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61-Year-Old Man With Dyspnea and Bilateral Foot Drop
Mayo Clin Proc, April 2002, Vol 77
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61-Year-Old Man With Dyspnea and Bilateral Foot Drop LEE D. CRANMER, MD, PHD*; KENNETH J. WARRINGTON, MD†; AND STEVEN R. YTTERBERG, MD‡
A
61-year-old man was transferred to Mayo Clinic, Rochester, Minn, because of dyspnea, rash, and bilateral leg weakness. He had a 16-year history of severe asthma. Eight weeks before our evaluation, the patient presented to his local physician because of cough, wheezing, dyspnea, and fever. Lower respiratory tract infection with asthma exacerbation was diagnosed, and he was treated with oral antibiotics and corticosteroids, in addition to bronchodilators by metered-dose inhaler (MDI). Six weeks later the patient was admitted to a local hospital because of persistent respiratory symptoms and fever unresponsive to outpatient therapy. At that time, his white blood cell (WBC) count was 32 × 109/L (reference ranges shown parenthetically) (3.5-10.5 × 109/L) with 62% eosinophils (0%-7%). Chest radiography revealed bilateral alveolar infiltrates. Bronchoscopy was negative for structural abnormalities, and culture of bronchoalveolar lavage fluid was negative. The patient was treated with nebulized bronchodilators and intravenously administered antibiotics and corticosteroids. During hospitalization, he developed a purpuric, nonblanching rash on his torso and lower extremities. Additionally, the patient complained of paresthesias in his distal lower extremities. The paresthesias gradually progressed, and he developed left hand weakness, bilateral lower extremity weakness, and difficulty with ambulation.
Eosinophilia is associated with various pathologic conditions. The patient’s presenting features of cough, dyspnea, and fever could be consistent with chronic eosinophilic pneumonia. Most patients have peripheral eosinophilia, elevated eosinophil count in bronchoalveolar lavage fluid, and peripheral infiltrates on chest radiographs.1 Allergic bronchopulmonary aspergillosis is also characterized by pulmonary infiltrates, commonly with central bronchiectasis. However, our patient’s multisystemic disease argues against both of these possibilities. Helminthiasis is often accompanied by eosinophilia. During their life cycle, some helminths migrate through the lungs of their hosts, causing transient infiltrates. Pulmonary involvement is a feature of disseminated strongyloidiasis in immunocompromised hosts and has been observed with corticosteroid use. Absence of travel to endemic areas argues against this possibility in our patient. The IHS is characterized by eosinophilia and multiorgan disease, including both pulmonary and neurologic findings. Pulmonary involvement in IHS typically includes persistent cough, rather than infiltrates. Cardiac involvement, which was not present in our patient, occurs in about 60% of patients with IHS. Moreover, this diagnosis requires eosinophilia of at least 6 months’ duration. Thus, IHS, although not entirely excluded, seems unlikely. A vasculitic syndrome should be considered likely. Vessels of any type, in any organ, can be affected, and multiorgan involvement is characteristic of this group of disorders. The pattern of organ involvement, in combination with serologic markers and histopathologic findings, can help distinguish between specific types of vasculitis. The patient was transferred to our hospital because of worsening neurologic symptoms and lack of response to therapy. On further questioning, he reported profound fatigue, malaise, and a recent 18-kg weight loss. His medical history included nasal polyposis and recurrent sinusitis with eosinophils noted on histological study of the nasal mucosa. The patient also had a history of stable coronary artery disease, hyperlipidemia, benign prostatic hypertrophy, gastroesophageal reflux disease, and adenomatous colonic polyps. Medications that the patient was taking at the time of transfer included intravenous methylprednisolone, salmeterol MDI, cromolyn sodium MDI, budesonide MDI, tamsulosin, metoprolol, pantoprazole, atorvastatin, buspirone,
1. Which one of the following is the most likely cause of this patient’s eosinophilia and pulmonary infiltrates? a. Chronic eosinophilic pneumonia b. Allergic bronchopulmonary aspergillosis c. Parasitic infection d. Idiopathic hypereosinophilic syndrome (IHS) e. Vasculitis
*Resident in Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minn. †Fellow in Rheumatology, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minn. ‡Advisor to resident and fellow and Consultant in Rheumatology, Mayo Clinic, Rochester, Minn. See end of article for correct answers to questions. Address reprint requests and correspondence to Steven R. Ytterberg, MD, Division of Rheumatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:363-366
