当前位置: 首页 > 期刊 > 《新英格兰医药杂志》 > 2005年第11期 > 正文
编号:11329259
Case 28-2005 — A 42-Year-Old Man with Weight Loss, Weakness, and a Rash
http://www.100md.com 《新英格兰医药杂志》
     Presentation of Case

    A 42-year-old man was admitted to another hospital because of weight loss, hematuria, hemoptysis, weakness, and a rash.

    He had been well until three years earlier, when his family had moved into a new home. Shortly thereafter he began to have shortness of breath, wheezing, and a cough. An environmental inspection of the home revealed mold infestation, and the house was thoroughly cleaned. His symptoms persisted, and evaluations by specialists in infectious diseases, pulmonary diseases, and allergies revealed no cause. During the next two years, his symptoms were controlled with bronchodilators and oral prednisone at a dosage that ranged from 10 to 80 mg per day. His symptoms recurred when the prednisone was reduced to less than 10 mg per day.

    In the eight months before admission, the patient had lost approximately 20 kg of weight because of a decrease in appetite. In the month before admission, he had had two episodes of hematuria; the first occurrence lasted several days and resolved without treatment, and the second episode began several days before admission. Two weeks before admission, he had gone to an alternative-medicine clinic in another state for vitamin therapy. Pedal edema was noted on examination at that visit, and the urinalysis was reported to show numerous red cells. The results of other laboratory tests are shown in Table 1 and Table 2. Furosemide (20 mg four times a day) and gatifloxacin were prescribed at the clinic. Pedal edema persisted, and several days after the visit, skin lesions developed on both lower legs, feet, and hands. During the week before admission, his wife noted that he was intermittently confused; he became weak and was unable to get out of bed. Two days before admission, he began to produce reddish, blood-tinged sputum when coughing. His wife took him to a nearby hospital, where he was admitted.

    Table 1. Hematologic and Immunologic Laboratory Values.

    Table 2. Blood Chemical Laboratory Values.

    The patient had not had nausea, vomiting, diarrhea, melena, or hematemesis. He worked as a lay minister, was a licensed practical nurse, and had worked in maintenance and as a painter in the past. He lived with his wife; she and his only daughter were well. He had never smoked or used illicit drugs and did not drink alcohol. He had allergies to numerous medications, including penicillin, sulfa drugs, erythromycin, and ofloxacin, and to latex. The medications he was taking on admission included 5 mg of prednisone daily, gatifloxacin, and furosemide.

    On examination, he appeared cachectic and older than his stated age. He was alert and cooperative. The blood pressure was 130/73 mm Hg, the pulse 114 beats per minute, the respiratory rate 18 breaths per minute, and the temperature 37.8°C. The height was 175 cm and the weight 56 kg. The oxygen saturation while the patient was breathing room air was 91 percent and improved to 98 percent when he was given 4 liters of oxygen by nasal cannula. There was no temporal or scalp tenderness; temporal wasting was present. The eyes and extraocular muscle function were normal. The neck was supple, without lymphadenopathy, carotid bruits, jugular venous distension, or thyromegaly. Auscultation of the lungs revealed scattered expiratory wheezes and coarse bronchial breath sounds. A cardiac examination revealed tachycardia with normal heart sounds and no murmurs, rubs, or gallops. The abdomen was soft, nontender, and nondistended; there was the possibility of hepatomegaly. A rectal examination revealed guaiac-positive stool. There was 1+ bilateral pedal edema that extended to slightly above the ankles. Palpable purpura was present from the middle of the calf to the toes on both legs and on the dorsal side of both hands. No lesions were seen on the palms or on the trunk. A neurologic examination was normal except for diffuse weakness, without focal abnormalities.

