CHRONIC DIFFUSE INTERSTITIAL (Restrictive)

Diseases

2 general categories
1. Chronic interstitial & Infilitrative diseases
a. Pneumoconioses
b. Intersitital fibrosis of unknown etiology
2. chest wall disorders
a. neuromuscular diseases
i. poliomyelitis
b. severe obesity
c. pleural diseases
d. kyphoscoliosis
Definition
a heterogeneous group of disorders characterized
predominantly by inflammation and fibrosis of the lung
interstitium associated with pulmonary function studies
indicative of restrictive lung disease.
Etiology
Unknown, some have intra-alveolar and interstitial
components
Features
1. Dyspnea
2. Tachypnea
3. End-inspiratory crackles
4. Eventual cyanosis, without wheezing or other FIBROSING DISEASES
evidence of airway obstruction
IDIOPATHIC PULMONARY FIBROSIS
Diagnostics
Other Name
CXR: ground-glass shadows (interstitial fibrosis)
Cryptogenic fibrosing alveolitis (Europe)
- bilateral lesions that take the form of small
Definition
nodules, irregular lines
a clinicopathologic syndrome marked by progressive
Note:
interstitial pulmonary fibrosis and respiratory failure
1. Distinguishable in early stages
Notable Feature
2. Advanced forms are hard to differentiate
a. End-stage lung / Honeycomb lung Histo pattern: Usual interstitial pneumonia (UIP)
i. Diffuse lung scarring
3. May result to - Also notable in:
a. secondary pulmonary HTN o CT diseases
b. R-sided HF (cor pulmonale) o Chronic hypersensitivity pneumonia
o Asbestosis

Etiology
Unknown
Pathogenesis
arises in genetically predisposed individuals prone to
aberrant repair of recurrent alveolar epithelial cell
injuries caused by environmental exposures
- Environmental factors
o cigarette smoking
o air pollution
o microaspiration
o metal fumes
o wood dust
o occupations
 farming
 hairdressing
 stone polishing
- Genetic factors
o Mutations in the TERT, TERC, PARN,
and RTEL1 genes
 15% familial: defects that
maintain telomeres
 25% sporadic: abnormal
shortening in peripheral blood
lymphocytes
o rare familial forms are associated with
mutations in genes encoding
components of surfactant
o a single-nucleotide polymorphism in the
Gross
promoter of the MUC5B gene
 increases the secretion of - Cobblestoned pleural surface of lung
MUC5B o retraction of scars along interlobular
 mucociliary clearance septa
- Age - firm, rubbery white areas of fibrosis
o disease of older individuals o in the lower lobes, the subpleural
o rarely <50 years regions, and along the interlobular septa
Micro
Hallmark: Patchy interstitial fibrosis
Earliest lesions: Fibroblastic foci
- exuberant proliferation of fibroblasts
Honeycomb fibrosis
- Formed as dense fibrosis causes the destruction
of alveolar architecture and the formation of
cystic spaces lined by hyperplastic type II
pneumocytes or bronchiolar epithelium

Other Morpho Features
- Diagnostic histologic changes
o areas of dense fibrosis and fibroblastic
foci identified even in advanced IPF (w/
adequate tests)
- Mild to moderate inflammation within the
fibrotic areas
o consisting of mostly lymphocytes
admixed with a few plasma cells,
neutrophils, eosinophils, and mast cells
- (+/-) Foci of squamous metaplasia and smooth
muscle hyperplasia
o with pulmonary arterial hypertensive
changes (intimal fibrosis and medial
thickening).
o In acute exacerbations, DAD may be
superimposed on these chronic changes.
NONSPECIFIC INTERSTITIAL PNEUMONIA
Epidemiology
Female nonsmokers in 60s
Etiology
Associated with CT dse, may be idiopathic
Morphology
1. Cellular pattern
o consists primarily of mild to moderate
chronic interstitial inflammation
 contain lymphocytes and a few
plasma cells
 uniform or patchy distribution.
2. Fibrosing pattern
o Diffuse or patchy interstitial fibrotic
lesions of roughly the same stage
o of development
 important distinction from UIP
(-) Fibroblastic foci, honeycombing, hyaline membranes,
and granulomas
Clinical Features
- dyspnea and cough of several months’ duration
Diagnostics

