Diffuse Alveolar Hemorrhage

Abigail R. Lara and Marvin I. Schwarz

Chest 2010;137;1164-1171
DOI 10.1378/chest.08-2084
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 CHEST Recent Advances in Chest Medicine

Diffuse Alveolar Hemorrhage

Abigail R. Lara, MD; and Marvin I. Schwarz, MD, FCCP

Diffuse alveolar hemorrhage (DAH) is often a catastrophic clinical syndrome causing respiratory
failure. Recognition of DAH often requires BAL as symptoms are nonspecific, hemoptysis is
absent in up to one-third of patients, and radiographic imaging is also nonspecific and similar to
other acute alveolar filling processes. Once the diagnosis is established, the underlying cause
must be established in order to initiate treatment. This review discusses the diagnosis of the
underlying histologies and the clinical entities that are responsible for DAH as well as treatment
options. CHEST 2010; 137(5):1164–1171

Abbreviations: ANCA 5 antineutrophilic cytoplasmic autoantibodies; DAH 5 diffuse alveolar hemorrhage;

IPH 5 idiopathic pulmonary hemosiderosis; MPA 5 microscopic polyangiitis; MPO 5 myeloperoxidase; PR3 5 proteinase 3;
SLE 5 systemic lupus erythematosus; WG 5 Wegener granulomatosis

Bleeding from the lung originates from the bron-

chial vessels, the pulmonary vessels, or the micro-
circulation of the lung. Bleeding of bronchial origin is
usually a result of bronchiectasis or endobronchial
malignancy. Pulmonary hemorrhage originating from
the small, medium, and large pulmonary vessels is
most commonly due to systemic vasculitis, which can
also involve the microcirculation. Vasculitides involv-
ing the microvasculature is known as pulmonary
capillaritis. Diffuse alveolar hemorrhage (DAH) is
a clinicopathologic syndrome describing the accumu-
lation of intraalveolar RBCs originating from the
alveolar capillaries. All causes of DAH have the
common denominator of an injury to the alveolar
microcirculation. The clinical syndrome includes
hemoptysis, anemia, diffuse radiographic pulmonary
infiltrates, and hypoxemic respiratory failure, which
can be severe. DAH is associated with a number
of clinical entities and several histologic subtypes.
The most common underlying histology of DAH is of a
Manuscript received August 27, 2009; revision accepted September
19, 2009.
Affiliations: From the Division of Pulmonary Sciences and Critical
Care, University of Colorado Health Sciences Center, Denver, CO.
Correspondence to: Marvin I. Schwarz, MD, FCCP, University of
Colorado Health Sciences Center, Division of Pulmonary Sciences
and Critical Care, 4200 E 9th Ave, Box C272, Denver, CO 80262;
e-mail: marvin.schwarz@ucdenver.edu
© 2010 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.08-2084
small vessel vasculitis known as pulmonary capillaritis,
usually seen with seropositive systemic vasculitides,
or a connective tissue disorder, bland pulmonary
hemorrhage, and diffuse alveolar damage due to a
number of injuries including drugs, coagulation disor-
ders, and infections. Pulmonary capillaritis may also
be a small vessel vasculitis limited to the lung. BAL
confirms the clinical diagnosis of DAH; however, a sur-
gical lung biopsy may be required to confirm the
underlying histology. In general, surgical lung biopsy
is considered if DAH is associated with negative
serology and not a part of a systemic disease. Treatment
is directed at the underlying diagnosis and typically
includes corticosteroids, immunosuppressive agents,
and occasionally plasmapheresis.
Definition
DAH is recognized by the clinical constellation
of hemoptysis, anemia, diffuse radiographic pulmo-
nary infiltrates, and hypoxemic respiratory failure.
The underlying histopathology of DAH includes
the presence of intraalveolar RBCs and fibrin and
the eventual accumulation of hemosiderin-laden
macrophages, which may take up to 48 to 72 h to
accumulate. Of the histologies that are associated
with DAH (pulmonary capillaritis, bland pulmonary
hemorrhage, diffuse alveolar damage, and miscella-
neous histology) pulmonary capillaritis is the most
common.

