Lecture # 2

Fall 2001

Marie E. Kavanagh, M.D.


Acquired pulmonary diseases of vascular origin

Pulmonary congestion

Pulmonary edema

Adult respiratory distress syndrome (ARDS) or

Shock lung

Pulmonary embolism

Pulmonary infarction

Pulmonary hypertension

Chronic obstructive pulmonary diseases

Pulmonary emphysema

Anatomical varieties

Centriacinar or Centrilobular emphysema

Panacinar or Panlobular emphysema

Paraseptal or Distal emphysema

Irregular emphysema

Etiological varieties

Compensatory emphysema

Senile emphysema

Obstructive emphysema

Bullous emphysema

Interstitial emphysema

Chronic bronchitis.

Bronchial asthma


Atopic asthma

Non atopic asthma

Drug induced asthma

Occupational asthma





Pulmonary infections


Bacterial pneumonia

Lobular pneumonia

Lobar pneumonia

Viral and Mycoplasma pneumonia

Pulmonary abscess

Pulmonary infections in immunocompromized patients

Fungal, bacterial and viral infections of the lungs.

Cytomegaloviral pneumonia

Pneumocystis carinii pneumonia

Pulmonary Aspergillosis

Cryptococcal infection of the lung

Legionella pneumophila infection




Fall 2001

Lecture # 2



Pulmonary congestion is an increase in the amount of blood in the pulmonary circulation that results from dilatation of the capillaries and the venules of the lungs, while pulmonary edema refers to the extravasation of fluid into the interstitial tissue of the lung and into the alveolar spaces. These two entities are so closely related that they are usually studied together, pulmonary congestion eventually leads to pulmonary edema.


There are several factors cited in the etiology of either or both of these conditions, and the type of edema varies with the factor involved .

Hydrostatic Edema is the result of hemodynamic disturbance of the pulmonary circulation of any origin. The best example is the pulmonary edema caused by congestive heart failure.

Oncotic Edema occurs when the oncotic pressure of the blood falls very low due to loss of albumin. This is the type of pulmonary edema resulting from nephrotic syndrome.

Permeability Edema results following an injury to the alveolo-capillary membrane that cause fluid extravasation into the interstitial tissue of the lung and into the alveolar spaces. The injury can be mechanical like in inhalation of foreign particle, or chemical, inhalation of toxic gas or fume, or infectious, viral or bacterial pneumonia. This permeability edema is often associated with hypoxia which explains its presence in case of ARDS.

Neurogenic edema occurs at high altitude and other undetermined situations for which the mechanism of production is not very clear.

Massive pulmonary edema is often a complication of drug overdose.


Pulmonary edema causes a decrease in the gas exchange at the level of the alveoli, leading to hypoxia (O²¯ ) and hypercapnia (Co²­ ).


The pathogenesis of pulmonary edema is the same regardless of the etiology. The blood vessels become congested and dilated, this causes a certain degree of stretching of the inter-endothelial junctions or in case of ARDS damage to the endothelial and epithelial lining resulting in a movement of fluid toward the interstitial tissue of the lungs. This fluid is drained via the lymphatics, but the capacity of the lymphatic system of the lungs being limited, the lymphatic drainage only starts at the level of the respiratory bronchioles, the excess fluid accumulates in the interstitial tissue when saturation point is attained, and from there, moves inside the alveolar spaces carrying with it few red blood cells that later will be taken by the alveolar macrophages. In permeability edema the fluid exudes from the damaged endothelial and epithelial lining.


On pathological examination, the gross characteristics of the pulmonary edema and the congestion are the same: The lungs are heavy, wet, and have a low degree of crepitance, the basal lobes being more severely affected.

On histological examination, the earliest changes consist of dilatation of the blood vessels and widening of the alveolar walls. When the edema settles, the alveolar spaces fill up with a pinkish granular fluid containing hemosiderin laden macrophages (heart failure cells). When the cause of the congestion is not corrected, the macrophages become more abundant and may fill the entire alveolar spaces condition known as "chronic passive congestion (CPC)" of the lung. A certain degree of fibrosis of the alveolar walls may occur, feature that is typical of pulmonary CPC seen in long term congestive heart failure


This syndrome also known by many other names that include:" Shock Lung", ‘Diffuse alveolar damage", "Traumatic wet lung", "White lung syndrome" is found in several clinical settings. This is a relatively new disease that became popular during the Vietnam war when many cases were described following war injuries (DaNang lung). The increased in the hydrostatic capillary pressure typical of cardiogenic edema is not found in the clinical setting of the ARDS. This is more specifically a permeability type of edema caused by ischemia secondary to hypoxia at the level of the capillaries of the lungs. The fluid extravasation in the interstitium is severe due to endothelial capillary damage (permeability edema). The patient is often dehydrated and shows some degree of hypoxia of the lung.

The clinical settings for this lesion are numerous and include:

Infectious processes like diffuse pulmonary infections, septic shock and pancreatitis, all these conditions are associated with margination of leukocytes and release of lytic enzymes causing necrosis

Severe trauma like extensive burns, radiation injury.

Toxic reaction like toxin inhalation, narcotic overdose, oxygen toxicity, all situations causing some degree of alveolar damage.

Hypersensitivity reaction

Major surgery either general surgery or cardiac surgery

Hemodynamic disturbances like it occurs in cases of pulmonary embolism, DIC syndrome, and multiple transfusions .(Right heart failure)

All these conditions have as common feature certain degree of hypoxia.


Regardless of the etiology, the basic rather obscure pathogenesis of the disease is based on the diffuse damage of the alveolar walls (DAD). The first damage to be noted is a diffuse necrosis of the endothelial lining of the capillaries that later extends to cause a diffuse necrosis of the epithelial lining of the alveoli, mainly of the pneumocytes type l. This necrosis in most cases is the result of hypoxia at the level of the capillaries, but when caused by oxygen toxicity, the free oxygen radicals seem to be responsible for the endothelial damage.

