key: cord-016110-mlwe7fzz
authors: Specks, Ulrich
title: Pulmonary Manifestations of Vasculitis
date: 2014-05-05
journal: Pulmonary Manifestations of Rheumatic Disease
DOI: 10.1007/978-1-4939-0770-0_10
sha: 
doc_id: 16110
cord_uid: mlwe7fzz

Respiratory manifestations in patients with a primary systemic vasculitis syndrome need to be separated into those caused by the vasculitis itself, those related to treatment complications, and those caused by unrelated or only indirectly related comorbidities such as obstructive sleep apnea. Respiratory tract involvement is most common in the ANCA-associated vasculitides. Respiratory manifestations are less frequent and less prominent in other forms of systemic vasculitis, but they may nevertheless represent significant management challenges and carry a poor prognosis. This chapter reviews the tracheobronchial and pulmonary parenchymal disease manifestations, their clinical presentation, and differential diagnosis for each of the vasculitis syndromes. A systematic differential diagnostic approach to the patient with diffuse alveolar hemorrhage is also provided.

The term "pulmonary vasculitis" has been used in different ways. Primarily, it refers simply to infl ammation of the walls of vessels of any size in the lower respiratory tract. The term is, however, also used for the systemic vasculitis syndromes that commonly or predominantly present with involvement of the respiratory tract, such as the vasculitis syndromes associated with antineutrophil cytoplasmic antibodies (ANCA). Pulmonary vasculitis is usually associated with a systemic disorder caused by a variety of immunologic mechanisms. In the context of a vasculitis syndrome, the lungs and lower airways can be affected by three major pathologic processes: (1) infl ammatory cell infi ltration and necrosis of the pulmonary parenchyma; (2) infl ammation of the tracheobronchial tree often leading to stenoses; and (3) pulmonary capillaritis causing diffuse alveolar hemorrhage (DAH). Beyond capillaritis, infl ammation of vessels of different sizes in the lung, including pulmonary arteries, veins, and bronchial arteries, are comparably rare manifestations of some unique vasculitis syndromes. Clinicians should also remember that not all respiratory symptoms occurring in patients with vasculitis are caused by infl ammation of pulmonary vessels or the underlying vasculitis syndrome, infection being the most important alternative diagnosis. This chapter reviews the pulmonary manifestations of the various vasculitis syndromes using the recently revised Chapel Hill Consensus defi nitions and nomenclature [ 1 ] .

Microscopic polyangiitis (MPA), granulomatosis with polyangiitis (Wegener's; GPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss; EGPA) are the three primary systemic small vessel vasculitis syndromes with prominent respiratory tract involvement [ 1 ] . In contrast to the other forms of vasculitis with predilections for larger vessels, most patients with active MPA and GPA as well as the majority of patients with active EGPA have ANCA. MPA and GPA will be discussed together as the same diagnostic and therapeutic principles apply. EGPA will be covered separately.

MPA is defi ned as necrotizing vasculitis with few or no immune deposits, affecting small vessels including capillaries, venules, or arterioles (polyangiitis). Necrotizing arteritis involving smalland medium-sized arteries may be present. Necrotizing glomerulonephritis is very common; pulmonary capillaritis resulting in alveolar hemorrhage occurs frequently [ 1 ] . GPA is characterized by necrotizing granulomatous infl ammation involving the respiratory tract and necrotizing vasculitis affecting small-to medium-sized vessels. The most commonly affected vessels are capillaries, venules, arterioles, and arteries, but the wall of the aorta can also be affected by necrotizing granulomatous infl ammation [ 1 ] . For these reasons the term "polyangiitis" is used for these syndromes [ 1 ] . It is the necrotizing granulomatous infl ammation that sets GPA apart from MPA. The diagnosis of GPA depends on the presence of clinical, pathologic, or radiographic evidence or surrogates of granulomatous infl ammation. The vasculitis of MPA is indistinguishable from that of GPA, and there may be substantial overlap between the syndromes. For these reasons, the therapeutic approach to patients with GPA and MPA is governed by the same principles, and most clinical studies and therapeutic trials have combined both diseases.

The following paragraphs will focus on respiratory manifestations of MPA and GPA other than pulmonary capillaritis. Other organ manifestations will be covered briefl y as they pertain to general treatment decisions. The pulmonary capillaritis of MPA and GPA will be discussed in more detail in the section on DAH.

The pathognomonic histopathologic features of GPA include neutrophilic microabscesses, fi brinoid necrosis, palisading histiocytes, and giant cells forming a granulomatous infl ammation pattern that is often referred to as "geographic necrosis" [ 2 ] . Focal vasculitis, thrombosis, and fi brous obliteration of vascular lumina may be seen in areas affected by this type of infl ammation which affects predominantly the upper respiratory tract and lungs, but may involve any organ. Atypical and rare histopathologic features of GPA include organizing pneumonia, bronchocentric infl ammation, and occasionally a marked number of eosinophils in the infl ammatory infi ltrates [ 3 ] . Tracheobronchial infl ammation, often representing unique treatment challenges, is another feature of GPA not shared with MPA [ 4 , 5 ] .

The etiology of MPA and GPA remains unknown. A multifactorial genetic predisposition for the development of ANCA-associated vasculitis seems to be required [ 6 , 7 ] . Environmental triggers such as exposure to silica and more commonly infections appear to be linked to the onset of the disease as well as to relapses by initiating and perpetuating an infl ammatory environment that leads to the production of ANCA, which in turn appear instrumental for the development of capillaritis [ 8 ] .

