Crit Care Clin 18 (2002) 855 879

Vasculitis: Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa, and Takayasu arteritis$
Stephen K. Frankel, MDa,b, Eugene J. Sullivan, MDc, Kevin K. Brown, MDa,b,*
Interstitial Lung Disease Program, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA b Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA c Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD 20847, USA
a

Making the diagnosis and managing the complications of vasculitis are among the most demanding challenges of intensive care unit (ICU) medicine for a number of reasons. Vasculitides are rare, with an incidence of 20 to 100 cases/ million and a prevalence of 150 to 450/million [1 4], and their signs and symptoms overlap with much more commonly seen infections, connective tissue diseases, and malignancies. The presentation of any given vasculitis is highly variable; rarely will a patient present with all the classic findings, making delays in the diagnosis extremely common. Classifying a vasculitis can be as challenging as making the diagnosis. Multiple schemes have been proposed, the most current classifications are based primarily on clinicopathologic presentation rather than etiology (Table 1) [5 11]. The current criteria are relatively insensitive and nonspecific as diagnostic tools and cannot be used as such [12 19]. Thus, the diagnosis of vasculitis relies upon the recognition of characteristic combinations of particular clinical, laboratory,
This work was supported by SCOR Grant No. HL67671 from the National Heart, Blood and Lung Institute. $ The views expressed in this manuscript are the professional opinions of the authors and do not necessarily reflect the official opinion of the US Food and Drug Administration or the Department of Health and Human Services. * Corresponding author. Interstitial Lung Disease Program, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206. E-mail address: brownk@njc.org (K.K. Brown). 0749-0704/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 7 0 4 ( 0 2 ) 0 0 0 3 1 - 3

856

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

Table 1 Classification of the vasculitides [8,13,23,74] Primary idiopathic vasculitis Small vessel WG CSS MPA Idiopathic pauci-immune GN Idiopathic capillaritis Medium vessel PAN Kawasaki disease Large vessel TA Giant-cell arteritis Primary immune-complex mediated vasculitis Goodpasture syndrome Henoch-Scho nlein purpura IgA nephropathy Secondary vasculitis SLE Rheumatoid arthritis Polymyositis/dermatomyositis Scleroderma Anti-phospholipid antibody syndrome Inflammatory bowel disease Hypocomplementemic urticarial vasculitis Essential cryoglobulinemia Drug-induced vasculitis (propylthiouracil, diphenylhydantoin) Paraneoplastic Among the primary vasculitides WG, CSS, and MPA are often grouped together as the ANCAassociated (or ANCA positive) vasculitides, whereas PAN, Kawasaki disease, TA, giant-cell arteritis, Henoch-Scho nlein purpura, and Goodpasture syndrome are considered ANCA negative.

radiologic, and pathologic features. Additionally, in the patient with a known diagnosis of vasculitis, identifying the cause of deterioration can be extremely difficult because active disease, complications of drug therapy, overwhelming infection, or a combination of these are common and present with overlapping features.

Making a new diagnosis Making a new diagnosis of vasculitis requires one to recognize its possibility in a critically ill patient. Careful attention must be paid to seemingly unrelated issues, such as rash, neuropathy, visual disturbances, ENT symptoms, weight loss, fatigue, myalgias, and arthralgias. Given that the differential diagnosis for these patients includes other clinically complex entities, such as collagen-vascular diseases or endocarditis, there is no substitute for a detailed clinical evaluation.

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

857

Whereas vasculitis often remains in the extended differential of any patient with multisystem disease, there are several clinical scenarios that should alert the critical care physician to seriously consider the diagnosis. Pulmonary hemorrhage syndromes Diffuse alveolar hemorrhage (DAH) is usually characterized by hemoptysis, dyspnea, and diffuse alveolar infiltrates. However, up to one third of patients with DAH do not have hemoptysis, so DAH must also be considered in patients with otherwise unexplained diffuse alveolar infiltrates or when diffuse lung disease complicates connective tissue disease, bone marrow transplantation, chemotherapy, and, particularly, new onset renal insufficiency [20]. Diagnosis is made with bronchoalveolar lavage (BAL); serially aspirated aliquots of fluid reveal a persistently bloody return. The differential diagnosis of DAH includes diseases associated with the histopathologic finding of capillaritis (including the primary idiopathic and secondary vasculitides) (Fig. 1) and in diseases associated with bland hemorrhage [21 23]. Specific entities are noted in Table 2. Acute glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) represents only 5% of acute renal failure patients but needs to be promptly and accurately differentiated from other more common causes of renal failure in the ICU (eg, acute tubular necrosis

Fig. 1. Histopathology of pulmonary capillaritis. Arrows identify infiltration and expansion of the alveolar septae by degenerating neutrophils.

858

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

Table 2 Differential diagnosis of pulmonary hemorrhage syndromes [21 23] Capillaritis WG CSS MPA Idiopathic pauci-immune GN Idiopathic pulmonary capillaritis Goodpasture syndrome Henoch-Scho nlein purpura SLE Rheumatoid arthritis Polymyositis/dermatomyositis Scleroderma Mixed connective tissue disease Primary anti-phospholipid antibody syndrome Essential cryoglobulinemia Behcet disease Bone marrow transplantation Drug-induced disease (chemotherapeutic agents, diphenylhydantoin, propylthiouracil) Bland hemorrhage Idiopathic pulmonary hemosiderosis, Coagulopathy Mitral stenosis Inhalation injury Drug-associated disease (chemotherapeutic agents, penicillamine, trimellitic anhydride, amiodarone, nitrofurantoin)

or prerenal azotemia). RPGN is generally identified by a rising BUN and creatinine and an active urinary sediment including red cell casts, dysmorphic red blood cells, hematuria, and proteinuria ( > 500 mg/d). Thus, a timely microscopic examination by skilled personnel is a critical component of the evaluation (casts degenerate over the first hour after excretion, so urine samples that are not read promptly may be falsely negative). Diagnostic considerations are found in Table 3 [24 28].

Table 3 Differential diagnosis of acute glomerulonephritis [24 28] WG CSS MPA Idiopathic pauci-immune GN Goodpasture syndrome Henoch-Scho nlein purpura IgA nephropathy SLE Essential cryoglobulinemia Postinfectious GN Membranoproliferative GN

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

859

Pulmonary-renal syndromes Pulmonary-renal syndrome describes a subset of diseases that present with DAH and GN [29]. Eighty percent of patients presenting with a pulmonary-renal syndrome have a primary small-vessel vasculitis (Wegener granulomatosis [WG], microscopic polyangiitis [MPA], or Churg-Strauss syndrome [CSS]) or Goodpasture syndrome [29 31]. The remaining 20% are composed of connective tissue diseases (primarily systemic lupus erythematosus [SLE]), cryoglobulinemia, and postinfectious disease.

