Suggestive Clinical Presentations

AAVs are usually multisystem diseases; however, there are cases in which these diseases could be limited to one organ system, as in renal-limited vasculitis with positive ANCA or the limited forms of WG. Despite these exceptions, most cases will involve more than one organ system during the course of the disease. Systemic constitutional manifestations including fever, malaise, and asthenia are present in most patients. The identification of patterns in the clinical presentation is critical for early diagnosis. For example, the concurrent development of pulmonary and renal manifestations of disease may suggest WG or MPA; onset of recurrent sinusitis or development of bilateral otitis media in a middle-age adult should trigger suspicion of WG, and new-onset refractory asthma with nasal polyposis should evoke consideration of CSS. As other diseases that could be more prevalent than AAV share these patterns, it is important to maintain a high index of suspicion for other conditions in the differential diagnosis of AAV. An overview of clinical syndromes associated with AAV and their differential diagnosis can be found in Table 1 .

Pulmonary symptoms, including dyspnea, cough, hemoptysis, and symptoms of obstructive lung disease are among the most common forms of presentation for AAV. The rapid onset of pulmonary hemorrhage induced by pulmonary capillaritis and diffuse alveolar hemorrhage (DAH) can be seen with WG and CSS, but is more characteristic of MPA. Cough productive of bloody sputum in the setting of progressive dyspnea is compatible with WG, but may be seen with a wide variety of other medical conditions such as bacterial pneumonia, pulmonary embolism, and many others. Recurrent obstructive pulmonary symptoms are suggestive of the predominantly eosinophilic involvement of CSS, but are not specific. Other presentations include pleuritis with or without pleural effusions and a more insidious onset of dyspnea caused by pulmonary hypertension or pulmonary fibrosis. The differential diagnosis of these pulmonary manifestations of AAV includes infections or postinfectious complications, drug-induced lung injuries (mainly for DAH), other connective tissue diseases (rheumatoid arthritis with pulmonary nodules or systemic lupus erythematosus inducing DAH), and cardiac disease.

Renal involvement is one of the main features of MPA and WG, present at some point in 70% or more of the cases, but it appears to be less common in CSS (about 25% of cases). Most episodes of renal involvement are preceded by constitutional symptoms including malaise, myalgias, arthralgias, fever, anorexia, and weight loss. Microscopic hematuria and proteinuria usually precede the deterioration in renal function, with a small proportion of patients presenting with gross hematuria or oliguria, as unilateral or bilateral ureteral stenoses can rarely occur with AAV. The differential diagnosis includes other causes of glomerulonephritis such as systemic lupus erythematosus (SLE), other vasculitides (eg, Henoch-Schönlein purpura), and postinfectious or drug-induced syndromes. A common pattern for AAV is the pulmonary-renal syndrome that includes DAH and glomerulonephritis. Most of these cases have been described to be in association with AAV. The differential diagnosis includes Goodpasture’s disease, drug-induced vasculitis, SLE, antiphospholipid syndrome, infections, and neoplasms (the last 3 through a thrombotic microangiopathic mechanism).

Head and neck involvement is the most common form of presentation in WG, but is virtually absent in MPA. In CSS, clinical series have reported that at least 50% of patients present with paranasal sinus disease, allergic rhinitis, or chronic rhinosinusitis with or without polyposis. In WG, the forms of presentation are multiple and can involve the nose (with nasal obstruction, epistaxis, saddle-nose deformities, perforation of the nasal septum), eye (eg, red-eye syndromes with scleritis, keratitis, naso-lacrimal disease, orbital disease, exophthalmos, diplopia), ear (eg, tinnitus, hearing loss, otorrhea), and upper airway (eg, pain, hoarseness, stridor, cough). In WG, the disease manifestations can be limited to the head and neck region, without including systemic constitutional symptoms. The presence of unexplained and recurrent nose or ear symptoms should raise suspicion for WG, although infectious and allergic conditions should be considered in the differential diagnosis. A condition to consider in cases of nasal septum damage is cocaine abuse, which can also present with false-positive serologic tests. Atypical ANCA (with discordance between cytoplasmic ANCA and anti-proteinase 3 [anti-PR3] antibody or perinuclear ANCA with anti-myeloperoxidase [anti-MPO] antibody) in patients with nasal septal damage and history of cocaine abuse may be caused by ANCA with reactivity to human neutrophil elastase.