Clinical Features On imaging, the lesions have the

- Begins insidiously with gradually increasing - bilateral, symmetric, predominantly lower lobe
dyspnea on exertion and dry cough. reticular opacities
- Mostly 55 to 75 years
Prognosis
- Hypoxemia, cyanosis, and clubbing (late)
- Course in px is unpredictable. - Better prognosis than UIP
- Usually there is slowly progressive respiratory - Cellular pattern (younger) than with the
failure fibrosing pattern
- Some patients have acute exacerbations and o better prognosis
follow a rapid downhill clinical course
Treatment
CRYPTOGENIC ORGANIZING PNEUMONIA
Definitive tx: Lung transplantation
Etiology
Slows dse progress/targeted therapy:
associated with
1. Tyrosine kinase inhibitor
2. TGF-β antagonist - viral and bacterial pneumonias
- inhaled toxins, drugs
Prognosis - connective tissue disease
Median survival: 3.8 years after dx - graft-versus-host disease in hematopoietic stem
cell transplant recipients
Pathogenesis o Usual interstitial pneumonia
o Bronchiolitis
a response to infection or inflammatory injury of the
lungs Prognosis
Radio Features Variable (determined by extent & histo pattern)
patchy subpleural or peribronchial areas of airspace
consolidation
RHEUMATIC ARTHRITIS
Histo Features
- pulmonary involvement (30-40%)
Mason bodies o chronic pleuritis, with or without
- polypoid plugs of loose organizing connective effusion
tissue o diffuse interstitial pneumonitis and
- within alveolar ducts, alveoli, bronchioles fibrosis
o intrapulmonary rheumatoid nodules;
Morpho Notes o follicular bronchiolitis
- tissue is all of the same age, and the underlying o pulmonary hypertension
lung architecture is normal - Caplan syndrome
- no interstitial fibrosis or honeycomb lung o Lung disease in rheumatoid arthritis +
pneumoconiosis
Clinical Features
SYSTEMIC SCLEROSIS (SCLERODERMA)
cough and dyspnea
- associated with diffuse interstitial fibrosis
Treatment (nonspecific interstitial pattern more common
- Some patients recover spontaneously than usual interstitial pattern) and pleural
- Most need treatment with oral steroids for 6 involvement
months or longer for complete recovery. LUPUS ERYTHEMATOSUS
Prognosis - patchy, transient parenchymal infiltrates or
dependent on the underlying disorder occasionally severe lupus pneumonitis, as well
as pleuritis and pleural effusions.

PULMONARY INVOLVEMENT IN AUTOIMMUNE

DISEASE PNEUMOCONIOSES

Note Definition

- Many autoimmune diseases are also referred to non-neoplastic lung reaction to inhalation of mineral
as connective tissue diseases because of their dusts encountered in the workplace, now also includes
frequent association with arthritis) can involve disease induced by chemical fumes and vapors dusts
the lung at some point in their course. encountered in the workplace, now also includes disease
induced by chemical fumes and vapors.
Produce pulmonary disease
o systemic lupus erythematosus
o rheumatoid arthritis
o progressive systemic sclerosis
(scleroderma)
o dermatomyositis-polymyositis

Histo patterns of pulmonary involvement

o Nonspecific interstitial pneumonia
 o allows direct interactions with
fibroblasts and interstitial macrophages
o Some particles may reach the lymph
nodes through lymphatic drainage
directly or within migrating
macrophages
 Initiate an adaptive immune
response to components of the
particulates or to self-proteins
modified by the particles
5. Activation of inflammasome
o following the phagocytosis of certain
particles by macrophages
o innate immune response amplifies the
intensity and the duration of the local
Pathogenesis reaction
6. Tobacco smoking
Specific factors that influence the development of dust-
o worsens the effects of all inhaled
borne pneumoconiosis:
mineral dusts, but particularly those
1. Dust retention caused by asbestos
o determined by dust concentration in
Note
ambient air, duration of exposure, and
effectiveness of clearance mechanisms - small percentage of exposed people develop
o influence that impairs mucociliary occupational respiratory diseases
clearance significantly increases the o implying a genetic predisposition to
accumulation of dust in the lungs their development
 cigarette smoking
2. Particle size
o most dangerous particles are from 1 to 5
µm in diameter
 particles of this size can reach
the terminal small airways
 air sacs and deposit in their
linings
3. Particle solubility and cytotoxicity
o influenced by particle size
o small particles
 composed of injurious
substances of high solubility
 more likely to produce rapid-
onset acute lung injury
o larger particles
 more likely to resist dissolution
and
 may persist within the lung
parenchyma for years
o tend to evoke fibrosing collagenous
pneumoconiosis (characteristic of
silicosis)
4. Particle uptake by epithelial cells or egress
across epithelial linings