Patients with known vasculitis Clinically severe vasculitis and disease flares Once a diagnosis is made, classification by severity of disease, such as that used by the European Vasculitis Study Group (Table 4) [32], is useful in guiding therapy. Patients requiring ICU admission generally fall into a clinical subgroup where vital organ function is threatened; that is, generalized, severe renal (or severe pulmonary [DAH], gastrointestinal [GI], or cardiac involvement), or refractory categories. Classifying patients in this way is useful because most physicians who treat vasculitis feel that the intensity of the immunosuppressive therapy should reflect the severity of the underlying disease. The clear majority of vasculitis patients respond to therapy; however, the drugs used to treat these entities have significant side effects and toxicities and must ultimately be tapered over time. Moreover, disease activity waxes and wanes such that 40% to 65% of patients with WG, 35% to 50% with MPA, 10% to 25% with CSS, 10% to 40% with polyarteritis nodosa (PAN), and 50% with Takayasu arteritis (TA) have one or more clinically significant disease flares [33 36]. These flares may manifest with signs and symptoms similar to the original presentation or with novel findings. Thus, the critical care physician must be alert to the potential for involvement of previously affected and unaffected organs. Distinguishing disease flares from infection or drug toxicity is always a diagnostic challenge and requires aggressive evaluation because therapy for

Table 4 European Vasculitis Study Group clinical subgrouping according to disease severity for ANCAassociated vasculitides Clinical subgroup Localized Early systemic Generalized Severe renal Refractory Constitutional symptoms No Yes Yes Yes Yes Typical ANCA status Negative Positive or negative Positive Positive Positive or negative Threatened vital organ function No No Yes Yes Yes Serum creatinine (mmol/L) < 120 < 120 < 500 > 500 Any

860

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

one may be contraindicated for the others. Approximately 25% to 50% of deaths in vasculitis patients are directly attributable to the vasculitis [33]. Drug toxicity The mainstays of therapy for the primary vasculitides are corticosteroids and cytotoxic agents (most notably cyclophosphamide, azathioprine, and methotrexate). Prolonged courses of these agents are required to control disease activity
Table 5 Complications of therapy for vasculitis Corticosteroids Constitutional symptoms: fatigue and malaise CNS: depression, psychosis, euphoria/mania, insomnia, and headache Ophtho: cataracts and glaucoma CV: hypertension, edema, and atherosclerosis GI: ulcers, dyspepsia, and pancreatitis ID: opportunistic infections Endo: weight gain, central distribution of adipose tissue, diabetes, adrenal suppression, hyperlipidemia, hypokalemia, hypocalcemia, osteoporosis/osteopenia, avascular necrosis, and myopathy Skin: easy bruisability and atrophy Cyclophosphamide Constitutional symptoms: fever, fatigue, and malaise Pulm: pneumonitis and pulmonary fibrosis GI: nausea, vomiting, anorexia, dyspepsia, stomatitis, and LFT abnormalities Renal/GU: hemorrhagic cystitis and bladder carcinoma Heme/Onc: leukopenia, thrombocytopenia, myelodysplasia, lymphoproliferative malignancies, and solid malignancies ID: opportunistic infections Endo: SIADH Reproductive: gonadal failure and teratogenesis Azathioprine Constitutional symptoms: fatigue and malaise GI: nausea, vomiting, anorexia, dyspepsia, diarrhea, hepatitis, cholestasis, hepatic fibrosis/cirrhosis, and hepatic veno-occlusive disease Heme/Onc: leukopenia, pure red cell aplasia, and thrombocytopenia ID: opportunistic infections Rheum: gout Reproductive: gonadal failure and teratogenesis Methotrexate Constitutional symptoms: fatigue, malaise, and weight loss CNS: depression and headache Pulm: pneumonitis and pulmonary fibrosis GI: stomatitis, nausea, vomiting, anorexia, dyspepsia, ulcers, diarrhea, LFT abnormalities, and hepatitic fibrosis/cirrhosis Renal/GU: renal failure Heme/Onc: leukopenia and thrombocytopenia ID: opportunistic infections Reproductive: gonadal failure and teratogenesis Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

861

and frequently produce drug-related complications. For example, in a series of 155 WG patients treated with cyclophosphamide, complications included pneumonia (21%), cystitis (12%), myelodysplastic syndrome (8%), sepsis (8%). and solid malignancy (5%) [37]. A summary of drug-related toxicities is found in Table 5. Infection Infection is a major cause of morbidity and mortality in patients with vasculitis [38 41]. The high incidence of serious infection is believed to be secondary to therapy with cytotoxic agents and glucocorticoids. A study of 207 patients by Bradley et al demonstrated clinically important infections in 10% of patients treated with cyclophosphamide for vasculitis in spite of adequate monitoring and the absence of leukopenia [42]. Glucocorticoids have likewise been independently shown to increase the risk of infectious complications in patients treated long term with >10 mg/d (>700 mg cumulative dose) [43]. Pneumonia and sepsis are the most common serious infections. Thus, when patients present with infiltrates, constitutional symptoms, or fever alone, the differential diagnosis must include infection as well as disease flare and drug toxicity.

Evaluation Imaging Chest radiographs and CT scanning often reveal lung involvement in many of the primary and secondary vasculitides even in the absence of pulmonary symptoms. Unfortunately, many of the radiographic findings are nonspecific and do not help distinguish between vasculitis and other diseases or among the vasculitides themselves. Diffuse alveolar infiltrates should raise concern for alveolar hemorrhage. Cavitary disease, especially when accompanied by nodular disease, should give consideration to WG in particular. Adenopathy is not common in vasculitis and is more suggestive of infection or malignancy. Laboratories Routine laboratories (CBC with differential, chemistries, LFTs, BUN, and creatinine) should be obtained in all patients. Identified abnormalities are generally nonspecific and do not help differentiate among diagnostic considerations. Expected abnormalities include a normocytic, normochromic anemia; leukocytosis; and thrombocytosis. Leukopenia in a patient with known vasculitis on immunosuppressive drugs is concerning for toxicity or infection. Urinalysis should be performed in all patients with suspected or proven vasculitis, including those with normal renal function. Proteinuria and microscopic hematuria are extremely common early renal findings in WG and MPA. Additionally, a spun urine should be examined for an active sediment by a qualified person.

862

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

Extensive cultures should be obtained in all patients. An elevated erythrocyte sedimentation rate (ESR) and elevated C-reactive protein (CRP) would also be expected in active vasculitis but again lack specificity. Antinuclear antibodies and rheumatoid factor may be positive in primary vasculitis, although high titers, extractable antigens, and specific disease-associated antibodies (dsDNA, SS-A/ SS-B, Smith antigen, anti-RNP, anti Scl-70, anti-centromere antibodies, aldolase, anti-PM, anti-JO-1) clearly favor connective tissue disease (CTD). Likewise, lupus anticoagulant and anticardiolipin antibodies may occur in vasculitis and CTD. Anti-GBM antibody should be obtained in all patients with pulmonary hemorrhage or pulmonary-renal syndrome and is pathognomonic for Goodpasture syndrome. IgE should be obtained when Churg-Strauss or eosinophilic pneumonia is suspected. Complement (C3 and C4) should be obtained whenever SLE remains in the differential, and a cryocrit should be obtained in patients with pulmonary hemorrhage or RPGN. Hepatitis B and C serologies may also be indicated because hepatitis B is associated with PAN and hepatitis C is associated with cryoglobulinemia. Antineutrophil cytoplasmic antibodies (ANCA) Since van der Woude first reported the association between ANCA and WG in 1985, the relationship of these antibodies to the primary vasculitides has been extensively investigated [44,45]. The sensitivity, specificity, and positive predictive value of c-ANCA (or anti-PR3) for WG and p-ANCA (or anti-MPO) for MPA, CSS, and pauci-immune idiopathic necrotizing GN are critical in determining the role of these antibodies in diagnosis [46 50]. C-ANCA has been shown to be highly sensitive (90% to 95%) in active, systemic WG but only 60% to 65% sensitive in organ-limited disease and 40% sensitive in remissions [47,51 53]. Specificity is approximately 90%, but rare cases of MPA and CSS have been reported as c-ANCA positive. Nevertheless, in the proper clinical setting, a positive c-ANCA/anti-PR3 has sufficient positive predictive value that biopsy may be deferred. On the other hand, p-ANCA and anti-MPO lack sufficient sensitivity and specificity to represent more than suggestive evidence of a diagnosis of CSS, MPA, or pauci-immune GN [46,48,54 58]. p-ANCA positivity may also be found in rheumatoid arthritis, Goodpasture syndrome, SLE, and elsewhere [59 63]. Considerable attention has been focused on the role of rising ANCA titers in predicting relapse in patients with vasculitis, but there is insufficient sensitivity and specificity of an isolated rise in ANCA to accurately predict disease relapse in WG or other vasculitides [52,64 67]. Bronchoscopy The chief function of bronchoscopy is to assess for infection and alveolar hemorrhage. Other potential benefits of bronchoscopy include the identification of endobronchial lesions amenable to biopsy (obviating the need for a more

