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PULMONARY DISEASE BOARD REVIEW MANUAL
PUBLISHING STAFF
PRESIDENT, PUBLISHER
Bruce M.White
Alveolar Hemorrhage
Syndromes
EXECUTIVE EDITOR
Debra Dreger
SENIOR EDITOR
Miranda J. Hughes, PhD
EDITOR
Becky Krumm
Series Editor:
Robert A. Balk, MD, FACP, FCCP, FCCM
Professor of Medicine, Director of Pulmonary and Critical Care
Medicine, Department of Medicine, Rush Medical College and
Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL
ASSISTANT EDITOR
Kathryn Charkatz
EDITORIAL ASSISTANT
Barclay Cunningham
SPECIAL PROGRAMS DIRECTOR
Barbara T.White, MBA
Contributing Author:
David P. Gurka, MD, PhD, FCCP
Assistant Professor of Medicine, Section of Pulmonary and Critical
Care Medicine, Department of Medicine, Rush Medical College and
Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL
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Table of Contents
ADVERTISING/PROJECT COORDINATOR
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Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Case Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
NOTE FROM THE PUBLISHER:
This publication has been developed without
involvement of or review by the American
Board of Internal Medicine.
Clinical Features and Initial Evaluation . . . . . . . . . . . . . . 4
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Alveolar Hemorrhage Syndromes. . . . . . . . . . . . . . . . . . . 7
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
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Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Board Review Questions and Answers . . . . . . . . . . . 10, 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Suggested Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cover Illustration by Dean Vigyikan
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Pulmonary Disease Volume 5, Part 1 1
®
PULMONARY DISEASE BOARD REVIEW MANUAL
Alveolar Hemorrhage Syndromes
Series Editor:
Robert A. Balk, MD, FACP, FCCP, FCCM
Contributing Author:
David P. Gurka, MD, PhD, FCCP
Professor of Medicine
Director of Pulmonary and Critical Care Medicine
Department of Medicine
Rush Medical College and
Rush-Presbyterian-St. Luke’s Medical Center
Chicago, IL
Assistant Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Department of Medicine
Rush Medical College and
Rush-Presbyterian-St. Luke’s Medical Center
Chicago, IL
I. INTRODUCTION
Alveolar hemorrhage is the occurrence of blood arising from and pooling in pulmonary acinar sacs. This
relatively uncommon finding is often associated with extrapulmonary and/or laboratory abnormalities that characterize a diverse group of disorders known as alveolar (or
pulmonary) hemorrhage syndromes. Alveolar hemorrhage syndromes are frequently immune-mediated but
may also involve drug or toxin exposure. Alveolar hemorrhage is often associated with renal disease.
There is no universally accepted classification
scheme for alveolar hemorrhage syndromes, although
in general they are grouped by extrapulmonary clinical
manifestations or by the histologic presence or absence
of capillaritis (Table 1). Pulmonary capillaritis was first
described by Spencer in 1957, in association with polyarteritis nodosa. The concept was refined by Mark and
Ramierez in 1985 in their report on patients with systemic vasculitides.
Pulmonary capillaritis is characterized by infiltration
of the alveolar interstitium by neutrophils, which leads to
fibrinoid necrosis of the capillary walls with leakage of
erythrocytes and neutrophils into the alveolar septa and
spaces. Fibrin thrombi can be found occluding the septal
capillaries as well as lining the alveolar sacs. Erythrocytes
are present in the interstitium and alveolar spaces in the
2 Hospital Physician Board Review Manual
presence of acute hemorrhage, and hemosiderin-laden
macrophages and free hemosiderin are markers of
recent or chronic hemorrhage. Inflammation of the pulmonary vasculature is usually indicative of a systemic vasculitis.
Although any form of bleeding diathesis or other
condition that increases pulmonary capillary pressure
(ie, mitral stenosis, pulmonary veno-occlusive disease,
pulmonary capillary hemangiomatosis) can manifest as
alveolar hemorrhage, this review will be restricted to
those entities, with as well as without capillary inflammation, in which the alveolar epithelium or capillary
endothelium is directly involved. Because the differential diagnosis of alveolar hemorrhage is broad (Table 1),
only the more common of these relatively rare syndromes will be discussed.
The relative frequencies of the causes of alveolar
hemorrhage are not well delineated. In one 6-year
series of patients from the University of Minnesota, the
most common cause of alveolar hemorrhage was
anti–glomerular basement membrane (anti-GBM) antibody disease, followed by the systemic vasculitides
(many types), pauci-immune glomerulonephritis, and
connective tissue diseases (eg, systemic lupus erythematosis).1 Another review, however, found Wegener’s
disease and other vasculitides to be nearly three times as
prevalent as anti-GBM antibody disease as a cause of
alveolar hemorrhage.2
Alveolar Hemorrhage Syndromes
II. CASE PRESENTATIONS
Table 1. Classification of Alveolar Hemorrhage
Syndromes
Alveolar hemorrhage with capillaritis
CASE PATIENT 1
A 24-year-old nurse without significant past medical
history presents with progressive dyspnea on exertion
associated with a nonproductive cough. For the past 2
weeks, she has had a nonresolving, flu-like illness with
arthralgias, myalgias, headache, low-grade fever, nausea, and vomiting. Three weeks earlier, she had presented with a lesion on her left lateral thigh; skin biopsy results were consistent with erythema nodosum. Her
laboratory results at that time were as follows: hemoglobin, 10 g/dL; blood urea nitrogen (BUN), 14 mg/dL;
creatinine, 1.0 mg/dL; erythrocyte sedimentation rate
(ESR), 55 mm/hour (standard reference value is < 20).
