1. CYPTOGENIC ORGNAISING
PNEUMONIA

2. Introduction
 Cryptogenic-organizing pneumonia (COP)/
 Idiopathic BOOP
 described in 1901 by Lange.

3. Introduction
Definition
 Defined histopathologically by intra-alveolar buds of
granulation tissue.
 Intermixed myofibroblasts and connective tissue
 Nonspecific Histopathological pattern
 With characteristic clinical and imaging features, defines
cryptogenic organising pneumonia
 No cause or peculiar underlying context is found.

4. Introduction
 Type of diffuse interstitial lung disease
 Idiopathic form of organizing pneumonia
 formerly called bronchiolitis obliterans organizing pneumonia or BOOP
 Affects the distal bronchioles, respiratory bronchioles, alveolar ducts,
and alveolar walls
 The primary area of injury is within the alveolar wall.
 Can be seen in association with connective tissue diseases, a variety of
drugs, malignancy, and other interstitial pneumonias called secondary
organising pneumonia.

5. A DISTINCT ENTITY AMONG THE IDIOPATHIC
INTERSTITIAL PNEUMONIAS
 Classify as Idiopathic Interstitial Pneumonias
 Idiopathic nature
 the possible confusion with other forms of idiopathic interstitial
pneumonias when the imaging pattern is infiltrative
 histopathological features of interstitial inflammation in the involved
areas.
 The previous terminology of BOOP was abandoned because the major
process is organising pneumonia, with bronchiolitis obliterans being
only a minor and accessory finding (which may even be absent).

6. EPIDEMIOLOGY
 The exact incidence and prevalence unknown
 Prevalence of 6 to 7 per 100,000 admissions has
been reported.
 20 year review of national statistics for Iceland, the
mean annual incidence was 1.1 per 100,000 .
 In separate reports, approximately 56 to 68 percent
of OP cases have been deemed cryptogenic rather
than secondary.

7. Aetiological diagnosis:
cryptogenic or not?
 Term used synonymously to idiopathic.
 although etymologically cryptogenic means of
hidden cause and
 Idiopathic means a self-governing disease.
 The disorder described is both cryptogenic and
idiopathic.
 It is only considered to be cryptogenic when a
definite cause or characteristic associated context is
not present.
 Therefore, the aetiological diagnosis is of major
importance before accepting the diagnosis of COP.

8. AETIOLOGY OF ORGANISING
PNEUMONIA
 Secondary Organizing Pneumonia
 Result from determined cause or
 occur in the context of systemic disorders
(e.g., connective tissue disease) or
 other peculiar conditions

9. Infectious causes of organising
pneumonia

10. Main Drugs as Cause of
Organizing Pneumonia

11. PATHOLOGY
 Excessive proliferation of granulation tissue.
 Loose collagen-embedded fibroblasts and myofibroblasts.
 Involving alveolar ducts and alveoli, with or without
bronchiolar intraluminal polyps
 Intraluminal plugs of granulation tissue may extend from
one alveolus to the adjacent one through the pores of
Kohn, giving rise to the characteristic "butterfly" pattern .

12. Histopathology Masson body
Masson body

13. KEY HISTOLOGIC FEATURES
KEY HISTOLOGIC FEATURES
1. Intraluminal organizing fibrosis in distal airspaces
( bronchioles, alveolar ducts, and alveoli)
2. Patchy and peribronchiolar distribution
3. Preservation of lung architecture
4. Uniform and recent temporal appearance
5. Mild interstitial chronic inflammation (eg, lymphocytes and edema)
6. Foamy macrophages are common in alveolar spaces, likely due to
bronchiolar obstruction

14. PERTINENT NEGATIVE FINDINGS
1 Absence of severe fibrotic changes (eg, honeycombing
2 Incidental scars or apical fibrosis may be present
3 Granulomas are absent
4 Giant cells are rare or absent
5 Lack of prominent infiltration of eosinophils or neutrophils
6 Absence of necrosis or abscess
7 Absence of vasculitis
8 Lack of hyaline membranes or prominent airspace fibrin.

15. PATHOGENESIS

16. PATHOGENESIS
 Alveolar epithelial injury is the first event
 Necrosis and sloughing of pneumocytes
 denudation of the epithelial basal laminae.
 Most basal laminae are not destroyed, although some gaps
are present.
 The endothelial cells are only mildly damaged
 Inflammatory cells (lymphocytes, neutrophils, some
eosinophils) infiltrate the alveolar interstitium.

