Emerging & Re-emerging Infectiious Diseases
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Understanding Emerging and Re-emerging Infectious Diseases (continued)

All of these agencies report data to the U.S. Public Health Service. NIH, the funding agency of this module, began in 1887 as the Laboratory of Hygiene; NIH is one of eight health agencies of the U.S. Public Health Service. It supports health-related research aimed at understanding, preventing, treating, and controlling infectious and other diseases of humankind. The Public Health Service also operates the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the Food and Drug Administration (FDA). CDC staff investigate disease outbreaks, publish a summary of current epidemiological reports, and sponsor a variety of education programs, research projects, and reference laboratories. FDA monitors the safety of our food, medicines, and many other products that we use daily. Finally, the World Health Organization (WHO) provides international surveillance and control of disease. Among other efforts, WHO coordinates multinational vaccination campaigns.

Treatment of Infectious Diseases

While literally meaning "destroyer of life," the term "antibiotic" has become the most commonly used word to refer to a chemical substance used to treat bacterial infections. The term "antimicrobial" has a somewhat broader connotation, generally referring to anything that inhibits the growth of microbes. Technically, the term antimicrobial does not encom-pass the "antihelminthic" drugs because worms are not microscopically small. Antimicrobials can be either microbistatic (inhibiting the replication of the microbe) or microbicidal (actually killing the target microorganism). In the former case, a combination of therapy and immunity may be required to finally terminate the infection.

Treatment of bacterial diseases

Because bacteria are prokaryotes, it has been relatively easy to find and develop antibacterial drugs that have minimal side effects. These drugs target structural features and metabolic characteristics of prokaryotes that are significantly different from those in eukaryotic cells. Drugs used to treat bacterial diseases can be grouped into categories based on their modes of action. In general, these drugs inhibit cell wall synthesis, protein synthesis, nucleic acid synthesis, or other enzyme-catalyzed reactions.

The penicillins and cephalosporins all interfere with the synthesis of the peptidoglycan layer in prokaryotic cell walls. Because eukaryotes have neither the peptidoglycan components nor the enzymes that synthesize them, these drugs do not affect the host cells. A second class of drugs, including chloramphenicol, the tetracyclines, and erythromycin, bind to prokaryotic ribosomes and inhibit protein synthesis. Prokaryotic ribosomes are structurally different from eukaryotic ribosomes, so these drugs have minimal effect on eukaryotic cells. Nevertheless, some of them may be toxic to some human tissues when they are used in high doses or for prolonged periods of time.

Rifampicin is one of the antibiotics frequently used for treating tuberculosis. This drug inhibits prokaryotic RNA synthesis. DNA synthesis in prokaryotes may be inhibited by the fluoroquinolones. In contrast, the sulfonamides stop bacterial infections by inhibiting other enzymes. Sulfonamides interfere with the synthesis of folic acid, a vitamin necessary for nucleic acid synthesis. Most bacteria must synthesize their own folic acid because their membranes are impermeable to external folic acid. Mammalian cells are not affected by sulfonamides because they are unable to make their own folic acid and have evolved mechanisms for transporting external folic acid across their membranes.

Treatment of viral diseases

In general, drugs that effectively inhibit viral infections are highly toxic to host cells because viruses use the host's metabolic enzymes in their reproduction. For this reason, most illnesses due to viruses are treated symptomatically until the host's immune system controls and eliminates the pathogen (or the host dies). Antiviral drugs that are used typically target virus-specific enzymes involved in viral nucleic acid synthesis. One of the most familiar of these drugs is acyclovir, which is used to treat outbreaks of genital herpes. Amantadine is an antiviral drug sometimes used to prevent or moderate influenza among those at high risk of severe illness from the disease.

In addition to antiviral drugs that inhibit the replication of the HIV genome (such as AZT), AIDS patients today are also prescribed proteases that interfere with the packaging of the HIV genome into virus particles.

Treatment of fungal and parasitic diseases

The development of drugs to treat fungal, protozoan, and helminthic diseases is challenging because agents that kill or inhibit the growth of these eukaryotic organisms are also highly toxic to mammalian cells. Because fungi and protozoa are rapidly proliferating cells, drugs against these organisms tend to target key components of their replicative or biosynthetic pathways. Common antifungals inhibit sterol syntheses (the azole derivatives) or disrupt the cell membrane (polyenes like amphotericin B). Most antihelminthic drugs target adult worms, which are no longer growing and do not replicate. These drugs are often aimed at inhibiting fundamental processes, such as energy production and muscle function (for example, the benzimidazoles and avermectins), or at targets involved in egg production or larval development.

