Granulomatosis with polyangiitis (GPA), previously termed Wegener’s Granulomatosis, is an autoimmune small vessel vasculitis which is highly associated with antineutrophil cytoplasmic antibodies (ANCA) and has varied clinical manifestations. Diagnosis hinges on identifying a combination of clinical features of systemic vasculitis, positive ANCA serology, and histological evidence of necrotizing vasculitis, necrotizing glomerulonephritis, or granulomatous inflammation from a relevant organ biopsy. The American College of Rheumatology has also developed a classification criteria focusing specifically on nasal or oral inflammation, abnormal chest radiograph, and abnormal urinary sediment, along with granulomatous inflammation, which helps to distinguish GPA from other forms of systemic vasculitis. In the case presented below, the diagnosis of GPA was delayed as the patient had a concomitant atypical endobronchial carcinoid which predisposed to postobstructive pneumonia. Fortunately, the papular lesions that developed across her lower limbs prompted further investigations. The return of appropriate serology coincided with progression to alveolar hemorrhage, offering a more complete clinical picture, and when she responded to the combination of steroid, cyclophosphamide, and plasma exchange, the diagnosis of GPA was cinched.
Granulomatosis with polyangiitis (GPA), previously termed Wegener’s Granulomatosis, is an autoimmune small vessel vasculitis which is highly associated with antineutrophil cytoplasmic antibodies (ANCA) and has varied clinical manifestations, including systemic necrotizing vasculitis, necrotizing granulomatous inflammation, and necrotizing glomerulonephritis [
A 44-year-old Caucasian female with a history of asthma, rhinitis, and generalized joint pains presented for evaluation of recurrent dyspnea. She was initially admitted two months prior for suspected pneumonia. CT angiogram (CTA) showed diffuse bilateral pulmonary infiltrates and a large left mainstem endobronchial mass with a small focal area of lung parenchymal consolidation distal to the lesion. Bronchoscopy confirmed the presence of a partially obstructing mass and biopsy was positive for carcinoid tumor. She was treated with ceftriaxone and levofloxacin and was subsequently discharged with planned follow-up at the surgical outpatient clinic for evaluation of tumor resection. The patient subsequently lost insurance, precluding this assessment.
She presented six weeks later with worsening dyspnea but also noted a palpable petechial rash across both lower limbs. Chest X-ray (CXR) showed diffuse bilateral pulmonary opacities concerning multifocal pneumonia. CTA was negative for embolus but showed bilateral ground glass opacities. Skin biopsy revealed leukocytoclastic vasculitis (see Figure
Skin biopsy showing classic features of small vessel vasculitis with neutrophilic infiltration of the vessel walls, karyorrhexis, and fibrinoid necrosis of vessel walls as well as extensive extravasation of red blood cells.
She presented again two weeks later with worsening dyspnea, fever, and a nonproductive cough. She was hypoxic to 85% on room air that was responsive to supplemental oxygen and had bilateral, diffuse rhonchi on examination. She had a leukocytosis of 15,000/mm3 and CXR showed stable bilateral pulmonary infiltrates (see Figure
(a) CXR from admission showing bilateral extensive pulmonary infiltrates, suggestive of florid vasculitis. (b) CXR upon discharge emphasizing resolution of the pulmonary infiltrates following treatment with plasmapheresis, induction cyclophosphamide, and high dose methylprednisone.
Bronchoscopy image showing the gross carcinoid tumor in the left mainstem bronchus.
CTA chest showing bilateral ground glass opacities and highlighting the left endobronchial lesion (yellow circle).
Cell block section of bronchoalveolar lavage showing hemosiderin-laden macrophages (granular golden pigment) demonstrating alveolar hemorrhage.
Repeat chest CT scan nearly four months later revealed a significant improvement/resolution of the diffuse opacities throughout the bilateral lungs but commented on the stable 3 cm endobronchial mass of the left lower lobe bronchus, with slightly worsened distal consolidation of the left lower lobe.