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

863

invasive procedure) or the identification of pulmonary eosinophilia on BAL. Rarely is transbronchial biopsy (TBB) helpful in positively diagnosing vasculitis given the size of the sample and patchy nature of the diseases. In a study of TBB in patients with known WG, Schnabel et al found that only in 2 of 17 patients with WG did TBB provide histopathologic support for the WG diagnosis, whereas otolaryngologic biopsies in these same patients yielded positive results in 13 of 19 [68]. Biopsy Whereas a minority of patients may be diagnosed without tissue, biopsy remains a mainstay of diagnosis. Easily accessible sites, such as skin or ENT lesions, are preferred when disease is present and may often provide sufficient diagnostic material. Percutaneous renal biopsy is frequently performed in patients with active sediment and renal insufficiency but is rarely diagnostic. WG, MPA, CSS, pauci-immune necrotizing GN, and SLE may present with an identical pattern of focal, segmental necrotizing GN with crescent formation. Renal biopsy may be useful in ruling out Goodpasture syndrome, Henoch-Scholein purpura, or other non-GN lesions and, if obtained, should always be sent for immunofluorescence. Video-assisted thoracoscopic surgical lung biopsy often gives definitive pathology and may be performed safely in the majority of cases. If obtained, the surgeon and pathologist should coordinate closely to obtain formalin-fixed tissue for hematoxylin-eosin and special stains, frozen tissue for immunofluorescence, and samples in saline for culture.

Treatment Whereas the types of vasculitis and their severity can vary, the general approach to therapy remains the same: immunosuppression. In the ICU for a severely ill patient with vital organs at risk, this means aggressive immunosuppression. Treatment begins with corticosteroids. IV methylprednisolone (1 g/d for 1 to 3 days) is often preferred, although in less severe disease, prednisone (or its equivalent) at 1 mg/kg/d can be initiated. Depending upon the circumstances, oral cyclophosphamide at a standard 2 mg/kg/d (maximum dose 150 mg/d) is often begun in conjunction with corticosteroids. Although there is no question about the benefit of long-term cytotoxic therapy, given the potential toxicity and the relatively delayed onset of action, the early aggressive use of high-dose cytotoxics in the ICU is somewhat controversial. If intravenous (IV) therapy is planned, close attention must be paid to dosing given the changes in renal function, volume of distribution and marrow sensitivity that may occur in the critically ill patient. Plasma exchange may be considered in patients with severe renal involvement and possibly those with DAH. IV immune globulin (IVIG) and anti T-cell therapies (eg, antithymocyte globulin) can be considered for refractory disease.

864

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

Specific vasculitides Wegener granulomatosis (WG) Classically, WG has been characterized as a necrotizing, granulomatous vasculitis of small and medium vessels involving (1) the upper airway, (2) the lower respiratory tract, and (3) the kidney. However, as with all the vasculitides, rarely are all the typical features simultaneously present at the onset of illness. The National Institutes of Health experience with 158 patients followed for 24 years demonstrated that the most common initial manifestations involved the upper and lower respiratory tract (Table 6) [40,69 71]. Kidney manifestations were uncommon at the time of initial presentation ( < 40%) but ultimately developed in the majority (85%) of patients. The most helpful laboratory finding is a positive ANCA. In the setting of active systemic disease, this has a sensitivity of 90% to 95% and a specificity of 90% [53]. An active urine sediment with proteinuria, hematuria, red cell casts, or leukocyturia may be seen. Culture of affected organs is always necessary to rule out fungal or mycobacterial infection as an alternative cause of granulomatous disease. Chest imaging abnormalities may present with a variety of findings. In a study of 77 patients by Cordier et al, 69% of patients had nodular disease, 53% of patients had infiltrates (diffuse bilateral, patchy low density, or localized consolidation), and 43% had cavitary disease [72]. Bilateral disease is much
Table 6 Manifestations of WG [37,41,69,72] Clinical manifestations Pulmonary involvement, 70% 95% (cough, chest pain, hemoptysis dyspnea) Upper airway involvement, 70% 95% (rhinorrhea, epistaxis, sinusitis, otitis, hearing impairment, ear pain ulcerations, destructive lesions/bony deformities) Tracheobronchial involvement, 10% 55% (subglottic stenosis, bronchial stenosis, hemorrhage, endobronchial lesions) Renal involvement/GN, 50% 85% Cutaneous involvement, 45% 60% (purpura, ulcers, vesicles, or nodules) Musculoskeletal involvement, 30% 70% (arthralgias, myalgias, arthritis) Ocular involvement, 25% 55% Fever/weight loss, 15% 45% PNS/CNS involvement, 10% 30% Cardiac involvement, 5% 15% Radiologic findings Abnormal chest radiograph, 85% 100% Nodules, 55% 70% Infiltrates, 50% 70% Cavitary disease, 35% 50% Laboratory findings ANCA, 90% 95% (generalized, active WG); 60% (limited WG); 40% (remission) c-ANCA/anti-PR3, 85% 90% (generalized, active) ESR, 90 95 mm/h, mean value [70]; >40 in 81%[71] CRP elevated Rheumatoid factor positive, 50% 60%

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

865

more common than unilateral disease, and the infiltrates tend to evolve over the course of the illness. CT of the chest reveals the true nature and extent of the pulmonary disease. Common findings include bilateral nodules of variable size, number, and extent; cavitary disease; airspace disease with focal consolidation and ground glass attenuation; and bronchovascular cuffing [72,73]. Effusions are less common, and adenopathy is rare. Sinus films and sinus CT serve to diagnose upper airway involvement, and patients with external upper airway disease should undergo imaging to completely define their lesions. Histopathologically, the three critical findings in the diagnosis of WG are (1) small- and medium-vessel vasculitis (see Fig. 1), (2) necrotizing granulomata, and (3) an inflammatory infiltrate [15,74] (Fig. 2). A 1991 study of surgical pathology specimens in WG revealed vascular changes in 94% of biopsies, parenchymal necrosis in 84%, microabscesses surrounded by giant cells in 69%, poorly formed granulomas in 59%, and scattered giant cells in 79% [75]. Diagnostic histopathologic findings are most commonly found after surgical lung biopsy. The diagnostic yield of upper airway biopsies are significantly less than a surgical biopsy of the lung; however, the ease of access makes upper airway biopsy a reasonable first approach in the right setting. Treatment Combination therapy with glucocorticoids and cyclophosphamide is the standard of care for WG. The regimen most commonly used is 1 mg/kg/d of

Fig. 2. Histopathology of necrotizing granulomatous inflammation. Necrotizing granulomatous inflammation of the lung in WG. The granulomata are not associated with a vessel in this section, a common finding.