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 Pulmonary capillaritis has a unique histopathologic
appearance consisting of an interstitial neutrophilic
predominant infiltration, fibrinoid necrosis of the
alveolar and capillary walls, and leukocytoclasis.1 The
infiltrating neutrophils undergo cytoclasis, nuclear
debris accumulates within the interstitium, and there
is a subsequent loss of the integrity of the alveolar-
capillary basement membrane (Fig 1). It is the disrup-
tion of the alveolar-capillary basement membranes that
results in the accumulation of RBCs in alveolar spaces.
There is a distinction between pulmonary capillaritis
and pulmonary vasculitis. Pulmonary vasculitis refers to
inflammation of the lung vessels of any size, whereas
pulmonary capillaritis is confined to the microcircula-
tion of the lung (alveolar capillaries, arterioles, and
venules). However, both may be seen in systemic vascu-
litides and the connective tissue diseases.
Recently, there has been an effort to change the
eponym of Wegener granulomatosis (WG) to a more
scientific nomenclature of antineutrophilic cytoplas-
mic autoantibodies (ANCA)-associated granulomatous
vasculitis.2-4 This is not the first time that an eponym
has undergone a change (eg, Loeffler Syndrome and
simple pulmonary eosinophilia).5 Although the sugges-
tion to develop an alternative name for WG may have
evolved after the association of Dr Wegener and the
Nazi regime, it is our opinion that the alternative should
be used because it serves to describe the pathology,
and eponyms do not describe the disease process.
Etiology
Injury to the alveolar microcirculation resulting in
DAH may be localized to the lung (inhalation injuries,
diffuse alveolar damage) or associated with a systemic
disorder (vasculitis or connective tissue disease). The
causes of DAH are listed in Table 1. There is a spectrum
of disorders associated with DAH, but no prospective
studies estimate its relative frequency. A review of
34 cases of histopathologically confirmed DAH indi-
cated that capillaritis occurred in 88% of the cases.
In one report, the most common clinical cause of DAH
was WG (32%), followed by Goodpasture syndrome
Figure 1. Polymorphoneutrophils invading the capillary walls
(arrowhead) (A). RBC accumulation in the alveolar spaces and
leukocytoclasis (arrows) (B).
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© 2010 American College of Chest Physicians
(13%), idiopathic pulmonary hemosiderosis (IPH) (13%),
collagen vascular diseases (13%), and microscopic
polyangiitis (MPA) (9%). In another series, isolated
pauciimmune pulmonary capillaritis was the most
common cause of DAH associated with capillaritis.6 In
recipients of hematopoietic stem cell transplantation,
DAH was reported to occur in 5% of 3,806 patients.7
Clinical Presentation and Diagnosis
DAH appears at any age and often with an estab-
lished associated disease. DAH may also be the initial
manifestation of an underlying systemic disease. The
cardinal sign of DAH, hemoptysis, may be a dramatic
event or evolve over days to weeks; however, it may
be initially absent in up to 33% of DAH cases. The
natural course is unpredictable and varies in severity
but always should be considered a potentially life-
threatening event. The symptoms of DAH, other
than hemoptysis, are nonspecific and include fever,
chest pain, cough, and dyspnea. Nonpulmonary signs
and symptoms are those that accompany the underly-
ing systemic disease. In addition to history, physical
examination, and routine laboratory studies, directed
serologic testing for connective tissue disease and
systemic vasculitis is useful for establishing the
diagnosis (Table 2). In up to one-third of patients
with DAH, hemoptysis is absent and the diagnosis is
established after sequential BAL reveals worsening
RBC counts.8 Moreover, a falling hematocrit should
alert the clinician to the possibility of DAH. The chest
radiograph findings are nonspecific and consist of an
alveolar filling process that can be a patchy, focal, or
diffuse alveolar filling process (Fig 2). Chest CT scans
confirm the chest radiographic findings and more
accurately define the extent of disease. Flexible bron-
choscopy should be performed to establish the clinical
diagnosis of DAH and to exclude infections. Progres-
sively hemorrhagic BAL found in serial samples is
diagnostic of DAH but not the underlying cause.
Surgical lung biopsy may be required to establish the
cause if serologic testing or clinical history is unre-
vealing. Transbronchial biopsies are usually insufficient.
With recurrent episodes of DAH, interstitial fibrosis
or an obstructive lung disease most compatible with
emphysema can evolve.9,10
Specific Disorders Associated With DAH