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and oxycodone. He had been taking zafirlukast for about 18 months. This was replaced with montelukast 6 weeks before admission, which was discontinued 3 weeks before admission. On examination, the cachectic-appearing patient was afebrile, blood pressure was 116/76 mm Hg, heart rate was 96 beats/min, and respirations were 24/min. Oxygen saturation was 98% while the patient was breathing room air. His nasal mucosa was erythematous but without ulceration. A 4-mm ulcer was noted in his left pharyngeal pillar. Trace ankle edema was evident. Respiratory examination revealed bilateral expiratory wheezes and scattered inspiratory crackles at the lung bases. The patient had multiple discrete ecchymotic macules scattered on his arms, lower torso, and lower extremities. Muscle strength was diminished diffusely in all 4 extremities, and focal deficits, consistent with mononeuritis multiplex, were also present. He had a left wrist drop and bilateral foot drop. Proprioception in his toes was diminished. Findings on the rest of the examination were normal. 2. Which one of the following diagnostic tests would be most useful to evaluate the patient at this time? a. Erythrocyte sedimentation rate (ESR) b. Urinalysis c. Sural nerve biopsy d. Antinuclear antibody (ANA) e. Echocardiography Our patient has evidence of a multisystemic illness, including pulmonary and neurologic involvement, in the setting of eosinophilia and mild edema. Initial diagnostic testing should determine the extent of disease involvement of systems that might not be readily discernible by history and physical examination, followed by selective testing to confirm or refute diagnostic hypotheses. Laboratory testing also can provide objective, quantifiable measures of disease activity after treatment is initiated. The ESR is a nonspecific test of inflammation. If the ESR is elevated, it can be monitored to show treatment response, but the ESR is not helpful for making a specific diagnosis. Urinalysis is important at this time to document the presence of renal involvement. A sural nerve biopsy can aid in the diagnosis of mononeuritis multiplex, but tests to screen for other organ involvement are of more importance initially. A positive ANA is not diagnostic but suggests lupus or other connective tissue disease, disorders that can involve multiple organ systems. Ultimately, ANA will be useful, but characterization of the extent of involvement should be of primary importance at this stage. In a patient with eosinophilia, echocardiography can be used to screen for eosinophilic cardiac disease. This disease would be important to document in the eventual evaluation of this patient because
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of its adverse prognostic significance and need for an aggressive treatment approach. Initial laboratory findings were as follows: hemoglobin, 11.8 g/dL (13.5-17.5 g/dL); WBC count, 9.4 × 109/L with 0% eosinophils; platelet count, 334 × 109/L (150-450 × 109/ L); ESR, 30 mm/1 h (0-22 mm/1 h); and creatinine, 0.6 mg/ dL (0.8-1.2 mg/dL). Urinalysis was positive for glycosuria and proteinuria (predicted 24-hour protein, 1280 mg/24 h); urine microscopy revealed 1 to 3 red blood cells per highpower field (<1), 4 to 10 WBC per high-power field (1-3), occasional hyaline casts, and occasional granular casts and dysmorphic red blood cells. His plasma glucose level was 199 mg/dL (70-100 mg/dL). Results of liver function studies were abnormal: aspartate aminotransferase, 41 U/L (1231 U/L); alanine aminotransferase, 111 U/L (10-45 U/L); albumin, 2.8 g/dL (3.5-5.0 g/dL); and alkaline phosphatase, 347 U/L (98-251 U/L). ANA was negative, but antineutrophil cytoplasmic antibody (ANCA) assay was positive. Chest radiography showed mild hyperinflation in both lungs without infiltrates. Findings on bone marrow biopsy performed at the patient’s local institution were reviewed; the specimen showed slight hypercellularity with eosinophilia and unremarkable eosinophil maturation, consistent with secondary eosinophilia. 3. Which one of the following diagnoses is most likely based on the clinical and laboratory findings in our patient? a. Polyarteritis nodosa (PAN) b. Microscopic polyangiitis (MPA) c. Cryoglobulinemic vasculitis d. Churg-Strauss syndrome (CSS) e. Wegener granulomatosis (WG) PAN is characterized pathologically by focal segmental necrotizing vasculitis of medium- and small-sized arteries.2 Constitutional symptoms, motor deficits in the form of mononeuritis multiplex, purpuric skin lesions, kidney involvement, and gastrointestinal symptoms are common, but pulmonary involvement is rare. Microscopic polyangiitis is a focal segmental necrotizing vasculitis of smaller vessels than typically involved in PAN.2,3 Renal involvement is prominent in MPA, and many patients experience pulmonary disease in the form of alveolar hemorrhage, pneumonitis, and pleuritis. Neither PAN nor MPA is associated with eosinophilia. Cryoglobulinemic vasculitis is an immune complex– mediated vasculitis affecting small vessels, often caused by hepatitis C infection. Purpuric skin lesions, weakness, arthralgias, and peripheral neurologic findings, including mononeuritis multiplex and motor or sensory polyneuropathy, are common, but pulmonary involvement is rare. ANCA assays are negative, and eosinophilia is not a feature of this illness. Churg-Strauss syndrome, a form of necrotizing vas-
