This document provides an overview of Acute Lung Injury (ALI), including: 1. The definition, history, epidemiology, and pathogenesis of ALI. It results from direct or indirect lung injury and involves endothelial and epithelial injury, neutrophil infiltration, and cytokine release. 2. The clinical presentation and stages of ALI from the acute/exudative stage with hyaline membrane formation to the proliferative/organizing stage and resolving/fibrotic stage. 3. Investigations for ALI including clinical criteria based on oxygenation and chest imaging findings typically showing bilateral infiltrates. Histopathology often reveals diffuse alveolar damage.

1. Acute Lung Injury (ALI)
Presenter: Dr Khushdeep Kaur

2. Definition
Pathogenesis
Targeted
therapy

3. • Introduction
• Aetiology, Pathogenesis
• Investigations & Diagnosis
• Role of a pathologist
• Histopathology patterns
• Approach to biopsy specimens
• Targeted therapies
• Conclusion

4. “A clinical defined condition,
representing a stereotypical pattern
of lung injury secondary to a wide
range of pulmonary and
extrapulmonary insults which
means different things to different
specialist groups.”
“

5. INTRODUCTION

6. History
In CLINICAL terms:
• World War I: Canadian physician used the
term ‘Shock Lung’
• 1967: Term “adult respiratory distress
syndrome” by Ashbaugh et al
• 1988: Murray et al- four point lung injury
scoring system.

7. • 1994: The American-European Consensus Conference on ARDS,
changed term to Acute Respiratory distress Syndrome & defined:
Acute Lung Injury Acute Respiratory
Distress syndrome
Onset Acute Acute
Oxygenation in mmHg
(PaO2 : FiO2)
<300 <200
Chest radiological
appearance
Bilateral pulmonary
infiltrations which may
or may not be
symmetrical
Bilateral pulmonary
infiltrations which may
or may not be
symmetrical
Pulmonary Wedge
Pressure (mmHg)
< 18 or no clinical
evidence of left atrial
hypertension
< 18 or no clinical
evidence of left atrial
hypertension

8. Mild Moderate Severe
PaO2/ FiO2 200-300 100-200 < 100
• 2012: Further refined , termed the Berlin definition
of ARDS. Defined ARDS by
 Timing (within 1 wk of clinical insult or onset of
respiratory symptoms);
 Severity based on the PaO2/FiO2 ratio on 5 cm of
continuous positive airway pressure (CPAP)
 Radiographic changes (bilateral opacities not fully
explained by effusions, consolidation, or atelectasis);
 Origin of oedema (not fully explained by cardiac failure
or fluid overload); and
 Divided into 3 categories:

9. • 2015: Riviello et al, :
Berlin definition under-estimates ARDS
incidence in low-income countries,
Suggested a further definition, termed the
Kigali modification, attempting to define ARDS
without access to imaging or advanced testing
modalities.

10. In PATHOLOGY literature:
• Katzenstein put forward the term ‘Acute lung
Injury’ & three stages in pathogenesis.
• Recently as per American Thoracic Society/
Europian Respiratory Society consensus
statement; term Acute interstitial pneumonitis
(AIP) for cases of Idiopathic lung injury with a
DADS pattern on histology.

11. Epidemiology
• Annual cases of more than 150 000 in USA
• Incidence 17-30 per l lakh.
• Average age : 60 yrs
• Mortality : 35-40% for the past two decades
• Ratio of ARDS to ALI = 70 %
• Usually underestimated.

12. AETIOLOGY
&
PATHOGENESIS

13. “Syndrome of inflammation and
increased permeability that is
associated with a constellation of
clinical, radiological and
physiological abnormalities, that
cannot be explained by but may
coexist with left atrial or pulmonary
capillary hypertension
.”

