Show Summary Details
Page of

Vasculitis and the lung 

Vasculitis and the lung
Chapter:
Vasculitis and the lung
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0051
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2021. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

date: 30 November 2021

Classification

These are rare conditions but are often seen in the specialist chest clinic (see Vasculitis and the lung p. [link] for an approach to diffuse alveolar haemorrhage). Clinical features can be non-specific and similar to those seen in other diseases, and diagnosis can therefore be difficult. Vasculitides are great ‘mimickers’ of other diseases, such as lung cancer or ARDS, and have a high untreated mortality. There is considerable overlap between the different vasculitides, which can make definitive diagnosis difficult. Suspect a diagnosis of vasculitis if:

  • Weight loss

  • Low-grade fever

  • Raised inflammatory markers

  • Chest disease is not improving or responding to treatment as expected:

    • Unexplained dyspnoea

    • Hypoxia

    • Unexplained desaturation on exercise

    • Haemoptysis

    • Sinus or nasal disease

    • Wheeze

    • CXR abnormalities/infiltrates

    • Abnormal kCO

  • Associated renal impairment or positive urine dip for blood or protein

  • Raised autoantibodies

  • No other clear diagnosis.

The 1° pathology in vasculitis is inflammation and necrosis of differing sized blood vessels. The pulmonary vessels are involved as part of a multi-systemic vasculitis process.

Small-vessel vasculitides

are the most common to involve the lung. Arterioles, capillaries, and venules located within the lung interstitium are affected. Neutrophil infiltration and subsequent fibrinoid necrosis cause vessel wall destruction. Necrotizing pulmonary capillaritis can also occur, characterized by a marked neutrophilic infiltration of the interstitium. Interstitial capillaries become damaged, allowing red blood cells to enter the alveolus; thus, alveolar haemorrhage is a feature of many of the small-vessel vasculitides.

New nomenclature for the vasculitides was released by the International Chapel Hill Consensus Conference in 2012, revising that of 1994 (see Table 51.1).

Table 51.1 Classification of vasculitis, based on the Revised International Chapel Hill Consensus, 2012

1° vasculitis

Lung involvement

ANCA

  • Small vessel

  • ANCA-associated vasculitis (AAV)

    • - Microscopic polyangiitis (MPA)

    • - GPA (Wegener’s)

    • - EGPA (Churg–Strauss)

  • Goodpasture’s disease

  • Frequent

  • Frequent

  • Frequent

  • Frequent

  • c/p-ANCA

  • c-ANCA in 75%,

  • p-ANCA in 15%

  • p-ANCA in 70%

  • p-ANCA in 10–20%

  • Medium-sized vessel

  • Polyarteritis nodosa (PAN)

Rare

Negative

  • Large vessel

  • Giant cell arteritis

  • Takayasu’s arteritis

  • Rare

  • Frequent

  • Negative

  • Negative

Further information

2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1–11.Find this resource:

Bosch X et al. ANCA. Lancet 2006;368:404–18.Find this resource:

Schwarz M, Brown K. Small vessel vasculitis of the lung. Rare diseases 10. Thorax 2000;55:502–10.Find this resource:

ANCA

ANCAs react with cytoplasmic granule enzymes in neutrophils and stain them in one of two ways:

  • Diffusely cytoplasmic pattern or c-ANCA

  • Perinuclear pattern or p-ANCA.

These autoantibodies may have a direct role in pathogenesis as well as being disease markers.

ANCA have two major specificities:

  • Antiproteinase 3 antibodies (anti-PR3)—associated with c-ANCA pattern

  • Antimyeloperoxidase antibodies (anti-MPO)—associated with p-ANCA pattern.

c-ANCA

(anti-PR3) targets PR3 and may suggest GPA (75% of cases are c-ANCA positive). Levels correlate with disease activity and extent. Also found in patients with MPA (45% of those with clinical disease will be c-ANCA positive).

p-ANCA

(anti-MPO) targets MPO and has a wider range of disease associations, including other vasculitides and autoimmune diseases, HIV, lung cancer, pulmonary fibrosis, and PEs.

