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):11641171
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

from the lung originates from the bronBleeding

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 involving the microvasculature is known as pulmonary
capillaritis. Diffuse alveolar hemorrhage (DAH) is
a clinicopathologic syndrome describing the accumulation 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
1164

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

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 disorders, and infections. Pulmonary capillaritis may also
be a small vessel vasculitis limited to the lung. BAL
confirms the clinical diagnosis of DAH; however, a surgical 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 pulmonary 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 miscellaneous histology) pulmonary capillaritis is the most
common.
Recent Advances in Chest Medicine

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 alveolarcapillary basement membrane (Fig 1). It is the disruption 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 microcirculation of the lung (alveolar capillaries, arterioles, and
venules). However, both may be seen in systemic vasculitides 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 cytoplasmic 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 suggestion 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 indicated 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

(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 established 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 lifethreatening 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 underlying 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 bronchoscopy should be performed to establish the clinical
diagnosis of DAH and to exclude infections. Progressively 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 unrevealing. 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

Figure 1. Polymorphoneutrophils invading the capillary walls

(arrowhead) (A). RBC accumulation in the alveolar spaces and
leukocytoclasis (arrows) (B).
www.chestpubs.org

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

Isolated pauciimmune pulmonary capillaritis is a

small-vessel vasculitis that is confined to the lung and
without clinical or serologic features of an associated systemic disease. In a series of 29 cases of biopsy-confirmed
CHEST / 137 / 5 / MAY, 2010

1165

Table 1Etiology and Histology of Diffuse Alveolar

Hemorrhage
Pulmonary capillaritis
ANCA-associated granulomatous vasculitis
Microscopic polyangiitis
Isolated pulmonary capillaritis (ANCA positive and negative)
SLE
Rheumatoid arthritis
Mixed connective tissue disorder
Scleroderma
Polymyositis
Primary antiphospholipid antibody syndrome
Henoch-Schnlein purpura
Behet Syndrome
IgA nephropathy
Goodpasture syndrome
Idiopathic glomerulonephritis (pauciimmune or immune
complex-related)
Acute lung transplant rejection
Idiopathic pulmonary fibrosis
Diphenylhydantoin
Retinoic acid toxicity
Autologous bone marrow transplantation
Myasthenia gravis
Cryoglobulinemia
Ulcerative colitis
Propylthiouracil
Bland pulmonary hemorrhage
IPH
Goodpasture syndrome
SLE
Coagulation disorders
Trimellitic anhydride
Isocyanate exposure
Penicillamine
Amiodarone
Nitrofurantoin
Mitral stenosis
Subacute bacterial endocarditis
Polyglandular autoimmune syndrome
Multiple myeloma
Diffuse alveolar damage
Bone marrow transplantation
Crack cocaine inhalation
Cytotoxic drug therapy
SLE
Radiation therapy
ARDS
ANCA 5 antineutrophilic cytoplasmic autoantibodies; IPH 5 idiopathic
pulmonary hemosiderosis; SLE 5 systemic lupus erythematosus.

pulmonary capillaritis, isolated pauciimmune pulmonary capillaritis was the most common cause of DAH.11
Overall, patients with isolated pauciimmune pulmonary capillaritis tend to have a better prognosis when
compared with DAH occurring in the setting of a
systemic vasculitis or collagen vascular disease.
IPH
IPH is a rare syndrome in which repeated episodes
of DAH occur resulting in chronic anemia and pulmonary fibrosis.12 The incidence in the adult population
1166

