CONTENTS
- Diffuse Alveolar Hemorrhage (DAH)
- ANCA-associated vasculitides
- Podcast
- Questions & discussion
- Pitfalls
clinical presentation
- (1) May present with hemoptysis (easier to diagnose). Unfortunately, about one third of patients don't have any hemoptysis upon presentation, despite having blood in the lungs.(25836645)
- (2) Many present solely with hypoxemic respiratory failure and diffuse pulmonary infiltrates. This can produce an ARDS-like picture that looks a lot like pneumonia (including symptoms of dyspnea, cough, and fever).
potential clues to the diagnosis
- Falling hemoglobin may be a clue supporting the presence of hemorrhage. Unfortunately, hemoglobin drops are extremely common and therefore nonspecific.
- Other features of the underlying disease process (e.g. granulomatosis with polyangiitis often causes a combination of pulmonary and renal failure, sometimes with involvement of the upper airway, skin, or eyes – more on this below).
#1/3) immediate findings due to diffuse alveolar hemorrhage
- Opacities may vary from ground glass to consolidation.
- Hemorrhage often has a central distribution:
- On chest X-ray: apices and costophrenic angles are spared. This may create a peri-hilar (“batwing”) distribution.
- On CT scan: peripheral sparing may be notable.
- If bleeding stops, the chest radiograph may improve within ~1-3 days.(Fishman 2023)
#2/3) subacute findings
- Ground-glass centrilobular nodules:
- These may take longer to develop (e.g., reflecting a recovery phase following a recent episode of alveolar hemorrhage).
- Nodules may have roughly uniform in size (1-3 mm).
- Distribution is typically diffuse (without a zonal predominance).
- Septal thickening:
- This may develop over a period of a few days, due to the accumulation of hemosiderin-laden macrophages within the interstitium.
- The combination of ground glass opacities plus septal thickening may create a crazy-paving pattern.
#3/3) pulmonary fibrosis
- Recurrent hemorrhage may eventually lead to pulmonary fibrosis (causing a reticular pattern, traction bronchiectasis, and eventually honeycombing). This eventually may cause episodes of hemorrhage to involve a superimposition of acute hemorrhage (i.e., ground glass opacities) on top of chronic fibrosis.
- Causes of recurrent hemorrhage include vasculitis or idiopathic pulmonary hemosiderosis.
other features reflective of an underlying etiology
- Occasionally, additional radiographic features may point to a specific underlying disorder. For example, various radiologic features of GPA (granulomatosis with polyangiitis) are discussed below.📖
two bronchoscopic tests for DAH
- (1) Serial bronchoalveolar lavage:
- Three syringes are sequentially flushed into a bronchus and then aspirated.
- If blood clears with repeated lavage, this suggests a bronchial source of bleeding.
- If lavages become sequentially bloodier, this suggests diffuse alveolar hemorrhage.
- This is generally the primary diagnostic test used. However, it's not perfect. Results may be subjective in borderline cases.
- (2) Hemosiderin-laden macrophages on cytopathology:
- >20% hemosiderin-laden macrophages supports a diagnosis of DAH.
- This may help clarify the diagnosis, especially if serial bronchoalveolar lavage is equivocal.
- Hemosiderin-laden macrophages don't appear until >24-72 hours after an acute pulmonary hemorrhage, so this test may be falsely negative initially.(Fishman 2023)
other roles for bronchoscopy
- Exclusion of infection: Fluid should be tested for viruses, bacteria, and possibly fungi (depending on clinical context).
- Bronchial inspection:
- Airways should ideally be carefully inspected to evaluate for any focal source of hemorrhage.
- If seen, tracheal ulceration/stenosis may sometimes support a diagnosis of GPA (granulomatosis with polyangiitis).
vasculitis (aka capillaritis; may be suggested by simultaneous nephritis producing a pulmonary-renal syndrome)
- ANCA-associated vasculitides:
- GPA (granulomatosis with polyangiitis).
- MPA (microscopic polyangiitis).
