strongly positive for centromere protein B. NTproBNP was elevated at 2100 ng/L, thyroid profile with TSH, free T3, and free T4 was normal.

Her chest radiogram showed normal lung parenchyma. Spirometry showed normal vital capacity with severely reduced diffusion lung capacity for carbon monoxide (40%), raising high suspicion for PH. Her 6-min walk distance was 240 m. Transthoracic echocardiogram showed severe tricuspid regurgitation, right ventricular systolic pressure of 94 mmHg, tricuspid annular plane systolic excursion of 10 mm and preserved left ventricular ejection fraction (60%), with no diastolic dysfunction. As the patient denied consent, right heart catheterization was deferred. A clinical diagnosis of systemic sclerosis-associated PH was made, and the patient was started on combination pharmacotherapy with Ambrisentan 10 mg and Tadalafil 20 mg once daily.

She presented to the emergency department after 2 weeks with complaints of increased shortness of breath, which had progressed to grade IV mMRC, and bilateral lower limb swelling. Her room air oxygen saturation was 86%, with a respiratory rate of 30 breaths/min, and her other vitals were stable as before. The chest radiograph showed bilateral costophrenic angle blunting [Figure 1]. Computed tomography pulmonary angiogram (CTPA) showed multiple sub-centimetric to enlarged mediastinal lymph nodes in the upper paratracheal, prevascular station along with intralobular and interlobular septal thickening with associated ground glass opacity in bilateral lungs with no evidence of pulmonary thromboembolism [Figure 2]. As the patient developed new-onset pulmonary edema with pulmonary vasodilators, they were stopped, and she was started on a diuretic therapy. Based on the findings mentioned above, a clinical and radiological diagnosis of PVOD was made. The patient was advised for a lung transplant, but it was unamenable due to financial constraints. After a multidisciplinary discussion with cardiology, rheumatology, and pulmonary medicine team, she was restarted on Ambrisentan (10 mg OD) and Riociguat (0.5 mg TDS) with diuretics under close supervision. She had clinical improvement in her dyspnea, and room air SpO₂ improved from 86% to 90%. Subsequently, on four-week follow-up visit, the six-minute walk distance increased to 280 m. She remains stable, with symptomatic improvement during the follow-up.

Figure 1.

Chest radiogram showing bilateral lower zone haziness with costophrenic angle blunting

Figure 2.

(a) Contrast-Enhanced Chest Tomography chest axial section showing right lower paratracheal and prevascular lymph nodes. (b) Contrast-Enhanced Chest Tomography chest axial section showing bilateral pleural effusion with ground glass opacities and interlobular septal thickening

DISCUSSION

PVOD is a rare cause of PAH, presenting with shortness of breath, fatigue, and eventually symptoms of right heart failure. It is associated with exposure to chemotherapeutic agents, organic solvents, tobacco exposure, and with autoimmune conditions.[7] Kothari et al. reported the first case of PVOD from India in 1995 in a 7-year-old boy, where the diagnosis was made after an autopsy.[6]

Systemic sclerosis is one of the common conditions associated with PVOD. A few case reports worldwide have shown an association between PVOD and SSc.[8,9,10,11] However, to the best of our knowledge, this is the first case to be reported to have PVOD in conjunction with systemic sclerosis in India.

The approach for diagnosing patients with PVOD has undergone a significant transformation. While surgical lung biopsy was once commonly required for a definitive histopathologic diagnosis, most experts now advocate for a clinical and radiological diagnostic approach. This involves an integrated evaluation for PH, utilizing a comprehensive array of clinical, high-resolution computed tomography (HRCT) chest imaging, and physiological, and hemodynamic findings. As a result, surgical lung biopsy is often deemed unnecessary for establishing a diagnosis in many patients.[12,13,14]

Chest HRCT has become the principal imaging modality for supporting the noninvasive diagnosis of PVOD. The classical triad of mediastinal lymph node enlargement, smooth thickening of the interlobular septa, and ground glass opacities in the CT chest have been described in PVOD.[12] Montani et al.[15] demonstrated that 75% of patients with histologically proven PVOD had at least two of the above-mentioned HRCT findings.

Moriya et al.[16] studied the correlation between the chest CT signs for PVOD in patients with SSc and pulmonary hemodynamics. They found that thickened interlobular septal wall, mediastinal lymph node enlargement, and ground glass opacity were present in 62%, 21%, and 21% of patients, respectively. They also showed that the patients with two or three of the above-mentioned findings had higher mean pulmonary artery pressure and lower diffusing capacity for carbon monoxide/alveolar volume than those with no or one CT chest finding. Our patient had all three classical CT findings of PVOD and a high RVSP of 94 mmHg.

The prognosis of patients diagnosed with PVOD is poor, with a 1-year mortality rate of 72% and mean survival of 1–2 years.[8] Because of the paucity of reported cases, no randomized therapeutic trials have been conducted, leaving uncertainty about the efficacy of current treatments in improving outcomes. Apart from lung transplantation, which may offer some hope, the existing treatments have a limited impact on disease progression.[17]

PAH-specific therapy can be administered with close clinical monitoring, as all classes of PAH-specific therapy can induce pulmonary edema.[7,18] Some theories propose that pulmonary edema results from a relative vasodilation primarily affecting pre-capillary resistance vessels rather than post-capillary vessels. This dilation is thought to result in increased blood flow, consequently elevating trans-capillary hydrostatic pressure.[18] Daraban et al.[19] reported a worsening in functional capacity in a patient with systemic sclerosis with bosentan therapy, leading to the diagnosis of PVOD. Similarly, our patient developed pulmonary edema on the ambrisentan and tadalafil combination, which was resolved with diuretics. The patient was restarted cautiously on Ambrisentan and riociguat combination under close clinical supervision, which she tolerated.

In conclusion, PVOD remains a poorly understood clinical entity with a poor prognosis. There is frequent deterioration with the use of pulmonary vasodilators, necessitating their judicious use in patients with PH. Moving forward, it is imperative to undertake additional research efforts to finely delineate the risk factors associated with this condition while simultaneously refining therapeutic approaches to achieve optimal outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.