Isolated Pauciimmune Pulmonary Capillaritis
Isolated pauciimmune pulmonary capillaritis is a
small-vessel vasculitis that is confined to the lung and
without clinical or serologic features of an associated sys-
temic disease. In a series of 29 cases of biopsy-confirmed
CHEST / 137 / 5 / MAY, 2010 1165
 Table 1—Etiology and Histology of Diffuse Alveolar is unknown but is reported to occur most commonly
Hemorrhage before the age of 30 years. In the pediatric popula-
Pulmonary capillaritis
tion the incidence is reported to be 0.24 in 1 million.13
ANCA-associated granulomatous vasculitis The histology lacks evidence of capillaritis and the
Microscopic polyangiitis alveolar basement membranes are thickened but
Isolated pulmonary capillaritis (ANCA positive and negative) remain intact. Recurrent episodes of DAH lead to
SLE
release of iron into the lung resulting in an abundance
Rheumatoid arthritis
Mixed connective tissue disorder of hemosiderin-laden macrophages.11,14 In advanced
Scleroderma cases of IPH, the lungs develop a distinctive brown
Polymyositis color due to the abundance of hemosiderin and
Primary antiphospholipid antibody syndrome have varying degrees of consolidation and fibrosis.
Henoch-Schönlein purpura
The cause and pathogenesis is unknown; however,
Behçet Syndrome
IgA nephropathy an immune process may be involved as IPH appears
Goodpasture syndrome to respond to immunosuppressant therapy. Although
Idiopathic glomerulonephritis (pauciimmune or immune IPH was included as a syndrome with DAH, it
complex-related) should be noted that it is a rare entity distinct in his-
Acute lung transplant rejection
Idiopathic pulmonary fibrosis
tology from other causes of DAH resulting from the
Diphenylhydantoin microcirculation.
Retinoic acid toxicity
Autologous bone marrow transplantation
Myasthenia gravis ANCA-Associated Granulomatous Vasculitis
Cryoglobulinemia
Ulcerative colitis
ANCA-associated granulomatous vasculitis is a
Propylthiouracil systemic vasculitis characterized by granulomatous
Bland pulmonary hemorrhage inflammation of the upper and lower respiratory tract,
IPH necrotizing vasculitis, and the presence of ANCA.
Goodpasture syndrome The ANCA associated with ANCA-associated granu-
SLE
Coagulation disorders
lomatous vasculitis is an antibody directed against
Trimellitic anhydride cytoplasmic proteinase 3 (PR3).15 Demographic data
Isocyanate exposure obtained from the WG Etanercept Trial varied
Penicillamine between the patients with limited vs severe disease.
Amiodarone Patients with DAH were defined as having severe
Nitrofurantoin
Mitral stenosis
disease, were older (mean age of 50 6 16 vs 41 6
Subacute bacterial endocarditis 16 years), and were more likely to be men. DAH was
Polyglandular autoimmune syndrome identified in 25% of the patients with more severe
Multiple myeloma disease.16 The pathogenesis of PR3-ANCA-positive
Diffuse alveolar damage vasculitis involves the cellular immune pathways
Bone marrow transplantation
Crack cocaine inhalation
resulting in granulomatous inflammation.15 The
Cytotoxic drug therapy percentage expression of PR3 on the surface of neu-
SLE trophils in patients with ANCA-associated granu-
Radiation therapy lomatous vasculitis correlates with higher rates of
ARDS
relapse.17 A retrospective analysis found rising titers
ANCA 5 antineutrophilic cytoplasmic autoantibodies; IPH 5 idiopathic of cytoplasmic-ANCA to have high sensitivity and
pulmonary hemosiderosis; SLE 5 systemic lupus erythematosus.
specificity (93% and 97%, respectively) in predicting
relapse or the presence of active disease.18,19 However,
a recent prospective study had a specificity of 75%
pulmonary capillaritis, isolated pauciimmune pulmo-
and a sensitivity of 71% for predicting relapse using
nary capillaritis was the most common cause of DAH.11
rising titers.20 Patients with persistently high titers of
Overall, patients with isolated pauciimmune pulmo-
PR3-ANCA after remission tend to have a higher risk
nary capillaritis tend to have a better prognosis when
of relapse than those who are ANCA negative.21 Current
compared with DAH occurring in the setting of a
treatment is concentrated for the induction of remission
systemic vasculitis or collagen vascular disease.
using corticosteroids and cyclophosphamide. Mainte-
IPH nance therapy after remission is achieved either with
methotrexate or azathioprine. Recently rituximab, a
IPH is a rare syndrome in which repeated episodes chimeric anti-CD20 monoclonal antibody, has been
of DAH occur resulting in chronic anemia and pulmo- shown to induce remission in patients with refractory
nary fibrosis.12 The incidence in the adult population ANCA-associated granulomatous vasculitis, but should

