Transcript Diffuse Alveolar Hemorrhage (DAH)

Diffuse Alveolar Hemorrhage
(DAH)
Internal Medicine Lecture
Howard M. Mintz, M.D.
October 14, 2004
Definition DAH
• Clinicopathological process defined by
alveolar hemorrhage documented by serial
bronchoalveolar lavage demonstrating red
blood cells and fibrin within alveolar spaces
• Bleeding typically occurs from the
pulmonary capillaries and less frequently
from precapillary arterioles and
postcapillary venules
Hallmarks of DAH
•
•
•
•
Hemoptysis (may be absent in 1/3 of cases)
Diffuse pulmonary infiltrates
Anemia
Hypoxemic respiratory failure
Etiologies of DAH
Many causes and clinical syndromes
Pathology of DAH
•
•
•
•
3 Broad histologic patterns identified
Pulmonary capillaritis
Bland pulmonary hemorrhage
Diffuse alveolar damage
Pulmonary Capillaritis I
• Most common of the histologic patterns
• First described by Spencer in 1957
• Neutrophilic interstitial infiltrate with
fragmentation of neutrophils
(leukocytoclasis) and pyknotic neutrophils
with release of cytokines
• Nuclear dust in interstitium and alveolar
spaces
Pulmonary Capillaritis II
• Disruption of the interstitium and capillaries
with leakage of blood and fibrin into
alveolar spaces
• Edema of basement membrane with
subsequent necrosis of interstitium and
eventual fibrosis
• Neutrophils are seen lining the interstitium
Diffuse Alveolar Damage
• Hyaline membrane formation, alveolar and
interstitial edema, microthrombi, and
capillary congestion are present
• See slide
Bland Alveolar Hemorrhage
• RBC’s in the alveolar spaces, but alveolar
walls appear normal except for type II
epithelial cell hyperplasia
• See slide
Clinical Presentation of DAH I
• Patients often have an underlying known
condition
• Hemoptysis can be acute or subacute, but
typically presents within one week of onset
• Majority of patients are less than forty years
old
• 1/3 do not have hemoptysis, but present
with dyspnea and cough
Clinical Presentation DAH II
• In patients without hemoptysis, diagnosis is
confirmed by the presence of blood on
serial BAL
• Anemia
• Pulmonary infiltrates
• Chest pain, nonspecific
• Symptoms of underlying disease processes
History in DAH
• Careful drug history
• Smoking history
• History of underlying illnesses such as
valvular heart disease, cytotoxic agents,
drugs
• Social history, in particular cocaine usage
• History of any renal, skin, or eye diseases
Physical Findings in DAH
• Nonspecific
• Fevers, rales, signs of consolidation
• Synovitis, iridocyclitis, myositis, palpable
purpura
Radiographic Findings in DAH
• Nonspecific, focal or generalized infiltrates
• Rapidly progressive bilateral infiltrates
• Interstitial fibrosis in presence of recurrent
disease
• Kerley’s B line suggestive of valvular
etiology, also in conditions associated with
myocarditis, venoocclusive disease
Laboratory Findings in DAH I
• Low or falling hematocrit or hemoglobin
• In the setting of chronic or recurrent
episodes, low serum iron
• Nonspecific elevations of white count
• Thrombocytopenia
• Elevation of ESR
• Proteinuria, microscopic hematuria, casts
suggest glomerulonephrits
Laboratory Findings in DAH II
• Hypoxemia
• Elevation of DLCO
• Restrictive pattern associated with fibrosis
or obstructive patterns with marked
emphysematous changes
• ANCA
• ABMA, IgG
ANCA in DAH Diagnosis
• Antineutrophilic cytoplasmic antibodies
(ANCA)first described in 1982 in
association with pauci-immune
glomerulonephritis
• ANCA described in association with
Wegener’s granulomatosis in 1985
• Subsequently described in microscopic
polyangitis (MPA) and limited renal
vasculitis
ANCA Testing
• Indirect immunofluorescence assay (IIA) is more sensitive
• Enzyme link immunosorbent assay (ELISA) is more
specific
• Best used in conjunction with IIA for screening and ELISA
for confirmation
• Two relative antigens in vasculitic diseases, proteinase 3
(PR3) and myeloperoxidase (MPO)
• Antigens are found in neutrophils and monocytes
• PR3-ANCA and MPO-ANCA
Immunofluorescence Patterns In
Vasculitis
• Sera from patients with suspected ANCA related vasculitis