- Anti-GBM disease (anti-glomerular basement membrane disease).
- Lupus.
- Antiphospholipid antibody syndrome.
- Cryoglobulinemia.
- IgA vasculitis (a.k.a. Henoch-Schonlein purpura).
- Some medications (penicillamine, phenytoin, hydralazine, nitrofurantoin).
- Isolated pulmonary capillaritis.
heart failure and related conditions
- Heart failure (especially mitral stenosis or mitral regurgitation).
- Negative pressure pulmonary edema.
- Neurogenic pulmonary edema.
infection
- Any infection (e.g. bacterial, viral).
medications & toxins
- Toxic exposures:
- Smoking crack (especially cut with levamisole).
- Vaping.
- Trimetallic anhydride (used in manufacturing plastics and epoxy resins).
- Medications (for complete listing see: Pneumotox.com)
- Allopurinol.
- Amiodarone.
- Amphotericin B.
- ATRA (All-trans retinoic acid).
- Carbamazepine.
- Chemotherapeutic agents (e.g., cytotoxic medications).
- Hydralazine.
- Methotrexate.
- Minocycline.
- Nitrofurantoin.
- Penicillamine.
- Phenytoin.
- Sirolimus.
- Sulfasalazine.
- Thyroid medications: Methimazole, propylthiouracil.
- Tumor Necrosis Factor antagonists.
severe hematologic derangement
- Antiphospholipid antibody syndrome.
- Promyelocytic leukemia (especially with differentiation syndrome 📖).
- Bone marrow transplantation may cause diffuse alveolar hemorrhage (especially when it involves high-dose chemotherapy and/or irradiation prior to transplantation).
- (Severe coagulopathy by itself generally doesn't cause DAH. However, if there is another cause of hemorrhage such as heart failure, coagulopathy may exacerbate that.)
labs to evaluate the etiology of diffuse alveolar hemorrhage
basics
- Complete blood count.
- Coagulation labs (PT, INR, fibrinogen).
- CRP (C-reactive protein) & ESR (erythrocyte sedimentation rate). A very high erythrocyte sedimentation rate (>100 mm/hr) supports vasculitis, whereas normal erythrocyte sedimentation rate argues against vasculitis.
- Urinalysis & urine microscopy (to evaluate for dysmorphic erythrocytes).
- ANCA, anti-MPO, and anti-PR3.
- anti-GBM antibody (anti-glomerular basement membrane).
- ANA (antinuclear antibody).
- Anticardiolipin antibody, anti-beta-2-glycoprotein I antibody.
may also consider:
- Infectious workup if pneumonia is suspected (e.g., blood cultures, procalcitonin, urinary antigens – more on this here).
- Cryoglobulin.
- Urine toxicology (mostly evaluating for cocaine).
- Complement levels (C3, C4, CH50).
- Anti-histone antibody (if medication-induced lupus is suspected).
- Anti-double-stranded DNA (if spontaneous lupus is suspected).
chest CT scan
diagnosis of diffuse alveolar hemorrhage
- Chest X-ray can be normal in milder diffuse alveolar hemorrhage.(25836645)
- CT findings due to DAH are discussed above. 📖
- CT may also help exclude alternative etiologies of hemoptysis (e.g. focal malignancy).
evaluating cause of diffuse alveolar hemorrhage
- GPA (granulomatosis with polyangiitis) may also cause nodules which can cavitate, or stenosis of large airways.
- Septal thickening, bilateral effusions, and dilation of the left atrium may suggest heart failure.
tissue diagnosis
- Tissue is not necessarily required prior to initiation of corticosteroid. The primary role role is often clarifying the diagnosis definitively, to guide longer-term immunosuppressive strategies.
- Tissue diagnosis be unnecessary in some situations (e.g., if clinical picture, labs, and bronchoscopy all support a diagnosis of granulomatosis with polyangiitis).