866

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

prednisone (or 15 mg/kg IV methylprednisolone per day) plus 2 mg/kg/d of oral cyclophosphamide (maximum 150 mg/d) [71]. Prednisone therapy is gradually tapered to off over 3 to 12 months, whereas cyclophosphamide is continued for 1 year after remission. Pulse IV cyclophosphamide has been studied as a substitute for oral therapy by the French Vasculitis Study Group and seems to be as effective as oral therapy in achieving an initial remission, but oral cyclophosphamide is superior in maintaining remission and preventing relapse [76 79]. Patients receiving cyclophosphamide must be monitored closely for drug-specific toxicity. Age >50 and renal involvement with impaired function are predictive of increased mortality [37,80]. Other drugs used in the maintenance of WG patients include methotrexate, trimethoprim/sulfamethoxazole, and azathioprine [81 85]. Moreover, there are active protocols for novel therapies, primarily in Europe, investigating agents such as mycophenolate mofetil (Cellcept), IVIG, and anti-thymocyte globulin and anti-tumor necrosis factor agents [86,87]. Churg-Strauss syndrome (CSS) CSS is characterized by the clinical triad of (1) asthma, (2) hypereosinophilia and (3) necrotizing vasculitis. Hence, diagnostic considerations often include entities such as chronic or acute eosinophilic pneumonia, hypereosinophilic syndrome, parasitic infections, drug reactions, allergic bronchopulmonary aspergillosis, and status asthmaticus. Additionally, recent concerns have developed regarding an association between leukotriene inhibitors and the development of CSS [88 90]. Although it seems likely that reductions in oral corticosteroid dose unmasked underlying CSS after the introduction of the new agent, this association is still under investigation [88]. Clinical presentation The classic presentation of CSS as described by Lanham et al includes a prodromal phase of rhinitis, sinusitis, and asthma lasting years followed by an eosinophilic phase characterized by peripheral eosinophilia, Loeffler syndrome, or eosinophilic pneumonia, and finally a vasculitic phase with multi-system involvement [91]. Any age or gender may be affected, although peak incidence seems to be in the fourth and fifth decades. The most frequent manifestations are noted in Table 7 [92]. Asthma is universal, although the severity and duration may be highly variable in individual patients. Respiratory failure and status asthmaticus represent a significant cause of mortality in CSS, and patients in remission frequently require oral corticosteroids to control their asthma. Although CSS may present with GN, the renal involvement is generally less common and less aggressive than in the other small-vessel vasculitides. GI involvement may be severe, with bleeding, perforation, or ischemia/infarct, and accounted for 8% of deaths in Lanhams series and 2 of 11 vasculitis-related deaths in Guillevins series [91,92]. Cardiac involvement may manifest as left ventricular (LV) dysfunction, myocardial fibrosis, mitral regurgitation, coronary vasculitis, pericarditis, pericardial

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879 Table 7 Manifestations of CSS [58,91,92,94,116] Clinical Asthma, 98% 100% Constitutional, 70% 80% Mononeuritis multiplex, 50% 80% Cutaneous involvement, 50% 80% Sinusitis, 20% 70% Arthralgias/myalgias, 30% 50% Cardiac involvement, 35% 50% GI involvement, 30% 60% Renal involvement, 10% 50% Radiologic Pulmonary infiltrates, 40% 75% Laboratory Eosinophilia, 90% 100% ANCA, 45% 70% p-ANCA, 35% 50% c-ANCA, 0% 10%

867

effusion, EKG abnormalities, or sudden death. Whereas cardiovascular complications probably occur in less than half of patients, they represent the single largest cause of mortality in CSS, accounting for up to 50% of vasculitis-related deaths [58,91 95]. Peripheral eosinophilia, defined as >1500 cells/mm3 (or >10%), is generally considered a diagnostic criterion (although rare diagnoses have been made in the absence of this). Likewise, IgE levels may be markedly elevated. ANCA is positive in approximately two thirds of patients and is generally p-ANCA/antiMPO [5,56,58,92,96]. If pleural or pericardial fluid is obtained, it is exudative with low glucose and marked eosinophilia [58]. Abnormalities on chest radiograph occur in 50% to 75% of patients with CSS and in up to 90% by CT [97 100]. Chest radiograph usually reveals patchy, multifocal, peripheral infiltrates but may also show reticulonodular opacities, bronchial wall thickening, or nodular disease. CT most commonly demonstrates bilateral, heterogeneous ground glass opacification plus or minus areas of focal consolidation. Other findings may include bronchial wall thickening, hyperinflation, mediastinal lymphadenopathy, interlobular septal thickening, nodules, or effusions [97,98,101]. Histopathology in CSS is distinguished by the presence of a focal, segmental, necrotizing small and medium vessel vasculitis plus the presence of eosinophil-rich extravascular infiltrates and necrotizing granulomas [17,58,74,102 105]. Treatment As with other small-vessel vasculitides, therapy is initiated with corticosteroids at up to 1 g/d of methylprednisolone for 1 to 3 days, then switching to 1 mg/kg/d of prednisone or equivalent. In patients with cardiac, GI, or CNS involvement or who are refractory to corticosteroid therapy alone, cyclophosphamide should be added

868

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

to the regimen at a dose of 0.6 g/m2 IV q month or 1 to 2 mg/kg/d (maximum 150 mg/d) PO (when cyclophosphamide is given IV, it should be given with aggressive hydration and Mesna to avoid excessive toxicity). With therapy, 5-year survival of up to 90% has been reported [58]. Microscopic polyangiitis (MPA) Clinical presentation MPA is a systemic, necrotizing small-vessel vasculitis. It often has a subacute, insidious prodromal phase of weight loss, fatigue, fevers, arthralgias, myalgias, or hemoptysis that may last weeks to months before the onset of the more acute characteristic form of the disease. Patients universally develop renal failure secondary to RPGN, and MPA must remain in the differential of any patient who presents with a primary RPGN. Commonly involved organ systems are noted in Table 8. Lung manifestations are similar to other small-vessel vasculitis, and pulmonary hemorrhage is a major contributor to morbidity and mortality. GI findings may include abdominal pain, bleeding perforated viscus, or infarct. Laboratory findings are most notable for an elevated creatinine, proteinuria, and active urine sediment [38]. In 25% to 50% of patients, an elevated rheumatoid factor may be found. Approximately 75% of patients have a positive ANCA with p-ANCA/anti-MPO antibodies accounting for the vast majority of cases [55]. Chest imaging reveals areas of infiltrate or consolidation in patients who have pulmonary hemorrhage. Although angiography is a useful tool in the diagnosis of classic PAN, in MPA angiography is usually normal.
Table 8 Manifestations of MPA [38,55,105,107,151] Clinical manifestations RPGN, 100% Constitutional symptoms, 70% 80% Arthralgias/myalgias, 50% 65% Cutaneous involvement, 50% 65% Mononeuritis multiplex, 15% 50% GI involvement, 30% 45% Pulmonary hemorrhage/hemoptysis, 10% 30% Ocular involvement, 0% 30% Cardiac involvement, 10% 20% Upper airway involvement, 0% 15% Radiologic manifestations Infiltrates, 10% 30% Microaneurysms, 0% 15% Laboratory findings Renal insufficiency, 70% 100% Proteinuria, 80% 90% Hematuria, 65% 90% p-ANCA, 50% 75% c-ANCA, 10% 15% Anti-MPO, 35% 65%