Antinuclear antibody (ANA) titer was weakly positive at
1:40, and rheumatoid factor and complement (C3 and
C4) levels were normal. She was taking no medications,
used neither tobacco nor illicit drugs, and had no allergies. She reported an involutional weight loss of 8 lbs
over the preceding 2 months.
On presentation, she is quite anxious, afebrile, normotensive without tachycardia or orthostatic changes,
and in no respiratory distress. With the exception of pale
conjunctiva and nailbeds, the remainder of the physical
examination is unremarkable. She has no skin lesions,
joint abnormalities, or adventitious cardiac or pulmonary
sounds. Laboratory data are significant for the following
values: hemoglobin, 6.9 g/dL, BUN, 18 mg/dL; creatinine, 1.3 mg/dL; ESR, 96 mm/hour. Neither thrombocytopenia nor coagulation abnormalities are found. Urinalysis reveals hematuria (> 200 erythrocytes/low-power
field) without pyuria or cellular casts. Chest radiograph
and computed tomographic (CT) scan of case patient 1
are shown in Figure 1.
CASE PATIENT 2
A 30-year-old man with a history of systemic lupus
erythematosus (SLE) since age 23 years and previous
episodes of alveolar hemorrhage presents with
hemoptysis that has been present for the past 4 weeks.
It initially manifested as blood-streaked sputum and
progressed to pure blood expectoration of 5 to 10 mL
per cough, 5 to 10 times per day. He denies fever,
chills, dyspnea, chest discomfort, rash, arthralgias,
epistaxis, or hematemesis. He has been treated empirically with three 1-week courses of antibiotics, and his
dose of prednisone has been increased from 20 mg
every other day to 40 mg daily; neither therapy has
been effective.
Systemic necrotizing vasculitides
Microscopic polyangiitis
Wegener’s granulomatosis
Behçet’s syndrome
Henoch-Schönlein purpura
Essential mixed cryoglobulinemia
Connective tissue disorders
Systemic lupus erythematosus
Antiphospholipid syndrome
Mixed connective tissue disease
Scleroderma
Rheumatoid arthritis
Pulmonary-renal syndromes
Anti–glomerular basement membrane antibody disease
Immune complex–associated glomerulonephritis
Pauci-immune glomerulonephritis
Alveolar hemorrhage without capillaritis
Idiopathic pulmonary hemosiderosis
Exogenous agents
Cocaine
D-penicillamine
Trimellitic anhydride
Lymphangiography
Other disorders
Diffuse alveolar damage
Mitral stenosis
Bleeding diatheses
Bone marrow transplantation
Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
Lymphangioleiomyomatosis
Tuberous sclerosis
On admission, his temperature is 97.2 °F, blood pressure is 114/84 mm Hg, pulse rate is 80 bpm, and respiration rate is 14 breaths/min. He has no nasal or oropharyngeal bleeding stigmata, his lungs are clear to
auscultation in all fields, he has no cardiac murmurs or
rubs, and there is no evidence of lower extremity edema
or asymmetry. Laboratory tests reveal a hemoglobin level
of 12.1 g/dL (his baseline value is 13.1 g/dL); normal
Pulmonary Disease Volume 5, Part 1 3
Alveolar Hemorrhage Syndromes
A
B
Figure 1. (A) Standard posteroanterior chest radiograph and (B) high-resolution noncontrast computed tomographic scan of the
patient described in case 1.The subtle diffuse alveolar filling shadows of the radiograph are visible in the computed tomographic scan
as diffuse “ground glass” opacities involving all the lobes.
platelet count, leukocyte count, and coagulation times;
BUN and creatinine levels of 23 mg/dL and 0.8 mg/dL,
respectively (not significantly elevated from his baseline
levels); and trace hematuria (4 erythrocytes/low-power
field). His complement levels are markedly depressed:
C3 level is 45 mg/dL (standard reference value is
80–180 mg/dL) and C4 level is 7 mg/dL (standard reference value is 16–60 mg/dL). ANA titer was 1:640 and
antibody to double-stranded DNA (dsDNA) was titered
to 1:80. Chest radiograph and chest CT are shown in
Figure 2.
• Which features of these cases suggest a diagnosis of
alveolar hemorrhage?
• What additional testing is needed to confirm the
diagnosis and determine the etiology?
III. CLINICAL FEATURES AND INITIAL
EVALUATION
PRESENTING SIGNS AND SYMPTOMS
Cough and dyspnea are the most common complaints in patients with alveolar hemorrhage. A complaint of “coughing up blood” must be carefully differentiated from epistaxis or hematemesis. Hemoptysis is
often not noted on initial presentation but, when present, can vary from mildly blood-tinged sputum to massive bleeding. Chest pain and pleuritis may accompany
4 Hospital Physician Board Review Manual
alveolar hemorrhage, and mild dyspnea can rapidly
progress to respiratory failure.
Malaise and fatigue are common manifestations of
anemia or uremia. A slight darkening of the urine can
denote hematuria. Extrapulmonary symptoms such as
weight loss, arthralgias, rashes, or purpura, when
accompanied by the nonspecific findings of malaise
and fatigue, often focus attention on the possible presence of an autoimmune or vasculitic process. Generally,
symptoms are of relatively short duration (a few weeks)
and are either persistent or recurrent. Information
gleaned from a careful history, such as occupational
exposures, infections, and medications, often gives
clues to etiology.
