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Successful pulmonary administration of

activated recombinant factor VII in diffuse
alveolar hemorrhage
Abstract

Introduction

Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with
autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell
transplantation. The clinical management of DAH is complex and the condition has a high
mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore
pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a
rational treatment option.

Methods

Six patients with acute, bronchoscopically confirmed DAH from a single intensive care unit
university hospital center were included in the study of acute DAH in critically ill patients. The
patients were treated with intrapulmonary administration of 50 μg/kg rFVIIa in 50 ml of sodium
chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was
repeated after 24 hours in case of treatment failure.

Results

An excellent response, defined as complete and sustained hemostasis after a single dose of
rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was
achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of
these patients, the BAL treatment was repeated twice; in another patient, the second dose of
rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic
effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the
PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased
significantly (p = 0.024) in all six patients following the local rFVIIa therapy.

Conclusion

Symptomatic therapy of DAH after intrapulmonary administration of one or more doses of

rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with
DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio.
Larger series should confirm the safety of this approach.

Introduction

Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication of mostly unknown

etiology and pathogenesis, although injury to alveolar capillary endothelium and alveolar
inflammation, resulting in the release of inflammatory cytokines, have been implicated [1,2]. The
disease is seen after hematopoietic stem cell transplantation (HSCT), after chemotherapy, and in
patients with autoimmune disorders [3]. The extensive pulmonary inflammation leads to
abundant intra-alveolar expression of tissue factor (TF), resulting in a several-fold increase in
molecular markers of thrombin generation in bronchoalveolar lavage (BAL) fluid [4]. Effective
local hemostatic strategies are lacking, and mortality rates exceed 50% in those who require
mechanical ventilator support [5]. We hypothesized that local administration of human
recombinant activated factor VIIa (rFVIIa) might be an effective treatment option.

Materials and methods

Six consecutive patients with pulmonary bleeding, of whom four had an inspiratory fractional
oxygen content (FiO2) demand of 1.0, not responding to conventional therapy were studied. At
our institution, treatment of pulmonary bleeding includes transfusion of fresh frozen plasma
(FFP) and platelet concentrate (PC) to normalize systemic coagulation ability, endotracheal and
intravenous (i.v.) administration of tranexamic acid, and if no hemostatic effect is obtained, this
is followed by continuous aprotinin i.v. infusion. The diagnosis of DAH was confirmed
bronchoscopically by identification of ongoing bleeding at the bronchial segmental level before
treatment with rFVIIa. The dose was approximately 50 μg/kg dissolved in 50 ml of saline
distributed evenly in the right and left main bronchi. In one non-intubated patient, rFVIIa was
administered as an inhalant at a dose of 50 μg/kg via a jet-driven nebulizer.

Treatment efficacy of rFVIIa was graded as an excellent, good, or poor response. An 'excellent'
response was defined as a complete and sustained hemostasis after a single treatment with
rFVIIa. The response was graded as 'good' when repeated intrapulmonary administration of
rFVIIa was required to obtain hemostasis. A 'poor' response was characterized by the lack of any
effect by rFVIIa on bleeding. The hemostatic effect and the oxygenation capacity were
statistically analyzed using the non-parametric tests, McNemar's test and Wilcoxon signed paired
rank test, respectively. A waiver of informed consent was obtained from the Institutional Review
Board.

Results

Patients

Patient 1

A 46-year-old male with chronic lymphocytic leukemia underwent allogenic non-myeloablative

stem cell transplantation (HSCT). The post-transplant course was complicated by severe graft-
versus-host disease (GvHD) of the skin, thrombocytopenia, and systemic cytomegalovirus
(CMV) infection, causing treatment-induced renal failure that necessitated hemodialysis (Table
1).

Table 1. Comparison of underlying disease, the effect of intrapulmonary rFVIIa therapy, and
survival of DAH

Nine months after HSCT, he was admitted to the intensive care unit (ICU) with septic shock,
which was treated with empiric antibiotics, vasoactive medication, and mechanical ventilation.
Seven days after ICU admission, the FiO2 requirement suddenly increased to 1.0 and fresh blood
was coming from the endotracheal tube. The platelet count was 10 × 109 per liter and the
activated partial thromboplastin time (APTT) was 40 seconds. Despite platelet transfusion to a
platelet count of more than 100 × 109 per liter and FFP administration to an APTT of less than 35
seconds (in addition to the standard treatment as described in Materials and methods), the
bleeding increased in severity. rFVIIa was administered intravenously in doses of up to 120
μg/kg without hemostatic effect. Bronchoscopy revealed fresh bleeding from both lungs. rFVIIa
(50 μg/kg) dissolved in saline was administered by BAL into the left and right main bronchi
simultaneously with the systemic i.v. administration of 50 μg/kg rFVIIa. This resulted in an
immediate cessation of the bleeding from the endotracheal tube. The arterial oxygen pressure
(PaO2)/FiO2 ratio increased the subsequent day. The hemostatic effect lasted for approximately
36 hours, after which bleeding recurred. The treatment was repeated twice also, and bleeding
ceased for more than 24 hours. Hereafter, the patient received rFVIIa (50 μg/kg) by BAL alone
twice, and bleeding ceased for 24 to 36 hours after each administration. Complete hemostasis
was obtained after the third BAL administration of rFVIIa and lasted for three months (Table 2).
The patient died three months after the first rFVIIa treatment, due to respiratory and circulatory
failure secondary to septic shock without evidence of active pulmonary bleeding. Postmortem
examination revealed no signs of acute respiratory distress syndrome (ARDS) in the alveoli or
thromboembolic complications.

Table 2. Comparison of hemostatic variables and oxygenation capacity before and after rFVIIa
in patients with DAH

Patient 2

A 63-year-old male with progressive neurosarcoidosis was treated with infusion of methotrexate.
After the second treatment, he developed pancytopenia and septic shock and was transferred to
the ICU, where he was intubated and mechanically ventilated. Fresh blood was observed from
the tracheal tube, and chest x-ray showed interstitial diffuse alveolar infiltrates indicating
pulmonary bleeding. Standard treatment was instituted, resulting in an increase in platelet count
from 18 × 109 per liter to 88 × 109 per liter with a reduction in APTT from 45 to 36 seconds
(Table 2). Multiple organ failure developed and increasing amounts of fresh blood were observed
from the tube while the FiO2 requirement increased from 0.7 to 1.0. A single dose (20 μg) of i.v.
desmopressin did not improve hemostasis. Bronchoscopy revealed ongoing bleeding from the
distal bronchial tree bilaterally. A 50 μg/kg dose of rFVIIa was administered via BAL, resulting
in immediate cessation of the pulmonary bleeding. Four hours after rFVIIa administration, FiO2
could be reduced to 0.8 and was further reduced to 0.6 the following morning (Table 2). Despite
continued improvement in pulmonary function, increasing circulatory instability secondary to
septic shock became evident and the patient died four days after rFVIIa treatment. No pulmonary
bleeding or thromboembolic complications were found after the intrapulmonary administration
of rFVIIa.