She subsequently underwent snare cautery, followed by argon photocoagulation debulking of the tumor. After procedure, there was more than 95% patency of the left mainstem bronchus. Origins for the left upper lobe and lingua could be easily identified; however the origin of the left lower lobe was likely encased by tumor. Pathology revealed an atypical carcinoid with 8 mitoses per 50 HPF (see Figure
Histology slide from the atypical carcinoid tumor. Nests of uniform, bland carcinoid cells with central nuclei and moderate cytoplasm, prominent vasculature surrounding the nests (H&E, ×20). Inset: infrequent mitoses (H&E, ×63).
The cardiothoracic service evaluated the patient thereafter stating that the tumor appeared to have extended into the left upper bronchus and that sleeve resection would not be an option. Furthermore, given her poor performance status and risk of impaired wound healing while on steroids she was a poor surgical candidate.
Follow-up PET and octreotide scans were equivocal for metastatic mediastinal adenopathy but confirmed no other disease spread. She subsequently received three cycles of cisplatin/etoposide with concurrent radiotherapy. Shortly after her third cycle she developed another flare of the GPA and was restarted on high dose prednisone 60 mg daily and cyclophosphamide. The exacerbation acutely progressed, resulting in respiratory failure secondary to diffuse alveolar hemorrhage. Unfortunately, the patient succumbed the same day.
Autopsy revealed the atypical carcinoid tumor involving the left mainstem bronchus, bronchopneumonia, interstitial lung disease, and extensive intra-alveolar hemorrhage. There was noted cardiomegaly with four-chamber dilatation but no evidence of acute myocardial infarction. The liver was enlarged with steatosis, and both the lungs and spleen demonstrated congestion. In summary, her death was believed to be as a result of respiratory failure secondary to extensive pulmonary hemorrhage in a background of interstitial lung disease and a clinical history of granulomatosis with polyangiitis.
Diagnosis of GPA is not always straightforward, especially when confounded by other disease processes. Furthermore, clinical manifestations of GPA can be highly varied and are dependent upon which organ system is affected by the vasculitis (see Table
Organ-based clinical features of granulomatosis with polyangiitis.
Constitutional | Malaise, myalgia, arthralgia, anorexia, weight loss, and pyrexia |
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Mucocutaneous and orbital | Oral ulcers, oral granulomatous lesions, episcleritis, scleritis, conjunctivitis, keratitis, uveitis, retinal vasculitis, retinal artery or venous thrombosis, retinal exudates, retinal hemorrhages, blurred vision, blindness, proptosis, and orbital granulomatous masses |
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Cutaneous | Infarcts leading to ulcers and gangrene; leukocytoclastic vasculitis that may be found on biopsy |
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Ear and nose | Sensorineural and conductive hearing loss, persistent/recurrent nasal discharge +/− bloody, nasal ulceration, nose bridge collapse, nasal granulomatous lesions, and parasinus and sinus inflammation |
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Upper airway | Subglottic or tracheal stenosis, stridor |
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Lower airway | Cough, dyspnea, wheeze, hemoptysis, small airway obstruction, pulmonary infiltrates and hemorrhage leading to respiratory failure, and pleuritis |
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Renal | Hematuria, proteinuria, cellular cast on urine cytology; renal impairment in the form of acute kidney injury, chronic kidney disease, or end stage renal disease; diffuse pauci-immune crescentic necrotizing glomerulonephritis on biopsy |
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Cardiovascular | Occlusive vascular disease, pericarditis, pericardial effusions, cardiomyopathy, valvular heart disease, ischemic heart disease, and heart failure |
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Gastrointestinal | Peritonitis, bowel ischemia secondary to mesenteric vasculitis |
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Central and peripheral nervous systems | Headache, meningitis, seizures, cerebrovascular accidents, spinal cord lesions, cranial nerve palsies, sensory or motor peripheral neuropathy, mononeuritis multiplex, and cerebral mass lesion |
Despite the absence of formal diagnostic criteria for GPA, the American College of Rheumatology (ACR) has established classification criteria (see Table
ACR classification criteria for granulomatosis with polyangiitis (formerly, Wegener’s Granulomatosis).