COAL WORKER’S PNEUMOCONIOSIS
Notes
- Contaminating silica in the coal dust favors the
development of progressive disease.
- In most cases, carbon dust itself is the major
culprit, and studies have shown that
- complicated lesions contain much more dust
than simple lesions.
- Coal workers may also develop emphysema
and chronic bronchitis independent of smoking
Etiology
inhalation of coal particles and other admixed forms of
dust
Lung Findings
spectrum of lung findings in coal workers:
- asymptomatic anthracosis
- simple coal workers’ pneumoconiosis
o with little to no pulmonary dysfunction
- complicated coal workers’ pneumoconiosis,
- progressive massive fibrosis
o lung function is compromised
Morpho Features
- Dark black carbon deposits (Gross & Micro
Feature)
- Anthracosis
o Most innocuous coal-induced
pulmonary lesion in coal miners
o Also seen in urban dwellers and tobacco
smokers
o Inhaled carbon pigment is engulfed by
alveolar or interstitial macrophages
 accumulate in the connective
tissue adjacent to the lymphatics
and in organized lymphoid
tissue adjacent to the bronchi or
in the lung hilus
Simple coal workers’ pneumoconiosis
- coal macules (1 to 2 mm in diameter)
- somewhat larger coal nodules
Coal macules
o consist of carbon-laden macrophages;
o nodules also contain a delicate network
of collagen fibers
o these lesions are scattered throughout
the lung
o upper lobes and upper zones of the
lower lobes are more heavily involved
o located primarily adjacent to respiratory
bronchioles,
 site of initial dust accumulation
- In due course dilation of adjacent alveoli occurs,
sometimes giving rise to centrilobular
emphysema
Complicated coal workers’ pneumoconiosis
- (progressive massive fibrosis)
- has a background of simple disease
- requires many years to develop
- has intensely blackened scars 1 cm or larger,
sometimes up to 10 cm in greatest diameter
- usually multiple
- Micro: lesion consists of dense collagen and
pigment
- Center of lesion is often necrotic
o Due to local ischemia

