Interstitial Lung Diseases(ILD)

By : Dr. Shaher M. Samrah | Done by : Ibrahim M. | sun. 26.11.11

Introduction
Interstitial Lung Diseases (ILD) are group of diseases that affect the
interstitium of the lungs, it includes a long list of diseases with different
prognosis and different management; so we should learn about the
presentation of the patients with ILD, and how to make approach for Dx.
In this lecture the doctor concentrates on four diseases of ILD:
Sarcoidosis, Idiopathic Pulmonary Fibrosis, Eosinophilic Granuloma and
Lymphangioleiomyomatosis.
The classical presentation for ILD is Idiopathic Pulmonary Fibrosis(IPF),
also known as "Usual interstitial pneumonitis", or as known in the past
"cryptogenic pneumonitis", which has fibrotic impact on the interstitium
of the lung. The patient comes to the hospital hypoxic with severe SOB,
the SOB is chronic and progressive. This disease has a poor prognosis, so
we have to rule out all other causes of ILD carefully.
The other example is Sarcoidosis: it's a multi-systemic disease; start in
the interstitium of the lung, unlike IPF which purely affects the Lung;
there is no fibrosis at the early stages, in contrast they have "noncaseating granulomas", but may end up as fibrosis in the late stages.

Interstitium
The interstitium of the Lung is : the space
between basement membrane of the
capillary endothelium and alveolar cell
epithelium, it contains fibroblast, collagen
and elastic fibers, interstitial matrix,
inflammatory cells like macrophages; B & T
lymphocytes, and proteins like 1 antitrypsin
which assists in elasticity of the lung and
causes early onset COPD if deficient.

Mechanisms of Injury
Inflammation : due to proteases of Neutrophils, oxidants
like "H2O2, OH", chemotactic factors or Immunologically
mediated by antibodies.
Mesenchymal cells chemotaxis like PDAF, Fibronectin.
Locally produced injurious products like O2 toxicity.
Drugs : usually chemotherapy drugs like Bleomycin,
Busulfan, Methotrexate.
Remember that :
Extracellular molecules deposits Bleomycin : is an antibiotic used in
Like Amyloidosis.
testicular carcinoma.
Vasculitis : like Goodpasture
Methotrexate : immunosuppressant
syndrome.
agent, used in rheumatoid arthritis.

Pathological Classification
Granulomatous reaction: Sarcoidosis.
Fibrosis: Silicosis & Asbestoses
Exudative: Vasculitis.
Mix.

Functional consequences of ILD

Mechanical: Stiff lungs -decreased compliance- followed by
shrinkage of the lung, also restrictive lung disease changes;
like decrease Vital capacity 'VC', decrease total lung
capacity ' TLC ', also there is decreased Diffusion capacity
'Dlco' because the O2 has to go through diseased and thick
interstitium from alveoli to blood capillaries.
Dyspnea: because of lung stiffness and the need for using
the accessory muscles even when not hypoxic, the work of
breathing increase and dyspnea results.
Tachypnea: because of activation of J-receptors.
Hypoxia: due to the increased Alveolar-arterial gradient.

Pulmonary hypertension : as a consequence of blood

vessels destruction and distortion, and the vasoconstriction
induced by hypoxia.

Remember!!
Hypoxia in general causes vasodilatation; except in the lung
where it causes vasoconstriction.
So in ILD the hypoxia causes vasoconstriction and then
vasoconstriction worsen the hypoxia itself and so on.
In ILD we have two elements that increase O2 requirement; ILD
itself and pulmonary HTN that's caused by hypoxia.

ILD Classification
Known causes:
Occupational: Asbestosis, Silicosis.
Hypersensitivity Pneumonitis: Farmers lung.
Drug induced: Chemotherapy, Antibiotics.
Poison induced.
Radiation induced: like breast cancer or lymphoma
radiation therapy. There is fibrosis and even hypoxia ,
but to consider it as radiation induced it must be
localized at the radiation beam site.
Unknown causes:
Sarcoidosis.
Idiopathic Pulmonary Fibrosis (IPF).
Connective tissue disease: like SLE, Scleroderma,
Rheumatoid arthritis, ankylosing spondylitis, those
are known diseases with unknown etiology.