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

is unknown but is reported to occur most commonly

before the age of 30 years. In the pediatric population the incidence is reported to be 0.24 in 1 million.13
The histology lacks evidence of capillaritis and the
alveolar basement membranes are thickened but
remain intact. Recurrent episodes of DAH lead to
release of iron into the lung resulting in an abundance
of hemosiderin-laden macrophages.11,14 In advanced
cases of IPH, the lungs develop a distinctive brown
color due to the abundance of hemosiderin and
have varying degrees of consolidation and fibrosis.
The cause and pathogenesis is unknown; however,
an immune process may be involved as IPH appears
to respond to immunosuppressant therapy. Although
IPH was included as a syndrome with DAH, it
should be noted that it is a rare entity distinct in histology from other causes of DAH resulting from the
microcirculation.
ANCA-Associated Granulomatous Vasculitis
ANCA-associated granulomatous vasculitis is a
systemic vasculitis characterized by granulomatous
inflammation of the upper and lower respiratory tract,
necrotizing vasculitis, and the presence of ANCA.
The ANCA associated with ANCA-associated granulomatous vasculitis is an antibody directed against
cytoplasmic proteinase 3 (PR3).15 Demographic data
obtained from the WG Etanercept Trial varied
between the patients with limited vs severe disease.
Patients with DAH were defined as having severe
disease, were older (mean age of 50 6 16 vs 41 6
16 years), and were more likely to be men. DAH was
identified in 25% of the patients with more severe
disease.16 The pathogenesis of PR3-ANCA-positive
vasculitis involves the cellular immune pathways
resulting in granulomatous inflammation.15 The
percentage expression of PR3 on the surface of neutrophils in patients with ANCA-associated granulomatous vasculitis correlates with higher rates of
relapse.17 A retrospective analysis found rising titers
of cytoplasmic-ANCA to have high sensitivity and
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%
and a sensitivity of 71% for predicting relapse using
rising titers.20 Patients with persistently high titers of
PR3-ANCA after remission tend to have a higher risk
of relapse than those who are ANCA negative.21 Current
treatment is concentrated for the induction of remission
using corticosteroids and cyclophosphamide. Maintenance therapy after remission is achieved either with
methotrexate or azathioprine. Recently rituximab, a
chimeric anti-CD20 monoclonal antibody, has been
shown to induce remission in patients with refractory
ANCA-associated granulomatous vasculitis, but should
Recent Advances in Chest Medicine

Table 2Serologic 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.
See Table 1 for expansion of other abbreviations.

not be considered as first-line therapy in Wegenerassociated DAH.22 Plasma exchange has also shown
usefulness if instituted early in the disease course.23-25
MPA
MPA is a systemic vasculitis that is confined to the
microvessels and is always associated with a focal
segmental necrotizing glomerulonephritis. It is distinguished from ANCA-associated granulomatous
vasculitis by the absence of upper airway involvement. DAH due to pulmonary capillaritis occurs in
up to one-third of patients and represents the only
pulmonary manifestation of MPA. DAH increases
the mortality of MPA. In the acute setting, 30% of
patients do not survive an episode of DAH; in those
www.chestpubs.org

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

Figure 2. Chest radiograph (A) and chest CT scan (B) showing

diffuse nonspecific alveolar infiltrates in a patient with diffuse
alveolar hemorrhage.

patients who survive an episode of DAH their 1-year

and 5-year survival is reduced to 82% and 68%,
respectively.26-28 MPA can be distinguished from
ANCA-associated granulomatous vasculitis by serologically demonstrating a perinuclear-ANCA directed
against neutrophil myeloperoxidase (MPO-ANCA).
Unlike ANCA-associated granulomatous vasculitis,
the level of MPO-ANCA titers is not associated with
disease activity.29 Recent animal studies suggest that
MPO-ANCA, and to a lesser degree PR3-ANCA, may
mediate disease by activating the alternative complement pathway, a self-sustaining pathway, and may
lend new insight into the severity of disease in ANCApositive diseases.30 Surgical lung biopsy is usually not
CHEST / 137 / 5 / MAY, 2010

1167

necessary in patients with suspected DAH in the setting of ANCA-positive disease provided infection has
been excluded. Treatment, as with ANCA-associated
granulomatous vasculitis, is glucocorticoids, cyclophosphamide, and plasmapheresis, and is the recommended 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 previously 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 distinguished 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 typical of an SLE flare and may be the only manifestation of the initial presentation of SLE. 36 The
histologic appearance of acute lupus pneumonitis is
varied and includes diffuse alveolar damage, organizing pneumonia, nonspecific cellular pneumonitis, 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 complement within the lung are central to the development
of parenchymal disease in SLE.38 Methylprednisolone 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. Escalating treatment in steroid-resistant DAH includes
azathioprine, cyclophosphamide, or intravenous g
globulin. The combination of high-dose intravenous
methylprednisolone and cyclophosphamide anecdotally is the most effective combination. In refractory 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, recurrences are to be expected.
1168