Clinical Features
- usually benign, causing little decrement in lung
function
- Even mild forms of complicated coal workers’
pneumoconiosis do not affect lung function
significantly
o <10%: progressive massive fibrosis
develops, leading to increasing
pulmonary dysfunction, pulmonary
hypertension, and cor pulmonale
- Once progressive massive fibrosis develops, it
may continue to worsen even if further exposure
to dust is prevented
- No convincing evidence that coal workers’
pneumoconiosis increases susceptibility to
tuberculosis, nor does it predispose to cancer in
the absence of smoking
- Indoor use of “smoky coal (bituminous) for
cooking & heating
o associated with an increased risk of lung
cancer death, even in those who do not
smoke
SILICOSIS
Definition
- common lung disease caused by inhalation of
proinflammatory crystalline silicon dioxide
(silica)
- accumulation of abundant lipoproteinaceous
material within alveoli
Presentation
- presents after decades of exposure as slowly
progressing, nodular, fibrosing pneumoconiosis
- heavy exposure over months to a few years can
result in acute silicosis
- onset:
o slow and insidious (10 to 30 years after
exposure; most common)
o accelerated (within 10 years of
exposure)
o rapid (weeks or months after intense
exposure to fine dust high in silica; rare)
Epidemiology
- dose and race are important in its development
- Risk: African American > Caucasian
- Workers:
o repair, rehabilitation, or demolition of
concrete structures such as buildings and
roads
o producing stressed denim by
sandblasting
o stone carvers
o jewelers using chalk molds
Pathogenesis
- Phagocytosis of inhaled silica crystals by
macrophages activates the inflammasome and
stimulates the release of inflammatory
mediators, particularly IL-1 and IL-18
 recruitment of additional inflammatory cells
 activates interstitial fibroblasts
 collagen deposition
- Silica occurs in both crystalline and amorphous
forms
o crystalline forms (including quartz,
cristobalite, and tridymite) are much
more fibrogenic
- lack of severe responses to silica in coal and
hematite miners due to coating of silica with
other minerals, especially clay components
o render the silica less toxic
- amorphous silicates are biologically less active
than crystalline silica
o heavy lung burdens of these minerals
may also produce lesions
Etiology
- associated with an increased susceptibility to
tuberculosis and a twofold increased risk of lung
cancer
 o TB: crystalline silica inhibits the ability
of pulmonary macrophages to kill
phagocytosed mycobacteria
Gross
Early stages
- tiny, barely palpable, discrete pale to blackened
(if coal dust is also present) nodules in the hilar
lymph nodes and upper zones of the lungs
As disease progress
- nodules coalesce into hard, collagenous scars
o some nodules may undergo central
softening and cavitation due to
superimposed tuberculosis or to
ischemia
- fibrotic lesions may also occur in the hilar
lymph nodes and pleura
Radiograph
Egg cell calcification
- thin sheets of calcification occur in the lymph
nodes
- calcium surrounding a zone lacking calcification
 disease progression
 continues to progress, expansion and
coalescence of lesions may produce
progressive massive fibrosis
Histo
Hallmark: a central area of whorled collagen fibers with
a more peripheral zone of dust-laden macrophages
*Examination of the nodules by polarized microscopy
reveals weakly birefringent silicate particles
Diagnostics
CXR
- a fine nodularity in the upper zones of the lung
Pulmonary function
- either normal or only moderately affected early
in the course
- most patients do not develop shortness of breath
until progressive massive fibrosis supervenes
o disease may continue to worsen even if
the patient is no longer exposed
o slow to kill, but impaired pulmonary
function may severely limit activity
ASBESTOS-RELATED DISEASES
Asbestos
- family of proinflammatory crystalline hydrated
silicates
- associated with pulmonary fibrosis and various
forms of cancer
- use is tightly restricted (high income countries
- lower control (lower income countries)
Asbestos-Related Diseases
1. Localized fibrous plaques or, rarely, diffuse
pleural fibrosis
2. Pleural effusions, recurrent
3. Parenchymal interstitial fibrosis (asbestosis)
4. Lung carcinoma
5. Mesothelioma
6. Laryngeal, ovarian, and perhaps other
extrapulmonary neoplasms, including colon
carcinoma
7. Increased risks for systemic autoimmune
diseases and cardiovascular disease also have
been proposed
Epidemiology
- More commonly after 20-30 years after first
exposure
o <10 years (rarely)
- potential hazards of even low-level exposure to
asbestos
o increased incidence of asbestos-related
cancers in family members of asbestos
workers has alerted the public
o necessity of expensive asbestos
abatement programs for environments
such as schools with low, but
measurable, airborne asbestos fiber
counts remains a matter of contention
 - Both lung carcinomas and mesotheliomas
(pleural and peritoneal) develop in workers
exposed to asbestos
Pathogenesis
- Disease-causing capabilities of the different
forms of asbestos depend on concentration,
size, shape, and solubility.
Asbestos acts as tumor initiator and tumor promoter
- oncogenic effects are mediated by reactive free
radicals generated by asbestos fibers,
o preferentially localize in the distal lung,
close to the mesothelial cells of the
pleura
o Toxic chemicals adsorbed onto the
asbestos fibers also likely contribute to