PHYSICAL EXAMINATION
Physical examination may reveal tachypnea and the
moist lung crackles of alveolar fluid accumulation.
Auscultatory findings of mitral stenosis (an opening
snap and diastolic rumble, best appreciated with the
patient in the left lateral decubitus position) should be
sought. Evaluation of the nasal mucosal surfaces for
bleeding sites or septal ulcers is often diagnostically
rewarding. A careful survey of the skin and musculoskeletal system is warranted to uncover signs of vasculitis or connective tissue disorders.
RADIOGRAPHIC EVALUATION
Standard posteroanterior and lateral chest radiographs are usually the only imaging procedures
Alveolar Hemorrhage Syndromes
A
B
Figure 2. (A) Standard posteroanterior chest radiograph and (B) standard noncontrast computed tomographic scan of the patient
described in case 2. The dense diffuse alveolar filling shadows of the posteroanterior film are visible in the computed tomographic scan
as dense airspace filling opacities sparing the upper lobes.
necessary for evaluation of alveolar hemorrhage. Diffuse
or patchy alveolar filling opacities are the most common
finding, although an interstitial pattern can be seen if
the bleeding is recurrent or chronic. CT scan better
highlights parenchymal masses, such as those found in
Wegener’s disease, or areas of bronchiectasis that may
account for hemoptysis. An echocardiogram may be
indicated to confirm the presence of mitral stenosis.
LABORATORY EVALUATION
Initial laboratory evaluation should include an arterial blood gas, a complete blood cell count with platelet
count, BUN and creatinine levels, coagulation studies,
urinalysis with microscopic evaluation for casts and
erythrocytes, and ESR. Special antibody studies, such as
ANA, rheumatoid factor, anti-GBM antibody, and antineutrophil cytoplasmic antibodies (ANCAs) are appropriate in patients with systemic complaints or abnormalities of renal function.
PULMONARY FUNCTION TESTS
Pulmonary function tests, including the measurement of carbon monoxide diffusion (DLCO), are performed in cases of suspected occult alveolar hemorrhage, as well as for monitoring patients with recurrent
hemorrhage. Spirometry results are often normal and
lung volumes may be normal. In cases of recurrent alveolar hemorrhage or some of the vasculitides, lung volumes may be reduced, reflecting the restrictive ventilatory defect of many autoimmune diseases.
Alveolar hemorrhage is one of the few disorders
(along with congestive heart failure, left-to-right intracardiac shunts, and polycythemia) that give rise to an
elevated DLCO, typically greater than 125% of the predicted value, reflecting binding of carbon monoxide to
the increased amount of pulmonary hemoglobin in
these disorders. Serial DLCO measurements are used to
monitor for occult exacerbations of alveolar hemorrhage in those patients with a predisposition to or history of the disease.
BRONCHOSCOPIC EVALUATION
Bronchoscopy is necessary to confirm the presence
of alveolar hemorrhage as well as to rule out focal endobronchial lesions that can present with hemoptysis. The
characteristic bronchoalveolar lavage of alveolar hemorrhage is apparent when sequential aliquots of a single
segmental lavage reveal fluid that becomes increasingly
hemorrhagic; the initial pink lavage becomes a darker
red color, often looking like pure blood at the end of
the procedure. Cytologic analysis of the lavage shows a
predominance of erythrocytes in acute alveolar hemorrhage and hemosiderin-laden macrophages in recent
or recurrent bleeding.
Transbronchial biopsies are rarely performed because
the size of the specimens is usually inadequate for performing fluorescent antibody staining. Furthermore, the
focal nature of some disorders may lead to sampling error.
Open lung biopsy may be needed to fully evaluate some
patients, although percutaneous renal biopsy is a less invasive procedure yielding sufficient tissue to diagnose those
patients with renal involvement.
Pulmonary Disease Volume 5, Part 1 5
Alveolar Hemorrhage Syndromes
Table 2. Laboratory Characteristics of Selected
Diseases Causing Alveolar Hemorrhage
Disease
Characteristics
Anti-GBM disease
Anti-GBM antibody present
SLE
Hypocomplementemia, ANA ↑
Wegener’s granulomatosis
C-ANCA present
Microscopic polyangiitis
P-ANCA present
Pauci-immune
glomerulonephritis
P-ANCA present; anti-GBM
antibody absent
Behçet’s syndrome
Circulating IgG immune
complexes
Henoch-Schönlein purpura
Circulating IgA immune
complexes
Idiopathic pulmonary
hemosiderosis
No extrapulmonary
abnormalities, no abnormal
serologies
ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; GBM = glomerular basement membrane; Ig = immunoglobulin;
SLE = systemic lupus erythematosis.
IV. DIAGNOSIS
EVALUATION OF CASE PATIENTS
Case Patient 1
Prior to bronchoscopy of case patient 1, pulmonary
function tests showed normal spirometry results and
lung volumes but a DLCO of 157% of the predicted
value. Alveolar hemorrhage was confirmed by lavage.
Because of her rapid rise in creatinine, a renal biopsy
was performed prior to obtaining the results of serologic studies. The biopsy showed focal segmental necrotizing glomerulonephritis; immunofluorescent and
electron microscopic studies of the biopsied tissue
failed to reveal immune deposits. Assay for serum antiGBM antibody was negative but assay for perinuclear
(P)-ANCA was positive; a specific antimyeloperoxidase
(anti-MPO) antibody was detected. A diagnosis of
pauci-immune glomerulonephritis with alveolar hemorrhage (ie, without immune complex deposition in
the biopsy tissue) was made.