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

869

Histopathology demonstrates a focal segmental necrotizing vasculitis with a mixed cell infiltrate affecting arterioles, capillaries, and venules without evidence of granulomata. Pulmonary capillaritis may be detected in up to 40% of cases [106]. Renal pathology is characterized by a crescentic, rapidly progressive, focal segmental necrotizing GN but is rarely diagnostic [107]. Treatment In the absence of therapy, MPA carries a very high mortality and morbidity, especially associated with renal failure. However, treatment with high-dose corticosteroids and cyclophosphamide has greatly improved the prognosis. In a recent study by Guillevin et al of 85 patients with MPA, patients receiving steroids and immunosuppressive therapy had a 74% 5-year survival rate compared with 52% of patients treated with steroids alone [55]. This benefit from the addition of cyclophosphamide to steroids alone has been proven in multiple studies [33,108 111]. Polyarteritis nodosa (PAN) Although most cases of PAN are idiopathic, hepatitis B infection with antigenemia is strongly associated with the development of PAN and is found in 7% to 22% of cases [112,113]. Identification of hepatitis-B associated cases is important because the treatment regimen for these patients differs from the standard therapy. Clinical presentation Although there is overlap, there are clinical manifestations of classic PAN distinct from those of the small-vessel vasculitides (Table 9) [16,114 117]. Constitutional symptoms are common at the time of diagnosis or preceding the diagnosis and may include low-grade fevers, weight loss, fatigue, and malaise
Table 9 Classic PAN [16,114 118] Clinical signs and symptoms Constitutional symptoms, 60% 70% Peripheral nervous involvement, 50% 70% Cutaneous manifestations, 45% 60% Myalgias/arthralgias/arthritis, 45% 50% Renal involvement, 30% 45% Hypertension, 30% 40% GI involvement, 30% 50% Pulmonary involvement, 20% 40% Cardiac involvement, 10% 20% Radiologic manifestations Abnormal chest radiograph, < 20% Abnormal angiography, 70% 100% Laboratory findings HBV infection, 7% 36% ANCA, < 10%

870

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

[115]. Renal involvement occurs in 30% to 60% of patients, but unlike in MPA or WG, in PAN it presents with a primary vascular nephropathy, not GN. Hypertension commonly occurs as a secondary phenomenon and can help distinguish between MPA and PAN. PAN may affect the heart in a small number of patients and present with LV dysfunction, EKG abnormalities, or coronary artery involvement. Lung involvement is extremely rare and argues against PAN. Laboratory evaluation demonstrates nonspecific abnormalities found with all vasculitides. ANCA positivity is uncommon [116]. Hepatitis B virus (HBV) infection should be confirmed or ruled out in all patients. Visceral angiography demonstrating microaneurysms, ectasia, stenoses, luminal irregularities, and occlusive lesions in medium-sized vessels in the mesenteric or renal beds (Fig. 3), although not pathognomonic, is highly suggestive of PAN. A recent study demonstrated occlusive arterial lesions in 98% and aneurysmal lesions in 61% of patients with biopsy-proven PAN [118]. Because peripheral nerve involvement and skin involvement are the two most common manifestations of PAN, these easily accessible sites often offer the opportunity to make a pathologic diagnosis. Histopathology demonstrates a focal segmental necrotizing vasculitis with a mixed cell infiltrate affecting mediumsized arteries and veins with or without concomitant small-vessel involvement and without evidence of granulomata [74]. Treatment Patients with classic PAN may be divided into three categories. The first category is PAN secondary to HBV infection. These patients should be treated

Fig. 3. Angiography of renal arterial aneurysms in PAN.

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

871

initially with corticosteroids to control the life-threatening manifestations of the vasculitis and anti-viral therapy to enhance clearance of the HBV (vidarabine and interferon-a2b have been used with good results by the French Vasculitis Study Group) [56,92,114,119]. Guillevin suggests that plasma exchange to further control vasculitic activity may be indicated. As with the ANCA-associated vasculitides, idiopathic PAN can be stratified by severity of disease [33,120]. The prospectively validated five-factor score (FFS) created by the French Vasculitis Study Group found that (1) proteinuria >1 g/d; (2) GI bleeding, perforation, infarct, or pancreatitis; (3) renal insufficiency; (iv) cardiomyopathy; or (v) CNS involvement correlate with a poor prognosis. Patients with no risk factors (ie, FFS = 0) may be treated with corticosteroids alone, whereas patients with one or more risk factors should be treated with corticosteroids plus cyclophosphamide. Five-year mortality is 12% for patients with an FFS = 0, 26% for patients with an FFS = 1, and 46% for patients with an FFS > 2 [120]. A recent North American study by Fortin et al confirms cardiac or renal involvement as key predictors of mortality (relative risk 2.9) and disease severity [121]. Additionally, whereas there is clear benefit with the addition of cyclophosphamide, there seems to be no difference in outcomes between oral versus IV cyclophosphamide and no benefit with the addition of plasma exchange [108,120,122 124]. Takayasu arteritis (TA) First described in Japan in 1908, 80% to 85% of cases of TA occur in patients < 40 years of age, and there is a female predominance [36,125 128]. TA affects the largest arteries with a predilection for the aorta and its large branches but may also affect the pulmonary vasculature in approximately 50% of cases and even the coronary arteries in a small number of cases. Clinical presentation As with other vasculitides, TA often begins with nonspecific constitutional symptoms, such as fever, fatigue, malaise, myalgias, arthralgias, and weight loss [36,126,129 135]. Carotodynia, or pain over the carotid arteries, is a particularly suggestive complaint, although this occurs in a minority of patients. Ultimately, patients develop the more characteristic features of the disease that result from vessel stenosis and occlusion, namely limb claudication, lightheadedness, syncope, headache, visual disturbances, hypertension secondary to renovascular stenoses, asymmetric blood pressure measurement, bruits, and diminished or absent pulses. There seem to be differences in the anatomic distribution of the disease in different populations. The Japanese report a high rate of ophthalmic, cerebrovascular, and cardiac involvement, whereas in Indian and Thai populations, abdominal aortic involvement and renovascular hypertension are more dominant [136 138]. Catastrophic complications that may bring patients to the ICU include aortic dissection or rupture, aortic valve regurgitation, CVA, hypertensive crisis, myocardial infarction or angina, heart failure, or sudden death. As with the other

872

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

vasculitides, nonspecific laboratory abnormalities may include an elevated ESR or CRP; a normocytic, normochromic anemia; or a mild thrombocytosis. Ultrasonography, MRI, CT angiography, and angiography all have a role in TA diagnosis, demonstrating the characteristic narrowings, occlusions, and aneurysms [139 142]. Stenotic lesions are significantly more common than aneurysmal lesions in TA (98% versus 27%) [36]. Whereas angiography has traditionally been considered the gold standard for defining vascular lesions in TA, as MR technology continues to advance, it is able to identify 98% to 100% of vascular lesions [139] (Fig. 4). Moreover, it is unique among the imaging modalities in that it may also be able to identify active sites of inflammation [143 145]. Histopathologic lesions may involve any and all layers of the large arteries and include inflammation, granuloma formation, and giant cells [74,146]. Intimal hyperplasia, degeneration of the elastic lamina and media, neovascularization, and adventitial fibrosis may also be present [127]. Treatment Glucocorticoids are the mainstay of therapy and induce remission in approximately 75% of patients with active disease [36,126,135,147]. Cases that are not adequately controlled with steroids alone are candidates for cytotoxic therapy. A

Fig. 4. MRI of TA reveals marked thickening of the pulmonary arteries (arrows). (From Lynch DA, Newell JD, Lee JS. Imaging of diffuse lung disease. Hamilton (ON): B.C. Decker; 2000. p. 106; with permission.)

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

873

1994 study suggests that methotrexate is an effective agent at inducing remissions in patients refractory to glucocorticoids alone and permits significant reductions in the steroid dose required to maintain remissions [148]. Surgery and, more recently, stentinghave a critical adjunctive role in managing localized vascular complications such as arch stenosis, carotid stenosis, renal artery stenosis, and aortic regurgitation [149,150].