17. PATHOGENESIS
The first intra-alveolar stage:
 Formation of fibrinoid inflammatory cell
clusters.
 Comprise prominent bands of fibrin together
with inflammatory cells (especially lymphocytes).
 Macrophages engulfing fibrin may be seen

18. PATHOGENESIS
 The second stage (fibroinflammatory buds)
 Fibrin is fragmented .
 Inflammatory cells less numerous.
 Fibroblasts migrate through gaps in the basal laminae
 Proliferate as demonstrated by the presence of mitotic
figures.
 Undergo phenotypic modulation (myofibroblasts).

19. PATHOGENESIS
 Proliferation of alveolar cells.
 Re -epithelialisation of the basal laminae.
 Crucial phenomenon for the preservation of
the structural integrity of the alveolar unit.

20. PATHOGENESIS
 The third and final stage (organisation)
 Characteristic ‘‘mature’’ fibrotic buds.
 Inflammatory cells have almost completely
disappeared
 No fibrin within the alveolar lumen.
 Concentric rings of fibroblasts alternate with layers
of connective tissue (mainly collagen bundles).

21. PATHOGENESIS
 Prominent capillarisation which is reminiscent
of granulation tissue in wound healing
 Vascular endothelial growth factor and basic
fibroblast growth factor are widely expressed
 Angiogenesis contribute to the reversal of buds
in organising pneumonia.

22. CLINICAL FEATURES
 Fifth or sixth decades of life
 Men = women
 Rarely reported in children.
 Not related to smoking.
 A seasonal (early spring) occurrence of COP
with relapse every year at the same period
has been reported.
 Recurrent catamenial COP has also been
mentioned

23. CLINICAL FEATURES…..
 Begin with a mild flu-like illness.
 Fever , cough, malaise and progressively mild
dyspnoea, anorexia and weight loss.
 Dyspnoea may be severe in the eventuality
of rapidly progressive disease.

24. CLINICAL FEATURES...
 Persistent nonproductive cough (72%)
 Dyspnea (66%)
 Fever (51 %)
 Malaise (48 %)
 Weight loss of greater than 10 pounds (57%)
 Hemoptysis is rarely reported as a presenting
manifestation of COP

25. CLINICAL FEATURES...
 Rare manifestations
 Chest pain, night sweats and mild arthralgia
 Since the most common manifestations are
nonspecific, diagnosis is often delayed (6–13
weeks).
 Three -fourths of the patients, symptoms are
present for less than two months.

26. CLINICAL FEATURES...
 One -half pt ,onset is acute onset of a flu-like
illness with fever, malaise, fatigue, and
cough.
 lack of response to empiric antibiotics for
community acquired pneumonia.
 Initial clue to the presence of a noninfectious,
inflammatory pneumonia.

27. Physical examination
 Inspiratory crackles (74 percent) .
 Wheezing is rare
 May be heard in combination with crackles.
 Clubbing < 5%.
 A normal pulmonary examination is found in
one-fourth of patients

28. EVALUATION
 Chest radiographic appearance.
 lack of clinical response to antibiotic therapy

29. Lab investigation
 Leukocytosis is present in about 50 percent of
patients with COP
 ESR and CRP increase in 70 to 80%

30. Chest radiograph
 Bilateral , patchy or diffuse, consolidation.
 Ground glass opacities in the presence of normal lung volumes
 A peripheral distribution of the opacities
 Recurrent or migratory pulmonary opacities are common ( 50%).
 Rare manifestation
 unilateral consolidative and ground-glass opacities
 Irregular linear or nodular opacities as the only radiographic
manifestation
 Other rare radiographic abnormalities include pleural effusion,
pleural thickening, hyperinflation, and cavities.

31. CXR

32. COMPUTED TOMOGRAPHIC SCANNING
 More extensive disease than expected from
review of the plain chest radiograph
 Patterns include
 patchy air-space consolidation
 ground-glass opacities
 small nodular opacities
 bronchial wall thickening with dilation Patchy
opacities
 Periphery and in the lower lung zone.

