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55-Year-Old Man With Purpura and Foot Pain

      A 55-year-old man presented to our emergency department with ankle pain and swelling. He had been in his usual state of health until 2 weeks before presentation, when he noticed difficulty walking, left knee pain, and a sore throat with dysphagia. He concurrently developed nonpruritic, nonpainful purpuric lesions distally on all 4 extremities. The arthralgias and edema progressed to include his right elbow and both hands. He reported painful oral sores, sporadic hemoptysis, dyspnea on exertion, and generalized myalgias and malaise. He denied chest pain, fevers, chills, epistaxis, vomiting, dysuria, or headache. Two days before presenting to our emergency department, he had been diagnosed as having pneumonia at an outside emergency department on the basis of infiltrates revealed on chest radiograph. He had received an antibiotic without symptomatic improvement.
      The patient returned to Minnesota 1 month before presentation after having lived 12 to 15 months in Colorado in dilapidated buildings with exposure to mice. On his return, he spent several weeks camping and sleeping outdoors. He denied any animal, tick, or rodent bites. His medical history was notable for schizoaffective disorder, controlled with fluoxetine and quetiapine, and Crohn disease, currently in remission. He had a distant history of drug and alcohol abuse but denied intravenous drug use. He had not been sexually active for several years.
      On physical examination, the patient appeared thin; his respirations were deep, and he was hemodynamically stable. His vital signs were as follows: temperature, 37.8 γC; heart rate, 100 beats/min; respiratory rate, 16 breaths/min; blood pressure, 115/78 mm Hg; and oxygen saturation, 97% on 2 L/min of oxygen via nasal cannula. Examination of the oropharynx revealed generalized erythema, a necrotic hard palate lesion, and smaller, exudative lesions on the soft palate, buccal mucosa, and uvula. Examination of the skin revealed well-defined, nonblanching, nontender, palpable purpuric lesions on the elbows, hands, knees, and lower legs. Some lesions were bullous. The neck was supple. Other physical examination findings included tender cervical and inguinal lymphadenopathy, bilateral pulmonary crackles on inspiration, and painful bilateral pedal edema.
      Laboratory findings (reference ranges provided parenthetically) on admission showed mild anemia (hemoglobin, 9.7 g/dL [13.5-17.5 g/dL]), leukocytosis (leukocytes, 20.6 × 109/L [3.5-10.5 × 109/L], of which 91% were neutrophils; 4%, lymphocytes; 3%, eosinophils; and 2%, monocytes), thrombocytosis (platelets, 857 × 109/L [150-450 × 109/L], and elevated D-dimer levels (1650 ng/mL [<301 ng/mL]). Electrolyte analysis yielded the following results: sodium, 133 mEq/L (135-145 mEq/L); potassium, 4.3 mEq/L (3.6-4.8 mEq/L); blood urea nitrogen, 40 mg/dL (8-24 mg/dL); and creatinine, 1.1 mg/dL (0.8-1.2 mg/dL). Alanine aminotransferase levels were normal (25 U/L [10-45 U/L]), as were total bilirubin levels (0.6 mg/dL [0.1-1.0 mg/dL]) and prothrombin time (11.0 seconds [8.4-12.0 seconds]). Chest radiograph showed bilateral (left greater than right) basilar and perihilar patchy infiltrates.
      • 1.
        At this point, which one of the following is the most appropriate next step?
        • a.
          Perform a lumbar puncture to exclude acute bacterial meningitis
        • b.
          Obtain blood cultures and administer broad-spectrum antibiotics
        • c.
          Obtain blood type and cross-match; transfuse 2 units of packed red blood cells
        • d.
          Administer a bolus of unfractionated heparin and initiate intravenous infusion
        • e.
          Transfuse 2 units of fresh frozen plasma
      Although our patient's purpuric rash suggested meningococcemia, he did not display typical findings of acute bacterial meningitis such as high fever, nuchal rigidity, or altered mental status. His disease had a progressive course with gradual onset; immediate lumbar puncture was unnecessary.
