Concomitant pleuritis and pericarditis developing during glucocorticoid therapy: a case report on granulomatosis with polyangiitis

Abstract

Granulomatosis with polyangiitis is an anti-neutrophil cytoplasmic antibody-associated vasculitis that manifests in various ways by affecting the small-sized vessels in multiple organs. Acute pleuritis and pericarditis are both rare among the different manifestations of granulomatosis with polyangiitis. The symptoms in each of the organs are often apparent at the time of diagnosis and tend to diminish with treatment. Organ damage and progression of the disease during treatment are uncommon. We encountered a patient with granulomatosis with polyangiitis who, after starting intravenous methylprednisolone pulse therapy, concurrently developed acute pleuritis and pericarditis. The patient was a 47-year-old Japanese man with myalgia in whom kidney dysfunction, proteinase 3-anti-neutrophil cytoplasmic antibody positivity, and a lung mass were detected. Granulomatosis with polyangiitis was diagnosed pathologically from a lung and a kidney biopsy. Acute pleuritis and pericarditis, which developed after the first course of intravenous methylprednisolone pulse therapy, both resolved following the second course. The present report indicates that secondary serositis such as pleuritis and pericarditis can develop in patients with granulomatosis with polyangiitis even during glucocorticoid therapy.

Introduction

Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) with low incidence in Japan [1]. GPA manifests in various ways by affecting the small-sized vessels in multiple organs. While pleuritis has been reported in 10% [2] and pericardial effusion in 4% [3] of patients with GPA, a concurrent development of pleuritis and pericarditis in GPA is rare, with only one case reported in the literature [4]. In that report, however, the histological diagnosis was not confirmed and details of the clinical course and effectiveness of the treatment for pleuritis and pericarditis were not documented.

Herein, we described a patient in whom pleuritis and pericarditis were concomitantly observed after the beginning of glucocorticoid therapy. By obtaining pathological specimens of the kidney and lung, we could confidently select intensive immunosuppressive therapy for his systemic vasculitis.

Case report

A 47-year-old Japanese man presented to our emergency room with general fatigue and gait disturbance due to a 3-week persistent myalgia in both thighs. He developed fever and a dry cough 4 days prior to presentation. His initial vital signs included a body temperature of 38.5 °C, a blood pressure of 114/72 mmHg, a heart rate of 104 bpm, a respiratory rate of 20 breaths/min, and oxygen saturation (SpO₂) of 97% on room air. On physical examination, there was no saddle-nose deformity, clear respiratory sounds, regular heart beats without any murmurs, and the abdomen was soft, flat, and non-tender. There was numbness in his right upper ulnar area and in both lower legs extending to the dorsum of the foot, which was inconsistent with the dermatomal distribution. There were no rashes. The laboratory findings included a white blood cell count of 17,000 /μL, a C-reactive protein (CRP) level of 25.17 mg/dL, and a creatinine level of 1.17 mg/dL (Table 1). The clinical course is illustrated in Fig. 1. A computed tomography (CT) of the chest obtained on admission showed a homogeneous mass in the right middle lobe (Fig. 2a). He was admitted to the respiratory department of the hospital. A lung abscess was suspected initially, however, there was no response to antibiotics. The right middle lobe was then partially resected with the visceral pleura under general anesthesia on day 9 for pathological examination of the antimicrobial-resistant mass to confirm some inflammatory changes of vasculitis. Post-operatively, a proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA) titer of 2,800 U/mL was found. Oral prednisolone (60 mg) immunosuppressive therapy was started on day 11. On day 15, the patient’s serum creatinine level was 1.3 mg/dL, urinary protein-creatinine ratio was 0.5 g/g, and 30–49 red blood cells per high-power field, including a proportion of dysmorphic red blood cells, indicating rapidly progressive glomerulonephritis. The Birmingham Vasculitis Activity Score was 19. After he was transferred to the nephrology department, high-dose intravenous methylprednisolone 500 mg was started on day 16 to control the aggravating vasculitis. On the next day, the patient was afebrile with an SpO₂ of 92–94% following supplemental oxygen cessation. An ultrasound-guided percutaneous renal biopsy was performed on day 18. There was a steady improvement in his general fatigue and a gradual attenuation of the myalgia and numbness in his lower limbs. On day 19, the laboratory data revealed a serum creatinine level of 1.02 mg/dL, and a urine protein-creatinine ratio of 0.2 g/g, indicating mild recovery.

Table 1.

