Typical Wegener’s granulomatosis (WG) is a small and medium-sized vessel vasculitis that primarily affects the upper respiratory tract, lungs, and kidneys. It is associated with antibodies to proteinase-3 (C-ANCA). We describe a near-fatal presentation of a C-ANCA positive patient with atypical clinical and pathological features who responded to a combination of immunosuppression and plasmapheresis.
A 23-year-old woman with no significant past medical history presented with three weeks of dyspnea, fevers and non-productive cough. She denied weight loss, night sweats, hematuria, joint pains, visual changes, or paresthesias. She had recently traveled to Wisconsin and Southern California. Physical examination was notable for normal upper respiratory and pulmonary findings and the absence of signs of neuropathy, uveitis, rash or arthritis. The chest radiograph showed multiple large cavities and areas of dense consolidation. The white blood cell count (WBC) was 10,300/mm3 and the hematocrit was 29%. Erythrocyte sedimentation rate was 103 mm/hour. Creatinine was normal. Urinalysis showed hematuria without proteinuria or red cell casts. C-ANCA (ELISA to proteinase-3) was positive at 16 Elisa Units/ml. Rheumatoid factor, antinuclear antibody, and antiglomerular basement membrane antibodies were negative. The activated partial thromboplastin time was 35.5 s. Bronchoscopy revealed numerous smooth, white endobronchial 1 cm nodules. Multiple bronchoscopic lung biopsies revealed necrotizing pneumonitis; smears and cultures for acid fast bacilli (AFB), fungi and bacteria were negative. Due to persistent diagnostic uncertainty, an open lung biopsy was performed. It showed small vessels with inflammatory cells, a few giant cells, acute hemorrhage, and multiple microthrombi. The patient was treated with empiric antibacterial and antifungal agents, and methylprednisolone 1 gm/day for three days. The patient improved symptomatically and was discharged on a tapering dose of prednisone, moxifloxacin and itraconazole. Due to the lack of definitive pathology for WG, cyclophosphamide was not initiated at that time. One week later, the patient returned in severe respiratory distress requiring intubation and mechanical ventilation. The chest radiograph showed new cavities with worsening opacification of both lungs, sparing only the apices. The WBC was 19,500/mm3 and the hematocrit was 26%. Bronchoscopy demonstrated diffuse alveolar hemorrhage(DAH). Repeated testing, including stains for pneumocystis, was negative. Bronchoalveolar lavage fluid showed hemosiderin-laden macrophages. Serology for antiglomerular basement membrane antibodies was negative. Cultures from the first admission showed no fungal or mycobacterial organisms. The patient required ventilatory support with 100% oxygen. Broad spectrum antibiotics were started, along with 1 gram of methylprednisolone daily for three days. After risks and benefits were discussed with the family, cylcophosphamide was started at a dose of 2mg/kg. In light of the DAH, plasmapheresis was initiated as well. Four days after this regimen was started, the oxygen fraction was able to be reduced to 0.6. Repeat bronchoscopy showed continued hemorrhage, so plasmapheresis was continued for a total of 10 sessions. Three weeks later, the patient was weaned from ventilatory support. Radiography showed improvement of the pulmonary cavities and consolidation. Two months after admission, the patient had no pulmonary symptoms and had returned to work.
This case report is notable for several reasons. First, C-ANCA-positive DAH was successfully treated with cylophosphamide, corticosteroids and plasmapheresis as previously described in a limited number of patients. Second, the pathology was notable for numerous microthrombi which is not a typical finding in WG. Only a few small studies have shown that C-ANCA stimulates tissue factor and the coagulation cascade and can cause microthrombi. Finally, cyclophosphamide was given despite the pathologist being unable to make a firm diagnosis of WG.
A C-ANCA positive patient with atypical clinical and pathological features was treated successfully with immunosuppression and plasmapheresis. In extreme situations, treatment must be initiated promptly even when diagnostic uncertainty remains.
Lewis Eisen, None.