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culitis associated with asthma and eosinophilia,4-6 can explain the clinical features of our patient’s illness. Wegener granulomatosis is a multisystemic vasculitis associated with granulomatous necrotizing inflammation.7 Upper airway, pulmonary, and renal involvement are especially prominent. Neurologic findings can include mononeuritis multiplex. Cutaneous manifestations, including purpura, are frequent. ANCA assays are positive in 55% to 88% of patients with WG. Although providing a good explanation for our patient’s clinical symptoms and some laboratory findings, WG cannot explain his eosinophilia. 4. Which one of the following diagnostic modalities would most likely confirm the suspected diagnosis in this patient? a. Characterization of the ANCA assay as peripheral or cytoplasmic pattern b. Hepatitis serologies c. Tissue biopsy d. Electromyography e. Abdominal angiography ANCA serologies can be helpful in the diagnosis and classification of vasculitis.8 Two patterns of ANCA have been described on immunofluorescence assay: cytoplasmic (c-ANCA) and perinuclear (p-ANCA). About 50% to 60% of patients with CSS are seropositive for ANCA,2,5 predominantly p-ANCA, whereas patients are infrequently positive for c-ANCA. However, a positive p-ANCA is nonspecific for CSS because this can be found in various other conditions, including MPA and glomerulonephritis. Hepatitis serologies are useful in the evaluation of patients with suspected vasculitis. Hepatitis B has been linked to PAN.2 Hepatitis C virus infection has been noted less frequently in PAN but is strongly associated with cryoglobulinemic vasculitis. Although cases of CSS associated with hepatitis C virus infection have been reported, an etiologic association with hepatitis is not commonly noted. By definitively showing necrotizing vasculitis, tissue biopsy is the most important of the diagnostic studies presented. Electromyography can be helpful in assessing neuropathy. Peripheral neuropathy, often in the form of mononeuritis multiplex, is found in 63% to 92% of reported cases of CSS.2,4-6 Although electromyography would be useful to document the neuropathy objectively and to assess its extent, it would not confirm the diagnosis of CSS. Abdominal angiography may show areas of narrowing and aneurysmal dilation in vessels, as can occur in PAN. With no abdominal symptoms, abdominal angiography would likely be of limited benefit in our patient. Our patient’s ANCA assay had a p-ANCA pattern; myeloperoxidase (MPO) antibodies were detected. Studies for cryoglobulins were negative. Serum protein electro-
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phoresis showed hypoalbuminemia with no monoclonal spike. Serologic tests for hepatitis B and C virus infection were negative. Computed tomography of the chest, abdomen, and pelvis showed no mass lesions or lymphadenopathy. Echocardiography revealed normal chamber sizes with an estimated left ventricular ejection fraction of 50% to 55%. No intracardiac thrombus or evidence of eosinophilic heart disease was seen. Sural nerve biopsy showed normal findings without evidence of small vessel vasculitis. Skin biopsy showed necrotizing vasculitis with eosinophilia, consistent with CSS. Although necrotizing vasculitis, perivascular eosinophilia, and granulomas are pathologic hallmarks of disease, not all are required for diagnosis.9 5. Which one of the following treatment approaches would most likely benefit our patient? a. High-dose corticosteroids alone b. High-dose corticosteroids with cyclophosphamide c. Cyclosporine d. Plasma exchange e. Interferon alfa Only a limited number of therapeutic trials for CSS have been reported. Corticosteroids alone or combined with cyclophosphamide have been shown to be efficacious.4,5,10 If a patient has life-threatening or major organ disease, both glucocorticoids and cyclophosphamide should be initiated. One patient with severe disease resistant to corticosteroids and cyclophosphamide responded favorably to cyclosporine. Interferon alfa has been reported to have a beneficial effect in patients with CSS in whom response to standard therapy was incomplete.11 Interferon alfa inhibits degranulation and effector function of eosinophils and results in a dose-dependent decrease in eosinophil count, which tends to parallel disease activity. At present, both cyclosporine and interferon alfa therapy should be considered secondline therapies for CSS. Plasma exchanges combined with corticosteroids and cyclophosphamide do not improve outcome in patients with CSS.10 Our patient received intravenous methylprednisolone (1 g/d) for 5 days, followed by oral prednisone, 60 mg/d. Because of progressive neurologic symptoms, oral cyclophosphamide was administered at 100 mg/d (2 mg/kg). Trimethoprim-sulfamethoxazole was added for prophylaxis for Pneumocystis carinii pneumonia. Corticosteroidassociated glucose intolerance was managed with dietary control and insulin. Gradually, our patient’s status improved, allowing transfer to a rehabilitation unit. He was dismissed home after several weeks. At dismissal, we recommended that he continue to receive prednisone and cyclophosphamide therapy until all signs of disease had disappeared. After that, gradual tapering of corticosteroid and cyclophosphamide therapy was to be initiated.