Classification criteria | |
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(1) Nasal or oral inflammation | Painful or painless oral ulcers or purulent or bloody nasal discharge |
(2) Abnormal chest radiograph | Pulmonary nodules, fixed pulmonary infiltrates, or pulmonary cavities |
(3) Abnormal urinary sediment | Microscopic hematuria with or without red cell casts |
(4) Granulomatous inflammation | Biopsy of an artery or perivascular area shows granulomatous inflammation |
The presence of two or more of these four criteria yields a sensitivity of 88 percent.
The presence of two or more of these four criteria yields a specificity of 92 percent.
Lung nodules and masses are the most common lesions, approximating 40–70% of patients [
Ground glass attenuation and consolidation are also common, occurring in up to 50% of patients with active disease. These usually develop as sequelae to alveolar hemorrhage [
Postobstructive pneumonia is characterized by a proximal airway obstruction with ensuing infection of the distal lung parenchyma. The obstruction effectively retards the normal drainage mechanism of the lung, predisposing to a protracted course of infection, resistant bacteria, and extended courses of antibiotics [
Distal airway involvement can also occur in GPA and is manifested by bronchial wall thickening and bronchiectasis [
Without treatment, the mortality of GPA at 1 year was 80% [
The cyclophosphamide-glucocorticoid combination has usually formed the backbone for induction therapy. However, with the attendant toxicities associated with cyclophosphamide, there has been a shift to limit its exposure by switching to alternate immunosuppressants following remission after three to six months, using intravenous pulsed therapy versus oral continuous therapy, and even avoidance of cyclophosphamide altogether in early disease [
Methotrexate is a reasonable substitute for less aggressive presentations in the absence of renal impairment [
Glucocorticoids are not employed as single-agent induction therapy; rather they are combined with other immunosuppressant therapies. Methylprednisolone 500–1000 mg intravenously daily for three days is followed by prednisolone 0.5–1 mg/kg/day for at least 4 weeks with a gradual taper to achieve the lowest dose effective at maintaining remission [
Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, provides an alternate option to cyclophosphamide in the induction therapy for GPA. It depletes circulating and tissue resident B cells by direct induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity [
Plasma exchange (PLEX) deserves special mention in the induction phase of severe disease. The therapeutic mechanism may relate to expeditious elimination of ANCA from the peripheral circulation, with the caveat that there is also parallel depletion of clotting factors and circulating cytokines [
Despite effective induction therapy, 70% of patients will relapse and up to 20% will ultimately develop refractory disease [
In an effort to spare cyclophosphamide exposure, sequential maintenance regimens that substitute cyclophosphamide with azathioprine or methotrexate have proven efficacious [
Other agents that have been used in maintenance therapy include leflunomide and mycophenolate mofetil. Often, the immune suppressive agents are combined with low-dose corticosteroid. Withdrawal of the steroid component results in a higher relapse rate [
With improved survival rates among patients diagnosed with GPA, there has been continuous evidence accrued hinting at an increased occurrence of cancer, including malignancies of the urinary bladder as well as the hematopoietic system, which has been attributed to cyclophosphamide [
A word on carcinoid tumors is as follows: Carcinoid tumors originate from enterochromaffin cells and are characterized by neuroendocrine differentiation. They are most commonly located in the gastrointestinal tract (68–74%) followed by the respiratory tract (25%) and very uncommonly within the thymus (2%) [
There are certain points that should be highlighted with this case. Firstly, though the adage follows that “common things are common,” this should not preclude one from exploring or, at least considering, alternate diagnoses. This becomes particularly evident when the proposed ailment does not improve with conventional therapy. As per our case, the patient was repeatedly treated for a postobstructive pneumonia, believed to be secondary to an obstructing endobronchial lesion. Furthermore, this marred her respiratory features, delaying the diagnosis of her underlying condition, that is, granulomatosis with polyangiitis. Secondly, the appropriate treatment at the appropriate time is paramount when coordinating care for complex disease processes. This patient received appropriate induction therapy, but in retrospect there could have probably been a greater emphasis on scheduling her maintenance therapy more expeditiously. Additionally, had the serology resulted earlier, there would have been less of a delay in initiating therapy and we may have been able to catch her in that critical window before she decompensated. Ultimately, this patient was concomitantly burdened with two severe conditions which made for a very intricate clinical course.
The authors declare that there is no conflict of interests regarding the publication of this paper.