Case Patient 2
Because of the patient’s history of SLE, previous
episodes of alveolar hemorrhage, and his current presentation, alveolar hemorrhage was strongly suspected.
DLCO was 83% of the predicted value, but serial DLCO in
the past showed his baseline to be 50% to 60% of the
6 Hospital Physician Board Review Manual
predicted value, owing to SLE-induced pulmonary fibrosis. Bronchoscopy was performed to rule out infection in
this immunocompromised host; only alveolar hemorrhage was found. Cytologic analysis of the lavage fluid
showed a large quantity of hemosiderin macrophages.
• How are the alveolar hemorrhage syndromes diagnosed?
• What are the immediate and long-term treatment
options for these patients?
DISCUSSION
The combination of cough, anemia, and a chest
radiograph showing patchy alveolar opacities—with or
without hemoptysis—strongly suggests alveolar hemorrhage. The differential diagnosis of hemoptysis is broad
and has been addressed in Volume 4, Part 1 of the
Pulmonary Disease Board Review Manual (Balk RA: Case
Studies in Pulmonary Emergencies).
Serologic and Immunologic Testing
After bronchoscopic confirmation of alveolar hemorrhage, patients with abnormal renal findings (ie, hematuria and/or renal insufficiency) or extrapulmonary
complaints require appropriate serologic testing and tissue fluorescent antibody staining to identify the correct
syndrome so that therapy can be initiated (Table 2).
The finding of hematuria excludes idiopathic pulmonary hemosiderosis from diagnostic consideration.
The presence of serum anti-GBM antibody confirms a
diagnosis of Goodpasture’s disease. Hypocomplementemia is a feature of alveolar hemorrhage due to
SLE or, occasionally, mixed cryoglobulinemia.
Serum ANCA levels are elevated in Wegener’s granulomatosis and in systemic necrotizing vasculitis (microscopic polyangiitis) as well as pauci-immune glomerulonephritis. Two types of ANCA can be measured.
Cytoplasmic (C)-ANCA is specific for proteinase 3, a
neutral protease found in cytoplasmic granules of neutrophils. C-ANCA is relatively sensitive and specific for
Wegener’s granulomatosis. P-ANCA is an autoantibody
to the neutrophilic MPO granule and is more likely to
be found in patients with pauci-immune glomerulonephritis or microscopic polyangiitis.
Fluorescent staining of tissue biopsy specimens for
the deposition of immunoglobulins (Ig) can assist in
narrowing the diagnosis. Linear deposition of IgG
along either alveolar or renal glomerular basement
membranes is found in Goodpasture’s disease.
Granular deposition of IgG is characteristic of SLE and
mixed cryoglobulinemia; granular IgA deposits indicate Henoch-Schönlein purpura. The absence of
Alveolar Hemorrhage Syndromes
immune deposits suggests systemic necrotizing vasculitis, pauci-immune glomerulonephritis, or idiopathic
pulmonary hemosiderosis.
V. ALVEOLAR HEMORRHAGE SYNDROMES
WEGENER’S GRANULOMATOSIS
Wegener’s granulomatosis is a systemic necrotizing
granulomatous inflammatory illness predominately
involving the upper and lower respiratory tracts and the
kidneys. Cutaneous and ocular disturbances also occur
in approximately 50% of affected individuals. The disease may be indolent or rapidly lead to renal failure.
Upper airway symptoms of sinusitis, initially thought
to be caused by allergy or infection but unresponsive to
the usual therapies, are the presenting complaints of
more than 70% of patients with Wegener’s granulomatosis.3 Cough and hemoptysis are early symptoms in
only 15% to 20% of cases but eventually develop in 30%
to 50% over the course of the illness. Pulmonary capillaritis is found in 40% to 50% of biopsy specimens, but
alveolar hemorrhage is relatively rare, occurring in only
5% to 8% of cases.
Hemoptysis is more often related to pulmonary
nodules or infection than to alveolar hemorrhage, but
alveolar hemorrhage is often an initial presentation
and heralds a fulminant, rapidly progressive course. If
alveolar hemorrhage is present with rapidly progressive
focal segmental necrotizing glomerulonephritis, acute
mortality can be as high as 65%, despite the institution
of therapy. The prognosis is much better in the more
common cases without alveolar hemorrhage. Remission can be induced in nearly 90% of these patients
and sustained in nearly half of them. A variant of
Wegener’s granulomatosis in which clinical involvement is limited to the respiratory tract carries an even
better prognosis.
The diagnosis requires the pathologic demonstration of vasculitis and necrotizing granulomata in the
appropriate clinical context of airway, renal, and other
systemic abnormalities. Tissue staining for immune
deposits is negative and no circulating immune complexes are found. The demonstration of C-ANCA in
serum in many cases can confirm the diagnosis, obviating biopsy. Transbronchial biopsies have been shown to
have a diagnostic yield of less than 10%;4 open-lung or
renal biopsies are preferred. Chest radiographs initially
show nodules, frequently cavitary (25%) or fleeting
alveolar opacities (25%). The frequency of these findings increases to 60% to 70% as the disease progresses.
CT may better delineate the often subtle nodular pulmonary lesions and reveal sinus involvement.