Greater than 90 % of patients with GPA are Caucasian. The clinical presentation of GPA varies from subacute nonspecifi c respiratory illness to rapidly progressive alveolar hemorrhage syndrome. The majority of disease manifestations of GPA affecting the upper and lower respiratory tract are caused by the necrotizing granulomatous infl ammation. Ear, nose, and throat symptoms affect more than 85 % of patients [ 9 ] . These may include rhinorrhea, purulent or bloody nasal discharge, nasal mucosal drying and crust formation, epistaxis, and serous otitis media. Deep facial pain from paranasal sinus involvement, nasal septal perforation, and ulceration of the vomer are important signs. Staphylococcus aureus is frequently detected in the nose and sinuses and has been linked to relapses of the disease [ 10 ] . Aphthous lesions of the nasal and oral mucosa and infl ammation and destruction of the nasal cartilage lead to a "saddle-nose deformity." Ulcerated lesions of the larynx and trachea are present in 30 % of untreated cases [ 4 ] . These may cause hemoptysis.

The diagnostic evaluation of patients suspected of having GPA or MPA should include screening for all possible organ manifestations and treatment toxicities and then be adjusted based on patient-specifi c symptoms. Measurement of nonspecifi c markers of infl ammation including erythrocyte sedimentation rate and C-reactive protein, complete blood count, serum chemistry panel, urine analysis, and microscopy and testing for ANCA and chest imaging constitutes the core of diagnostic screening. Pulmonary function testing should be performed if the patient has any respiratory symptoms or chest roentgenographic abnormalities.

Respiratory symptoms such as cough, hemoptysis, dyspnea, stridor, or chest wall pain are usually associated with roentgenographic abnormalities, but roentgenographic abnormalities may be asymptomatic [ 11 ] . Lung nodules or mass lesions which may or may not cavitate, can be singular, but are usually multiple and bilateral. They can range in size from a few millimeters to several centimeters. Alveolar infi ltrates should prompt consideration of DAH even in the absence of hemoptysis (see discussion later in this chapter). Unusual manifestations include lymphadenopathy, lobar consolidation, and large pleural effusions. Tracheobronchial lesions are common, may be asymptomatic, and only detectable by bronchoscopy. When airway stenoses occur, symptoms that can be mistaken for asthma include stridor or localized wheezes. Pulmonary function testing including inspiratory and expiratory fl ow-volume loops may provide important clues to the presence of airway narrowing. Bronchoscopic inspection of the tracheobronchial tree is recommended for patients with unexplained respiratory symptoms, abnormalities on pulmonary function test results, or radiographic abnormalities [ 5 , 12 ] .

MPA with MPO-ANCA can occasionally be associated with lung fi brosis, predominantly of the usual interstitial pneumonia (UIP) and sometimes of the nonspecifi c interstitial pneumonitis (NSIP) variety [ 13 ] . The causal relationship between the interstitial lung disease and MPA remains unclear. In most instances the lung fi brosis precedes the development of vasculitis or is detected at the time of fi rst vasculitis disease manifestations. In such patients the MPA disease manifestations respond to immunosuppressive therapy as expected, whereas the lung fi brosis generally does not.

Treatment of MPA and GPA follows several general principles. First is the distinction of disease categories based on disease severity. Second is the separation of treatment phases into a remission induction phase, followed by a remission maintenance phase. Third is the distinction between symptoms caused by damage from the disease itself or treatment and those attributable to active infl ammation. Lastly, all therapeutic interventions need to be paired with adjunctive measures aimed at minimizing treatment toxicities, or designed to repair damage.

To stratify remission induction therapy, patients' disease activity is categorized as "limited or non-severe disease" or "severe disease." "Severe disease" is either life-threatening or threatening an affected organ with irreversible loss of function. This includes alveolar hemorrhage, glomerulonephritis, eye involvement (except mere episcleritis), and nervous system involvement including sensorineural hearing loss. "Limited or non-severe disease" includes essentially all patients with disease activity that does not qualify as "severe" by our defi nitions. The term "limited disease" used in the United States comprises what European investigators have referred to as "early-systemic disease" as well as "localized disease." Even though this separation is not based on well-defi ned biological distinctions, most disease manifestations leading to the categorization as "severe disease" are caused by capillaritis. In contrast, most symptoms leading to the classifi cation as "limited or non-severe" disease are the result of necrotizing granulomatous infl ammation. Patients with limited GPA have a more protracted disease course, a greater likelihood of experiencing a disease relapse following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders (e.g., saddle-nose deformity).

Therapy for MPA and GPA follows similar principles and is based on randomized controlled trial results. Methotrexate (MTX) given once a week at a dose of up to 25 mg in combination with daily oral prednisone is considered the standard of care for patients with non-severe GPA [ 14 ] . For remission induction in severe GPA and MPA, CYC at a dose of 2 mg/kg/day in combination with prednisone has been the standard of care until recently [ 9 , 15 ] . Rituximab (RTX) has now been proven to be an effective and safe alternative for CYC, and for patients presenting with a severe disease relapse RTX was shown to be superior to CYC [ 16 , 17 ] .

Once remission has been induced and the prednisone taper is well under way, CYC should be switched to either azathioprine (AZA, preferred in patients with renal involvement and any degree of renal insuffi ciency) or MTX [ 18 ] . MTX and AZA are equivalent for remission maintenance, whereas another randomized controlled trial showed that mycophenolate mofetil (MMF) is not as effective as AZA for remission maintenance [ 19 ] . Thus, the use of MMF for remission maintenance can only be supported for patients who have failed MTX and AZA, or who have contraindications for both agents. The Wegener's Granulomatosis Etanercept trial (WGET), in which MTX was used for remission maintenance, confi rmed that long-term remission remains an elusive goal for many patients, as remission was maintained in less than half of the patients [ 20 ] . The RTX in ANCA-associated Vasculitis (RAVE) trial showed that a single 4-week infusion series of RTX was as effective as 18 months of conventional cytotoxic therapy with CYC followed by AZA, even though patients in the RTX treatment arm of that trial received no further therapy following the original infusion therapy [ 17 ] . Several recent studies including the RAVE trial have shown that PR3-ANCA (versus MPO-ANCA), the diagnosis of GPA (versus MPA), and relapsing disease (versus new diagnosis) represent risk factors for subsequent relapses even when patients are maintained on AZA for maintenance therapy [ 17 , 21 , 22 ] .