In many other cases, leukocytes aggregation with the secretion of lytic substances and lysosomal enzymes seems to be responsible for the damage to the capillary endothelium.


The damage to the capillaries leads to all the alterations found in the affected lungs:

Increase permeability of the vessel leads to leakage of fluid in the interstitium and in the alveolar space causing pulmonary edema (Permeability edema)

Blood extravasation causes pulmonary hemorrhage

Necrosis of the pneumocytes leads to formation of hyaline membrane

Decrease production of surfactant leads to focal atelectasis of the lung.


On examination, the lungs show changes compatible with pulmonary edema and minimal congestion, they appear uniformly dark red with focal areas of atelectasis probably due to the lack of surfactant created by the diffuse destruction of the pneumocytes. Focal areas of intraalveolar hemorrhage may also be present.

On microscopic examination, three different phases of the disease can be identified:

An Acute or exudative phase that lasts 1 - 6 days.

A Subacute or proliferative phase that lasts 4 - 10 days

A Chronic or fibrotic phase that appears within 8 days from the onset.

Acute or Exudative phase. The changes of this early phase of the disease appear within 12 to 48 hours of the initial insult. During this phase, the main findings consist of :

Neutrophilic and monocytic cells infiltrate the interstitium and the alveoli. Hyaline membranes made of cellular debris and fibrin can be seen along the walls of the alveolar ducts.

Sloughing of the pneumocytes type1 with relative sparing of the pneumocytes type 2 can also be noted.

Subacute or Proliferative phase. During this stage of the disease that usually starts after a week or so, the main findings are :

Proliferation of the pneumocytes type 2 starts,

Some resolution of the hyaline membranes occurs.

Pulmonary edema and congestion are the main features,

Regeneration of the pneumocytes type 1 begins.

Chronic or Fibrotic phase. During this late phase of the disease, fibrosis is a prominent feature.

Variable degrees of obliteration of alveolar and bronchiolar spaces are observed

Decrease in the number of pulmonary capillaries.

During the entire course of the disease, RBC's, protein-rich exudate and iron-laden macrophages are scattered in the interstitium and the alveolar spaces.


This syndrome that is associated with chronic liver disease consists of abnormal pulmonary gas exchange and evidence of intrapulmonary vascular dilatation.

The pathogenesis of this syndrome considers a defect in the synthesis and metabolism by the diseased liver of certain pulmonary vasoactive substances (prostaglandins, nitric oxide, vasoactive peptides, calcitonin, glucagon). This defect leads to the intrapulmonary vascular dilatation at the precapillary and capillary level more prominent in the middle and lower lobes of the lung. This causes some degree of hypoxemia. Because of the dilatation of the capillaries there is a decrease of arterial partial pressure of oxygen (Po2) since the diffusion of the oxygen molecules to the center of the capillaries necessary for the proper oxygenation of the hemoglobin is affected.

This is a progressive lesion that can be alleviated to a certain degree by supplemental oxygen therapy, but the ultimate improvement with reversal of the lesion occurs with liver transplant. The diagnosis is made by Contrast- Enhanced Echocardiography, Perfusion lung scanning and Pulmonary angiography. The results of these tests show vascular dilatation ranging from 15 to 500 μm.




Most occlusions of the pulmonary vascular system are the result of embolism of the pulmonary arterial system, rarely however a thrombus may form directly in the pulmonary circulation. The usual embolus is a thromboembolus that originates most often in the deep veins of the leg.

Pulmonary embolism is a very common cause of death, the third after myocardial infarction and stroke. It is often a complication of an underlying disease like cancer, or heart disease. On occasion, it could complicate a laborious delivery or it can occur in women taking oral contraceptive hormones.

Because of the complex dual pulmonary circulation, the outcome of a pulmonary embolism is not always an infarct, it depends on different factors:

The size of the embolus and the number of emboli

The site of the embolus

The nature of the embolus

and most important The state of the bronchial circulation.




The clinical consequences range from a transient discomfort to sudden death. Considering all the factors:

When the embolus is large enough to lodge in the main pulmonary artery, (about 5% of the cases), it often straddles at the bifurcation of the artery causing a massive pulmonary embolism and forms what is known as a " Saddle Embolus ". A saddle embolus usually causes a sharp increase in the pulmonary artery blood pressure that in turn exercises tremendous strain on the right ventricle , this causes an electromechanical dissociation of the heart that is often associated with sudden death or an acute cor pulmonale (acute right heart failure). When the occlusion is total, due to interruption pulmonary blood flow, the cardiac outflow drops to zero and it is followed by cardiac collapse and death. In such cases, the ischemic necrosis characteristic of an infarct does not occur.



An embolus that lodges in a medium size artery, which occurs in 10% of the cases, is known as a major pulmonary embolism.

The emboli small enough to penetrate the distal vascular system of the lung are usually multiple and are the most common (85% of the cases), they are known as minor pulmonary embolisms.

The result of the major and the minor emboli depends mainly on the adequacy of the pulmonary circulation or more specifically of the bronchial arteries.

- If the circulation is adequate, the bronchial arteries supply enough blood to the lung tissue to keep the stroma alive and prevent an infarction. But a certain degree of damage occurs at the level of the endothelial and epithelial layers of the capillaries. Since the two vascular systems (pulmonary and bronchial) anastomose at the level of the capillaries the result is then suffusion of blood in the lung with preservation of the underlying lung tissue (pulmonary hemorrhage). After resorption of the blood, the architecture of the lung can be restored.