Laboratory data on the initial visit

White blood cell (/μL)	17,000	IgG (mg/dL)	905
Hemoglobin (g/dL)	13.0	IgA (mg/dL)	244
Platelet (104/μL)	51.8	IgM (mg/dL)	69
Total protein (g/dL)	5.7	CH50 (U/mL)	63.9
Albumin (g/dL)	2.4	C3 (mg/dL)	116
AST (U/L)	34	C4 (mg/dL)	12
ALT (U/L)	45	ANA	< 40
LDH (U/L)	175	PR3-ANCA (U/mL)	2,800
BUN (mg/dL)	13.8	MPO-ANCA (U/mL)	< 1.0
Creatinine (mg/dL)	1.17	anti-GBM (U/mL)	< 2.0
Sodium (mmol/L)	139	HBs-Ag	(–)
Potassium (mmol/L)	3.8	HCV	(–)
Chloride (mmol/L)	101	IGRA	(–)
Glucose (mg/dL)	128
Hemoglobin A1c (%)	5.9
CRP (mg/dL)	25.17

ANA antinuclear antibody, PR3-ANCA proteinase-3-anti-neutrophil cytoplasmic antibodies, MPO-ANCA myeloperoxidase-anti-neutrophil cytoplasmic antibodies

Fig. 1.

The clinical course of a patient with granulomatous polyangiitis who developed pleuritis and pericarditis. mPSL methylprednisolone, PSL prednisolone, IVCY intravenous cyclophosphamide, RBC red blood cells

Fig. 2.

Changes in the lung lesion and pericardium. a A computed tomography scan of the chest on admission. A 3-cm homogeneous mass with clear margins was detected in the middle lobe of the right lung (arrowhead). b A computed tomography scan of the chest on day 20 after admission. The scan shows pleural thickening of the right lung (arrowhead) with a loculated pleural effusion. c, d An electrocardiogram and echocardiogram acquired on day 20. The widespread ST-segment elevation and mild pericardial effusion (arrowhead) suggest acute pericarditis

From day 20, his SpO₂ gradually declined and his respiratory rate deteriorated to 24 breaths/min; supplemental oxygen was restarted at 2 L/min with a nasal cannula when the SpO₂ had decreased to 85%. The patient’s temperature was up to 38 °C but there was no cough or sputum. A chest CT revealed a large pleural effusion with passive atelectasis and thickened parietal pleura in the right lung (Fig. 2b). Thoracentesis confirmed the exudative pleural effusion (serous bloody appearance with total protein of 4.0 g/dL, lactate dehydrogenase of 443 U/L, Neutrophils of 69%, Lymphocytes of 31%). No bacteria were detected in the pleural effusion culture. From these findings, we diagnosed an acute AAV-related pleuritis and did not use antibacterial drugs. In the electrocardiogram performed to exclude the hypoxemia due to ischemic heart disease, a wide range of ST-segment elevation was observed (Fig. 2c). Transthoracic echocardiogram revealed normal cardiac wall motion but also showed pericardial effusion (Fig. 2d). Based on these findings, acute AAV-related pericarditis was diagnosed. By the second course of intravenous methylprednisolone pulse therapy starting on day 24 to treat the exacerbation of AAV, a chest X-ray showed improved parenchymal opacity and the pleural effusion decreased promptly within 2 days. The respiratory rate improved to 15 breaths/min and supplemental oxygen was withdrawn on day 29. The electrocardiographic pattern reversed to normal on day 31.

Pathologic examination of the right middle lobe on day 9 had revealed cavity formation. The granulomatous arteritis was found mainly in the surrounding pulmonary artery wall (Fig. 3a, b). The visceral pleura demonstrated deposition of fibrin with mild neutrophil infiltration, suggesting acute pleuritis (Fig. 3c). Renal pathology revealed necrotizing glomerulonephritis (Fig. 3d) that was classified as focal subtype according to the Berden criteria [5].

Fig. 3.

Pathologic findings. a The cavity formation in the lung is attributable to ischemic necrosis. b Elastica-Masson staining of a lung tissue specimen at 100 × magnification. Granulomas can be seen around the pulmonary artery wall. The internal elastic lamina is partially broken (arrowhead). c Hematoxylin–eosin staining of a pleural tissue sample at 400 × magnification shows mild pleuritis with areas containing vasodilation with mild neutrophil infiltration (arrowhead) and deposition of fibrin on the surface of the visceral pleura. d Periodic acid-Schiff staining of a renal tissue sample at 400 × magnification. There are no obvious granulomas, but the necrotizing tuft can be observed. Immunostaining reveals a pauci-immune pattern

On day 32, the patient had a serum creatinine of 1.57 mg/dL, a urinary protein-creatinine ratio of 0.5 g/g, and more than 100 red blood cells per high-power field, indicating worsening of his renal function. A course of intravenous cyclophosphamide pulse was administered at a dose of 600 mg. Thereafter, the patient’s general fatigue improved. However, his serum creatinine level remained at 2.0 mg/dL; therefore, another course of intravenous cyclophosphamide pulse was started on day 45.