Large airway involvement in GPA may call for specialized management beyond standard immunosuppression [ 5 ] . Subglottic stenosis is often addressed with dilation procedures paired with local injection of long-acting glucocorticoids with or without mitomycin C [ 23 ] . Stenosis of the large airways may require bronchoscopic interventions, including dilation by rigid bronchoscope, YAG-laser treatment, and the placement of silicone airway stents, or balloon dilations which can be performed with the fl exible bronchoscope [ 5 ] . Tracheobronchial infections, like nose or sinus infections, are thought to play a role in the pathogenesis of the disease by promoting relapses. For this reason, it is advisable to provide antimicrobial therapy based on culture and susceptibility results from bronchial washings. The application of topical glucocorticoids may spare patients with tracheobronchial involvement from ongoing oral glucocorticoid therapy. Lastly, pneumocystis jerovecii pneumonia is a well recognized and potentially fatal complication of immunosuppressive therapy for GPA that can easily be prevented [ 24 ] . Pneumocystis pneumonia prophylaxis is recommended for all patients with GPA receiving any kind of immunosuppression including being B-cell depleted after RTX therapy [ 25 ] .

The Chapel Hill Consensus defi nes EGPA as "eosinophil-rich and granulomatous infl ammation involving the respiratory, and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia" [ 1 ] . EGPA is included among the ANCA-associated vasculitides, but only 40-70 % of patients with active EGPA have detectable ANCA prior to treatment. If ANCA is detectable it is usually of the P-ANCA/MPO-ANCA type [ 26 , 27 ] . EGPA is primarily distinguished from GPA and MPA by a high prevalence of asthma and peripheral blood and tissue eosinophilia. Three distinct disease phases which may not always follow in sequence have been described for the disease [ 28 ] . A prodromal allergic phase with asthma may last for a number of years. The eosinophilic phase with prominent peripheral and tissue eosinophilia may also last a number of years, and the manifestations may remit and recur over this time period. The differential diagnosis for patients in this phase of the disease includes parasitic infection and chronic eosinophilic pneumonia. The vasculitic phase consisting of systemic vasculitis may be life-threatening. This is usually the last phase and may be masked or prevented by glucocorticoid therapy used for the management of earlier phases. Asthma usually predates the vasculitic phase by a mean of 7 years (range 0-61). "Formes frustes" of EGPA have also been described with eosinophilic vasculitis and/or eosinophilic granulomas in isolated organs without evidence of systemic disease [ 29 ] .

Pulmonary parenchymal involvement in the form of transient alveolar-type infi ltrates occurs in 38 % of patients. These have a predominantly peripheral distribution and are indistinguishable from infi ltrates seen in chronic eosinophilic pneumonia [ 26 ] . Nodular lesions are rare in EGPA. In contrast to GPA and MPA, alveolar hemorrhage is exceedingly rare (<5 % of cases). Renal involvement in EGPA is less prominent than in GPA or MPA and does not generally lead to renal failure [ 30 ] . In contrast, peripheral nerve involvement, typically in the form of mononeuritis multiplex, is more frequent [ 26 , 27 , 31 ] . Skin, heart, central nervous system, and abdominal viscera may also be involved.

The classic histopathologic picture consists of necrotizing vasculitis, eosinophilic tissue infi ltration, and extravascular granulomas. However, not all features are found in every case, and they are not pathognomonic of the condition. Particularly the fi nding of a "Churg-Strauss granuloma" on skin biopsy should not be confused with the diagnosis of EGPA. This type of necrotizing extravascular granuloma may be seen in EGPA as well as in other systemic autoimmune diseases including GPA and rheumatoid arthritis. Recent studies suggest that a more vasculitic disease phenotype is associated with the presence of ANCA, but this was not confi rmed by all studies. There remains substantial overlap of organ manifestations between patients with EGPA who are ANCA positive and those who are ANCA negative [ 26 , 27 , 31 ] .

Several case studies and limited populationbased incidence estimates have indicated that leukotriene receptor blocking agents may lead to unmasking of vasculitic symptoms in asthmatics, by allowing dose reductions or discontinuation of oral glucocorticoid therapy. There is currently no evidence suggesting that these agents directly cause the disease or need to be avoided in EGPA.

The overall mortality of EGPA is lower than that of GPA or MPA and not signifi cantly different from the normal population [ 26 ] . Most reported deaths are secondary to cardiac involvement [ 31 ] .

Systemic glucocorticoids remain the mainstay of therapy. There are no randomized controlled trials that provide clear guidance. Treatment approaches following the principles applied to the management of ANCA-associated vasculitis have been adopted for EGPA. Accordingly, CYC should be added to glucocorticoids for remission induction in all patients with disease manifestations that threaten the patient's life or the function of a vital organ, i.e., particularly those with central-or peripheral nerve involvement, glomerulonephritis, heart involvement, or alveolar hemorrhage [ 32 ] . MTX, AZA, and MMF have all been used as glucocorticoid-sparing agents in less severe disease and for remission maintenance. Refractory disease, and disease dominated by diffi cult-to-control eosinophilic infl ammation, has been reported to respond to interferon-alpha therapy, and more recently anti-interleukin-5 therapy [ 33 , 34 ] . RTX has also been used successfully in EGPA, particularly ANCA-positive patients with renal disease, but the data are still scarce, and it cannot be recommended to use RTX instead of CYC for patients with severe EGPA [ 35 ] .