- If the pulmonary circulation is inadequate, embolism of a small pulmonary artery may lead to infarction of the underlying tissue, this happens in about 10% of the cases of pulmonary embolism. The emboli that usually cause infarction are often multiple and affect most commonly the lower lobes of the lungs. These small minor emboli when they recur repeatedly are also a major cause of pulmonary hypertension.




On pathological examination of a pulmonary infarct, the affected area usually follows the outline of a pulmonary lobule or a pulmonary lobe (wedge-shaped) with the apex directed towards the hilus of the lung. The early changes consist of hemorrhage of the lung tissue with a red-blue discoloration and fibrin deposit on the pleural surface. In older infarcts, the margins become well demarcated by proliferation of fibrous tissue forming a grayish-white outline.

On microscopic examination, features of ischemic necrosis can be seen underneath a diffuse infiltration of blood. In older lesions, organization of the embolus and the infarct can occur.

Other factors may affect the outcome of a pulmonary embolism, for example if secondary bacterial invasion occurs, inflammatory infiltrate in the form of PMN invades and replaces the necrotic tissue, in such a situation, the lesion is known as a " Septic Infarct ".



Substances other than the normal components of the blood may enter the lumen of the pulmonary blood vessels and lead to an occlusion, some of the most common are:

Air embolus usually results from the puncture of a large vein

Amniotic fluid embolus may complicate childbirth. This is often associated with a coagulopathy caused by the release of thromboplastic substances from the amniotic material.

Fat, atheromatous material and bone marrow emboli are often the result of severe trauma of fat-containing tissue and of the bone, or an atheromatous plaque may rupture inside the arterial lumen, this is a very important cause of ARDS. Rib fracture resulting from resuscitation procedures is often the cause of the bone marrow emboli found at autopsy.

Tumor embolus is the result of the invasion of the venous and arterial system of the lung by malignant tumor cells (ex: renal cell carcinoma)

Foreign body embolus is found mostly in IV drug users

Parasite eggs may enter the venous circulation and form an embolus.


Normally the blood pressure in the pulmonary circulation is low, about 1/8th of the general systemic circulation. In certain circumstances however, the pressure of the pulmonary circulation may rise to very high level causing a syndrome known as " pulmonary hypertension ".

The factors generally responsible for the pulmonary hypertension syndrome are:

Increased pulmonary vascular resistance more specifically at the pre-capillary arteries and arterioles level. (DILD) (Diffuse interstitial lung diesease)

Chronic obstructive lung diseases. (COPD)

Recurrent multiple minor pulmonary emboli.

Heart diseases specially the ones that cause an intrinsic increase in the left

heart pressure.

Rarely however no underlying cause can be found, the condition is

then called " idiopathic pulmonary hypertension ".

Pulmonary hypertension may lead to Chronic Cor Pulmonale.

The pathological changes are the same regardless of the etiology and consist of sclerosis of the pulmonary blood vessels, mostly the arteries, sclerosis that varies with the size of the vessels.

In the large elastic arteries, non-ulcerated atheromatous plaques are present on the intima .

In the medium sized muscular arteries, there is marked hypertrophy of the media, thickening of the intima and fibrosis of the adventitia.

In the small arteries, duplication of the intima and of the external elastic membrane is a common finding.

The arterioles are the most affected and show marked hypertrophy of the media with severe narrowing of the lumen that may contain organized thrombi.


COPD Or Central Air Flow Obstruction

This is a group of chronic lung diseases characterized by recurrent intrapulmonary obstruction of the air flow, situation often associated with a high morbidity and mortality rate. The best known of such diseases are:


Chronic bronchitis

Chronic Bronchial Asthma



The term pulmonary emphysema describes any permanent dilatation of the pulmonary air spaces beyond the terminal bronchioles (acini) with destruction of their walls, this latter feature being the most important alteration for the diagnosis. There are no criteria for the in vivo diagnosis of emphysema since the definition is based on the post-mortem anatomical findings.


Emphysema is more common among males, in people with a history of cigarette smoking, in people exposed to certain industrial fumes and in people living in areas with a high concentration of air pollutant. Genetics and familial predisposition have also been considered as etiological factors. Pulmonary emphysema and chronic bronchitis share the same etiological factors and are often present in the same individual.


Pathogenesis of emphysema

The pathogenesis of emphysema is based on the permanent loss of elasticity of the respiratory units due to destruction of the elastin component of the alveolar septa by a mechanical factor or through the presence of an oxidant - exogenous or endogenous. Elastase the enzyme necessary for this catabolic process is secreted by the neutrophils and controlled by the elastase inhibitor (a 1 -antitrypsin PiZZ). The ideal balance existing between the elastase and anti-elastase (elastase inhibitor a 1 antitrypsin) is disrupted in cases of emphysema due either to a massive production of elastase by the neutrophils during inflammation or to the absence or insufficiency of the anti-elastase in a 1 antitrypsin deficiency. The increase production of elastase or the absence of the antielastase leads to progressive destruction of the elastin component of the human lung tissue leading to emphysema.


Several types of emphysema have been described and are classified according to their distribution inside the pulmonary lobule and the pattern of destruction of the acini.


- Centriacinar or centrilobular emphysema. In this type of emphysema, only the central or proximal portions of the acini are affected. The distal parts are not involved in the process. The affected structures are dilated and their walls are disrupted. In areas, black carbon pigment and few inflammatory cells can be seen in the wall of the dilated structures. The etiological factors involved in the production of this variety of emphysema that affects mostly the upper lobes are cigarette smoking and coal dust inhalation, the pathogenesis in these cases is through the presence of exogenous oxidants. The upper lobes of the lungs are more severely affected by this type of emphysema.


