CYPTOGENIC ORGNAISING PNEUMONIA

DR.YOGESH GIRHEPUNJE

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 organising pneumonia

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

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Key histologic featuresKey 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

Pertinent negative findings1 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

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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.

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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.

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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.

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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

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Computed tomographic scanning  More extensive disease than

expected from review of the plain chest radiograph

Patterns include patchy air-space consolidation ground-glass opacitiessmall 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 organising pneumonia

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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.

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Marked hypoxaemia with possible

orthodeoxia because of alveolar right

to left shunting.

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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 eosinophilic pneumonia

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 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.

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

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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

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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

Fulminant disease

Persistent or gradually worsening

disease

CYPTOGENIC ORGNAISING PNEUMONIA

Reassessed at 8 to 12 week /microlide

Oral glucocorticoids /+ Cytotoxic therapy

Pulse therapy with

glucocorticoidSurgical

Resection

THANKS