      Because the patient had a possible infection (patchy pulmonary infiltrates on chest radiograph) and met 2 of the 4 systemic inflammatory response syndrome criteria (tachycardia [heart rate >90 beats/min] and leukocytosis [white blood cell count >12.0 × 109/L]), he required treatment for sepsis until it could be ruled out. Evidence of endorgan dysfunction in our patient would have been grounds for a diagnosis of severe sepsis and would have necessitated aggressive intravenous fluid resuscitation. However, for our patient, who had normal blood pressure and no signs of organ hypoperfusion, the most appropriate next step was to obtain blood cultures and administer broad-spectrum antibiotics.
      Immediate transfusion is unwarranted because the patient's anemia is not sufficiently severe. Immediate treatment with heparin is also unnecessary because a pulmonary embolus or deep venous thrombosis would not explain the patient's symptoms or chest radiograph findings despite the elevated D-dimer levels. D-dimer levels greater than 500 ng/mL had a specificity of only 25% in patients who underwent pulmonary arteriography for a suspected pulmonary embolism.
      • Goldhaber SZ
      • Simons GR
      • Elliott CG
      • et al.
      Quantitative plasma D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism.
      Patients with disseminated intravascular coagulation (DIC) and active bleeding should receive fresh frozen plasma. The patient's thrombocytosis, likely secondary to an acute phase reaction, and normal coagulation parameters excluded DIC, making the administration of fresh frozen plasma unnecessary. Although patients with DIC can have purpura, the finding is nonspecific. In addition to active bleeding, other common clinical manifestations of DIC include renal dysfunction and platelet levels less than 100 × 109/L.
      The emergency department obtained blood cultures and admitted the patient. He received broad-spectrum antibiotic therapy with doxycycline, ceftriaxone, and clindamycin. He remained afebrile (peak temperature, 37.8μC) and hemodynamically stable.
      • 2.
        Which one of the following tests would most facilitate diagnosis?
        • a.
          Erythrocyte sedimentation rate (ESR)
        • b.
          Antinuclear antibody (ANA) assay
        • c.
          Urinalysis
        • d.
          Lymph node biopsy
        • e.
          Serum protein electrophoresis
      The next test should help determine the extent of disease in organ systems. Our patient's clinical presentation and initial laboratory evaluations led us to suspect a multisystem process, including the skin (purpuric rash with some palpable nodules), lungs (bilateral infiltrates on chest radiograph), peripheral vasculature (pretibial and pedal edema), musculoskeletal system (migratory, large joint polyarthritis), and upper respiratory tract (necrotic ulcerations of oral mucosa). He also presented with constitutional symptoms (fever, lymphadenopathy, lethargy, and malaise) suggestive of a systemic process.
      Obtaining ESR and ANA titers could provide further evidence of an active inflammatory process, but both tests act as nonspecific disease markers. The ESR has shortcomings as a diagnostic test because it indirectly measures many acute phase reactants. Anemia can also elevate ESR titers. The absence of ANA titers holds negative predictive value in patients suspected of having systemic lupus erythematosus (SLE). Our patient's elevated ANA titers did not facilitate diagnosis because similarly elevated titers occur in patients with SLE, rheumatoid arthritis, vasculitis, or other connective tissue disorders, as well as in many healthy adults. If SLE were suspected, the anti-double-stranded DNA antibody test provides greater specificity.
      Urinalysis to assess for an inflammatory process of the genitourinary system such as glomerulonephritis is the most appropriate next test. Normal creatinine levels do not imply normal renal function. Decreased glomerular filtration could be present but not yet reflected in serum creatinine levels.
      Our patient had constitutional symptoms and hematologic abnormalities on presentation. Because clinical findings did not suggest lymphoma, lymph node biopsy, which can be overly invasive, was unnecessary. Serum protein electrophoresis facilitates the evaluation of immunodeficiency states and lymphoproliferative disorders such as multiple myeloma or Waldenström macroglobulinemia. However, neither serum protein electrophoresis nor lymph node biopsy was likely to focus the currently broad diagnostic algorithm in our patient with multisystem disease.
