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By MAHAVEER SINGH

WARD 31 LNH AND MAMC, NEW DELHI

Definition
Epidemiology

Classification
Pathogenesis

Diagnosis
Treatment Final comments

HAMMAN and RICH were the first to describe (in

1935 and 1944) four patients who died of rapidly progressive lung disease characterized by diffuse interstitial pneumonia and fibrosis.

ILD is a heterogeneous syndrome with the following common clinical features:


1. Exertional dyspnea
2. Bilateral diffuse infiltrates on chest radiographs 3. Physiological abnormalities with a restrictive lung defect,

decreased diffusing capacity (DLco) and abnormal alveolararterial oxygen gradient (PAO2 PaO2) at rest or with exertion.
4. Histopathology

with

varing

degrees

of

fibrosis

and

inflammation with or without evidence of granulomatous or secondary vascular changes in the pulmonary parenchyma.

It is more frequent than previously recognized. Incidence ranges from 3 to 26 per 100.000 per year. The prevalence of preclinical and undiagnosed ILD

in the community is 10 recognized.

times that of clinically

Among these, IPF is the most common,

representing at least 30% of the incident cases.

Interstitial Lung Disease (ILD)/DPLD


ILD of known cause, eg, drugs or association, eg, collagen vascular disease Idiopathic interstitial pneumonias Granulomatous ILD, eg, sarcoidosis Other forms of ILD, eg, LAM, HX, etc

Idiopathic pulmonary fibrosis

IIP other than idiopathic pulmonary fibrosis

Desquamative interstitial pneumonia Acute interstitial pneumonia Nonspecific interstitial pneumonia (provisional)

Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia

ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304.

Histologic Pattern
Usual interstitial pneumonia Nonspecific interstitial pneumonia Organizing pneumonia Diffuse alveolar damage Respiratory bronchiolitis

Clinical/Radiologic/Pathologic Diagnosis
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Desquamative interstitial pneumonia Lymphoid interstitial pneumonia

Desquamative interstitial pneumonia


Lymphoid interstitial pneumonia

Diagnosis IPF/UIP NSIP

Radiology
Fibrosis, HC GGO +/- fibrosis GGO, nodules, consolidation

Distribution
Basilar, peripheral Basilar, peripheral Patchy upper lungs, small airways, alveolar

Pathology
Temporal heterog., FF, fibrotic and normal lung, microscopic HC Diffuse interstitial inflammation +/- fibrosis Granulation tissue plugs in alveolar ducts and alveoli Hyaline membranes, immature fibroblasts in alveolar spaces and interstitium to variable degree Respiratory bronchiolitis surrounded by Ms in alveoli Alveolar Ms in air spaces diffusely in the biopsy Lymphoid hyperplasia

COP

AIP

GGO, consolidation
Bronchiectasis, GGO GGO, consolidation GGO, nodules, cysts

Diffuse, random
Upper lungs, bronchocentric Basilar, peripheral, alveolar Patchy

RB-ILD

DIP
LIP

HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage

Four proposed mechanisms and potential variations in lung responses to inhaled agents Inhaled environmental agents

(fumes, dust, smoke) Genetic predisposition

Delivery & persistence Biochemical

Alveolar epithelial cell injury

Wound healing (inflammation, coagulation, epithelial/endothelial repair)

Immunologic Fibrotic

Chronic airflow obstruction

Normal

Pulmonary fibrosis

Inflammatory hypothesis
Epithelial Cell Apoptosis Angiogenesis

Abnormal Matrix Turnover


Th1 versus Th2 Cytokines Growth Factor Production

Altered Fibroblast Phenotypes


Myofibroblast Recruitment and Maintenance

LUNG INJURY

Etiologic agent Recurrent vs single Endothelial vs epithelial

Histopathologic Pattern
DIP RB-ILD LIP COP NSIP AIP UIP

Inflammation

Fibrosis

Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

Clinical History Physical Laboratory PFTs

Radiology Chest X-ray HRCT

Pathology Surgical lung biopsy

Primary care physicians

Pulmonologists

Radiologists

Pathologists

Multidimensional and multidisciplinary

History

The patient's age, cigarette-smoking status and sex may provide useful clues. Thorough medical history that must include a review of environmental factors, occupations, exposures, medication, and drug usage and family medical history.

