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CLINICAL ASPECTS OF INFECTIOUS DISEASE
Fever, pain, and swelling are the universal signs of infection. Beyond this, the particular organs involved and the speed of the process dominate the signs and symptoms of disease. Cough, diarrhea, and mental confusion represent disruption of three different body systems. On the basis of clinical experience, physicians have become familiar with the range of behavior of the major pathogens. However, signs and symptoms overlap consid-erably. Skilled physicians use this knowledge to begin a deductive process leading to a list of suspected pathogens and a strategy to make a specific diagnosis and provide patient care. Through the probability assessment, an understanding of how the diseases work is a distinct advantage in making the correct decisions.
A major difference between infectious and other diseases is that the probabilities described above can be specifically resolved, often overnight. Most microorganisms can be isolated from the patient, grown in artificial culture, and identified. Others can be seen microscopically or detected by measuring the host specific immune response. Preferred modalities for diagnosis of each agent have been developed and are available in clinic, hospital, and public health laboratories all over the world. Empiric diagnosis made on the basis of clinical findings can be confirmed and the treatment plan modified accordingly. The new molecular methods, which detect molecular structures or genes of the agent, are not yet practical for most infectious diseases.
Over the past 60 years, therapeutic tools of remarkable potency and specificity have be-come available for the treatment of bacterial infections. These include all the antibiotics and an array of synthetic chemicals that kill or inhibit the infecting organism but have minimal or acceptable toxicity for the host. Antibacterial agents exploit the structural and metabolic differences between bacterial and eukaryotic cells to provide the selectivity necessary for good antimicrobial therapy. Penicillin, for example, interferes with the syn-thesis of the bacterial cell wall, a structure that has no analog in human cells. There are fewer antifungal and antiprotozoal agents because the eukaryotic cells of the host and those of the parasite have close metabolic and structural similarities. Nevertheless, hosts and parasites do have some significant differences, and effective therapeutic agents have been discovered or developed to exploit them.
Specific therapeutic attack on viral disease has posed more complex problems, be-cause of the intimate involvement of viral replication with the metabolic and replicative activities of the cell. Thus, most substances that inhibit viral replication have unaccept-able toxicity to host cells. However, recent advances in molecular virology have identified specific viral targets that can be attacked. Scientists have developed some successful an-tiviral agents, including agents that interfere with the liberation of viral nucleic acid from its protective protein coat or with the processes of viral nucleic acid synthesis and replica-tion. The successful development of new agents for human immunodeficiency virus has involved targeting enzymes coded by the virus genome.
The success of the “antibiotic era” has been clouded by the development of resistance by the organisms. The mechanisms involved are varied but most often involve a muta-tional alteration in the enzyme, ribosome site, or other target against which the antimicro-bial is directed. In some instances, the organisms acquire new enzymes or block entry of the antimicrobic to the cell. Many bacteria produce enzymes which directly inactivate an-tibiotics. To make the situation worse, the genes involved are readily spread by promiscu-ous genetic mechanisms. New agents that are initially effective against resistant strains have been developed, but resistance by new mechanisms usually follows. The battle is by no means lost but has become a never-ending policing action.
The ultimate outcome with any disease is its prevention. In the case of infectious diseases, this has involved public health measures and immunization. The public health measures depend on knowledge of transmission mechanisms and interfering with them. Water disinfection, food preparation, insect control, handwashing, and a myriad of other measures prevent humans from coming in contact with infections agents. Immunization relies on knowledge of immune mechanisms and designing vaccines that stimulate pro-tective immunity.
Immunization follows two major strategies, live and inactivated vaccines. The former uses live but attenuated organisms that have been modified so they do not produce disease but still stimulate a protective immune response. Such vaccines have been effective but carry the risk that the vaccine strain itself may cause disease. This event has been ob-served with the live oral polio vaccine. Although this rarely occurs, it has caused a shift back to the original Salk inactivated vaccine. This issue has reemerged with a debate over strategies for the use of smallpox immunization to protect against bioterrorism. This vac-cine uses vaccinia virus, a cousin of smallpox, and its potential to produce disease on its own has been recognized since its original use by Jenner in 1798. Serious disease would be expected primarily in immunocompromised individuals, who represent a significantly larger part of the population (eg, from cancer chemotherapy, AIDS) than when smallpox immunization was stopped in the 1970s. Could immunization cause more disease than it prevents? The question is difficult to answer.
The safest immunization strategy is the use of organisms that have been killed or, bet-ter yet, killed and purified to contain only the immunizing component. This approach re-quires much better knowledge of pathogenesis and immune mechanisms. Vaccines for meningitis use only the polysaccharide capsule of the bacterium, and vaccines for diph-theria and tetanus use only a formalin-inactivated protein toxin. Pertussis (whooping cough) immunization has undergone a transition in this regard. The original killed whole-cell vaccine was effective but caused a significant frequency of side effects. A purified vaccine containing pertussis toxin and a few surface components has reduced side effects while retaining efficacy.
The newest approaches for vaccines require neither live organisms nor killed, purified ones. As the entire genomes of more and more pathogens are being reported, an entirely genetic strategy is emerging. Armed with knowledge of molecular pathogenesis and immunity and the tools of genomics and proteomics, scientists can now synthesize an immunogenic protein without ever growing the organism itself. Such an idea would have astonished even the great microbiologists of the past two centuries.
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