Infections and other rheumatic conditions (eg, rheumatoid arthritis, sarcoidosis) should be considered in cases of scleritis. Endocrine (eg, hyperthyroidism) and neoplastic (eg, lymphoma) processes are in the differential in cases of exophthalmos and orbital pseudotumor.

Both the central and peripheral nervous systems can be affected by any of the AAVs. The clinical manifestations of central nervous system disease are a consequence of small-vessel vasculitis or granulomatous involvement and include strokelike symptoms with sensory or motor deficit, cognitive dysfunction, epilepsy, cranial nerve involvement, and meningitis. Peripheral nervous system involvement is common for all AAVs in the form of peripheral neuropathy, but seems to be more prevalent in CSS and MPA (50%–76%) than in WG (10%–50%). Mononeuritis multiplex and symmetric polyneuropathies are described as the most common patterns of neurologic presentation in almost equal proportions. These have a predilection for the lower extremities with the peroneal nerve being the most commonly involved although the cubital, median, and radial nerves in the upper extremities can also be affected. Paresis, pain, and hypoesthesia are common features at presentation. The differential diagnosis in both the central and peripheral nervous system manifestations associated with AAV is extremely wide and includes infections causing focal lesions (eg, tuberculosis, nocardia) or seeding (eg, endocarditis), neoplasms (eg, lymphoma), demyelinating diseases (eg, acute demyelinating encephalomyelitis, multiple sclerosis), stroke or ischemic neuropathy, metabolic or toxic neuropathies, and other vasculitic or autoimmune conditions such as polyarteritis nodosa or SLE.

Cutaneous manifestations are common in all forms of AAV, affecting at least 40% to 50% of patients with WG, MPA, or CSS at some point of the disease. Palpable purpura, digital ischemia or necrosis, and subcutaneous nodules with or without necrosis are frequent forms of presentation. Livedo racemosa can be present in CSS and MPA, and oral or nasal ulcers are manifestations suggestive of WG especially in combination with gingival hyperplasia. These cutaneous manifestations should be distinguished from those happening in other connective tissue diseases that frequently present with palpable purpura, such as cryoglobulinemia and Henoch-Schönlein purpura. Livedo racemosa, a syndrome closely related to livedo reticularis, can be a manifestation of SLE, antiphospholipid syndrome, or polyarteritis nodosa. Hypersensitivity (cutaneous small vessel vasculitis) can be undistinguishable from AAVs that are otherwise asymptomatic. Finally, infections (eg, endocarditis), nutritional deficiencies (eg, scurvy), drug reactions, or paraneoplastic syndromes could present as cutaneous rashes simulating AAV.

Other clinical manifestations that may suggest the presence of an AAV include musculoskeletal symptoms such as myalgias, myositis, arthralgias, or frank arthritis. Cardiac involvement, as a result of vasculitic myocarditis, presents as dyspnea, chest pain, and palpitations in 23% to 45% of patients with CSS, although the prevalence of subclinical functional cardiac abnormalities is higher. Episodes of recurrent deep venous thrombosis in a suggestive clinical setting could support a diagnosis of WG or CSS, as this complication has been reported to have an increased incidence in patients diagnosed with these conditions.

Laboratory Testing and ANCA

The initial basic laboratory workup for suspected AAV must include a complete blood count with differential, a metabolic panel including serum creatinine and transaminases, a urinalysis, and inflammatory markers (sedimentation rate and/or C-reactive protein). The threshold should be very low for ordering tests to exclude hepatitis B and C, along with testing for cryoglobulins.

Normochromic, normocytic anemia is a feature common to all AAVs. Eosinophilia is suggestive of CSS, but can be also observed in WG and MPA. Thrombocytosis or normal platelet counts are typical in AAV, whereas thrombocytopenia is uncommon in AAV and should raise suspicion for other conditions such as SLE or cryoglobulinemia related to hepatitis C infection. The urinalysis can reveal hematuria and/or proteinuria (usually in the non-nephrotic range) and may indicate renal involvement earlier in the course of the disease than the serum creatinine. Large amounts of proteinuria should increase suspicion for SLE or other diseases associated with glomerulonephritis. Elevation of serum transaminases should trigger prompt exclusion of hepatitis C (cryoglobulinemia) and hepatitis B (polyarteritis nodosa)–related diseases. Elevations in inflammatory markers are common, but their absence does not rule out the presence of an AAV.