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

Other Connective Tissue Diseases

DAH with underlying pulmonary capillaritis is an
infrequent occurrence in mixed connective tissue
disease, rheumatoid arthritis, polymyositis, dermatomyositis, 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 antiglomerular basement membrane antibody disease-associated
DAH, is likely the result of autoantibodies directed
against the NC1 domain of the a3 chain of the basement 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 damage to the alveolar basement membrane, thus allowing the development of autoantibodies.56,57 Bland
hemorrhage is the most common underlying histology, 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 antibasement membrane antibodies. In patients with
negative circulating antibasement membrane antibodies, a lung or renal biopsy with immunofluorescence
revealing linear antibody deposition within the alveolar 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 efficacy in the treatment of rheumatoid arthritis, should
be considered in patients with ANCA-associated vasculitis that is refractory to standard therapy.63,64 Treatment with rituximab results in depletion of B cells
that produce pathogenic autoantibodies and reduces
the cellular interaction by decreasing both the production 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 transplant rejection was first described in five patients in
Recent Advances in Chest Medicine

1998.66 Since then, the mechanism of the acute rejection with DAH has been studied further.67-69 A necrotizing, 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 biopsies performed; M. Zamora, personal communication).
Treatment consists of IV corticosteroids and plasmapheresis 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 significantly with the type of hematopoietic stem cell
transplant, with a reported frequency of 1% to 21%
in autologous and 2% to 17% in allogeneic hematopoietic 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 approximately 15%.76,77 Protective strategies, such as reducing the intensity of the conditioning regimen, do not
appear to decrease the risk of DAH.7 The pathogenesis 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,
www.chestpubs.org

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

establishment of diagnosis, and aggressive treatment

likely decreases the morbidity and mortality associated 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.

References
1. Colby TV, Fukuoka J, Ewaskow SP, Helmers R, Leslie KO.
Pathologic approach to pulmonary hemorrhage. Ann Diagn
Pathol. 2001;5(5):309-319.
2. Matteson EL, Woywodt A. Eponymophilia in rheumatology.
Rheumatology (Oxford). 2006;45(11):1328-1330.
3. Woywodt A, Matteson EL. Wegeners granulomatosis
probing the untold past of the man behind the eponym.
Rheumatology (Oxford). 2006;45(10):1303-1306.
4. Woywodt A, Haubitz M, Haller H, Matteson EL. Wegeners
granulomatosis. Lancet. 2006;367(9519):1362-1366.
5. Sharma OP, Bethlem EP. The pulmonary infiltration with
eosinophilia syndrome. Curr Opin Pulm Med. 1996;2(5):380-389.
6. Travis WD, Colby TV, Lombard C, Carpenter HA. A
clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol.
1990;14(12):1112-1125.
7. Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME,
Peters SG. Diffuse alveolar hemorrhage in hematopoietic
stem cell transplant recipients. Am J Respir Crit Care Med.
2002;166(5):641-645.
8. 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(3):192-202.
9. Schwarz MI, Mortenson RL, Colby TV, et al. Pulmonary
capillaritis. The association with progressive irreversible
airflow limitation and hyperinflation. Am Rev Respir Dis.
1993;148(2):507-511.
10. Hunt DP, Weil R, Nicholson AG, Burke MM, Du Bois RM,
Wells AU. Pulmonary capillaritis and its relationship to
development of emphysema in hypocomplementaemic urticarial vasculitis syndrome. Sarcoidosis Vasc Diffuse Lung Dis.
2006;23(1):70-72.
11. Jennings CA, King TE Jr, Tuder R, Cherniack RM, Schwarz MI.
Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med.
1997;155(3):1101-1109.
12. Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary
haemosiderosis revisited. Eur Respir J. 2004;24(1):162-170.
13. Kjellman B, Elinder G, Garwicz S, Svan H. Idiopathic pulmonary haemosiderosis in Swedish children. Acta Paediatr
Scand. 1984;73(5):584-588.
14. Green RJ, Ruoss SJ, Kraft SA, Duncan SR, Berry GJ, Raffin TA.
Pulmonary capillaritis and alveolar hemorrhage. Update on
diagnosis and management. Chest. 1996;110(5):1305-1316.
15. Franssen CF, Stegeman CA, Kallenberg CG, et al.
Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Kidney Int. 2000;57(6):2195-2206.
16. Stone JH; Wegeners Granulomatosis Etanercept Trial
Research Group. Limited versus severe Wegeners granulomatosis: baseline data on patients in the Wegeners
CHEST / 137 / 5 / MAY, 2010

1169

17.

