A 32-year-old man presented with a 3-month history of fever, weight loss, sinusitis, arthralgias, and dyspnea. He had been treated with several courses of antibiotics for presumed sinusitis with no improvement. Computed tomography (CT) of the chest to evaluate his dyspnea showed multiple cavitary, pulmonary nodules (Figure 78-1). He was a lifetime nonsmoker and denied risk factors for tuberculosis. Bronchoalveolar lavage with bacterial, fungal, and mycobacterial stains and cultures were all negative. Transbronchial biopsy showed nonspecific inflammation and was negative for malignancy. Laboratory evaluation revealed anemia, elevated sedimentation rate, elevated C-reactive protein (CRP), and acute kidney injury (creatinine [1.9 mg/dL]). Urinalysis showed microscopic hematuria, red blood cell casts, and proteinuria. A renal biopsy was pursued and showed a pauci-immune, necrotizing glomerulonephritis (Figure 78-2). Antineutrophil cytoplasmic antibody (ANCA) testing was positive for a cytoplasmic staining pattern (c-ANCA) with specificity to proteinase-3 (PR3). A diagnosis of granulomatosis with polyangiitis (GPA, Wegener) was made. The patient was treated with high doses of glucocorticoids and oral cyclophosphamide with successful induction of remission. Six months later, he was transitioned to azathioprine.

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  GPA is a necrotizing, granulomatous, systemic vasculitis affecting the small- to medium-sized blood vessels.

  
  
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  Overall, estimated incidence is 8 to 10 cases per million per year. Estimated prevalence in the United States is 26 cases per million.¹

  
  
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  Males are affected slightly more frequently than females.

  
  
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  Peak age at onset is between 64 and 75 years; it is uncommon in the pediatric population.¹

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  The causative agent in GPA is unknown.

  
  
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  Human leukocyte antigen (HLA)-DPB1, HLA-DRB1, and polymorphisms in genes encoding key regulators of the immune response such as CTL4A and PTPN22 have been associated with increased risk of GPA.^1,2

  
  
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  Alpha-1-antitrypsin deficiency has been associated with GPA.³

  
  
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  Infection with Staphylococcus aureus and silica exposure have also been associated with GPA.¹

  
  
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  GPA is characterized by the presence of ANCA antibodies in c-ANCA with specificity to PR3.

  
  
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  In vitro studies suggest a pathogenic role for ANCA antibodies. In these studies ANCA can activate neutrophils to damage endothelial cells and induce a necrotizing vasculitis.⁴

  
  
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  While the exact mechanism of vasculitis in GPA is unknown, it has been hypothesized that the ANCA antibodies interact with target antigens on primed neutrophils and monocytes, causing endothelial and tissue damage.⁴

Clinical Features

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  GPA has a predilection for the upper and lower respiratory tracts, and the kidney.

  
  
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  Constitutional symptoms include fever, weight loss, and fatigue. Arthralgias and myalgias are common.

  
  
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  Upper airway manifestations are observed in more than 70% of patients with GPA at presentation and include sinusitis, nasal sores or crusting, septal perforation, epistaxis, saddle-nose deformity (Figure 78-3), otitis media, and conductive and/or sensorineural hearing loss.

  
  
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  Symptoms of hoarseness or stridor may indicate tracheal disease that can cause subglottic or tracheal stenosis (Figure 78-4).

  
  
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  Pulmonary symptoms may include cough, dyspnea, or hemoptysis.

  
  
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  Renal involvement may be clinically silent and noted on testing but if present, can rapidly progress to renal failure.

  
  
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  Other manifestations include scleritis, orbital masses, cutaneous vasculitis, cranial neuropathies, mononeuritis multiplex, gastrointestinal vasculitis, and central nervous system involvement with pachymeningitis, pituitary involvement, cerebral vasculitis, or thrombotic events.