IgA vasculitis is an immune-complex-mediated disease characterized by IgA1-dominant immune deposits affecting predominantly capillaries, venules, and arterioles leading to acute purpura, arthritis, colicky abdominal pain, and nephritis. Proliferative and necrotizing glomerulonephritis is usually mild. Immunofl uorescence microscopy shows large deposits of IgA in the skin and kidney. IgA vasculitis is more common in children (mean age of patients, 17 years), but adults can also be affected. The triad of purpura, arthritis, and abdominal pain is present in approximately 80 % of patients. Joint involvement affecting the large joints is typically monoarticular and transient causing pain that is out of proportion to the objective evidence of synovitis. Peritonitis and melena are common.

Pulmonary manifestations of IgA vasculitis are rare. Only 36 cases have been reported to date, and capillaritis has been documented histopathologically only in a minority of them. As in the skin and glomeruli, IgA deposits along the pulmonary capillary walls are pathognomonic for the disease. Half of the patients with IgA vasculitis associated DAH required mechanical ventilation and almost a third of the reported patients died [ 36 ] .

Cryoglobulinemic vasculitis is characterized by circulating cryoglobulins and their deposits in small vessels including capillaries, venules, and arterioles. Half of all cases are linked to Hepatitis C Virus infection [ 37 ] . Compared to skin, peripheral nerve, and renal involvement, capillaritis of the lung leading to DAH is rare (3 %), but associated with a high mortality (80 %) [ 37 ] . RTX is now the preferred immunosuppressive agent for cryoglobulinemic vasculitis [ 38 ] .

Another rare small vessel vasculitis is hypocomplementemic urticarial vasculitis (HUV). HUV is characterized by urticaria, hypocomplementemia, anti-C1q antibodies, and vasculitis of small vessels [ 1 ] . Signs and symptoms consist of fever, arthralgias, arthritis, angioedema, uveitis, episcleritis, abdominal pain, glomerulonephritis, and seizures occurring at variable frequencies and combinations. The reported pulmonary complications of HUV are not directly caused by vasculitis. Obstructive pulmonary disease, often severe, occurs in up to 66 % patients [ 39 ] . Its immunologic etiology remains unclear, and cannot always be related to smoking.

Polyarteritis nodosa (PAN) is not associated with ANCA and does not affect capillaries. Therefore, it does not cause glomerulonephritis or alveolar hemorrhage. However, case reports of classic PAN affecting the bronchial or bronchiolar arteries have been reported as the cause of occasional lung hemorrhage. Most cases of classic PAN diagnosed today are associated with viral infections, specifi cally hepatitis B and C. Consequently, antiviral therapy plays a prominent role in the management of such cases in addition to immunosuppression [ 40 ] . In contrast to MPA, classic PAN rarely relapses.

Giant cell arteritis (GCA) represents a generalized infl ammatory disorder involving large-and medium-sized arteries. GCA is the most common form of vasculitis in elderly patients of the Northern hemisphere. Granulomatous infl ammation of vessel walls can be found in 60 % of temporal artery biopsy specimens, and the aorta may also be affected possibly leading to thoracic aortic aneurysms in the elderly.

Respiratory symptoms have been reported in up to 25 % of patients, but are usually mild and of little consequence. However, respiratory symptoms can sometimes be the initial presentation of GCA. Therefore, GCA should be considered in elderly patients presenting with new onset of cough, hoarseness, or throat pain without other identifi able cause [ 41 ] . An elevated sedimentation rate may lead to the correct diagnosis, and cough, hoarseness, and throat pain usually resolve promptly with glucocorticoid therapy. Pleural effusion or multinodular pulmonary lesions associated with GCA have also been reported on rare occasions raising questions about a possible overlap with GPA since the latter may also involve the temporal arteries. Therapy of GCA continues to be based on the use of glucocorticoids without proven alternative. The glucocorticoid-sparing role of MTX for GCA remains controversial.

Takayasu's arteritis (TA) is a large vessel vasculitis affecting predominantly the aorta and its major branches in young patients most commonly affecting women [ 1 ] . It is not limited to patients of Asian descent. Constitutional symptoms, low grade fever, and arthralgias are often early disease manifestations. More characteristic features of this chronically relapsing disease include variable pulses of the extremities and claudication of affected vascular territories. Renovascular hypertension, pulmonary hypertension, and ischemia of affected organs can be disabling.

The pulmonary manifestations are caused by a unique arteriopathy affecting the large-and medium-sized pulmonary vessels. Pulmonary artery stenoses and occlusion as well as pulmonary hypertension can occur in up to half of all patients as a result of progressive defects in the outer media of the arteries and ingrowth of granulation tissue-like capillaries associated with thickened intima and subendothelial smooth muscle proliferation. The infl ammatory infi ltrate of the vessel wall consists of lymphocytes, plasma cells, and giant cells. The involvement of pulmonary arteries which is often asymptomatic can be detectable by conventional angiography, perfusion scan, magnetic resonance angiography, or PET scanning [ 42 ] . Chest roentgenograms are usually normal, but computed tomography may show areas of low attenuation as a result of regional hypoperfusion, subpleural reticulolinear changes, and pleural thickening. Fistulas can form between pulmonary artery branches and bronchial arteries. Nonspecifi c infl ammatory interstitial lung disease has also been reported.