18.

19.
20.

21.

22.

23.

24.

25.

26.
27.

28.
29.
30.

31.

32.
33.
34.

Granulomatosis Etanercept Trial. Arthritis Rheum. 2003;

48(8):2299-2309.
Rarok AA, Stegeman CA, Limburg PC, Kallenberg CG.
Neutrophil membrane expression of proteinase 3 (PR3) is
related to relapse in PR3-ANCA-associated vasculitis. J Am
Soc Nephrol. 2002;13(9):2232-2238.
van der Woude FJ, Rasmussen N, Lobatto S, et al.
Autoantibodies against neutrophils and monocytes: tool for
diagnosis and marker of disease activity in Wegeners granulomatosis. Lancet. 1985;1(8426):425-429.
Tervaert JW, van der Woude FJ, Fauci AS, et al. Association
between active Wegeners granulomatosis and anticytoplasmic antibodies. Arch Intern Med. 1989;149(11):2461-2465.
Boomsma MM, Stegeman CA, van der Leij MJ, et al.
Prediction of relapses in Wegeners granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum. 2000;43(9):2025-2033.
Sanders JS, Huitma MG, Kallenberg CG, Stegeman CA.
Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCA titres to treatment.
Rheumatology (Oxford). 2006;45(6):724-729.
Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA,
Schroeder DR, Specks U. Rituximab for refractory Wegeners
granulomatosis: report of a prospective, open-label pilot trial.
Am J Respir Crit Care Med. 2006;173(2):180-187.
Sugimoto T, Deji N, Kume S, et al. Pulmonary-renal syndrome,
diffuse pulmonary hemorrhage and glomerulonephritis, associated with Wegeners granulomatosis effectively treated with
early plasma exchange therapy. Intern Med. 2007;46(1):49-53.
Nguyen T, Martin MK, Indrikovs AJ. Plasmapheresis for diffuse alveolar hemorrhage in a patient with Wegeners granulomatosis: case report and review of the literature. J Clin
Apher. 2005;20(4):230-234.
Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke
DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney
Dis. 2003;42(6):1149-1153.
Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic
polyangiitis: clinical and laboratory findings in eighty-five
patients. Arthritis Rheum. 1999;42(3):421-430.
Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review
of the literature. Groupe dEtudes et de Recherche sur les
Maladies Orphelines Pulmonaires (GERMOP). Medicine
(Baltimore). 2000;79(4):222-233.
Schwarz MI, Brown KK. Small vessel vasculitis of the lung.
Thorax. 2000;55(6):502-510.
Falk RJ, Nachman PH, Hogan SL, Jennette JC. ANCA glomerulonephritis and vasculitis: a Chapel Hill perspective. Semin
Nephrol. 2000;20(3):233-243.
Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC.
Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies.
Am J Pathol. 2007;170(1):52-64.
Jayne D, Rasmussen N, Andrassy K, et al; European Vasculitis
Study Group. A randomized trial of maintenance therapy for
vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36-44.
Betensley AD, Yankaskas JR. Factor VIIa for alveolar hemorrhage in microscopic polyangiitis. Am J Respir Crit Care Med.
2002;166(9):1291-1292.
Rojas-Serrano J, Pedroza J, Regalado J, et al. High prevalence
of infections in patients with systemic lupus erythematosus
and pulmonary haemorrhage. Lupus. 2008;17(4):295-299.
Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar hemorrhage in systemic lupus erythematosus: presentation and
management. Chest. 2000;118(4):1083-1090.