Summary Identification, diagnosis, and management of the primary vasculitides and their attendant complications is a challenging task for the critical care physician. However, with appropriate therapy, the morbidity and mortality of these diseases can be markedly improved and allow the individual patient to return to their previous functional state.

References
[1] Cotch MF, Hoffman GS, Yerg DE, et al. The epidemiology of Wegeners granulomatosis: estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population based data sources. Arthritis Rheum 1996;39:87 92. [2] Gonzalez-Gay MA, Garcia-Porrua C. Systemic vasculitis in adults in northwestern Spain, 1988 1997: clinical and epidemiologic aspects. Medicine (Baltimore) 1999;78:292 308. [3] Haugeberg G, Bie R, Bendvold A. Primary vasculitis in a Norwegian community hospital: a retrospective study. Clin Rheumatol 1998;17:364 8. [4] Watts RA, Lane SE, Bentham G, et al. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43:414 9. [5] Conron M, Beynon HLC. Churg-Strauss syndrome. Thorax 2000;55:870 7. [6] Dolman KM, Gans RO, Vervaat TJ, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993;342:651 2. [7] Guillevin L, Lhote F, Gherardi R. The spectrum and treatment of virus-associated vasculitides. Curr Opin Rheumatol 1997;9:31 6. [8] Jennette JC, Falk RJ. Small-vessel vasculitis. New Engl J Med 1997;337:1512 23. [9] Kawachi Y, Nukaga H, Hoshino M, et al. ANCA-associated vasculitis and lupus-like syndrome caused by methimazole. Clin Exp Dermatol 1995;20:345 7. [10] Specks U. Pulmonary vasculitis. In: Schwarz MI, King TE, editors. Intersitial lung disease. 3rd edition. Hamilton (ON): B.C. Decker; 1998. p. 507 34. [11] van den Bogaerde J, Beynon HLC. Pulmonary vasculitis and rheumatic diseases. Semin Respir rit Care Med 1998;19:57 67. [12] Jennette JC, Falk RJ. Clinical and pathological classification of ANCA-associated vasculitis: what are the controversies? Clin Exp Immunol 1995;101(Suppl 1):18 22. [13] Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37:187 92. [14] Jennette JC, Falk R, Andrassay K, et al. Nomemclature of systemic vasculitides. Arthritis Rheum 1990;37:187 92. [15] Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegeners granulomatosis. Arthritis Rheum 1990;33:1101 7. [16] Lightfoot RW, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33:1088 93. [17] Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for

874

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879 the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis. Arthritis Rheum 1990;33:1094 100. Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagosis of vasculitis. Ann Intern Med 1998;129:345 52. Sorensen SF, Slot O, Tvede N, et al. A prospective study of vasculitis patients collected in a five year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis 2000;59:478 82. Zamora MR, Warner ML, Tuder R, et al. Diffuse alveolar hemorrhage and systemic lupus erthematosus (SLE): clinical presentation, histology, survival and outcome. Medicine (Baltimore) 1997;76:192 202. Green RJ, Ruoss SJ, Kraft SA, et al. Pulmonary capillaritis and alveolar hemorrhage: update on dignosis and management. Chest 1997;110:1305 16. Schwarz MI. Diffuse alveolar hemorrhage. In: Schwarz MI, King TE, editors. Interstitial lung disease. 3rd edition. Hamilton (ON): B.C. Decker; 1998. p. 535 58. Schwarz MI, Brown KK. Small vessel vasculitis of the lung. Thorax 2000;55:502 10. Bolton WK. Rapidly progressive glomerulonephritis. Semin Nephrol 1996;16:517 26. Couser WG. Glomerulonephritis. Lancet 1999;353:1509 15. Erwig LP, Rees AJ. Rapidily progressive glomerulonephritis. J Nephrol 1999;12(Suppl 2): S111 9. Jennette JC, Falk RJ. Diagnosis and management of glomerulonephritis and vasculitis presenting as acute renal failure. Med Clin North Am 1990;74:893 908. Madaio MP, Harrington JT. The diagnosis of glomerular diseases. Arch Intern Med 2001;161: 25 34. Jayne DR. Pulmonary-renal syndrome. Semin Respir Crit Care Med 1998;19:69 77. 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 5. Saxena R, Bygren P, Arvastsin B, et al. Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome. J Intern Med 1995;238:143 52. Jayne D. Update on the European Vasculitis Study Group Trials. Curr Opin Rheumatol 2001; 13:48 55. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001;44:666 75. Gordon M, Luqmani RA, Adu D, et al. Relapses in patients with a systemic vasculitis. Q J Med 1993;86:779 89. Guillevin L. Treatment of classic polyarteritis nodosa in 1999. Nephrol Dial Transplant 1999; 14:2077 9. Kerr GS, Hallahan CW, Giordano J, et al. Takayasus arteritis. Ann Intern Med 1994;120: 919 29. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegeners granulomatosis. Arthritis Rheum 2000;43:1021 32. Adu D, Howie AJ, Scott DG, et al. Polyarteritis and the kidney. Q J Med 1987;62:221 37. Hogan SL, Nachman PH, Wilkman AS, et al. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996;7:23 32. Matteson EL, Gold KN, Bloch DA, et al. Long-term survival of patients with Wegeners granulomatosis from the American College of Rheumatology Wegeners granulomatosis criteria cohort. Am J Med 1996;101:129 34. Romas E, Murphy BF, dApice AJ, et al. Wegeners granulomatosis: clinical features and prognosis in 37 patients. Aust N Z J Med 1993;23:168 75. Bradley JD, Brandt KD, Katz BP. Infectious complications of cyclophosphamide treatment for vasculitis. Arthritis Rheum 1989;32:45 53. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 1989;11:954 63.

[18] [19] [20]

[21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

[34] [35] [36] [37] [38] [39]

[40]

[41] [42] [43]