Therapy for TA relies on immunosuppression with glucocorticoids and MTX [ 43 ] . Unfortunately, many patients relapse when the glucocorticoid dose is reduced below 15 mg daily. Antitumor necrosis factor-alpha agents may also be useful. Vascular bypass procedures may restore perfusion to areas affected by severe arterial stenoses, but the results are only temporary [ 44 ] .

Behçet's disease (BD) is a rare chronically relapsing systemic infl ammatory disorder characterized by aphthous oral ulcers and at least two or more of the following: aphthous genital ulcers, uveitis, cutaneous nodules or pustules, or meningoencephalitis [ 1 ] . The reported prevalence varies widely between different ethnic groups, for instance 1:16,000 in Japan but 1:200,000 in the United States. The disease is associated with the major histocompatibility complex antigen HLA-B51. The mean age of patients at the onset of BD is 35 years, and men are predominantly affected. Respiratory manifestations of BD consist of cough, hemoptysis, chest pain, and dyspnea [ 45 ] . The vasculitis of BD is immune-complex mediated, and may affect vessels of all sizes. Secondary thrombosis with major venous occlusion can occur. Anticoagulation may not be effective for prevention of thrombosis, but aspirin 80 mg/day has been advocated. Destruction of the elastic lamina of pulmonary arteries causing aneurysm formation, secondary erosion of bronchi, and arterial-bronchial fi stulae may result in massive hemoptysis, which can be fatal. Computed tomography or magnetic resonance angiography is recommended for detection of pulmonary artery aneurysms. Recurrent pneumonia, organizing pneumonia, and bronchial obstruction resulting from mucosal infl ammation have also been described.

Therapy of the underlying disease consists of immunosuppression. Prednisone alone may not be suffi cient to control the vasculitis. The addition of other drugs, such as colchicine, chlorambucil, MTX, cyclosporin, or AZA, is recommended. The use of biologic agents, in particular anti-TNF agents and RTX, has also been reported recently. The addition of AZA or CYC to glucocorticoids may result in resolution of pulmonary aneurysms. Anticoagulation should be avoided once pulmonary artery aneurysms have been identifi ed, but coil embolization of identifi ed aneurysms may prevent fatal hemorrhage. The prognosis of pulmonary involvement overall remains poor. About one third of patients die within 2 years of developing pulmonary involvement, most from fatal pulmonary hemorrhage.

Infectious processes, particularly infections with Aspergillus and Mucor species, invade vascular structures and produce secondary vasculitis. Certain drugs and chemicals can induce a systemic vasculitis picture that mimics MPA. Other uncommon secondary vasculitic entities include benign lymphocytic angiitis and granulomatosis, bronchocentric granulomatosis, and necrotizing sarcoid angiitis.

Diffuse hemorrhage into the alveolar spaces is often referred to as DAH syndrome . The clinical course of DAH is unpredictable and, therefore, should always be considered potentially lifethreatening. Patients usually seek care because of nonspecifi c symptoms, including dyspnea, cough, and possibly fever. Diffuse alveolar fi lling defects on chest roentgenogram are usually found, and anemia and hypoxemia may be prominent at the time of presentation. Hemoptysis is common, but DAH should be considered in the differential diagnostic evaluation of any patient with alveolar infi ltrates on chest roentgenogram even in the absence of hemoptysis. DAH can result from a variety of underlying or associated conditions that cause a disruption of the alveolarcapillary basement membrane integrity including immunological infl ammatory conditions causing immune-complex deposition or capillaritis (e.g., anti-GBM disease (Goodpasture's), systemic lupus erythematosus (SLE), ANCA-associated vasculitis), direct chemical/toxic injury (e.g., from toxic or chemical inhalation, abciximab use, all-trans-retinoic acid, trimellitic anhydride, or smoked crack cocaine), physical trauma (e.g., pulmonary contusion), and increased vascular pressure within the capillaries (e.g., mitral stenosis or severe left ventricular failure) (Table 10 .1 ). Pulmonary alveolar hemorrhage can also be associated with thrombocytopenia (<50,000 cells/μL), other abnormal coagulation variables, renal failure (creatinine concentration, ≥2.5 mg/ dL), and occasionally with a history of heavy smoking. Only the vasculitis syndromes giving rise to DAH will be discussed here.

Bronchoalveolar lavage (BAL) is the best diagnostic modality to confi rm the presence of DAH. Progressively more bloody return indicates alveolar origin of active bleeding. A positive iron stain in more than 20 % of all alveolar macrophages recovered by BAL is indicative of DAH, even in the absence of ongoing active bleeding. In patients with an established diagnosis of vasculitis, BAL should be performed in any patient with new alveolar infi ltrates to differentiate infection, DAH, and other infl ammatory infi ltrates such as eosinophilic pneumonia. Once DAH is established the additional diagnostic approach is aimed at the rapid identifi cation of the underlying cause and at prompt implementation of appropriate therapy.

History and physical examination can provide important fi rst clues about the specifi c etiology of DAH. Exposure to inhalational toxins including trimellitic anhydride or pyromellitic dianhydrate, drug abuse such as crack cocaine abuse, and smoking should be identifi ed. The past medical history may reveal comorbidities that can cause DAH, including mitral stenosis, coagulation disorders, recent bone marrow or hematopoietic stem cell transplantation, preexisting autoimmune disorders, and therapeutic drugs. The initial physical exam fi ndings may also point towards a specifi c systemic autoimmune disease as cause of the DAH. Laboratory testing performed during an evaluation of DAH should assess the acuity, progression, or stability of the disease process, uncover potential other organ involvement, and help to identify a specifi c underlying cause. Thus, initial laboratory testing should consist of a complete blood count, metabolic panel, urine analysis, and microscopy, and determine the current coagulation status (APTT, INR). Baseline markers of infl ammation (erythrocyte sedimentation rate and C-reactive protein) are helpful to monitor subsequent responses to therapy. Specifi c autoantibody testing for a potential underlying systemic disease process should also be initiated promptly, including testing for ANCA, anti-GBM antibodies, antinuclear antibodies, anti-double-stranded DNA antibodies, and antiphospholipid antibodies, as well as determination of cryoglobulins, complement, and creatinine kinase levels.