Granulomatosis with polyangiitis (Wegener’s): presentation and diagnosis

Definition and epidemiology

Necrotizing vasculitis affecting small and medium-sized vessels, especially in the upper and lower respiratory tract and also the kidneys. Associated granulomata. Renamed in 2011.

  • Unknown cause

  • ♂ = ♀

  • 3/100, 000, 80–97% Caucasian

  • Any age, but most common between 40 and 55y.

Clinical features

  • ENT In 90%, upper airways involvement will be the first presenting sign. Nasal congestion and epistaxis, with inflamed, crusty, ulcerated nasal mucosa. Nasal septum perforation. Late sign is a saddle nose deformity. Sinusitis is common and may be painful. Otitis media. Subglottic stenosis, causing upper airway obstruction, dyspnoea, voice change, and cough. Abnormal flow–volume loops

  • Lung Affected in 85–90% of patients. Haemoptysis, cough, dyspnoea. Pleuritic chest pain

  • Kidney Affected in 77% of patients. Haematuria, proteinuria, and red cell casts. Only 10% have renal impairment initially, but 80% will have involvement during their disease course. Characteristic progressive deterioration of renal function

  • Systemic Fever and weight loss

  • Other organ systems (skin, eyes, joints, CNS) Vasculitic skin rash, with granulomatous involvement in 46%. Muscle and joint pains. Conjunctivitis, scleritis, proptosis, eye pain, visual loss. Mononeuritis multiplex and CNS disease.

Investigations

Consider:

  • CXR Flitting cavitating pulmonary nodules, consolidation, or pulmonary infiltrates, alveolar haemorrhage, parenchymal distortion, large and small airway disease, pleural effusion, bronchiectasis. Can look like neoplasms, infection, or fluid overload

  • HRCT of chest

  • O2 saturations

  • FBC, U&E, CRP, ESR

  • Serum ANCA, especially c-ANCA, is sensitive and fairly specific. Present in 90% of patients with extensive GPA and 75% with limited. p-ANCA positive in 5–10% of patients with GPA. Combining indirect immunofluorescence with specific immunoassays for antibodies to PR3 and MPO increases sensitivity and specificity for GPA and MPA to over 90%. Remember ANCA can be negative, especially in disease confined to the respiratory tract. ANCA titres rise prior to a relapse and are higher when disease is active, and this can act as a guide to starting treatment. However, high ANCA levels in the absence of clinical symptoms or signs may not represent active disease, and, therefore, ANCA levels should not be used in isolation to determine treatment. Also consider CRP ± ESR

  • Urine dipstick and microscopy Red cell casts

  • PFTs, including kCO

  • Image sinuses Bony destruction makes GPA likely

  • Bronchoscopy May show inflammation and ulceration of larynx, trachea, and bronchi. Scarring and stenosis may be seen. BAL is neutrophilic, also with eosinophils and lymphocytes. TBB is unlikely to be diagnostic

  • Biopsy

    • Respiratory tract and nose—granulomata in association with medium- and small-vessel necrotizing vasculitis and surrounding inflammation. Nasal biopsies are often non-specific and may not be diagnostic

    • Renal biopsy—focal segmental or diffuse necrotizing glomerulonephritis. Pauci-immune and granulomata rare. Not specific for GPA

    • Skin biopsy—leukocytoclastic vasculitis ± granulomata.

Diagnosis

Biopsy and ANCA are key to diagnosis. Biopsy whichever site is affected. May be nasal, lung (open or thoracoscopic), skin, or renal. If there is evidence on urine dip of renal vasculitis, this may be the best and easiest biopsy site. Disease may be patchy in nature, requiring repeat biopsies if the first is negative. High c-ANCA and anti-PR3 is highly suggestive of GPA.