the oncogenicity of the fibers.
- Smoking
o adsorption of carcinogens in tobacco
smoke onto asbestos fibers
 basis for the remarkable synergy
between tobacco smoking and
the development of lung
carcinoma in asbestos workers
o enhances the effect of asbestos by
interfering with the mucociliary
clearance of fibers
Once phagocytosed by macrophages, asbestos fibers
activate the inflammasome and stimulate the release
of proinflammatory factors and fibrogenic mediators
- initial injury: bifurcations of small airways and
ducts
o asbestos fibers land, penetrate, and are
directly toxic to pulmonary parenchymal
cells
 alveolar and interstitial macrophage attempt
to ingest and clear the fibers
Long-term deposition of fibers and persistent release of
mediators (e.g., reactive oxygen species, proteases,
cytokines, and growth factors)
 generalized interstitial pulmonary
inflammation and fibrosis.
2 distinct geometric forms of asbestos*
1. Serpentine chrysotile (90%)
o more flexible
o curled structure
olikely to become impacted in the upper
respiratory passages and removed by the
mucociliary elevator
o More soluble
 once trapped in the lungs,
chrysotiles are gradually
leached from the tissues
2. Amphiboles
o Less prevalent
o More pathogenic (With respect to
induction of mesothelioma)
 malignant tumor derived from
the lining cells of pleural
surfaces
o Pathogenicity related to aerodynamic
properties and solubility
o straight, stiff
 may align themselves with the
airstream
 delivered deeper into the lungs
 can penetrate epithelial cells
and reach the interstitium
*both are fibrogenic, and increasing doses are associated
with a higher incidence of asbestos-related diseases
Morphology
- Diffuse pulmonary interstitial fibrosis
o distinguished by the presence of
asbestos bodies
- Asbestos bodies
o golden brown, fusiform or beaded rods
with a translucent center
o consist of asbestos fibers coated with an
iron-containing proteinaceous material
o arise when macrophages phagocytose
asbestos fibers
o iron is presumably derived from
phagocyte ferritin
- Pleural plaques
o most common manifestation of asbestos
exposure
o well-circumscribed plaques of dense
collagen that are often calcified
o develop most frequently on the anterior
and posterolateral aspects of the parietal
pleura and over the domes of the
diaphragm
o size and number not correlated to
level and time of exposure
o (-) asbestos bodies
 o Rare to w/o asbestos exposure
o Asbestos exposure induces pleural
effusion (rarely)
 Usually serous, may be bloody
o Diffuse visceral pleural fibrosis (rare)
 Advanced: bind lung to thoracic
wall
- Ferruginous bodies
o Other inorganic particulates may
become coated with similar iron-protein
complexes
- Fibrosis (Respi bronchioles & alveolar ducts)
 Involve adjacent alveolar sacs and alveoli
 fibrosis distorts the architecture
 create enlarged airspaces enclosed by thick
fibrous walls
 affected regions become honeycombed
vs Usual Interstitial Fibrosis: pattern of fibrosis is
histologically alike, with fibroblastic foci and varying
degrees of fibrosis
vs Coal Workers’ Pneumoconiosis and Silicosis:
asbestosis begins in the lower lobes and subpleurally,
with the middle and upper lobes becoming affected as
fibrosis progresses
- scarring may trap and narrow pulmonary arteries
and arterioles, causing pulmonary hypertension
and cor pulmonale
Clinical Features
- similar to those caused by other diffuse
interstitial lung diseases
- Dyspnea (first manifestation)
o Provoked by exertion, but later present
even at rest
- Cough w/ sputum
o Due to smoking > asbestosis
- honeycomb pattern
o advancement of the pneumoconiosis
- disease may remain static or progress to
respiratory failure, cor pulmonale, and death
- Asx pleural plaques are usually
o detected on radiographs as
circumscribed densities
Diagnostics
CXR: irregular linear densities, particularly in both
lower lobes
Prognosis
- Asbestosis complicated by lung or pleural
cancer is associated with a particularly grim
prognosis
COMPLICATIONS OF THERAPIES
DRUG-INDUCED LUNG DISEASES
- Increasing prescription drugs
o cause a variety of acute and chronic
alterations in lung structure and
function, interstitial fibrosis,
bronchiolitis obliterans, and eosinophilic
pneumonia
Cytotoxic drugs for cancer therapy
- e.g. Bleomycin
- pulmonary damage and fibrosis
o result of direct toxicity and by
stimulating the influx of inflammatory
cells into the alveoli
Amiodarone
- Class III antiarrhythmic
- preferentially concentrated in the lung
- causes significant pneumonitis in 5% to 15% of
patients receiving it
- cough induced by angiotensin-converting
enzyme inhibitors is very common
Illicit intravenous drug abuse
- most often causes lung infections
 - particulate matter used to cut drugs may lodge in - may occur without antecedent, clinically
the lung microvasculature, apparent, acute radiation pneumonitis.
- produce granulomatous inflammation and - At most severe form, chronic radiation
fibrosis pneumonitis and associated progressive fibrosis
can lead to cyanosis, pulmonary hypertension,
RADIATION-INDUCED LUNG DISEASES
and cor pulmonale
Radiation pneumonitis
- well-known complication of radiotherapy for
GRANULOMATOUS DISEASES
thoracic tumors
o lung SARCOIDOSIS
o esophageal
o breast Definition
o mediastinal systemic granulomatous disease of unknown cause that
- most often involves the lung within the radiation may involve many tissues and organs
field
- occurs in acute and chronic forms Epidemiology