Langerhans cell Histiocytosis (Eosinophilic

Granuloma).
Alveolar hemorrhage syndromes/ Vasculitis :
Goodpasture Syndrome, wegener's granuloma.
Chronic Eosinophilic Pneumonia (CEP).

There is a long list of ILD classification the doctor didn't

read them, please refer to the slides #( 11-14) if you're
interested.

X-Ray Findings
Reticular / Reticulo-nodular diffuse infiltration.
Increase lung markings.
Lymphadenopathy, like in Sarcoidosis.
Fibrosis: Honeycomb changes like in IPF.
Granulomatous diseases like Sarcoidosis and Ankylosing
Spondylitis: mainly show upper lobe lesion on CXR.
Connective tissue diseases: mainly show Lower lobes lesions
on CXR.

Note!!
Inhalation injury like TB affect upper lobes more !!
Circulation and antibodies related diseases : affect Lower lobes !!

This is reticular diffuse lung

infiltration on CXR, indicate
marked diffuse interstitial
fibrosis, we can also see
normal sized heart, the
other differential diagnosis
we should put in mind is
pulmonary edema but
usually is accompanied with
congestive heart failure.

This is a CT- scan shows

honeycomb changes
detected in cross
section.

Approach to diagnose ILD

We start by history taking and Physical examination :
Assess symptoms severity. Detect extra pulmonary
manifestation in systemic diseases like sarcoidosis; and rule
out secondary causes like rheumatoid arthritis in which
joint pain associated, or scleroderma which is presented by
deformities and esophagitis.
Pulmonary Function Test 'PFT': We have restrictive lung
findings on spirometry; like decrease TLC and VC, also we
detect decrease Diffusion capacity 'Dlco'.
Labs : We screen for Connective Tissue diseases like
rheumatoid arthritis; and SLE where we ask for cANCA in
case of Vasculitis suspicion. Kidney Function Test 'KFT' is
also helpful in Vasculitis and as a routine test.
X-RAY : To assess the severity of ILD we ask for Chest X-Ray
'CXR', High resolution CT "HRCT" which is similar to the
classical CT scan with thicker slices to observe lung
parenchyma better; but without contrast.
Biopsy : We do either Bronchoscopy and get TBBx "Trans
bronchial biopsy", or we do Open lung biopsy which is
invasive and has a risk for pneumothorax. Nowadays,
studies showed that in IPF the fibrosis is very characteristic;
so we don't need invasive procedure like biopsy to confirm
Dx; the characteristic CT scan findings are enough to
diagnose idiopathic pulmonary fibrosis 'IPF'.

Sarcoidosis
Idiopathic, multi-systemic disease characterized
histologically by Noncaseating Granuloma.
Noncaseating Granuloma 'NCG' is not specific for
sarcoidosis : so remember that the caseating granuloma is
always TB, but Noncaseating is either sarcoidosis, "early
stage TB", Fungal infection ,Vasculitis, , Beryllium, Silicosis
and maybe malignant lesion like lymphoma.
We should differentiate between them; because
management is different; imagine treating misdiagnosed
fungal infection as sarcoidosis with IV steroids; this will
worsen the situation and could kill the patient.
It affects Young (20-40), Females more than males, and
more in Blacks. There is high Dx rate in TB community,
because in any patient if we find lymph node we call it TB
then upon biopsy we find it sarcoidosis, so there is a higher
diagnosing rate in TB community.

Symptoms :
Mostly asymptomatic; diagnosed accidently by enlarged
lymph nodes on CXR, then Noncaseating granuloma upon
biopsy; here we don't need treatment when we rule out
other causes.
Acute Symptoms: Fever, Lfgrens syndrome which is
"Triad of Skin lesion (Erythema Nodosum), Polyarthritis and
bilateral Hilar Lymphadenopathy".
In Chronic sarcoidosis we have: Pulmonary symptoms like;
Cough, SOB, chest pain, or we have extra-Pulmonary
symptoms.

