Post on 16-Jul-2015
CYPTOGENIC ORGNAISING PNEUMONIA
Introduction
Cryptogenic-organizing pneumonia (COP)/
Idiopathic BOOP
described in 1901 by Lange.
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.
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.
A DISTINCT ENTITY AMONG THE IDIOPATHICINTERSTITIAL 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).
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.
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.
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
Infectious causes of organisingpneumonia
Main Drugs as Cause of Organizing Pneumonia
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 .
Histopathology Masson body
Masson body
KEY HISTOLOGIC FEATURESKEY HISTOLOGIC FEATURES1. 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
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.
PATHOGENESIS
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.
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
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).
PATHOGENESIS
Proliferation of alveolar cells.
Re -epithelialisation of the basal laminae.
Crucial phenomenon for the preservation of
the structural integrity of the alveolar unit.
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).
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.
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
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.
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
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.
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.
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
EVALUATION
Chest radiographic appearance.
lack of clinical response to antibiotic therapy
Lab investigation
Leukocytosis is present in about 50 percent of patients with COP
ESR and CRP increase in 70 to 80%
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.
CXR
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.
Rarely
multiple nodules or masses that may
cavitate, micronodules, irregular reticular opacities in a subpleural location, and crescentic or ring-shaped opacities
Imaging features
Three main characteristic imaging patterns
1. Multiple alveolar opacities (typical COP)
2. Solitary opacity (focal COP)
3. Infiltrative opacities (infiltrative COP)
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
Typical cryptogenic organisingpneumonia
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
solitary focal opacity
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.
Infiltrative lung disease.
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.
Marked hypoxaemia with possible
orthodeoxia because of alveolar right to left
shunting.
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
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 eosinophilicpneumonia
BRONCHOALVEOLAR LAVAGE
Other (nondiagnostic) BAL include
Foamy macrophages, mast cells, plasma cells
Decreased CD4/CD8 T cell ratio.
Increase in activated T lymphocytes
Increased levels of Th1 related cytokines, including interferon (IFN)-y, interleukin (IL)-12 and IL-18.
Transbronchial lung biopsy
Inadequate for definitive confirmation of COP
Exclusion of other concomitant processes
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
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’’.
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.
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.
SEVERE AND/OR OVERLAPPING COP
COP may progress to fibrosis and
honeycombing
Especially in patients with the infiltrative
imaging pattern of organising pneumonia
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
TREATMENT
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
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
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
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.
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.
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
Failure to respond to systemic glucocorticoids
Review the initial diagnostic testing results
Cytotoxic therapy
Cytotoxic agent is usually started while
maintaining oral prednisone
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
Failure to respond to systemic glucocorticoids
Macrolide antibiotic
Cyclosporine has been used in combination with glucocorticoids to treat rapidly progressive disease
Inability to taper glucocorticoidsor 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.
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)
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
Focal organizing pneumonia
Resection of a solitary lung nodule containing focal organizing pneumonia is adequate initial therapy for most patients
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.
Comparison of outcome in COP and IPF
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
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
Symptomatic for less than two months
Clinical presentation that mimics community-
acquired pneumonia
Approximately half of cases are heralded by a
flu-like illness
CXR shows multiple ground-glass or
consolidative opacities.
PFT- Restrictive pattern with an associated
gas transfer defect
FOB to r/o other cause.
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.
Treatment
Therapy depend on the
Severity of symptoms and
Pulmonary function impairment presentation,
Radiographic extent of disease, and the rapidity of progression.
mild stable disese
Focal organizing pneumonia
Fulminantdisease
Persistent or gradually
worsening disease
CYPTOGENIC ORGNAISING PNEUMONIA
Reassessed at 8 to 12 week /microlide
Oral glucocorticoids /+ Cytotoxictherapy
Pulse therapy with glucocorticoid
Surgical Resection
THANKS