    The results of chest radiography were normal. An electrocardiogram showed sinus tachycardia with nonspecific inferior T-wave abnormalities. Specimens of sputum, blood, and urine were obtained for cultures. A urinalysis showed 3+ occult blood without protein; the sediment contained innumerable red cells and 0 to 5 white cells per high-power field and no bacteria or casts. The results of other laboratory tests are shown in Table 1 and Table 2. Furosemide was discontinued; hydrocortisone, ceftriaxone, fluconazole, and insulin were given intravenously, with normal saline. The patient was admitted to the intensive care unit and placed in respiratory isolation. Dexamethasone, given intravenously, and vitamin K, given subcutaneously daily for three days, were added to his medications.

    On the second hospital day, a nephrology consultant suggested changing the intravenous fluid to 5 percent dextrose in water with the addition of bicarbonate. The systolic blood pressure ranged between 120 and 130 mm Hg and the diastolic blood pressure between 60 and 70 mm Hg, the heart rate was 80 beats per minute, and the respiratory rate 10 to 15 breaths per minute. Computed tomography (CT) of the chest showed a mild thickening of the bronchial walls bilaterally. There were no pulmonary, mediastinal, or hilar masses; pleural effusions; or bronchiectasis. CT scanning of the sinuses showed extensive opacification of ethmoid air cells with milder mucosal thickening in the maxillary sinuses. The left frontal sinus was hypoplastic and the right was completely opacified. The results of laboratory tests are shown in Table 1 and Table 2. The cultures of blood, urine, and sputum were negative for bacteria.

    On the third hospital day, he was transferred out of the intensive care unit. The vital signs were normal. A neurology consultant found that the patient was weak and intermittently mildly lethargic and confused. There was no aphasia. A motor examination revealed total right foot drop with 4/5 strength in both arms and the left leg, 1/5 strength in the right leg, and mild weakness of the left lower leg. There was muscle tenderness to palpation in all limbs. Knee and ankle reflexes were absent, and there was no Babinski sign; biceps reflexes were +. There was a loss of sensation to pinprick, vibration, and temperature stimuli of the right lower leg. The patient had mild tremulousness on finger-to-nose testing. Gait testing was not done because of his weakness. A limited nerve-conduction study showed decreased motor response at the extensor digitorum brevis and tibialis anterior muscles. The sensory response of the right median nerve was absent. No conduction block was identified. Needle electromyography was not done because of a risk of bleeding.

    A test for antineutrophil cytoplasmic antibodies was positive at a titer of 1:256, but the pattern (perinuclear vs. cytoplasmic) was unclear. Enzyme-linked immunosorbent assay was positive for antimyeloperoxidase antibody at greater than 100 units (normal, less than 9), and that for anti–serine protease 3 antibody was negative at 1.1 units (normal, less than 3.5). The results of other laboratory tests are shown in Table 1 and Table 2.

    A diagnostic procedure was performed and the results sent to this hospital for interpretation.

    Differential Diagnosis

    Dr. Myles Wolf: This patient is a 42-year-old man with a three-year history of steroid-dependent asthma, several months of weight loss, and now, acute renal failure with hematuria, hemoptysis, palpable purpura, eosinophilia, and polyneuropathy. The clinical course suggests a systemic disease with a chronic component, followed by deterioration that was subacute and is now acute, with multisystem involvement.

    This patient presents with concomitant diagnostic and immediate-management problems that must be approached separately. The acute renal failure and hemoptysis are potentially life-threatening and must be aggressively treated during or even before beginning the diagnostic evaluation. Although there are many causes of acute renal failure or hemoptysis, those that could explain other features of this patient's complex presentation are limited. I will, therefore, focus first on the features that have the shortest lists of potential causes, in order to develop a working differential diagnosis most efficiently.

    Purpura

    Purpura and petechiae are skin lesions that do not blanch with direct pressure and thus reflect dermal or subcutaneous bleeding.1 The possible causes of purpura can be categorized according to blood-vessel structure (Table 3). In the presence of normal vessels, petechiae and purpura result from abnormalities in the number or function of platelets or from coagulation defects. Examples include immune or thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and purpura fulminans, such as that due to meningococcemia and other infections such as Rocky Mountain spotted fever. As an alternative possibility, primary injury to blood vessels, such as that associated with vasculitis or type 1 cryoglobulinemia, can result in dermal and subcutaneous hemorrhage without platelet or coagulation dysfunction. Diseases that lead to purpura or petechiae often involve the kidneys.