Infancy and childhood:


Follicular bronchiolitis

Cellular interstitial pneumonia


Acute idiopathic pulmonary hemorrhage of infancy

Before age 40:


Familial idiopathic pulmonary fibrosis Metabolic storage disorders

Hermansky pudalic syndrome


Other inherited interstitial lung diseases Collagen vascular disease- associated ILD LAM Pulmonary Langerhanscell granulomatosis Sarcoidosis

After age 50: IPF 1 in 500 people over the age of 75 yrs.

Gender clearly affects the way patients present with

pulmonary fibrosis: Men tend to present later in the disease, whereas women tend to present earlier.
Women : Collagen vascular disease- associated ILD LAM Tuberous sclerosis Men: Pneumoconiosis IPF Hypersensitivity pnuemonitis

Smoking related ILD : 1. Desquamative interstitial pneumonia. 2. RBILD. 3. Pulmonary Langerhans cell histiocytosis. 4. IPF. 5. Rheumatoid arthritis associated ILD. 6. Acute eosinophilic pneumonia.

Cigarette smoking is associated with a 1.6- to 2.3-fold

excess risk of pulmonary fibrosis.


The recognition that theses diseases are related to

smoking is not just a matter of cinematic the


cornerstone of therapy for theses patients is smoking cessation, in absence of which,

immunosuppressive therapy may have no effect whatsoever.

Acute onset (days to weeks):


AIP Acute pneumonitis from collagen vascular disease

(especially SLE) COP Drugs DAH Eosinophilic lung disease Hypersensitivity pneumonitis

Subacute (weeks to months):


Collagen vascular disease- associated ILD COP Drugs Subacute hypersensitivity pneumonitis

Chronic (months to years):


Chronic hypersensitivity pneumonitis
Collagen vascular diseaes- associated ILD IPF and NSIP Occupation related lung diseases.

History (cont.)
Farming

or exposure to known causes of hypersensitivity pneumonitis including birds, drugs, humidifiers. History of aspiration, dysphagia, arthritis, recurrent sinusitis, pneumothorax, muscle and skin symptoms, dry and gritty eyes, dry mouth and hemoptysis.

Physical examination of the respiratory system is rarely helpful in

the diagnostic evaluation of interstitial lung diseases.

The classical late inspiratory Velcro rales or inspiratory crackles,

occur not only in most patients with IPF but also in many other interstitial lung diseases. late inspiratory rhonchi inspiratory squeks found in some cases of ILD like RB-ILD.

The scaterred

In end stage disease there may be feature of cor pulmonale.

Among patients with ILD clubbing is found in 25-50% of

patients with IPF and 50% of patients with DIP and 75% of patients with ILD from rheumatoid arthritis.

Extrathoracic findings can be insightful e.g.


Skin abnormalities, peripheral lymphadenopathy

and

hepatosplenomegally

are

commonly

associated with sarcoidosis.


Iridocyclitis, uveitis or conjunctivitis may be

associated with sarcoidosis.

Characteristic skin rashes and lesions occur in collagen

vascular diseases, disseminated histocytosis-X, tuberous sclerosis and neurofibromatosis.


Signs of arthritis may be associated with sarcoidosis or

collagen vascular diseases


Sclerdactyly, Raynaud's phenomenon and telangiectatic

lesions are characteristics features of scleroderma and

CREST syndrome.
Epilepsy, mental retardation in tuberous sclerosis. Diabetes insipidus in Langerhans cell granulomatosis

First review previous chest radiographs as this

allows the clinician to ascertain the onset, progression, chronicity and stability of patient's disease. A rare patient with ILD will present with a normal chest radiograph. When radiographic abnormalities are noted, their distribution and appearance are useful in narrowing the differential diagnosis of ILD.

Mid/upper lung field disease: sarcoidosis,

silicosis, ankylosing spondylitis, histiocytosis X.


Lower lung field predominance: asbestosis,

idiopathic pulmonary fibrosis, collagen vascular

disease.
Kerley

B lines: congestive heart failure,

lymphangitic carcinoma, LAM.