33. Rarely
 multiple nodules or masses that may
 cavitate, micronodules, irregular reticular
opacities in a subpleural location, and
crescentic or ring-shaped opacities

34. Imaging features
 Three main characteristic imaging patterns
1. Multiple alveolar opacities (typical COP)
2. Solitary opacity (focal COP)
3. Infiltrative opacities (infiltrative COP)

35. Typical COP
 Multiple alveolar opacities
 Usually bilateral and peripheral, migratory.
 Size varies from a few centimetres to a whole
lobe
 Air bronchogram in consolidated opacities.
 HRCT:- the density of opacities ranges from
ground glass to consolidation and more
opacities are detected than on chest
radiographs

36. Typical cryptogenic organising
pneumonia

37. Solitary focal opacity
 Not characteristic
 Diagnosis made from histopathology of a
nodule or a mass excised.
 Often located in the upper lobes, may be
cavitary.
 May be totally asymptomatic and discovered
by routine chest radiographs.
 Does not relapse after surgical excision

38. solitary focal opacity

39. Infiltrative COP
 Associated with interstitial and
superimposed small alveolar opacities on
imaging.
 Some cases overlap with other types of
idiopathic interstitial pneumonias, especially
IPF and NSIP.
 May consist of a poorly defined arcade-like or
polygonal appearance –perilobular pattern.

40. Infiltrative lung disease.

41. Pulmonary function tests
 Most common - mild to moderate restrictive
changes
 obstructive defect < 20 %.
 Diffusing capacity (DLCO) is reduced
 Resting and/or exercise arterial hypoxemia >
80%
 SpO2may be normal or reduced at rest, but
commonly is decreased with exertion.

42.  Marked hypoxaemia with possible
orthodeoxia because of alveolar right to left
shunting.

43. Flexible bronchoscopy
 BAL findings are nonspecific but indicate in
all pt
 To r/o other cause
 In diffuse disease, the right middle lobe or
lingula is lavaged most commonly to
optimize fluid recovery

44. BRONCHOALVEOLAR LAVAGE
BAL findings
 Increases in lymphocytes (20 to 40%),
 Neutrophils (5 to 10%)
 Eosinophils (5 to 25%)
 level of lymphocytes being higher than that
of eosinophils
 Elevated eosinophils (> 25%) may suggest an
overlap with idiopathic chronic eosinophilic
pneumonia

45. BRONCHOALVEOLAR LAVAGE
 Other (nondiagnostic) BAL include
 Foamy macrophages, mast cells, plasma cells
 Decreased CD4/CD8T cell ratio.
 Increase in activatedT lymphocytes
 Increased levels ofTh1 related cytokines,
including interferon (IFN)-y, interleukin (IL)-
12 and IL-18.

46. Transbronchial lung biopsy
 Inadequate for definitive confirmation of
COP
 Exclusion of other concomitant processes

47. Surgical lung biopsy
 Open or thoracoscopic lung biopsy
 Obtain an adequate sample of lung tissue
(eg, >4 cm diameter in the greatest
dimension when inflated)
 The location based on areas of abnormality
identified on the HRCT
 Accessibility of these areas.
 Samples are sent for histopathologic and
microbiologic analysis

48. Histopathological diagnosis of
organising pneumonia
 The hallmark is the presence of buds of
granulation tissue
 fibroblasts–myofibroblasts embedded in
connective tissue.
 Extend from one alveolus to the next
through the interalveolar giving
characteristic ‘‘butterfly pattern’’.

49. SEVERE AND/OR OVERLAPPING COP
 Present with widespread opacities on
imaging and hypoxaemia.
 Corresponding to the criteria for acute lung
injury or the ARDS.
 May require mechanical ventilation
(noninvasive or with tracheal intubation) or
progress to death.
 When corticosteroid treatment is delayed.

50. SEVERE AND/OR OVERLAPPING COP
 A recently described condition overlapping
with ARDS both clinically and pathologically
 Onset is acute and progression may be
fulminating or subacute.
 lung biopsy - intra-alveolar fibrin ‘‘fibrin balls’’
without classic hyaline membranes.

51. SEVERE AND/OR OVERLAPPING COP
 COP may progress to fibrosis and
honeycombing
 Especially in patients with the infiltrative
imaging pattern of organising pneumonia

52. SEVERE AND/OR OVERLAPPING COP
 In some patients, acute exacerbation of
idiopathic interstitial pneumonia may
comprise organising pneumonia at lung
biopsy
 Superimposed organising pneumonia was
found on explant specimens from a patient
with UIP who underwent lung
transplantation

53. TREATMENT

54. Mild stable disease
 Minimal symptoms
 Near normal or normal pulmonary function
tests
 Mild radiographic involvement
 spontaneous remission may occasionally
occur
 Reassessed at 8 to 12 week intervals

55. Mild stable disease
 Macrolides - who prefer to avoid
glucocorticoid therapy.
 Clarithromycin 250 to 500 mg twice a day
 to anti-inflammatory rather than
antimicrobial effects

56. Persistent or gradually
worsening disease
 Progressive symptoms
 Moderate pulmonary function test Impairment
 Diffuse radiographic changes
 Initial therapy- oral glucocorticoids
 Associated with rapid improvement
 Initial dose of prednisone of 0.75 to 1 mg/kg per
day
 Maximum of 100 mg/day given as a single oral
dose in the morning

57. Persistent or gradually
worsening disease
 Maintaining the initial oral dose for four to
eight weeks
 If the patient is stable or improved,
 Prednisone dose is gradually tapered to 0.5
to 0.75 mg/kg per day (using ideal body
weight) for the ensuing four to six weeks
 After three to six months, the dose is
gradually tapered to zero if the patient
remains stable or improved.