-Panacinar or Panlobular emphysema. In this variety of emphysema, the entire pulmonary acinus from the terminal bronchiole to the alveolar wall is dilated. This type of emphysema which is more common in the lower lobes and more severe at the base of the lungs. 00It seems to be a complication of a deficiency or a decrease production of Alpha 1 antitrypsin or protease inhibitor (anti-elastase) or could be the result of an obstruction.


- Paraseptal or Distal acinar emphysema. In this variety of emphysema, only the distal segments of the acini are dilated, the proximal areas are of normal size. The damage is more severe underneath the pleura, along the fibrous septa and around scar tissue, location that can explain the numerous cases of spontaneous pneumothorax complicating this lesion.



-Irregular emphysema. This is the most common form of emphysema encountered at autopsy. It does not follow a regular pattern inside the acinus. It is usually associated with extensive scar formation in the lungs, like in the presence of healed pulmonary tuberculosis, pulmonary sarcoidosis and chronic bronchitis. The pathogenesis of the irregular type of emphysema is not well understood.

It is usually asymptomatic.


Histopathologic changes common to all the different varieties of emphysema include:

Abnormal fenestration of the alveolar walls,

Destruction of the interalveolar septa,

Effacement of the respiratory bronchioles and of the alveolar ducts.

Fusion of several alveoli to form large air spaces containing free-floating segments of tissue.

Thinned out and avascular septa


There are few other varieties of pulmonary emphysema that do not follow the classical anatomical definition of the disease, they are classified according to the etiological factors involved in their production. Few of them are so common to be worth a description.

- Senile emphysema. This term describes the unusual over-inflation of the lung tissue that occurs with age. This is due mainly to the loss of elasticity of the respiratory bronchioles, the alveolar duct and to the decrease of the capillary bed of the alveoli. There is no real destruction of the lung tissue.

- Compensatory emphysema. When there is loss of lung tissue either by surgery or otherwise, the remaining lung parenchyma compensates by over-inflating. There is no disruption of the alveolar walls.

- Bullous emphysema. When the peripheral air spaces, part of the "physiologic dead space" of the lung are large enough to form large blebs and bullae, usually larger than 1cm, they become visible underneath the pleura or at the apex of the lung, the term bullous emphysema is then applied to such lesion. This type of emphysema is often complicated by spontaneous pneumothorax and causes pressure on the surrounding tissue or organs.

- Obstructive emphysema or over-inflation. This occurs when a partial obstruction of the airway or a complete obstruction with an inadequate collateral air supply to the lung creates a one way valve allowing air to enter but not to exit the lung. The air trapped distal to the occlusion causes some degree of dilatation of the acini. In this type of emphysema, there is no permanent damage to the alveoli that can return to their original size when the obstruction is removed.

- Interstitial emphysema. This term describes the presence of air within the interstitial tissue of the lung, in the soft tissue of the mediastinum, or in the subcutaneous tissue. This can be due to the rupture of an alveolar septum following a sudden increase of air pressure in the alveoli, like it occurs with a paroxysmal cough, or it could be the result of a chest wound. The presence of air bubbles along the septae and the soft tissue gives a characteristic look described as a "string of pearl". The air usually resorbs from the tissue following the closing of the point of entrance.


This condition, common among heavy smokers and inhabitants of smog-laden cities, is a major contributor to the group of chronic obstructive pulmonary diseases. It is more frequent among middle aged men, and 90% of the cases are found in chronic smokers.


Clinically, any condition associated with repeated episodes of persistent cough with copious sputum production of more than 3 months duration is considered as a chronic case of bronchitis.


The pathogenesis of this lesion is very simple: The smoke, the chemical fume or the pollutant cause irritation of the mucosa, hyperplasia of the mucus glands and of all the mucus secreting apparatus, resulting in excessive mucus production and disruption of the normal function of the cilia in the respiratory epithelium and retention of the secretion. These alterations lead to secondary infection by any of the pathogenic microorganisms like the Hemophilus influenza, the Pneumococcus, or the Streptococcus. A dormant case of chronic bronchitis may be exacerbated by a viral infection of the upper respiratory tree, the virus most commonly involved are the adenovirus and the Rhinovirus.






The pathological changes of chronic bronchitis show a wide variety:

- The epithelial lining may show hypertrophy, hyperplasia specially of the mucus producing apparatus, or show some metaplastic changes. In other areas the mucosa may be atrophic.

- Variation in the proportion of mucus to serous cells and an increase in the size of the glands. This increase can be evaluated with the Reid index which provides a measure of the proportion of bronchial glands relative to the thickness of the entire wall of the bronchi (normal=0.4, chronic bronchitis=0.7). ( Refer to picture # 3)

- Narrowing of the airway passages .

- Another constant feature is an inflammatory infiltrate composed mainly of PMN and lymphocytes.

- The smaller bronchi and bronchioles are severely affected, their mucosa is congested and edematous, their lumen contains excessive amount of mucus or mucopurulent secretion.

- In the bronchioles there is certain degree of mucoid metaplasia (presence of goblet cells), narrowing of the lumen that may be occluded by mucus plug, inflammatory infiltrate and fibrosis of the wall.

- Some degree of squamous metaplasia and atypical dysplasia may be found on the epithelial lining of the bronchial tree.

Because of the severity of the lesion in the small bronchioles, and because the earliest changes occur in the bronchioles, this condition has often been referred to as a Small airway disease.




Increase in the ratio of mucus versus serous glands

Increased gland size

Decreased lumen size

Inflammatory infiltrate of the walls


Congestion of the vessels

Edema of the walls

Obstruction of the lumen with mucopurulent exudate

Squamous metaplasia of the lining epithelium


Most severely and earliest affected

Mucoid metaplasia ,Squamous metaplasia of epithelium

Dysplastic change of epithelium

Mucus plug in lumen


The definition of bronchial asthma was classically based on the sudden paroxysmal narrowing of the airways (bronchospasm) in response to stimulation of the bronchial mucosa by elements from various sources. This characterization of the disease was mainly focusing on the rapid response obtained when treated with bronchodilator drugs.