Pleural plaques/ thickening: asbestosis.

Pleural effusion: congestive heart failure, lupus,

rheumatoid arthritis, LAM, drug induced.


Hilar

adenopathy:

sarcoidosis

(bilateral

and

symmetrical), lymphangitic carcinoma (unilateral).


Preserved lung volumes: sarcoidosis, histiocytosis X,

LAM.
Thin

walled cysts (better seen on HRCT):

histiocytosis X, LAM.

Photographic negative of pulmonary edema:

Chronic eosinophilic pneumonia.


Recurrent pneumothorax:

Langerhans cell granulomatosis. LAM Tuberous sclerosis. Neurofibromatosis.

CT and HRCT scans are more sensitive and have a greater ability to

detect anatomic abnormalities than do chest radiograph.


Its impressive sensitivity help both in ruling out a diagnosis of ILD and

in defining the parenchymal, pleural and mediastinal abnormalities in


these disorders.
It helps the surgeon to identify areas of non-fibrotic, active disease and

relatively unaffected areas to guide appropriate site selection for biopsy.

HRCT helps in

identifying "active and reversible glass attenuation) and

inflammation"

(ground

irreversible

fibrotic

manifestations

(traction

bronchiectasis, bronchiolectasis and honeycombing).


Extensive fibrotic changes suggest end or advanced stage

disease with limited potential for both invasive diagnostic and therapeutic approaches which could be

toxic.

Computed tomography and high-resolution CT images


HRCT has the potential for differentiating sarcoidosis,

lymphangitic carcinomatosis and bronchiolitis.


The presence of cystic images within the parenchyma

raises the possibilities of three major cystic ILD;


LAM,

Tuberous

sclerosis

and

Langerhans

cell

granulomatosis
In LAM and Tuberous sclerosis, the cysts are numerous,

thin walled, typically less than 2 mm in diameter and

distributed throughout the pulmonary parenchyma.


In Langerhans cell granulomatosis cysts are bizar shaped

and distributed predominantly in the upper lobes.

In acute hypersensitivity pneumonitis HRCT

show multifocal diffuse ground glass attenuation despite a normal chest radiograph. Smokers with symptomatic RBILD typically have patchy ground glass attenuation on HRCT. IPF is characterized by patchy subpleural and basilar fibrosis. A normal HRCT does not exclude the presence of microscopic ILD in a patient with a high pretest probability of the disorder.

Regardless of the cause, a restrictive lung defect

and decreased diffusing capacity (DLco) are the predominant physiological abnormalities seen in ILD.
Decreased FEV1, FVC, TLC The (PAO2 PaO2) difference, at rest or with

exercise may be normal or increased.

Differential diagnosis by function:


When there is a decrease in MVV out of proportion to

the decrease in FEV1 and a decrease in maximal


inspiratory pressures, diseases such as polymyositis, scleroderma and SLE should come to mind.
A mixed

pattern of obstructive and restrictive when ILD coexists with COPD or

abnormalities may be present in LAM, tuberous sclerosis and Asthma.

ILD associated with asthma or recurrent bronchospasm

include; Churg-Strauss syndrome, ABPA, Sarcoidosis (endobronchial) and tropical pulmonary eosinophilia.
Resting pulmonary function tests:

interstitial

Document the existence, gauge the severity and provide clues that are useful in the differential diagnosis of ILD. Also they are useful in the monitoring of clinical progression of the disease or response to therapy.

Exercise affords the most sensitive diagnostic and

physiological test for ILD. The degree of arterial


hypoxemia induced by exercise and the alveolararterial difference in P02 (PAO2 PaO2 gradient) correlate well with the degree of pulmonary fibrosis.

Include:
Complete blood count, leucocytic differential ESR Chemistry profile (calcium, liver function tests, electrolytes,

renal function tests)


Screening for collagen vascular diseases and urine analysis.
When

appropriate,

creatinine

kinase,

aldolase,

and

angiotensin converting enzyme levels should be measured.

Provide additional information, especially when tissue

abnormalities tend to be distributed in peribronchiovascular areas e.g. Sarcoidosis, LAM and Lymphangitic carcinomatosis and eosinophilic pnuemonia.