    Table 3. Differential Diagnosis of Purpura and Petechiae, According to Vascular Architecture.

    In this case, the platelet count was normal, there is little reason to suspect primary platelet dysfunction, and although there were mild increases in the prothrombin time, there is no evidence to suggest sepsis or disseminated intravascular coagulation. The distribution of the rash, which spares the palms, is uncharacteristic of Rocky Mountain spotted fever. Therefore, vasculitis is the most likely cause of the skin findings.

    Neurologic Deficits

    The patient also has a variety of neurologic deficits. The decreased reflexes and the distribution of the deficits, for which no single central lesion could account, suggest that the patient has a peripheral polyneuropathy. There is an asymmetric distribution of both sensory and motor abnormalities that appears to affect individual peripheral nerves rather than specific fiber types, and there is no glove-and-stocking distribution to suggest a toxic neuropathy. The constellation of findings is characteristic of mononeuritis multiplex.1 Mononeuritis multiplex can occasionally be caused by demyelinating disease, such as chronic inflammatory demyelinating polyneuropathy, but demyelination would have been characterized on nerve-conduction studies as conduction blocks, which were not present in this patient.2 Vasculitis is the most common cause of mononeuritis multiplex; other causes include amyloidosis, sarcoidosis, and the idiopathic hypereosinophilic syndrome. The mechanism of mononeuritis multiplex in vasculitis is ischemia due to inflammatory necrosis of vasa nervorum with resulting axonal degeneration. Vasculitis is the most likely explanation for this patient's neurologic findings.

    Eosinophilia

    The patient has peripheral-blood eosinophilia, with an initial absolute eosinophil count of approximately 5000 at presentation.3 The levels quickly decreased, probably because of the administration of dexamethasone. Eosinophilia is encountered in parasitic infections, certain hematologic cancers such as Hodgkin's disease or eosinophilic leukemia, allergic diseases such as drug reactions, asthma or allergic vasculitis (the Churg–Strauss syndrome), and idiopathic hypereosinophilic syndrome.3 The patient had been treated recently with gatifloxacin, despite a reported allergy to ofloxacin, and with furosemide, despite a sulfa allergy, but his symptoms had long preceded the initiation of these drugs. There is no history of travel or immune suppression to raise a suspicion of parasitic infections, which also would not explain the purpura and neuropathy. The cancers mentioned would not explain the purpura. The idiopathic hypereosinophilic syndrome is a consideration because it is associated with chronic eosinophilia and variable tissue infiltration with organ dysfunction. A primary myeloproliferative disease with clonal eosinophilic expansion involving a tyrosine kinase fusion protein has recently been shown to belong to a subgroup of cases of the idiopathic hypereosinophilic syndrome; this condition may respond to imatinib therapy.4 However, vasculitis with renal involvement and positive tests for antineutrophil cytoplasmic antibodies would not be expected. A constellation that includes these symptoms is more characteristic of the Churg–Strauss syndrome.

    Acute Renal Failure

    Acute renal failure — the fourth prominent feature of this case — has progressed rapidly over the course of only a few weeks. There are many causes of acute renal failure,5 but with purpura, mononeuritis multiplex, and systemic symptoms that suggest vasculitis, rapidly progressive glomerulonephritis is the most likely pattern of renal injury.6 Furthermore, rapidly progressive glomerulonephritis is a medical emergency that necessitates urgent management decisions and thus absolutely must not be missed. Delays in diagnosis or initiation of therapy could lead to permanent renal failure. This patient was treated with gatifloxacin in the setting of gross hematuria and pyuria, presumably for a possible urinary tract infection. A common pitfall in the early management of rapidly progressive glomerulonephritis is the misinterpretation of hematuria and pyuria, which actually reflect intrarenal inflammation, as signs of urinary tract infection. Clinicians should be particularly attuned to this possibility in men, who have a low risk of urinary tract infection. Finally, although this patient did initially respond somewhat to intravenous hydration, prerenal azotemia clearly could not explain all his medical problems.