A lung biopsy is not always necessary to obtain a specifi c diagnosis for a DAH syndrome. Factors deserving careful consideration before performing a biopsy include the risks of the biopsy procedure, the likelihood of obtaining a diagnostic piece of tissue, the likelihood of the biopsy fi ndings to alter the therapeutic approach, and the risks associated with the chosen therapy. Most lung biopsies obtained from patients with DAH will show either pulmonary capillaritis or a "bland histology" in which the pulmonary architecture is well preserved and infl ammatory changes are minimal. The histopathologic diagnosis of pulmonary capillaritis requires the fi ndings of alveolar wall infi ltration with infl ammatory cells centered on capillary walls and small veins and fi brinoid necrosis of alveolar and vessel walls. The infl ammatory cells are usually neutrophils, but can be eosinophils or monocytes. Leukocytoclasis, a phenomenon describing pyknotic cells and nuclear fragments from neutrophils associated with cell apoptosis, is also an important feature of capillaritis. Capillaritis usually causes and may culminate in the destruction of the underlying lung architecture. Capillaritis needs to be distinguished from the predominant intra-alveolar neutrophilic infi ltration associated with active infections and from mere neutrophil margination related to surgical trauma.

Most of the syndromes associated with pulmonary capillaritis leading to DAH have been discussed in the previous sections of this chapter. The subsequent paragraphs will describe a few unique syndromes or conditions that may also be associated with DAH and variable degrees of capillaritis.

MPA and GPA combined represent the most common causes of pulmonary capillaritis. Alveolar hemorrhage caused by capillaritis in the setting of MPA or GPA may be subtle or rapidly progressive. Its course is unpredictable and this condition should always be considered lifethreatening or severe disease regardless of how well maintained oxygenation may be at the time of presentation. The presence of renal disease, the requirement of mechanical ventilation, and advanced age have all been identifi ed as factors portending a worse prognosis [ 46 -48 ] . Early implementation of defi nitive therapy is crucial, and the application of 1-3 daily doses of 1 g of methyl-prednisolone intravenously is considered standard prior to implementation of additional standard therapy for severe disease. The RAVE trial had shown that patients with severe GPA or MPA with DAH achieve the same outcomes as all other patients with severe GPA or MPA [ 16 ] . However, patients requiring mechanical ventilation because of their DAH were excluded from participation in the trial.

For some patients with GPA and MPA the combination of glucocorticoids and CYC or RTX may not be suffi cient to induce a remission quickly. Plasma exchange (PLEX) has been advocated for early consideration in patients who present with DAH as well as for those presenting with rapidly progressive glomerulonephritis and renal failure. The MEPEX (Methyl-prednisolone versus Plasma Exchange) trial compared three pulses of intravenous methyl-prednisolone to 2 weeks of PLEX (7 × 60 mL/kg) in addition to standard therapy for severe disease (oral prednisone and CYC) in 156 patients who presented with a serum creatinine level of 5.5 mg/dL or greater [ 49 ] . Even though this trial showed signifi cantly better patient and renal survival at 6 months, there was no long-term advantage of PLEX and there were too few patients with DAH to allow a subset analysis. Only one single-center cohort study focusing on MPA with DAH in 20 patients admitted to an intensive care unit described 100 % survival of these patients when PLEX was added to standard immunosuppressive therapy [ 50 ] . The role of PLEX in severe AAV is currently undergoing further investigation. If DAH is uncontrolled despite aggressive immunosuppressive therapy and PLEX, the endobronchial application of recombinant-activated factor VII may be considered as salvage therapy. In patients who survive DAH caused by MPA or GPA, lung function usually recovers well.

This rare condition is by defi nition not a systemic form of vasculitis [ 51 ] . This isolated pulmonary capillaritis of unknown etiology is histopathologically indistinguishable from the pauciimmune capillaritis seen in ANCA-associated vasculitis. No specifi c autoantibodies have been identifi ed in these patients. This disorder represents a diagnosis of exclusion, and these patients are best treated with an immunosuppressive regimen that follows the guidelines for severe MPA.

Anti-glomerular basement membrane antibody disease (anti-GBM disease) or Goodpasture syndrome is a rare autoimmune disease caused by autoantibodies directed against the NC1-domain of the alpha-3 chain of basement membrane collagen type IV. This epitope is only accessible for autoantibodies in the basement membranes of kidneys and lungs. DAH occurs in about half of patients with anti-GBM disease and requires an additional inhalational injury, particularly smoking, to render the antigen accessible for the autoantibodies and for the development of the pulmonary disease manifestation. Anti-GBM disease rarely causes isolated alveolar hemorrhage in the absence of renal disease. Even though patients usually have serum anti-GBM autoantibodies, the diagnosis of anti-GBM disease cannot be established without histopathologic documentation of linear immunoglobulin G deposits along the basement membranes in lung or kidney. Whether anti-GBM disease represents a true vasculitis is a matter of defi nition. As the glomerulus is a capillary structure, its infl ammation by defi nition represents a form of capillaritis. This is the main reason for the inclusion of anti-GBM disease in the nomenclature and defi nitions of the Chapel Hill classifi cation. Yet, the prominent histopathologic fi nding in the lung of patients with anti-GBM disease is the "bland histopathology," whereas capillaritis represents a secondary histopathologic feature that has also been described in some patients [ 52 ] . Early implementation of immunosuppressive therapy in conjunction with PLEX is the key to a favorable outcome in patients with anti-GBM disease [ 53 ] . Lung function usually recovers fully from anti-GBM disease, but chronic renal failure is common and defi nes the overall outcome of the disease.

