Ahs

1. Alveolar Hemorrhage
Syndromes
Dr Ajay sudhakar
Chair – Dr Reshmi S nair

2. • Bleeding into the alveolar spaces of the lungs characterizes the
syndrome of diffuse alveolar hemorrhage (DAH)
• Is due to disruption of the alveolar capillary basement membrane
• This disruption is caused by injury or inflammation of the arterioles,
venules, or alveolar septal capillaries
• Hemoptysis is the usual presenting symptom; however it is not always
present, even when hemorrhage is severe

3. Causes
• Broadly divided in to auto-immune causes and non auto-immune causes
• Non auto-immune causes include
 Endobronchial tumors
 Arteriovenous malformations or aneurysms
 Ulcerative tracheobronchitis
 Haemorrhagic pneumonia
 Bronchiectasis

4.  Uremia
 Thrombocytopenia or coagulopathy
 Pulmonary veno-occlusive disease
 Infections
 Massive pulmonary embolism

5. Causes

6. Histopathologic patterns
Pulmonary Capillaritis – Seen in SLE, IPH, Anti GBM disease
Bland pulmonary hemorrhage – SLE, IPH, severe coagulopathies
Mitral
stenosis, Trimellitic anhydride
inhalation
Diffuse alveolar damage – ARDS of any cause, SLE, crack cocaine
inhalation, infections in
immunocompromised host

7. Diffuse Alveolar Damage
• DAD is the underlying lesion of ARDS and can lead to alveolar
hemorrhage
 Acute respiratory distress syndrome (any cause)
 Cytotoxic drug toxicity

8.  Systemic lupus erythematosus
 Crack cocaine inhalation
 Infections in the immunocompromised host

9. Clinical Presentation
• Typically includes
Hemoptysis
Anemia
Diffuse pulmonary infiltrates
Hypoxemic respiratory failure
• Hemoptysis may be absent in one third of patients

10. Symptoms may develop acutely in hours or days, or sub acutely in weeks to months.
Hemoptysis is present in 40–80% of cases but is rarely abundant even in severe AH.
Dyspnea is of variable severity.
Systemic symptoms (fever, myalgias, arthralgias)
AH can present as acute respiratory distress syndrome (ARDS) requiring admission to the
intensive care unit

11. CXR
• The chest radiograph findings in DAH are nonspecific and most
commonly show new patchy or diffuse opacities
• AH may appear as ground-glass alveolar opacities, consolidation with
air bronchogram, or multiple nodules reflecting acinar filling
• Pulmonary apices and costo-diaphragmatic angles may be relatively
spared
• Pleural effusion is uncommon

12. CXR
Following cessation of bleeding CXR normalize within 24-72 hrs
Above - idiopathic RPGN – resolution of lesions seen following treatment

13. HRCT chest
• Ground glass or consolidative opacities that are
usually diffuse and bilateral, but may
occasionally be unilateral.
• These opacities tend to be more central than
peripheral.
• However, HRCT is not essential for the
diagnosis of AH and it may be delayed in an
unstable patient

14. Diagnosis
• Presumptive diagnosis-clinical, serological and Broncho alveolar
lavage fluid.
• Grossly bloody BAL fluid, large no. of hemosiderin laden
macrophages and the absence of purulent secretions or evidence of
infection strongly support Alveolar hemorrhage

15. Lung Biopsy
 Extensive intra-alveolar hemorrhage and necrotizing
pulmonary capillaritis[endothelitis]
 Hemosiderin laden macrophages[siderophages] is a clue to prior episodes of
alveolar hemorrhage
Capillaritis seen in many disorders – SLE, Collagen Vascular Disorders, anti-GBM
d/s, B.M transplant recipients and drug induced alveolar hemorrhage

16. Additional pathologic features seen in patients with underlying
granulomatous vasculitis - granulomas, necrosis or eosinophils
• Immunofluorescent stains [lung or kidney] or serologic markers
[antiGBM ab or ANCA] are required to diff. various causes of
autoimmune alv.hge.
• Linear deposits of IgG along alveolar septa is pathognomonic for anti-
GBM disease

17. • A granular or “lumpy-bumpy” pattern of immune complex deposits -
S.L.E, Systemic necrotising vasculitis, or immune complex mediated
idiopathic rapidly progressive glomerulonephritis
• IgA deposition – suspect IgAV(HSP) and IgA nephropathy
• Only few deposits by immunofluorescence or electron microscopy
(therefore called pauci-immune) in patients with GPA, MPA, or
isolated pulmonary capillaritis

18. • Difficult to do in patients with respiratory failure
• Complications include infection and air leaks
• Histological features are often non specific

19. Percutaneous Kidney Biopsy
Necrotising glomerulonephritis is a cardinal feature of most immune-
mediated alveolar hge syndromes.
Strong association of autoimmune alveolar hge and
glomerulonephritis
Should be done in any suspected Alveolar hge with abnormalities in
urinalysis or R.F.T