Depending on the clinical picture, tests for other autoimmune diseases should be ordered. For example, the absence of serum antinuclear antibody essentially rules out SLE as a possibility. Other examples include measurement of serum creatine-kinase tests as an initial screening in cases where there is a suspicion of autoimmune myositis; rheumatoid factor and anticyclic citrullinated peptide antibody testing in cases of suspected rheumatoid vasculitis; and serum complement levels to assess for diseases characterized by complement deposition such as SLE or postinfectious glomerulonephritis. Antiglomerular basement membrane antibodies (anti-GBM) represent a special case, given that their utility is not limited to the differential diagnosis with Goodpasture’s disease, but they confer valuable prognostic information (more severe disease) and have therapeutic implications (possible indication for plasmapheresis) in cases of rapidly progressive glomerulonephritis and pulmonary-renal syndromes.

Indirect immunofluorescence (IIF) testing for neutrophil cytoplasmic antibodies (ANCA) and enzyme-linked immunosorbent assays (ELISAs) for antibodies directed against PR3 and MPO are useful tests that, when applied in the right clinical setting, provide support for the diagnosis of an AAV. The predictive values of these tests are greatly decreased when they are applied in inappropriate clinical scenarios, as multiple conditions can have false positive tests in ANCA testing ( Table 2 ). Commonly, IIF ANCA testing is ordered first; if positive, results are confirmed with ELISA tests for antibodies to PR3 and MPO. However, the simultaneous ordering of these tests could also be advocated in view of the long turnaround times for these ELISA tests, the occasional occurrence of negative IIF ANCA with positive ELISA PR3 or MPO, and the reported added clinical value of the combination of tests. Typically, the cytoplasmic staining (c-ANCA) is associated with WG and the perinuclear staining (p-ANCA) is associated with MPA, although these patterns are not absolute, as cases of WG could present with positive p-ANCA and cases of MPA could present with positive c-ANCA tests. Thus, positive IIF ANCA tests should always be confirmed with ELISA testing. IIF p-ANCA and ELISA MPO for MPA are regarded as less sensitive tests than their IIF and ELISA counterparts for WG. “Atypical” ANCA patterns can present in association with AAV but these are more commonly seen with other autoimmune or inflammatory conditions. ANCA testing is less sensitive in cases of CSS, with positive results in 26% to 48% of cases, but patients with CSS and renal involvement have been reported to have positive ANCA test results in higher proportions (75%). It is important to remember that at least 10% of patients with biopsy-confirmed AAV will not have a positive result for either IIF ANCA or ELISA tests.

Pulmonary

Radiologic evaluation is important in cases of suspected AAV involving the lungs. Findings on plain radiographs and computed tomography (CT) suggestive of WG include the presence of nodules or cavities with irregular and thin walls; these are usually multiple (in ∼75% of cases) and bilateral, with a slight predilection for the subpleural and peribronchovascular regions. These cavities could be easily mistaken for septic emboli, metastases, or lung abscesses. In addition, WG can present with localized or diffuse patchy areas of air-space consolidation caused by pulmonary hemorrhage and thickening of the trachea or bronchi seen on radiographs or chest CT. MPA usually presents with a pattern suggestive of DAH that includes the development of patchy or diffuse bilateral airspace opacities with a predilection for the lower lung zones. Chest CT findings consistent with pulmonary fibrosis, including ground-glass and reticular opacities, septal thickening, and honeycombing, have been increasingly described in patients with MPA and are theorized to be secondary to recurrent subclinical pulmonary bleeding. CSS usually presents with transient and symmetric areas of ground glass opacity or consolidation, with a predilection for the periphery of the lung fields, airway wall thickening, unilateral or bilateral pleural effusions, or nodules.

The role of bronchoscopy is usually restricted to ruling out conditions in the differential diagnosis, evaluation of cases suspicious for DAH, and the assessment of endobronchial lesions. The samples provided by transbronchial biopsies are often insufficient to make a proper diagnostic assessment in cases of WG, although a good yield has been reported in cases of suspected CSS. Unless a case is overwhelmingly characteristic and there is an absolute contraindication, surgical lung biopsy by video-assisted thoracoscopic surgery is the procedure of choice to establish diagnosis in cases suspected of pulmonary involvement by AAV. This procedure has low morbidity and mortality and the yield of the pulmonary tissue for precisely establishing the diagnosis and ruling out conditions in the differential of AAV is very good.