      Urinalysis demonstrated leukocyte and oval fat body casts with 11 to 20 red blood cells (<25% dysmorphic) and 1 to 3 white blood cells per high-powered field. Gram stains and cultures were negative. A 24-hour urine collection sample contained 1014 mg of protein. These findings suggested active glomerulonephritis. Computed tomography of the chest subsequently revealed bilateral consolidation and interstitial infiltrates, scattered bilateral nodules, and no mediastinal lymphadenopathy. The patient tested negative for human immunodeficiency virus.
      • 1.
        Given the clinical presentation, laboratory findings, and radiologic evaluation, which one of the following is the most appropriate next test?
        • a.
          Serology for Rocky Mountain spotted fever (RMSF)
        • b.
          Histoplasma antibody screen
        • c.
          Lyme disease screening enzyme-linked immunosorbent assay
        • d.
          Rheumatoid factor measurement
        • e.
          Antineutrophilic cytoplasmic antibody (ANCA) assay
      The patient had a progressive, multisystem disease with subacute onset involving the skin, joints, lungs, kidneys, and mucous membranes. Few conditions other than infection or systemic inflammatory conditions cause this constellation of findings.
      Rocky Mountain spotted fever is a tick-borne illness. The patient's history of substantial outdoor exposure in the summer months placed him at risk for tick-borne disease. Rocky Mountain spotted fever is most prevalent in the southern and southeastern United States. The etiologic agent is the gramnegative intracellular bacterium Rickettsia rickettsii. Symptoms typically develop 5 to 7 days after exposure. Manifestations include nonspecific abdominal pain followed by development of a maculopapular, erythematous, nonpruritic rash with distal to proximal progression. Serology for RMSF was deemed unnecessary in our patient because he presented several weeks after possible tick exposures, had not traveled to the southeastern United States, and had purpuric lesions that were atypical for RMSF.
      Our patient was at risk of histoplasmosis because he resided in the upper midwest. However, histoplasmosis infection, which typically occurs in the lungs and rarely disseminates, was unlikely in our patient with multisystem disease. Even disseminated histoplasmosis, which usually occurs in immunocompromised patients, rarely involves the renal system and skin to the extent observed in our patient. Therefore, our patient's symptoms did not warrant a histoplasma antibody screen.
      Also a tick-borne illness, Lyme disease is characterized by erythema migrans, a classic red rash with central clearing. Other clinical findings include generalized fatigue, myalgias, arthralgias, and fever. Patients do not typically manifest upper respiratory or gastrointestinal symptoms and signs. Although our patient had risk factors for exposure to Lyme disease, his rash and extent of organ involvement were not typical of this condition.
      Our patient had a peripheral polyarthritis also found in rheumatoid arthritis. Rheumatoid arthritis typically involves distal, small joints and is characterized by morning stiffness and joint erosions on radiograph. Because our patient's polyarthritis was progressive and affected large joints, measurement of rheumatoid factor would not facilitate diagnosis.
      If small-vessel vasculitis is suspected, ANCA testing should be performed. Diseases that are associated with reaction between ANCA and either proteinase 3 (PR3) or myeloperoxidase (MPO) antigens include Wegener granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS). Vasculitis was suspected in our patient because he presented with systemic, nonspecific findings (arthralgias, fatigue, and lethargy) and signs of specific organ dysfunction (microhematuria and pulmonary infiltrates). The cutaneous palpable purpura coupled with oropharynx ulcerations and areas of necrosis suggest a vasculitic rather than an infectious process. The most appropriate next step in this case is ANCA evaluation.
      Vasculitis evaluation revealed a strongly positive PR3 antigen (>100 U/mL) on enzyme-linked immunosorbent assay. Cytoplasmic ANCA (c-ANCA) titer was 1:512 on indirect immunofluorescence. The MPO antigen, perinuclear ANCA (p-ANCA), and ANA test results were negative.
      • 1.
        Given these test results and the clinical syndrome, which one of the following is the most likely diagnosis?
        • a.
          Churg-Strauss syndrome
        • b.
          Microscopic polyangiitis
        • c.