58. Persistent or gradually
worsening disease
 Routine follow up with CXR and PFT every two to
three month.
 Chest radiograph may change before the patient
develops significant symptoms.
 Follow the patient clinically for the next year
 Repeat the chest radiograph approximately
every three months.

59. Persistent or gradually
worsening disease
 At the first sign of worsening or recurrent
disease.
 Prednisone dose should be increased to the
prior dose or reinstituted promptly

60. Failure to respond to systemic
glucocorticoids
 Review the initial diagnostic testing results
 Cytotoxic therapy
 Cytotoxic agent is usually started while
maintaining oral prednisone

61.  Cyclophosphamide :
 Initial dose is 1 to 2mg/kg per day (given as a
single daily dose) up to a maximum of
150 mg/day
 Start at 50 mg daily and slowly increase the
dose over two to four weeks

62. Failure to respond to systemic
glucocorticoids
 Macrolide antibiotic
 Cyclosporine has been used in combination
with glucocorticoids to treat rapidly
progressive disease

63. Inability to taper glucocorticoids
or intolerance of adverse effects
 Half of patients experience at least one
clinical relapse during the course of their
disease.
 Patients with persistent or frequently
recurrent (>3) episodes
 Require long-term treatment
with prednisone and a glucocorticoid-sparing
agent.

64. Fulminant disease
 Rapidly progressive a
 extensive disease
 Requiring high flow supplemental oxygen
 Glucocorticoids
 Methylprednisolone 125 to 250 mg every 6
hours or a pulse of 750 to 1000 mg given once
daily for 3 to 5 days)

65.  Once the patient shows signs of
improvement (usually within five days)
 Glucocorticoid therapy is transitioned to
oral prednisone at a dose of 0.75 to
1 mg/kg per day (using ideal body weight) to
a maximum of 100 mg/day.
 mycophenolate mofetil in combination with
intravenous methylprednisolone

66. Focal organizing pneumonia
 Resection of a solitary lung nodule containing
focal organizing pneumonia is adequate
initial therapy for most patients

67. PROGNOSIS
 Two -thirds of patients treated with
glucocorticoids shows complete resolution
 One -third of patients experience persistent
symptoms, abnormalities on pulmonary
function testing, and radiographic disease.

68. Comparison of outcome in COP
and IPF

69.  The overall prognosis of COP is much better
than that of other interstitial lung diseases,
such as idiopathic pulmonary fibrosis, fibrosis
nonspecific interstitial pneumonia, and acute
interstitial pneumonia

70. SUMMARY AND RECOMMENDATIONS
 One of the idiopathic interstitial pneumonias
 When organizing pneumonia is seen in association
with other processes, such as connective tissue
diseases, a variety of drugs, malignancy, or other
interstitial pneumonias, it is called secondary
organizing pneumonia
 fifth or sixth decades of life
 Men and women affected equally

71.  Symptomatic for less than two months
 Clinical presentation that mimics community-
acquired pneumonia
 Approximately half of cases are heralded by a
flu-like illness

72.  CXR shows multiple ground-glass or
consolidative opacities.
 PFT- Restrictive pattern with an associated
gas transfer defect
 FOB to r/o other cause.

73.  Surgical lung biopsy - definitive diagnosis.
 Histopathology :
 Excessive proliferation or “plugs” of
granulation tissue within alveolar ducts and
alveoli, associated with chronic inflammation
in the surrounding alveoli.

74. Treatment
 Therapy depend on the
 Severity of symptoms and
 Pulmonary function impairment
presentation,
 Radiographic extent of disease, and the
rapidity of progression.

75. mild stable
disese
Focal
organizing
pneumonia
Fulminant
disease
Persistent or
gradually
worsening
disease
CYPTOGENIC ORGNAISING
PNEUMONIA
Reassessed at 8 to
12 week /microlide
Oral glucocorticoids /+ Cytotoxic
therapy
Pulse therapy with
glucocorticoid
Surgical
Resection

76. THANKS