Lecture 3

Fall 2001

Marie E. Kavanagh, M.D.


Outline of lecture # 3

Pulmonary tuberculosis

Primary tuberculosis

Ghon complex

Miliary tuberculosis

Secondary tuberculosis

Chronic progressive tuberculosis

Diffuse interstitial diseases of the lungs

Diseases of known etiology


Pathogenesis of the pneumoconioses

Coal worker pneumoconiosis


Progressive massive fibrosis


Berylliosis, Acute and Chronic.


Hypersensitivity pneumonitis

Drug induced pulmonary fibrosis

Diseases of unknown etiology affecting the diffusing capacity of the lungs.


Pulmonary Amyloidosis

Pulmonary Hemorrhagic Syndrome

Goodpasture syndrome

Idiopathic pulmonary hemosiderosis

Idiopathic Pulmonary Fibrosis

Pulmonary alveolar proteinosis

Desquamative interstitial pneumonitis

Hamman Rich syndrome

Pulmonary eosinophilia

Loeffler syndrome

Tropical eosinophilia

Chronic eosinophilic pneumonia.



Lecture # 3

FALL 2001

Through the end of the nineteenth century and the early 20th century, pulmonary tuberculosis was considered a very severe disease that was inevitably fatal, a disease not only of individuals but also a disease of communities with an epidemic curve that can be traced to certain specific groups and certain given areas. With the development of the BCG (Bacille Calmette Guérin) vaccine, early diagnosis and appropriate treatment, there was a steady decline in the number of cases and the gravity of the disease reaching a plateau of about one million new cases a year throughout the entire world. With the discovery of certain drugs and a very intensive public health awareness, tuberculosis became almost entirely eradicated in some areas of the world, but had remained endemic in certain others. In recent years however, with the assault on the immune system, either therapeutic (chemotherapy) or infectious (AIDS), and the use of crack-cocaine drug and also with the emergence of multidrug-resistant mycobacteria, there has been an increase in the number of cases of tuberculosis reported throughout the world. The emergence of the multidrug resistant microorganisms is for the most parts due to poor compliance of the patients to a prescribed drug regimen. In NY city for example 20% of new cases of tuberculosis are caused by bacilli resistant to at least two of the antituberculous drugs, Isoniazid because of mutation in catalase and Rifampin because if mutation in RNA polymerase. These new cases are reported mainly in individuals emigrating from endemic areas of the world and in the AIDS population.


Two species of Mycobacteria cause the disease in humans: The Mycobacteria tuberculosis hominis and the Mycobacteria tuberculosis bovis. Not all individuals exposed to the bacteria develop the disease; most people become sensitized, develop an asymptomatic lesion and are converted to tuberculin reactors as can be demonstrated with the Mantoux or the Tine tests in which purified protein derivatives (PPD) of the bacilli are injected intradermal to provoke an area of induration in sensitized individuals. Falsely negative reactions can result from non related diseases (viral infections, vaccination, drugs, steroid & hormone therapy, malnutrition, neoplasm, immunosuppression).

The pathogenicity of the M. Tuberculosis relies on its ability to survive destruction by the macrophages and to induce a delayed hypersensitivity reaction.

The persistence of the microorganisms in the system is due to certain attributes of the M.Tuberculosis that make it very tenacious. This tenacity depends on the presence of certain factors:

A cord factor- made basically of glycolipid causes some irregularity in pattern of growth of the microorganism

The LAM factor- Lipoarabinomannan- is a polysaccharide present in the M.Tuberculosis that inhibits the macrophage activation by the interferon-g , and stimulates TNF-a (Tumor Necrosis Factor Alpha) secretion responsible for the tissue damage, weight loss & fever. The LAM is also responsible for the suppression of T cells proliferation.

Opsonization and uptake of the microorganisms by the macrophages without the actual elimination of the M.Tuberculosis explains the persistence so characteristic of the disease. The macrophages serve as reservoir for the microorganisms that survive for a long period of time.

Heat-shock protein found in the microorganisms triggers an autoimmune reaction.

The cell mediated or type IV hypersensitivity reaction to the M.Tuberculosis explains the massive tissue destruction so characteristic of the disease.

The lungs are usually the first organ to be affected by the mycobacterium tuberculosis also known as the Koch bacillus since it is transmitted through inhalation of infective droplets. The result is a granulomatous infection of the lungs for which the initial signs and symptoms vary depending on whether it is a primary, a secondary or a progressive form of tuberculosis.