    Diagnosis of Rapidly Progressive Glomerulonephritis

    In this case, there are several clues from other organ systems to suggest renal vasculitis with rapidly progressive glomerulonephritis, but these clues are not always present. For example, the most aggressive form of rapidly progressive glomerulonephritis is anti–glomerular basement membrane disease, which may be associated with pulmonary hemorrhage (Goodpasture's syndrome) but is often associated with isolated renal involvement. Under what circumstances, then, should clinicians consider rapidly progressive glomerulonephritis, an uncommon but potentially lethal syndrome that must be recognized early? In addition to vasculitic rashes, other clues include the presence of systemic symptoms, such as weight loss or fever; a history of chronic upper respiratory disease, such as chronic sinusitis or otitis media; recurrent epistaxis; or, as in this case, a prolonged history of steroid-dependent asthma. Joint pain, myalgia, and arthralgia are common. Overt pulmonary hemorrhage should always suggest a pulmonary–renal vasculitis syndrome, but other pulmonary findings such as nodules, fleeting infiltrates, and anemia that is out of proportion to the degree of renal dysfunction (patients can become iron-deficient owing to chronic blood loss in the alveoli) should also raise the suspicion of pulmonary hemorrhage and rapidly progressive glomerulonephritis.

    The key to the diagnosis is careful examination of the urine sediment, which often reveals dysmorphic red cells or red-cell casts. When these are present, underlying nephritis is likely. However, in a clinical setting in which all signs and symptoms must be viewed with suspicion, even a nonspecific urinary sediment cannot rule out rapidly progressive glomerulonephritis, particularly when the sediment is examined only by laboratory personnel as part of routine testing and without knowledge of the clinical history. High-grade proteinuria (>2+) is also a suggestive finding, but its absence is an unreliable sign, since the most severe cases of glomerulonephritis are often associated with minimal proteinuria.

    Causes of Rapidly Progressive Glomerulonephritis

    The causes of rapidly progressive glomerulonephritis can be classified into three main groups, categorized according to mechanism and appearance on immunofluorescence staining of renal-biopsy specimens (Table 4).6 A direct antibody-mediated attack on the glomerular basement membrane occurs with anti–glomerular basement membrane disease and is characterized by linear deposition of IgG on the glomerular basement membrane. Granular staining of the glomerular basement membrane occurs with diseases in which renal injury is caused by the inflammatory response to the deposition of circulating immune complexes, such as systemic lupus erythematosus and poststreptococcal glomerulonephritis. Other causes include type 2 and type 3 cryoglobulinemia, which are often due to chronic hepatitis C infection but may also be caused (rarely) by subacute bacterial endocarditis or other infectious diseases with chronic immune stimulation. Henoch–Sch?nlein purpura is another cause of rapidly progressive glomerulonephritis that features prominent skin involvement and, in adults, variable gastrointestinal and joint involvement. It is characterized by granular IgA deposition.

    Table 4. Causes of Rapidly Progressive Glomerulonephritis, According to the Results of Immunofluorescence Staining of Renal-Biopsy Specimens.

    The third group is termed pauci-immune glomerulonephritis because of the sparse immunofluorescence staining. Diseases in this group typically have positive titers for antineutrophil cytoplasmic antibodies, with specificity for either myeloperoxidase or proteinase 3. The primary diseases in this group are Wegener's granulomatosis, microscopic polyarteritis, and the Churg–Strauss syndrome.