Acute radiation pneumonitis - Mostly <40, but affects any age group
- F, but varies per country and population
- lymphocytic alveolitis or hypersensitivity - Rare in Chinese and Southeast Asians
pneumonitis - Patterns of organ involvement vary w. race
- US: highest in Southeast
Epidemiology
o 10 African-Americans: 1 Caucasians
- occurs 1 to 6 months after irradiation - Various clinical presentation are protean
- 3% to 44% of patients, depending on dose and o MC: bilateral hilar lymphadenopathy or
age parenchymal lung involvement (90% of
cases)
Clinical Features
o 2nd: Eye and skin
- - mycobacterial and fungal infections and
- Fever berylliosis, can also produce noncaseating
- dyspnea out of proportion to the volume of lung granulomas
irradiated o the diagnosis is one of exclusion
- pleural effusion
Etiology
- pulmonary infiltrates
- unknown
Morpho Features
Pathogenesis
- diffuse alveolar damage associated with atypia
of hyperplastic type II pneumocytes and - sarcoidosis is a disease of disordered immune
fibroblasts regulation in genetically predisposed individuals
- Epithelial cell atypia and foam cells within - several immunologic abnormalities in the local
vessel walls (radiation damage) milieu of sarcoid granulomas that suggest a cell-
mediated immune response to an unidentified
Treatment
antigen
- With steroid therapy, these symptoms may
Abnormalities involved:
resolve completely
- other cases progress to chronic radiation 1. Intra-alveolar and interstitial accumulation of
pneumonitis (pulmonary fibrosis) CD4+ T cells
 CD4/CD8 T-cell ratios ranging from 5:1 to
Chronic radiation pneumonitis
15:1
- pulmonary fibrosis o pathogenic involvement of CD4+
helper T cells
 o oligoclonal expansion of T-cell - Schaumann bodies
subsets as determined by analysis of o Laminated concretions composed of
T-cell receptor rearrangement, calcium and proteins
consistent with an antigen-driven - Asteroid bodies
proliferation o stellate inclusions
2. Increased levels of T cell–derived Th1 cytokines
o IL-2
 T-cell expansion
o interferon (IFN)-γ
 macrophage activation
3. Increased levels of several cytokines in the local
environment
o favor recruitment of additional T cells
and monocytes
o contribute to the formation of
granulomas
o TNF
 released at high levels by
activated alveolar macrophages
 concentration in the
bronchoalveolar fluid is a
marker of disease activity
4. Impaired dendritic cell function
Systemic immunologic abnormalities*
1. Anergy to common skin test antigens
o Candida or tuberculosis purified protein
derivative (PPD)
2. Polyclonal hypergammaglobulinemia,
o another manifestation of helper T-cell
dysregulation
*frequently observed
Evidence of genetic influences includes familial and
racial clustering of cases and the association with certain
human leukocyte antigen (HLA) genotypes (e.g., HLA-
A1 and HLA-B8)
Morpho Features
- Virtually every organ in the body has may be
affected
- Involved tissues contain well-formed non-
necrotizing granulomas
o composed of aggregates of tightly
clustered epithelioid macrophages, often
with giant cells
o Central necrosis (unusual)
o Chronic: granulomas may become
enclosed within fibrous rims or may
eventually be replaced by hyaline
fibrous scars