Respiratory Pathology

Bassam Mansour, MD, EDICM

Head, Pulmonary Division
The Lebanese University, Faculty of Medicine
Head, Pulmonary & Critical Care Medicine
Zahraa Hospital University Medical Center
Idiopathic Interstitial Pneumonias

Hypersensitivity Pneumonitis
 Definition

❖ Hypersensitivity Pneumonitis (HP) or extrinsic allergic

alveolitis is an immunologic-induced, non-IgE-mediated
inflammatory lung disease resulting from the
sensitization & subsequent recurrent exposure to any of
a wide variety of inhaled dusts.
 Epidemiology

❖ The incidence of HP in exposed populations varies

widely.

❖ A survey of 1,000 farmers in Wisconsin revealed

precipitins in 8.5% & clinical manifestations in one half .

❖ In an agricultural area of Scotland, HP incidence ranged

from 2.3 to 8.6%.
 Epidemiology

❖ Individuals belonging to Pigeon breeder clubs have

precipitins in 40 to 50% and disease manifestations in
from 6 to 21%.

❖ Reports of outbreaks of HP resulting from microbially

contaminated office buildings and industrial sites have
reported attack rates of 15% and up to 70% of those
exposed.
 Epidemiology
❖ Since the disease is present in only a minority of
exposed individuals, host factors must be important.
These factors remain unknown:
❖ Studies show that HP is less frequent in nonsmokers.
❖ Atopic patients are not at increased risk.
❖ Concomitant viral infections & exposure may play a
role.
 Pathology
❖ There is a diffuse predominantly mononuclear &
lymphocytic inflammation of the terminal bronchioles,
interstitium, and alveoli.

❖ There is little, if any, involvement of the larger airways.

❖ Lymphocytes & monocytes accumulate & often organize

into granulomas & may progress to fibrosis.
 Pathology
❖ Lymphocytes & monocytes
aggregating to form interstitial &
alveolar granulomas.
❖ We also note Multinucleated
Giant Cells & Central Fibrosis.
 Inciting Agents
❖ The disease is caused by the inhalation of an organic
dust or inorganic chemicals in a sensitized individual.
❖ A major factor is the size of the particle:
❖ Particles > 10 mcm are intercepted by the nose.
❖ Particles 5 - 10 mcm are cleared by the ciliary transport
mechanism or cause extrinsic asthma.
❖ Particles 0.3 - 5 mcm may reach the alveolar spaces where are
cleared by pulmonary macrophages or cause a hypersensitivity
reaction.
 Inciting Agents
❖ HP was once thought to be primarily an occupational
hazard, it is now known to be a recreational, avocational,
& environmental hazard as well. The list of offending
agents seems to be ever-expanding.
❖ The associated diseases have been given colorful &
descriptive names:
❖ Bagassosis is caused by exposure to moldy sugar cane.
❖ Farmer’s lung is caused by the inhalation of one of the
thermophilic actinomycetes, such as Micropolyspora faeni.
 Inciting Agents
❖ These actinomycetes cause the best known of the HP
syndromes; these are organisms that grow exuberantly
in hay that has not been properly dried or stored.
❖ Farm workers are exposed when the stored hay that
subsequently raked or turned over.
❖ They were also have been isolated from the soil,
manure, and grain compost.
❖ The thermophilic actinomycetes also grow in air
conditioners, home humidifiers, hot air furnaces,
swimming pools, hot tubs, and fire place.
 Inciting Agents
❖ Inhalation of animal products can also lead to HP; serum
proteins, urine proteins, dried excrement, feathers…
❖ The best-known example is bird fancier’s lung, but also
gerbil keeper’s lung, turkey handler’s lung…
❖ Highly reactive chemicals that are capable of forming
hapten-protein complexes with airway proteins have
been shown to cause HP like exposure to toluene
diisocyanate.
❖ Drugs have also been shown to cause an “HP-like
illness.” The best known is probably amiodarone, but
also gold, minocycline, cocaine…
 Clinical Presentation

❖ The clinical picture of HP is very similar regardless of the

inciting agent.

