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