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

875

[44] Davies DJ, Moran JE, Niall JF, et al. Segemental necrotizing glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? BMJ 1982;285:606. [45] Van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegeners granulomatosis. Lancet 1985;1(8426):425 9. [46] Choi HK, Liu S, Merkel PA, et al. Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: metaanalysis with a focus on myeloperoxidase antibodies. J Rheumatol 2001;28:1584 90. [47] Cohen-Tervaert JW, van der Woude FJ, Fauci AS, et al. Association between active Wegeners granulomatosis and anticytoplasmic antibodies. Arch Intern Med 1989;149:2461 5. [48] Gross WL. Antineutrophil cystoplasmic autoantibody testing in vasculitides. Rheum Dis Clin North Am 1995;21:987 1011. [49] Gross WL, Schnabel A, Tranbandt A. New perspectives in pulmonary angiitis: from pulmonary angiitis and granulomatosis to ANCA associated vasculitis. Sarcoidosis Vasc Diffuse Lung Dis 2000;17:33 52. [50] Savige J, Gillis D, Benson E, et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin Pathol 1999;111:507 13. [51] Boomsma MM, Stegeman CA, van der Leij MJ, et al. Prediction of relapses in Wegeners granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000;43:2025 33. [52] Kerr GS, Fleisher TA, Hallahan CW, et al. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titers in patients with Wenegers granulomatosis. Adv Exp Med Biol 1993;336:411 4. [53] Noille B, Specks U, Ludemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med 1989;111:28 40. [54] Cohen Tervaert JW, Goldschmeding R, Elema JD, et al. Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 1990;33:1264 72. [55] Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis. Arthritis Rheum 1999;42:421 30. [56] Guillevin L, Visser H, Noel LH, et al. Antineutrophil cytoplasm antibodies in systemic polyarteritis nodosa with and without hepatitis B virus infection and Churg-Strauss syndrome - 62 patients. J Rheumatol 1993;20:1345 9. [57] Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for antineutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int 1998;53:743 53. [58] Solans R, Bosch JA, Perez-Bocanegra C, et al. Churg-Strauss syndrome: outcome and longterm follow-up of 32 patients. Rheumatology 2001;40:763 71. [59] Mulder AH, Broekroelofs J, Horst G, et al. Anti-neutrophil cytoplasmic antibodies (ANCA) in inflammatory bowel disease: characterization and clinical correlates. Clin Exp Immunol 1994; 95:490 7. [60] Mulder AH, Horst G, Haagsma EB, et al. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology 1993;17:411 7. [61] Mulder AH, Horst G, van Leeuwen MA, et al. Antineutrophil cytoplasmic antibodies in rheumatoid arthritis: characterization and clinical correlations. Arthritis Rheum 1993;36: 1054 60. [62] Schnabel A, Csernok E, Isenberg DA, et al. Antineutrophil cytoplasmic antibodies in systemic antibodies in systemic lupus erythematosus: prevalence, specificities, and clinical significance. Arthritis Rheum 1995;38:633 7. [63] Zauli D, Ghetti S, Grassi A, et al. Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology 1997;25:1105 7. [64] Ara J, Mirapeix E, Rodriguez R, et al. Relationship between ANCA and disease activity in small vessel vasculitis patients with anti-MPO ANCA. Nephrol Dial Transplant 1999;14:1667 72. [65] Cohen P, Guillevin L, Baril L, et al. Persistence of antineutrophil cytoplasmic antibodies

876

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879 (ANCA) in asymptomatic patients with systemic polyarteritis nodosa or Churg-Strauss syndrome: follow-up of 53 patients. Clin Exp Rheumatol 1995;13:193 8. Gaskin G, Savage CO, Ryan JJ, et al. Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis. Nephrol Dial Transplant 1991;6:689 94. Jayne DR, Gaskin G, Pusey CD, et al. ANCA and predicting relapse in systemic vasculitis. Q J Med 1995;88:127 33. Schnabel A, Holl-Ulrich K, Dalhoff K, et al. Efficacy of transbronchial biopsy in pulmonary vaculitides. Eur Respir J 1997;10:2738 43. Anderson G, Coles ET, Crane M, et al. Wegeners granulomatosis: a series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society Research Committee. Q J Med 1992;83:427 38. Fauci AS, Haynes BF, Katz P, et al. Wegeners granulomatosis: propsective clinical and therapeutic expeience with 85 patients for 21 years. Ann Intern Med 1983;98:76 85. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegeners granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488 98. Cordier J-F, Valeyre D, Guillevin L, et al. Pulmonary Wegeners granulomatosis: a clinical and imaging study of 77 cases. Chest 1990;97:906 12. Reuter M, Schnabel A, Wesner F, et al. Pulmonary Wegeners granulomatosis: correlation between high-resolution CT findings and clinical scoring of disease activity. Chest 1998; 114:500 6. Lie JT. Illustrated histopathologic classification criteria for selected vasculitic syndromes. Arthritis Rheum 1990;33:1074 87. Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegeners granulomatosis. Am J Surg Pathol 1991;15:315 33. Aasarod K, Iversen BM, Hammerstrom J, et al. Wegeners granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant 2000;15:611 8. Guillevin L, Cordier JF, Lhote F, et al. A prospective multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegeners granulomatosis. Arthritis Rheum 1997;40:2187 98. Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum 1998; 42:2019 20. Hoffman GS, Leavitt RY, Fleisher TA, et al. Treatment of Wegeners granulomatosis with internmittent high-dose intravenous cyclophosphamide. Am J Med 1990;89:399 402. Mahr A, Girard T, Agher R, et al. Analysis of factors predictive of survival based on 49 patients with systemic Wegeners granulomatosis and prospective follow-up. Rhematology 2001; 40:492 8. Hoffman GS, Leavitt RY, Kerr GS, et al. The treatment of Wegeners granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322 9. Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in the treatment of Wegeners granulomatosis: long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 2000;43:1836 40. Leavitt RY, Hoffman GS, Fauci AS. Response: the role of trimethoprim/sulfamethoxazole in the treatment of Wegeners granulomatosis. Arthritis Rheum 1988;31:1073 4. Ohtake T, Kobayashi S, Honjou Y, et al. Generalized Wegeners granulomatosis responding to sulfamethoxazole-trimethoprim monotherapy. Intern Med 2001;40:666 70. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of forty-two Wegeners granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995;38:608 13. Cohen Tervaert JW, Stegeman CA, Kallenberg CG. Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis. Curr Opin Nephrol Hypertens 2001;10:211 7. Stone JH, Uhlfelder ML, Hellmann DB, et al. Etanercept combined with conventional treatment

[66]

[67] [68] [69]

[70] [71] [72] [73]

[74] [75] [76] [77]

[78]

[79] [80]

[81] [82]

[83] [84] [85] [86] [87]

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

877

[88] [89] [90]

[91] [92] [93] [94] [95] [96] [97]

[98] [99] [100] [101] [102] [103] [104] [105] [106]

[107] [108]

[109] [110]

[111]

in Wegeners granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001;44:1149 54. Weller PF, Plaut M, Taggart V, et al. The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 2001;108:175 83. Weschler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000;117:708 13. Weschler ME, Garpestad E, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998;279:455 7. Lanham J, Elkon K, Pusey C, et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984;63:65 81. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999;78:26 37. Davidson AG, Thompson PJ, Davies J, et al. Prominent pericardial and myocardial lesions in the Churg-Strauss syndrome (allergic granulomatosis and angiitis). Thorax 1983;38:793 5. Guillevin L, Guittard T, Bletry O, et al. Systemic necrotizing angiitis with asthma: causes and precipitating factors in 43 cases. Lung 1987;165:165 72. Morgan JM, Raposo L, Gibson DG. Cardiac involvement in Churg-Strauss syndrome shown by electrocardiography. Br Heart J 1989;62:462 6. Cohen-Tervaert JW, Goldschmeding R, Elema JD, et al. Antimyeloperoxidase antibodies in the Churg-Strauss syndrome. Thorax 1991;46:70 1. Buschman DL, Waldron JA, King TE. Churg Strauss pulmonary vasculitis: high resolution computed tomography scanning and pathologic findings. Am Rev Respir Dis 1990;142: 458 61. Choi YH, Im J-G, Han BK, et al. Thoracic manifestations of churg-strauss syndrome. Chest 2000;117:117 24. Leavitt RY, Fauci AS. Pulmonary vasculitis. Am Rev Respir Dis 1986;134:149 66. Staples CA. Pulmonary angiitis and granulomatosis. Radiol Clin North Am 1991;29:973 82. Worthy SA, Muller NL, Hansell DM, et al. Churg-Strauss syndrome: the spectrum of pulmonary CT findings in 17 patients. Am J Roentgenol 1998;170:297 300. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951;27:277 301. Cottin V, Cordier JF. Churg-Strauss syndrome. Allergy 1999;54:535 51. Katzenstein AL. Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung: a review. Am J Clin Pathol 2000;114:767 72. Lhote F, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Semin Respir Crit Care Med 1998;19:27 45. Akikusa B, Sato T, Ogawa M, et al. Necrotizing alveolar capillaritis in autopsy cases of microscopic polyangiitis: incidence, histopathologenesis and relationship with systemic vasculitis. Arch Pathol Lab Med 1997;121:144 9. DAgati V, Chander P, Nash M, et al. Idiopathic microscopic polyarteritis nodosa: ultrastructural observations on the renal vascular and glomerular lesions. Am J Kidney Dis 1986;7:95 110. Gayraud M, Guillevin L, Cohen P, et al. Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 1997;36: 1290 7. Guillevin L, Lhote F. Treatment of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 1998;41:2100 5. Guillevin L, Cevallos R, Durand-Gasselin B, et al. Treatment of glomerulonephritis in microscopic polyangiitis and Churg-Strauss syndrome: indications of plasma exchanges, meta-analysis of 2 randomized studies on 140 patients, 32 with glomerulonephritis. Ann Med Interne (Paris) 1997;148:198 204. Nachman PH, Hogan SL, Jennette JC, et al. Treatment response and relapse in antineutrophil

