September 22, 1997
Pathology #15					       Transcriber:  Emily Carlson
Monday, September 15, 1997   10am		       Reviewed by:  Dr. Hewan-Lowe
Lecturer:  Dr. Karlene Hewan-Lowe		       Peer reviewer:  Forrest Carson

Pneumonia:
Pulmonary Infections in the Immune Competent Host

This lecture follows Dr. Hewan-Lowe's handout. We are responsible for everything on the handout, whether it was mentioned in class or not. The page numbers in the handout correspond to Robbins. If you have any questions for Dr. Hewan-Lowe, her email address is: khewanl@emory.edu

Normal lung histology:

There are 3 lobes in the right lung, and only 2 lobes in the left lung. The right main stem bronchus is more vertical than the left bronchus. Therefore, there is more of a danger of aspirating (vomit, etc) into the right lung than into the left lung.
 
The tracheobronchial tree is lined by pseudostratified, ciliated columnar epithelium. The trachea and bronchi have cartilage in their walls. However, there is no cartilage in the terminal bronchioles. Smooth muscle surrounds the bronchioles and bundles of smooth muscle are also present in the trachea and bronchi (this plays a role in diseases like asthma). Also, the alveolar septa are thin and delicate in normal lungs, allowing for gas exchange.
 
Type I pneumocytes (squamous) line the alveolar septa. There are also scattered Type II pneumocytes that secrete surfactant. The type II pneumocytes are involved in the repair of damaged alveolar septal epithelium (e.g. in viral pneumonia). Type I cells, although significantly fewer in number than type II cells, account for 95% of the alveolar surface area. (Grippi, p.7)

I. PULMONARY DEFENSE MECHANISMS

A. FILTERING & CLEARANCE:

Filtering mechanisms:
Nasal vibrissa (hairs) filter large particles, and the branching of the tracheobronchial tree filter particles of varying sizes. Particles larger than 10um are deposited largely in the turbulent air flow of the nose and upper airways; particles of 3-10 um lodge in the trachea and bronchi by impaction; and smaller particles are deposited in the terminal airways and alveoli.
 
Clearance mechanisms:
The mucociliary escalator and alveolar clearance. Mucous is secreted by goblet cells in the bronchial epithelium and by mucous glands in the larger bronchi. The mucous forms a blanket over the bronchial epithelium which can trap particles and infectious agents. The cilia are present on the ciliated epithelial cells. The cilia beat the mucous upward from the alveolar space toward the mouth, where it is either swallowed or coughed up.
 
Another clearance mechanism is the alveolar macrophages, which phagocytize particles and infectious agents that are not eliminated by the mucociliary elevator. Some macrophages travel to the lymph nodes and may reenter the bronchioles. Macrophages in the region of the mucociliary escalator are moved towards the mouth .

B. IMMUNE SYSTEM (Bronchial Associated Lymphoid Tissue - BALT)

This consists of local aggregates of lymphoid tissue scattered along the bronchi. The tissue secretes immunoglobulins to neutralize toxins and noxious bacteria. It also allows macrophages to come into the bronchi and help with clearance. The macrophages are motile cells, so they can simply move freely between the air space and the adjacent lung tissue.

The role of BALT:
macrophages travel to the BALT and present their contents (bacteria, viruses, etc) so that antibodies can be made to it.
 
Pneumonia can result whenever these defense mechanisms are impaired or whenever the host resistance is lowered. The clearing mechanisms can be interfered with by many factors, such as:
  1. Loss or suppression of the cough reflex (coma, anesthesia, drugs, chest pain)
  2. Injury to the mucociliary apparatus (impaired ciliary function or destruction of ciliated epithelium due to smoke, inhalation of corrosive gases, viral diseases, or immotile cilia syndrome)
  3. Interference with the phagocytic or bactericidal action of alveolar macrophages (alcohol, tobacco smoke, anoxia, & oxygen intoxication)
  4. Pulmonary congestion and edema
  5. Accumulation of secretions in conditions such as cystic fibrosis & bronchial obstruction.
SLIDE:
Alveolar clearance mechanism.
The thin, delicate alveolar septum is lined predominantly by type I pneumocytes (normal lung). In the alveolar space, there are many macrophages. In this slide, the macrophages are brown due to hemosiderin pigment. The patient had bled into the lungs (ex intra-alveolar hemorrhage that is a consequence of heart failure), causing the hemosiderin pigment uptake. Also, the macrophages may take up anthracotic (black) pigment due to environmental pollutant

 

II. BRONCHIECTASIS

Inflammation and permanent dilatation of the bronchi and bronchioles. We will be able to see inflammation microscopically, and just dilated bronchi (some of which contains pus) on gross observation of the lung.