14. Aetiology
DIRECT
LUNG INJURY
INDIRECT
LUNG INJURY
IDIOPATHIC
 Pneumonia (Bacterial,
Viral, fungal)
 Aspiration of gastric
contents.
 Inhalation Injury
 Therapeutic drug
reactions e.g. Bleomycin
& Methotrexate.
 Pulmonary contusion/
Blast Injury
 Fat Emboli
 Near drowning
 Reperfusion/ re-
expansion lung injury
 Radiation Injury
 Altitude
 Systemic sepsis especially
Gram negative bacilli
 Major extra thoracic trauma
with/ without fat emboli
 Acute pancreatitis
 Drug overdose e.g.- Opiates,
barbiturates
 Transfusion of blood
products
 Disseminated intravascular
coagulation
 Systemic poisoning
 Eclampsia
 Acute Interstitial
Pneumonitis (AIP)*
*Hamman
Rich
Syndrome

15. Pathogenesis
• Model of “Lung Injury & Remodelling”.
• Involves a complex array of physiological, molecular
and cellular mechanisms.
Resulting from:
• Endothelial Injury
• Epithelial Injury
• Neutrophil mediated Injury
• Cytokine mediated Inflammation & Injury
• Oxidant mediated Injury
• Involvement of Coagulation pathway
• Fibrosing Alveolitis

16. Common theme is imbalance, between ….
Neutrophil recruitment and activation and
mechanisms of neutrophil clearance
Pro and anti inflammatory cytokines,
Procoagulants and anticoagulants,
Oxidants and antioxidants,
Proteases and protease inhibitors
High altitude Pulmonary Oedema (HAPE)
Ventilator Induced Lung Injury
Transfusion Related Acute Lung Injury

17. Alveolar lining cells
Type I Type II
Percentage of Cells 90 % 10%
Shape Flat Cuboidal
Function • Provide lining for
alveoli
• Replace type I
damaged cells
• Produce surfactant
• Transport ions &
fluids
Destruction leads to • Disruption of Alveolar
capillary barrier
integrity
• Lung interstitial fluid,
proteins, neutrophils,
RBCs & fibroblasts
leaks into the alveoli.
• Decreased &
abnormal surfactant
production.
• Atelactasis
• Impaired replacement
of type I cells,
• impaired removal of
fluid from the lungs.

18. Increased
microvascular
permeability

19. Mechanism

20. Mechanism

21. Role of Chemical Mediators-
The Imbalance
Cellular factors Injury Pro
(Ameliorates ALI)
Anti
(Resolution of ALI)
 P-Selectin, ICAM-1,
CD11/18,
 Increased Stuffiness
 C5a, Lk B4, IL-8,
Endotoxins
 GM-CSF, G-CSF
Neutrophil
Mediated
Injury
(Retained &
Activated)
 Protease- Neutrophil
Elastase,
 Collagenase&
Gelatinase
 PAF & Leukotrienes
 Alpha 1 Antitrypsin
 Alpha 2-
Macroglobulin
 CC16 (Neutrophil
chemotaxis Inhibitor)
 Monocytes
 Endothelial cells
 Fibroblasts
 Epithelial Cells
 Inflammatory Cells
Cytokine
Mediated
Injury
(Influx of
Neutrophils
& toxic
Mediators)
 IL-1
 TNF-alpha
 IL-8
 Nuclear localisation
of NFkB
(Regulates expression of
ICAM-1, IL-1,IL-6,
TNF-a)
 Receptor antagonist
for IL-1
 Soluble TNF receptors
 IL-10, IL-11
 Auto-antibodies IL-8

22. Cellular
factors
Injury Pro
(Ameliorates
ALI)
Anti
(Resolution of
ALI)
 Alveolar
Macrophages
 Endothelial cells
 Epithelial Cells
Oxidant Mediated
Injury
(of Fatty Acids,
Proteins, DNA)
 Reactive Oxygen
Species
 Reactive Nitrogen
Species
 Anti-oxidants-
SOD, Vitamin E,
 Vitamin C,
 Glutathione
Endothelial Cells Coagulation Cascade
& Endothelial Injury
 Tissue Factor
 PAI-1
 Fibrin
 VWF
 Endothelin 1
 Protein C
 Myofibroblasts
 Fibroblasts
 Inflammatory
Cells
 Epithelial Cells
Fibrosing Alveolitis  IL1
 Procollagen III

24. Molecular Mechanisms
• Innate Immunity-Pattern Recognition Receptors
(PRPs): Recognise
Non endogenous Pathogen –
associated molecular patterns
(PAMPs)
 Initiate Inflammatory Cascade
 Release of TNF-a, IL-1b, IL-8
 Stimulate Autophagy/ apoptosis
 Induce production of Anti-bacterial
molecules
 NLRs
 TLR signalling pathway- TLR4 &
TLR-2
Endogenous Danger -
associated molecular patterns
(DAMPs)
 Produce IL-8
(Neutrophil recruitment---NETs)
 Later interaction with anti-IL-8:
interaction with FcgRII receptor-
Neutrophil apoptosis