This form of tuberculosis occurs in patients lacking previous contact or previous immunity to the Koch bacilli. The result of the infection is the formation of a single pulmonary lesion known as the GHON FOCUS.

The Ghon focus consists of a central area of soft caseous necrosis surrounded by inflammatory infiltrate and walled of by an area of granulation tissue containing multinucleated Langhan's giant cells. The focus of tuberculosis is often located under the pleura either on the lower part of the upper lobe or the upper part of the lower lobe, it measures 1 to 1.5cm in diameter. The TB bacilli of the Ghon focus drain through the lymphatics to infect the hilar lymphnodes, the combination of the Ghon focus and the affected lymphnodes form the GHON COMPLEX.

In 90% of adults with adequate immune system, mostly with the cellular immunity playing an important role in the host defense against the progression of the disease, the Ghon complex heals, becomes fibrotic and eventually calcifies. Most of the bacilli die, but few may remain viable for years and when the immune system fails, these bacilli can be reactivated.

Progressive Primary or Miliary Tuberculosis

In a small percentage of adults and a great percentage of children under 5years, the primary lesion may become a progressive primary form of tuberculosis. This is usually due to extension of the Ghon focus, formation of satellite lesions, spreading of the infectious material through the lymphatics resulting in involvement of the opposite lung. In this miliary form of tuberculosis, both lungs and some times distant organs are seeded with very small foci of Tuberculous granulomata.


Secondary pulmonary tuberculosis may be due to the reactivation of an old dormant primary focus (5 to 10%), it may follow a subclinical case of primary tuberculosis, or it may be due to reinfection by exogenous bacilli. In all cases, secondary tuberculosis occurs in a previously sensitized patient.


The disease can be followed through several stages.

The lesion begins as a tubercle, the microorganisms searching for high oxygen tension, usually settle in the apical portion of one or both lungs.

A tubercle is no larger than 3cm and consists of a central area of caseous necrosis surrounded by granulomatous tissue containing the typical Langhans giant cells and the epithelioid cells. The tubercle is separated from the surrounding tissue by a layer of fibrous tissue infiltrated with lymphocytes With adequate treatment, eventually, the fibrous process that starts at the periphery of the tubercle progressively invades and replaces the necrotic area, but, on occasion, the center of the lesion may remain soft. Carbon particles can be identified in the fibrous tissue. The microorganism may be demonstrated early in the disease by the use of a special acid fast stain, either in the sputum of affected patients or in the lung tissue.

The hilar lymphnodes affected by primary tuberculosis may also reactivate and form a secondary focus. The pleura may also show lesions of secondary tuberculosis with pleural effusion (Tuberculous pleuritis) or empyema, and eventually fibrotic reaction or even calcification of the pleural tissue.

A poorly treated case of pulmonary tuberculosis may evolve to the progressive form.




Several tubercles usually coalesce to form larger lesions. When a pulmonary tubercle or a larger lesion erodes inside a bronchiole, the content of the tubercle drains inside the airways it not only sends sattelite lesions it also leaves a cavitary lesion with an increased oxygen tension, factor that facilitates further growth of the microbacteria. These cavitary lesions which are characteristic of secondary tuberculosis, can be located in one or in several lobes, they are lined with a yellowish-gray caseous necrotic material surrounded by fibrous tissue. One old form of treatment consisted in creating artificial pneumothorax aimed at collapsing the existing pulmonary cavity.

Erosion of a tubercle inside a blood vessel may lead to hemoptysis which is a common complication of the progressive form of tuberculosis.

If left untreated the tuberculous process may progress rapidly to an overwhelming disease affecting other organs.

Drug susceptibility studies should be done on every new case of tuberculosis. A full course of treatment should be done to curtail the spread of the disease, at least four different anti-tuberculous drugs should be used in the treatment of any active lesion. Surgical resection of the affected areas of the lungs that has been abandoned for a while should be used in certain drug resistant cases. But not every patient is a good candidate for surgery, certain conditions have to be considered namely: Persistent positive smear and culture of sputum, Localized lesions , Adequate lung reserve and good general condition


This category of pulmonary lesions representing about 15% of non infectious respiratory diseases includes various entities having in common a progressive fibrosis of the pulmonary interstitial tissue leading to a reduction of the diffusing capacity of the lungs. The clinical characteristics are those of a restrictive rather than obstructive disease. Many of the entities are of known etiology, few, however may be idiopathic.