Patient 3

A 44-year-old male with acute myeloid leukemia (AML) developed high fever and hemoptysis
14 days after induction of a combination of chemotherapy comprising cytarabine, amsacrine, and
etoposide. Chest x-ray showed bilateral infiltrations, and BAL revealed Stenotrophomonas
maltophilia. The patient was admitted to the ICU, where mechanical ventilation was instituted
with an FiO2 of 1.0, and was started with inotropic support and antimicrobial therapy (i.v.
ceftazidime and inhalation of colistin). Pulmonary bleeding increased despite standard treatment
(Table 2). Bronchoscopy revealed ongoing bleeding from the distal bronchial tree bilaterally, and
rFVIIa (50 μg/kg) was administered by BAL. The bleeding ceased and the FiO2 was decreased to
0.45 over the next 24 hours. Over the next 12 days, the situation stabilized and improvement of
the pulmonary and the circulatory functions was observed and the patient could be weaned off of
the ventilator and discharged from the ICU. No pulmonary bleeding or thromboembolic
complications were observed after the intrapulmonary administration of rFVIIa.

Patient 4

A 34-year-old woman was suspected of having Wegener's granulomatosis on the basis of

eosinophilia, positive anti-neutrophil cytoplasmatic antibodies, hematuria, and proteinuria.
Treatment with systemic corticosteroids was instituted, but due to respiratory distress and the
presence of hemoptysis, the patient was admitted to the ICU. Chest x-ray showed interstitial
subtle bilateral alveolar infiltrates indicating pulmonary bleeding. The patient was intubated and
mechanically ventilated with an FiO2 of 1.0, and systemic antibiotic treatment was initiated in
conjunction with pulse treatment with methylprednisone (1,000 mg intravenously every day for
three days and then 40 mg every day). Treatment including continuous aprotinin infusion was
instituted. The pulmonary bleeding ceased, FiO2 demand was reduced to 0.35, and
antifibrinolytic treatment was discontinued. Twelve hours after discontinuation of aprotinin,
fresh pulmonary bleeding again became apparent, together with an increase in FiO2 requirements
to 1.0. The bleeding was refractory to standard treatment, including aprotinin. Bronchoscopy
revealed ongoing bleeding at the segmental level, and rFVIIa (50 μg/kg) was administered by
BAL, leading to immediate cessation of the bleeding; FiO2 was reduced to 0.3 at six hours after
rFVIIa treatment, and the patient was extubated the following morning.

A biopsy from the skin showed perivascular eosinophilic infiltration indicating Churg-Strauss
vasculitis, and the patient responded to the corticosteroid therapy treatment with regression of
paresis and normalization of urine tests. Three days after extubation, bleeding from the lungs
reoccurred together with an increase in O2 demand. To avoid re-intubation, rFVIIa was
administered through a jet nebulizer with a prompt hemostatic effect. The aerosolized rFVIIa
was repeated twice over the following 12 hours. A sustained hemostasis and a decrease in O2
requirements from 15 to 4 liters/minute were obtained. The further clinical course was
uneventful, and the patient was discharged from the ICU three days later.

Patient 5

A 44-year-old HIV-positive female with chronic hemodialysis requirement, severe critical illness
polyneuropathy, and enterocolitis due to Clostridium difficile infection, for which she received
i.v. vancomycin, underwent surgery due to gastrointestinal bleeding. Postoperatively, she was
transferred to the ICU, receiving mechanical ventilator support, and developed ventilator-
associated pneumonia due to Pseudomonas aeruginosa, which was treated successfully with
broad-spectrum antibiotics. In addition, a systemic CMV infection developed for which she was
treated with Foscarnet, leading to stabilization over the following weeks. At 51 days after ICU
admission, however, fresh bleeding occurred from the tracheotomy but did not respond to
standard treatment as described previously. BAL revealed localized bleeding at the segmental
level bilaterally, and rFVIIa (50 μg/kg) dissolved in 50 ml of sodium chloride was administered
with 25 ml in each main bronchus. The pulmonary bleeding ceased but reappeared within 24
hours after the treatment, and rFVIIa administration by BAL was repeated. Hereafter, the
bleeding ceased to occur. The patient expired due to infection and respiratory insufficiency 115
days after rFVIIa treatment, without any signs of thromboembolic complications.

Patient 6

A 63-year-old male with AML underwent non-myeloablative stem cell transplantation. The post-
transplant course was complicated by GvHD of the skin and temporary poor graft function with
pancytopenia. Six months post-transplant, the patient was transferred to the ICU due to
respiratory insufficiency secondary to pulmonary infection. The patient was intubated and
mechanically ventilated with an FiO2 of 0.45. Diagnostic BAL showed fresh blood at segmental
levels bilaterally, but the focus of bleeding could not be identified. The platelet count was 35 ×
109 per liter and APTT was 40 seconds, for which the patient received FFP to achieve an APTT
of less than 30 seconds and PCs to achieve a platelet count of more than 80 × 10 9 per liter but
without significant effect on the bleeding. The patient received empirical broad-spectrum
antibiotics and antimycotics, resulting in a decrease of the C-reactive protein over the next five
days. Twelve days after ICU admission, the pulmonary bleeding increased and the FiO 2 demand
was increased to 0.6. The patient had a normal TEG (thrombelastografic in vitro coagulation)
profile, a platelet count of 80 × 109 per liter, and an APTT of 27 seconds, indicating a localized
coagulopathy. Due to further increase in bleeding and FiO2 demand, a diagnostic BAL was
performed, showing fresh bleeding bilaterally at segmental levels; rFVIIa at a dose of 50 μg/kg
dissolved in 50 ml of saline was administered, resulting in immediate cessation of the pulmonary
bleeding. The FiO2 was reduced to 0.35 within the next eight hours, and the patient was
extubated the following morning. Three days after treatment with local pulmonary rFVIIa, the
patient was discharged from the ICU without further bleeding episodes.

Discussion

DAH is a clinical syndrome with acute onset of alveolar infiltrates and hypoxemia, yielding
progressively diffuse alveolar bleeding. Clinical features include dyspnea, cough, hemoptysis,
abnormal chest x-ray with bilateral alveolar infiltrates, and hypoxia usually accompanied with
fever [6,7]. The treatment of DAH is empiric in as much as the condition is a life-threatening
medical emergency with no specific or proven effective therapy. Treatment with high-dose
steroids may be beneficial when given early [7], but overall mortality remains high;
plasmapheresis has been advocated, but there is no evidence that this intervention is successful in
the treatment of ongoing low-volume critical bleeding [8].

Here, we report a series of six patients of DAH verified by bronchoscopy in mechanically

ventilated patients. There was no or insufficient hemostatic effect of standard therapy including
transfusion of FFP and PCs, i.v. infusion of aprotinin, and tranexamic acid intravenously or via
the endotracheal route (Table 1).

rFVIIa is an approved agent for the i.v. treatment of bleeding episodes in patients with
hemophilia A or B with inhibiting antibodies toward factor VIII or factor IX, respectively. Factor
VII initiates clot formation by its interaction with TF [9,10]. The FVIIa-TF complex activates
factor X. In high doses (80 to 100 μg/kg), however, activated FVII also activates factor X in the
absence of TF, probably by activation of factor X bound to the surface of activated platelets.
Activated factor X activates prothrombin to thrombin, which in turn converts fibrinogen to fibrin
[10].

