Chronic pleuritis leading to severe pulmonary restriction: a rare complication of Degos disease

Abstract

This case demonstrates chronic fibrosing pleuritis, as a rare pulmonary aetiology for mortality in patients with Degos disease or malignant atrophic papulosis (MAP). Knowledge of this unusual complication will help physicians identify this entity early and provide appropriate treatment.

Patients with MAP die from gastrointestinal and brain involvement within 2–3 years of diagnosis. This case is unique as the patient survived for 9 years and died secondary to respiratory failure, which had not been reported before. Our patient was a young man, diagnosed with MAP at the age of 17. His skin and gastrointestinal disease were controlled with eculizumab and parenteral treprostinil. The patient developed severe restrictive pulmonary disease, required ventilatory support, and died from respiratory failure. An autopsy revealed chronic fibrosis pleuritis. Longer surviving patients with MAP might suffer from significant respiratory disease. Pulmonary function test should be obtained to identify subclinical respiratory limitation.

Background

Degos disease, Köhlmeier-Degos disease or malignant atrophic papulosis (MAP), is a rare and fatal obliterative vasculopathy. Less than 200 cases have been reported in the literature.¹ A German physician, Köhlmeier, described the first case in 1941.² Degos et al presented the second case in 1942.³ MAP is a multifocal disease that commonly affects the integumentary, gastrointestinal tract and nervous system. The skin manifestation is characterised by the emergence of 0.5–1 cm papular lesions, with an atrophic and porcelain-white centre, which is pathognomonic of the disease. The depressed centre develops over time due to wedge-shaped infarction following thrombotic occlusion of the vessels at the dermal layer of the skin.⁴ A similar process in the gastrointestinal tract leads to recurrent bowel infarction and perforation, leading to peritonitis and sepsis. Meningitis, encephalitis, myelitis, thrombosis of cerebral vessels, and massive intracranial haemorrhage can indicate nervous system involvement.⁵ Complications of gastrointestinal and nervous system disease are responsible for patient demise in 50% of cases.¹ Cardiopulmonary and ocular involvement can also occur. Cases of pleural effusion have been reported but were rarely associated with substantial morbidity or mortality. In this paper, we report a case of MAP, where the patient died from respiratory failure due to restrictive lung disease. Although the ventilatory limitation was thought to be due to chest wall infarction, on autopsy, severe adhesion of the lung and pleura to the chest wall secondary to chronic fibrosing pleuritis was found to be the responsible. Awareness of rapidly evolving pleural fibrosis in MAP could have translated into a more aggressive search for a solution for this patient.

Case presentation

A 23-year-old man was evaluated in the office for worsening shortness of breath in July 2015. His history included Degos disease that was diagnosed clinically and supported histologically by skin biopsy in 2009. The disease course was complicated by intestinal perforation in December of 2009 requiring multiple laparotomies and prolonged hospitalisation. He was started on eculizumab. Initially, biweekly, that was later intensified to every week due to intermittent episodes of abdominal pain resulting in multiple ED visits. In late 2010, subcutaneous treprostinil therapy was initiated with an improvement of his abdominal pain and skin lesions. Eculizumab therapy was continued biweekly. Between 2010 and 2013, he underwent several thoracenteses for recurrent exudative left pleural effusion. He was completely independent and attending college. In October 2013, a left-sided indwelling pleural catheter (IPC) was placed. After successful auto-pleurodesis, the IPC that was removed in February 2014. In September 2014, the parenteral treprostinil was changed to oral treprostinil formulation. In January 2015, the patient developed new right-sided exudative pleural effusion requiring drainage. His other medical problems included atrial flutter and depression. His medications were aspirin, atenolol, propafenone, eculizumab and oral treprostinil. He denied any history of smoking or alcohol use. At the office, during the evaluation, his vital signs were a blood pressure of 130/65 mm Hg, a pulse of 84 beats/min, a temperature of 36.6°C, a respiratory rate of 22 breaths/min and oxygen saturation of 97% on room air. Physical examination showed healed skin lesions. Diminished breath sound was auscultated bilaterally. No abdominal pain or tenderness was noted.

Investigations

A chest X-ray (figure 1), thoracic CT (figure 2) and pulmonary function test (PFT) (figures 3 and 4) were obtained to evaluate the shortness of breath.

Figure 1.

Chest X-ray showing minimal right-sided pleural effusion, increased linear opacities in bilateral lower lung zone and thickening of the minor fissure.

Figure 2.

Coronal section of the thoracic CT demonstrating bibasilar interlobular and fissural thickening and small loculated pleural effusion.

Figure 3.