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 Table 2—Serologic and Radiologic Evaluation of
Diffuse Alveolar Hemorrhage

Nonspecific findings
Leukocytosis
Any cause
Thrombocytopenia
Cytotoxic drugs
Antiphospholipid syndrome
SLE
Increased sedimentation rate
Any cause
Urine red blood cell casts
Any systemic vasculitis
SLE, mixed connective tissue disease
Goodpasture syndrome
Abnormal PT, PTT, INR
SLE
Coagulation disorders
Drugs
Chest radiographic and CT scan infiltrates
Patchy or diffuse, often with apical and peripheral sparing
Any cause
Air bronchograms
Any cause
Specific findings
ANA
Connective tissue disease
Rheumatoid factor
Connective tissue disease
ANCA-associated granulomatous vasculitis
Cytoplasmic-ANCA
ANCA-associated granulomatous vasculitis
Microscopic polyangiitis (less common)
Perinuclear-ANCA
Microscopic polyangiitis
ANCA-associated granulomatous vasculitis
Specific radiologic findings on chest radiograph and/or CT scan
Kerley B lines
PVOD, mitral stenosis
Nodules, cavities
WG
Rheumatoid arthritis
ANA 5 antinuclear antibody; INR 5 international normalized ratio;
PT 5 prothrombin time; PTT 5 partial thromboplastin time; PVOD 5
pulmonary veno-occlusive disease; WG 5 Wegener granulomatosis. Figure 2. Chest radiograph (A) and chest CT scan (B) showing
See Table 1 for expansion of other abbreviations. diffuse nonspecific alveolar infiltrates in a patient with diffuse
alveolar hemorrhage.
not be considered as first-line therapy in Wegener-
associated DAH.22 Plasma exchange has also shown
usefulness if instituted early in the disease course.23-25 patients who survive an episode of DAH their 1-year
and 5-year survival is reduced to 82% and 68%,
MPA respectively.26-28 MPA can be distinguished from
ANCA-associated granulomatous vasculitis by sero-
MPA is a systemic vasculitis that is confined to the logically demonstrating a perinuclear-ANCA directed
microvessels and is always associated with a focal against neutrophil myeloperoxidase (MPO-ANCA).
segmental necrotizing glomerulonephritis. It is dis- Unlike ANCA-associated granulomatous vasculitis,
tinguished from ANCA-associated granulomatous the level of MPO-ANCA titers is not associated with
vasculitis by the absence of upper airway involve- disease activity.29 Recent animal studies suggest that
ment. DAH due to pulmonary capillaritis occurs in MPO-ANCA, and to a lesser degree PR3-ANCA, may
up to one-third of patients and represents the only mediate disease by activating the alternative comple-
pulmonary manifestation of MPA. DAH increases ment pathway, a self-sustaining pathway, and may
the mortality of MPA. In the acute setting, 30% of lend new insight into the severity of disease in ANCA-
patients do not survive an episode of DAH; in those positive diseases.30 Surgical lung biopsy is usually not