During the last decade, with the introduction of modern research tools, the focus was placed on the importance of inflammation in the pathogenesis of bronchial asthma that is now defined as an inflammatory disease with great tendency toward chronicity and permanent changes in the structure of the airway walls. The later feature places bronchial asthma in the category of chronic obstructive pulmonary diseases. The management of the disease is now focused on the control of the inflammatory process preventive and symptomatic .

The inflammatory reaction, now considered the main characteristic of bronchial asthma, involves multiple cellular elements and inflammatory mediators that are responsible for the symptomatology and the pathology of the disease.


The pathogenesis is based on the action of the different components of the inflammatory process namely the inflammatory cells and the inflammatory mediators. The exact mechanism of action of specific cells or mediators is not fully demonstrated for all the different types of asthma , it is based on the study of the atopic form of asthma , the most common and the most intensively studied.


This form of asthma usually diagnosed during childhood is often associated with a long family history of atopic diseases.

The stimulus usually an extrinsic environmental antigen (dust, pollen, animal dander, food) triggers the inflammatory reaction in a person with a genetic predisposition and hyperresponsiveness of the airways.

Few genes have been identified as being responsible for the reaction, they are:

The HLA complex involved in the antigen presentation

The T-cell receptor complex responsible for the activation of the T-cells

The Genes responsible for cytokine production & function, the IL-4 & IL-5

The Genes controlling the Beta2 adrenergic receptors that monitor dilatation and constriction of the bronchi.

Initial sensitization to the antigen that is required for the full development of an acute asthma attack occurs in the following sequence in the airway:

The inhaled antigens stimulate the T cells to release cytokines (IL-4 & IL-5),

the cytokines then promote IgE production by the B cells, growth of mast cells ,

growth & activation of eosinophils. At this stage a skin test is positive for the

offending antigen, a type 1 IgE-mediated hypersensitivity reaction.

Subsequent exposure to the inhaled allergen triggers an IgE- mediated reaction that occurs in two stages: An acute response and A late phase reaction.


When a presensitized individual inhales an offending antigen, the sensitized mast cells located on the mucosal surface of airway release chemical mediators that in turn open up the intercellular junctions of the mucosa and allow the penetration of the antigen in the submucosal area. Once the antigen reaches the subepithelial area it will cause several other reactions that include:

Stimulation of the subepithelial vagal receptor leading to bronchoconstriction.

Vasodilatation and increase vascular permeability leading to edema and increase mucus production.

Release of cytokines by the subepithelial mast cells resulting in an influx of other cellular elements namely: leukocytes (neutrophils, monocytes, lymphocytes, basophils and mainly eosinophils).

This acute inflammatory reaction lasts for 2 to 4 hours and is usually followed by the late-phase reaction.


The mediators necessary for this late reaction are produced by the leukocytes recruited during the early phase either through the cytokines produced by the mast cells, through chemotactic factors, though other inflammatory cells already present in the bronchi, through the epithelial lining cells of the bronchi or through the vascular endothelial cells.

Some of the mediators have strong effect on the eosinophils that are stimulated and the major proteins of the eosinophils are responsible for the epithelial damage that impairs the bronchociliary action and the constriction of the airway.

The mediators that have been so far identified as factors in the pathogenesis of bronchial asthma include:

Leukotrienes C4, D4 & E4, very potent mediators, responsible for bronchospasm, increase vascular permeability and increase mucus production.

Acetylcholine responsible for the smooth muscle contraction

Histamine a potent bronchoconstrictor

Prostaglandin D2 responsible for bronchoconstriction and vasodilatation

Platelet Activating Factors responsible for the aggregation of the platelets and release of histamine and serotonin from their granules.

The symptoms of an acute phase of bronchial asthma may spontaneously abate or with anti-inflammatory therapy on which the emphasis is greatly focused lately.

But on occasions, an attack may not respond to treatment, condition known as "status asthmaticus" that may be fatal due to severe hypoxia.


This variety of asthma also referred to as infectious asthma is triggered by an infection usually viral in nature (rhinovirus, parainfluenza virus) or very rarely bacterial. In these cases there is no family history of asthma, no other allergies and the IgE level is usually normal. A certain degree of hyperirritability of the bronchial epithelium may result from the inflammatory reaction of the mucosa.

Certain fungi, mainly the aspergillus, may trigger an asthma attack.

Drug induced asthma attack. In sensitive individuals, a very small dose of the drug may trigger a severe asthma attack. One well documented case of such asthma is caused by aspirin. In aspirin-triggered-asthma there is increased production of leukotrienes with their bronchoconstrictor effect, due probably to an interference with the metabolic pathway of arachidonic acid. It may be associated with other symptoms like urticaria, allergic rhinitis and in the long run nasal polyps. Drug induced asthma may also occur with the use of ibuprofen The drugs seem to interfere with the production of prostaglandin.

Occupational asthma is caused by the fumes, the dusts of organic and chemical substances found in many industries. The common feature to all cases is that a very minute amount of the chemical is enough to trigger the asthma attack.

Certain emotional stresses,some strenuous exercises and the cold weather have been known to provoke asthma attacks in sensitive persons. The pathogenesis of the reaction seems to be based on the rapid heat loss resulting from the rapid breathing occurring in such conditions.


The basic pathological finding in bronchial asthma following the sudden bronchial spasm is trapping of air distal to a mucus plug causing the respiratory distress very characteristic of this disease.

