vasculitis, churg strauss syndrome

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 pulmonary capillaritis



SLE

Rheumatoid arthritis

Polymyositis/dermatomyositis

Scleroderma

Mixed connective tissue disease

Primary anti-phospholipid antibody syndrome


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




IgA nephropathy

SLE


Postinfectious GN

Membranoproliferative GN


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


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


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


Rheum: gout


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



Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone.


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.


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


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.


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%


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.


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


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%


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%


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)


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%


Pulmonary hemorrhage/hemoptysis, 10%–30%

Ocular involvement, 0%–30%


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%


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.


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%


Pulmonary involvement, 20%–40%


Radiologic manifestations

Abnormal chest radiograph, < 20%

Abnormal angiography, 70%–100%

Laboratory findings

HBV infection, 7%–36%

ANCA, < 10%


[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.


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.


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


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.)


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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