Head and Neck

Ear, nose, and throat manifestations of WG, including sinusitis, septal perforations, and saddle-nose deformities, are commonly seen in the limited forms of the disease. This has diagnostic and therapeutic implications, as patients with limited disease can have negative ANCA by IIF and negative anti-PR3 and anti-MPO by ELISA, even during active flares of their clinical disease ; therapeutic choices can be less aggressive in cases of limited AAV.

CT of the head and neck is a sensitive test that can reveal changes in the sinus cavities of patients with WG, including mucosal thickening, sinus opacification, sclerosing otitis, and bony destruction or thickening. CT or magnetic resonance imaging (MRI) evidence of involvement of the lacrimal region or retro-orbital masses can support ophthalmic compromise by WG. MRI could be helpful in demonstrating the inflammatory nature of retro-orbital masses in AAV. Ophthalmologic examination in patients with suspected WG should include a slit-lamp examination and fundoscopy to assess for the presence of scleritis, keratitis, uveitis, and retinal lesions. Otolaryngologic examination in patients with suspected WG or CSS of the head and neck should include otoscopy, flexible fiberoptic laryngoscopy, nasal endoscopy, and audiometry. Tissue biopsy varies in its diagnostic yield according to the site involved by suspected AAV. In cases of retro-orbital masses it can help differentiating the granulomatous involvement of WG from other conditions such as lymphomas, sarcoidosis, Graves’ disease, and orbital pseudotumor. The paranasal sinuses are additional areas where the biopsies for WG may be considered, but the diagnostic yield for findings specific for WG is relatively low. Similarly, biopsies of the oral cavity, larynx, external or middle ear, and subglottic region can be technically challenging and often nondiagnostic. In cases of suspected CSS, biopsies of nasal polyps seem to have a low diagnostic yield when compared with other organ systems.

Renal

Renal-limited forms of AAV without signs of systemic involvement are occasionally reported and are considered to be rare. Besides the syndrome of glomerulonephritis, WG can rarely present with ureteral stenosis, papillary necrosis, perirenal hematomas, and renal masses. An association between WG and a higher incidence of renal cell carcinoma has been described. Thus, in cases of WG presenting in association with renal masses, the preferred procedure may be nephrectomy instead of fine-needle biopsy to avoid peritoneal seeding of the potential malignancy.

Renal biopsy plays a crucial role in patients with glomerulonephritis and suspected AAV by allowing differentiation from conditions that induce deposition of immune complexes in the glomerulus. AAV induces glomerulonephritis by mechanisms that do not depend on immune-complex deposition and as a consequence are labeled as “pauci-immune” glomerulonephritis, as opposed to conditions such as SLE, postinfectious glomerulonephritis, and endocarditis that usually induce glomerulonephritis through immune-complex and complement deposition. Immunofluorescent staining of renal biopsy material usually allows for the differentiation of AAV from anti-GBM–induced disease, which is characterized by linear deposition of IgG in the basement membrane.

Features of AAV common in renal histopathology include fibrinoid necrosis, cellular and fibrous crescents, glomerulosclerosis, and periglomerular infiltrates. Features reflecting chronicity (eg, glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriosclerosis) are more commonly found in MPA and renal-limited AAV than in WG, possibly because of earlier diagnoses of the former two conditions than of the latter. Granulomatous reactions, although useful for establishing a diagnosis of AAV, are rarely found on kidney biopsy (2%–4% of cases). CSS has histopathological features indistinguishable from the other AAVs, and even eosinophilic interstitial infiltrates, which are rarely present, are not specific for its diagnosis. With the exception of granulomas, other histopathological characteristics of AAV do not allow for a differentiation of other conditions in the differential diagnosis, making immunoflorescence staining an essential feature of the renal biopsy.