Standard therapy for Wegener’s granulomatosis consists of vigorous immunosuppression with high-dose
corticosteroids and cytotoxic agents, usually cyclophosphamide. The finding of either alveolar hemorrhage or
rapidly progressive glomerulonephritis (RPGN) warrants aggressive therapy with “pulse” steroids of 1 g per
day of methylprednisolone with concomitant high-dose
cyclophosphamide (3–5 mg/kg body weight per day).
This regimen is continued for 3 to 5 days before lowering the doses to 1 mg/kg per day of prednisone (or
equivalent corticosteroid) and 2 mg/kg per day of
cyclophosphamide. Tapering of the steroid is initiated
once the disease remits. Tapering of the cyclophosphamide dose should not take place until at least a year
after remission has been achieved.
Remission can be induced in 50% of patients within
12 months and in 90% within 24 months, and maintained in half of these patients for months to years
before relapse.3,4 Serial testing of C-ANCA as an early
marker of relapse or disease activity is of limited value,
as is the use of trimethoprim-sulfamethoxazole to sustain remission.
Patients with child-bearing potential should be
advised of the teratogenic risks of cytotoxic therapy and
offered sperm or ova banking procedures.
MICROSCOPIC POLYANGIITIS
Microscopic polyangiitis is a systemic necrotizing vasculitis of small vessels (capillaries, venules and arterioles)
with RPGN and pulmonary involvement. Men are more
frequently affected than women by a ratio of 2:1, and the
average age of onset is 50 years. Most patients present with
arthralgias or constitutional symptoms (typically fever)
that often antedate the diagnosis of microscopic polyangiitis by months to years. Twenty-five percent to thirty percent of patients have alveolar hemorrhage at some point
in their disease, usually from alveolar capillaritis or
bronchial arteritis. It is second only to Wegener’s as a vasculitic cause of alveolar hemorrhage.2 Like Wegener’s disease, microscopic polyangiitis is a pauci-immune vasculitis, but it lacks the granulomatous inflammation of
Wegener’s. Complement levels are normal. Rheumatoid
factor is found in 40% to 50% of patients; ANA titer is positive less frequently. ANCA is present in 75% of patients,
with anti-MPO P-ANCA being the most prevalent form.
Therapy for alveolar hemorrhage associated with
microscopic polyangiitis is similar to that for Wegener’s
disease: “pulse” steroids with high-dose cyclophosphamide, with cyclophosphamide maintenance until
remission.
Pulmonary Disease Volume 5, Part 1 7
Alveolar Hemorrhage Syndromes
BEHÇET’S SYNDROME
Behçet’s syndrome is a multisystem disease characterized by recurrent aphthous stomatitis, genital and
oral ulcers, iridocyclitis, thrombophlebitis, cutaneous
vasculitis, arthritis, and meningoencephalitis. Immune
complexes may be found in the circulation as well as in
pulmonary and glomerular capillaries. Alveolar hemorrhage occurs in 5% to 10% of cases and can arise from
pulmonary capillaritis, inflammatory destruction of pulmonary arteries, rupture of bronchial artery aneurysms,
and pulmonary infarction. Pulmonary complaints of
cough, hemoptysis, chest pain, and fever are more common in men than in women. Death generally occurs
within 6 years of the first episode of hemoptysis. Alveolar
hemorrhage was the cause of death in 40% of the patients in one series.5 Therapy of alveolar hemorrhage
associated with Behçet’s syndrome is administration of
corticosteroids with cytotoxic immunosuppression.
HENOCH-SCHÖNLEIN PURPURA
Although primarily a disease of children, HenochSchönlein purpura may occur in adults as well. It is a
syndrome comprising palpable purpura (leukocytoclastic vasculitis), glomerulonephritis, arthralgias, arthritis,
abdominal pain, gastrointestinal hemorrhage, and, in
5% to 10% of patients, pulmonary involvement with
bleeding from capillaritis or pulmonary infarctions.
Serologic tests for ANA and rheumatoid factor are typically negative. IgA immune complexes can be found in
the circulation as well as in immune deposits along alveolar or renal basement membranes. Therapy is usually
with corticosteroids.
It is postulated that exposure to some insult (eg,
tobacco smoke, inhalation injury, infection) exposes
more of the basement membrane antigen for the IgG
autoantibody to bind. The antigen is the carboxylterminal fragment of type IV (α) collagen, found mainly in alveoli, glomeruli, renal interstitial tubules, and
choroid plexus. Linear deposition of IgG along the
membrane leads to complement binding and activation with subsequent fragmentation of the basement
membrane. This pattern occurs in clinically uninvolved
alveolar or renal tissue as well. Granular deposits indicative of the entrapment of circulating immune complexes are not seen.
Therapy is directed toward rapid reduction in the
serum levels of anti-GBM antibodies and in the inflammatory response induced by their deposition.
Treatment may need to be initiated before the results of
serum anti-GBM tests have returned, because long-term
survival depends on the extent of renal involvement,
and renal function can decline dramatically.
Plasmapheresis is used to quickly remove circulating
anti-GBM antibodies and is often continued for 2 to
4 weeks. Treatment with high-dose pulse corticosteroids
(1 g per day for 3 days) followed by at least 1 month of
1 mg/kg body weight of prednisone per day with a subsequent taper blunts the inflammation of anti-GBM
antibody deposition and impairs the continued production of antibody. A 6-month course of cyclophosphamide (Cytoxan), given daily at 2 to 3 mg/kg body
weight, or monthly in intravenous pulses of 750 to
1000 mg/M2 body surface area, is frequently added to
provide longer-term reduction in antibody formation.