    Finally, other diseases that can mimic rapidly progressive glomerulonephritis must be considered. These diseases include polyarteritis nodosa, which causes a medium-vessel vasculitis that affects the kidney and is associated with neuropathy, purpura, and systemic infarcts but characteristically spares the lungs; cholesterol-embolism syndrome or allergic interstitial nephritis (both of which can involve prominent eosinophilia); the thrombotic microangiopathies; acute tubular necrosis; and multiple myeloma.

    This patient probably has the Churg–Strauss syndrome with rapidly progressive glomerulonephritis. The normal complement levels argue against most immune-complex diseases. Henoch–Sch?nlein purpura, which has normal complement levels, could not explain the eosinophilia or the results of the test for antineutrophil cytoplasmic antibodies. Neither anti–glomerular basement membrane disease nor type 1 cryoglobulinemia could account for most of the extrarenal manifestations. And in similar fashion, there is little reason to suspect that this condition is a thrombotic microangiopathy, myeloma, or atheroembolic disease.

    The Churg–Strauss Syndrome

    The Churg–Strauss syndrome is a form of vasculitis that affects small-to-medium-sized vessels, usually heralded by a prodrome of eosinophilia and asthma that is often steroid-dependent. This syndrome can progress to systemic vasculitis that is complicated by upper and lower respiratory symptoms and dermatologic, neurologic, cardiac, gastrointestinal, and renal involvement.7 The use of leukotriene antagonists or high-dose inhaled steroids in adults with asthma has been reported to be associated with development of the Churg–Strauss syndrome in some patients.8 Although we do not know exactly what medications this patient had taken in addition to oral steroids, it has been suggested that, rather than causing the Churg–Strauss syndrome, these agents unmask the disorder by permitting a reduction in the patients' steroid doses.9 The patient under discussion had eosinophilia, asthma, hemoptysis, sinusitis, purpura, peripheral-nerve disease, renal involvement, and — perhaps — early gastrointestinal involvement marked by weight loss and heme-positive stools. In addition, the waxing and waning confusion, which could represent delirium, might also suggest involvement of the central nervous system. Renal involvement in the Churg–Strauss syndrome is usually less severe than in other types of vasculitis that are positive for antineutrophil cytoplasmic antibodies but overlap among the types of small-vessel vasculitis can occur. A prominent tubulointerstitial–eosinophilic component may occur, and this could account for the severity of the renal dysfunction.

    The diagnostic procedure was probably a percutaneous, ultrasonographically guided kidney biopsy. It would have revealed a segmental, necrotizing glomerulonephritis with crescent formation and, possibly, prominent eosinophilic infiltration of the renal interstitium. Another diagnostic approach, given the concern about bleeding that precluded electromyography, would have been to perform a right sural-nerve biopsy in search of vasculitis of the vasa nervorum. Given the high clinical suspicion of rapidly progressive glomerulonephritis and the hemoptysis, which can be the harbinger of a life-threatening pulmonary hemorrhage,10 I would urgently initiate pulse-dose, intravenous corticosteroid and cyclophosphamide therapy even before the diagnostic studies. I strongly doubt that early administration of these agents would cloud the interpretation of the pathological specimens, whereas withholding therapy, even for a matter of days, could prove costly.

    Dr. Nancy Lee Harris (Pathology): Are there any questions or comments for Dr. Wolf?

    A Physician: There is no mention of proteinuria in the laboratory reports.

    Dr. Wolf: The importance of interpreting the urine sediment and, specifically, the absence of proteinuria in this case requires emphasis. In this clinical setting, if severe proteinuria or red-cell casts are clearly demonstrable, then the diagnosis is virtually certain. However, even if red-cell casts or clinically significant proteinuria is absent, clinicians cannot afford to fall into the trap of ruling out rapidly progressive glomerulonephritis, since proteinuria is often minimal.

    Clinical Diagnosis

    Systemic vasculitis, probably the Churg–Strauss syndrome.

    Dr. Myles Wolf's Diagnosis

    The Churg–Strauss syndrome, with rapidly progressive glomerulonephritis and eosinophilic tubulointerstitial nephritis.

