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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,*
aInterstitial Lung Disease Program, Department of Medicine,
National Jewish Medical and Research Center, Denver, CO 80206, USAbDivision of Pulmonary Sciences and Critical Care Medicine, Department of Medicine,
University of Colorado Health Sciences Center, Denver, CO 80262, USAcCenter for Drug Evaluation and Research, US Food and Drug Administration,
Rockville, MD 20847, USA
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 clinico-
pathologic 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,
0749-0704/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S0749 -0704 (02 )00031 -3
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: [email protected] (K.K. Brown).
Crit Care Clin 18 (2002) 855–879
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 overlap-
ping features.
Making a new diagnosis
Making a new diagnosis of vasculitis requires one to recognize its possibil-
ity 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.
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-Schonlein 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 ANCA-
associated (or ANCA positive) vasculitides, whereas PAN, Kawasaki disease, TA, giant-cell arteritis,
Henoch-Schonlein purpura, and Goodpasture syndrome are considered ANCA negative.
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879856
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, chemother-
apy, 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.
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 857
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 micro-
scopic 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 2
Differential diagnosis of pulmonary hemorrhage syndromes [21–23]
Capillaritis
WG
CSS
MPA
Idiopathic pauci-immune GN
Idiopathic pulmonary capillaritis
Goodpasture syndrome
Henoch-Schonlein 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)
Table 3
Differential diagnosis of acute glomerulonephritis [24–28]
WG
CSS
MPA
Idiopathic pauci-immune GN
Goodpasture syndrome
Henoch-Schonlein purpura
IgA nephropathy
SLE
Essential cryoglobulinemia
Postinfectious GN
Membranoproliferative GN
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879858
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 Good-
pasture syndrome [29–31]. The remaining 20% are composed of connective
tissue diseases (primarily systemic lupus erythematosus [SLE]), cryoglobuline-
mia, 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 ANCA-
associated vasculitides
Clinical
subgroup
Constitutional
symptoms Typical ANCA status
Threatened vital
organ function
Serum creatinine
(mmol/L)
Localized No Negative No < 120
Early systemic Yes Positive or negative No < 120
Generalized Yes Positive Yes < 500
Severe renal Yes Positive Yes > 500
Refractory Yes Positive or negative Yes Any
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 859
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 methotrex-
ate). 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) 855–879860
and frequently produce drug-related complications. For example, in a series of
155 WG patients treated with cyclophosphamide, complications included pneu-
monia (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 independ-
ently 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 com-
mon 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 consid-
erations. 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, in-
cluding 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.
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 861
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, aldo-
lase, anti-PM, anti-JO-1) clearly favor connective tissue disease (CTD). Like-
wise, lupus anticoagulant and anticardiolipin antibodies may occur in vasculitis
and CTD. Anti-GBM antibody should be obtained in all patients with pulmon-
ary hemorrhage or pulmonary-renal syndrome and is pathognomonic for Good-
pasture 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 pre-
dictive 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 deter-
mining 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) 855–879862
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 immunofluores-
cence. 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 immunosup-
pression. 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 refrac-
tory disease.
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 863
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) 855–879864
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.
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 865
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]. More-
over, there are active protocols for novel therapies, primarily in Europe, investi-
gating 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 asper-
gillosis, 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 asso-
ciation 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
Lanham’s series and 2 of 11 vasculitis-related deaths in Guillevin’s series [91,92].
Cardiac involvement may manifest as left ventricular (LV) dysfunction, myo-
cardial fibrosis, mitral regurgitation, coronary vasculitis, pericarditis, pericardial
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879866
effusion, EKG abnormalities, or sudden death. Whereas cardiovascular compli-
cations 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/anti-
MPO [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, hyperin-
flation, 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 andmedium 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
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%
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 867
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 ANCAwith
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) 855–879868
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 com-
pared 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 anti-
genemia 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%
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 869
[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, lumi-
nal 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 medium-
sized 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 cate-
gory 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) 855–879870
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 insuf-
ficiency; (iv) cardiomyopathy; or (v) CNS involvement correlate with a poor
prognosis. Patients with no risk factors (ie, FFS = 0) may be treated with corti-
costeroids 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, myo-
cardial infarction or angina, heart failure, or sudden death. As with the other
S.K. Frankel et al. / Crit Care Clin 18 (2002) 855–879 871
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, asMR 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 approx-
imately 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) 855–879872
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, stenting—have 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.
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