High and repeated i.v. doses of rFVIIa have been reported to have some hemostatic effect in
patients with DAH [11-13]. As described in this report, however, i.v. administration of a very
high dose of rFVIIa did not induce hemostasis in our first patient with DAH. This led us to
explore the effect of local pulmonary administration of rFVIIa, and the efficacy of this treatment
was demonstrated in six consecutive patients with DAH of different etiologies. The rFVIIa was
administered at a dose of approximately 50 μg/kg via BAL in six patients and as a nebulized
aerosol on one occasion. The intervention with local intrapulmonary rFVIIa had a significant
hemostatic effect (p = 0.031). To our knowledge, this is the first time an effective treatment of
DAH using symptomatic treatment with local intrapulmonary rFVIIa has been reported.

Clinical observation supports the hypothesis that pulmonary hemostasis can be induced more
effectively from the alveolar side in DAH and than from the endothelial side. This viewpoint is
supported by the fact that alveolar TF is demonstrated in high concentrations in inflammatory
pulmonary conditions like ARDS [14], pneumonia [15], and after lipopolysaccharide challenge
locally in the alveoli [16]. The mode of action of the observed alveolar hemostasis is most likely
primarily explained by the TF-dependent pathway, where alveolar TF is expressed during the
inflammatory phase of DAH. On the other hand, TF pathway inhibitor (TFPI) is a strong
inhibitor of the local activation of factor X to Xa by the FVIIa-TF complex. In acute lung injury,
TFPI produced by alveolar macrophages may be increased 20-fold [17]. Our observations
indicate that intrapulmonary administration of FVIIa overrides the anticoagulant effect of TFPI
(Figure 1).

Figure 1. Rationale for the local mode of action of intra-alveolar human

recombinant activated factor VII (rFVIIa) in diffuse alveolar hemorrhage (DAH). Intravenous
rFVIIa does not reach the alveoli in a sufficient concentration (1) in contrast to the airway route
(2). Alveolar tissue factor (TF)-FVIIa complex activates coagulation factor IX and X. TF and TF
pathway inhibitor (TFPI) are constitutively expressed in the airspace, secondary to inflammation
induced in DAH (3). TFPI counteracts the activation effect of the FVIIa-TF complex. Alveolar
rFVIIa in high concentration counteracts the TFPI anticoagulation (4).

A safety issue of the local rFVIIa treatment, however, is the possible risk of inducing widespread
alveolar fibrin deposition (that is, hyaline membrane formation), which is a hallmark of ARDS.
There were, however, no signs of developing ARDS in the six treated patients because the
oxygenation capacity, as reflected by the PaO2/FiO2 ratio, increased significantly in the six
patients after the pulmonary rFVIIa administration (Figure 2). The benefit, the hemostatic effect,
was excellent in three patients and good in three patients (that is, a statistically significant
treatment effect was observed in all patients) (Table 2). The benefit-to-risk ratio of local rFVIIa
treatment in DAH therefore seems to be high.

Figure 2. Oxygenation capacity before and after local pulmonary human

recombinant activated factor VII (rFVIIa) therapy. A significant improvement in PaO2/FiO2
(arterial oxygen pressure/inspiratory fractional oxygen content) ratio was observed after the
hemostatic treatment (*p = 0.024, Wilcoxon signed paired rank test).

Conclusion

A new symptomatic therapy, involving intrapulmonary administration of rFVIIa, to stop the life-
threatening critical bleeding in DAH is documented in six consecutive patients with DAH. It
seems that pulmonary hemostasis occurs most likely from the alveolar side in DAH and to a
much lesser extent from the lung vascular endothelial side, a viewpoint that is supported by the
clinical observation of the patients with DAH and by the well-described pathophysiology of the
lung as a hemostatic organ, with TF-dependent and TF-independent modes of action. But
irrespective of the mode of action, FVIIa has a potentially high benefit-to-risk ratio when
administered via the local intrapulmonary route. These findings warrant further exploration of
the local pulmonary effect of rFVIIa and the safety of this novel treatment strategy in patients
with DAH
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651925/

Diffuse Alveolar Hemorrhage

Moo Suk Park, M.D., Ph.D.

Author information ► Article notes ► Copyright and License information ►

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Abstract

Diffuse alveolar hemorrhage (DAH) is a life-threatening and medical emergency that can be
caused by numerous disorders and presents with hemoptysis, anemia, and diffuse alveolar
infiltrates. Early bronchoscopy with bronchoalveolar lavage is usually required to confirm the
diagnosis and rule out infection. Most cases of DAH are caused by capillaritis associated with
systemic autoimmune diseases such as anti-neutrophil cytoplasmic antibody-associated
vasculitis, anti-glomerular basement membrane disease, and systemic lupus erythematosus, but
DAH may also result from coagulation disorders, drugs, inhaled toxins, or transplantation. The
diagnosis of DAH relies on clinical suspicion combined with laboratory, radiologic, and
pathologic findings. Early recognition is crucial, because prompt diagnosis and treatment is
necessary for survival. Corticosteroids and immunosuppressive agents remain the gold standard.
In patients with DAH, biopsy of involved sites can help to identify the cause and to direct
therapy. This article aims to provide a general review of the causes and clinical presentation of
DAH and to recommend a diagnostic approach and a management plan for the most common
causes.

Keywords: Pulmonary Alveoli, Hemorrhage, Capillaries, Vasculitis, Antibodies, Antineutrophil

Cytoplasmic, Diagnosis, Review

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Introduction

Diffuse alveolar hemorrhage (DAH) is a life-threatening condition caused by a variety of

disorders associated with hemoptysis, anemia, diffuse lung infiltration, and acute respiratory
failure. DAH originates from the pulmonary microcirculation, including the alveolar capillaries,
arterioles, and venules and is usually diffuse, but may also be focal. DAH should be
distinguished from other causes of pulmonary hemorrhage caused by localized pulmonary
abnormalities and the bronchial circulation. Early bronchoscopy with bronchoalveolar lavage
(BAL) is generally required to confirm the diagnosis of DAH and rule out infection.

Systemic vasculitis is one of the most common causes of DAH and can be pathologically defined
by the presence of cellular inflammation, vessel destruction, tissue necrosis, and eventually,
organ dysfunction. The lung is the site frequently involved in systemic vasculitis. The clinical
features of each patient's disease are determined by the site, size, and type of vessel involved.
Because the clinical presentation of the disease underlying DAH is highly variable, the
identification of a cause is very difficult. Thus, particular attention should be paid to the pattern
of findings or clinical scenarios. The diagnosis of DAH relies on the clinician's recognition
combined with clinical, laboratory, radiologic, and pathologic features.

Early recognition is crucial because prompt diagnosis and treatment are required for survival.
Despite advances in the identification and management of DAH, it remains a condition with high
morbidity and mortality. This article aims to provide a general review of the clinical presentation
and causes of DAH and to recommend a diagnostic approach and management plan for the most
common causes.

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Definition

DAH is a distinct clinicopathologic syndrome of pulmonary hemorrhage that originates from the
pulmonary microcirculation, including the alveolar capillaries, arterioles, and venules. It presents
with hemoptysis, anemia, diffuse lung infiltration, and acute respiratory failure. The diagnosis is
confirmed by the observation of the accumulation of red blood cells (RBCs), fibrin, or
hemosiderin-laden macrophage in the alveolar space on pathologic biopsy1. Hemosiderin, a
product of hemoglobin degradation, appears at least 48-72 hours after bleeding and is helpful in
distinguishing DAH from surgical trauma. Mild interstitial thickening, organizing pneumonia, or
diffuse alveolar damage can also be seen2.

