BY GREGORY TAYLOR, DO, & SCOTT LAGERVELD, DO
A 54-year-old man with a significant past medical history of atrial fibrillation and congestive heart failure presented to the ED with a chief complaint of difficulty walking. He was evaluated at an outside hospital two months earlier, and was found to have methicillin-resistant Staphylococcus aureus bacteremia, lower extremity cellulitis, and acute decompensated congestive heart failure (CHF). He clinically improved over one week, his autoimmune workup was negative, and he was discharged. He failed to follow up with nephrology, cardiology, and dermatology, and stopped taking his medications soon after discharge.
He presented to our ED with worsening lower extremity edema, dyspnea on exertion, worsening skin lesions for six months, and frequent nose bleeds for three days. The patient had no hematemesis, melena, hematochezia, no prior EGD, or colonoscopy. His medications were apixaban, digoxin, and furosemide.
His vitals on arrival were a temperature of 97.7°F, blood pressure of 196/92 mm Hg, heart rate of 97 bpm, respiratory rate of 32 bpm, weight of 487 pounds, and oxygen saturation of was 92% on room air. He had respiratory distress with conversational dyspnea and dried blood in the right nostril. Cardiopulmonary exam revealed an irregularly irregular rhythm and rales in the lung bases. His lower extremities had 3+ pitting edema with associated chronic venous stasis changes. His lymphadenopathy exhibited clear drainage with superficial ulcerations and no evidence of inflammation. His ECG revealed atrial fibrillation at 82 bpm with no acute ischemic changes.
Pertinent laboratory evaluations revealed a white blood cell count of 8.2, hemoglobin of 11.7 d/dL (baseline of 12 d/dL), mean corpuscular volume of 75, troponin of 0.08 ng/mL (0-0.04), BNP of 1664 pg/mL (0-100), hyponatremia of 128, hypokalemia of 3.5, BUN-to-creatinine ratio of 16:0.8, aspartate aminotransferase of 61 U/L (10-37 U/L), alanine aminotransferase of 56 U/L (9-47 U/L), alkaline phosphatase of 190 U/L (44-140 U/L), INR of 3.2, total bilirubin of 5.3 mg/dL (0.1-1.2 mg/dL), and direct bilirubin of 3.0 mg/dL (<0.3 mg/dL). His thyroid-stimulating hormone was within normal limits.
A chest radiograph demonstrated cardiomegaly, pulmonary vascular congestion, bilateral pleural effusions, and opacification over the right upper lobe, likely representing fluid trapped within the fissure. (Image A.) This constellation of findings was consistent with CHF. Ultrasound of the abdomen revealed mild hepatomegaly with no evidence of hepatic abnormality. CT of the abdomen and pelvis revealed prominent venous vasculature and diffuse anasarca. The patient was placed on BiPAP and given IV furosemide, and a nitroglycerine drip. Echocardiography showed an ejection fraction of 40%, right ventricular dysfunction, dilation, and pulmonary hypertension. His abnormal liver function tests and coagulopathy were suspected secondary to the congestive hepatopathy of CHF. He improved clinically and was admitted for acute decompensated heart failure.
By day five, his lower extremity skin lesions diffused to all extremities and resembled hemorrhagic bullae. He developed periorbital ecchymosis and sinusitis. The patient's erythrocyte sedimentation rate was elevated at 106 mm/hr, his c-reactive protein (CRP) was elevated at 20 mg/L, and he had a positive rheumatoid factor of 37 IU/mL (0-20). His clinical presentation suggested a type of vasculitis, but the serology and tissue evidence was lacking. The patient had a negative ANCA and proteinase 3 antibody at the outside hospital. His vitals remained stable and his congestive hepatopathy and coagulopathy improved.
On day six, his ecchymotic lesions had spread to the eyelids and nose, appearing as violaceous patches with vesicular formation, and a biopsy was done. That evening, his condition acutely worsened with altered mental status and respiratory distress. He appeared diaphoretic, lethargic, and minimally responsive, with coarse breath sounds bilaterally. He was intubated and started on broad-spectrum antibiotics for presumed acute hypoxic and hypercapnic respiratory failure secondary to health care-associated pneumonia.
CT head and brain scans without contrast were negative. (Image B.) We could not rule out underlying airspace disease. He continued to deteriorate and was subsequently placed on vasopressors. His laboratory evaluation was notable for new-onset hematuria. Repeat vasculitis workup revealed a C3 of 69 (79-152), C4 of 10 (16-38), and proteinase 3 (PR3) antibody of 171 (<20). He was started on 1 mg/kg corticosteroids with associated stress ulcer prophylaxis for granulomatosis with polyangiitis.
Blood cultures came back positive for Staphylococcus aureus on day nine. A punch biopsy was notable for leukocytoclastic vasculitis. His c-ANCA antibody was positive with a c-ANCA titer >1:160 (<1:20). Immunosuppressive medication was held in light of underlying septic shock. He was deemed too unstable for a kidney or lung biopsy. On day 10, he began hemorrhaging into his endotracheal tube, raising suspicion for diffuse alveolar hemorrhage or disseminated intravascular coagulation. His INR was now 2.6 from 1.87, lactate dehydrogenase was 411, and fibrinogen was 78 from 175. He was given fresh frozen plasma and cryoprecipitate, began six rounds of plasmapheresis, and underwent emergent bronchoscopy revealing diffuse hemorrhagic and friable mucosa. The next day the patient appeared temporarily stable.