The basic pathogenesis common to all the conditions starts with an inflammatory infiltrate of the alveolar septae (alveolitis). Several factors are involved in the pathogenesis of the initial alveolitis:

This includes direct toxicity from chemicals having damaging effect on the endothelium and epithelium of the distal unit of the lungs, but more important are the damaging effects of the proteases and the toxic oxygen-free radicals secreted by the influx of neutrophils in the area. The neutrophils are attracted to the area by the chemotactic factors secreted by the alveolar macrophages. Certain degree of cell-mediated immune reaction also play a role in the pathogenesis of the alveolitis.

The alveolitis is then followed by progressive fibrosis of the interstitial tissue of the lungs. The result is the formation of dilated, non -functional air spaces surrounded by thick, fibrous rigid walls, alterations known as "honeycomb lungs " that usually leads to secondary pulmonary hypertension, right sided heart failure with cor pulmonale.


The medical conditions of known etiology leading to the diffuse interstitial fibrosis of the lungs are numerous, they are a large component of the environmental and occupational pathology.

These include:

The Pneumoconioses resulting from inhalation of occupational and environmental inorganic dusts.

The hypersensitivity pneumonitis resulting from inhalation of organic dusts responsible mostly of granulomatous lesions on the respiratory tract.

The pulmonary lesions resulting from drug injury, inhalation of toxic substances and infectious diseases of the lungs.



The term Pneumoconioses is used to describe the reaction of the lungs to a group of clinical disorders caused by inhalation of inorganic material. The source of these inorganic substances may be air pollution, chemical and physical agents, or certain drugs.

In the past, the Pneumoconioses were primarily encountered in workers of hazardous occupations, but with industrialization, these disorders became more widespread and can be found anywhere but most often in the urban areas where they are a major component of the environmental pathology.

The common pneumoconioses caused by inhalation of the inorganic dust particles include:

Coal worker pneumoconiosis (CWP) due to the inhalation of coal dust.

Silicosis or Nodular pneumoconiosis caused by inhalation of silica particles.

Berylliosis or Diffuse pneumoconiosis caused by inhalation of beryllium particles is the only true granulomatous pneumoconiosis.

Asbestosis, another form of diffuse pneumoconiosis caused by the inhalation of asbestos fibers.

Asbestosis and Silicosis are considered non granulomatous because of the transitory nature of the granulomatous reaction that is promptly replaced with fibrous tissue.

The degree of involvement of the lungs is determined by many factors:

1. The concentration of the pollutant in the air which determine the amount of particles retained in the lungs. Minimum 100/106 per cubic foot.

2. The size and the shape of the particles, (< 2 to 3 microns), the most offensive measure 1.5 microns.

3. The nature, fibrogenicity and solubility of the substance.

4. The duration of exposure to the agent.

5. The contribution of cigarette smoking to the disease that disturbed the ciliary function in the bronchi.


The development of the pneumoconiosis requires the inhalation of particles of inorganic material small enough to penetrate the terminal respiratory units of the lung, as far as the alveoli. When the particles reach the alveoli, they are engulfed by the macrophages and transported toward the respiratory bronchioles; from there, most of the particle-laden macrophages are expelled from the lung through the action of the ciliated epithelium, but a great number of the macrophages enter the interstitial tissue of the lung where they are taken by the lymphatics. The macrophages have no destructive effect on the inorganic particles, they merely act as a transport vehicle for the particles. When the macrophages eventually die, they release the inorganic material to the surrounding tissue. The dust particles that remain in the lymphatic system settle in foci of lymphoid collections mostly at the division of the large vessels, under the pleura and in the hilar lymph nodes.

Depending on the nature of the inorganic particle, variable degree of reactive fibrosis may occur around the foreign substance. The fibrotic reaction usually starts at the level of the small bronchioles and extends to the alveoli. The result is a loss of elasticity of the respiratory unit followed by emphysematous dilatation of the acini and disturbance of the pulmonary functions. As the disease progresses, the fibrosis affects the perilymphatic and perivascular areas leading to the development of pulmonary hypertension. Since the extent of the disease is dose related, further exposure to the offending agent may lead to "PROGRESSIVE MASSIVE FIBROSIS of the lungs(PMF).

The pathogenesis is about the same for all the pneumoconioses, the differences lie in the pathological findings.

Most of the particles that reach the alveoli are small (less than 2m), the larger ones (2-10m) deposit in the bronchi and bronchioles and are removed by the mucociliary action. Only one of the pneumoconiosis, asbestosis, is caused by particles larger than the usual size, the needle-like shape of the asbestos fibers is the important factor in the development of the disease.