    Pathological Discussion

    Dr. R. Neal Smith: A renal biopsy was performed at the other hospital, and slides from the biopsy specimen were sent to our department for a consultation. Tissue was not available for direct immunofluorescence analysis or for electron microscopy. Six of 12 glomeruli contained segmental necrosis (Figure 1A). The interstitium (Figure 1B) contained an inflammatory infiltrate including eosinophils that was associated with focal destruction of tubules and peritubular capillaries. Small arteries were not present within the specimen, so we were unable to assess them for vasculitis.

    Figure 1. Renal-Biopsy Specimen (Hematoxylin and Eosin Stain).

    A glomerulus is shown in Panel A, with an area of necrosis (arrows). The inset, lower right, shows fibrinoid necrosis at a higher magnification. Interstitial inflammation was also present (Panel B), with numerous eosinophils (inset) and a red-cell cast (arrow).

    Evaluation of the sample of serum sent to our laboratory for the determination of antineutrophil cytoplasmic antibodies and anti–glomerular basement membrane antibodies identified antimyeloperoxidase antibodies (with a titer of 1:84) but no anti–glomerular basement membrane antibodies; the latter finding ruled out the diagnosis of Goodpasture's syndrome.11 Although tissue was not available for use in assessing the presence of immune complexes by immunofluorescence and electron microscopy, the pattern of the glomerular necrosis, the interstitial inflammation with tubulitis, and the positive test for antineutrophil cytoplasmic antibodies were sufficient for a diagnosis of glomerulonephritis associated with antineutrophil cytoplasmic antibodies. This condition was the cause of the patient's rapidly progressive renal failure.12,13,14

    Combined with the clinical history of asthma, neuropathy, and peripheral-blood eosinophilia, these findings were diagnostic of renal involvement by the Churg–Strauss syndrome.12,13 The necrotizing glomerulonephritis seen in the Churg–Strauss syndrome can range from the isolated involvement of a few glomeruli to necrosis of most glomeruli.15,16,17 Interstitial inflammation is common in renal disease associated with antineutrophil cytoplasmic antibodies and may be the chief renal manifestation of disease.18 The presence of antimyeloperoxidase antibodies is highly sensitive and specific in this clinical setting for vasculitis associated with antineutrophil cytoplasmic antibodies.19,20,21

    Dr. Harris: Dr. Henry Rose, a nephrologist at Berkshire Medical Center, has seen this patient for follow-up.

    Dr. Henry Rose: This man had been quite ill for two years. His wife thought he was dying and in desperation took him to another state for an alternative-medicine approach to his condition. While there, he became acutely ill and was admitted to a local hospital. On admission, the patient was very dehydrated; his creatinine level fell rapidly with hydration and moderate doses of corticosteroids. After a renal biopsy, intravenous treatment with 60 mg of methylprednisolone was administered twice daily, and the patient's renal function and general condition improved. Treatment with 60 mg of oral prednisone per day was begun, and the patient was transferred on the 15th hospital day to the rehabilitation facility at the hospital where I practice. I asked that the renal-biopsy slides be sent to Massachusetts General Hospital for review and added oral cyclophosphamide, 75 mg per day, to his treatment regimen. The patient was discharged to a nursing home after four weeks.

    Three months after his initial admission to the hospital, he had returned home, had put back on most of the weight he had lost, no longer had fevers, and felt well. Fourteen months after presentation, he still feels well and is able to work. The creatinine level is 1.1 mg per deciliter; the erythrocyte sedimentation rate, the urine sediment, and the blood eosinophil counts are normal; and tests for antineutrophil cytoplasmic antibodies are negative. He continues to receive treatment with a slow prednisone taper, currently at 18 mg per day, and also cytoxan, at 75 mg per day. His appearance is slightly cushingoid with some residual peripheral neuropathy, and he is no longer insulin-dependent.