It may disclose certain distinctive abnormalities e.g.

Tight, uniform, well formed non caseating granulomas of sarcoidosis. Smooth muscle proliferation of LAM. Lymphatic metastasis of malignant cells. Giant cell granulomas are suggestive of hard metal pneumoconiosis.
It is diagnostic if an infectious agent or malignancy

is detected.

"Bronchoalveolar lavage"

Surgical lung biopsy remains the gold standard

for diagnosis. It is, however, by no means always definitive: the size of specimens, site of biopsy, expertise of pathologists and interobserver differences among pathologists are factors that may preclude a conclusive diagnosis. The site of the biopsy should be chosen on the basis of HRCT findings and ideally be at the interface of involved and less involved lung tissue. A biopsy of more than one site in the lung is more helpful.

TGLB or open lung biopsies merit consideration as

the final diagnostic step. Which patient are suitable candidates for these procedures? Unexplained dyspnea on exertion or abnormal results on pulmonary function testing favor such interventions (normal chest radiographs or HRCT scans do not negate the need for tissue diagnosis). On the other hand, not all patients with typical clinical features compatible with IPF require surgical lung biopsy for definitive diagnosis.

Major Criteria Exclusion of other known causes of ILD Evidence of restriction and/or impaired gas exchange HRCT: bibasilar reticular abnormalities with minimal ground glass opacities TBB or BAL that does not support an alternative diagnosis

Minor Criteria Age > 50 years Insidious onset of otherwise unexplained dyspnea on exertion

Duration of illness > 3 months


Bibasilar, inspiratory, Velcro crackles

All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.

The therapeutic regimen used for patients with

ILD needs to be tailored to the patient and the disease process (disease-specific intervention). Avoidance of the offending agent or its environment. The use of corticosteroids, alone or in combination with immunosuppressives (azathioprine, cyclophosphamide) is currently recommended for most patients with chronic fibrotic lung disorders. However the clinical response is variable and unpredictable, some ILDs generally have a better prognosis and response more favorably than do others.

Glucocorticoid therapy is recommended for

symptomatic ILD patients with eosinophilic pneumonias, COP, CTD, sarcoidosis, hypersensitivity pneumonitis, acute inorganic dust exposures, acute radiation pneumonitis, DAH, and drug-induced ILD. A common starting dose is prednisone, 0.51 mg/kg in a once-daily oral dose . This dose is continued for 412 weeks, at which time the patient is reevaluated. If the patient is stable or improved, the dose is tapered to 0.250.5 mg/kg and is maintained at this level for an additional 412 weeks, depending on the course.

Azathioprine (AZA) in patients who have responded to

glucocorticoids but need a glucocorticoid-sparing agent, have an incomplete response, or have not responded, but are not rapidly progressing. AZA is usually started at 50 mg/day and increased by 25 mg increments every 7 to 14 days up to 1.5 to 2.0 mg/kg per day, but not exceeding a maximum total dose of 200 mg/day.

IPF is the most common form of idiopathic interstitial

pneumonia. IPF has a distinctly poor response to therapy and a bad prognosis. Patients with IPF and coexisting emphysema [combined pulmonary fibrosis and emphysema (CPFE)] are more likely to require long-term oxygen therapy and develop pulmonary hypertension and may have a more dismal outcome than those without emphysema.

scattered foci of proliferating fibroblasts are a

consistent finding. The extent of fibroblastic proliferation is predictive of disease progression. There is no effective therapy for IPF. Chronic microaspiration secondary to gastroesophageal reflux may play a role in the pathogenesis and natural history of IPF.

HRCT lung scans typically show patchy, predominantly basilar, subpleural

reticular opacities, often associated with traction bronchiectasis and honeycombing .


Atypical findings that should suggest an alternative diagnosis include extensive

ground-glass abnormality, nodular opacities, upper or midzone predominance, and prominent hilar or mediastinal lymphadenopathy

Patients with IPF may have acute deterioration

secondary to infections, pulmonary embolism, or pneumothorax. Heart failure and ischemic heart disease are common problems in patients with IPF, accounting for nearly one-third of deaths. These acute exacerbations are defined by worsening of dyspnea within a few days to 4 weeks; newly developing diffuse ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with the UIP pattern; worsening hypoxemia; and absence of infectious pneumonia, heart failure, and sepsis.