He began hemorrhaging out of his mouth and orogastric tube on day 15, with immediate concern for gastrointestinal hemorrhage. The massive transfusion protocol was activated, and he underwent emergent EGD revealing a large duodenal bulb ulcer with an active bleeding visible vessel. (Image C.) He received 16 mL of epinephrine injection, balloon tamponade, and hemoclip placement x5. He remained on norepinephrine, vasopressin, octreotide, and a pantoprazole infusion. By day 17, he was exhibiting volume overload status post multiple blood products, refractory hyperkalemia, and worsening renal function (creatinine was now 3.7 from 1.2). Decision was made to proceed with modified sustained low-efficiency dialysis, but it was stopped secondary to hypotension. Later that day, he started hemorrhaging again from his orogastric tube. His family elected to terminally wean, and time of death was called minutes later.
Granulomatosis with polyangiitis (GPA) is a rare multisystemic vasculitis affecting small- to medium-sized vessels. GPA is associated with necrotizing granulomatous inflammation that may affect the lungs, kidneys, skin, and rarely the gastrointestinal tract. This immune-mediated disorder can lead to extensive tissue damage through an initiating inflammatory event and a specific immune response. A group of autoantibodies termed ANCAs help diagnose GPA and similar forms of vasculitis. c-ANCAs, sensitive and highly specific for GPA, are directed against proteinase 3. (The Johns Hopkins Vasculitis Center. http://bit.ly/2SZSx46.)
This condition affects roughly three out of 100,000 people, occurring in men and woman equally. (An Bras Dermatol2015;90[3 Suppl 1]:101; http://bit.ly/2SYNjFs; J Am Board Fam Pract 2003;16:555.) GPA can occur at any age, but it most often occurs between 40 and 65. (J Periodontal Implant Sci 2015;45:247; http://bit.ly/2SWqv9t.)
GPA can present and progress slowly over months or explosively over days. The respiratory tract and kidney are often involved, though the serious complications can also involve the small and large bowels. The overall 10-year survival rate approaches 75 percent, but the degree of baseline organ damage and existing co-morbidities are markers of poor outcome, as our case demonstrated. (Rheumatology [Oxford] 2002;41:572.)
A Must-Recognize Disease
GPA poses a significant diagnostic challenge given its diverse clinical presentations, from nonspecific constitutional complaints such as fever, weight loss, and fatigue to diffuse hemorrhage. (The Johns Hopkins Vasculitis Center. http://bit.ly/2SZSx46.) Common manifestations include conjunctivitis, necrotizing scleritis, chronic sinusitis, rhinitis, epistaxis, saddle nose deformity, petechiae/vesicles/hemorrhagic bullae, pulmonary infiltrates, hemoptysis, hematuria, and diffuse alveolar hemorrhage. (UpToDate. Nov. 26, 2018; http://bit.ly/2STqQK6.)
Diagnosing GPA is generally confirmed with a tissue biopsy; renal and lung biopsies are most specific. (Prz Gastroenterol 2016;11:270; http://bit.ly/2T1ZaCV.) Tissue biopsies commonly reveal neutrophilic transmural inflammation of the vessel walls, as noted in our patient, termed leukocytoclastic vasculitis. (J Med Case Rep2014;8:297; http://bit.ly/2T0hJHI; J Diabetic Foot Complications 2015;7:1; http://bit.ly/2T2CmD7.) A presumptive diagnosis can also be made if there is a high probability based on clinical findings, including a positive c-ANCA, alveolar hemorrhage, pulmonary nodules, or new-onset destructive rhinosinusitis, in combination with a low likelihood of another etiology. (The Johns Hopkins Vasculitis Center. http://bit.ly/2SZSx46; UpToDate. Nov. 26, 2018; http://bit.ly/2STqQK6; UpToDate. Jan. 4, 2017; http://bit.ly/2SX920z.)
ANCA testing sensitivity varies depending on disease progression. c-ANCA has been shown to be most specific and PR3-ANCA most sensitive for GPA, approaching >90% in the setting of clear signs or symptoms. (J Med Case Rep2014;8:297; http://bit.ly/2T0hJHI; J Diabetic Foot Complications 2015;7:1; http://bit.ly/2T2CmD7.) Initial ANCA testing for our patient was negative at his prior hospital, but his c-ANCA and PR3-ANCA came back positive later on day seven.
GPA can also present with anything from an ulcer or rash to fulminant multisystem failure. Severe potential complications include diffuse alveolar hemorrhage, gastrointestinal hemorrhage, or rapidly progressive glomerulonephritis, as our patient demonstrated, becoming fatal within days. Poorer survival has been associated with older age and baseline organ damage. Our patient had a significant past medical history and multiple co-morbidities in the setting of septic shock, contributing to his overall extremely high mortality rate.
If left untreated, GPA is fatal. Prednisone may slow the progression, but it is insufficient by itself and often requires the addition of an immunosuppressant like cyclophosphamide. (The Johns Hopkins Vasculitis Center. http://bit.ly/2SZSx46.) Our patient was started on monthly oral cyclophosphamide and daily prednisone given the septic shock and concern for worsening clinical status if daily cyclophosphamide was used.
Recognizing GPA is a true diagnostic challenge given its diverse clinical presentations. As a rapidly progressive and potentially fatal vasculitic process, GPA is a must-recognize disease.
Dr. Taylor is completing his emergency medicine residency at Beaumont Hospital in Farmington Hills, MI, a teaching hospital of Michigan State University, where Dr. Lagerveld is on staff as core faculty for the emergency medicine residency program and serves as the director of ultrasound.