INTRODUCTION TO LOWER RESPIRATORY TRACT INFECTIONS

General Goal: To know the major mechanisms of defense in the LRT, the major mechanisms invaders use to avoid the defenses of the LRT, and the common modes of transmission.

Specific Educational Objectives: The student should be able to:

1. describe most common modes of transmission of pneumonia.

3. describe defense mechanisms the body uses to protect itself from infections.

4. the mechanisms microbes use to infect the LRT.

Reading: Mosby's Color Atlas and Text of Infectious Diseases by Christopher P. Conlon and David R. Snydman. pp. 67-76.

Lecture: Dr. Neal R. Chamberlain

References: 

• Of the LRT infections pneumonia remains the most common infections seen in the community and among hospitalized patients. Despite the use of antibiotics the mortality associated with pneumonia is still quite high. In 2000 pneumonia and influenza were the seventh leading cause of death in the United States (24.3 deaths per 100,000 population). Approximately, 1.8 cases of pneumonia were reported for every 100 Americans in 1996. Pneumonia is also a very common case of nosocomial infections ranking third in occurrence behind urinary tract infections and surgical wound infections (33% of the infections acquired in the hospital).

1. The respiratory tract is usually divided into three parts.
• I. The Upper Respiratory tract: This includes the nose, paranasal sinuses, and throat.
• II. The Respiratory Airways: This includes the trachea, bronchi, and bronchioles.
• III. The Lungs: This includes the respiratory bronchioles, alveolar ducts, alveolar sacs, and the alveoli.
2. The alveoli are lined with two types of cells, the Type 1 and Type 2 pneumocyte. The Type 1 pneumocyte is a very large thin cell stretched over a very large area. This cell can not replicate and is susceptible to a large number of toxic insults. Type 1 pneumocytes are responsible for gas exchanges occurring in the alveoli. The Type 2 granular pneumocyte is smaller, roughly cuboidal cell that is usually found at the alveolar septal junctions. This cell is responsible for the production and secretion of surfactant. The Type 2 pneumocyte can replicate in the alveoli and will replicate to replace damaged Type 1 pneumocytes.

1. Particles from 2 um to 0.2 um can go all the way down inside the alveoli avoiding the defenses of the upper respiratory tract and the mucociliary elevator. (Note: Most bacteria and all viruses are 2 mm and smaller.)
2. The following defense mechanisms in the alveoli protect the parenchymal cells from invasion by microorganisms.
• Alveolar macrophages (the most important)
• Complement components
• Alveolar lining fluid containing surfactant, phospholipids, neutral lipids, IgG, IgE, IgA, secretory IgA, certain complement components, Factor B, and other unidentified agents that maybe important in activation of alveolar macrophages.
• B cells, T cells, and null cells that can elicit a localized immune response to infection.
• Lymphoid tissue associated with the lungs.
Once a microorganism arrives in the alveoli it can be opsonized by IgG in the fluid lining the alveoli. These organisms will then be ingested by the macrophage. If no specific antibody to the organism is present then the macrophage may still be able to phagocytize the invader however, at a slower rate. Once the microorganism is phagocytized the macrophage will destroy the organism, if it can, and present microbial antigens on the surface to awaiting B and T cells. Once activated the B and T cells can produce more antibody and/or activate the macrophage. Meanwhile the macrophage is also releasing factors that help bring in polymorphoneutrophils (PMN) from the blood stream and initiate an inflammatory response. Along with the PMNs come more antibodies and complement components useful in destroying the invader. The invaders can also at this time leave the lung and get into the general circulation. This is probably why systemic signs of infection (fever, malaise, myalgia, etc.) occur in pneumonia.

1. To kill the microorganism in the alveoli it must be phagocytized by the alveolar macrophage. If these microbes can avoid phagocytosis or survive once phagocytized they can survive in the lung. Microorganisms have developed a number of ways to avoid phagocytosis. Once phagocytized certain organisms can survive in the phagocyte.
2. Mechanisms used to avoid phagocytosis.
• Capsule production. (S. pneumoniae, H. influenza, B. anthracis, N. meningitidis, K. pneumoniae)
• Toxin production. These toxins could include cytotoxins, leukocidins, and exotoxins. (examples; S. aureus produces leukocidins and cytotoxins. P. aeruginosa produces exotoxin A which destroys cells much like the diphtheria toxin does.)
• Being too large to phagocytize. Parasites and fungi are often too large for the phagocyte to engulf.
• Replication inside cells. Viruses and Chlamydia sp. are obligate intracellular parasites that replicate inside the cells of the lung avoiding the phagocyte.
• Mimicry. Some parasites produce surface proteins which are very similar to host proteins or acquire host proteins and appear to the phagocyte as self. Some bacteria produce proteins that cause host proteins to bind to their surfaces (ex. protein A/Staphylcoccus aureus)
3. Mechanisms used to survive in the phagocyte.
• Inhibition of lysosome fusion with the phagosome. (Toxoplasma gondii, Aspergillus sp., Chlamydia psittaci)
• Escape from the phagosome. (Mycobacterium leprae, Trypanosoma cruzi, Influenza virus escapes the phagolysosome)
• Resistance to killing and digestion in the phagolysosome. (Mycobacterium tuberculosis, Nocardia sp., Yersinia pestis)
• Growth in the phagocytic cell. (M. tuberculosis, Legionella pneumophila, Cytomegalovirus)
• Entry into the phagocyte other than by phagocytosis. Some organisms avoid destruction by getting into the phagocyte's cytoplasm. No phagosome-lysosome fusion occurs and the organisms can survive in the phagocyte. (Toxoplasma gondii, some enveloped viruses)