Extra-Pulmonary symptoms
ENT: Hoarseness of the voice , Xerostomia (dryness mouth),
hearing loss.
Eye: Uveitis and impaired vision, enlarged Lacrimal glands
which is characteristic for sarcoidosis because no other
similar disease can cause it.

Skin: Erythema Nodosum seen in many diseases include

sarcoidosis in the shin of the lower extremities, Lupus
Pernio "see Figure below"; it is redness involve the nose saddle
and the cheeks; it differs from SLE as it is more diffused.
Heart: Heart Block, Arrhythmias, cardiomyopathy.
Nervous System: Bells palsy, Meningeal signs.
Parotid gland: Heerfordts syndrome or Uveoparotid fever
which is "Parotid gland enlargement + Fever + Facial palsy+
Ant. Uveitis"
Liver: Hepatomegaly
Joints: Arthritis.
Blood: leucopenia, anemia; so we should be careful when
treating with steroids because of infection.
Endocrine: Hypercalcemia & Hypercalciuria, increase
vitamin D activity, so we pay attention to steroid induced
osteoporosis, Sarcoidosis may also cause pituitary Diabetes
insipidus which cause dehydration and hypernatremia.

Lupus Pernio

SLE

Diagnosis of Sarcoidosis
As usual we start by Hx and physical examination.
Labs: In the past they used to measure Angiotensin
Converting Enzyme level (ACE), but because it increases in
any case of inflammation and it's not specific, this is only
helpful in assessing the responding for treatment, or
measuring disease activity.
Pulmonary Function Test: indicates restrictive changes, and
decreased Diffusion capacity as any ILD.
Chest X-ray is used for staging: see the figure next page.
Stage I: bilateral Hilar lymph nodes on CXR but no ILD.
Stage II: bilateral Hilar lymph nodes with ILD.
Stage III: ILD without fibrosis but no lymph nodes on
CXR.
Stage IV: Fibrotic changes also without lymph nodes
on CXR.
So sarcoidosis starts as lymph nodes on CXR; and ends up as
fibrosis. Remember also that those stages may be skipped;
so stage I may all of a sudden goes to stage IV skipping stage
II and III. Keep in mind also that it's irreversible progression;
it can't back off to an earlier stage if it progresses to an
advanced stage.
Biopsy: here the biopsy is important: we might use
Transbronchial biopsy or mediastinoscopy, the later one is
more helpful than open lung biopsy; because it goes more
medially in the mediastinum to the lymph nodes to take a
biopsy. Bronchoalveolar lavage also helpful; it reveals
increase in CD4+ T-lymphocyte. Gallium scan: not
important, because it's expensive, inconvenient, difficult,
and not used any more.

Those are the stages of sarcoidosis

Prognosis
Good prognosis.
Most cases are self-limiting, (85%) of cases resolve in
within 2 years.
10-15% of cases: have chronic and progressive
course.
Mortality rate is 1-6%.

Causes of death
Pulmonary: respiratory failure, infection, mycetomas,
hemoptysis.
- Mycetomas : is a fungus inside a cavity with
destruction of lung parenchyma, that
commonly affect blood vessels and cause
severe hemorrhage.
Cardiac: heart block, arrhythmias, cardiomyopathies,
congestive heart failure.
Kidney may also be involved with renal failure.

Sarcoidosis treatment
In the 85% of self limiting cases; we don't need treatment, but we treat
in those cases:
Pulmonary Indications for treatments:
Moderate or severe lung disease; we can't wait , we should
treat before fibrosis takes place.
Progressive lung disease.
Extra-Pulmonary Indications:
Threatened organ failure like heart, CNS, Eye...etc
Persistent Hypercalcemia.
Disfiguring skin lesion like lupus Pernio .
Severe constitutional symptoms; like generalized weakness,
fatigue, fever, insomnia..etc
Management includes: Steroids, Immunosuppressive, cytotoxic
agents; or Lung transplantation, Single lung is enough.