25. STAGES
Acute/
Early/
Exudative
Proliferative /
Organising
Late/ Resolving/
Fibrotic

26. Pathophysiology Clinical Features
ACUTE
(<7 days)
• Loss of integrity of normal alveolar
capillary base
• Alveolar flooding with protein rich
fluid.
• Hyaline Membrane formation
• Acute respiratory failure
• Hypoxemia resistant to
oxygen therapy.
• Auscultation: Diffuse, fine
crepitations
RESOLVING
(7-21 days)
• Type II alveolar cells proliferate.
• Differentiate into type I cells
• Na ions move via type II (Active
transport)
• Water flows through type I
• Soluble & non soluble proteins
remove
• Resorption of Hyaline Membrane.
• Resolution of hypoxemia
• Improved lung
compliance
FIBROTIC
(>21 days)
• Alveolar spaces filled with
inflammatory cells, blood vessels,
abnormal & excessive deposition of
extracellular matrix proteins
• Interstitial & alveolar fibrosis
• Partial resolution of pulmonary
oedema
• Continued hypoxemia
• Decreased pulmonary
compliance.
• Right Heart Failure

27.  Gradual resolution
 Continued interstitial fibrosis,
architectural remodeling,
progressive respiratory
compromise-residual functional
impairment.

28. Transfusion Related Acute Lung Injury
(TRALI)
• Increasingly being recognised from a clinical
standpoint.
• Clinical syndrome
• Antibodies to WBCs in transfused blood
components.
• Mild dyspnoea to fulminate respiratory
failure.
• *Limited data

29. Ventilator Induced Lung Injury
• As a consequence of high volume ventilation
• Resulting in
 Enhanced oedema in the injured lung
 Increased pulmonary oedema in uninjured lung!!!!!
• Underlying Mechanisms:
 Alveolar Overdistension
 Capillary Stress failure- Endothelial & Epithelial Injury
?Release of Metalloproteinases
?Oxidative stress
? Proinflammatory Cascade (TNF-a, IL-1)
ARDS network : Ventilation with TV of 6 ml/kg
predicted body weight associated with reduced
mortality

30. High altitude Pulmonary Oedema
(HAPE)
• Most frequent cause of death from altitude
related illnesses.
• 1960: Reported to be non-cardiogenic form of
pulmonary oedema.
• Young patients (2nd to 4th decade) with no
known pulmonary or cardiac comorbidties &
no past history.
• Precipitating Factor: Rapid ascent of
altitudes> 2500 m.

31. • Clinical Features & Examination:
Decreased exercise performance with fatigue
& weakness
Worsening Dry cough
Dyspnoea, headache, nausea, palpitation,
Facial Palor & peripheral cyanosis (Peripheral
vascoconstriction)
Tachypnoea, Tachycardia, Low grade fever
Chest widespread crepitations
No clinical evidence of heart failure
Elevated pulmonary aretey pressure.
Corresponding Radiology

32. Pathogenesis
• Poorly understood
• Combination of :
Increased capillary pressure (?)
Increased microvascular permeability
• Associated with increased Endothelin1,
Leukotriene E4

33. INVESTIGATIONS
&
DIAGNOSIS

34. “ARDS/ ALI is typically a diagnosis
based on clinical and radiologic
features with Diffuse alveolar
damage (DAD) being the
histologic counterpart.”

35. Clinical Diagnosis
Well defined criterias.
With arterial blood gas analysis.

36. Radiological Diagnosis
A. Chest X-Ray findings:
1. Early exudative phase:
Chest radiographs show 3 general findings:
(1) A bilateral, whiteout appearance;
(2) Asymmetric (patchy) consolidations; and
(3) A central bat-wing, consolidative appearance
Radiologic hallmarks:
 Geographic distribution of the patchy ground-glass
densities,
 Areas of lobular sparing and lower lobe consolidation
2. Fibrotic phase:
Chest radiographs may have an interstitial appearance

37. B. CT Scan Findings:
 Bilateral abnormalities in almost all the patients,
predominantly dependent abnormalities (86%)
 Patchy abnormalities (42%)
 Homogeneous abnormalities (23%)
 Ground-glass attenuation (8%)
 Mixed ground-glass appearance and consolidation
(27%)
 Basilar predominant abnormalities (68%)
 Areas of consolidation with air bronchograms (89%)
CT scans -more detailed and more reliable information
(esp in later stages)in areas of consolidation and fibrosis.