ANTI–GLOMERULAR BASEMENT MEMBRANE ANTIBODY
DISEASE
Anti-GBM antibody disease is also known as Goodpasture’s disease. The lung and kidney are the only two
organs involved in anti-GBM antibody disease. In most
cases, both are affected simultaneously, although alveolar hemorrhage is often the presenting symptom. Renal
disease is the sole manifestation in only 20% to 40% of
cases; alveolar hemorrhage alone is extremely uncommon (< 10% of cases).7 The presence of cutaneous
vasculitis or arthralgias excludes the diagnosis of antiGBM antibody disease. In general, patients are young,
between 20 and 30 years of age, and male (less than one
third are women). In older patients, the sex distribution
is nearly equal and the disease more often spares the
lungs. Smoking is an additional risk factor for alveolar
hemorrhage in anti-GBM antibody disease: in 80% of
nonsmokers, the disease was limited to the kidney, and
almost all smokers had alveolar hemorrhage.1
GLOMERULONEPHRITIDES
Two forms of idiopathic pulmonary-renal syndrome
are characterized by finding an RPGN (acute renal
insufficiency with erythrocyte casts in the urine) in association with alveolar hemorrhage; these are the
immune complex–mediated and pauci-immune forms.
In neither disorder is there involvement of any other
organs, although these two entities may be variants of
microscopic polyangiitis. Alveolar hemorrhage is rare in
immune complex–mediated RPGN. Like Wegener’s
granulomatosis and microscopic polyangiitis, pauciimmune RPGN lacks any immunoreaction product in
tissue specimens. Alveolar hemorrhage is often a presenting finding and occurs in approximately 50% of
afflicted individuals. Differentiation from anti-GBM
antibody disease, which is also limited to lung and kidney involvement by definition, is provided by the
absence of linear IgG deposition in histologic specimens and the absence of serum anti-GBM antibody.
8 Hospital Physician Board Review Manual
Alveolar Hemorrhage Syndromes
P-ANCA is often detected. Therapy is with combination
high-dose corticosteroids and cytotoxic agents, often
requiring pulse therapy to treat severe rapidly progressive renal dysfunction or life-threatening alveolar hemorrhage.
SYSTEMIC LUPUS ERYTHEMATOSUS
Alveolar hemorrhage is a rare (< 2%) complication
of SLE. It is associated with high mortality and is recurrent in survivors. Alveolar hemorrhage is the presenting
manifestation in 10% to 20% of patients but most often
occurs in established cases. Unlike in acute lupus pneumonitis, which can also present with hemoptysis, dyspnea, fever, cough, and diffuse alveolar opacities on chest
radiograph, pleural and pericardial effusions are absent
and hemoglobin concentrations are significantly
reduced. Serologic evidence for SLE as a cause of alveolar hemorrhage includes an increase in the ANA titer
along with serum hypocomplementemia. In a recent
review from the University of Colorado, overall mortality of patients with SLE and alveolar hemorrhage was
42%.6 Poor prognostic factors were the need for
mechanical ventilation (62% mortality), the presence
of any infection (78% mortality), and the use of cytotoxic therapy (70% mortality). Effective therapy consisted of prolonged (more than 3 days) pulse steroids
with or without plasmapheresis. Empiric broadspectrum antibiotic therapy should be employed prior
to an aggressive search for infection.
ALVEOLAR HEMORRHAGE DUE TO EXOGENOUS
AGENTS
D-Penicillamine, used as both a chelating agent and
an antirheumatic drug, has been reported to produce a
complex of alveolar hemorrhage with glomerulonephritis that has been termed drug-induced Goodpasture’s syndrome. Unlike in anti-GBM antibody disease, serum anti-GBM antibodies are absent, there is a
history of ingestion of the drug, and there is granular
(rather than linear) deposition of IgG and C3 along
involved basement membranes. Because the pathogenesis appears to be immune complex–mediated, cessation of the drug and immunosuppressive therapy combined with plasmapheresis have been used in a few
cases with good effect.
Trimellitic anhydride, an acid anhydride used in the
manufacture of plastics, paints, and resins, has been
shown to induce isolated alveolar hemorrhage, usually
1 to 3 months after exposure. It is believed that inhalation of fumes, especially when used as a spray in a hightemperature coating process, induces formation of antibodies to trimellitic anhydride–conjugated proteins.
These antibodies, found in the circulation and respiratory tract, may be pathogenic. A Coombs’ test–positive
hemolytic anemia is often found. Therapy is avoidance
of the compound.
Cocaine, especially smoking of the freebase form,
has been implicated in cases of massive hemoptysis and
alveolar hemorrhage. Postmortem examinations of the
lungs of cocaine abusers who died from unrelated causes have demonstrated hemosiderin-laden macrophages. The etiology of the association of alveolar hemorrhage and cocaine use is unclear.
IDIOPATHIC PULMONARY HEMOSIDEROSIS
Idiopathic pulmonary hemosiderosis is a diagnosis
of exclusion characterized by recurrent alveolar hemorrhage without other organ involvement. Pulmonary
histology shows only “bland” alveolar hemorrhage with
hemosiderin accumulation. Serology testing is negative,
ESR is not elevated, and iron deficiency anemia is common. IgA levels may be elevated. It is predominately a
disease of children, but adults older than 30 years comprise 20% of reported cases and generally have a milder
course. An association with celiac disease has been recognized, and therapy of the celiac disorder has resulted
in remission of the idiopathic pulmonary hemosiderosis. Chronic parenchymal bleeding can lead to the
development of pulmonary fibrosis with subsequent
respiratory insufficiency and finger clubbing. Magnetic
resonance imaging may have a role in distinguishing
alveolar hemorrhage from other causes of pulmonary
radiographic abnormalities, especially in small children
in whom bronchoscopy may be technically difficult.