    Dr. Harris: Dr. Wolf, given this patient's history of asthma before the renal failure developed, should a test for antineutrophil cytoplasmic antibodies be part of the workup of adult-onset asthma?

    Dr. Wolf: I would say no for several reasons. First, it would be extremely costly, since asthma is so common and the Churg–Strauss syndrome is so rare; also, because of the low prevalence, the positive predictive value of the test for antineutrophil cytoplasmic antibodies would be poor. Finally, for many patients who have a disease associated with antineutrophil cytoplasmic antibodies, the test for these antibodies becomes positive only when renal involvement develops.

    Dr. Robert T. McCluskey (Pathology): The prevasculitic phases of the Churg–Strauss syndrome and, to some extent, of Wegener's granulomatosis are of unknown pathogenesis and unrelated to the presence of antineutrophil cytoplasmic antibodies. When either antimyeloperoxidase antibodies or anti–proteinase 3 antibodies develop, however, vasculitis develops in the patients, and the most important components of the vasculitis are glomerular and pulmonary capillaritis. We rarely see vasculitis involving arteries in a renal-biopsy specimen; we see segmental necrotizing glomerular lesions, as in this patient, followed by the formation of crescents. The renal pathology in the Churg–Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis, and primary pauci-immune necrotizing and crescentic glomerulonephritis is identical, and there is very good evidence that all these conditions are mediated by the antibodies against either proteinase 3 or myeloperoxidase.

    Anatomical Diagnosis

    Necrotizing glomerulonephritis and tubulointerstitial nephritis with antibodies to myeloperoxidase; renal involvement by the Churg–Strauss syndrome.

    Source Information

    From the Nephrology Division, Department of Medicine (M.W.), and the Department of Pathology (R.N.S.), Massachusetts General Hospital, Boston; the Nephrology Division, Department of Medicine, Berkshire Medical Center, Pittsfield, Mass. (H.R.); and the Departments of Medicine (M.W.) and Pathology (R.N.S.), Harvard Medical School, Boston.

    References

    Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512-1523.

    Trojaborg W. Acute and chronic neuropathies: new aspects of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, an overview and an update. Electroencephalogr Clin Neurophysiol 1998;107:303-316.

    Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592-1600.

    Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201-1214.

    Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448-1460.

    Hricik DE, Chung-Park M, Sedor JR. Glomerulonephritis. N Engl J Med 1998;339:888-899.

    Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. Lancet 2003;361:587-594.

    Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf 1999;21:241-251.

    Wechsler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000;117:708-713.

    Specks U. Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol 2001;13:12-17.

    Niles JL, Bottinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 1996;156:440-445.

    Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004;117:39-50.

    Niles JL. Antineutrophil cytoplasmic antibodies in the classification of vasculitis. Annu Rev Med 1996;47:303-313.

    Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135:921-930.

    Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951;27:277-301.

    Clutterbuck EJ, Evans DJ, Pusey CD. Renal involvement in Churg-Strauss syndrome. Nephrol Dial Transplant 1990;5:161-167.

    D'Agati V, Chander P, Nash M, Mancilla-Jimenez R. Idiopathic microscopic polyarteritis nodosa: ultrastructural observations on the renal vascular and glomerular lesions. Am J Kidney Dis 1986;7:95-110.

    Koss MN, Antonovych T, Hochholzer L. Allergic granulomatosis (Churg-Strauss syndrome). Am J Surg Pathol 1981;5:21-28.

    Stone JH, Talor M, Stebbing J, et al. Test characteristics of immunofluorescence and ELISA tests in 856 consecutive patients with possible ANCA-associated conditions. Arthritis Care Res 2000;13:424-434.

    Choi HK, Liu S, Merkel PA, Colditz GA, Niles JL. Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: metaanalysis with a focus on antimyeloperoxidase antibodies. J Rheumatol 2001;28:1584-1590.

    Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis. Kidney Int 2003;63:1079-1085.(Myles Wolf, M.D., M.M.Sc.)