39. Biochemical & Molecular Markers
• BAL fluid, Pulmonary Oedema Fluid:
High protein content
• Molecular markers:

40.  Pathological diagnosis
Bronchoscopic
lavage specimens:
 Specific
organisms.
 For cytology:
Reactive
epithelial cells,
Alveolar
macrophages,
Neutrophils
Biopsies (Only Wedge biopsies) are
uncommonly required for diagnosis.
Performed in cases where:
Presentation is not straightforward,
Specific infection is being considered,
Therapeutic response is disappointing.
Autopsy cases.
DAD is the main pathologic pattern of
lung injury.
Most findings are autopsy based.

41. What is the role of a Pathologist???
 Patel et al: Most wedge biopsy specimens did show DAD,
however other diagnostic findings in nearly one-third of
cases that prompted a change in therapy. Most of these
involved the discovery of a definitive infectious aetiology.
 Pathologist can help:
 Evaluation a specific infectious cause
 Increase sensitivity of Chest radiograph (esp in later
stages)so that steroids could be added at the beginning of
the fibrotic process in ARDS.
 Help correlate with clinical findings and thus
understanding the pathogenesis better- evolution of new
targeted therapies.

42. HISTOLOGIC
PATTERNS
ASSOCIATED WITH
ALI/ ARDS

43. Histologically 5-6 patterns
I. Diffuse Alveolar Damage (DAD)
II. Acute Fibrinous and Organizing Pneumonia
(AFOP)
III. Eosinophilic Pneumonia (EP)
IV. Diffuse alveolar haemorrhage (DAH) with
capillaritis.
Organizing Pneumonia (OP): As a differential.

44. I. Diffuse Alveolar Damage (DAD)
• Multiple aetiologies
• Unknown cause: Acute Interstitial pneumonia
• Clinical presentation: Severe hypoxemia
requiring mechanical ventilation.
• Radiography: “White out lungs”
• Classic histologic manifestation.
• Histologically: Divided into two (or three) phases:
A. The acute/exudative phase
B. Organizing/proliferative phase.
C. Repair Phase

45. A. Acute/ Exudative phase
 Gross (Autopsy): Heavy, dark, airless, wet lungs.
Exuding blood stained. Patchy changes: dorsal & Basal
regions
Microscopy:
 Widespread collapse
 Intense capillary congestion
 Mild Interstitial oedema &Distension of lymphatics
(Congestive Atelectasis)
 Earliest change Day 2: intra-alveolar oedema &
interstitial widening (Ultrastructural)
 Day 4-5: Hyaline membrane reaches peak.
Inflammation is generally sparse.
• Thrombi present can be extensive.*

46. Acute phase

47. Thrombi in DAD

48. B. Organizing/ Proliferative phase.
• Microscopy:
 Both epithelial & connective tissue proliferation.
 Marked type II pneumocyte hyperplasia.
 Hyaline membrane disappears and gets incorporated
into the alveolar septae or shed off into the alveolar
space
 Atelectatic induration.
 Uniform interstitial fibrosis: loose and myxoid (Bluish
grey on H&E).
 Squamous metaplasia may be pronounced.
Marked cytologic atypia/ mitotic figures- mimics
malignancy.

49. Organizing phase

50. Organizing phase

51. Squamous
metaplasia

52. DAD with
Adenovirus

53. C. Repair Phase
• Gross:
Contracted or firm,
Firm sponge like pattern on cut surface
• Microscopy:
Diffuse intra-alveolar fibrosis
Interstitial fibroblast proliferation
Marked interstitial oedema

54. • TRALI:
Vary from pulmonary oedema with neutrophil
accumulation in alveolar capillaries ( & spaces) to
DAD with classic hyaline membrane.
• High altitude Pulmonary Oedema
(HAPE):
Widespread hyaline membranes
Pneumonitis with neutrophilic infiltration
Interstitial oedema
Microthrombi