are incubated in ethanol fixed neutrophils
• Two distinct patterns of fixation identified, c-ANCA with
cytoplasmic pattern and p-ANCA with perinuclear pattern
• c-ANCA pattern is typically associated with antibodies
against PR3
• p-ANCA is typically associated with antibodies against
MPO
• See photographics
Immunofluorescence Utility and Errors
• Tests are visually graded and inspected
• Tests are not specific and false positives and
negatives can occur
• IIA testing should be confirmed with ELISA
testing for PR3 and MPO
Specific Examples of DAH
• Capillaritis-Microscopic Polyangiitis
• Diffuse Alveolar Damage-Crack
Cocaine
• Bland Hemorrhage-Amiodarone
Microscopic Polyangiitis (MPA) I
• Rare disease with prevalence estimated 3 cases per million
• Etiology is unknown
• Small vessel involvement including arterioles, venules, and
or capillaries
• Immune complexes are not demonstrated
• Typical presentation is that of renal failure with
glomerulonephritis and hemoptysis with capillaritis
• Histopathologically segmental distribution, neutrophilic
infiltration, and fibrinoid necrosis (See slide)
MPA II
• ANCA is positive in about 75% of patients
• p-ANCA is present with MPO by ELISA in 85% of
patients
• c-ANCA is rare with PR3 by ELISA
• Systemic disease
• Skin manifestations including splinter hemorrhages and
purpura
• Musculoskeletal with arthralgias, myalgias, arthritis
• Gastrointestinal with abdominal pain and GI hemorrhage
• Neurological with peripheral neuropathy
MPA II
• ANCA is positive in about 75% of patients
• p-ANCA is present with MPO by ELISA in 85% of
patients
• c-ANCA is rare with PR3 by ELISA
• Systemic disease
• Skin manifestations including splinter hemorrhages and
purpura
• Musculoskeletal with arthralgias, myalgias, arthritis
• Gastrointestinal with abdominal pain and GI hemorrhage
• Neurological with peripheral neuropathy
MPA III
• Prominent gastrointestinal signs and symptoms and lack of
upper airway disease helps distinguish from Wegener’s
• Classical polyarteritis nodosa rarely involves the lung
• 45% of patients have circulating immune complexes but
tissue localization is rare, pauci-immune disease
• 33% of patients have antibodies to hepatitis C or B
• Treatment same as for Wegener’s
• Survival about 65% with recurrence associated with
tapering of therapy
• Case report in which MPA eventually developed features
of WG
The histologic section from a right middle lobe open lung biopsy showed
extensive hemorrhaging in the alveolar spaces
Maimon, N. et al. Chest 2003;124:2384-2387
Pulmonary Interstitial Fibrosis & MPA
• Report of six cases of PIF in which patients
were ANCA positive and eventually
diagnosed with MPA
• The diagnosis of PIF may precede that of
MPA by many years
• See CT
Diffuse alveolar consolidation with air bronchogram involving the entire right
lung field
Maimon, N. et al. Chest 2003;124:2384-2387
Cocaine History & Mechanisms of
Action
•
•
•
•
First isolated from coca leaves in 1859
Part of the original formulation of Coke, removed in 1906
First reported deaths occurred in 1893
Potent sympathomimetic and CNS stimulant based on its
ability to block reuptake of catecholamines & serotonin
• Cocaine HCL boiled with baking soda and extracted with
ether or alcohol, yields heat stable “Crack” or “Rock”
• Smoked and reaches the CNS within seconds with half life
of 60-90 minutes
• Frequently mixed with marijuana or tobacco
Crack Cocaine with Diffuse
Alveolar Damage
• Cocaine is abused in two forms, cocaine HCl and cocaine
alkaloidal
• The alkaloidal form or “crack” cocaine is lipid soluble and
resistant to thermal breakdown
• Rapidly absorbed from the lung via pulmonary capillary
network
• Euphoria is similar to that of intravenous usage
• Smoking of “crack” is also associated with absorption of
impurities, ignition products and thermal breakdown
products of cocaine
BAL in Crack Lung Users
• Up to 40% of of “crack” cocaine users have hemosiderin
stained alveolar macrophages. <1% of nonsmokers at
autopsy have this finding. ~9% of smokers have this
finding.