Spirometry (A) showing reduced forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁) with a preserved FEV₁/FVC ratio consistent with severe pulmonary restriction. The total lung capacity (TLC) is severely diminished. When compared with spirometry obtained 2 years prior (B), there has been a significant worsening of all parameters.

Figure 4.

Flow-volume loop showing a severe reduction of the inspiratory reserve volume (A) (IRV) when compared with previous flow-volume loop 2 years prior (B) characteristic of intra-pulmonary restriction. ERV, expiratory reserve volume.

PFT revealed severe restrictive physiology. The restriction was thought to have resulted from the chest wall infarction.

Differential diagnosis

The aetiology for the restrictive ventilatory defect can be divided into pulmonary and extra-pulmonary. Pulmonary causes include fibrosis, interstitial pulmonary oedema, airway occlusion, atelectasis, lung resection and thickened pleura. Obesity, pleural effusion, cardiomegaly, chest wall stiffness, kyphoscoliosis, neuromuscular weakness and diaphragmatic paralysis comprise the extra-pulmonary causes. The chest X-ray and CT scan helped in the exclusion of most of these diseases, including pulmonary fibrosis, large pleural effusion and diaphragmatic palsy. Areas of pleural thickening and small loculated effusions were noted; however, this can be seen following auto pleurodesis (from IPC use) and chronic exudative pleural effusion, especially after repeated thoracentesis. Since MAP is a vaso-obliterative disease, the restriction was presumed to be secondary to chest wall stiffness possibly due to chest wall infarction.

Treatment

The patient was managed conservatively for the restrictive lung disease. Subcutaneous treprostinil therapy was reinitiated.

Outcome and follow-up

Over the next 18 months, the shortness of breath progressed to conversational dyspnoea. In 2017, he was diagnosed with constrictive pericarditis after he experienced worsening lower extremity oedema and hepatomegaly. He underwent pericardiectomy in 2018 and required prolonged venoarterial extracorporeal membrane oxygenation support. He required hospitalisation for 5 months. Eventually, he was discharged home and was ventilator dependent with a tracheostomy. He was doing well but unfortunately in September 2018, suffered from a sudden onset of severe hypoxia and cardiorespiratory arrest. He was resuscitated after 10 min but had an anoxic brain injury. He was made comfortable at his parent’s request. An autopsy showed thickened pleura and severe adhesion of the lungs with the pleura and chest wall. The pleural microscopy was consistent with chronic pleuritis. No pleural effusion or pulmonary embolus was identified. There was no evidence of skeletal muscle infarction.

Discussion

We have presented a case of MAP with a significant ventilatory defect that resulted in the patient’s death. Pleural thickening and severe adhesion of the lungs and pleura to the chest wall were responsible for the restrictive physiology on PFT. The pleural changes were secondary to chronic pleuritis.

Even after seven decades, research has not completely elucidated the aetiology and pathogenesis of MAP. Several hypotheses have been proposed. Primary vasculitis or a thrombotic process have been suggested to cause MAP.^{1 6 7} Studies have shown heightened thrombogenicity and reduced fibrinolysis in patients with MAP.^{7 8} Endothelial dysfunction, either primary or secondary to an infectious aetiology, has also been considered.⁹ Although parvovirus B19 DNA has been identified in endothelial cells of patients with MAP, their role in pathogenesis is uncertain.¹⁰ No definitive proof exists that any single mechanism is causative, and it is more likely that multiple factors are responsible.¹ Activation of complement and deposition of membrane attack complex (MAC) (C5b-9) on endothelial cells resulting in cellular injury was recently identified in four patients and possibly represented a common late pathway for vascular damage.¹⁰ This discovery provided an important advancement in the understanding of MAP pathogenesis and an opportunity to effectively treat or at least slow the progression of the disease. Eculizumab, a monoclonal antibody that binds complement component five (C5), prevents the generation of MAC and has been shown to prevent thrombogenesis of the microcirculation and reversal of complement deposition.¹¹ In addition to causing thrombosis of capillaries and venules, MAP uniquely affects small and medium-sized arteries, a feature that distinguishes it from other catastrophic endotheliopathy syndromes, like purpura fulminans.¹⁰ It is important to emphasise that eculizumab does not prevent fibro-intimal hyperplasia and obliterative changes in the larger vessels as these changes are not complement-mediated.¹¹ Pathological lesions similar to MAP have also been observed in other autoimmune diseases.^{12 13}