❖ It may present acute, subacute, and chronic. The chronic

form, appears to be the final common pathway for
either multiple episodes of acute HP or prolonged
subacute disease.
 Clinical Presentation
Acute HP
❖ Commonly caused by a brief but intense exposure.
❖ 4 to 8 h after the exposure, abrupt onset of flu like
illness: cough, dyspnea, tachypnea, rales, chills, fever,
malaise, diaphoresis, headache, & myalgias.
❖ The symptoms last 12 - 24 h, peaking at 8 to 12 h.
❖ In between attacks, the patient is usually asymptomatic.
❖ The acute febrile episode occurs after each contact with
the responsible antigen.
 Clinical Presentation
Subacute HP
❖ Attributable to a less intense but more prolonged
exposure.
❖ The onset is insidious resembling chronic bronchitis with
chronic cough, exertional dyspnea, malaise, anorexia,
fatigue, and weight loss.
❖ Symptoms are much less specific & are not readily
associated with the exposure .
❖ The diagnosis is challenging to even the most astute
clinician.
 Clinical Presentation
Chronic HP

❖ Unrecognized subacute disease can progress to chronic

HP if avoidance of the culprit agent is not done.

❖ Signs and symptoms of chronic HP are those of any

chronic pulmonary fibrosis where lung damage occurs.

❖ The entire picture becomes indistinguishable from end-

stage IPF of any cause.
 Pathogenesis

❖ HP occurs in the setting of exposure to dust and particles

of the correct size and composition:
❖ The size must be 0.5 - 5 m.
❖ Must be capable of providing an antigenic stimulus for not all
particles of this size will cause the syndrome.
❖ Must be relatively resistant to degradation to persist long
enough in lung tissue & allow sensitization.
 Pathogenesis
❖ HP occurs in the setting of exposure to dust and particles
of the correct size and composition:
❖ The patient must have been sensitized during a previous
exposure.
❖ The period of sensitization is variable and may be as short as
several months or may require a number of years of exposure.
❖ Not all of exposed will become sensitized, & the disease may
not occur, upon being re-exposed, in all who do.
❖ Individual susceptibility is important but not well
characterized.
 Pathogenesis

❖ Proinflammatory cytokines (Interferon gamma, IL10,

TNF) activate alveolar macrophages, cause an influx of
CD8 lymphocytes, facilitate granuloma formation, and
promote the development of fibrosis.
 Pathogenesis
❖ Type III or IV reaction alone cannot explain all the
observed phenomena & there is little evidence for a
type I or II.
❖ It is possible that an immune complex-mediated
hypersensitivity reaction initiates acute lung injury.
❖ This is followed by T-cell-mediated hypersensitivity
mechanisms that perpetuate the ALI, induce the
inflammation, granuloma formation, and interstitial
fibrosis seen in subacute and chronic disease.
❖ This is an active area of ongoing research.
 Diagnosis
❖ The diagnosis is made on a combination of characteristic
symptoms, physical findings, radiographic changes, PFT
results, & immunologic test results.

❖ A high index of suspicion should be maintained in

patients with recurrent bouts of an influenza-like illness
or interstitial lung disease, leading to a complete
occupational, avocational, & environmental history
 Diagnosis
Imaging

❖ The CXR can be normal or have subtle reticulonodular

changes in 40 to 45% of cases.

❖ Commonly a picture of scattered patchy interstitial

infiltrates that may coalesce is seen.

❖ Abnormalities usually return to normal days to weeks

after the acute episode.
 Diagnosis / CXR

❖ Subtle reticulonodular changes

indicating an the interstitial
process.
 Diagnosis
Imaging

❖ HRCT typically shows: centrilobular micronodules &

widespread ground-glass opacities.

❖ In the proper setting a pattern of centrilobular ground-

glass nodules on HRCT is fairly specific for HP.