A number of agents that interfere with collagen

synthesis have been tested: Pirfenidone (A pyridone molecule)


IFN--1b (A glycoprotein) Colchicine D-Penicillamine (A chelating agent). N-acetylcysteine (Antioxidant). Captopril (ACE inhibitor). Bosentan (Endothelin-1 receptor antagonist). Imatinib mesylate (A protein-tyrosine kinase

inhibitor).

Pirfenidone is an orally active, small molecule drug

that inhibits the synthesis of TGF-beta. The typical starting dose is 200mg, taken 3 times a day. Gastrointestinal (GI) events (nausea, dyspepsia, vomiting, and anorexia), skin disorders (rash, photosensitivity reaction), and dizziness are most common side effects of the perfenidone.

NSIP

is a subacute restrictive process with a presentation similar to that of IPF but usually at a younger age, most commonly in women who have never smoked. It is often associated with a febrile illness.
The key histopathologic feature of NSIP is the

uniformity of interstitial involvement across the biopsy section and little or no honeycombing .

HRCT shows bilateral, subpleural ground-glass

opacities, often associated with lower lobe volume loss. Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual.

The majority of patients with NSIP have a good

prognosis (5-year mortality rate estimated at <15%), with most showing improvement after treatment with glucocorticoids, often used in combination with azathioprine.

The onset is usually in the fifth and sixth decades.

The presentation may be of a flulike illness with

cough, fever, malaise, fatigue, and weight loss. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.

HRCT shows areas of air-space consolidation, ground-

glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone.

This is a rare, smoking-related, diffuse lung disease

that primarily affects men between the ages of 20 and 40 years.


The most common clinical manifestations at

presentation are cough, dyspnea, chest pain, weight loss, and fever.
Pneumothorax occurs in ~25% of patients. Hemoptysis

and diabetes insipidus are rare manifestations.

The combination of ill-defined or stellate nodules (2

10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH.

HRCT that reveals a combination of nodules and thin-

walled cysts is virtually diagnostic of PLCH. The nodular lesions are poorly defined and are distributed in a bronchiolocentric fashion with intervening normal lung parenchyma.

Discontinuance of smoking is the key treatment,

resulting in clinical improvement in one-third of patients. Most patients with PLCH experience persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.

Hydroxychloroquine:

is effective for control of cutaneous sarcoid and has been successfully used to treat sarcoid-associated hypercalcemia, arthritis, neurological disease, and pulmonary disease. Infliximab and etanercept (TNF-alpha inhibitor). Pentoxifyllin and Thalidomide (TNF-alpha antagonists). Methotrexate (10-25mg / week).

Infliximab.
Bosentan.

Granulocyte Macrophage Colony Stimulating Factor

(GM-CSF):

A cytokine that stimulates the granulocytes, macrophages, dendritic cells, and bone marrow precursors of platelets. Administered by either S.C injection or aerosolized form. It has recently been demonstrated to effectively control disease course and provide a very useful alternative to traditional therapy of whole lung lavage

Estrogen-containing

medications

should

be

discontinued. Oophorectomy, progesterone, Tamoxifen and luteinizing hormone-releasing hormone analogs have been used with limited success. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.

Beraprost sodium: prostacyclin analogue.

Sildenafil : phosphodiestrase inhibitor.


Bosentan: endothelin-1 antagonist. Theses medications may have beneficial effects that

extend beyond vasodilatation, including anti-fibrotic and anti-inflammatory effects

Other measures
Plasmapheresis is indicated in intractable and severe cases of

alveolar hemorrhage syndrome resistant to corticosteroids and immunosuppressives.


Supplemental oxygen is indicated to maintain adequate oxygen

saturation.
Unless

contraindicated,

all

patients

should

receive

pneumococcal and periodic influenza vaccinations.


Other supportive measures such as rehabilitation are indicated

in appropriate patients.
Lung transplantation is a viable surgical option for selected

patients who don't respond to currently available therapeutic regimens .