The Acute form of asthma will on examination show over-distended lungs with alternate small areas of collapse, the small bronchi are dilated and inflamed and contain mucus plugs, the bronchioles are often occluded by a thick mucus plug.

On histological examination, the mucus plug contains the Curshman spirals made of shed epithelial cells, eosinophils and Charcot Leyden crystals. The Charcot Leyden crystals are needle-like structures made of eosinophilic granules that coalesce. Compact clusters of epithelial cells known as Creola bodies can be identified in coughed up sputum. The bronchial walls are edematous and infiltrated with inflammatory cells, mainly eosinophils. The mucus glands are very active.

In early cases, no residual changes can be seen in the structural framework of the bronchi after the acute attack has subsided.

In chronic cases however, some permanent changes occur:

The basement membranes becomes hypertrophic

The muscle layers are also hypertrophic due to prolonged bronchoconstriction

The mucus glands of the bronchi all become hypertrophic.

The epithelium is edematous and infiltrated with inflammatory cells , mostly eosinophils, and may even show some degree of squamous metaplasia.

Repeated asthma attacks, common in refractory cases, lead to permanent emphysematous changes of the acini, permanent dilatation of the bronchi, more pronounced in the upper lobes, and chronic bronchitis. These features that complicate an already impaired pulmonary function place bronchial asthma in the category of chronic obstructive pulmonary diseases.


Bronchiectasis is classically described as a permanent abnormal dilatation of the bronchial airways proximal to the terminal bronchioles, secondary to a chronic necrotizing infection of the bronchi and the bronchioles.

The etiological factors involved in this condition are numerous and include:

* Bronchial obstruction (tumor, foreign body)

* Bronchial infection (bronchitis, necrotizing pneumonia)

* Congenital malformations (Pulmonary sequestration and Kartagener syndrome),

*Cystic fibrosis ( bronchiectasis is the most serious complication of CF

*Scar formation, bronchial asthma, and in many cases however, no underlying cause can be found.

Bronchiectasis can occur at any age

Pathogenesis .

The pathogenesis of this condition is based on two main factors:

Repeated attacks of obstruction

Infection of the bronchi leading to permanent dilatation of the airways. In the absence of obstruction, repeated bouts of infection may destroy the bronchial walls and lead to permanent dilatation, condition known as post infective bronchiectasis. The microorganisms responsible for the infection can be the Staphylococcus, the Streptococcus, the Enteric bacillus, the Pneumococcus or the Hemophilus.

On pathological examination, bilateral involvement of the lower lobes is the usual pattern. The changes that are more advanced in the small bronchi and in the bronchioles, the larger bronchi are usually spared. The dilated bronchi are either tubular or cylindroid, saccular or fusiform, their lumen is often filled with a suppurative yellow-green exudate tinted with blood. The mucosa is edematous and few cystic structures may be noted.

On microscopic examination, the affected bronchial walls are heavily infiltrated with inflammatory cells, the mucosal surface is eroded in areas and in other areas may show squamous metaplastic changes. The bronchial lumen is filled with inflammatory exudate. When the inflammatory process goes beyond the bronchial walls, small abscesses may form that may later be walled-off by fibrous tissue leading to the formation of a cyst; this residual cyst may be difficult to distinguish from a congenital bronchogenic cyst.


The infectious diseases of the lungs -whether they are called pneumonia, bronchopneumonia , may be caused by a virus, a bacteria, a fungus a mycoplasma and various other microorganisms.

There is a general rule known as the rule of third that applies to most infectious processes of the lung.

One third of pulmonary infections is of unknown etiology

One third is due to the Streptococcus pneumoniae

One third includes infections by various organisms in which

One third is Primary atypical pneumonia (PAP)

One third is viral

One third is made of:

Anaerobic organisms ex: TB


Special microorganisms

The pulmonary infections of known etiology however are in most cases of bacterial origin and are called bacterial pneumonia.


Bacterial pneumonia is an exudative consolidation of the lung tissue secondary to bacterial invasion.

The classification of the pneumoniae is based on several factors: the etiology, (ex: pneumococcal pneumonia, staphylococcal pneumonia etc..) or on the nature of the infection ( ex: Suppurative pneumonia, Fibrinous pneumonia) or the classification may be based on the anatomical distribution (ex: lobar, lobular or interstitial pneumonia). The etiological classification is more important clinically since it provides the data for the appropriate mode of treatment. The anatomical distribution of the different types of pneumonia is important for the pathological description of the disease, and in the radiological diagnosis. All the different factors are considered in making the diagnosis of pneumonia.

Pneumonia remains a major cause of death in the terminal phase of many systemic diseases.


The lower segment of the lungs, distal to the second division of the bronchi, is basically sterile. Any infection affecting this area requires the presence of a predisposing factor that may include:

Conditions that prevent the elimination of bronchial secretion leading to accumulation of secretion, bacterial proliferation followed by development of pneumonia. Ex:

Suppression of cough reflex that can also lead to aspiration of the content of the upper GI tract.

Functional impairment of the cilia, Interference with the macrophages function.

Pulmonary congestion and pulmonary edema.

Several forms of pneumonia have been described.


LOBULAR PNEUMONIA OR BRONCHOPNEUMONIA. This patchy consolidation of the lungs is very common among children and in the very old due to the increased susceptibility to pathogenic organisms during these periods of life.

Bronchopneumonia may be caused by any microorganism, the Staphylococci, the Streptococci, the Pneumococci, the Hemophilus, the Pseudomonas, the Coliform bacilli or certain fungi like the Candida, the Aspergillus and the Mucor.