Therapy is generally supportive, with transfusions and
supplementation of iron and oxygen. Immunosuppressive therapy has been advocated to treat acute
hemorrhage, but the rarity of the disease precludes controlled studies.
ALVEOLAR HEMORRHAGE ASSOCIATED WITH BONE
MARROW TRANSPLANTATION
In a review of autologous bone marrow transplant
recipients for lymphoma or solid tumors, alveolar hemorrhage occurred in 21% of these patients, with a mortality
rate of 80%.7 This was a relatively early finding, occurring
an average of 12 days post-transplant. Patients with alveolar hemorrhage had higher platelet counts than those
without alveolar hemorrhage; leukemic patients with
thrombocytopenia had relatively benign alveolar hemorrhage. Risk factors for fulminant alveolar hemorrhage
included: age older than 40 years, severe mucositis,
transplantation for solid tumor, azotemia, and a rising
leukocyte count. The hypothesis was put forth that the
Pulmonary Disease Volume 5, Part 1 9
Alveolar Hemorrhage Syndromes
pretransplant conditioning regimen damaged alveolar
structures that were then ruptured by the increase in circulating cells as the marrow engrafted. Therapy was supportive and generally ineffective.
•
•
VI. CONCLUSION
Although relatively rare, alveolar hemorrhage can
present explosively, with massive hemoptysis, or insidiously, with dyspnea and fatigue. It is most often associated with extrapulmonary—usually renal—disease.
Rapid recognition is imperative because the hemorrhage itself can be life-threatening or concurrent renal
dysfunction can quickly lead to renal failure. Therapy
should generally be initiated with high-dose steroids
and cytotoxic therapy while awaiting the results of histologic and serologic testing.
•
VII. SUMMARY POINTS
•
• Alveolar hemorrhage is the pooling of blood in the
pulmonary alveoli. It frequently occurs in association
with extrapulmonary diseases, most often renal disease.
• Alveolar hemorrhage syndromes are frequently
immune-mediated but may also involve drug or
toxin exposure.
• Cough and dyspnea are the most common complaints in patients with alveolar hemorrhage.
Hemoptysis may or may not be present.
• If alveolar hemorrhage is accompanied by extrapulmonary symptoms such as weight loss, arthralgias, or
rashes, the possibility of an autoimmune or vasculitic
disease process should be pursued.
• Alveolar hemorrhage can usually be evaluated with
plain posteroanterior and lateral chest radiographs.
Diffuse or patchy alveolar filling opacities are the
most common finding.
• Initial laboratory testing should include arterial
blood gas, complete blood cell count with platelet
count, BUN and creatinine levels, coagulation studies, urinalysis with microscopic evaluation for casts
and erythrocytes, and ESR.
• In patients with systemic manifestations or signs of
renal disease, antibody studies such as measurement
of ANA, rheumatoid factor, anti-GBM antibody, and
ANCA should be performed.
• Pulmonary function tests (including measurement
of DLCO) should be performed in cases of suspected
10 Hospital Physician Board Review Manual
occult alveolar hemorrhage and to monitor patients
with recurrent hemorrhage.
Bronchoscopy is necessary to confirm the presence
of alveolar hemorrhage and to rule out focal endobronchial lesions that can present with hemoptysis.
Therapy for alveolar hemorrhage should be directed
at the underlying disorder. It most frequently
involves administration of corticosteroids and cytotoxic immunosuppression. Because alveolar hemorrhage and any associated renal dysfunction are lifethreatening, therapy should be initiated while
awaiting the results of serologic and histologic testing.
Pauci-immune vasculitides most commonly associated
with alveolar hemorrhage are Wegener’s granulomatosis, microscopic polyangiitis, and pauci-immune
glomerulonephritis. Other alveolar hemorrhage syndromes associated with immunologic mechanisms
include Behçet’s syndrome, Henoch-Schönlein purpura, anti-GBM disease, and SLE.
Alveolar hemorrhage may be caused by exposure to
toxic agents, most notably D-penicillamine, trimellitic anhydride, and cocaine.
BOARD REVIEW QUESTIONS
Part 1. Choose the single best answer for each of the following questions.
1.
Diffuse alveolar hemorrhage with capillaritis is
characterized by all of the following EXCEPT:
A) Lymphocytic invasion of the interstitium
with fibrinoid necrosis and capillary thrombosis
B) Loss of integrity of the alveolar capillary membrane with leakage of erythrocytes into the
alveolar space
C) Hemosiderin accumulation in the alveolar
macrophages and the lung parenchyma
D) Organization of the alveolar hemorrhage
2.
All of the following statements regarding alveolar
hemorrhage are true EXCEPT:
A) It can be caused by crack cocaine
B) It can be caused by use of penicillamine
C) It develops with renal disease on exposure to
trimellitic anhydride
D) Hemoptysis can be delayed
E) The presence of Kerley’s B lines implies
underlying mitral stenosis
Alveolar Hemorrhage Syndromes
Which of the following statements regarding alveolar hemorrhage in bone marrow transplant patients
is true?