DAH is associated with pulmonary capillaritis, bland pulmonary hemorrhage, diffuse alveolar
damage, and miscellaneous histology. Pulmonary capillaritis is the most common finding3.
Pulmonary capillaritis has a unique histopathologic appearance, consisting of an interstitial
neutrophilic predominant infiltration, fibrinoid necrosis of the alveolar and capillary walls,
leukocytoclasis caused by systemic vasculitis, anti-glomerular basement membrane (GBM)
disease, and classic autoimmune disease2. The infiltrating neutrophils undergo cytoclasis and
nuclear debris accumulates within the interstitium, and there is a subsequent loss of the integrity
of the alveolar capillary basement membrane. Systemic vasculitis can also involve the
microcirculation. Pulmonary capillaritis may also be a small vessel vasculitis limited to the lung.
Pulmonary vasculitis refers to inflammation of the lung vessels of any size, whereas pulmonary
capillaritis is confined to the microcirculation of the lung3.

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Etiology and Classification

A number of diseases can cause DAH. In general, DAH occurs in three characteristic patterns
which reflect the nature of the underlying vascular injury (Table 1). Any source of injury to the
alveolar microcirculation can theoretically cause alveolar hemorrhage4,5.
Table 1

Causes of diffuse alveolar hemorrhage

1. DAH associated with vasculitis or capillaritis

Most cases of DAH are caused by pulmonary capillaritis and are closely associated with
systemic vasculitis and findings such as anti-neutrophil cytoplasmic antibody (ANCA)-
associated vasculitis, anti-GBM disease, systemic lupus erythematosus (SLE), and collagen
vascular diseases (CVDs). It is also seen with several other conditions, including the use of
certain drugs and transplantation.

2. Bland pulmonary hemorrhage (without capillaritis or vasculitis)

In this pattern, RBCs leak into the alveoli without any evidence of inflammation or destruction of
the alveolar capillaries, venules, and arterioles. The epithelial lesions are usually microscopic
and are scattered geographically. Anti-GBM diseases and SLE can induce both pulmonary
capillaritis and bland pulmonary hemorrhage.

3. DAH associated with another process or condition

In this third category of DAH, alveolar hemorrhage is caused by processes other than pulmonary
vascular inflammation or the direct extravasation of RBCs, such as diffuse alveolar damage,
inhalation, or cytotoxic drug therapy.

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Clinical Presentations, Symptoms, and Signs

DAH can be defined by the presence of hemoptysis, diffuse alveolar infiltrates, a drop in
hematocrit, and hypoxemic respiratory failure. Hemoptysis may develop for a few hours or a few
days, but up to one-third of patients do not have hemoptysis. The alveolar infiltrates can be
unilateral, and a drop in hematocrit or hemoglobin can be difficult to document. DAH may be
presented in acute, subacute, or repetitive patterns with variable severity. Therefore, DAH must
be considered in patients with otherwise unexplained alveolar infiltrates. Non-specific cough,
dyspnea, chest pain, and fever may develop. Underlying systemic symptoms may also be
present. Thus, a high index of clinical suspicion is essential. Two possible clinical scenarios are
described in the following sections4.

1. DAH with associated systemic symptoms and signs

Certain clues from a patient's clinical history that should raise suspicion for DAH are: 1) recent
infection suggesting Henoch-Schönlein purpura or cryoglobulinemic vasculitis, 2) use of a
possibly offending drug such as an anticoagulant, D-penicillamine, nitrofurantoin, amiodarone,
propylthiouracil, cocaine, or sirolimus, 3) exposure to toxic agents such as trimellitic anhydride,
insecticides, or pesticides, or 4) a known co-morbid condition such as systemic vasculitis, CVD,
mitral valve disease, or solid organ or stem cell transplantation4.
Clinical scenarios suggestive of vasculitis are: 1) DAH, 2) acute glomerulonephritis (GN), 3)
pulmonary-renal syndrome, 4) deforming or ulcerating upper airway disease, 5) cavitary or
nodular disease on chest imaging, 6) palpable purpura, 7) mononeuritis multiplex, or 8)
multisystem disease6.

If sinus disease, skin manifestations, pulmonary parenchymal nodules, and cavitary lesions
coexist with positivity for anti-proteinase 3 (PR3) C-ANCA and biopsy-proven granuloma, then
Wegener's granulomatosis (WG) should be considered. DAH with GN and skin manifestations,
positivity for P-ANCA, and necrotizing non-granulomatous lesions on end-organ biopsy may
lead to a diagnosis of microscopic polyangiitis (MPA). Churg-Strauss syndrome (CSS) should be
considered if asthma, eosinophilia, pulmonary infiltrates, and DAH coexist. In young smokers
with GN and DAH presenting as either bland alveolar hemorrhage or pulmonary capillaritis,
Goodpasture's syndrome or anti-GBM disease are possible diagnoses.

2. DAH without systemic symptoms and signs

When the above conditions have been considered but no suggestive findings are found, the
following four conditions should be considered: 1) anti-GBM disease in limited pulmonary form
or onset, for which positivity to the antibody with linear deposits in the lungs would be
diagnostic, 2) pulmonary-limited MPA, which would be positive for positive anti-
myeloperoxidase (MPO) P-ANCA, 3) pauci-immune isolated pulmonary capillaritis, which
would show evidence of neutrophilic pulmonary capillaritis upon biopsy, or 4) idiopathic
pulmonary hemosiderosis, a diagnosis of exclusion, when the biopsy shows evidence of acute,
subacute, and chronic bland DAH and no evidence of vasculitis in young age4.

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Diagnostic Approach

Since DAH represents a medical emergency, a thoughtful and thorough approach to the
diagnosis of DAH is critical to appropriate management. The diagnosis of DAH relies on the
clinician's recognition combined with specific clinical, laboratory, radiologic, and pathologic
features. The two important goals of the clinical evaluation are: 1) establishing the diagnosis of
DAH and 2) identifying the underlying cause7. Although individual cases of DAH may require
modification, the recommended approach is outlined in the following sections (Figure 1).

Figure 1

Diagnostic approach in patients with diffuse alveolar hemorrhage. FOB: fiberoptic bronchoscopy; BAL:
bronchioloalveolar lavage; Bx: biopsy; Cx: culture; DAH: diffuse alveolar hemorrhage; Dx: diagnosis;
Hx: history; CHF: congestive heart failure; MV: mitral ...
1. Careful history taking and physical examinations

Careful attention should be given to the presence of symptoms such as hemoptysis, cough and
dyspnea, and any pre-existing medical conditions. A detailed drug and occupational history
should be taken. In patients who present with hemoptysis, focal sources of pulmonary
hemorrhage and upper airway and gastrointestinal bleeding sources must be excluded.
Congestive heart failure, pneumonia, and other acute presentations of diffuse parenchymal lung
disease must be also considered1.

A careful evaluation of the eyes for evidence of episcleritis or retinal vasculitis, the nasopharynx
for nasal septal erosion or saddle nose deformities, and the skin for leukocytoclastic vasculitis
should be conducted. DAH may represent the primary manifestation of an underlying systemic
vasculitis or CVD, so the absence of historical or physical evidence should not eliminate these as
possible causes1.