1170

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

35. Caas C, Tobn GJ, Granados M, Fernndez L. Diffuse

alveolar hemorrhage in Colombian patients with systemic lupus
erythematosus. Clin Rheumatol. 2007;26(11):1947-1949.
36. Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve
cases of acute lupus pneumonitis. Medicine (Baltimore).
1975;54(5):397-409.
37. Boulware DW, Hedgpeth MT. Lupus pneumonitis and antiSSA(Ro) antibodies. J Rheumatol. 1989;16(4):479-481.
38. Churg A, Franklin W, Chan KL, Kopp E, Carrington CB.
Pulmonary hemorrhage and immune-complex deposition in the lung. Complications in a patient with systemic
lupus erythematosus. Arch Pathol Lab Med. 1980;104(7):
388-391.
39. Hoshi K, Matsuda M, Ishikawa M, et al. Successful treatment
of fulminant pulmonary hemorrhage associated with systemic
lupus erythematosus. Clin Rheumatol. 2004;23(3):252-255.
40. Cheema GS, Quismorio FP Jr. Interstitial lung disease
in systemic lupus erythematosus. Curr Opin Pulm Med.
2000;6(5):424-429.
41. Badsha H, Teh CL, Kong KO, Lian TY, Chng HH. Pulmonary
hemorrhage in systemic lupus erythematosus. Semin Arthritis
Rheum. 2004;33(6):414-421.
42. Schwarz MI, Sutarik JM, Nick JA, Leff JA, Emlen JW,
Tuder RM. Pulmonary capillaritis and diffuse alveolar hemorrhage. A primary manifestation of polymyositis. Am J Respir
Crit Care Med. 1995;151(6):2037-2040.
43. Schwarz MJK, Talmadge, E. Interstitial Lung Disease. 2nd
ed. St. Louis, MO: Mosby-Year Book; 1993.
44. Tazelaar HD, Viggiano RW, Pickersgill J, Colby TV. Interstitial
lung disease in polymyositis and dermatomyositis. Clinical
features and prognosis as correlated with histologic findings.
Am Rev Respir Dis. 1990;141(3):727-733.
45. Griffin MT, Robb JD, Martin JR. Diffuse alveolar haemorrhage associated with progressive systemic sclerosis. Thorax.
1990;45(11):903-904.
46. Nishi K, Myou S, Ooka T, Fujimura M, Matsuda T. Diffuse
cutaneous systemic sclerosis associated with pan-serositis, disseminated intravascular coagulation, and diffuse alveolar haemorrhage. Respir Med. 1994;88(6):471-473.
47. Bar J, Ehrenfeld M, Rozenman J, Perelman M, Sidi Y, Gur H.
Pulmonary-renal syndrome in systemic sclerosis. Semin Arthritis
Rheum. 2001;30(6):403-410.
48. Horiki T, Fuyuno G, Ishii M, et al. Fatal alveolar hemorrhage
in a patient with mixed connective tissue disease presenting
polymyositis features. Intern Med. 1998;37(6):554-560.
49. Schwarz MI, Zamora MR, Hodges TN, Chan ED, Bowler RP,
Tuder RM. Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective
tissue disease. Chest. 1998;113(6):1609-1615.
50. Torralbo A, Herrero JA, Portols J, Barrientos A. Alveolar
hemorrhage associated with antineutrophil cytoplasmic
antibodies in rheumatoid arthritis. Chest. 1994;105(5):15901592.
51. Gertner E, Lie JT. Pulmonary capillaritis, alveolar hemorrhage, and recurrent microvascular thrombosis in primary
antiphospholipid syndrome. J Rheumatol. 1993;20(7):12241228.
52. Asherson RA, Cervera R, Piette JC, et al. Catastrophic
antiphospholipid syndrome. Clinical and laboratory features
of 50 patients. Medicine (Baltimore). 1998;77(3):195-207.
53. Gertner E. Diffuse alveolar hemorrhage in the antiphospholipid syndrome: spectrum of disease and treatment.
J Rheumatol. 1999;26(4):805-807.
54. Wiedermann FJ, Mayr A, Schobersberger W, et al. Acute respiratory failure associated with catastrophic antiphospholipid
syndrome. J Intern Med. 2000;247(6):723-730.
Recent Advances in Chest Medicine