- Renal biopsy or surgical lung biopsy both have high yield, if both organs are affected (~85%).(26523024)
- Renal biopsy is safer and less invasive than lung biopsy. It also may provide prognostic information about the likelihood of renal recovery.
- Surgical lung biopsy requires intubation and lung resection – making this more invasive and risky. This is usually helpful only in patients with isolated pulmonary involvement (e.g., to evaluate for isolated pulmonary capillaritis). (31376892)
- Skin biopsy may be considered if vasculitic lesions are present (undoubtedly the safest option).
- Supportive care of hypoxemic respiratory failure (e.g., oxygen).
- Coagulation optimization:
- Treat the underlying disorder, for example:
- Discontinue any causative medications.
- For patients with ANCA vasculitis, specific treatment is discussed further below. 📖
common presentations to ICU
- (1) Diffuse alveolar hemorrhage (more on this above 📖).
- (2) Renal failure (e.g., requiring emergent hemodialysis).
- (3) Pulmonary-Renal syndromes (#1 + #2).
ANCA-associated vasculitides are the most common cause of pulmonary vasculitis, including two in particular:
- GPA (granulomatosis with polyangiitis) is the most common (previously known as Wegener's Granulomatosis).
- MPA (microscopic polyangiitis) is the second most common. MPA is generally similar to GPA, but it involves fewer organs (primarily the kidney, lung, skin, and peripheral nerves).
- The treatment for GPA and MPA is nearly identical. Therefore, precise differentiation between these entities isn't critical.
- (Eosinophilic granulomatosis with polyangiitis is also an ANCA-associated vasculitis, but it rarely causes diffuse alveolar hemorrhage.)
lab findings in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
lab findings in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
urinalysis
- Hematuria +/- proteinuria may be seen.
- Hematuria is more indicative of active nephritis, whereas proteinuria may be seen in between disease flares due to chronic renal damage.
- Among all patients who initially present with GPA, only ~20% will have glomerulonephritis. However, the rates of glomerulonephritis will be higher among patients with active diffuse alveolar hemorrhage.(34022023)
- Urine microscopy showing evidence of glomerulonephritis (e.g., erythrocyte casts) supports a diagnosis of vasculitis.
ANCA, anti-MPO, anti-PR3
- ANCA testing involves staining cells for any antibodies that bind to cytoplasmic antigens. This turns around rapidly, but is less specific for vasculitis. Alternatively, individual testing for anti-myeloperoxidase (MPO) & anti-Protease-3 (PR3) is more specific for vasculitis. For critically ill patients, it may expedite matters to order all three tests up-front. However, for non-critical patients, the recommended approach is simply to test for anti-MPO and anti-PR3.(32934123)
specificity of ANCA
- Anti-MPO or Anti-MP3 are fairly specific for vasculitis. However, these may also occur in chronic infections (e.g., endocarditis, tuberculosis, HIV, HCV).(31358311) Some patients with interstitial lung disease and anti-MPO antibodies may later develop clinical features of microscopic polyangiitis.(Fishman 2023)
- ANCA positivity without anti-MPO or anti-PR3 antibodies may occur in a variety of non-vasculitic disorders (e.g., autoimmune or malignant).(31358311)
- p-ANCA in particular may be seen in various other disorders (e.g., connective tissue diseases, inflammatory bowel disease, or liver disease).(Fishman 2023)
sensitivity of ANCA
- Sensitivity varies depending on the disease and the level of systemic disease activity.
- ANCA-negative patients usually have disease limited to the kidney.(Fishman 2023)
Patients often have waxing/waning symptoms for weeks or months before presentation. Symptoms may involve a variety of organs:
constitutional symptoms
- Fever, arthralgia, myalgia.
- Weight loss.
HEENT
- Eye:
- Conjunctivitis, scleritis, uveitis.
- Retro-orbital pseudotumors.
- Nose:
- Ulceration, epistaxis.
- Saddle deformity.
- Rhinitis, sinusitis.
- Ear:
- Otitis media.
- Hearing loss.