2. Laboratory studies

In initial diagnostic studies, culture of blood and other affected organs must be obtained to
exclude infection. Although the findings are generally nonspecific, routine laboratory tests such
as a complete blood count with differential, chemistry, liver tests, blood urea nitrogen, and
creatinine should be obtained. An elevated erythrocyte sedimentation rate and C-reactive protein
are expected in active vasculitis but lack specificity. Urinalysis with microscopic examination
should be obtained in all patients. Proteinuria and microscopic hematuria are common early
findings in WG and MPA. Anti-GBM disease should be screened in all patients with DAH or a
pulmonary-renal syndrome. In most patients with DAH, serum ANCA, anti-GBM antibodies,
antinuclear antibody (ANA), and anti-phospholipid antibodies should be obtained.

ANA and rheumatoid factor may be positive in primary vasculitis, but high titers and disease-
specific antibodies such as dsDNA, SS-A/SS-B, anti-ribonucleoprotein, and anti-JO-1 favor a
CVD. Total IgE should be obtained when CSS is being considered. Complement (C3 and C4)
should be obtained whenever SLE is in the differential6.

C-ANCA is primarily associated with antibodies directed against PR3. The P-ANCA pattern is
observed in the context of antibodies directed against a wide variety of intracellular antigens; it is
most commonly associated with MPO. C-ANCA is highly sensitive (90-95%) in active, systemic
WG, with a specificity of approximately 90%. However, a positive P-ANCA lacks sensitivity
and provides no more than suggestive evidence of CSS, MPA, or idiopathic pauci-immune GN
because it can be found in a wide variety of settings, including rheumatoid arthritis and
Goodpasture's syndrome6.

In stable patients, the diffusion capacity for carbon monoxide can be measured and, if elevated,
favors a diagnosis of DAH8. Recent alveolar hemorrhage increases the diffusion capacity for
carbon monoxide, whereas hemorrhage that occurs more than 48 hours before testing is unlikely
to cause significant elevation.
3. Radiologic findings

Plain chest X-rays and computed tomography scans often show abnormalities even in the
absence of clinically significant symptoms. Chest X-rays may show patchy or diffuse alveolar
opacities. Recurrent episodes of hemorrhage may lead to reticular interstitial opacities due to
pulmonary fibrosis, usually with minimal honeycombing. Computed tomography may show
areas of consolidation interspersed with areas of ground-glass attenuation and preserved normal
areas. These findings are generally nonspecific. Cavities, nodules, and diffuse ground glass
opacification with DAH is suspicious of vasculitis. Lymph node adenopathy is not a common
finding and is more suggestive of infection or malignancy4,6,9.

4. Bronchoscopy

Early bronchoscopy is indicated in most patients who are suspected to have DAH. Bronchoscopy
is used primarily to document alveolar hemorrhage and exclude infection. A rising RBC count in
sequential BAL aliquots from the same location is considered diagnostic of DAH. BAL
specimens should be sent for routine bacterial cultures and fungal, viral, and Pneumocystis
carinii studies when indicated. The use of transbronchial biopsy (TBB) in patients with
suspected DAH is controversial2. Due to the small size of the specimens and the mechanical
disruption of tissue architecture that generally occurs, TBB is rarely used in identifying the cause
of DAH10.

5. Diagnostic biopsy

Although a confident diagnosis may occasionally be made without tissue biopsy, diagnostic
biopsy remains key to diagnosis. Diagnostic tissue may be obtained from easily accessible sites,
such as the skin or upper airway lesions10.

If systemic vasculitis, Goodpasture's syndrome, or CVD is suspected, renal biopsy is preferred

and should be obtained immediately. In addition to conventional histopathology,
immunofluorescence (IF) and electron microscopy studies should be performed when
appropriate. A renal biopsy with direct IF is usually helpful if there are laboratory abnormalities
suggestive of renal insufficiency or GN. Light microscopy showing focal segmental necrotizing
GN is not by itself sufficient to differentiate between the GN seen in WG, MPA, Goodpasture's
syndrome, or SLE. However, direct IF will show clumpy immune complex deposition in SLE,
linear immune complex deposition along the basement membranes in Goodpasture's syndrome,
and scanty or no immune deposits in the pauci-immune GN typical of MPA or WG2.

In patients in whom the diagnosis of DAH is still in question after a thorough clinical evaluation
or in whom the underlying cause of DAH is still unclear after appropriate serologic testing,
surgical biopsy should be entertained. When the lung is clinically involved, surgical lung biopsy
almost always provides definitive pathologic evidence. Although useful in confirming DAH,
surgical lung biopsy is generally unable to identify the underlying cause11. The biopsy samples
should be processed so as to have tissues in saline for culture, frozen tissue for IF, and formalin-
fixed tissue for standard hematoxylin and eosin staining.
Go to:

Treatment and Management

Therapy for DAH consists of treating both the autoimmune destruction of the alveolar capillary
membrane and the underlying condition. Corticosteroids (CS) and immunosuppressive agents
remain the gold standard for most patients. Recombinant-activated human factor VII seems to be
a promising new therapy, but further evaluation is needed.

Immunosuppressive agents are the mainstay of therapy for DAH, especially if associated with
systemic or pulmonary vasculitis, Goodpasture's syndrome, or CVDs. Most experts recommend
intravenous methylprednisolone (Solu-Medrol) at up to 500 mg every 6 hours, although lower
doses seem to have similar efficacy, for 4 or 5 days, followed by a gradual taper to maintenance
doses of oral steroids4.

Other immunosuppressive drugs such as cyclophosphamide (CYC), azathioprine (AZA),

methotrexate (MTX), mycophenolate mofetil (MMF), and etanercept may be used in DAH,
especially in severe cases refractory to first-line therapy with CS. Plasmapheresis (PE) is
indicated for DAH associated with Goodpasture's syndrome or other vasculitic processes in
which the titers of pathogenic immunoglobulins and immune complexes are very high.

Before the institution of immunosuppressive therapy, patients with systemic vasculitis had a
mortality rate of 75%. CS therapy alone improved mortality, but the 5-year mortality remained at
50%. A major breakthrough occurred when CYC was added to CS, which lowered the 5-year
mortality to 12%12. Despite this impressive progress, the mortality of patients with systemic
vasculitis who receive treatment still remains high. Therefore, the goals of therapy in patients
with systemic vasculitis are the prevention of disease-related mortality or morbidity and the
minimization of treatment-related complications.

1. General principles

The backbone of therapy for vasculitis is the early identification of disease followed by the rapid
initiation of disease control with immunosuppression. The severity of the disease generally
dictates the intensity of the initial treatment and the risk of complication. Therapy is often
divided into two phases: An initial "remission-induction" phase controls active disease, and a
"maintenance" phase, which uses less intensive therapy, maintains disease remission while
lowering the risk of adverse medication related events.

Treatment recommendations depend on an accurate determination of disease severity. Although

severity and prognosis are dependent on a number of factors, the most important of which seems
to be the severity of disease activity as measured by the number of organ systems involved, the
degree of renal disease, and the presence of DAH. Based on these associations, the European
Vasculitis Study Group (EUVAS) has devised a clinically useful grading system (Table 2) in
which the patient's disease is categorized as 1) limited, 2) early, generalized, 3) active,
generalized, 4) severe, or 5) refractory13,14.
Table 2

The severity of vasculitis and treatment options according to European vasculitis (EUVAS) grading

2. Remission-induction therapy

1) Limited disease

Limited disease refers to localized disease of the upper airway. These patients have no systemic
symptoms, no impairment of end organ function, and no renal involvement. In this setting,
therapy can often be limited to a single agent, such as CS, AZA, or MTX.