• Endothelin (ET)-1, an endothelium-derived vasoconstrictor
peptide, indicator of cell damage is also found in a higher
proportion of “crack” cocaine users. ET-1 is found in a
high proportion of BAL samples from “crack” users and is
felt to be a marker of alveolar capillary damage
• BAL in “crack” cocaine users have an absolute increase in
hemosiderin stained alveolar macrophages
Iron content of alveolar macrophages (AM)
Janjua, T. M. et al. Chest 2001;119:422-427
Ferritin content of alveolar macrophages recovered
Janjua, T. M. et al. Chest 2001;119:422-427
Prominent hemosiderin-laden AMs in the BAL fluid of a CS (left, A), which are
absent in the BAL fluid of a TS (middle, B) or a NS (right, C)
Baldwin, G. C. et al. Chest 2002;121:1231-1238
Increased percentage of hemosiderin-positive AMs in the BAL specimen of
cocaine smokers
Baldwin, G. C. et al. Chest 2002;121:1231-1238
Acute Lung Injury with Crack
• Typically develops within 1-48 hours
• 25% of users with develop respiratory symptoms including
fever, cough, nonspecific chest pain, hemoptysis, back
pain, hyperpnea, dyspnea, melanoptysis, wheezing
• Diffuse pulmonary infiltrates, eosinophilic pleural
effusions, acute lung injury pattern
• Eosinophilia
Crack Pulmonary Injuries I
• Barotrauma, ischemia, provocation of
inflammatory damage, and direct cellular toxicity
• Barotrauma is the result of Valsalva maneuver
after inhalation and the forceful inhalation of air
into partners. Pneumothoraces,
pneumomediastinum, and pneumopericardium
• Ischemia is the result of the vasoconstrictive
properties
• Severe bronchospasm in patients with preexisting
asthma
Crack Cocaine Pulmonary Injuries II
• Case of bilateral infiltrates and bilateral hilar adenopathy
mimicking sarcoid, probably induced by contaminants in
crack
• The morphologic features of squamous metaplasia and
mucus gland hypertrophy similar to that of cigarette
smokers, possibly increased risk of lung cancer
Microenvironment and Cocaine
• Cocaine inhibits alveolar macrophages ability to
kill most bacteria and tumor cells in vitro
• Cocaine users are unable to kill bacteria using
nitric oxide as an antibacterial effector molecule
• These changes may predispose to increase
pulmonary infections in these users.