MAP is a multisystem disease. The diagnosis is usually made from skin manifestations, and histopathological findings can be supportive. The presence of papular skin lesions with an atrophic porcelain-white centre and a violaceous telangiectatic peripheral rim is diagnostic (figure 5).¹ Internal organ involvement might occur concurrently or later. Limited infarction of the intestinal wall might result in micro or overt perforation and spillage of the intestinal content into the peritoneal cavity and peritonitis. Sepsis often ensues, and patients require multiple surgical interventions during their lifetime. Thrombosis of the cerebral vessels, intracranial haemorrhage, meningitis, encephalitis, and myelitis have been reported. Other, unusual presentations include eye symptoms and serositis.^{14 15} Serositis affecting pleural and pericardial membranes are underrecognised complications of MAP. Historically, patients with MAP have a 50% mortality within 2–3 years of diagnosis primarily from the brain and gastrointestinal disease.¹ Pulmonary involvement is of limited consequences. However, it is conceivable that chronic serositis and pleuro-pericardial disease occurs later in the natural evolution of the disease. Our patient died from respiratory failure due to the severe pulmonary restriction as a result of chronic pleuritis. To our knowledge, no such case has been previously reported.

Figure 5.

Typical lesions of Degos disease involving the skin and the intestine.

During life, the aetiology for the patient’s rapid decline in pulmonary function was unclear. His PFTs were consistent with severe restriction. In retrospect, this patient would have benefited significantly from early pleurectomy. The fibrosing pleuritis rendered him ventilator-dependent, and his death was a result of respiratory failure. Although pleuritis and pleural effusion are not uncommon in systemic inflammatory diseases, pleural fibrosis causing significant lung restriction is rare.^{16 17} One subtle clue that was possibly overlooked was the progressive reversal of the ratio between inspiratory reserve volume (IRV) and expiratory reserve volume (ERV) on the flow-volume loop (figure 4). In healthy individuals, with a normal PFT, the ratio of IRV to ERV is 2 to 1. In patients with restrictive lung disease, preservation of the normal ratio points towards an extra-pulmonary cause of restriction. Whereas a reduction or reversal of the ratio is indicative of pulmonary aetiology for restrictive physiology. A comparison of the two flow-volume loops (figure 4), 2 years apart, showed a significant reversal of the ratio in our patient.

The patient survived for 9 years since the diagnosis of MAP. His disease remained somewhat stable, and he did not suffer from any additional episode of bowel perforation since 2010 or showed evidence of worsening brain involvement. We believe that treatment with eculizumab and treprostinil conceivably controlled his disease better and even prolonged his life. It is possible that a significant lengthening of the survival period allowed for the identification of organ system failures that typically evolve slowly. Including our case, patients who suffered from a significant pleuro-pericardial disease, had a survival for at least 5 years following the diagnosis of MAP.^{15 18 19} There is no standardised treatment protocol for MAP. Treatment with antiplatelet, antithrombotic and anti-inflammatory agents have been tried with inconsistent success.¹ Eculizumab was effective in multiple reports, but the positive response was not universal.^{1 11 20} The potential role of treprostinil in the treatment of MAP was discovered incidentally. In a patient with pulmonary hypertension from systemic lupus erythematosus (SLE), who also had papular porcelain-white skin lesions, treatment of pulmonary hypertension with subcutaneous treprostinil resulted in the involution of the skin lesions.²¹ Our patient also demonstrated an improvement of his skin as well as the systemic disease following initiation of treprostinil. A few months before the onset of the respiratory difficulty, subcutaneous treprostinil was changed to the oral formulation. It is possible that the oral absorption of the prostacyclin analogue was not adequate and resulted in the rapid progression of the disease, causing pleural infarction, pleuritis and adhesion to the chest wall resulting in severe restrictive lung disease. However, efficacy of treprostinil can only be definitively proven by prospective studies.

This case sheds light on an unusual manifestation of MAP. Chronic fibrosing pleuritis causing respiratory failure and death has not been reported before. Due to the rarity of MAP and early fatality, the natural history in long-term survivors is not well known. With improved understanding of the pathophysiology and advent of new therapeutic avenues, the survival might improve soon posing new challenges in the management of these unfortunate individuals. We believe that knowledge of this rare complication might help in early identification and appropriate treatment, resulting in better outcome and prolongation of life.

Learning points.

• Chronic serositis can cause significant morbidity and mortality in MAP, especially in longer surviving patients.

• Chronic pleuritis causing severe respiratory failure can develop rapidly and unless definitively treated by pleurectomy can result in ventilator dependence.

• Pulmonary function test should be obtained with any pulmonary manifestation or at the earliest hint of respiratory compromise. Careful evaluation of spirometry and flow-volume loop is of utmost importance.

• Treatment with eculizumab and parenteral prostaglandin analogue might stabilise the disease and prolong life.