The patient was discharged on day 48. There was no recurrence of the serositis thereafter. However, increase in his serum creatinine level and CRP level, and general malaise were detected on day 93; a third course of intravenous cyclophosphamide pulse was started at this time. Thereafter, the serum CRP level decreased, but the serum creatinine level was not improved. Consequently, a single dose of 630 mg rituximab was administered on day 117. The patient’s serum creatinine level and symptoms of malaise then gradually improved. There was no recurrence of serositis for more than 2 years.

Discussion

We have encountered a rare case of GPA with combination of acute pericarditis and pleuritis. Although there was subtle clinical signs of pleuritis at the initial presentation, the acute serositis had become apparent after starting the corticosteroid therapy.

Pulmonary involvement such as pulmonary effusions are common in patients with GPA. It is reportedly found in 48–73% of cases at the initial evaluation, and in 85–92% of patients during the course of the illness [2]. Pleuritis and/or pericarditis in patients with GPA, however, is a rare manifestation [6] and its clinical response to the conventional therapy remains unclear. The few reports available on the histology of pleuritis coexisting with AAV indicate that the findings are characteristic of fibrinous pleuritis [7]. In the present case, pathological specimens obtained by lung lobectomy revealed fibrin deposits directly beneath the visceral pleura with perivascular lymphocyte and neutrophil infiltration, which was consistent with AAV-related acute pleuritis. These findings suggested that the mild pleuritis existed before the surgical intervention.

Autoimmune-mediated pericarditis ranges from 2 to 24% of overall acute pericarditis cases [8], most of which were caused by eosinophilic granulomatosis with polyangiitis. While cardiac involvement in patients with GPA has also been regarded as rare, some cardiac manifestations, namely pericarditis, myocarditis, and coronary arteritis, have recently been reported [9]. The French Vasculitis Study Group found that cardiac involvement is a risk factor of poor overall prognosis and increased relapse in GPA patients [10]. Previous autopsy cases have shown that patients with AAV who develop ischemic heart disease have been identified to have coronary artery vasculitis and necrosis accompanied with the pericarditis [11, 12]. Prompt treatment is important to prevent these patients from developing autoimmune-mediated pericarditis. Case reports such as these are important to inform the clinical decision of rare complications following standardized therapy in GPA patients.

A GPA patient’s symptomatic decline during the course of remission-induction therapy can often confound our clinical judgement. In the present case, we should consider the reason why the pleuritis and the pericarditis were concomitantly manifested just after starting corticosteroid pulse therapy for GPA. The drug administration schedule might have been insufficient against the disease progression, resulting in developing the serositis. Once we found that the patient had severe vasculitis with pulmonary and renal involvement, we immediately decided to infuse a methylprednisolone pulse of 500 mg following oral prednisolone of 30 mg/day. According to the European Vasculitis Society (EUVAS) glucocorticoid oral regimen [13], the dose was recommended to be tapered to 0.5 mg/kg/day at the second week after initiation, and our tapering speed was regarded as not too fast in this case as well. Depending on the severity of the disease, methylprednisolone pulse therapy of 500–1000 mg is clinically used to treat the vasculitis. The exacerbation of vasculitis might not have been encountered if a higher dose pulses of 1000 mg were administered in this case.

As a clinical feature of this patient, the very high titer of PR3-ANCA was prolonged. The PR3-ANCA is regarded to be a sensitive marker of the disease activity and to suggest or predict relapse and guide therapeutic decisions [14]. Although the PR3-ANCA and CRP values in Fig. 1 seemed to be serologically improving with glucocorticoid treatment, we considered these findings did not suggest that the severe systemic disease itself had totally subsided. Given the appearance of pleurisy, persistent hematuria, and slowly deteriorating renal function, we needed to continue aggressive remission-induction therapy following intravenous cyclophosphamide and rituximab.

In summary, we have encountered a case of secondary pleuritis and pericarditis that manifested during induction of corticosteroid therapy for GPA. By obtaining the pathological specimens of the kidney and lung, we could confidently continue to pursue intensive immunosuppressive therapy. The pleuritis and pericarditis responded well to intravenous glucocorticoid pulse therapy within a few days.

Funding

No funding was involved in this study.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exist.

Informed consent

Informed consent was obtained from the individual participant included in the study.