55. Salama AD, Pusey CD. Immunology of anti-glomerular basement membrane disease. Curr Opin Nephrol Hypertens.
2002;11(3):279-286.
56. Donaghy M, Rees AJ. Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to
glomerular basement membrane. Lancet. 1983;2(8364):13901393.
57. Lazor R, Bigay-Gam L, Cottin V, et al; Groupe dEtudes
et de Recherche sur les Maladies Orphelines Pulmonaires
(GERMOP); Swiss Group for Interstitial and Orphan Lung
Diseases (SIOLD). Alveolar hemorrhage in anti-basement
membrane antibody disease: a series of 28 cases. Medicine
(Baltimore). 2007;86(3):181-193.
58. Lombard CM, Colby TV, Elliott CG. Surgical pathology of
the lung in anti-basement membrane antibody-associated
Goodpastures syndrome. Hum Pathol. 1989;20(5):445-451.
59. Magro CM, Morrison C, Pope-Harman A, Rothrauff SK,
Ross P Jr. Direct and indirect immunofluorescence as a diagnostic adjunct in the interpretation of nonneoplastic medical
lung disease. Am J Clin Pathol. 2003;119(2):279-289.
60. Mathew TH, Hobbs JB, Kalowski S, Sutherland PW, KincaidSmith P. Goodpastures syndrome: normal renal diagnostic
findings. Ann Intern Med. 1975;82(2):215-218.
61. Tobler A, Schrch E, Altermatt HJ, Im Hof V. Anti-basement
membrane antibody disease with severe pulmonary haemorrhage and normal renal function. Thorax. 1991;46(1):68-70.
62. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression.
Ann Intern Med. 2001;134(11):1033-1042.
63. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of
B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572-2581.
64. Stasi R, Stipa E, Del Poeta G, Amadori S, Newland AC,
Provan D. Long-term observation of patients with antineutrophil cytoplasmic antibody-associated vasculitis treated
with rituximab. Rheumatology (Oxford). 2006;45(11):14321436.
65. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis
Rheum. 2003;48(6):1484-1492.
66. Badesch DB, Zamora M, Fullerton D, et al. Pulmonary capillaritis: a possible histologic form of acute pulmonary allograft
rejection. J Heart Lung Transplant. 1998;17(4):415-422.
67. Astor TL, Weill D, Cool C, Teitelbaum I, Schwarz MI,
Zamora MR. Pulmonary capillaritis in lung transplant recipi-

www.chestpubs.org

Downloaded From: https://journal.publications.chestnet.org/ on 11/12/2012

68.

69.

70.
71.
72.

73.
74.
75.

76.

77.
78.

79.

ents: treatment and effect on allograft function. J Heart Lung

Transplant. 2005;24(12):2091-2097.
Magro CM, Klinger DM, Adams PW, et al. Evidence that
humoral allograft rejection in lung transplant patients is
not histocompatibility antigen-related. Am J Transplant.
2003;3(10):1264-1272.
Magro CM, Deng A, Pope-Harman A, et al. Humorally mediated posttransplantation septal capillary injury syndrome as a
common form of pulmonary allograft rejection: a hypothesis.
Transplantation. 2002;74(9):1273-1280.
Sibley RK, Berry GJ, Tazelaar HD, et al. The role of transbronchial biopsies in the management of lung transplant
recipients. J Heart Lung Transplant. 1993;12(2):308-324.
Robinson JA. Apheresis in thoracic organ transplantation.
Ther Apher. 1999;3(1):34-39.
Bittner HB, Dunitz J, Hertz M, Bolman MR III, Park SJ.
Hyperacute rejection in single lung transplantationcase
report of successful management by means of plasmapheresis and antithymocyte globulin treatment. Transplantation.
2001;71(5):649-651.
Matulis M, High KP. Immune reconstitution after hematopoietic stem-cell transplantation and its influence on respiratory
infections. Semin Respir Infect. 2002;17(2):130-139.
Afessa B, Peters SG. Chronic lung disease after hematopoietic stem cell transplantation. Clin Chest Med. 2005;26(4):
571-586, vi.
Lewis ID, DeFor T, Weisdorf DJ. Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow
transplantation: cryptic etiology and uncertain therapy. Bone
Marrow Transplant. 2000;26(5):539-543.
Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166(10):
1364-1368.
Gupta S, Jain A, Warneke CL, et al. Outcome of alveolar
hemorrhage in hematopoietic stem cell transplant recipients.
Bone Marrow Transplant. 2007;40(1):71-78.
Majhail NS, Parks K, Defor TE, Weisdorf DJ. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage
following hematopoietic stem cell transplantation: related and
high-risk clinical syndromes. Biol Blood Marrow Transplant.
2006;12(10):1038-1046.
Roychowdhury M, Pambuccian SE, Aslan DL, et al. Pulmonary
complications after bone marrow transplantation: an autopsy
study from a large transplantation center. Arch Pathol Lab
Med. 2005;129(3):366-371.

CHEST / 137 / 5 / MAY, 2010

1171