DAH as a result of immune-complex-mediated pulmonary capillaritis is a rare but usually severe complication of SLE. The onset of DAH in patients with SLE is usually abrupt, but hardly ever the fi rst sign of the disease. The disease presentation is usually rapidly progressive with pulmonary infi ltrates and fever, mimicking infection, and hemoptysis may be absent. Consequently, the differentiation of DAH from infection in SLE usually requires a diagnostic BAL. Mechanical ventilation, infection, and CYC therapy were reported as negative prognostic factors in one report. The reported mortality of DAH in SLE varies between 0 and 90 % [ 54 -56 ] . Treatment consists of glucocorticoids and CYC. The use of PLEX has been suggested, but its benefi t remains unproven.

Respiratory complications are very common in most other types of collagen vascular or connective tissue disorders. Yet, pulmonary capillaritis presenting as DAH is rare. Isolated cases have been reported with polymyositis, rheumatoid arthritis, and mixed connective tissue disease. Consequently, serologic testing performed as part of an evaluation of DAH should include studies aimed at the identifi cation of these potential underlying disease entities.

DAH resulting from capillaritis can also be a rare complication of primary antiphospholipid syndrome (APS). Other respiratory complications include pulmonary embolism and infarction, pulmonary microthrombosis, and pulmonary arterial thrombosis with secondary pulmonary hypertension, all resulting from the hypercoagulability characterizing this disorder. However, primary pulmonary hypertension as well as adult respiratory distress syndrome can also occur.

The clinical presentation of DAH in primary APS is nonspecifi c and consists of cough, dyspnea, fever, and bilateral pulmonary infi ltrates. As DAH can also occur in the context of adult respiratory distress syndrome, and hemoptysis is absent in over half of the reported patients with APS and DAH, BAL should be performed early to establish the diagnosis. Tissue necrosis from microthrombosis as well as pulmonary capillaritis has been implicated as causes of DAH in APS. The capillaritis of APS is immune-complex mediated. The coexistence of thrombosis and capillaritis with DAH represents a therapeutic dilemma, as anticoagulation may need to be interrupted to control the hemorrhage, and patients often require placement of an inferior vena cava fi lter. The largest single-center report comprising 17 patients and review of 24 cases published in the literature indicates a high mortality of about 40 % despite aggressive immunosuppressive therapy [ 57 ] . Glucocorticoid therapy alone is usually ineffective, as is monotherapy with agents like AZA or MMF. PLEX in addition to immunosuppressive therapy is often considered, but its effi cacy remains questionable in patients with APS and DAH. Best results were obtained with cyclophosphamide or RTX, sometimes in combination.

Five months prior to presentation at the emergency room of a tertiary care center, this young man had developed maxillary sinusitis, unresponsive to broad spectrum antibiotics. This lingered until he experienced signifi cant worsening of sinusitis symptoms 3 months later. At that time he also developed epistaxis prompting an evaluation by an allergist. A couple of weeks later he developed acute left-sided hearing loss, night sweats, and migratory large joint arthralgias. By this time he had already lost 10 lb of weight due to malaise and lack of appetite. Four months after the onset of fi rst symptoms he was hospitalized at a local rural hospital, where he was found to have dry cough, bilateral episcleritis, lower extremity palpable purpura, and nodular lesions on chest roentgenogram. A rheumatology evaluation at the local hospital led to testing for ANCA, and a nasal biopsy was obtained. Renal function and urinary sediment were normal. The ANCA test was positive for C-ANCA and PR3-ANCA, and the nasal biopsy reportedly showed "granulomas." The patient was treated for 3 days with intravenous methylprednisolone and dismissed on oral prednisone 40 mg twice daily to be tapered to 30 mg daily over the course of the next 3 weeks. He was scheduled for initiation of RTX infusions 375 mg/m 2 as an outpatient. Scheduling diffi culties led to a delay in initiation of the infusions. Three weeks later, while on prednisone 30 mg daily he had noted signifi cant worsening of symptoms consisting of cough and malaise.

At this time he presented to the emergency room of a tertiary referral center with cough, malaise, and bilateral alveolar infi ltrates on chest roentgenogram ( Fig. 10.1a ) . He denied hemoptysis. The patient's room air oxygenation was 93 %, respiratory rate 20 per minute, temperature (continued) 36.6 °C, pulse 78 beats per minute, blood pressure 114/64. Physical examination of eyes, ears, nose, heart, and lungs was unremarkable. Hemoglobin was 11.0 g/dL, white blood count 23.3 × 10 9 /L, platelet count 405 × 10 9 /L, and lymphocyte and CD4 count are normal. An electrolyte panel and urinalysis and microscopy were normal. The patient's only medications consisted of prednisone and trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis. The patient was dismissed from the emergency room for further outpatient evaluation by rheumatology the next day. A CT scan of the chest is obtained (Fig. 10 .1b ) and after consultation with a pulmonologist a bronchoscopy with BAL is performed. This shows progressively bloody return indicative of alveolar hemorrhage. Over the next several hours the patient's respiratory status worsens, hemoglobin drops to 8.8 g/dL, and patient is admitted to the medical intensive care unit and requires mechanical ventilation. His course is complicated by the development of bilateral pneumothoraces requiring bilateral chest tube placement. Methyl-prednisolone is given at a dose of 1 g/ day for 3 days, and one dose of RTX, 375 mg/ m 2 , is given, followed 48 h later by eight daily sessions of PLEX. Ten days after admission to the intensive care unit he is transferred to the general ward where the second chest tube is removed (Fig. 10.1c ) . Following completion of PLEX, he receives completion of the RTX course (the remaining three once weekly doses). Following recovery he completes the taper of the prednisone dose to complete discontinuation before month 6. He has not relapsed over the course of the last 3 years. However, he has been retreated once with RTX without glucocorticoids following reconstitution of B-cells and recurrence of PR3-ANCA positivity.