Pathological examination of the lungs reveals scattered foci of inflammatory exudate involving mostly the base of the lungs. The involved areas are firm, and in long standing cases slightly elevated, dry grayish-red in color. The size of the inflammatory foci vary from 2 to 4 cms in diameter,in staphylococcal infection however the foci have a tendency to converge and form large abscesses.

On microscopic examination, the bronchi, the bronchiole and the alveolar spaces are filled and infiltrated with inflammatory exudate reach in PMN leukocytes. In case of abscess formation a central area of necrosis may be surrounded by granulation tissue.

With appropriated treatment the inflammatory infiltrate may resorb and the normal architecture of the lung may be restored, but in complicated cases, the affected area may be permanently replaced by scar tissue.

In very young children, the alveolar walls may be the most affected by the inflammatory process condition known as Interstitial pneumonia that is ordinarily caused by the E.coli or the Beta Hemolytic Streptococci.


Lobar pneumonia may occur at any age, but unlike bronchopneumonia it is rarely seen in children and in the very old. It consists of an exudative consolidation of a large portion of the lung, sometime of an entire lobe due to the invasion by a pathogenic organism. In about 95% of bacterial pneumonia the Pneumococci (Streptococci pneumoniae) are the offending agents, types 1,2,3,& 7 are the most common and the type 3 the most virulent. The spread of the pneumococci is facilitated by their thick mucoid capsule that prevents their immediate phagocytosis. Other microorganisms like the Staphylococci, other strains of Streptococci, the Hemophilus or rarely the klebsiella may be the cause of a lobar pneumonia.


On pathological examination, four stages are classically described in the evolution of the disease, but with successful treatment, the disease may not progress to the advanced stages.

- Stage of congestion. In this very early stage of the disease, pulmonary edema and congestion with minimal inflammatory infiltrate are the main features. The lungs are heavy and subcrepitant, the alveolar spaces contain fibrinous material and few inflammatory cell.


- Stage of red hepatization. During this stage of the disease, the pleural surface is covered with fibrinous exudate, the lung parenchyma is red, firm in consistency and has the physical appearance of liver tissue. On microscopy the alveolar spaces are filled with fibrin mixed with large numbers of bacteria laden PMN leukocytes admixed with red blood cells. Proliferation of the microorganisms and margination of the leukocytes with their lytic enzymes cause some degree of damage to the endothelial lining of the blood vessels leading to leaking of blood in the extravascular spaces, these extravasated red blood cells mask the architecture of the underlying lung tissue.

Appropriate treatment at this stage ma reverse the process, however refractory cases and cases that are not properly treated reach the last two stages of the disease that include:

- Stage of grey hepatization. During this late stage of the pneumonia, the cut surface of the lung is grayish-brown and dry. The pleura is usually covered with the inflammatory exudate and the pleural cavity may contain purulent material (empyema). On microscopic examination, the alveolar spaces are filled with an exudate made of cell debris, fibrin and blood components. Due to resorbtion of fluid, the exudate retracts from the alveolar walls leaving a clear space between the infiltrate and the alveolar septae.


- Stage of resolution. During this last stage of the disease. the pleural surface may show some adhesion, the lung tissue becomes soft and the exudate semi-fluid, result of enzymatic digestion. The semi-fluid exudate can be either expectorated or taken by the macrophage, progressively clearing the alveolar spaces. If the damage to the walls is not too extensive repair of the lining epithelium usually occurs, but if the necrosis was too extensive, normal restoration of the lung parenchyma may not always be possible, and scar formation is the usual outcome.


Complications that may follow a bacterial pneumonia include:

Formation of tenacious secretion and organization

Abscess formation



When the pneumonia is caused by the type 3 Pneumococcus , by the Klebsiella, or the Friedlander bacillus, the latter representing 10% of all hospital acquired pneumonia, there is production of a thick tenacious mucoid secretion that cannot be expectorated through the bronchi. Enzymatic liquefaction of the tenacious secretion with appropriate exogenous enzymes is necessary in order to clear the lungs of the thick exudate.

When the pneumonia is due to the Staphylococcus, severe necrosis of the lung tissue may lead to abscess formation, with residual scar tissue after healing. Multiple small abscesses are also characteristic of Klebsiella pneumonia in which case the onset is insidious and the prognosis worse.

Following extensive necrosis certain degree of organization of the lung tissue may occur leading to a non functional organ due the obliteration of the air spaces and the blood vessels of the areas.

The possibility of bacteremia is always present in any infectious disease of the lung.

The prognosis of bacterial pneumonia has improved tremendously with antibiotics, however in the presence of a depressed immune system either through a debilitating disease or through chemotherapy the mortality rate of a bacterial pneumonia may reach as high as 60%, and the opportunistic micro organisms can cause fatal cases of pneumonia (Pneumocystis carinii).


Pneumonia caused by a virus or the mycoplasma have been labeled atypical (PAP) because of the unusual distribution of the pathology in the lung. The inflammatory process is atypical, the viruses are rather cytopathic/cytoproliferative causing damage to the cells without the neutrophilic reaction. The monocytic type of reaction affects the alveolar septae and the interstitial tissue of the lung with minimal intra alveolar exudate, which explained the term Interstitial pneumonitis that was often used to describe this disease.

The viruses ordinarily responsible for the disease are the Respiratory syncytial virus, which is the most common, the Influenza virus type A, B,C and the Rhinovirus. On occasion some rare types of virus like the Coxsackie and the Echo virus may cause a case of pneumonia. The Rickettsial and the Chlamydiae have been known to cause a rare type of interstitial pneumonia.

The clinical manifestations of the primary atypical pneumonia are characterized by a dry unproductive cough. When the pneumonia is caused by the Mycoplasma or the Adenovirus, the cold agglutinin titers are elevated. Secondary bacterial infection may complicate the clinical picture.


