Adherence.

For any organism to cause disease, it must first gain a foothold within the respiratory tract to grow to sufficient numbers to produce symptoms. Therefore, most etiologic agents of respiratory tract disease must first adhere to the mucosa of the respiratory tract. The presence of normal flora and the overall state of the host affect the ability of microorganisms to adhere. Surviving or growing on host tissue without causing overt harmful effects is termed colonization. Except for those microorganisms inhaled directly into the lungs, all etiologic agents of disease must first colonize the respiratory tract before they can cause harm.

Streptococcus pyogenes possess specific adherence factors such as fimbriae comprised of molecules such as lipoteichoic acids and M proteins. These molecules appear as a thin layer of fuzz surrounding the bacteria. Staphylococcus aureus and certain viridans streptococci are other bacteria that posses these lipoteichoic acid adherence complexes. Many gram-negative bacteria (which do not have lipoteichoic acids), including Enterobacteriaceae, Legionella spp., Pseudomonas spp., Bordetella pertussis, and Haemophilus spp., also adhere by means of proteinaceous finger-like surface fimbriae. Viruses possess either a hemagglutinin (influenza and parainfluenza viruses) or other proteins that mediate their epithelial attachment.

Toxins.

Certain microorganisms are almost always considered to be etiologic agents of disease if they are present in any numbers in the respiratory tract because they possess virulence factors that are expressed in every host. These organisms are listed in Box 69-2. The production of extracellular toxin was one of the first pathogenic mechanisms discovered among bacteria. Corynebacterium diphtheriae is a classic example of a bacterium that produces disease through the action of an extracellular toxin. Once the organism colonizes the upper respiratory epithelium, it produces a toxin that is disseminated systemically, adhering preferentially to central nervous system cells and muscle cells of the heart. Systemic disease is characterized by myocarditis, peripheral neuritis, and local disease that can lead to respiratory distress. Growth of C. diphtheriae causes necrosis and sloughing of the epithelial mucosa, producing a “diphtheritic (pseudo) membrane,” which may extend from the anterior nasal mucosa to the bronchi or may be limited to any area between—most often the tonsillar and peritonsillar areas. The membrane may cause sore throat and interfere with respiration and swallowing. Although nontoxic strains of C. diphtheriae can cause local disease, it is much milder than disease associated with toxigenic strains.

Some strains of Pseudomonas aeruginosa produce a toxin similar to diphtheria toxin. Whether this toxin actually contributes to the pathogenesis of respiratory tract infection with P. aeruginosa has not been established. Bordetella pertussis, the agent of whooping cough, also produces toxins. The role of these toxins in production of disease is not clear. They may act to inhibit the activity of phagocytic cells or to damage cells of the respiratory tract. Staphylococcus aureus and beta-hemolytic streptococci produce extracellular enzymes capable of damaging host cells or tissues. Extracellular products of staphylococci aid in the production of tissue necrosis and the destruction of phagocytic cells and contribute to the abscess formation associated with infection caused by this organism. Although S. aureus can be recovered from throat specimens, it has not been proved to cause pharyngitis. Enzymes of streptococci, including hyaluronidase, allow rapid dissemination of the bacteria. Many other etiologic agents of respiratory tract infection also produce extracellular enzymes and toxins.

Microorganism Growth.

In addition to adherence and toxin production, pathogens cause disease by merely growing in host tissue, interfering with normal tissue function, and attracting host immune effectors, such as neutrophils and macrophages. Once these cells begin to attack the invading pathogens and repair the damaged host tissue, an expanding reaction ensues with more nonspecific and immunologic factors being attracted to the area, increasing the amount of host tissue damage. Respiratory viral infections usually progress in this manner, as do many types of pneumonias, such as those caused by Streptococcus pneumoniae, S. pyogenes, Staphylococcus aureus, Haemophilus influenzae, Neisseria meningitidis, Moraxella catarrhalis, Mycoplasma pneumoniae, Mycobacterium tuberculosis, and most gram-negative bacilli.

Avoiding the Host Response.

Another virulence mechanism present in various respiratory tract pathogens is the ability to evade host defense mechanisms. S. pneumoniae, N. meningitidis, H. influenzae, Klebsiella pneumoniae, mucoid P. aeruginosa, Cryptococcus neoformans, and others possess polysaccharide capsules that serve both to prevent engulfment by phagocytic host cells and to protect somatic antigens from being exposed to host immunoglobulins. The capsular material is produced in such abundance by certain bacteria, such as pneumococci, that soluble polysaccharide antigen particles can bind host antibodies, blocking them from serving as opsonins. Vaccine consisting of capsular antigens provides host protection to infection, indicating that the capsular polysaccharide is a major virulence mechanism of H. influenzae, S. pneumoniae, and N. meningitidis.

Some respiratory pathogens evade the host immune system by multiplying within host cells. Chlamydia trachomatis, Chlamydia psittaci, Chlamydia pneumoniae, and all viruses replicate within host cells. They have evolved methods for being taken in by the “nonprofessional” phagocytic cells of the host to where they thrive within the intracellular environment. Once within these cells, the organism is protected from host humoral immune factors and other phagocytic cells. This protection lasts until the host cell becomes sufficiently damaged that the organism is then recognized as foreign by the host and is attacked. A second group of organisms that cause respiratory tract disease comprises organisms capable of survival within phagocytic host cells (usually macrophages). Once inside the phagocytic cell, these respiratory tract pathogens are able to multiply. Legionella, Pneumocystis jiroveci (Pneumocystis carinii), and Histoplasma capsulatum are some of the more common intracellular pathogens.

Mycobacterium tuberculosis is the classic representative of an intracellular pathogen. In primary tuberculosis, the organism is carried to an alveolus in a droplet nucleus, a tiny aerosol particle containing tubercle bacilli. Once phagocytized by alveolar macrophages, organisms are carried to the nearest lymph node, usually in the hilar or other mediastinal chains. In the lymph node, the organisms slowly multiply within macrophages. Ultimately, M. tuberculosis destroys the macrophage and is subsequently taken up by other phagocytic cells. Tubercle bacilli multiply to a critical mass within the protected environment of the macrophages, which are prevented from accomplishing phagosome-lysosome fusion capable of destroying the bacteria. Having reached a critical mass, the organisms spill out of the destroyed macrophages, through the lymphatics, and into the bloodstream, producing mycobacteremia and carrying tubercle bacilli to many parts of the body. In most cases, the host immune system reacts sufficiently at this point to kill the bacilli; however, a small reservoir of live bacteria may be left in areas of normally high oxygen concentration, such as the apical (top) portion of the lung. These bacilli are walled off, and years later, an insult to the host, either immunologic or physical, may cause breakdown of the focus of latent tubercle bacilli, allowing active multiplication and disease (secondary tuberculosis). In certain patients with primary immune defects, the initial bacteremia seeds bacteria throughout a compromised host, leading to disseminated or miliary tuberculosis. Growth of the bacteria within host macrophages and histiocytes in the lung causes an influx of more effector cells, including lymphocytes, neutrophils, and histiocytes, eventually resulting in granuloma formation, then tissue destruction and cavity formation. The lesion consists of a semisolid, amorphous tissue mass resembling semisoft cheese, from which it received the name caseating necrosis (death of cells or tissues). The infection can extend into bronchioles and bronchi from which bacteria are disseminated via respiratory secretions and coughing. Aerosolized droplets are produced by coughing and contain organisms that are inhaled by the next susceptible host. Other portions of the patient’s lungs may become infected as well through aspiration (inhalation of a fluid or solid).