This case offers the following teaching and discussion points:

• The development of symptoms and disease manifestations is quite typical in this patient. Despite this, the diagnosis of GPA is often delayed. • Glucocorticoids alone can only temporize and do not control this systemic disease process very well at doses below 60 mg daily without prompt implementation of defi nitive therapy. • Even though the combination of ENT disease with pulmonary nodules could be interpreted as "non-severe" disease allowing the choice of MTX in combination with glucocorticoids as fi rst remission induction regimen, the severe constitutional symptoms (night sweats and weight loss) and the presence of palpable purpura suggest a rapidly progressive disease process with developing features of capillaritis. The provided information does not allow the distinction between conductive or sensorineural hearing loss, and we don't know whether the eye infl ammation was merely episcleritis or early scleritis. Sensorineural hearing loss and scleritis are clearly severe disease manifestations. The classifi cation as severe disease for treatment purposes made at the outside hospital is certainly appropriate. For a newly diagnosed patient with severe GPA, cyclophosphamide or RTX is equally effective. However, in this young man who wanted to preserve his fertility, RTX is the preferred choice for that reason.

• Without prompt implementation of defi nitive therapy, the disease progresses, and in this case DAH developed. • DAH presents without hemoptysis in a large proportion of patients, and the absence of hemoptysis should not dissuade from suspecting it, particularly in a patient with preexisting diagnosis of GPA. Infection is the alternative explanation for the chest roentgenographic changes at the time of presentation to the emergency room. • DAH of any degree of severity should be considered as potentially life-threatening, and patients should be closely monitored until a defi nitive diagnosis is established, defi nitive therapy has been initiated, and control of disease activity has been ascertained. • Bronchoscopy with BAL for the evaluation of suspected DAH should be conducted in a safe setting, where worsening of the respiratory status that can be associated with the procedure can be treated with the necessary supportive measures. • Once disease activity is controlled and the pulmonary bleeding stops, alveolar hemorrhagic infiltrates clear fast, unless diffuse alveolar damage with ARDS develops. • Survivors of DAH usually experience complete recovery of lung function. • The role of PLEX in this patient's course remains unclear. There is currently no data from a randomized controlled trial that applies to patients with DAH caused by ANCA-associated vasculitis.

revised International Chapel Hill Consensus Conference nomenclature of vasculitides

Wegener's granulomatosis in the 1990s-a pulmonary pathologist's perspective

Common and uncommon manifestations of Wegener's granulomatosis

Tracheobronchial involvement in Wegener's granulomatosis

Airway involvement in Wegener's granulomatosis

The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis

Genetically distinct subsets within ANCA-associated vasculitis

Pathogenesis of ANCA-associated vasculitis

Wegener granulomatosis: an analysis of 158 patients

Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis

Wegener's granulomatosis in the chest: high-resolution CT fi ndings

Pulmonary function and highresolution CT fi ndings fi ve years after disease onset in patients with Wegener's granulomatosis

Prevalence and outcome of pulmonary fi brosis in microscopic polyangiitis

Methotrexate for Wegener's granulomatosis: what is the evidence?

A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies

Rituximab versus cyclophosphamide for ANCA-associated vasculitis

Effi cacy of remission-induction regimens for ANCA-associated vasculitis

Azathioprine or methotrexate maintenance for ANCA-associated vasculitis

Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial

Etanercept plus standard therapy for Wegener's granulomatosis

Classifi cation of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specifi city for myeloperoxidase or proteinase 3 in disease recognition and prognosis

Revisiting the classifi cation of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis

Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis

Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis

Pneumocystis pneumonia in patients treated with rituximab

Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists

Prevalence and clinical signifi cance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome

Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome

Formes frustes of Churg-Strauss syndrome

Renal involvement in Churg-Strauss syndrome

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and longterm followup of the 383 patients enrolled in the French Vasculitis Study Group cohort

The fi ve-factor score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort

Interferon-a treatment of four patients with the Churg-Strauss syndrome

Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome

Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab

Pulmonary hemorrhage in Henoch-Schonlein purpura: case report and systematic review of the english literature

Alveolar hemorrhage in cryoglobulinemia-an indicator of poor prognosis

Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature

Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic fi ndings in 18 patients

Treating polyarteritis nodosa: current state of the art

Respiratory tract symptoms as a clue to giant cell arteritis

Pulmonary artery involvement in Takayasu arteritis. PET/CT versus CT angiography

Advances in the medical and surgical treatment of Takayasu arteritis

Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients

Pulmonary vasculitis in behcet disease: a cumulative analysis

Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature

Alveolar haemorrhage in ANCA-associated vasculitides: 80 patients' features and prognostic factors

Longterm outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: a retrospective cohort study

Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis

Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis

Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis

Surgical pathology of the lung in anti-basement membrane antibodyassociated Goodpasture's syndrome

Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression

Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome

Alveolar hemorrhage in systemic lupus erythematosus: presentation and management

Diffuse alveolar hemorrhage in systemic lupus erythematosus: a single center retrospective study in Taiwan

Primary antiphospholipid syndrome-associated diffuse alveolar hemorrhage