- Mouth:
- Gingival hyperplasia (“strawberry gingivitis”).(33563462)
- Oropharyngeal ulcerations.
- Pharynx: voice change.
pulmonary involvement
- Airway involvement may cause dyspnea, stridor, cough, and hemoptysis (discussed further below 📖).
- Diffuse alveolar hemorrhage may cause hypoxemic respiratory failure, with or without hemoptysis (discussed further above 📖).
- Nodules may occur, with subsequent cavitation causing hemoptysis.
renal failure
- Can be a dominant feature, or may be subclinical.
skin
- Palpable purpura (due to leukocytoclastic vasculitis).
- Nodules, ulcers, or pyoderma gangrenosum-like lesions.
neurologic
- Mononeuritis multiplex (e.g., wrist drop, foot drop).
- Cranial nerve dysfunction, meningitis, ischemic stroke, or pituitary dysfunction can occur.(33563462)
Microscopic polyangiitis causes only diffuse alveolar hemorrhage. Granulomatosis with polyangiitis may cause diffuse alveolar hemorrhage, plus it may also cause a variety of additional radiologic abnormalities (airway involvement and/or pulmonary nodules).
diffuse alveolar hemorrhage
- This causes radiologic abnormalities discussed above. 📖
nodules or masses are the most common finding in GPA
- Multiple nodules are generally seen (usually <10), but some patients may have a single pulmonary nodule.
- Size ranges from a few millimeters to 10 cm.
- Nodules may be sharply or poorly demarcated (e.g., with a halo sign in up to 15%).
- Distribution:
- Nodules are evenly distributed between the upper and lower lung zones.
- Distribution tends to favor the subpleural regions.
- Cavitation occurs in ~25% of nodules >2 cm.(33563462) This initially yields a thick-walled, irregular cavity. Over time, this evolves into a thin-walled cavity. Air-fluid levels are rare (if present, air-fluid levels may suggest superinfection).
- Nodules may regress or reappear spontaneously. An increase in the size and number of nodules correlates with disease progression. (Walker 2019)
tracheobronchial involvement due to GPA
basics
- Tracheobronchial involvement may occur in ~20% of patients, predominantly affecting women (9:1).(Murray 2022)
symptoms may include
- Dyspnea, stridor.
- Cough, hemoptysis.
- Clinical manifestations of atelectasis or postobstructive pneumonia. (Fishman 2023)
- Tracheoesophageal fistula.(33563462)
imaging
- Overall, the laryngeal and subglottic trachea are usually the predominant sites of airway involvement. However, any level of the airway can be involved.
- Tracheal wall thickening:
- This may be easily missed (e.g., if it doesn't cause tracheal stenosis).
- Wall thickening is often focal, ~2-4 cm in length.(Rosado-de-Christenson 2022)
- Involves the posterior membrane.
- Wall thickening may be smooth or nodular.
- Dense, irregular calcification of the tracheal cartilage can develop.
- Tracheal stenosis:
- Stenosis most often occurs in the subglottic location.
- Subglottic stenosis can progress independently from the systemic disease.(ERS handbook 3rd ed.) Consequently, GPA should be considered among patients who present with isolated subglottic tracheal stenosis. (Rosado-de-Christenson 2022)
- Polypoid mass lesions (inflammatory pseudotumors) may occur. (ERS handbook 3rd ed.)
- Distal airway involvement may cause bronchiectasis, atelectasis, and/or pneumonia. (Rosado-de-Christenson 2022)
bronchoscopy
- About half of patients have visible bronchoscopic abnormalities.(34022023) These may include stenosis, ulceration, and/or inflammatory pseudopolyps.
- Biopsy has poor yield (<20%), generally showing no necrotizing granulomas or vasculitis. (Murray 2022; ERS handbook 3rd ed.)
treatment pathway for granulomatosis with polyangiitis, or microscopic polyangiitis
treatment pathway for granulomatosis with polyangiitis, or microscopic polyangiitis
antibiotics
- Initially it may not be entirely clear that a patient has vasculitis, rather than pneumonia.