Differential diagnosis of GPA

Malignancy, TB, sarcoidosis, ABPA, Goodpasture’s disease (anti-GBM disease with pulmonary haemorrhage and nephritis), SLE, MPA, connective tissue disease.

Granulomatosis with polyangiitis (Wegener’s): management

Involve the renal team, and share care of the patient. See Chapter 54 for immunosuppressive drug details.

  • Standard regimen for generalized or organ-threatening disease (e.g. active/progressive pulmonary or renal disease or CNS disease):

    • Induce remission with oral prednisolone (1mg/kg/day, tapering weekly to a dose of 15mg or less daily by 3 months) and cyclophosphamide, orally (2mg/kg/day, up to 200mg/day) or IV (pulses at 2- or 3-week intervals, 15mg/kg), for 3–6 months. Reduce cyclophosphamide dose in elderly (e.g. reduce oral dose by 25% if >60y and by 50% if >75y) and in setting of renal impairment. Taper cyclophosphamide dose to maintain WCC >4 × 109/L and neutrophils >2 × 109, to reduce infection risk (see Vasculitis and the lung p. [link] for more detail)

    • The aim is to prevent irreversible tissue necrosis. There is evidence that this regime induces remission in 80% of patients at 3 months and 90% at 6 months

    • After induction of remission (at 3–6 months), consider switch from cyclophosphamide and prednisolone to maintenance therapy with prednisolone and either azathioprine (2mg/kg/day for 12 months, then reduce to 1.5mg/kg/day; check TPMT levels; see Vasculitis and the lung pp. [link][link]) or methotrexate (15mg once/week, increase to maximum of 20–25mg once/week by week 12; see Vasculitis and the lung p. [link]). This avoids the morbidity associated with long-term cyclophosphamide use. Both azathioprine and methotrexate have been demonstrated to maintain remission, although the evidence favours use of azathioprine

    • Restart the regime if the patient relapses—this may occur in 50%

  • For severe life-threatening disease (e.g. rapidly progressive renal failure or massive pulmonary haemorrhage):

    • Plasma exchange/plasmapheresis (7 × 4L exchanges over 2 weeks) has been shown to be more effective than methylprednisolone in the treatment of GPA. In patients with severe pulmonary haemorrhage, it is also effective and can be given along with fresh frozen plasma

    • In addition, treat with pulsed methylprednisolone (500–1, 000mg/day, depending on body weight for 3 days) and IV cyclophosphamide (15mg/kg, reduce if elderly or renal impairment)

    • Dialysis for renal failure

    • After induction of remission (over 3–6 months), switch from cyclophosphamide to azathioprine or methotrexate with prednisolone as maintenance therapy

  • For localized disease or early systemic disease (without threatened organ involvement):

    • Prednisolone with either methotrexate or oral/pulsed cyclophosphamide. Use of methotrexate avoids cyclophosphamide-related toxicity but may be associated with a higher relapse rate. Localized disease may still be serious (e.g. retro-orbital involvement), and, in these situations, cyclophosphamide should be considered

  • Duration of treatment Maintenance therapy is recommended to continue for at least 24 months after initial disease remission, as relapses are common. Some recommend continuing treatment for up to 5y, particularly if the ANCA remains positive

  • PCP prophylaxis with co-trimoxazole is recommended (960mg 3×/week) in patients receiving cyclophosphamide and prednisolone. There is some evidence that co-trimoxazole alone may be effective in the treatment of especially limited GPA, although the reasons for this are not clear—it may be due to suppression of nasal Staphylococcus aureus carriage, the presence of which is associated with an increased risk of relapse

  • Osteoporosis prophylaxis should be considered

  • Follow-up monthly for 3 months, then 3–6-monthly. Monitor FBC, U&E, CRP, LFT, ANCA, CXR, and kCO. Rising ANCA titres are a poor predictor of relapse; in the absence of other features of a relapse, follow up more closely, but do not increase immunosuppression solely on this basis. Withdrawal of immunosuppression in the setting of a persistently positive ANCA is associated with relapse, however