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DISCUSSION Our patient had necrotizing vasculitis associated with asthma, eosinophilia, pulmonary infiltrates, mononeuritis multiplex, and cutaneous lesions. Churg-Strauss vasculitis was tentatively diagnosed before transfer to our institution, but inadequate response to therapy led to reconsideration of the diagnosis. The American College of Rheumatology has established classification criteria for CSS.12 Four of the following 6 findings are required for the diagnosis: history of asthma, peripheral blood eosinophilia (>10%), mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormalities, and a biopsy specimen containing a blood vessel with extravascular eosinophilic inflammation. Our patient met all of these criteria. Serologic tests for ANCA antibodies can be helpful in evaluating patients with suspected vasculitis but are nonspecific. The c-ANCA and p-ANCA patterns detected by immunofluorescence microscopy reflect recognition of different antigens by autoantibodies in patients’ sera. Antibodies to proteinase 3 produce a c-ANCA pattern. Antibodies to several different antigens can produce a p-ANCA immunofluorescence pattern, but only those directed toward MPO are clinically important. The presence of a positive c-ANCA reacting with proteinase 3 or p-ANCA reacting with MPO is highly specific for one of the ANCAassociated forms of vasculitis—WG, MPA, or CSS. ANCA assays are not sensitive for CSS. Only about one half of patients with CSS have a positive ANCA, usually with a pANCA pattern and specificity for MPO.5 The cause of CSS is unknown. Leukotriene inhibitor use has been implicated in some cases of CSS, but a true causal relationship has not been shown.9 In individuals with corticosteroid-dependent asthma, CSS has developed when systemic corticosteroid therapy was tapered after addition of inhaled steroid therapy. Similarly, onset of CSS has been associated with tapering of systemic corticosteroid therapy after control of asthma with leukotriene inhibitors. This has led to speculation that the pathogenetic mechanism involves corticosteroid dose tapering in susceptible individuals, made possible by the leukotriene inhibitor therapy. However, in at least 2 cases, CSS was associated with leukotriene inhibitor use without prior systemic corticosteroid therapy. Our patient fits in this latter group. However, therapy issues may be incidental; the important association may be the presence of asthma. In case reports of patients with CSS associated with leukotriene inhibitors, treatment has relied primarily on systemic corticosteroid therapy. Adjunctive immunosuppression with use of cyclophosphamide, azathioprine, or methotrexate has been used in patients not responding to corticosteroid therapy. Success with this approach has not
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been absolute because some patients have required longterm, high-dose corticosteroid therapy to prevent relapse. We discontinued leukotriene inhibitor therapy in our patient and initiated an immunosuppressive regimen of highdose corticosteroids and cyclophosphamide. The rarity of classic CSS, let alone that associated with leukotriene inhibitors, has hampered attempts at defining the efficacy of possible therapies in a randomized manner. Several promising treatments are available. Immunosuppressive therapy for CSS with corticosteroids and cyclophosphamide is effective.10 Case reports have suggested benefit from treatment with intravenous immunoglobulin. Case reports have also shown that cyclosporine and interferon alfa therapy may be beneficial.11 These results await more definitive confirmation in the treatment of this difficult clinical problem.
REFERENCES 1.
2. 3.
4.
5.
6.
7. 8.
9.
10.
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12.