2) Early, generalized disease

Early, generalized disease is differentiated from active generalized disease by the presence or
absence of impaired organ function. Treatment recommendations for these two subsets have
traditionally been similar, with CYC plus CS being the first-line therapy for both conditions.
MTX is also an acceptable first-line therapy for early generalized disease, and, given the
potentially more favorable side-effect profile, the combination of MTX plus CS is increasingly
being used.

3) Active, generalized disease

CYC plus CS has remained the principal first-line therapy for the treatment of active, generalized
vasculitis12. Recent evidence suggests that pulsed intravenous CYC may be as effective as oral
CYC while having fewer side effects.

4) Severe disease

Severe disease is defined by the functional impairment of critical organs, such as severe renal
disease (creatinine>5.7 mg/dL), DAH, or other life-threatening disease. Recent studies suggest
that patients with severe disease should receive a combination of CYC, CS, and PE therapy. The
addition of PE therapy to the standard CYC plus CS regimen has been shown to be superior to
high-dose, pulsed, intravenous steroids at restoring renal function in patients with severe renal
impairment and DAH15. Additional therapy, described in a case report, for patients with
intractable DAH include activated human factor VII, which was used to induce hemostasis16. As
described in a case report, extracorporeal membrane oxygenation has also been used to buy time
until the onset of action of other interventions17.
5) Refractory disease

Patients who have not responded to the aggressive use of cytotoxic agents, high-dose CS, or PE
are deemed to have refractory disease. For this group, the physician must consider the use of
novel or experimental agents. Treatments such as intravenous immunoglobulin, anti-tumor
necrosis factor-α therapy with infliximab, T-cell depletion therapy with antithymocyte globulin,
and B-cell depletion therapy with rituximab (a monoclonal anti-CD20 antibody) have been used.
In a recent series of 11 patients with active ANCA-associated vasculitis, rituximab was used to
treat patients who had received maximal doses or had other contraindications to CYC therapy.
Remission was induced in all 11 patients, and ANCA titers became undetectable in eight
patients18.

3. Maintenance therapy

Maintenance therapy used to maintain control of the disease requires less immunosuppression
and should be associated with fewer and less severe adverse effects. After the induction of
clinical remission with an agent such as CYC, patients generally convert to AZA or MTX19,20.
Additional agents that have been used in select patients include MMF, leflunomide, and
cyclosporine. However, etanercept was not effective for the maintenance of disease remission in
WG patients21. In the absence of a disease flare, maintenance therapy is generally continued for
12 to 18 months. A longer duration of therapy should be considered for patients at high risk for
relapse.

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Specific Disorders and Causes of DAH

Table 3 summarizes the common causes and diagnostic features of DAH.

Table 3

Summary of clinical and laboratory findings for the common causes of diffuse alveolar hemorrhage

1. Wegener's granulomatosis

WG is a systemic vasculitis that primarily affects middle-aged adults and is characterized by

necrotizing granulomatous inflammation. In 1936, Wegener published a report on a new disease
that would be differentiated from periarteritis nodosa. In 1954, Godman and Churg described a
detailed diagnostic triad classic for Wegener's consisting of necrotizing granulomatous
inflammation of the upper and lower respiratory tract, generalized necrotizing vasculitis
involving the small arteries and veins, and necrotizing GN22,23.

Of the ANCA-associated vasculitis, WG is the most common. The upper and lower respiratory
tracts are typically affected, with destruction of the nasal septum and sinuses and cavitating
lesions in the lungs. Involvement of the kidney is common, with histopathologic lesions of focal
segmental necrotizing GN. The eyes, skin, and other organs may also be involved. Frequently,
the complete triad is not present at initial presentation. The diagnosis of WG is commonly made
serologically, with a positive C-ANCA. A positive C-ANCA or anti-PR3 is found in 85% to 95%
of active systemic disease but is less frequently seen (60-65% sensitive) in organ-limited disease
and is even less common (40% sensitive) in remissions. Its specificity is approximately 90%6.

In cases in which the diagnosis remains uncertain, surgical biopsy of the affected organs
(primarily the lungs) may show typical necrotizing granulomatous lesions. DAH either can
complicate an established case of WG or represent the initial manifestation of the disease. DAH
is often subclinical and recurrent in WG. This pattern of frequently recurring DAH is seen with
ANCA-associated vasculitis and CVD1.

Treatment with high-dose CS and CYC is the initial therapy recommended for DAH that
complicates WG. AZA may be substituted for CYC after remission. Intravenous
immunoglobulin may be effective for persistent disease. Mortality is considerable and most often
caused by acute respiratory failure, renal failure, or superimposed infection as a result of
immunosuppressive therapy. Poor outcomes are correlated with advanced age, more severe renal
impairment, alveolar hemorrhage, and anti-PR3 positivity.

2. Allergic Angitis with Granuloma (CSS)

In 1951, Churg and Strauss reported a new entity separate from periarteritis nodosa presenting
with fever, severe asthma, and hypereosinophilia, with evidence of systemic vasculitis. The
syndrome is characterized by the triad of 1) asthma, 2) hypereosinophilia, and 3) necrotizing
vasculitis. A three-phase presentation is also seen, with an initial atopy/sinusitis/asthma phase,
followed by an eosinophilic phase, and finally the vasculitic phase. Although DAH and GN may
occur, they are much less common than in the other small-vessel vasculitides. ANCA positivity
is seen less frequently than in WG, with a positive P-ANCA (or anti-MPO) seen in 35% to 75%
of patients with active disease. A positive C-ANCA has been described in up to 10% of patients.
Necrotizing, small-vessel vasculitis and an eosinophil-rich cellular infiltrate with necrotizing
granulomas are seen histopathologically22,23.

The use of CS to treat asthma may delay the manifestations of tissue eosinophilia and vasculitis
until they are tapered. CSS generally responds well to CS. The role of cytotoxic agents such as
CYC is not as clearly defined as in WG24,25.

3. Microscopic polyangiitis

MPA is considered to be a small vessel variant of polyarteritis nodosa. Distinguishing MPA from
WG can be difficult because the clinical presentation, histopathologic findings, and serologic
findings can be similar. Occasionally, a diagnosis of MPA is ruled out after the development of
the typical clinical and serologic features of WG. The most consistent pathologic feature in MPA
is a focal segmental necrotizing GN, also seen in WG, other vasculitides, Goodpasture's
syndrome, and CVD1.
GN with lung involvement is seen in up to 30% of patients with MPA. In patients who develop
lung disease, DAH with pathologic capillaritis is the most common manifestation. Joint, skin,
peripheral nervous system, and gastrointestinal involvement are also relatively common. A
positive serum P-ANCA (or MPO) strongly supports the diagnosis and can help distinguish
MPA from WG. A positive P-ANCA is seen in 50% to 75% of patients and anti-MPO is seen in
35% to 65% of patients, whereas a positive C-ANCA is seen in 10% to 15% of patients. Focal,
segmental necrotizing vasculitis and a mixed inflammatory infiltrate without granuloma are seen
histopathologically6.