- It is often reasonable to start antibiotics and steroid initially, until additional data is available.
- Antibiotics should ideally be stopped within 24-48 hours (e.g., based on culture data, CT scan data, and/or procalcitonin).
steroid
- Steroid should be started once there is a high level of suspicion for vasculitis.
- Patients with severe manifestation (e.g., glomerulonephritis, respiratory failure) are usually started on pulse-dose steroid (500 mg to 1,000 mg of methylprednisolone daily, for three days).
- The optimal dose of the steroid pulse is unknown. Numerous sources suggest that either 500 mg or 1,000 mg daily may be used (including the Canadian vasculitis guidelines and the PEXIVAS trial). (26523024, 32053298, 31358311, 33927768, 32934123, Fishman 2023)
- The most recent Canadian guidelines caution that steroid pulses have never been shown to be beneficial, but have been associated with increased risk of infection.(32934123) If steroid pulses are used, it may be wise to limit the dose and duration (e.g., 500 mg/day methylprednisolone for three days).
- Following the three-day steroid pulse, steroid dose is reduced to 1 mg/kg prednisone daily (up to a maximum of 80 mg) with a slow taper.(31358311, 32934123)
- Addition of high-dose inhaled steroid may be useful for patients with tracheobronchial involvement from granulomatosis with polyangiitis.(Fishman 2023)
additional immunosuppressive agent for remission induction
- In addition to steroid therapy, either rituximab or cyclophosphamide is needed for induction of remission. This will usually be determined by rheumatology consultation.
- PJP prophylaxis should be started, although it may be wise to delay this a few days until the dust settles.(33916214, 32934123)
- (After remission has been achieved, maintenance of remission is often achieved with azathioprine, rituximab, or methotrexate.)(34022023)
coagulation management
- If there is active pulmonary hemorrhage, any coagulopathy should be aggressively reversed (see the chapter on anticoagulation reversal. 📖)
- Once hemorrhage has stopped, DVT prophylaxis should be started.
discontinue any offensive medications
- Rarely, medication may cause an ANCA-positive vasculitis or diffuse alveolar hemorrhage.
- Review the medication list and discontinue drugs associated with vasculitis/pneumonitis. Pneumotox.com may be helpful here.
complications to beware of:
- DVT (deep vein thrombosis) & pulmonary embolism:
- Vasculitis increases risk of thrombosis.
- Large series of patients with vasculitis often include one or two patients who die from a pulmonary embolism.
- DVT prophylaxis should be started after alveolar hemorrhage has subsided.
- Avoid placing hemodialysis catheter in femoral vein for prolonged duration.
- Fungal pneumonia (usually aspergillosis):
- Pulse-dose steroid renders patients susceptible to fungal pneumonia.
- Consider this in patients who improve, but later deteriorate with signs of pneumonia.
(disutility of plasma exchange)
- Plasma exchange has face validity, since it would remove causative antibodies. However, this is an invasive procedure which can cause coagulopathies (due to removal of coagulation proteins). Additionally, passage of blood through artificial membranes could activate neutrophils, making matters worse. To date, plasma exchange is not supported by any robust evidence for the management of ANCA vasculitis.
- The PEXIVAS trial is the largest and most modern trial to evaluate the use of plasma exchange for patients with ANCA vasculitis and either renal failure or pulmonary hemorrhage. Plasma exchange offered no benefits beyond the use of systemic corticosteroid.(32053298) This trial indicates that plasma exchange should not be routinely utilized in ANCA vasculitis.
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- Pulmonary vasculitis can easily be misdiagnosed as pneumonia. Clues to this diagnosis may include:
- Renal failure, urine sediment with RBCs.
- More hemoptysis than would be expected for bronchitis/pneumonia.
- More diffuse infiltrates on CXR and CT than with most pneumonias.
- Smoldering rheumatologic symptoms for weeks/months prior to admission.
- Treatment should be initiated before a final diagnosis is reached.
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