Marchand E, Reynaud-Gaubert M, Lauque D, Durieu J, Tonnel AB, Cordier JF, Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Idiopathic chronic eosinophilic pneumonia: a clinical and follow-up study of 62 cases. Medicine (Baltimore). 1998;77:299-312. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Lupus. 1998;7:238-258. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421-430. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the ChurgStrauss syndrome. Medicine (Baltimore). 1984;63:65-81. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients. Medicine (Baltimore). 1999;78:26-37. Sehgal M, Swanson JW, DeRemee RA, Colby TV. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc. 1995; 70:337-341. Langford CA, Hoffman GS. Wegener’s granulomatosis. Thorax. 1999;54:629-637. Ahmed AE, Peter JB, Shoenfeld YY. ANCA testing: new developments and clinical implications. Clin Rev Allergy Immunol. 1998; 16:303-311. Weller PF, Plaut M, Taggart V, Trontell A. The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol. 2001;108:175-183. Guillevin L, Lhote F, Cohen P, et al. Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis: a prospective, randomized trial in sixty-two patients. Arthritis Rheum. 1993;38:1638-1645. Tatsis E, Schnabel A, Gross WL. Interferon-alpha treatment of four patients with the Churg-Strauss syndrome. Ann Intern Med. 1998; 129:370-374. 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). Arthritis Rheum. 1990;33:1094-1100.
Correct answers: 1. e, 2. b, 3. d, 4. c, 5. b
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61-Year-Old Man With Dyspnea and Bilateral Foot Drop LEE D. CRANMER, MD, PHD*; KENNETH J. WARRINGTON, MD†; AND STEVEN R. YTTERBERG, MD‡
A
61-year-old man was transferred to Mayo Clinic, Rochester, Minn, because of dyspnea, rash, and bilateral leg weakness. He had a 16-year history of severe asthma. Eight weeks before our evaluation, the patient presented to his local physician because of cough, wheezing, dyspnea, and fever. Lower respiratory tract infection with asthma exacerbation was diagnosed, and he was treated with oral antibiotics and corticosteroids, in addition to bronchodilators by metered-dose inhaler (MDI). Six weeks later the patient was admitted to a local hospital because of persistent respiratory symptoms and fever unresponsive to outpatient therapy. At that time, his white blood cell (WBC) count was 32 × 109/L (reference ranges shown parenthetically) (3.5-10.5 × 109/L) with 62% eosinophils (0%-7%). Chest radiography revealed bilateral alveolar infiltrates. Bronchoscopy was negative for structural abnormalities, and culture of bronchoalveolar lavage fluid was negative. The patient was treated with nebulized bronchodilators and intravenously administered antibiotics and corticosteroids. During hospitalization, he developed a purpuric, nonblanching rash on his torso and lower extremities. Additionally, the patient complained of paresthesias in his distal lower extremities. The paresthesias gradually progressed, and he developed left hand weakness, bilateral lower extremity weakness, and difficulty with ambulation.
Eosinophilia is associated with various pathologic conditions. The patient’s presenting features of cough, dyspnea, and fever could be consistent with chronic eosinophilic pneumonia. Most patients have peripheral eosinophilia, elevated eosinophil count in bronchoalveolar lavage fluid, and peripheral infiltrates on chest radiographs.1 Allergic bronchopulmonary aspergillosis is also characterized by pulmonary infiltrates, commonly with central bronchiectasis. However, our patient’s multisystemic disease argues against both of these possibilities. Helminthiasis is often accompanied by eosinophilia. During their life cycle, some helminths migrate through the lungs of their hosts, causing transient infiltrates. Pulmonary involvement is a feature of disseminated strongyloidiasis in immunocompromised hosts and has been observed with corticosteroid use. Absence of travel to endemic areas argues against this possibility in our patient. The IHS is characterized by eosinophilia and multiorgan disease, including both pulmonary and neurologic findings. Pulmonary involvement in IHS typically includes persistent cough, rather than infiltrates. Cardiac involvement, which was not present in our patient, occurs in about 60% of patients with IHS. Moreover, this diagnosis requires eosinophilia of at least 6 months’ duration. Thus, IHS, although not entirely excluded, seems unlikely. A vasculitic syndrome should be considered likely. Vessels of any type, in any organ, can be affected, and multiorgan involvement is characteristic of this group of disorders. The pattern of organ involvement, in combination with serologic markers and histopathologic findings, can help distinguish between specific types of vasculitis. The patient was transferred to our hospital because of worsening neurologic symptoms and lack of response to therapy. On further questioning, he reported profound fatigue, malaise, and a recent 18-kg weight loss. His medical history included nasal polyposis and recurrent sinusitis with eosinophils noted on histological study of the nasal mucosa. The patient also had a history of stable coronary artery disease, hyperlipidemia, benign prostatic hypertrophy, gastroesophageal reflux disease, and adenomatous colonic polyps. Medications that the patient was taking at the time of transfer included intravenous methylprednisolone, salmeterol MDI, cromolyn sodium MDI, budesonide MDI, tamsulosin, metoprolol, pantoprazole, atorvastatin, buspirone,