Idiopathic Pulmonary Fibrosis (IPF)

Specific clinical syndrome of unknown etiology.
Affects middle aged or elderly (>40).
More in Males (2:1); unlike sarcoidosis which is more
common in females.

Clinical presentation:
insidious
Progressive SOB; exertional than at rest, with
nonproductive Cough, and Cyanosis.
weight loss, fatigue, anorexia.
On examination:
Chest: Velcro-inspiratory crackles; which is an early
inspiratory crackles; it results from taking breath that
opens fibrotic alveoli; it differs from congestive heart
failure crackles as these are end inspiratory phase.
Clubbing : is not a specific sign, has Long list of DDx.

IPF diagnosis
We start with Hx, and Physical examination.
Labs: we should rule out secondary causes of ILD like
connective tissue diseases; because this disease has a
bad prognosis and high mortality so we should
carefully rule out all other treatable possibilities.
PFT: Restrictive changes TLV, VC, and decreased DLco
"diffusion capacity".

ABG: Hypoxia.
CXR: changes are more prominent in the lower lobes
and the periphery; subpleurally.
HRCT-Chest: findings range from ground glass to
Honeycomb changes or mix; depending on the stage
of the disease. This HRCT distribution is diagnostic
and characteristic, and no need for biopsy if founded.
We can't do Transbronchial biopsy; because we need
large biopsy to diagnose IPF, so we need open lung
biopsy.

We see fibrotic changes in the lower lobes

and peripherally, we don't see effusion
because it's rare in IPF, no mediastinal
deviation because fibrosis is bilateral, note
that upper lobes are spared. If we do
Bronchoalveolar lavage we found
neutrophiles unlike sarcoidosis where we
found CD4+ T-lymphocytes, the normal limit
for neutrophiles is 1%, more than this is
pathological and contributed by IPF in this
case.

Histopathological classification: not important

Usual interstitial pneumonia (UIP) most common.
Desquamative interstitial pneumonia (DIP) better prognosis
than UIP.
Nonspecific interstitial pneumonia (NSIP).

IPF management
Because the disease is not treatable we give nonspecific treatment :
Indication for treatment: Deteriorating or significant Symptoms +
inflammatory changes (ground-glass opacities) on HRCT.
Steroids.
Immunosuppressive or Cytotoxic agents: Azathioprine,
Cyclophosphamide.
Antifibrotic agents: Colchicine, D-Penicillamine, -interferon (not
used in sarcoidosis).
Lung transplantation: single
When we have a disease that has a long list of medications; the response
is very poor because the disease is untreatable.

Prognosis: Poor
Causes of death:
Cor pulmonale.
Respiratory failure (3-8 years after onset of Symptoms).
Malignancy (Adenocarcinoma) is more common and hard to
diagnose in this case because the whole lung is fibrotic.

Eosinophilic Granuloma :
Langerhans cell granulomatosis.
Smokers, M>F.
They have Lytic bone lesion, pituitary Diabetes insipidus like
that in sarcoidosis.

Causes pneumothorax in up to 50%.

Chest HRCT: diffuse centrilobular nodules and cysts
formation. See figure below
We take lung Biopsy.
Bronchoalveolar lavage: reveals increase Langerhans cell.
Management: Stop smoking + sometimes Steroids.

HRCT image from a patient with pulmonary Langerhans cell

Histiocytosis showing diffuse centrilobular nodulation and
cyst formation.

Lymphangioleiomyomatosis (LAM)
Exclusively premenopausal women
Immature smooth muscle proliferation in the lymphatic,
vascular and alveolar wall.
HRCT-Chest: Diffuse thin walled cystic lesion.
Recurrent Pneumothorax, hemoptysis, Chylothorax because
it affects the lymph.
Management.:
No Estrogen, and advice against pregnancy.
Anti-Estrogen (progesterone), Oophorectomy.

HRCT image from a patient with lymphangioleiomyomatosis showing

characteristic thin-walled cysts throughout the parenchyma

The END
Done By : Ibrahim Mahmoud