Pathological Examination. Regardless of the etiology, the changes associated with this atypical pneumonia are about the same and may affect a part of a lobe, an entire lobe or both lungs.

The affected areas are reddish-blue in color and congested, and are covered with a smooth pleura. Red frothy fluid exudes from the cut surface, but no purulent necrosis and no consolidation of the lung tissue are never noted.

On microscopy, the alveolar septae are widened by edema fluid and inflammatory cells namely lymphocytes, histiocytes, few plasma cells and very rare polymorphonuclear leukocytes. The alveolar spaces are usually empty or may be lined with a pink hyaline membrane, result of alveolar cells damage.

When the pneumonia is complicated by a secondary bacterial infection, the changes then become compatible with those of a bacterial pneumonia.

Few specific histopathological changes characteristic of certain virus should be noted: some degree of inflammatory exudate may be present in the alveolar spaces in cases of herpes simplex, varicella and adenovirus infection. In the Cytomegalo-viral infection the typical epithelioid giant cells with intranuclear inclusion body can be identified.


This is a focal suppurative necrosis of the lung tissue that may occur at any age. There are multiple conditions that may be complicated by a lung abscess, the most common cause being aspiration of septic material. Other causes of pulmonary abscess include: oropharyngeal surgery, sinus and bronchial infections, bronchiectasis, dental extraction, bacterial pneumonia or a septic embolus. Secondary infection of a penetrating chest wound, some congenital diseases like Kartagener syndrome and pulmonary sequestration may lead to the formation of a pulmonary abscess.

Any microorganism may be responsible but the most commonly involved are the Streptococci, the Staphylococci, the pneumococci and the Klebsiella. The diagnostic is made by correlating the history, physical manifestations with the Xray and bronchoscopic findings.

On pathological examination, the abscesses may be single or multiple, varying in size from a few mm to 6cm in diameter and located in any area of the lungs. When the abscess is secondary to aspiration it is most often located in the right lung and is usually single, when it develops as a complication of a pneumonia or bronchiectasis the cavities are often multiple and located at the base of either lung. When the abscess is a complication of a septic embolus it may be located in any area of the lungs.

On examination, the abscess cavity or cavities may be filled with a suppurative exudate or if in communication with a bronchus may contain a mixture of air and necrotic material. The surrounding tissue is usually infiltrated with inflammatory cells, separated from the surrounding lung parenchyma by granulation tissue and encased in a layer of fibrous tissue.


With the wide spread use of chemotherapy and radiotherapy and the prevalence of immune deficiency syndrome, pulmonary opportunistic infections with non pathogenic microorganisms and fungi became a serious medical problem since the immunocompromized individual is a higher risk of opportunistic infections.

These infections may be caused by a variety of microorganisms including:

A virus ex: Cytomegalovirus.

A fungus ex: Cryptococcus, Pneumocystis carinii or Aspergillus

An innocuous type of bacteria ex: Legionella pneumophilia and pseudomonas.

Cytomegalovirus infection (CMV) is characterized by an interstitial pneumonitis. The pneumocytes, the capillary endothelial cells and the pulmonary macrophages are enlarged and contain basophilic intranuclear inclusions. Other pulmonary changes consist of edema and focal hyaline membrane formation.

Pneumocystis carinii pneumonia (PCP) has become one of the major cause of death in patients with the Acquired Immune Deficiency Syndrome. This microorganism once classified as a protozoa is now considered as a fungus. The cytoplasmic extensions of the microorganism destroys the lining of the alveoli, resulting in an intraalveolar precipitate of a foamy, amorphous exudate containing cell debris. The parasites cannot be visualized with ordinary H&E stain, it requires a special silver Gomori stain that can demonstrate the trophozoid and the cystic forms of the parasite.

CMV & PCP often coexist in the same patient when affected with AIDS.


Aspergillus is not only a potent allergen responsible for severe case of allergic asthma attacks, it is also responsible for a necrotizing type of pneumonia in immunocompromized patients.

The pulmonary lesions consist of sharply demarcated areas of necrosis with hemorrhagic borders. The hyphae of the fungus may be identified inside a lesion. On occasion, a colony of the fungi may grow inside a pre-existing pulmonary cavity and form what is known as an Aspergilloma that is usually separated from the surrounding lung tissue by a clear zone of demarcation.

Nocardia and Toxoplasma are other rare microorganisms that can cause a pneumonia in immunocompromized individuals

Cryptococcal Pneumonia. Cryptococcus, a major cause of fungal meningitis may at times be responsible for a pulmonary lesion in immunocompromized patients. The pulmonary lesion, which is usually a granulomatous reaction, may be localized or diffuse, is the most striking feature of the disease. The fungus can be identified in the sputum of affected individuals by a special India ink staining


This pulmonary lesion caused by a small gram negative rod, the Legionella pneumophila is responsible for various cases of pneumonia in immunocompromized hospitalized patients and in immunocompetent individuals, most cases being nosocomial in nature. It affects both children and adults and the serogroup 1 being the most common.

The pattern of the infection is that of a lobular pneumonia, in which fibrino-purulent areas of necrosis surrounded by microbacteria-laden macrophages are scattered throughout the alveolar septa, while the alveolar spaces are lined with hyaline membrane. The walls of the arteries and of the veins may also be infiltrated with inflammatory cells, feature that can lead to a disseminated intravascular coagulation syndrome. The process may progress to a lobar pneumonia with fusion of the scattered necrotic areas, this is often associated with fibrinous pleuritis.

Urinary test measuring the legionella urinary antigen of L pneumophilia serogroup 1 and a PCR (polymerized chain reaction) assay are available to confirm the diagnosis.

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File updated August 22, 2001.

© M. E. Kavanagh, M.D