1. Which one of the following is the most likely cause of this patient’s eosinophilia and pulmonary infiltrates? a. Chronic eosinophilic pneumonia b. Allergic bronchopulmonary aspergillosis c. Parasitic infection d. Idiopathic hypereosinophilic syndrome (IHS) e. Vasculitis
*Resident in Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minn. †Fellow in Rheumatology, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, Minn. ‡Advisor to resident and fellow and Consultant in Rheumatology, Mayo Clinic, Rochester, Minn. See end of article for correct answers to questions. Address reprint requests and correspondence to Steven R. Ytterberg, MD, Division of Rheumatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:363-366
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and oxycodone. He had been taking zafirlukast for about 18 months. This was replaced with montelukast 6 weeks before admission, which was discontinued 3 weeks before admission. On examination, the cachectic-appearing patient was afebrile, blood pressure was 116/76 mm Hg, heart rate was 96 beats/min, and respirations were 24/min. Oxygen saturation was 98% while the patient was breathing room air. His nasal mucosa was erythematous but without ulceration. A 4-mm ulcer was noted in his left pharyngeal pillar. Trace ankle edema was evident. Respiratory examination revealed bilateral expiratory wheezes and scattered inspiratory crackles at the lung bases. The patient had multiple discrete ecchymotic macules scattered on his arms, lower torso, and lower extremities. Muscle strength was diminished diffusely in all 4 extremities, and focal deficits, consistent with mononeuritis multiplex, were also present. He had a left wrist drop and bilateral foot drop. Proprioception in his toes was diminished. Findings on the rest of the examination were normal. 2. Which one of the following diagnostic tests would be most useful to evaluate the patient at this time? a. Erythrocyte sedimentation rate (ESR) b. Urinalysis c. Sural nerve biopsy d. Antinuclear antibody (ANA) e. Echocardiography Our patient has evidence of a multisystemic illness, including pulmonary and neurologic involvement, in the setting of eosinophilia and mild edema. Initial diagnostic testing should determine the extent of disease involvement of systems that might not be readily discernible by history and physical examination, followed by selective testing to confirm or refute diagnostic hypotheses. Laboratory testing also can provide objective, quantifiable measures of disease activity after treatment is initiated. The ESR is a nonspecific test of inflammation. If the ESR is elevated, it can be monitored to show treatment response, but the ESR is not helpful for making a specific diagnosis. Urinalysis is important at this time to document the presence of renal involvement. A sural nerve biopsy can aid in the diagnosis of mononeuritis multiplex, but tests to screen for other organ involvement are of more importance initially. A positive ANA is not diagnostic but suggests lupus or other connective tissue disease, disorders that can involve multiple organ systems. Ultimately, ANA will be useful, but characterization of the extent of involvement should be of primary importance at this stage. In a patient with eosinophilia, echocardiography can be used to screen for eosinophilic cardiac disease. This disease would be important to document in the eventual evaluation of this patient because
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of its adverse prognostic significance and need for an aggressive treatment approach. Initial laboratory findings were as follows: hemoglobin, 11.8 g/dL (13.5-17.5 g/dL); WBC count, 9.4 × 109/L with 0% eosinophils; platelet count, 334 × 109/L (150-450 × 109/ L); ESR, 30 mm/1 h (0-22 mm/1 h); and creatinine, 0.6 mg/ dL (0.8-1.2 mg/dL). Urinalysis was positive for glycosuria and proteinuria (predicted 24-hour protein, 1280 mg/24 h); urine microscopy revealed 1 to 3 red blood cells per highpower field (<1), 4 to 10 WBC per high-power field (1-3), occasional hyaline casts, and occasional granular casts and dysmorphic red blood cells. His plasma glucose level was 199 mg/dL (70-100 mg/dL). Results of liver function studies were abnormal: aspartate aminotransferase, 41 U/L (1231 U/L); alanine aminotransferase, 111 U/L (10-45 U/L); albumin, 2.8 g/dL (3.5-5.0 g/dL); and alkaline phosphatase, 347 U/L (98-251 U/L). ANA was negative, but antineutrophil cytoplasmic antibody (ANCA) assay was positive. Chest radiography showed mild hyperinflation in both lungs without infiltrates. Findings on bone marrow biopsy performed at the patient’s local institution were reviewed; the specimen showed slight hypercellularity with eosinophilia and unremarkable eosinophil maturation, consistent with secondary eosinophilia. 3. Which one of the following diagnoses is most likely based on the clinical and laboratory findings in our patient? a. Polyarteritis nodosa (PAN) b. Microscopic polyangiitis (MPA) c. Cryoglobulinemic vasculitis d. Churg-Strauss syndrome (CSS) e. Wegener granulomatosis (WG) PAN is characterized pathologically by focal segmental necrotizing vasculitis of medium- and small-sized arteries.2 Constitutional symptoms, motor deficits in the form of mononeuritis multiplex, purpuric skin lesions, kidney involvement, and gastrointestinal symptoms are common, but pulmonary involvement is rare. Microscopic polyangiitis is a focal segmental necrotizing vasculitis of smaller vessels than typically involved in PAN.2,3 Renal involvement is prominent in MPA, and many patients experience pulmonary disease in the form of alveolar hemorrhage, pneumonitis, and pleuritis. Neither PAN nor MPA is associated with eosinophilia. Cryoglobulinemic vasculitis is an immune complex– mediated vasculitis affecting small vessels, often caused by hepatitis C infection. Purpuric skin lesions, weakness, arthralgias, and peripheral neurologic findings, including mononeuritis multiplex and motor or sensory polyneuropathy, are common, but pulmonary involvement is rare. ANCA assays are negative, and eosinophilia is not a feature of this illness. Churg-Strauss syndrome, a form of necrotizing vas-