  • Relapses Treat minor relapses with an increase in the prednisolone dose. Treat major relapses with cyclophosphamide and increasing prednisolone; consider IV methylprednisolone, plasma exchange

  • Refractory disease Liaise with specialist; consider alternative therapies such as infliximab, high-dose IV immunoglobulin, rituximab, anti-thymocyte globulin, or CAMPATH 1H (alemtuzumab, anti-CD52). Mycophenolate or leflunomide are alternatives to azathioprine or methotrexate. Exclude underlying infection, malignancy, and non-compliance.

Prognosis

Limited disease

with pulmonary, but no renal, involvement and an often negative c-ANCA test has a better prognosis. However, this can progress over time to extensive disease, with classical destructive sinusitis, nephritis, and vasculitis and strong c-ANCA positivity, and is associated with higher mortality. Untreated, 80% of people with extensive GPA will die in 1y. Overall, 75–90% of patients can be brought into remission with treatment, although 50% relapse in 5y, and long-term follow-up is required.

Microscopic polyangiitis

At least as common as GPA and may be hard to distinguish. Managed in the same way.

  • Incidence ♂ = ♀, mean age 50, mainly Caucasians

  • Kidneys Main organ affected by a small-vessel necrotizing vasculitis, causing proteinuria and haematuria. Renal biopsy shows focal segmental glomerulonephritis with fibrinoid necrosis and sparse immune deposits

  • Pulmonary involvement occurs in 30–50% of patients, with pleurisy, asthma, haemoptysis, and pulmonary haemorrhage. CXR may be suggestive of pulmonary haemorrhage

  • p-ANCA positive, often c-ANCA also.

Treatment

with immunosuppression: steroids and cyclophosphamide (see Vasculitis and the lung pp. [link][link]).

Future developments

It had been thought that anti-TNF-α‎ agents were likely to have a role in acute vasculitis and seemed to work best in granulomatous disease. An RCT of etanercept plus standard therapy for GPA showed no significant effect on remission rates (N Engl J Med 2005;352:351–61). Further studies are ongoing of other anti-TNF-α‎ agents.

B-cell depletion with the monoclonal anti-CD20 antibody rituximab. This is used for non-Hodgkin’s lymphoma, SLE, RA. Encouraging results in small studies of ANCA-positive vasculitis, but no RCT as yet.

Mycophenolate for immunosuppression in vasculitis to induce remission. Used post-transplant. A large study vs azathioprine is underway.

Further information

Lapraik C et al. British Society of Rheumatology and British Heath Professionals in Rheumatology guidelines for the management of adults with ANCA associated vasculitis. Rheumatology 2007;46:1615–16.Find this resource:

Langford C, Hoffman G. Wegener’s granulomatosis. Rare diseases 3. Thorax 1999;54:629–63.Find this resource:

Frankel SK et al. Update in the diagnosis and management of pulmonary vasculitis. Chest 2006;129:452–65.Find this resource:

Goodpasture’s disease

Definition and epidemiology

Linear deposition of IgG on the basement membranes of alveoli and glomeruli, which damages collagen and in the lungs allows leakage of blood.

  • Anti-GBM antibodies are detectable in blood

  • Alveolar haemorrhage and glomerulonephritis

  • Important differential diagnosis of pulmonary-renal syndrome

  • Annual incidence of 1 case per million

  • ♂:♀ = 4:1

  • Commonest age 20–30y

  • Second peak when women in their late 60s are affected by glomerulonephritis alone

  • Cause unknown. Often a preceding viral infection. Smokers at greater risk of pulmonary haemorrhage, but not of Goodpasture’s disease

  • HLA-DR2 association in 60–70%.