This form of pneumoconiosis is secondary to the inhalation of coal dust. The pulmonary reaction ranges from a simple ANTHRACOSIS which is a focal pigmentation of the lung tissue, to extensive fibrosis resulting from prolonged and intense accumulation of coal dust particles in the lungs, condition that leads to PROGRESSIVE MASSIVE FIBROSIS (PMF) of the lung.

With massive , concentrated and prolonged exposure to cal dust, like it occurs in the coal mines, the entire lung may be infiltrated by the carbon particles, which cause a black discoloration of the organs, condition known as "black lung".

The pathological changes vary with the degree of involvement of the organ.


With minimal deposit of carbon particles, condition known as Anthracosis, the lung does not show any substantial fibrosis, the coal particles being low fibrogenic substances. The changes consist of alternate areas of black pigmentation separated by pink non affected lung tissue. The upper lobes are usually the most affected, and the carbon particles are more concentrated under the pleura, around the blood vessels and in the interstitium of the lungs.


With additional and prolonged exposure to the coal dust, a more advanced lesion known as coal pneumoconiosis develops. It is characterized by the formation of Coal macules composed of an aggregation of carbon-loaded macrophages. The coal macules are more abundant around the venules, the lymphatics and the hilar lymph nodes and are often surrounded by emphysematous reaction (centriacinar emphysema) of the lung tissue. At this point, the macrophages that cannot digest the inorganic particles start to die, liberating fibrogenic substances that are responsible for the moderate fibrotic reaction of the interstitial tissue of the lung. The carbon particles liberated by the macrophages are deposited in the fibrous tissue where they can be identified.


With prolonged exposure to coal dust and associated factors like cigarette smoking, hypersensitivity reaction, pulmonary infection (ex: TB), the disease may progress to a more advanced stage that eventually leads to Progressive Massive Fibrosis (PMF) which is the end stage of most extensive interstitial disease of the lung.

The superior segments of the upper and lower lobes are usually more affected. Some respiratory bronchioles and blood vessels are often trapped inside large areas of fibrosis causing a decrease of blood supply. The result is liquefaction necrosis of the center of the nodule with secondary cavitation of the lesion.

The coal dust is often mixed with silica particles that are extremely fibrogenic and cause a more severe condition known as anthraco-silicosis.

In many cases, a combination of the coal worker pneumoconiosis and rheumatoid arthritis may be found in the same patient, condition known as Caplan's syndrome.


This type of pneumoconiosis is the result of inhalation of silica dust in the form of silicon dioxide also known as quartz or free silica. The size of the particle is a very important factor in the pathogenesis of the disease, the particles measuring 2 to 3 microns in diameter are the most pathogen since they can penetrate the distal portion of the respiratory units. These types of particles are found in many industries. The disease may appear from one to two years after a massive and intense exposure to the silica particles, in which case an acute disease is induced, or it may take 10 to 15 years of constant low level exposure to cause a chronic case of silicosis. In Southern Africa for example Silicosis is a major problem in the regions where "mining " is one of the main branch of industry.

Silica particles are powerful fibrogenic stimuli, but the fibrosis is not established from the start of the disease which goes through several steps before a well established case of silicosis can be diagnosed.


The first response of the tissue to the silica dust is the accumulation of macrophages and proteinaceous exudate around the particles. This mixture is found mostly in the respiratory bronchioles and inside the alveolar spaces (alveolitis) and is more abundant in the lower lobes of the lungs.

The silica particles are then engulfed by the macrophages, silica being cytotoxic causes the rapid death of the macrophages that release the ingested silica particles together with fibroblastic stimulating factors. These free particles are re-ingested by new macrophages. This constant turnover creates a transitory granulomatous-like reaction of the tissue that is progressively and quickly replaced by nodules of fibrous tissue leading to the chronic form of the disease.




The first sign of fibrosis is evidenced by the presence of scattered small nodules that give a sandy feeling to the lungs. The small nodules then merge into larger ones composed of concentric layers of connective tissue, several large nodules may be enclosed in a thick layer of collagenous tissue. A characteristic feature of silicosis is the presence of birefringent particles of silicon dioxide in cleft-like spaces located between the connective tissue layers. This finding is very important in the differential diagnosis of silicosis with other granulomatous diseases of the lungs or other fibrotic nodular pneumoconiosis. When the periphery of the lung becomes involved with the fibrotic process, the pleural cavity may be obliterated.