20. Bright linear IF staining along glomerular basement membrane- anti
GBM disease.
A lumpy bumpy IF pattern consistent with immune complex
deposition - Collagen vascular disorders and idiopathic immune
complex mediated G.N.
 Negative IF stains are characteristic –Pauci-immune
glomerulonephritis of necrotising vasculitis

21. Autoimmune DAH – Pathology and serology

22. Therapy of immune mediated alveolar
hemorrhage
• Corticosteroids –Standard therapy for all immune mediated alveolar hge
syndromes
• For systemic necrotising vasculitis - Cyclophosphamide or other
immunosuppressives are combined with corticosteroids

23. • For severe fulminant autoimmune alv.hge - High dose intravenous
[pulse] methyl prednisolone 1gm daily for 3 days.
• Rapid resolution of bleeding can occur within 24-72 hrs of initiation
of therapy.
• Following the 3 day pulse corticosteroid 60-120mg per day or
equivalent of methyl pred –should be continued until bleeding is
controlled.

24. • Plasmapheresis-is a central component of therapy for anti-GBM
disease
• Plasmapheresis –in patients with severe or progressive alveolar hge
refractory to medical therapy.
• Mechanical ventilatory support with PEEP - In fulminant cases of
alveolar hge refractory to medical therapy

25. Goodpasture syndrome
Prototype of pulmonary renal
syndromes account for 18-32% of
immune- mediated alveolar hge
Manifests as alveolar hge and
RPGN
 Males of 20-45years
 Etiology is not known.
Exposure to inhaled hydrocarbons,
and antecedent viral illness
particularly influenza
 Anti-GBM antibody demonstration
in tissue or serum is the
cornerstone of the diagnosis

26. Clinical Features
• Progressive dyspnea, widespread alveolar infiltrates ,hypoxemia and
hemoptysis[80-94%]
• A cardinal feature is Glomerulonephritis
-microscopic hematuria, red cell casts, or proteinuria
• In the absence of therapy progressive renal insufficiency ensues and
results in ESRF within days to weeks of onset of symptoms

27. • Oliguria, severe renal failure or >50% crescents
on renal biopsy are associated with poor
prognosis.
• G.N occur without alveolar hge - 1/3 of pts.
• Alveolar hge alone is rare
• With cessation of bleeding infiltrates may
resolve within 24-36hrs

28. • DLCO increases
• Anemia >90% and can be profound.
• Serum iron and ferritin levels decreased.

29. • The demonstration of anti-GBM antibodies in tissue [typically kidney]
or in serum
• Anti GBM ab are highly sensitive >95% and specific >97%.
• Bright linear deposits of IgG and complement C3 along glomerular
B.M are pathognomonic of anti-GBM disease

30. • Height of serum anti GBM ab does not correlate with severity of
disease
• Change in titer over time may be a guide to efficacy of therapy
• Rise in titer – Relapse and falls as the disease remits

32. Systemic vasculitis
• ANCA associated vasculitides
• Wegener’s granulomatosis
• MPA
• CSS

33. Wegener’s granulomatosis(GPA)
• Granulomatosis with polyangiitis
• Most common of the pulmonary vasculitides
• It typically involves the upper resp tract, lower resp tract and kidney
with varying degrees of disseminated vasculitis
• Alveolar hge is a rare complication

34. • RPGN is present in >90% of pts.
• C-ANCA is seen in >90% of pts with active generalized GPA
• Oral cyclophosphamide [2mg/kg/day] plus Prednisone is the treatment of choice
• With this regimen remissions achieved in 70-93% with early mortality < 15%
• Methotrexate -limited disease or those with toxicity from cyclophosphamide

35. Churg strauss syndrome(Allergic
Angiitis and Granulomatosis)
• Rare small vessel vasculitis associated with prominent allergic
component, asthma and eosinophils in blood or involved tissues
• Pulmonary involvement - primarily asthma - is present in virtually all
cases
• Focal infiltrates found in CXR in 30-70%

36. • Diffuse alveolar hge is a rare complication
• Granulomas, eosinophils, and palisading
histiocytes in extravascular tissues are
hallmark of the disorder

37. • Pronounced granulomatous and eosinophilic components
distinguish it from other vasculitides
• In the classic form of CSS, vasculitis develops after several
year history of atopy or asthma.
• ESR , C-reactive protein and blood eosinophil count are
elevated in > 80% during acute phase of vasculitis or
exacerbations
• p-ANCA seen in 40% pts

38. Microscopic Polyangiitis(MPA)
• Glomerulonephritis and pulmonary capillaritis manifesting as alveolar hge
• Rare
• Involves small vessels and extension to larger vessels occurs in a minority
of cases
• Small vessels are always spared in classic PAN
• Neither granulomas nor eosinophils are prominent in MPA [in contrast to
WG or CSS]

39. • Circulating ANCA are found in 50-90% of
pts with MPA .
• Alveolar hge which is rarely observed in
Classic PAN is found in 30-50% of pts
with MPA and is often the most life
threatening manifestation.