Clinical features

  • Haemoptysis in 80–90%—more common in smokers

  • Cough, dyspnoea, fatigue, and weakness

  • Examination: inspiratory crackles common.

Investigations

  • Serum electrolytes show impaired renal function and often renal failure

  • FBC Iron deficiency anaemia

  • Urine dip and microscopy Haematuria, proteinuria, granular and typically red blood cell casts. Occasionally macroscopic haematuria

  • Anti-GBM and autoantibody screen

  • CXR± CT Diffuse bilateral patchy airspace shadowing in mid- and lower zones. May see air bronchograms

  • PFTs Restrictive defect with raised kCO if alveolar haemorrhage present.

Diagnosis

Renal biopsy usually shows diffuse crescentic glomerulonephritis. Linear IgG deposition detected by immunofluorescence or immunoperoxidase. Lung biopsy shows active intra-alveolar haemorrhage, with collections of haemosiderin-laden macrophages. These are not specific changes but may also show linear immunofluorescence staining of IgG.

Differential diagnosis

GPA, other pulmonary renal syndromes.

Management

  • Involve the renal team, and share care of the patient

  • Plasma exchange improves the speed of response to immunosuppression

  • High-dose steroids and cyclophosphamide

  • May need dialysis. Renal function may not improve, and renal transplant is only an option later if anti-GBM antibody levels become low

  • Recurrence is uncommon once disease is controlled. It usually responds to further immunosuppression. Residual defects in PFTs frequent.

Prognosis

Rapidly progressive pulmonary haemorrhage and renal failure. Usually fatal if not treated.

Churg–Strauss syndrome/eosinophilic granulomatosis with polyangiitis

Definition and epidemiology

Asthma, blood eosinophilia, and an eosinophilic granulomatous inflammation of the respiratory tract, with necrotizing vasculitis affecting small and medium-sized vessels.

  • Rare, 2.4 per million population, but 64 per million of an asthmatic population (who may have been misdiagnosed with asthma)

  • Middle-aged adults

  • ♂:♀ ≈ 2:1

  • Unknown cause. Montelukast was postulated as a possible cause, but this is now thought unlikely. Development of Churg–Strauss syndrome/EGPA in people on montelukast probably related to their decreased steroid dose ‘unmasking’ Churg–Strauss syndrome/EGPA, or as part of an increasing treatment regime in those with uncontrolled asthma, later diagnosed as Churg–Strauss syndrome/EGPA.

Clinical features

A diagnosis of Churg–Strauss syndrome/EGPA can be made if four of the following six criteria are present:

  • Asthma—may have had for years, often maturity onset, difficult to control, associated with rhinitis and nasal polyps

  • Blood eosinophilia >10%

  • Vasculitic neuropathy such as mononeuritis multiplex (occurs in 75%)

  • Pulmonary infiltrates

  • Sinus disease

  • Extravascular eosinophils on biopsy findings.

    (American College of Rheumatology criteria, 1990)

  • Also may have:

    • Myositis and cardiac failure, cardiomyopathy, coronary artery inflammation, pericardial effusion

    • Eosinophilic infiltration of mesenteric vessels, causing GI disturbance

    • Alveolar haemorrhage

    • Rarely, proteinuria caused by renal disease with focal segmental glomerulonephritis. Renal failure is rare

    • Skin nodules and purpura

    • Myalgia and arthralgia

    • Fever and weight loss.

Typical pattern of disease has three phases: beginning with asthma, then developing blood and tissue eosinophilia, then going on to systemic vasculitis. The asthma precedes the vasculitis, often by years (mean 8y).

Investigations

  • CXR Fleeting peripheral pulmonary infiltrates and bilateral multifocal consolidation

  • HRCT Ground-glass inflammation, pulmonary nodules, bronchial wall thickening, or alveolar haemorrhage

  • Bronchoscopy BAL Marked eosinophilia

  • Pathology Extravascular tissue eosinophilia, necrotizing angiitis, granulomata

  • Serum markers Peripheral blood eosinophilia. p-ANCA and anti-MPO positive in two-thirds. ANCA levels may not correlate with disease activity, but blood eosinophilia is a good guide.