Silicosis is often complicated with pulmonary tuberculosis, anthracosis and at time may be associated with rheumatoid arthritis forming the Caplan syndrome.


Beryllium, a metal used in the aerospace industry and in the manufacture of fluorescent light, is a potent allergen that may cause extensive damage to the lung in sensitive individual, condition known as berylliosis. The cases of berylliosis reported today are mostly found in people involved in the extraction of the metal from the crude ore. Individual susceptibility to the metal is a very important factor since only few of the people exposed to the vapor or the dust of the beryllium develop the disease.

Berylliosis may be acute or chronic.

Acute berylliosis. The acute form of the disease is usually the result of exposure to the soluble salt of beryllium, and is considered a form of hypersensitivity pneumonitis. Upon exposure, the patient develops a form of chemical pneumonitis with congestion, edema and inflammatory infiltrate of the lung tissue. With further evolution of the disease, the exudate present inside the alveoli starts to organize and later is completely replaced by fibrous tissue that also involve the walls of the alveoli. The result is a decrease in the diffusion capacity of the lungs, the cause of death in most of the cases. No granulomata are noted in the acute form of the disease.

Chronic berylliosis. The chronic form of berylliosis may develop from two weeks to decades after exposure to the beryllium dust. The mechanism of the initial lesion is a cell (T cell) mediated immune reaction.

The characteristic lesion is the formation of granulomata in the interstitial tissue of the lungs specially in the subpleural areas, around the blood vessels and around the bronchi. The granulomata are usually hard and contain Langhans or foreign body giant cells enclosing three different types of inclusion bodies : Spiculated crystals (3 to 10 micron in diameter), Schauman bodies ( 50 micron) and Asteroid bodies. Heavy lymphocytic infiltrate is often present around the granulomata , feature that is considered a good factor in the prognosis of the disease.

The pulmonary lesions of beryllium are often associated with granulomatous lesions in other areas of the body, like in the liver, the kidney, the spleen, the lymph nodes and the skin, but this disease does not predispose to tuberculosis or to lung cancer.

Chronic berylliosis should be carefully differentiated from other granulomatous lesions of the lung like tuberculosis and sarcoidosis.


Inhalation of asbestos fibers is a major cause of respiratory pathology in the industrial world. Asbestos is a type of fibrous silicate found almost everywhere, the heaviest concentration being in the industries. Three major forms of asbestos fibers are known, the chrysolite which is the most common, the crocidolite and the amosite. Each variety has a different geographic distribution.

The effects of asbestos on the respiratory system has been extensively studied and publicized not only because of the non-neoplastic pulmonary and pleural lesions like the diffuse interstitial fibrosis of the lung (DILD), pleural effusion, pleural plaques, but also because of the high incidence of bronchogenic carcinoma (15%) and pleural mesothelioma (7%) that often result from exposure to the asbestos fibers. One common feature to all the variants of the disease is a long exposure (at least ten years) to asbestos.


This is the only type of pneumoconiosis caused by a larger than usual fiber (50-100m/.5-1m). The elongated shape of the asbestos fibers allows them to enter the terminal unit of the lungs. The inhaled fibers reach as far as the respiratory units of the lungs (more abundant at the bifurcation of the alveolar ducts) where they are taken by the macrophages and the epithelial cells. Most of the fibers are expectorated, but many penetrate the wall of the respiratory units and settle in the lymphatics, in the interstitial tissue and under the pleura. The fibers phagocytized by the macrophages are coated with hemosiderin, ferritin and glycoprotein to form the asbestos bodies which are the hallmarks of the disease. The non phagocytized fibers remain uncoated. Asbestos fibers are fibrogenic (cause fibrotic reaction) and carcinogenic (predispose to malignancies).


The initial reaction of the tissue to asbestos fibers is a form of bronchiolitis and alveolitis associated with a transitory granulomatous reaction of the lungs. Asbestos being a potent fibrogenic material, diffuse interstitial fibrotic reaction soon replace the granulomatous lesions.

The first lesions to be identified are the transitory granulomata containing giant cells, granulomata that are more abundant in the lower lobe of the lungs. The diffuse fibrotic reaction that follows starts around the respiratory bronchioles and the alveolar ducts, and progressively affects the more distal areas of the lungs.

In the more advanced form of the disease, there is marked fibrotic reaction of the alveolar septa, with focal areas of emphysema developing around the fibrous tissue (honeycomb lung). The fibrous process affects also the pleura which becomes thickened and calcified forming the pleural plaques.