A. PATHOGENESIS

1. BRONCHIAL OBSTRUCTION

A bronchus or bronchiole could become obstructed and passively dilate distal to the point of obstruction (on the alveolar side). Secretions would pool in the dilated airway, the surrounding lung parenchyma would collapse and the obstruction would prohibit clearance mechanisms from getting rid of noxious substances. Any bacteria trapped in the pooled secretions could cause infection, leading to inflammation that could destroy the bronchial wall, leading to further dilatation.

The lung around the bronchus collapses (atelectasis) due to absorption of air. With the decrease in the usual lung elastic forces, the bronchi passively dilate. The lung must be re-expanded in order for elastic forces to maintain tone and rigidity. The chronically inflamed bronchi are distal to the obstruction.

2. INFECTION

Infection produces bronchial wall inflammation, with weakening and further dilatation. Also, extensive bronchial and bronchiolar damage causes endobronchial obstruction and worsens the bronchiectasis of bronchi in the atelectatic areas.

Atelectasis= (collapse of the lung); absence of gas from a part or the whole of the lungs, due to failure of expansion or resorption of gas from the alveoli. Atelectasis may also be due to external compression caused by pleuritis or pleural effusions. Primary atelectas

Bronchiectasis usually affects the lower lobes bilaterally, particularly those air passages that are most vertical, and is most severe in the more distal bronchi and bronchioles. The airways are dilated, sometimes up to four times the normal size. These dilatations may produce long, tube-like enlargements called cylindroid bronchiectasis, or fusiform or even saccular bronchiectasis.

Characteristically, the bronchi and bronchioles can be followed out to the pleural surfaces. In a normal lung, the bronchioles cannot be followed beyond a point 2-3 cm from the pleural surfaces.

The histology findings vary in bronchiectasis. In the full-blown case, there is acute and chronic inflammatory exudation within the walls of the bronchi/bronchioles. In cases of severe inflammation, the necrosis totally destroys the bronchial/bronchiolar walls and forms a lung abscess. There is also destruction of pseudostratified columnar epithelium. Squamous metaplasia is the replacement of the pseudostratified, columnar epithelium by squamous cells during the repair (healing after the infection subsides).

B. ASSOCIATED CONDITIONS
Cystic Fibrosis (aka Mucoviscidosis)-
autosomal recessive disorder, affecting the exocrine glands in the lung. The defect is on chrom 7. The gene codes for the protein Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a chloride channel. Mutations in the gene are manifested by mucus plugging of bronchi and bronchioles, and the development of brochiectasis.
 
Kartagener's Syndrome
Immotile cilia syndrome (will be covered again in a later lecture). This is also an autosomal recessive disorder, in which there is a problem with the microtubules in the cilia, leading to lack of motility of the cilia. The immotile cilia cause a failure of the mucociliary escalator. Therefore, there is a pooling of secretions (with noxious agents and bacteria), which leads to inflammation and bronchiectasis.

SLIDE: Gross appearance of bronchiectasis. The bronchi are wider than the accompanying pulmonary artery (that's how we know it's dilated). The bronchi will stay dilated all the way up to the pleura (not found in normal lung). In asthma, there may be mucus impaction in the bronchioles.

SLIDE: Resected lung specimen with severe bronchiectasis. Fungal (Aspergillus) COLONIZATION (grungy, brown-gray material) is present in the dilated bronchi. There are gray areas of fibrosis in the lung parenchyma.

SLIDE: Cystic fibrosis lung specimen. There are dilated bronchi filled with pus.

SLIDE: Histology of bronchiectasis. There are neutrophils and other inflammatory cells in the bronchial wall. There is squamous metaplasia as a repair mechanism. Intercellular bridges are an identifying features of squamous epithelium.

 

III. BACTERIAL PNEUMONIAS

Bacterial invasion of the lung parenchyma evokes exudative solidification (consolidation) of the pulmonary tissue. In these cases, most of the inflammation is in the lung parenchyma (alveolar spaces), not in the bronchial wall.

In patients with terminal illnesses, the endpoint is often pneumonia. Viral pneumonias may cause a superimposed bacterial pneumonia because the virus impairs the immune system of the host. Patients who are hospitalized for chronic disease can develop nosocomial (hospital-acquired) pneumonias which are likely to be caused by antibiotic resistant organisms.

LOBAR PNEUMONIA-
acute bacterial infection of a large portion of a lobe or of an entire lobe; the classic organism associated with lobar pneumonia is Streptococci pneumoniae (aka Pneumococci). Classic lobar pneumonia is now infrequent, owing to the effectiveness with which antibiotics abort these infections and prevent development of full-blown lobar pneumonia.
BRONCHOPNEUMONIA-
consolidation is diffuse and patchy (perhaps bilateral); organisms associated with bronchopneumonia tend to be suppurative organisms, such as Staphylococci, Streptococci, Hemophilus, Pseudomonas, and Coliforms.
 