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culitis associated with asthma and eosinophilia,4-6 can explain the clinical features of our patient’s illness. Wegener granulomatosis is a multisystemic vasculitis associated with granulomatous necrotizing inflammation.7 Upper airway, pulmonary, and renal involvement are especially prominent. Neurologic findings can include mononeuritis multiplex. Cutaneous manifestations, including purpura, are frequent. ANCA assays are positive in 55% to 88% of patients with WG. Although providing a good explanation for our patient’s clinical symptoms and some laboratory findings, WG cannot explain his eosinophilia. 4. Which one of the following diagnostic modalities would most likely confirm the suspected diagnosis in this patient? a. Characterization of the ANCA assay as peripheral or cytoplasmic pattern b. Hepatitis serologies c. Tissue biopsy d. Electromyography e. Abdominal angiography ANCA serologies can be helpful in the diagnosis and classification of vasculitis.8 Two patterns of ANCA have been described on immunofluorescence assay: cytoplasmic (c-ANCA) and perinuclear (p-ANCA). About 50% to 60% of patients with CSS are seropositive for ANCA,2,5 predominantly p-ANCA, whereas patients are infrequently positive for c-ANCA. However, a positive p-ANCA is nonspecific for CSS because this can be found in various other conditions, including MPA and glomerulonephritis. Hepatitis serologies are useful in the evaluation of patients with suspected vasculitis. Hepatitis B has been linked to PAN.2 Hepatitis C virus infection has been noted less frequently in PAN but is strongly associated with cryoglobulinemic vasculitis. Although cases of CSS associated with hepatitis C virus infection have been reported, an etiologic association with hepatitis is not commonly noted. By definitively showing necrotizing vasculitis, tissue biopsy is the most important of the diagnostic studies presented. Electromyography can be helpful in assessing neuropathy. Peripheral neuropathy, often in the form of mononeuritis multiplex, is found in 63% to 92% of reported cases of CSS.2,4-6 Although electromyography would be useful to document the neuropathy objectively and to assess its extent, it would not confirm the diagnosis of CSS. Abdominal angiography may show areas of narrowing and aneurysmal dilation in vessels, as can occur in PAN. With no abdominal symptoms, abdominal angiography would likely be of limited benefit in our patient. Our patient’s ANCA assay had a p-ANCA pattern; myeloperoxidase (MPO) antibodies were detected. Studies for cryoglobulins were negative. Serum protein electro-
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phoresis showed hypoalbuminemia with no monoclonal spike. Serologic tests for hepatitis B and C virus infection were negative. Computed tomography of the chest, abdomen, and pelvis showed no mass lesions or lymphadenopathy. Echocardiography revealed normal chamber sizes with an estimated left ventricular ejection fraction of 50% to 55%. No intracardiac thrombus or evidence of eosinophilic heart disease was seen. Sural nerve biopsy showed normal findings without evidence of small vessel vasculitis. Skin biopsy showed necrotizing vasculitis with eosinophilia, consistent with CSS. Although necrotizing vasculitis, perivascular eosinophilia, and granulomas are pathologic hallmarks of disease, not all are required for diagnosis.9 5. Which one of the following treatment approaches would most likely benefit our patient? a. High-dose corticosteroids alone b. High-dose corticosteroids with cyclophosphamide c. Cyclosporine d. Plasma exchange e. Interferon alfa Only a limited number of therapeutic trials for CSS have been reported. Corticosteroids alone or combined with cyclophosphamide have been shown to be efficacious.4,5,10 If a patient has life-threatening or major organ disease, both glucocorticoids and cyclophosphamide should be initiated. One patient with severe disease resistant to corticosteroids and cyclophosphamide responded favorably to cyclosporine. Interferon alfa has been reported to have a beneficial effect in patients with CSS in whom response to standard therapy was incomplete.11 Interferon alfa inhibits degranulation and effector function of eosinophils and results in a dose-dependent decrease in eosinophil count, which tends to parallel disease activity. At present, both cyclosporine and interferon alfa therapy should be considered secondline therapies for CSS. Plasma exchanges combined with corticosteroids and cyclophosphamide do not improve outcome in patients with CSS.10 Our patient received intravenous methylprednisolone (1 g/d) for 5 days, followed by oral prednisone, 60 mg/d. Because of progressive neurologic symptoms, oral cyclophosphamide was administered at 100 mg/d (2 mg/kg). Trimethoprim-sulfamethoxazole was added for prophylaxis for Pneumocystis carinii pneumonia. Corticosteroidassociated glucose intolerance was managed with dietary control and insulin. Gradually, our patient’s status improved, allowing transfer to a rehabilitation unit. He was dismissed home after several weeks. At dismissal, we recommended that he continue to receive prednisone and cyclophosphamide therapy until all signs of disease had disappeared. After that, gradual tapering of corticosteroid and cyclophosphamide therapy was to be initiated.