          Wegener granulomatosis
        • d.
          Henoch-Schönlein purpura (HSP)
        • e.
          Polyarteritis nodosa (PAN)
      Criteria for diagnosis of CSS, a necrotizing small-vessel vasculitis of the airway, include asthma, paranasal sinusitis, pulmonary infiltrates, mononeuritis multiplex, eosinophilia greater than 10% of the white blood cell differential, and evidence of vasculitis on pathology specimens.
      • Masi AT
      • Hunder GG
      • Lie JT
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).
      This patient had no evidence of asthma, eosinophilia, or mononeuritis multiplex, making CSS unlikely.
      Microscopic polyangiitis presents commonly with kidney disease, fever, weight loss, and skin findings that include purpura and nodules, making it clinically similar to WG. However, this patient's oral ulcerations typify upper respiratory tract findings of WG, not MPA. Also, p-ANCA/MPO occurs more commonly in MPA than the c-ANCA/PR3 pattern observed in our case.
      • Guillevin L
      • Durand-Gasselin B
      • Cevallos R
      • et al.
      Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.
      Therefore, MPA is not the diagnosis.
      This patient has WG. Not only does he meet clinical criteria as outlined by the 1990 guidelines of the American College of Rheumatology (see Discussion),
      • Leavitt RY
      • Fauci AS
      • Bloch DA
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.
      but he also has a positive c-ANCA/PR3 pattern. Although specific results vary, studies generally agree that the specificity of cANCA for WG exceeds 80%.
      • Hoffman GS
      • Specks U
      Antineutrophil cytoplasmic antibodies.
      Findings for HSP, a vasculitis occurring predominantly in children aged 3 to 15 years, include palpable purpura, joint pain, abdominal pain, and kidney disease without evidence of coagulopathy. Although 10% of cases occur in adults, HSP has no known association with PR3- or MPO-ANCA.
      Unlike CSS, MPA, and WG, PAN is a systemic vasculitis of both small and medium-sized arteries. Clinical manifestations include systemic symptoms of lethargy, weakness, fever, weight loss, and arthralgias associated with hypertension and mononeuropathies or polyneuropathies.
      • Lightfoot Jr, RW
      • Michel BA
      • Bloch DA
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa.
      In our case, PAN is very unlikely because it rarely involves the pulmonary system or a positive ANCA result.
      Evaluation identified no infectious or hematologic etiologies for the patient's disease manifestations. Blood, skin, and synovial fluid cultures showed no growth. Hepatitis B and C studies were negative. Peripheral blood smear revealed hypochromic and microcytic erythrocytes.
      • 1.
        Given the severity of this patient's disease, which one of the following is the most appropriate initial treatment regimen?
        • a.
          Glucocorticoids and cyclophosphamide
        • b.
          Glucocorticoids and methotrexate
        • c.
          Glucocorticoids and azathioprine
        • d.
          Glucocorticoids and intravenous immunoglobulin
        • e.
          Glucocorticoids and plasmapheresis
      The early-onset anti-inflammatory effects of intravenous or oral glucocorticoids make them part of the initial standard treatment regimen for patients with WG. Treatment of severe, organ-threatening WG requires intravenous glucocorticoids, whereas limited disease can be managed with oral prednisone. If WG is severe, additional treatment is required. Our patient meets the criteria for severe disease because of his microhematuria with urinary casts.
      • Stone JH
      • Wegener's Granulomatosis Etanercept Trial Research Group
      Limited versus severe Wegener's granulomatosis: baseline data on patients in the Wegener's granulomatosis etanercept trial.
      Other markers of severe disease include hypoxemia and neurologic changes. Cyclophosphamide, in addition to glucocorticoids, is the most effective initial treatment regimen for severe, organ-threatening WG.
      For patients with limited disease that does not endanger organ systems or life, weekly oral methotrexate is the treatment of choice.
      • Specks U
      Methotrexate for Wegener's granulomatosis: what is the evidence? [editorial].
      It limits toxicity associated with prolonged cyclophosphamide use such as bladder cancer, myelodysplasia, and lymphoma. Azathioprine can help maintain but does not induce remission.