Diagnosis

Predominantly a clinical diagnosis. Pathological confirmation of eosinophilic tissue infiltration or vasculitis desirable. Biopsy easiest site affected, such as skin, kidney, or open or thoracoscopic lung biopsy.

Differential diagnosis

ABPA, sarcoidosis, drug and parasitic causes of eosinophilic pneumonias, HP, hypereosinophilic syndrome.

Management

Depends on severity of disease at presentation.

  • If isolated pulmonary disease, oral prednisolone 1mg/kg (max 60mg/day) for 1 month or until no evidence of disease, then slowly decrease over 1y, with increases if symptoms recur

  • If unwell or with alveolar haemorrhage, pulsed methylprednisolone IV for 3 days, followed by high-dose oral steroids, with or without cyclophosphamide (see Vasculitis and the lung pp. [link][link])

  • In cardiac or GI disease, relapse, or life-threatening situations, such as requiring organ support, cyclophosphamide should be added (see Vasculitis and the lung pp. [link][link])

  • Plasma exchange is of no benefit

  • Treatment is aimed at reversing organ damage and reducing relapse rate

  • To maintain remission, prednisolone and one other immunosuppressant drug are usually required. Cyclophosphamide is often changed to azathioprine after 4–6 months

  • Prophylactic co-trimoxazole should be given (960mg 3×/week), and consider bone protection for steroids

  • Follow up regularly, with checks on FBC and eosinophil count, CXR.

Prognosis

Good prognosis if isolated pulmonary disease. Good response to steroids. May continue to have asthma, despite control of vasculitis, which can be severe and difficult to control. Poor prognosis associated with cardiac disease and severe GI disease, causing bleeding, perforation, or necrosis. Untreated, 5y survival rate is 25%. Also associated with worse prognosis: proteinuria >1g/24h, renal insufficiency, CNS involvement. Cardiac disease is the main cause of death.

Further information

Noth I et al. Churg–Strauss syndrome. Lancet 2003;361:587–94.Find this resource:

Vasculitis and the lung http://www.vasculitis-uk.org.

Vasculitis and the lung http://www.vasculitis.org.

Rare pulmonary vasculitides

Polyarteritis nodosa

  • Similar to MPA but affects medium-sized vessels

  • May exist as an ‘overlap’ disorder with GPA or Churg–Strauss/EGPA

  • Lung involvement is rare

  • Sometimes associated with previous hepatitis B or rarely hepatitis C infection.

Takayasu’s arteritis

  • Predominantly young women, often Asian

  • Vasculitis affecting the aorta and its major branches. Large and medium-sized pulmonary vessels affected, but involvement is usually silent. Pulmonary artery stenosis and occlusion common, occasionally with mild PHT

  • Presents with fevers and weight loss. Absent or weak upper limb peripheral pulses, particularly on left (as left axillary artery comes off aortic arch), and arterial bruits

  • Diagnosis made by angiography

  • Treatment Steroids may reduce symptoms but do not affect mortality. Angioplasty and surgical procedures may reduce the complications. Spontaneous remissions may occur.

Giant cell arteritis

  • Commonest form of systemic vasculitis affecting large and medium-sized vessels

  • 24 cases per 100, 000. Predominantly elderly ♀

  • Presents with non-specific symptoms of fever and weight loss; also headache, scalp tenderness, and jaw pain. Amaurosis fugax and visual loss due to optic neuritis

  • Pulmonary complications occur in 9–25% of cases. They are relatively minor, with cough, sore throat, and hoarseness. PFTs and CXR normal

  • Diagnosis High ESR, temporal artery biopsy showing pan-arteritis and giant cell formation

  • Treatment Good response to oral steroids. Continue for 1–2y.