55. Differential diagnosis of DAD
Acute Eosinophilic pneumonia
Non specific interstitial pneumonia, fibrosing
type
Usual Interstitial pneumonia
Organisisng pneumonia pattern
Acute fibrinous & organising pneumonia

56. II. Acute Fibrinous and Organizing
Pneumonia (AFOP)
• Recent entity.
• Presentation: Subacute clinical course to severe
respiratory failure.
• Mortality: similar to DAD
• ?? Histologic variant of DAD
• Role of pathologist: Recognise its association with
ALI and understanding its spectrum of potential
clinical associations.
• Diagnosed on a large biopsy specimen only.

57. • Histopathology:
 Patchy or diffuse.
 No true hyaline membrane.
 Alveolar spaces filled with organizing fibrin balls.
 Alveolar septae may show interstitial widening or
lymphocytic infiltrates
 Significant Neutrophils Or Eosinophils should not be
seen.
 Organising fibroblastic tissue with a retained central
fibrinous core.
• Differentials:
 DAD
 Eosinophilic pneumonia/ partially treated.
 Alveolar haemorrhage

58. Acute Fibrinous and Organizing
Pneumonia

59. III. Eosinophilic Pneumonia
• Subclinical course to fulminate respiratory
failure, associated with fever(Acute Eosinophilic
Pneumonia).
• Etiology: Toxic inhalation, drug reaction,
Infection esp parasites or fungus, Idiopathic
• Exquisitely sensitive to steroid therapy: dramatic
recovery.
• May not be associated with peripheral blood
eosinophilia - Underscores the role of
pathologist.

60. • Histopathology:
Hyaline membrane identical to acute phase DAD.
Intra-alveolar fibrin and macrophages admixed
with eosinophils.
Eosinophilic microabscesses in interstitium.
Eosinophils may infiltrate blood vessel wall.
• Differential:
DAD
AFOP
Chrug Strauss syndrome.

61. Acute Eosinophilic
pneumonia

62. IV. Diffuse Alveolar Haemorrhage with
Capillaritis
• Occasionally may present with fulminate respiratory
failure.
• Histopathology:
 Diffuse intra-alveolar blood admixed with
hemosiderin laden macrophages with coarsely
granular and golden brown pigment.
 Capillaritis: Significant neutrophilic infiltrates within
the alveolar septae with resultant vascular necrosis.
(minimal or absent involvement of the air spaces)
 Associated hyaline membrane.
 Organising fibroblastic tissue forming “dumbbell”
shapes crossing the alveolar septae.

63. Neutrohilic
Capillaritis
Healing
capillaritis

64. Haemosiderin secondary to
alveolar haemorrhage
Associated with
cigarette smoking

65. • Role of pathologist:
To identify patterns of alveolar haemorrhage
(Acute / active) associated with ALI especially
in association with immune mediated
disorders.
Procedural or pathologicaly significant
haemorrhage.

66. Organizing Pneumonia (OP)
• Subacute clinical course.
• An important differential for different
histologic patterns associated with ALI
• Formerly termed-Bronchiolitis obliterans
organising pneumonia (BOOP)
• Idiopathic : Cryptogenic Organising
pneumonia. (COP)

67. • Diagnosis on a large biopsy specimen
• Histopathology:
Air space organization
Patchy accumulation of intra-alveolar
organising fibroblastic tissue, centered around
bronchioles.
Alveolar septae show mild chronic inflammation.
Significant fibrosis should not be present and the
intervening lung should be relatively normal.
Pneumocyte hyperplasia not prominent.
• Differential:
Organising DAD

68. Organising Pneumonia

69. APPROACH
TO
BIOPSY SPECIMENS

70. Clinical correlation & communication with the
clinician is critical
Definitive diagnosis only on wedge biopsy
specimen.
When a diagnosis of acute lung injury is
suspected, assess :
(1) Hyaline Membrane (if fortunate enough!!!)
(2) Presence of intra-alveolar oedema and/or
myxoid interstitial fibrosis,
(2) Presence of marked pneumocyte hyperplasia,
especially with bizarre cytologic features,
(3) Presence of alveolar fibrin or debris.