Treatment with high-dose CS and CYC or AZA is recommended. PE is of unclear benefit. As in

WG, intravenous immunoglobulin may be useful for resistant cases. Factor VIIa has also been
used successfully26.

4. Isolated pulmonary capillaritis

Occasional cases of DAH show no evidence of concomitant systemic involvement but show
capillaritis upon histopathologic examination. Isolated pulmonary capillaritis appears to be small
vessel vasculitis confined to the lungs. Some cases are associated with serum P-ANCA
positivity, but most are pauci-immune. While isolated pulmonary capillaritis after treatment with
all-trans retinoic acid has been observed, most cases are sporadic. Although mechanical
ventilation due to respiratory failure is common, a positive response to CS and CYC has been
reported. Most patients improve while on therapy, and recurrent disease is infrequent1,27.

5. Goodpasture's syndrome (anti-GBM disease)

The diagnosis of Goodpasture's syndrome, or anti-GBM disease, is reserved for cases of DAH
and GN in which anti-GBM Ab (autoantibodies directed against the NC1 domain of the α3 chain
of the type IV collagen in the basement membrane) appears in the serum or tissue. The typical
patient is a young male smoker, although elderly persons, women, and nonsmokers are also
affected. DAH may be facilitated by alveolar permeability, which is increased in most
smokers28.

More than 90% of patients with Goodpasture's syndrome have serum anti-GBM Ab. In persons
without circulating antibody, the diagnosis may be confirmed by lung or preferably kidney
biopsy demonstrating linear deposition of antibody along the alveolar or GBM that is visible by
direct IF. However, in up to 10% of patients with Goodpasture's syndrome, DAH is present
without renal involvement and is identical to isolated pulmonary capillaritis, and lung biopsy
with IF studies can aid in the differentiation of the two diseases. Bland hemorrhage is the most
common underlying histology, but pulmonary capillaritis is sometimes seen. In such cases,
kidney biopsy still shows the typical linear antibody deposition. About 30% of anti-GBM
positive sera have P-ANCA (MPO) and C-ANCA (PR3) also occurs29.

Treatment of Goodpasture's syndrome requires a combination of CS, CYC or AZA, and PE. In
the few cases with isolated DAH, treatment with CS alone may be effective. Cases of refractory,
life-threatening Goodpasture's syndrome have been reported to respond to MMF and rituximab.
The 2-year survival rate in Goodpasture's syndrome is approximately 50%1.
6. SLE and CVDs

By far the most common underlying CVD in DAH is SLE. DAH, usually caused by pulmonary
capillaritis, affects 4% of patients with SLE but is life threatening when it occurs. In the majority
of cases of DAH associated with SLE, GN is also present, and 80% of these cases occur in young
female patients with known SLE. In immunosuppressed patients with SLE, infectious pneumonia
should be excluded as the cause of DAH. DAH is distinguished from acute lupus pneumonitis by
sequential BAL. Acute lupus pneumonitis presents with similar clinical and radiographic features
as DAH. However, it also has the systemic symptoms typical of an SLE flare and may be the
only manifestation of the initial presentation of SLE. Direct IF examination of SLE-associated
DAH reveals granular deposits of immunoglobulin and complement in the alveolar interstitium
and intra-alveolar blood vessels1,3.

High-dose pulse methylprednisolone (1 g given in divided doses for 3 days) can be given to
those with DAH or acute lupus pneumonitis. Anecdotally, the combination of high-dose
intravenous methylprednisolone and CYC is known to be the most effective combination. In
refractory cases, PE has been used. The overall mortality rate for SLE-associated DAH is
approximately 50% and recurrences after treatment are frequent3.

DAH has been described in rheumatoid arthritis, scleroderma, polymyositis, dermatomyositis,

anti-phospholipid antibody syndrome, and mixed connective tissue disease. Treatment options
are similar to those outlined for DAH in SLE1.

7. Bone marrow transplantation (BMT)

DAH occurs in approximately 5-20% of BMT recipients and the reported mortality rate ranges
from 50% to 100%. Risk factors for the development of DAH in BMT recipients include older
age, total body radiation, myeloablative conditioning regimens, and severe acute graft-vs-host
disease. Dyspnea, fever, and cough are the most common complaints. Hemoptysis is less
frequently observed in BMT recipients compared with other causes of DAH with a rate of
approximately 15%. The pathogenesis 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. The majority of patients with DAH require
mechanical ventilation and CS is the mainstay of treatment, but its effectiveness is still
uncertain3.

Go to:

Conclusion

DAH is a clinicopathologic syndrome caused by many disorders and should be considered a life-
threatening event. Common causes of DAH are systemic vasculitis such as WG, CSS, and MPA,
Goodpasture's syndrome, CVD, BMT, drugs, and idiopathic conditions. DAH should be
suspected in any patient with alveolar infiltrates on chest X-ray, hypoxemia, anemia, and
hemoptysis. Careful attention to the medical history, physical examination, and a targeted
laboratory evaluation often reveals the underlying cause. Patients suspected to have DAH should
generally undergo bronchoscopy and BAL. In patients with evidence of DAH and renal
involvement, kidney biopsy should be considered to identify the underlying cause and to direct
therapy. A systematic approach to early recognition, establishment of diagnosis, and aggressive
treatment will likely decrease the morbidity and mortality associated with DAH
 http://www.merckmanuals.com/professional/pulmonary_disorders/diffuse_alveolar_hemorrh
age_and_pulmonary-renal_syndrome/diffuse_alveolar_hemorrhage.html

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage. There are
numerous causes, but autoimmune disorders are most common. Most patients present with
dyspnea, cough, hemoptysis, and new alveolar infiltrates on chest imaging. Diagnostic tests are
directed at the suspected cause. Treatment is with immunosuppressants for patients with
autoimmune causes and respiratory support if needed.

Diffuse alveolar hemorrhage is not a specific disorder, but a syndrome that suggests a differential
diagnosis and a specific sequence of testing.

Pathophysiology

Diffuse alveolar hemorrhage results from widespread damage to the pulmonary small vessels,
leading to blood collecting within the alveoli. If enough alveoli are affected, gas exchange is
disrupted. The specific pathophysiology and manifestations vary depending on cause. For
example, isolated pauci-immune pulmonary capillaritis is a small-vessel vasculitis limited to the
lungs; its only manifestation is alveolar hemorrhage affecting people aged 18 to 35 yr. Idiopathic
pulmonary hemosiderosis is diffuse alveolar hemorrhage with no detectable underlying disorder;
it occurs mainly in children < 10 yr and is thought to be due to a defect in the alveolar capillary
endothelium, possibly due to autoimmune injury.