1. Inhalation of small airborne infectious particles (airborne transmission). Most microorganisms that cause pneumonia are able to survive on airborne droplets. These droplets can float in the air for quite a long time and if still infectious can sometimes cause pneumonia.
2. Aspiration of resident naso-oropharyngeal flora or large airborne particles after deposition in the naso-oropharynx (aspiration pneumonia). Usually aspiration of material into the lungs occurs during sleep. Certain people aspirate more than others during sleep and as a result have more problems with LRT infections. Other groups of people bothered by aspiration related LRT infections are alcohol abusers, drug abusers, and comatose patients.
3. Hematogenous spread to the lung from another site of infection. People with endocarditis, septic pelvic or jugular thrombophlebitis may also experience LRT infections. Pneumonia acquired by hematogenous spread to the lungs often times is bilateral and uniform. Pneumonia transmitted by bronchogenic infection (inhalation, aspiration) are usually unilateral and tend to localize in the lung.
4. Direct extension from a contiguous site of infection. Entamoeba histolytica can cause pneumonia by direct extension from an amebic abscess in the liver. Influenza and Respiratory Syncytial Viruses can spread from the upper respiratory tract to the LRT via infection of the respiratory epithelium.
5. Exogenous penetration and contamination of the lung can occur due to accidental trauma (car accident) or surgery.

F. Pathogenesis of Pneumonia

1. A microorganism enters the alveoli and proceeds to grow in the rich environment provided by the lung. Oftentimes the organism contains a capsule or is intracellular and can avoid phagocytosis for a period of time. As a result of tissue injury an inflammatory response occurs. Tissue injury can occur due to exotoxins produced by a bacteria, cell lysis caused by a virus, or death of alveolar macrophages and dumping of their lysosomal contents in the alveoli due to growth of an organism in the phagocyte. Vascular permeability increases and PMNs arrive at the area attempting to contain and eliminate the organisms. Along with PMNs come many of the serum components. Meanwhile other alveolar macrophages are being recruited to the area of inflammation. This accumulation of microorganism, immune cells, and serum components causes the alveoli to fill up and can result in spread to other alveoli in close proximity. This inflammatory response is what is described as an opacity or consolidation when viewing a roentgenograph (a X-ray film). Not only are serum components coming into the alveoli but certain products made by the microorganism are able to leave the lung and exert systemic effects. Examples include endotoxin from gram negative bacteria eventually resulting in fever and septic shock, and cell wall components of gram positive bacteria that can eventually lead to fever production and septic shock. All of the microbial products producing or indirectly resulting in systemic changes have yet to be clearly determined.
2. The deleterious effects on the host fall into two categories:
• Systemic effects such as fever, shock, (particularly associated with gram negative bacteria) and wasting (chronic tuberculosis).
• Interference with the ability of the lungs to carry out air exchange. This can be due to thickening of the membrane that separates erythrocytes from inspired air in the alveoli, and inflammation in the alveoli resulting in regional mismatches in the ventilation and perfusion of the lungs.

• The following are the organisms that can cause pneumonia. (*Note: not a complete list)

H. Complications of Pneumonia- Basically there are two types of complications

1. Complications that occur during the acute phase of the infection.
• Pleural effusion: Sterile effusion into the pleural space surrounding the lungs.
• Empyema: A pleural effusion that is grossly purulent (contains bacteria and white blood cells).
• Fluid and electrolyte: Dehydration and hypernatremia (high concentration of sodium in the blood).
• Hematologic: Anemia seen in chronic pneumonia, disseminated intravascular coagulation (usually gram negative pneumonia), and thrombocytopenia (Influenza binding to platelets).
• Hepatic: Bacterial pneumonias can commonly be associated with mild elevations of liver enzymes without evidence of liver invasion. Sometimes jaundice can occur and can indicate a poor prognosis.
• Renal: In cases of severe pulmonary infections protein catabolism markedly increases. This results in an azotemia (nitrogenous products in the blood). This condition is transient and renal damage does not occur (No large increase in creatinine).
2. Chronic complications
• Abnormalities in pulmonary function: Usually manifested as a decrease in arterial PO₂.
• Chronic pneumonia
• Bronchiectasis: Is a disorder characterized by irreversible destruction and dilatation of airways.