A) It most commonly occurs late after transplant
(more than 100 days post-transplant)
B) It occurs with worsening neutropenia
C) It commonly occurs in association with severe
thrombocytopenia
D) It is less severe in patients with leukemia than
in those with solid tumors or lymphoma
Part 2. For the following questions, more than one
answer may be correct.
9.
Immune deposits can be found in lung tissue sections in which of the following alveolar hemorrhage syndromes?
A) Goodpasture’s disease
B) Systemic lupus erythematosis
C) Idiopathic pulmonary hemosiderosis
D) Henoch-Schönlein purpura
E) Microscopic polyangiitis
10. Which of the following statements regarding therapy for alveolar hemorrhage are true?
A) Therapy often can be held pending histologic
diagnosis
B) Therapy should include plasmapheresis when
Goodpasture’s disease is suspected
C) Empiric therapy with steroids and cytotoxic
agents should be given
D) Therapy should empirically include broadspectrum antibiotics
E) Therapy has been established by prospective
randomized trials
ANSWERS
5. B
10. B, C, D
All of the following statements regarding HenochSchönlein purpura are true EXCEPT:
A) It presents with a purpuric rash and glomerulonephritis
B) It is an immune complex–mediated disease
C) Circulating antibody directed against IgG is
found
D) Serum tests for antinuclear antibody (ANA)
and rheumatoid factor are usually negative
E) Pulmonary involvement in the form of alveolar hemorrhage is relatively rare (< 10%)
8.
4. A
9. A, B, D
6.
Which of the following statements regarding
Wegener’s granulomatosis is true?
A) A focal segmental necrotizing glomerulonephritis is uncommon
B) Typical histology consists of medium-vessel
involvement, tissue necrosis, and granulomatous inflammation
C) There is always a cutaneous leukocytoclastic
vasculitis
D) Only histologic analysis can differentiate it
from systemic necrotizing vasculitis
Which of the following statements regarding idiopathic pulmonary hemosiderosis is true?
A) The diagnosis is one of exclusion
B) It is predominantly a disease of older adults
C) Typical chest radiograph findings include
multiple nodules
D) Finger clubbing is rarely seen
3. B
8. D
5.
Which of the following statements regarding Goodpasture’s disease is true?
A) Lung and renal disease appear simultaneously in most cases
B) The highest incidence is in women aged 30
through 40 years
C) In younger age groups the disease is more
likely to be limited to the renal system
D) There is no relationship between severity of
the renal disease and outcome
7.
2. C
7. A
4.
Which of the following statements regarding alveolar hemorrhage syndromes is true?
A) DLCO is initially high and increases with time
if there is no further bleeding
B) Henoch-Schönlein purpura is characterized
by circulating immune IgA complexes
C) Only 20% of patients with Goodpasture’s
disease and alveolar hemorrhage are smokers
D) There is evidence of systemic vasculitis in
Goodpasture’s disease
E) Anti–glomerular basement membrane (antiGBM) antibodies are specific for Wegener’s
granulomatosis
1. A
6. C
3.
Pulmonary Disease Volume 5, Part 1 11
Alveolar Hemorrhage Syndromes
REFERENCES
1. Leatherman JW, Davies SF, Hoidal JR: Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in immune and idiopathic disorders. Medicine
(Baltimore) 1984;63:343–361.
2. Dweik RA, Arroliga AC, Cash JM: Alveolar hemorrhage
in patients with rheumatic disease. Rheum Dis Clin North
Am 1997;23:395–410.
3. Hoffman GS, Kerr GS, Leavitt RY, et al: Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med
1992;116:488–498.
4. Duna GF, Galperin C, Hoffman GS: Wegener’s granulomatosis. Rheum Dis Clin North Am 1995;21:949–986.
5. Schwarz MI, Cherniack RM, King TE Jr: Diffuse Alveolar
Hemorrhage and Other Rare Infiltrative Disorders. In
Textbook of Respiratory Medicine, 2nd ed. Murray JF, Nadel
JA, eds. Philadelphia: WB Saunders, 1994:1889–1912.
6. Zamora MR, Warner ML, Tuder R, Schwarz MI: Diffuse
alveolar hemorrhage and systemic lupus erythematosus:
clinical presentation, histology, survival, and outcome.
Medicine (Baltimore) 1997;76:192–202.
7. Young KR Jr: Pulmonary Hemorrhage Syndromes. In
Textbook of Pulmonary and Critical Care Medicine. Bone RC,
Dantzker DR, George RB, et al, eds. St. Louis: Mosby,
1993. Vol 2, Part M, Chapter 10.
SUGGESTED READINGS
Cahill BC, Ingbar DH: Massive hemoptysis: assessment and
management. Clin Chest Med 1994;15:147–167.
Green RJ, Ruoss SJ, Kraft SA, et al: Pulmonary capillaritis and
alveolar hemorrhage: update on diagnosis and management.
Chest 1996;110:1305–1316.
Lhote F, Guillevin L: Polyarteritis nodosa, microscopic
polyangiitis, and Churg-Strauss syndrome: clinical aspects and
treatment. Rheum Dis Clin North Am 1995;21:911–947.
Primack SL, Miller RR, Muller NL: Diffuse pulmonary hemorrhage: clinical, pathologic, and imaging features. AJR Am J
Roentgenol 1995;164:295–300.
Copyright 1998 by Turner White Communications Inc., Wayne, PA. All rights reserved.
12 Hospital Physician Board Review Manual