The pathognomonic feature of asbestosis, the asbestos body composed of a large asbestos fiber coated with protein (mucopolysaccharide) containing iron granules can be demonstrated in the pulmonary lesions inside the giant cells or freely in the fibrous tissue. The term ferruginous body is often used to describe the coated fibers that appear like elongated segmented structures on light microscope (dumbell) and like irregular fibrillar structures on electron microscopy. The uncoated fibers are not visible with the light microscope.

The malignancies and the pleural lesions of asbestos exposure are studied later in the appropriate context.


This immunologically mediated pulmonary reaction (type lll reaction), some times referred to as extrinsic allergic alveolitis is due to the inhalation of organic dusts and related antigens. The organic dusts most commonly involved are the thermophilic bacteria , commonly found in heated water reservoirs like the humidifiers and air conditioners, certain fungi (farmers lung), animal proteins (pigeon breeders disease). The nitrogen dioxide that emanate from the bacterial products is responsible for the lesions characteristics of the silo-filler disease, this may eventually lead to bronchiolitis obliterans . The alveolar reaction is similar to that of the bronchi during an asthma attack, the symptoms appear some four to six hours after exposure. Removal of the offending antigen may prevent the progress to the chronic form of the disease.


In the acute form of the disease, the histological picture is that of an interstitial pneumonitis (type lll immune complex). When the disease becomes subacute and later chronic, inflammatory infiltrate of the interstitial tissue with lymphocytes, plasma cell and foamy macrophages can easily be identified, later granulomatous reaction(type lV delayed hypersensitivity) and interstitial fibrosis replace the inflammatory infiltrate. In few patients some intraalveolar infiltrate may be present.


Certain chemotherapeutic agents like bleomycin, busulfan, cyclophosphamide and methotrexate to name a few can cause a toxic form of alveolitis that may eventually progress to interstitial pulmonary fibrosis in long term use. The same type of pulmonary lesions can be seen following prolonged administration of some anti-arrhythmic drugs and some antibiotics ex: nitrofuradantin.


The contribution of tobacco and marijuana (cannabis) to diseases of the lung is a subject that has been studied in great extent.

Tobacco in the form of cigarette smoking is the major cause of emphysema and chronic bronchitis (COPD). It is also the most important and the most preventable cause of bronchogenic carcinoma. The risk of developing the carcinoma seems to be related to the level of tar and nicotine in the cigarettes, which led to a reduction in the number of cases of carcinoma of the lung in people using the low tar/nicotine type of cigarettes. But, the incidence of COPD is not affected by the low tar -nicotine cigarette use.

The use of Cannabis, the active substance in marijuana, seems to cause some degree of metaplasia and dysplasia in the epithelium of the bronchi since marijuana yields about 100 to 500% more carcinogenic substance than tobacco.

But the contribution of marijuana in the etiology of carcinoma of the lung is still very controversial.



There is a group of diseases, most of unknown etiology, that can lead to diffuse infiltrative fibrosis of the lungs, or to the deposition of ectopic substance on the wall of the terminal units of the lungs.The result is a decrease in the diffusing capacity of the organ.

The more commonly encountered are:


Diseases associated with a defect in collagen synthesis

Pulmonary hemorrhagic syndrome

(44) Goodpasture syndrome

Idiopathic pulmonary hemosiderosis,

Idiopathic Pulmonary fibrosis

Pulmonary alveolar proteinosis

Desquamative interstitial pneumonitis

Hamman rich syndrome.


This multisystem disease of unknown etiology considered a type lV hypersensitivity reaction , more frequently found among the young, the women and the blacks, is characterized by generalized non caseating granulomatous lesions of the organs. The lungs are involved in 90% of the cases but only 40% of the cases will have pulmonary symptoms at the time of diagnosis. Abnormal pulmonary function tests will be noticeable before XRay evidence of any pulmonary lesions which is the base for staging this disease seen in the following table:

Staging of Pulmonary Sarcoidosis in Symptomatic Patients
% of X-Ray Finding
X-Ray Finding
40 - 60%
Hilar, mediastinal or paratracheal adenopathy
15 - 30 %
Hilar, mediastinal or paratracheal adenopathy. Pulmonary infiltrate.
10 - 15%
Parenchymal pulmonary anomalies without adenopathy
Pulmonary fibrosis or evidence of severe destructive lung disease without adenopathy


There is no specific diagnosis test for Sarcoidosis, however, there are few useful tests, although not specific, that can be used to monitor the inflammatory reaction and the cellular activity of the sarcoid granuloma.