• Marijuana has similar adverse effects. Inhibits
phagocytosis Staph aureus
• Both drugs frequent smoked together
Distribution of Vc and DMCO in the cross-sectional cohort is shown
Kleerup, E. C. et al. Chest 2002;122:629-638
Chronic Exposure to Crack
•
•
•
•
•
•
•
•
•
Pulmonary fibrosis
Diffuse alveolar hemorrhage
Hemosiderosis
Pulmonary infarction
Eosinophilic interstitial lung disease
Bullous emphysema
Medial artery hypertrophy
Noncardiogenic pulmonary edema
Increased risk of pneumonia, multifactorial problem
Treatment of Crack Lung
• Need to make history of exposure
• Supportive
• Role of steroids unproven, helpful in those
patients with bronchospasm
• Screen for HIV and concomitant drugs
• Drug treatment
Amiodarone Lung Disease
•
•
•
•
•
Drugs characteristics
Expanding scope of the problem
Clinical presentations
Radiographic presentations
Diagnosis and therapeutic options
Trends in receipt of clinically serious, domestic spontaneous adverse event
reports (1,941) in association with amiodarone (all forms) with further
indication of the subset of reports coded for parenchymal lung injury (n =
280)
Brinker, A. et al. Chest 2004;125:1591-a-1592-a
Incidence of atrial fibrillation in the therapy group vs the control group
Kerstein, J. et al. Chest 2004;126:716-724
Comparison of length of stay (los) in the amiodarone group and the control
group
Kerstein, J. et al. Chest 2004;126:716-724
PHD Amiodarone Usage 1997-2003
Bolus Vials
Amiodarone Annual Usage
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
1
2
3
4
Year
5
6
7
Characteristics of Amiodarone I
• Principal metabolite is desethyl-aminodarone or
DEAm
• DEAm and amiodarone are toxic to lung tissue
• Propensity for accumulation in lung tissue with a
ratio of plasma to lung of 1:500
• DEAm and amiodarone also have a propensity to
accumulate in the liver and skin
• Amiodarone and DEAm are localized in
lysosomes and block the removal of phospholipids
Characteristics of Amiodarone II
• Amiodarone drug levels do not predict the development of
pulmonary toxicity
• DEAm levels are higher in patients who develop
amiodarone pneumonitis that controls
• The foamy macrophage on BAL is characteristic of
amiodarone exposure and its absence bespeaks against this
diagnosis
• Clearance of amiodarone is very slow with biopsies
demonstrating the drug after one year of cessation of
therapy
Characteristics of Amiodarone III
• Clinically the development of amiodarone infiltrates is
associated with a prolonged radiographic resolution
because of the prolonged deposition of this agent
• Each molecule of amiodarone and DEAm contain two
iodines
• The presence of the iodines explains the frequent
development of thyroid dysfunction in patients receiving
amiodarone
• The iodine also explains the increase in CT density in liver
and lung in patients diagnosed with pulmonary toxicity
Amiodarone Pulmonary Toxicity
• First clinical description in 1980, although drug was
introduced in 1969 in Europe
• Rat models have demonstrated the toxicity since 1987
• The histological features of amiodarone toxicity are
relatively distinctive in nature, foamy macrophages
• There is a relative dose relationship between total
cumulative dose and incidence of toxicity
• Reintroduction of agent to patient with previous toxicity
results in recurrence of syndrome
Relationship Between Dose and Incidence of
Toxicity to Amiodarone
• Estimated that 50% of patients receiving 1200 mg per day
will develop toxicity
• Estimated incidence 5% to 15% if dose is greater than or
equal to 500 mg per day
• Estimated incidence 0.1% to 0.5% in dose is less than 200
mg per day
• Overall incidence is probably in the range of 4% to 6%
Onset of Toxicity to Amiodarone
•
•
•
•
•
Majority of cases will occur within one year of exposure
May occur following loading intravenous dose
Cases described after 10 years of therapy
Can develop following cessation of therapy
Toxicity increases in certain patient populations including
advanced age, cardiac surgery, pulmonary surgery, ARDS,
insertion of ICD
• Common denominator is exposure to high FIO2 during
surgery, similar to situation in bleomycin pulmonary
toxicity and radiation