71. • Additional features to evaluate :
(1) Microorganisms and viral inclusions
(Special stains) esp in DAD & AFOP.
(2) Eosinophils, suggesting the possibility of AEP,
(3) Coarse hemosiderin and capillaritis,
suggesting an immune-mediated vasculitis.
In patient with known respiratory failure: A
descriptive diagnosis with a comment that the
findings are suggestive of, or consistent with,
acute lung injury

72. Aspergillus with
organising pneumonia

73. Small Biopsy Specimen:
Eosinophilic pneumonia

74. Small Biopsy specimen: ALI

75. Treatment
 GENERAL:
 Nutritional support
 Glycaemic control
 DVT prophylaxis
 Stress ulceration prophylaxis
 Antibiotics for associated infection
 Early recognition & treatment of underlying infection
 VENTILATION:
 Aim is low volumes with permissive hypercapnia,
providing adequate oxygenation (PaO2 > 8kaPa)
without inducing further ventilator induced injury to lung.
 FLUID MANAGEMENT:
 Conservative fluid management rather than liberal.

76. Role of pharmacotherapy: NO, Exogenous
surfactant, Intravenous Salbutamol, GM-CSF,
Activated Protein C is still under research.
A. Activated Protein C (Drotrecogin alpha /
Xigris).
Possible mechanisms:
(1)Antithrombotic properties: Through cleavage
of factors Va and VIIIa and fibrinolytic activity
through inhibition of plasminogen activator
inhibitor-1 (PAI-1)
(2) Anti-inflammatory properties (e.g., inhibition
of cytokine release)

77. B. Neutralizing TNF
Excellent animal data.
Large clinical trials of anti-TNF
monoclonal antibodies showed a very
small reduction in mortality
C. IL-1 Antagonism
Three randomized trials: Only 5%
mortality improvement.
D. PAF-degrading enzyme
Great phase II trial.
E. Antithrombin III

78. Conclusion
• Clinically defined condition. With consistent high
mortality over past two decades.
• Histopathology mainly restricted to autopsy
specimens.
• Many patterns other than DAD.
• Pathologist may help define specific infectious
aetiology.
• Advances in understanding the pathogenesis/
mechanisms of progressive fibrosis versus resolution
may help develop therapeutic targets relevant to a
broad range of progressive fibrotic lung diseases and
not just ALI/ ARDS.

79. Definition
Pathogenesis
Targeted
therapy

80. References
• Bernard GR, Artigas A, Brigham KL, et al. The American-
European Consensus Conference on ARDS: definitions,
mechanisms, relevant outcomes and clinical trial coordination.
Am J Respir Crit Care Med. 1994;149(3):818–824.
• Avecillas JF, Freire AX, Arroliga AC. Clinical epidemiology of
acute lung injury and acute respiratory distress syndrome:
incidence, diagnosis, and outcomes. Clin Chest Med.
2006;27(4):549–557.
• Butt Y, Kurdowska A, Allen T C. Acute Lung Injury: A Clinical
and Molecular Review; Arch Pathol Lab Med. 2016 (140):345–
350
• Caironi P, Carlesso E, Gattinoni L. Radiological imaging in acute
lung injury and acute respiratory distress syndrome. Semin
Respir Crit Care Med.2006;27(4):404–415.
• M Flanagan. Recent Advances in Histopathology 2016 (24)

81. • Laycock H, Rajah A. Acute lung injury & acute Respiratory
syndrome: A review article. British Medical Journal of
Medical Practitioners, June 2010 (3).
• Beasley M B. The Pathologist’s Approach to Acute Lung
Injury, Arch Pathol Lab Med, 2010(134):719–727
• Patel SR, Karmpaliotis D, Ayas NT, et al. The role of open-lung
biopsy in ARDS. Chest. 2004;125(1):197–202 Jhonson E R,
Matthay M A. Acute Lung Injury: Epidemiology, Pathogenesis,
and Treatment, J Aerosol Med pulm Drug Deliv. 2010 Aug;
23(4): 243–252.
• Ragaller M, Richter T. Acute lung injury and acute respiratory
distress syndrome. J Emerg Trauma Shock, 2010 ; 3(1): 43–
51.
• Lorraine B. Ware. Pathophysiology of Acute Lung Injury and
the Acute Respiratory Distress Syndrome. Semin Respir Crit
Care Med, 2006(27): 337-49.

82. THANK YOU