The serum level of Angiotensin Converting Enzyme (ACE) shows some elevation in 50 to 80% of patient with active sarcoid lesion. The ACE is also elevated in other conditions like lymphoma, hyperthyroidism and alcoholic hepatitis .

The Gallium-67 Scanning is positive in two third of patients. It is also positive with other inflammatory lesions of the lung.

The Kveim test consisting in intradermal injection of a sterile suspension of known sarcoid tissue (spleen extract) will show a non caseating granulomatous formation at the site on injection in affected individuals in 2 to 3 weeks. This test is not used very frequently because of the unavailability of the serum and the delay in the reaction.

The following two tests are based on the fact that the lymphocytic infiltrate that surrounds the sarcoidosis granulomas is made almost exclusively of T-Helper lymphocytes.

Bronchoalveolar lavage shows an increase in the T Helper/T Suppressor ratio. This can also be seen in TB and lymphoma.

The serum level of a soluble form of Interleukin-2 secreted by the T-helper cells is elevated denoting cellular activity.

The most reliable tool for the diagnosis of the disease remains the study of a trans-bronchial lung biopsy.

Diagnostic Yield of Transbronchial Biopsies
Diagnostic Yield
70 - 90%
85 - 95%
80 - 90%

PATHOLOGY The lesions of sarcoidosis consisting of few small nodules scattered throughout the lung tissue, affect most severely the lower lobes of the lungs. The pathology is more visible on microscopic examination that shows a lung parenchyma seeded with multiple small non-caseating granulomata of the interstitium, but more numerous and symmetrically arranged around the blood vessels, around the bronchi and the lymphatics. The sarcoidosis granulomata undergo rapid fibrotic degeneration and hyalinization counting for the diffuse pulmonary fibrosis resulting from prolonged disease. Schaumann bodies and asteroid bodies are common features and are present in about 88% of sarcoidosis granulomata. A rim of lymphocytes made mainly of T-Helper cells surround the granulomatous lesion. Only rarely a granuloma may undergo central necrosis.

Long standing and extensive disease leads to the development of Bronchiectasis, cystic changes and pulmonary fibrosis that may evolute to a honeycomb lung.

The hilar lymphnodes are often affected and the pattern of involvement of these nodes is referred as "Potato adenopathy".

The pleural involvement is not very common and consists of pleural thickening, spontaneous pneumothorax and pleural effusion of an exudate made mostly of lymphocytes.


Amyloidosis refers to a group of diseases characterized by the deposition of abnormal protein material in extracellular spaces.

Primary systemic amyloidosis.

The deposition of amyloid may be the result of an immunoglobulin disorder in which case it is a widespread process that affects multiple organs including the lungs. This variant is known as Primary systemic amyloidosis, it is often associated with multiple myeloma. The pulmonary involvement by this variant of the disease always carries a poor prognosis.

Secondary systemic amyloidosis.

The deposition of amyloid may be the result of associated systemic diseases in which case it is known as Secondary amyloidosis. The systemic diseases known to cause systemic deposition of amyloid include tuberculosis, chronic renal diseases, syphilis, osteomyelitis, inflammatory bowel disease, bronchiectasis, chronic inflammation, rheumatoid arthritis, leprosy and certain type of cancer. The pulmonary involvement in this variant is not very common.

Localized Pulmonary Amyloidosis. Tracheobronchial amyloidosis

In this variant of the disease, the deposition of amyloid is limited to the respiratory tract without involvement of other organs. The deposition may affect the entire tracheobronchial tree or may be localized in the lungs. The pattern may be diffuse (diffuse interstitial amyloidosis) or nodular (amyloidoma), with areas of calcification.

The course of pulmonary amyloidosis may not be benign, the patients often die of respiratory failure or recurrent pneumonia as a result of bronchial obstruction.


This includes the Goodpasture syndrome and the Idiopathic pulmonary hemosiderosis.


In this autoimmune disease of unknown etiology, there is production of antibodies against the basement membrane of the pulmonary capillaries and the renal glomeruli that seem to have a common antigenic determinant. The antigen is either an inherent component (self antigen) or has been deposited in the basement membrane (in situ immune complex formation). The antibody complex that is produced by a type 2 cytotoxic reaction causes extensive damage to the basement membrane of the interstitial pulmonary capillaries causing a necrotizing hemorrhagic interstitial pneumonitis. It also damages the glomerular basement membrane and produces a rapidly progressive type of glomerulonephritis. These features are characteristic of the Goodpasture syndrome, condition more commonly seen among males.