Radiographic Presentations in Amiodarone
Pulmonary Toxicity
•
•
•
•
•
•
Subacute pneumonitis
Single of multiple subpleural masses
Pulmonary fibrosis
Organizing pneumonia
ARDS
Alveolar hemorrhage
Subacute Amiodarone Pneumonitis
• Patchy or diffuse infiltrates
• Suggestion of RUL predominance on plain
radiographic examination, usually not confirmed
by HRCT, bilateral process
• Alveolar interstitial pattern on HRCT
• Increased attenuation on HRCT
• Pleural effusion rare
Subpleural Masses in Amiodarone Lung
Disease
•
•
•
•
Single or multiple
Typically abut the pleura
Chest pain and pleural rub
DDX includes pulmonary infarction,
malignancy, pneumonia, lymphoma
Pulmonary Fibrosis with Amiodarone
• Very uncommon, <0.1% of cases
• Setting of prior acute pneumonitis from amiodarone or
resolving phase of illness or as initial presentation
• Differs from idiopathic pulmonary fibrosis by the rapidity
of disease progression and history of amiodarone usage
• Reticular infiltrates at the bases with typical signs &
symptoms of ILD
• Irreversible
• Not felt to be steroids responsive
Organizing Pneumonia from Amiodarone
• Indistinguishable from other forms of
organizing pneumonia
• Migratory infiltrates may occur
• See radiographs
ARDS from Amiodarone
• Settings cardiac surgery, pulmonary resection, and
following defibrillator implantation (J. Intern
Medicine Med 2001, Liverani up to 10%
incidence) lung biopsy for diagnosis
• 50% fatality
• Rapidly progressive pulmonary infiltrates with
hypoxemic respiratory failure
• Poorly responsive to therapy
Subclinical Disease from Amiodarone
•
•
•
•
•
•
•
Setting of chronic therapy
Plain radiographs typically normal
HRCT ground glass infiltrates
Typically responds to cessation of drug
Unclear if it is progressive
Biopsy foamy cells and inflammatory cells evident
Gallium scans positive, but T99 more sensitive
Diagnosis and Management I
• Clinical lab: increase in LDH sensitive, but not
specific, increased ESR, and some leukocytosis
• PFT’s most sensitive with reduction in DLCO as
first abnormality.
• A fall in DLCO does not necessarily indicate
pulmonary toxicity, only 1/3 of patients develop
overt disease
• A fall of 15% is cutoff for sensitivity and 30% for
specificity according to Mayo study
Diagnosis and Management II
• Stable DLCO is indicative of absence of toxicity, but fall
should be confirmed with HRCT/nuclear
• No clear cut benefit to routine screening, but study for
Canada suggests baseline chest x-ray and PFT’s, serial
studies in patients with new symptoms
• BAL is nonspecific, finding of foamy macrophages is not
indicative of toxicity, only exposure
• HRCT and nuclear imaging important in confirmation of
diagnosis
• KL6, high molecular weight, glycoprotein, type II
pneumocytes, increased
Diagnosis and Management III
• Cessation of drug is mainstay of therapy
• Steroids help in certain cases, but not uniformly
• Steroids must be tapered very slowly and over a prolonged
period of time. Early mortality is increased in patients not
started on steroids.
• Radiographic and PFT improvement follow clinical
improvement
• Permanent reduction in DLCO is possible.
• Recurrent disease with cessation of steroids is frequently
resistant to therapy
Diagnosis and Management IV
• Steroids 0.75 mg/kg to 1.0 mg/kg or methylprednisolone or
equivalent.
• Treat at least for six months, preferably for one year
• No reduction in dosage until objective evidence of
improvement
• Incidence is higher in patients with COPD as is mortality
• Mortality up to 33%
• 2/3 of patients will develop recurrent disease if reexposed
to the medication, DO NOT RECHALLENGE!!
Diagnosis and Management V
• Clinical clues to suggest condition would include
concomitant skin discoloration, thyroid dysfunction,
myeloid suppression, photosensitivity, corneal deposits
with chronic therapy
Potential Mechanism of Toxicity for
Amiodarone
• Hamster alveolar macrophages are sensitive
to amiodarone
• When amiodarone is added to preparation
of hamster alveolar macrophages, the
membrane potential declines
• Following the decline in the membrane
potential, decline in intracellular ATP
• Decline in cell viability identified