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DISCUSSION Our patient had necrotizing vasculitis associated with asthma, eosinophilia, pulmonary infiltrates, mononeuritis multiplex, and cutaneous lesions. Churg-Strauss vasculitis was tentatively diagnosed before transfer to our institution, but inadequate response to therapy led to reconsideration of the diagnosis. The American College of Rheumatology has established classification criteria for CSS.12 Four of the following 6 findings are required for the diagnosis: history of asthma, peripheral blood eosinophilia (>10%), mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormalities, and a biopsy specimen containing a blood vessel with extravascular eosinophilic inflammation. Our patient met all of these criteria. Serologic tests for ANCA antibodies can be helpful in evaluating patients with suspected vasculitis but are nonspecific. The c-ANCA and p-ANCA patterns detected by immunofluorescence microscopy reflect recognition of different antigens by autoantibodies in patients’ sera. Antibodies to proteinase 3 produce a c-ANCA pattern. Antibodies to several different antigens can produce a p-ANCA immunofluorescence pattern, but only those directed toward MPO are clinically important. The presence of a positive c-ANCA reacting with proteinase 3 or p-ANCA reacting with MPO is highly specific for one of the ANCAassociated forms of vasculitis—WG, MPA, or CSS. ANCA assays are not sensitive for CSS. Only about one half of patients with CSS have a positive ANCA, usually with a pANCA pattern and specificity for MPO.5 The cause of CSS is unknown. Leukotriene inhibitor use has been implicated in some cases of CSS, but a true causal relationship has not been shown.9 In individuals with corticosteroid-dependent asthma, CSS has developed when systemic corticosteroid therapy was tapered after addition of inhaled steroid therapy. Similarly, onset of CSS has been associated with tapering of systemic corticosteroid therapy after control of asthma with leukotriene inhibitors. This has led to speculation that the pathogenetic mechanism involves corticosteroid dose tapering in susceptible individuals, made possible by the leukotriene inhibitor therapy. However, in at least 2 cases, CSS was associated with leukotriene inhibitor use without prior systemic corticosteroid therapy. Our patient fits in this latter group. However, therapy issues may be incidental; the important association may be the presence of asthma. In case reports of patients with CSS associated with leukotriene inhibitors, treatment has relied primarily on systemic corticosteroid therapy. Adjunctive immunosuppression with use of cyclophosphamide, azathioprine, or methotrexate has been used in patients not responding to corticosteroid therapy. Success with this approach has not
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been absolute because some patients have required longterm, high-dose corticosteroid therapy to prevent relapse. We discontinued leukotriene inhibitor therapy in our patient and initiated an immunosuppressive regimen of highdose corticosteroids and cyclophosphamide. The rarity of classic CSS, let alone that associated with leukotriene inhibitors, has hampered attempts at defining the efficacy of possible therapies in a randomized manner. Several promising treatments are available. Immunosuppressive therapy for CSS with corticosteroids and cyclophosphamide is effective.10 Case reports have suggested benefit from treatment with intravenous immunoglobulin. Case reports have also shown that cyclosporine and interferon alfa therapy may be beneficial.11 These results await more definitive confirmation in the treatment of this difficult clinical problem.
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Correct answers: 1. e, 2. b, 3. d, 4. c, 5. b
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