On pathological examination, the lungs contain areas of red-brown induration, the alveolar walls show focal areas of necrosis and some fibrous thickening of the septae. The lining epithelium of the alveoli is hypertrophic, the basement membrane show linear deposit of immunoglobulin that can be best demonstrated with immunofluorescence study. The alveolar spaces show some degree of intraalveolar hemorrhage and contain hemosiderin laden macrophages. In chronic cases, there is a diffuse fibrosis of the interstitial tissue of the lung.


This rare disease of unknown etiology affecting mostly children, is characterized by repeated episodes of intraalveolar hemorrhage.

The hemosiderin resulting from the blood digestion by the macrophages is deposited in the alveolar septae. Few hemosiderin laden macrophages can be seen inside the alveolar spaces.

The pathological changes leading to the interstitial fibrosis of the lungs consist of degeneration, shedding followed by hyperplasia of the alveolar epithelium, dilatation of the blood vessels and then finally interstitial fibrosis.


This group includes few rare entities that may or may not lead to diffuse fibrosis of the interstitium of the lungs. The most common are:


This pulmonary disorder, of unknown etiology, differs from the other ones by the fact that the main pathological changes are not in the interstitium of the lung but in the alveolar spaces.

Inside the alveoli there is a PAS positive , homogeneous, granular precipitate rich in protein and phospholipid in which can be found cell debris and laminated bodies. The alveolar walls

are lined with hyperplastic pneumocytes type 2 but no inflammatory cells. One theory for the presence of the protein in the alveoli is that the hyperplastic pneumocytes type ll are actively secreting the protein in the form of surfactant.

This lesion does not progress to interstitial fibrosis of the lungs. The decrease in the respiratory functions is due to obliteration of the alveoli by the proteinaceous material.


This disease of unknown etiology causes patchy areas of consolidation of the lungs that usually respond dramatically to steroid therapy.

At the early stages of the disease, examination of the lung reveals congestion, edema and inflammatory infiltrate of the alveolar septae, the cellular infiltration consists mostly of lymphocytes, plasma cells, histiocytes and rare eosinophils.

With further evolution of the disease, the septae become fibrotic, and the inflammatory infiltrate consists only of plasma cells and lymphocytes. The most striking feature at this stage of the disease is the presence of numerous mononuclear cells inside the alveolar spaces, these macrophages contain lipid vacuoles and PAS positive granules. The septal linings may show some degree of hyperplasia.


For a long period this syndrome was considered a form of DIF (Diffuse Interstitial Fibrosis) of the lung based on the changes found in long standing cases. Now with re-evaluation of the symptoms, this condition is placed in a different category, and is now considered a form of ARDS triggered by immune mechanism.

This is a pulmonary disorder that affects primarily the male between the ages of 30 to 50years. It is known by many other names, some reflecting the basic pathological changes, like DIF for the diffuse idiopathic fibrosis of the lungs based on the long standing changes. High levels of immune complex are found in the blood of the affected individual.

During the early stage of the disease, the pathological changes consist of pulmonary edema, hyaline membrane formation and mononuclear infiltrate of the lungs, features compatible with ARDS. As the disease progresses there is some degree of hyperplasia of the pneumocytes type ll replacing the necrotic type I pneumocytes.

Later the alveolar septae become fibrotic, fibrosis that progressively obliterates the alveolar spaces. At this stage, the lung tissue becomes solid in areas separated by over distended alveolar spaces, typical picture of the honeycomb lungs.


This is a group of pulmonary disorders characterized by increased infiltration of the lung tissue by eosinophils without secondary fibrotic reaction of the interstitium.

Three variants of this disease have been described:

1. The Loeffler's syndrome or Simple pulmonary eosinophilia in which the alveolar septae are diffusely infiltrated with eosinophils and giant cells. This disorder is considered as a type l allergic reaction. Focal hyperplasia of the epithelial linings may be present.

2. The tropical eosinophilia which is usually associated with infestation with microfilaria parasites.

3. Chronic pulmonary eosinophilia and Chronic eosinophilic pneumonia that are either allergic or immunological in nature.

The end result of the progressive fibroblastic proliferation and collagen deposition characteristic of the previously described entities is an idiopathic fibrosis of the interstitium of the lung leading to non functioning organs.
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File updated September 18, 2000

© M. Kavanagh, M.D.