❖ In chronic stages, imaging is indistinguishable from

IPF/UIP with a reticular pattern throughout the lung
fields & honeycombing is common.
 Diagnosis / HRCT

❖ Centrilobular micronodules &

ground-glass opacities.

❖ Also seen are patchy interstitial

infiltrates that may coalesce.
 Diagnosis
PFT’s

❖ PFT most commonly shows a restrictive impairment &

impairment of the diffusing capacity.

❖ These abnormalities returns to normal in between acute

episodes but may require several weeks.

❖ Progressive and irreversible restrictive changes are

found in the chronic form of the disease.
 Diagnosis
❖ Skin testing is neither appropriate nor practical.
❖ Serum precipitins are Ag specific complement-fixing Ab
of the IgG class, although IgM and IgA are also detected.
❖ Precipitating Ab to the offending agent are found in >
90% of patients with clinical disease.
❖ These Ab are not for screening & are not useful in the
absence of a clinical suspicion of HP.
❖ BAL: ↑ lymphocytes (65% vs 6%), with a low CD4/CD8
ratio.
 Diagnosis
Pathology
❖ A biopsy is often useful in establishing a diagnosis.
❖ Histopathology is distinctive & varies following the stage
of the disease.
❖ Pathologic diagnosis is easier on surgical biopsy rather
than transbronchial lung biopsy.
❖ Acute HP: alveolar and interstitial accumulation of
leukocytes, fluid, and macrophages in a centrilobular
distribution.
 Diagnosis
Pathology
❖ In the subacute or chronic phases: biopsy shows a
predominant lymphocyte, plasma cell, and macrophage
infiltration in the alveolar wall and interstitium:
❖ 70% show a loose noncaseating granulomas.
❖ 65% show varying degrees of fibrosis.
❖ 60% show bronchiolitis obliterans.

❖ The typical biopsy shows of cellular bronchiolitis, a

lymphocytic interstitial pneumonitis, & poorly formed
noncaseating granulomas.
 Diagnosis

❖ 6 criteria are suggested for diagnosis:

1. Exposure to a known offending Ag.
2. Positive precipitating antibodies to the offending Ag.
3. Recurrent episodes of symptoms.
4. Inspiratory crackles on examination.
5. Symptoms occurring 4 to 8 h after exposure.
6. Weight loss.
 Therapy
❖ Avoidance of re-exposure is key & may require a job
change, discarding a hobby, or moving to a new home.
❖ These changes may not be well received as 75% of
pigeon breeders with HP were still breeding pigeons at a
10-year follow-up!
❖ Changes in industrial procedures have proven beneficial.
❖ Antipyretics & O2 may be needed; bronchodilators
generally are not beneficial.
 Therapy
❖ Corticosteroids, (prednisone: 0.5 to 1 mg/kg) for 1 to 4
weeks, may decrease toxicity of the acute form but
probably offer no long-term advantage.

❖ Longer periods of treatment may be necessary for the

subacute form (up to 6 months), but remain of variable
benefits.

❖ Once the chronic phase has developed, any treatment is

of marginal benefit.
 Prognosis
❖ In the acute form, recovery is usually complete.

❖ Symptoms disappear in 12 to 48 h

❖ Fatigue, lassitude, and exertional dyspnea may last for

several weeks.

❖ The patient usually is asymptomatic between attacks.

 Prognosis

❖ In the subacute form, with avoidance, symptoms can

completely disappear .

❖ With continued exposure 30 to 60% of patients with

farmer’s lung were disabled in 5 years and 10 to 15%
were dead. This also means that 40 to 70% did not suffer
clinical deterioration despite continued exposure.
 Prognosis
❖ Pigeon breeders in Mexico had a 5-year mortality of
30%.

❖ Some experienced progression of the disease despite

avoidance of repeated exposure.

❖ In the chronic form, progressive functional deterioration

to respiratory insufficiency is likely, but progression to
end-stage disease is not a uniform finding.
Respiratory Pathology

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