40. Systemic Lupus Erythematosus
• Alveolar hemorrhage is a rare but potentially catastrophic complication
• Circulating ANA >99%
• Glomerulonephritis is usually lacking
• Invariably accompanied by other manifestations of active SLE
• Diffuse bilateral alveolar infiltrates, dyspnea,
hypoxemia and hemoptysis are characteristic

41. • Differentiate the pulmonary infiltrates from other complications of
SLE – lupus pneumonitis, CCF, pulmonary embolism, opportunistic
infections, uremia
• Lung biopsy may be done to exclude alternative diagnosis(difficult in
critically ill patients, and is non specific)
• Granular deposits of IgG or C3 found in 50% of cases of alveolar hge
complicating SLE

42. Alveolar hemorrhage in
immunocompromised
• Alveolar hemorrhage may reflect injury to pulmonary endothelial or epithelial
cells (secondary to chemotherapy or radiation toxicity), thrombocytopenia
(secondary to bone marrow toxicity), pulmonary edema, pulmonary
malignancies, and diverse infectious and nonspecific interstitial pneumonias

43. • Nonimmune causes of DAH in this patient population –
1. Coagulopathy
2. thrombocytopenia or platelet dysfunction,
3. renal failure
4. congestive heart failure
5. bronchopulmonary Kaposi sarcoma
6. infections

44. Alveolar hemorrhage in bone marrow
transplantation
• Opportunistic infections, thrombocytopenia
• Unrelated to infection too
• Risk factors –
1. age >40 years
2. thoracic or total body irradiation
3. acute severe graft versus host disease (GVHD)
4. renal failure
5. airway inflammation

45. • Usually develop 10 to 40 days after BMT
• Mechm – Diffuse injury to pulmonary vasculature secondary to
chemo/radiation therapy coupled with increased inflammatory
response in airways
• Serosanguinous or bloody BAL fluid with negative stains for infection
supports DAH

46. • Clinically – Progressive dyspnea, hypoxemia, respiratory failure
• High dose pulse IV corticosteroids is the Rx
• Unfortunately bloody BAL may be seen in infectious causes of
pneumonia(esp CMV or aspergillus) – so corticosteroid administration
can prove disastrous
• Response present – taper steroids over 2-6 weeks

47. Alveolar hemorrhage complicating HIV
infection
• Subclinical episodes of AH are common
• Thrombocytopenia, coagulopathy, renal failure, CMV pneumonia and
Kaposi sarcoma – more common in HIV pts with AH
• CMV may induce vascular injury or thrombotic microangiopathy – Rx
with Ganciclovir may be curative in CMV related DAH
• Opportunistic pathogens and Kaposi sarcoma account for most cases
of DAH in HIV pts

48. Alveolar hemorrhage due to exogenous
agents
• Propylthiouracil
• Chemotherapy – cyclophosphamide, bleomycin
• Trimellitic anhydride – used to manufacture plastics
• Crack cocaine(smoking cocaine)
• Immediate avoidance of the drug is essential
• Rx with Corticosteroids
• Anti coagulants, thrombolytic agents or platelet inhibitors – cause bland pulm hge
without capillaritis

49. • Crack cocaine(smoking cocaine)
• Immediate avoidance of the drug is essential
• Rx with Corticosteroids
• Anti coagulants, thrombolytic agents or platelet inhibitors – cause
bland pulm hge without capillaritis

50. Alveolar hemorrhage due to molds
• Exposure to Stachybotrys chartarum and other toxigenic fungi can cause DAH in infants
• Acute respiratory distress, progressing to respiratory failure requiring mechanical
ventilatory support, may occur
• High-dose IV corticosteroids
• Long-term management mandates removal of infants from the residential environment
to avoid relapse
• This syndrome has rarely been reported in adults, but must be considered in water-
damaged homes where mold/fungal contamination exists

51. Idiopathic pulmonary hemosiderosis
• Exceptionally rare cause of DAH
• Infants and children
• Associated with milk/gluten sensitivity
• Clinical features same as other causes of DAH but extrapulmonary and
renal involvement is lacking
• Lung biopsy – Fresh alveolar hge, patchy interstitial fibrosis, aggregates of
hemosiderin laden macrophages from prior episodes of alveolar hgs

52. • Serum and tissue antibodies are absent(like ANCA, immune complexes, anti-GBM antibody)
• Recurrent episodes of DAH over several years are characteristic
• 25% - spontaneous resolution without long term sequelae
• Sequelae – pulmonary fibrosis, progressive resp failure, cor-pulmonale
• During acute episodes CXR : Bilateral alveolar infiltrates
• Following cessation of bleeding CXR will normalise within 1-2 weeks

53. • CT Scan: Ground glass opacities
• Iron deficiency anemia is characteristic
• Pathogenesis is unknown

54. • In children association between
1. Cow’s milk hypersensivity
2. Coeliac disease,
3. IgA monoclonalgammopathy
4. AIHA
• Treatment – Corticosteroids, Azathioprine, CYC