Etiology

Many disorders can cause alveolar hemorrhage; they include

 Autoimmune disorders (eg, systemic vasculitides, Goodpasture syndrome, antiphospholipid

antibody syndrome, connective tissue disorders)
 Pulmonary infections (eg, invasive aspergillosis, hantavirus infection)
 Toxic exposures (eg, trimellitic anhydride, isocyanates, crack cocaine, certain pesticides)
 Drug reactions (eg, propylthiouracil , diphenylhydantoin, amiodarone , methotrexate,
nitrofurantoin , bleomycin , montelukast , infliximab )
 Cardiac disorders (eg, mitral stenosis)
 Coagulation disorders caused by diseases or anticoagulant drugs
 Isolated pauci-immune pulmonary capillaritis
 Idiopathic pulmonary hemosiderosis
 Bone marrow or solid organ transplantation

Symptoms and Signs

Symptoms and signs of milder diffuse alveolar hemorrhage are dyspnea, cough, and fever;
however, many patients present with acute respiratory failure, sometimes leading to death.
Hemoptysis is common but may be absent in up to one third of patients. Most patients have
anemia and ongoing bleeding with a decreasing Hct. Children with idiopathic pulmonary
hemosiderosis may have failure to thrive and iron deficiency anemia.

There are no specific physical examination findings.

Other manifestations depend on the underlying disorder (eg, diastolic murmur in patients with
mitral stenosis).

Diagnosis

 Chest x-ray
 Bronchoalveolar lavage
 Serologic and other tests to diagnose the cause

Diagnosis is suggested by dyspnea, cough, and hemoptysis accompanied by chest x-ray findings
of diffuse bilateral alveolar infiltrates if one suspects diffuse alveolar hemorrhage; bronchoscopy
with bronchoalveolar lavage (BAL) is strongly recommended to confirm the diagnosis,
particularly when manifestations are atypical or an airway source of hemorrhage has not been
excluded. Specimens show blood with numerous erythrocytes and siderophages; lavage fluid
typically remains hemorrhagic or becomes increasingly hemorrhagic after sequential sampling.

Evaluation of the cause:

Further testing for the cause should be done. Urinalysis is indicated to exclude
glomerulonephritis; serum BUN and creatinine also should be done. Other routine tests include
CBC, coagulation studies, platelet counts, and serologic tests (antinuclear antibody, anti–double-
stranded DNA [anti-dsDNA], antiglomerular basement membrane [anti-GBM] antibodies,
antineutrophil cytoplasmic antibodies [ANCA], antiphospholipid antibody) to look for
underlying disorders; perinuclear-ANCA (p-ANCA) titers are elevated in some cases of isolated
pauci-immune pulmonary capillaritis. Diagnosis of idiopathic pulmonary hemosiderosis involves
demonstration of iron deficiency anemia and hemosiderin-laden macrophages in BAL fluid or
lung biopsy specimens when there is no evidence of small-vessel vasculitis (pulmonary
capillaritis) or another diagnosis; it is confirmed by lung biopsy.

Alveolar
Hemorrhage
Other tests depend on clinical context. When patients are stable, pulmonary function tests may be
done to document lung function. They may show increased diffusing capacity for carbon
monoxide (DLco) due to increased uptake of carbon monoxide by intra-alveolar Hb; however,
this finding, which is consistent with hemorrhage, does not assist with establishing a diagnosis.
Echocardiography may be indicated to exclude mitral stenosis. Lung or kidney biopsy is
frequently needed when a cause remains unclear or the progression of disease is too rapid to
await the results of serologic testing.

Prognosis

Patients can require mechanical ventilation and even die as a result of hemorrhage-associated
respiratory failure. Recurrent alveolar hemorrhage causes pulmonary hemosiderosis and fibrosis,
both of which develop when ferritin aggregates within alveoli and exerts toxic effects. COPD
occurs in some patients with recurrent diffuse alveolar hemorrhage secondary to microscopic
polyarteritis.

Treatment

 Corticosteroids
 Sometimes cyclophosphamide or plasma exchange
 Supportive measures

Treatment involves correcting the cause. Corticosteroids and possibly cyclophosphamide

are used to treat vasculitides, connective tissue disorders, and Goodpasture syndrome. Plasma
exchange may be used to treat Goodpasture syndrome. Corticosteroids are also used to treat
idiopathic pulmonary hemosiderosis; immunosuppressants are added for nonresponders. Several
studies have reported successful use of recombinant activated human factor VII in treating severe
unresponsive alveolar hemorrhage, but such therapy is controversial because of possible
thrombotic complications.

Other possible management measures include supplemental O2, bronchodilators, reversal of any
coagulopathy, intubation with bronchial tamponade, protective strategies for the less involved
lung, and mechanical ventilation.
 http://Radiopaedia.org/articles/diffuse-alveolar-haemorrhage

Diffuse alveolar haemorrhage

Dr Ayush Goel and Dr Yuranga Weerakkody et al.

Diffuse alveolar haemorrhage (DAH) is a subset of diffuse pulmonary haemorrhage when

bleeding is diffuse and directly into the alveolar spaces. It can occur in a vast number of clinical
situations and at time can be life threatening.

Pathology

Blood tends to fill alveolar spaces as multiple sites.

Causes

It can occur with a number of causes which include:

 pulmonary vasculitides (particularly small vessel vasculitides): a pulmonary capillaritis is

considered the most common underlying lesion associated with diffuse alveolar haemorrhage
o ANCA associated pulmonary vasculitides
 Granulomatosis with polyangiitis (formerly Wegeners granulomatosis)
 microscopic polyangiitis
 idiopathic pauci immune pulmonary capillaritis
 Churg-Strauss vasculitis
o non ANCA associated pulmonary vasculitides: Goodpasture syndrome
 certain connective tissue disorders
o systemic lupus erythematosus 2-3: considered commonest associated connective tissue
disorder to result in diffuse alveolar haemorrhage
o mixed connective tissue disease 8
 coagulative disorders
 medications: excessive antiplatelet therapy 9
 inhaled toxins
 conditions causing back pressure
o mitral valve disease
 mitral stenosis
 mitral regurgitation
o pulmonary veno-occlusive disease
 haemorrhage complicating multifocal infection
 haemorrhage complicating diffuse alveolar damage
 haemorrhage complicating widespread pulmonary malignancy
 post bone marrow transplantation 1
 pulmonary haemosiderosis
 antiphospholipid syndrome 6
Radiographic features

Plain film: chest radiograph

The clinical context is crucial in image interpretation. The exact pattern may differ dependant on
the underlying cause. In general, the typical feature on plain film during an acute diffuse alveolar
haemorrhage is a diffuse infiltrative opacification pattern 5. At times there may a slight
predilection towards the mid zones 5 with some apical sparing 8.

CT: HRCT Chest

The HRCT pattern can vary with time of onset of the haemorrhage and the clinical context is
crucial in image interpretation.

 acute phase
o can range from lobular or lobar areas of ground-glass opacities to predominant
consolidation
o ground-glass opacity is generated by subtotal alveolar filling with blood and is
accompanied by apparent prominence of segmental and subsegmental bronchi, which has
been referred to as the “dark bronchus sign"
 2–3 days
o intralobular lines and smooth interlobular septal thickening superimpose on areas of
ground-glass opacity
o may sometimes give rise to a crazy-paving pattern 10
o these can often resolve
 between chronic recurrent bleeding events
o ill-defined centrilobular nodules
 reflecting intra-alveolar accumulation of pulmonary macrophages
 usually uniform in size (1-3 mm)
 diffusely distributed
 no zonal predominance
 with severe repeated haemorrhage: may progress with features of interstitial fibrosis

Complications

Repeated episodes can lead to an organising pneumonia, collagen deposition in small airways
and ultimately pulmonary fibrosis 7-8.