      • Jayne D
      • Rasmussen N
      • Andrassy K
      • European Vasculitis Study Group
      • et al.
      A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.
      In our case, intravenous immunoglobulin and plasmapheresis were not indicated as initial treatment.
      Our patient received 1 g/d of intravenous methylprednisolone for 3 days with an extremely favorable clinical response. We prescribed 60 mg/d of prednisone for the 10 days after hospital discharge followed by 40 mg/d of prednisone for 6 weeks. We initiated 150 mg/d of oral cyclophosphamide. The patient received 80/400 mg/d of oral trimethoprim-sulfamethoxazole after hospitalization as prophylaxis for Pneumocystis pneumonia.

      DISCUSSION

      Wegener granulomatosis is an idiopathic, systemic, small-vessel vasculitis characterized by necrotizing granulomatosis inflammation of the upper and lower respiratory tracts and glomerulonephritis.
      • Leavitt RY
      • Fauci AS
      • Bloch DA
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Prevalence and annual incidence rates range from 24 to 157 per million and 3 to 14 per million, respectively.
      • Mahr AD
      • Neogi T
      • Merkel PA
      Epidemiology of Wegener's granulomatosis: lessons from descriptive studies and analyses of genetic and environmental risk determinants.
      Wegener granulomatosis affects patients in midlife, with the mean age of onset in the fifth decade.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      • Wegener's Granulomatosis Etanercept Trial (WGET) Research Group
      Etanercept plus standard therapy for Wegener's granulomatosis.
      Men possess a slightly higher risk of developing WG, and it remains rare in black people.
      • Wegener's Granulomatosis Etanercept Trial (WGET) Research Group
      Etanercept plus standard therapy for Wegener's granulomatosis.
      Upper respiratory symptoms such as sinusitis, otitis media, ear pain, and oral lesions are the most common reasons for clinical presentation. Onset of symptoms precedes diagnosis by a median of 4.7 months.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Other common findings at diagnosis include pulmonary involvement (45% of patients), such as infiltrates or nodules on chest radiograph, hemoptysis, or pleuritis; fever (23%); glomerulonephritis (18%); or skin changes (13%). Our patient's bullous skin lesions are an atypical manifestation of WG. As observed in our case, two-thirds of patients develop musculoskeletal symptoms at some point in the disease process, which can lead to an erroneous diagnosis of rheumatoid arthritis in patients with WG who have a positive rheumatoid factor.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      The American College of Rheumatology developed 4 criteria for WG, 2 of which have 88% sensitivity and 92% specificity for WG: (1) nasal or oral inflammation characterized by oral ulcers or bloody/purulent nasal discharge; (2) nodules, infiltrates, or cavitary lesions on chest radiograph; (3) microhematuria or red blood cell casts in the urine; and (4) intra-arteriolar or periarteriolar granulomatous inflammation on biopsy.
      • Leavitt RY
      • Fauci AS
      • Bloch DA
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.
      Untreated, WG carries a 1-year mortality of up to 80%.
      • Walton EW
      Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis).
      Initial care includes glucocorticoids, and disease severity dictates the choice of concomitant medications. Patients with non-life-threatening or limited disease (frequently defined by lack of renal involvement) benefit from weekly oral methotrexate therapy for remission induction.
      • Specks U
      Methotrexate for Wegener's granulomatosis: what is the evidence? [editorial].
      Relapse remains a common problem for patients with WG. A recent study with a mean follow-up of 27 months showed relapse rates of 57% despite therapy.
      • Wegener's Granulomatosis Etanercept Trial (WGET) Research Group
      Etanercept plus standard therapy for Wegener's granulomatosis.
      Despite optimal treatment, patients with WG develop substantial morbidity, often due to renal insufficiency or treatment toxicity. A series of 158 patients reported a 20% mortality rate, with more than half of those cases directly attributable to WG.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Wegener granulomatosis remains a severe disease. Although appropriate diagnosis improves short-term outcomes, long-term prognosis remains guarded.

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