The stages of inflammation in lobar pneumonia distinguish lobar pneumonia from bronchopneumonia. In the first stage of inflammation, there is CONGESTION, the lung is heavy, boggy and red. It is characterized by vascular engorgement, intra-alveolar fluid with few neutrophils, and numerous bacteria. The stage of RED HEPATIZATION that follows is characterized by massive confluent exudation with red cells (congestion) and neutrophils and fibrin filling the alveolar spaces. The lobe now appears distinctively red, firm and liver-like.

The next stage is GRAY HEPATIZATION, with progressive disintegration of red cells and persisitent accumulation of fibrinosuppurative exudate, appearing grayish-yellow, In the final stage of resolution, the consolidated exudate within the alveolar spaces undergoes progressive enzymatic digestion to produce a granular, semifluid debris that is resorbed, ingested by macrophages or coughed up. Some pneumonias may also undergo organization, intralveolar growth of fibroblasts.

Pleural fibrinous reaction to the underlying inflammation may similarly resolve, although it often undergoes organization leaving fibrous thickening or permanent adhesions.
 

SLIDE: Bronchopneumonia in lung, with Staphylococcus. Several different patchy areas are involved. Here, we have focal areas of inflammation, in contrast to large, confluent areas of inflammation in lobar pneumonia. In bronchopneumonia, well-developed lesions are usually 3-4 cm in diameter, slightly elevated, dry, granular, gray-red to yellow, and poorly delimited at their margins.

Histologically, the reaction usually comprises a suppurative, neutrophil-rich exudate that fills the bronchi The gross distribution of the inflammatory cells allows us to distinguish lobar pneumonia from bronchopneumonia. Under the microscope, there are inflammatory cells in the alveolar spaces in both types of bacterial pneumonia.

Complications of pneumonia include:

  1. Abscess formation
  2. Spread of infection to the pleural cavity, causing empyema (an intrapleural fibrinosuppurative reaction)
  3. Organization of the exudate
  4. Bacterial dissemination to the heart valves, pericardium, brain, kidneys, spleen, or joints

 

IV. VIRAL AND MYCOPLASMAL PNEUMONIAS:

This is actually a misnomer. Viruses do cause viral pneumonia. But, mycoplasma and rickettsial organisms also produce the same type of inflammatory response in the lung. The viral mycoplasma pneumonia is also known as Primary Atypical Pneumonia (PAP). This is "atypical" because of a lack of alveolar exudate. PAP's are better designated as interstitial pneumonitis (there are also intersititial pneumonitis of unknown cause).

There is no obvious consolidation as there is with lobar pneumonia. The pleura is smooth, and pleuritis or pleural effusions are infrequent. The alveolar septa are widened and edematous and usually have a mononuclear inflammatory infiltrate. There may be alveolar damage similar to that seen in Adult Respiratory Distress Syndrome.

Histology of viral pneumonia: hyaline membranes, interstitial mononuclear cell infiltrate, reactive epithelial cells. Sometimes, these reactive alveolar epithelial cells exhibit a characteristic viral cytopathic effect (e.g. measles, CMV, and adenovirus pneumonia).

SLIDE: An X-ray of a patient with viral pneumonia shows a "diffuse whiteout of both lung fields." The lungs are heavier (up to 1400 grams) than normal (400-500 grams). The cut surface of that lung feels more solid, with a red, slightly watery appearance, like raw meat.

SLIDE: Histology. The alveolar space may contain some fluid and very few cells. On the surface of the alveolar septum are hyaline membranes (pink, fibrin exudate).

SLIDE: Measles pneumonia. Widening of the septa, interstitial mononuclear cell infiltrate, reactive epithelial cell and a cell showing a viral cytopathic effect- multinucleated giant cells, called "Warthin-Finkeldy" giant cells.

SLIDE: Cytomegalovirus pneumonia. There is a widened septum, with mononuclear cells. The cells and the nuclei enlarge. There are "owl's eye" inclusions of the viral particles in the nuclei. Viral particles are also present in the cytoplasm. CMV is more common in immunocompromised hosts (e.g. AIDS patients).

 

V. LUNG ABSCESSES

Causes:
any inflammatory condition (bacterial pneumonias, bronchiectasis) besides viral pneumonia. Lung abscesses often occur with bacterial pneumonia, bronchiectasis, aspiration, etc.

When the abscesses are small and multiple, the abscesses are usually due to bacterial pneumonia. When the abscesses are large and only one or two abscesses are present, they are usually due to aspiration. The cardinal histologic change in all abscesses is suppurative destruction of the lung parenchyma. Some abscesses have a central cavity.

SLIDE: Histology of a lung abscess. There are dying cells, inflammatory cells, and necrotic tissue....no normal tissue to be found.

SLIDE: Wall of the lung abscess, with fibroblasts and inflammatory cells, forming a distinct margin between the lung abscess and the lung parenchyma.

Handout: Lung Lecture