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necessary in patients with suspected DAH in the set-
ting of ANCA-positive disease provided infection has
been excluded. Treatment, as with ANCA-associated
granulomatous vasculitis, is glucocorticoids, cyclo-
phosphamide, and plasmapheresis, and is the recom-
mended regimen for induction of remission.31
Recombinant factor VIIa has been used to treat severe
DAH in MPA with unremitting respiratory failure.
The mechanism of factor VIIa treatment is the
enhancement of thrombin generation on the surface
of activated platelets at the sites of hemorrhage.32
Systemic Lupus Erythematosus
DAH occurs in 4% of patients with systemic
lupus erythematosus (SLE) admitted to the hospital
and pulmonary capillaritis is usually the underlying
cause.8 In an immunosuppressed patient with SLE,
infectious pneumonia should be excluded as the
cause of DAH.33 In the majority of DAH associated
with SLE, glomerulonephritis is also present, and
in 80% the DAH occurs in patients with known
SLE.8 These are most often young females with a
mean age of 27 years. The mortality had been previ-
ously reported to be as high as 50%; however, with
the use of aggressive treatment with glucocorticoids
and cyclophosphamide, the mortality associated
with DAH in SLE is declining.8,34,35 DAH is distin-
guished from acute lupus pneumonitis using
sequential BAL. Acute lupus pneumonitis presents
with similar clinical and radiographic features as
DAH; however, it also has systemic symptoms typi-
cal of an SLE flare and may be the only manifes-
tation of the initial presentation of SLE. 36 The
histologic appearance of acute lupus pneumonitis is
varied and includes diffuse alveolar damage, orga-
nizing pneumonia, nonspecific cellular pneumoni-
tis, or a combination of these histologic patterns,
but capillaritis is not present.37 Immune complexes
are frequently found in the lung. The deposition of
immune complexes and the activation of comple-
ment within the lung are central to the development
of parenchymal disease in SLE.38 Methylpredniso-
lone is recommended (1-2 mg/kg/d in divided
doses). High-dose pulse methylprednisolone (1 g
given in divided doses for 3 days) can be given to
those with DAH or acute lupus pneumonitis. Esca-
lating treatment in steroid-resistant DAH includes
azathioprine, cyclophosphamide, or intravenous g
globulin. The combination of high-dose intravenous
methylprednisolone and cyclophosphamide anec-
dotally is the most effective combination. In refrac-
tory cases, plasmapheresis has been used; however,
survival does not appear to be improved.35,39-41 In a
patient with SLE who has established DAH, recur-
rences are to be expected.
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Other Connective Tissue Diseases
DAH with underlying pulmonary capillaritis is an
infrequent occurrence in mixed connective tissue
disease, rheumatoid arthritis, polymyositis, dermato-
myositis, primary antiphospholipid syndrome, and
scleroderma.42-54 The DAH may be the presenting
manifestation or complicate a preexisting disease.
Treatment options are similar to those outlined for
DAH in SLE.
Goodpasture Syndrome (Antiglomerular
Basement Membrane Antibody Disease)
Goodpasture syndrome, also known as antiglomer-
ular basement membrane antibody disease-associated
DAH, is likely the result of autoantibodies directed
against the NC1 domain of the a3 chain of the base-
ment membrane collagen type 4.55 The clinical
expression of the disease occurs only in the lungs
and the kidneys. DAH is common in antiglomerular
basement membrane disease, particularly in cigarette
smokers. It is postulated that smoking mediates dam-
age to the alveolar basement membrane, thus allow-
ing the development of autoantibodies.56,57 Bland
hemorrhage is the most common underlying histol-
ogy, but pulmonary capillaritis is sometimes seen.58
Patients with Goodpasture syndrome tend to be men
in their 20s who also smoke. More than 90% of patients
with Goodpasture disease have circulating anti-
basement membrane antibodies. In patients with
negative circulating antibasement membrane antibod-
ies, a lung or renal biopsy with immunofluorescence
revealing linear antibody deposition within the alveo-