878

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879 cyctoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996;7:33 9. Boki KA, Dafni U, Karpouzas GA, et al. Necrotizing vasculitis in Greece: clinical, immunological and immunogenetic aspects: a study of 66 patients. Br J Rheumatol 1997;36: 1059 66. Guillevin L, Lhote F, Cohen P, et al. Polyarteritis nodosa related to hepatits B virus. Medicine (Baltimore) 1995;72:238 53. Guillevin L, Lhote F. Distinguishing polyarteritis nodosa from microscopic polyangiitis and implications for treatment. Curr Opin Rheumatol 1995;7:20 4. Guillevin L, Houng Du LT, Godeau P, et al. Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in 165 patients. Br J Rheumatol 1988;27:258 64. Guillevin L, Lhote F, Amouroux J, et al. Antineutrophil cytoplasmic antibodies, abnormal angiograms and pathologic findings in polyarteritis nodosa and churg-strauss syndrome: indications for the classification of vasculitides of the polyarteritis nodosa group. Br J Rheumatol 1996;35:958 64. Kirkland GS, Savige J, Wilson D, et al. Classical polyarteritis nodosa and microscopic polyarteritis with medium vessel involvement a comparison of the clinical and laboratory features. Clin Nephrol 1997;47:176 80. Stanson AW, Friese JL, Johnson CM, et al. Polyarteritis nodosa: spectrum of angiographic findings. Radiographics 2001;21:151 9. Guillevin L, Lhote F, Sauvaget F, et al. Treatment of polyarteritis nodosa related to hepatitis B virus with interferon-alpha and plasma exchanges. Ann Rheum Dis 1994;53:334 7. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and churgstrauss syndrome: a prospective study in 342 patients. Medicine (Baltimore) 1996;75:17 28. Fortin P, Larson M, Watters A, et al. Prognostic factors in systemic necrotizing vasculitis of the polyarteritis nodosa group: a review of 45 cases. J Rheumatol 1995;22:78 84. Guillevin L, Fain O, Lhote F, et al. Lack of superiority of steroids plus plasma exchange to steroids alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome: a prospective, randomized trial in 78 patients. Arthritis Rheum 1992;35:208 15. Guillevin L, Jarrousse B, Lok C, et al. Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange: a prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa. J Rheumatol 1991;18:567 74. 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 1995;38:1638 45. Cid MC, Font C, Coll-Vinent B, et al. Large vessel vasculitides. Curr Opin Rheumatol 1998; 10:18 28. Hall S, Barr W, Lie JT, et al. Takayasus arteritis: a study of 32 North American patients. Medicine (Baltimore) 1985;64:89 99. Kerr GS. Takayasus arteritis. Rheum Dis Clin North Am 1995;21:1041 57. Waern AU, Andersson P, Hemmingsson A. Takayasus arteritis: a hospital region based study on occurrence, treatment and prognosis. Angiology 1983;34:311 26. Hall S, Buchbinder R. Takayasus arteritis. Rheum Dis Clin North Am 1990;16:411 22. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasus disease). Circulation 1978;57:27 35. Lupi-Herrera E, Sanchez-Torres G, Marchushamer J, et al. Takayasus arteritis: clinical study of 107 cases. Am Heart J 1997;93:94 103. Nakao K, Ikeda M, Kimata S-I, et al. Takayasus arteritis: clinical report of eight-four cases and immunological studies of seven cases. Circulation 1967;35:1141 55. Sharma BK, Jain S, Sagar S. Systemic manifestations of Takayasu arteritis: the expanding spectrum. Int J Cardiol 1996;54:S149 54.

[112]

[113] [114] [115] [116]

[117]

[118] [119] [120] [121] [122]

[123]

[124]

[125] [126] [127] [128] [129] [130] [131] [132] [133]

S.K. Frankel et al. / Crit Care Clin 18 (2002) 855879

879

[134] Sharma BK, Sagar S, Singh AP, et al. Takayasu arteritis in India. Heart Vessels Suppl 1992; 7:37 43. [135] Shelhamer JH, Volkman DJ, Parrillo JE, et al. Takayasus arteritis and its therapy. Ann Intern Med 1985;103:121 6. [136] Moriwaki R, Noda M, Yajima M, et al. Clinical manifestations of Takayasu arteritis in India and Japan. Angiology 1997;48:369 79. [137] Numano F. Differences in clinical presentation and outcome in different countries for Takayasus arteritis. Curr Opin Rheumatol 1997;9:12 5. [138] Suwanwela N, Piyachon C. Takayasu arteritis in Thailand: clinical and imaging features. Int J Cardiol 1996;54(Suppl):S117 34. [139] Yamada I, Nakagawa T, Himeno Y, et al. Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three-dimensional MR angiography. J Magn Reson Imaging 2000;11:481 7. [140] Yamada I, Nakagawa T, Himeno Y, et al. Takayasu arteritis: evaluation of the thoracic aorta with CT angiography. Radiology 1998;209:103 9. [141] Yamada I, Numano F, Suzuki S. Takayasus arteritis: evaluation with MR imaging, Radiology 1993;188:89. [142] Yamada I, Shibuya H, Matsubara O, et al. Pulmonary artery disease in Takayasus arteritis: angiographic findings. Am J Roentgenol 1992;159:263 9. [143] Atalay MK, Bluemke DA. Magnetic resonance imaging of large vessel vasculitis. Curr Opin Rheumatol 2001;13:41 7. [144] Choe YH, Han BK, Koh EM, et al. Takayasus arteritis: assessment of disease activity with contrast-enhanced MR imaging. Am J Roentgenol 2000;175:505 11. [145] Tanigawa K, Eguchi K, Kitamura Y, et al. Magnetic resonance imaging detection of aortic and pulmonary artery wall thickening in the acute stage of Takayasu arteritis: improvement of clinical and radiologic findings after steroid therapy. Arthritis Rheum 1992;35:476 80. [146] Vinijchaikul K. Primary arteritis of the aorta and its main branches (Takayasus arteriopathy): a clinicopathologic autopsy study of eight cases. Am J Med 1967;43:15. [147] Hall S, Hunder GG. Treatment of Takayasus arteritis. Ann Intern Med 1986;104:288. [148] Hoffman GS, Leavitt RY, Kerr GS, et al. Treatment of glucocorticoid resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37:578 82. [149] Giordano JM, Leavitt RY, Hoffman G, et al. Experience with surgical treatment of Takayasus disease. Surgery 1991;109:252 8. [150] Sharma BK, Jain S, Bali HK, et al. A follow-up study of balloon angioplasty and de-novo stenting in Takayasu arteritis. Int J Cardiol 2000;75:S147 52. [151] Savage CO, Winearls CG, Evans DJ, et al. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med 1985;56:467 83.