Nervous System

Peripheral nervous system involvement could be the first manifestation of an AAV, but in these cases the differential diagnosis is broad, including neuropathies of ischemic (eg, diabetic, amyloid), inflammatory (eg, sarcoidosis, idiopathic, medium-vessel vasculitis), infectious (eg, leprosy, HIV, Lyme disease), and malignant (eg, paraneoplastic) etiologies. Electromyographies with nerve conduction studies are helpful tools in better defining the neurologic syndromes (eg, mononeuropathy, mononeuritis multiplex, symmetric or asymmetric polyneuropathy) and identifying a nerve suitable for biopsy. Findings on nerve conduction studies reveal that the predominant pattern of involvement is indicative of axonal degeneration and the needle electromyogram usually reveals denervation on the muscle groups supplied by the involved nerves. A controversy exists about the need to perform a muscle biopsy along with a nerve biopsy when vasculitis is in the differential. One point of view is that the muscle portion rarely provides the diagnosis when the nerve biopsy is negative, but others conclude that the histopathology of the muscle may provide specific findings and increase the diagnostic yield. The sural and peroneal nerves, along with the anterior tibialis and gastrocnemius muscles, are the preferred areas for biopsy. On nerve histopathology the findings are usually nonspecific, with perivascular infiltration of inflammatory cells, axonal degeneration, and necrotizing changes that can be active, inactive, or healed.

All AAVs can involve the central nervous system and cause focal lesions through vasculitic involvement of central nervous system (CNS) vessels or granulomatous involvement of the brain parenchyma or meninges. In WG, these granulomas can form primarily in the central nervous system, or they can be an extension from those in the ears or sinuses. Even in cases of severe central nervous system involvement by AAV, ANCA testing can be consistently negative. A rare but well-described presentation of WG is chronic pachymeningitis with negative or atypical testing for ANCA and positive ELISA tests MPO or PR3. These cases of meningeal inflammation should be suspected in patients presenting with headache, encephalopathy, and cranial nerve involvement. Subclinical cognitive impairment is present in about 30% of patients with a small-vessel vasculitis and usually correlates with MRI findings. MRI can demonstrate patterns of abnormalities consistent with vasculitic CNS involvement such as the forms of meningitis or parenchymal lesions with inflammation, hemorrhage, or ischemia; these findings are not specific for AAV or other forms of vasculitis. Lumbar puncture with cerebrospinal fluid analysis is important to aid in the differentiation between infectious and inflammatory conditions, including bacterial, viral, or tuberculous meningoencephalitis (the latter can present with positive IIF testing for ANCA and ELISA for PR3 and MPO ). Finally, a brain or meningeal biopsy is a procedure that, albeit invasive, is sometimes necessary when no other tissue can be feasibly biopsied.

Skin

Skin biopsy is a simple procedure that can be very informative in patients suspected of having AAV. An ideal biopsy extends to the subcutaneous tissue in the most tender, red, or purpuric lesion that is less than 48 hours old. The pathologic features of vasculitis are more likely to be present at this stage and the yield of the direct immunofluorescence (DIF) testing is optimal. Deep biopsies will reveal involvement of larger vessels, which occasionally occurs in WG and should be expected in vasculitides that affect medium-size vessels, such as polyarteritis nodosa. Ulcerated lesions are not optimal for biopsy; the edge of superficial ulcers is preferred should biopsy be performed. DIF is an essential part of a cutaneous biopsy when vasculitis is in the differential diagnosis. The physician performing the procedure should be aware that the diagnosis of AAV is being entertained, as the processing of the sample for DIF is different than for routine histopathology. Ideally, 2 distinct biopsy samples for histopathology and DIF should be obtained, as splitting an individual sample could produce crush artifacts and significantly decrease the yield of the biopsy.

Papular lesions in WG usually exhibit a pattern similar to a leukocytoclastic vasculitis, with neutrophilic infiltrates around dermal small vessels. Medium-sized vessel inflammation can be seen in ulcers and infarcts. Urticarial, granulomatous, and neutrophilic lesions (similar to pyoderma gangrenosum) are histopathological features that could also be found in WG. The inflammatory neutrophilic infiltrates around small vessels will be similar in cases of CSS but could be enriched for eosinophils. The absence of granulomatous lesions will support a diagnosis of MPA, but given that this finding is rare even in proven cases of WG and other features are nonspecific, it is difficult to distinguish among the small and medium vessel vasculitides based solely on histopathological grounds. Lack of deposition of immune complexes and complement on DIF examination can differentiate AAV from leukocytoclastic vasculitis, cryoglobulinemia, SLE, and Henoch-Schönlein purpura, in which different patterns of deposition are found.