lar or glomerular basement membrane confirms the
diagnosis.59 However, in up to 10% of patients with
Goodpasture syndrome, DAH is present without renal
involvement and is identical to isolated pulmonary
capillaritis. Lung biopsy with immunofluorescence
studies distinguishes the two.60,61 Treatment with
immunosuppression and plasma exchange has improved
outcomes in these patients.62 Rituximab, a chimeric
anti-CD20 monoclonal antibody that has shown effi-
cacy in the treatment of rheumatoid arthritis, should
be considered in patients with ANCA-associated vas-
culitis that is refractory to standard therapy.63,64 Treat-
ment with rituximab results in depletion of B cells
that produce pathogenic autoantibodies and reduces
the cellular interaction by decreasing both the pro-
duction of cytokines that maintain mononuclear cells
and the production of immune complex formations
that help to sustain the disease.65
Lung Allograft Rejection
Pulmonary capillaritis as a form of acute lung trans-
plant rejection was first described in five patients in
Recent Advances in Chest Medicine
1998.66 Since then, the mechanism of the acute rejec-
tion with DAH has been studied further.67-69 A necro-
tizing, pauciinflammatory septal capillary injury
pattern was noted. Immunofluorescent staining
revealed a septal capillary deposition of antibodies
specific for complement factors and immunoglobulin
subtypes.67 Differentiating between acute cellular
rejection and posttransplant capillaritis requires tissue
biopsy and can be found concomitantly in . 50% of
cases. Isolated pulmonary capillaritis, however, is an
infrequent occurrence (approximately 10% of all biop-
sies performed; M. Zamora, personal communication).
Treatment consists of IV corticosteroids and plasma-
pheresis in severe cases.69-72
Bone Marrow Transplant
Pulmonary complications develop in 30% to 60% of
all bone marrow transplant recipients and are the cause
of death in up to 60%.73,74 DAH occurs in approximately
5% of allogeneic and autologous recipients and has a
reported mortality rate ranging from 50% to 100%.7,75
Of the recipients that develop DAH as a pulmonary
complication and survive, the 6-month76 mortality
is 38%.77
The frequency of DAH does not appear to vary sig-
nificantly with the type of hematopoietic stem cell
transplant, with a reported frequency of 1% to 21%
in autologous and 2% to 17% in allogeneic hematopoi-
etic stem cell transplant recipients.7 Risk factors for
the development of DAH in bone marrow transplant
recipients include older age, total body radiation,
myeloablative conditioning regimens, and severe acute
graft-vs-host disease.7,78 Clinically, these patients
present with hemoptysis less frequently compared
with other causes of DAH with a rate of approxi-
mately 15%.76,77 Protective strategies, such as reduc-
ing the intensity of the conditioning regimen, do not
appear to decrease the risk of DAH.7 The pathogen-
esis of DAH in bone marrow transplant recipients
has yet to be clearly established, but it has been
suggested that tissue injury, inflammation, and the
associated cytokine release play important roles.
Lung biopsy reveals diffuse alveolar damage and
DAH.79 The majority of patients with DAH require
mechanical ventilation and corticosteroids are the
mainstay of treatment, although their effectiveness
remains uncertain.74,78
Summary
DAH is a clinicopathologic syndrome that results
from a variety of conditions and should be considered
a life-threatening event. Once believed to be a rare
syndrome, DAH is being recognized with increasing
frequency. A systematic approach to early recognition,
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© 2010 American College of Chest Physicians
establishment of diagnosis, and aggressive treatment
likely decreases the morbidity and mortality associ-
ated with untreated or unrecognized DAH.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be
discussed in this article.
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CHEST / 137 / 5 / MAY, 2010 1171
 Diffuse Alveolar Hemorrhage
Abigail R. Lara and Marvin I. Schwarz
Chest 2010;137; 1164-1171
DOI 10.1378/chest.08-2084
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