Malaria, a protozoan disease, was successfully treated for many years with chloroquine. In recent decades, Plasmodium species that are resistant to this drug have appeared and spread to areas where malaria is a common threat. In those areas, a combination of the drugs sulfonamide and pyrimethamine is frequently used to treat the disease.

Resistance to antimicrobial agents

One of the ongoing problems scientists and medical workers face in the fight against infectious diseases is the development of resistance to the agents used to control them. The phenomenon of resistance has been known since almost the beginning of antibiotic use. For example, penicillin was introduced for clinical use in treating bacterial infections in the 1940s. As early as 1943, Alexander Fleming, the discoverer of penicillin, observed that some bacteria were resistant to the drug and warned that indiscriminate use of penicillin would lead to the proliferation of resistant pathogenic bacteria. By 1946, medical staff at a London hospital estimated that 14 percent of the staphylococcal strains isolated from their patients were resistant to penicillin. Today, more than 90 percent of these bacteria are resistant. In an environment of widespread penicillin use, selection for resistant bacteria occurred; that is, the pathogenic organisms evolved.

The same process has occurred for many other antimicrobial drugs. Alarmingly, many pathogens are simultaneously acquiring resistance to multiple drugs. For example, some strains of Mycobacterium tuberculosis are resistant to all of the currently available drugs used for treatment.

Mechanisms of antimicrobial resistance

Antibiotic resistance appears as a result of changes in genes or the acquisition of genes that allow the pathogen to evade the action of antimicrobial drugs. Resistance mechanisms include structural changes in or around the target molecule that inhibit the drugs' ability to bind to it; reduced permeability of the cell membrane to the drug, actively pumping the drug out of the cell after it has entered; and production of enzymes that inactivate the antibiotic after it has been taken up by the cell. Microbes that produce larger-than-normal amounts of the target molecule may be "less susceptible" (as opposed to resistant) to a drug, meaning it takes a higher drug level to adversely affect that microbe.

Transfer of antimicrobial-resistance genes

Bacteria have many methods for developing resistance. Antibiotic resistance initially arises as mutations to existing genes; however, many (probably most) bacteria acquire these genes rather than experience the mutation themselves. Resistance genes are transferred to other members of the same species and across species by a variety of bacterial genetic-exchange mechanisms. Many gram-negative bacteria, including Escherichia coli and Salmonella species, can transfer extra-chromosomal genetic material called plasmids via the process of conjugation. Bacteria endowed with the plasmids have numerous pili along their surfaces; one of these extends to a plasmid-lacking bacterium as a conjugation tube. The plasmid then replicates, and one copy travels through the conjugation tube into the recipient bacterium. One large class of plasmids is called resistance plasmids because they carry genes that confer antibiotic resistance. Many resistance plasmids carry genes for resistance to multiple antibiotics; thus, one conjugation event can simultaneously transfer resistance to several antibiotics.

Some species of bacteria are capable of taking up free-floating bits of DNA from their environments in a process known as bacterial transformation. If they take up a DNA fragment containing an antibiotic-resistance gene, they may become resistant to that antibiotic. Another mechanism of genetic exchange in bacteria is transduction. Bacteria are subject to viral infection. When a bacteria cell is infected, the virus takes over the cell's metabolism, directing synthesis of its genetic material and production of the components of the viral particle. Simultaneously, the host bacterial DNA is degraded. In the last stage of virus production, its genetic material is encapsulated in a protein coat. Occasionally, a piece of the host bacterial DNA may be packaged in a viral particle. The resulting "transducing particle," like a normal viral particle, has the ability to attach to a recipient bacterium and transfer its genetic material into the cell. However, in this case, the transferred genetic material may be a bacterial gene that provides resistance to an antibiotic.

Finally, many transposons carry antibiotic-resistance genes. Transposons are sequences of DNA that are capable of inserting themselves randomly into genomes. Because they do not appear to rely on specific genetic sequences of the target insertion site, they can readily move across species.

Although mutations that result in antibiotic resistance, and, less so, bacterial genetic exchange, are rare events, they need occur only once. In an environment of heavy antibiotic use, the forces of natural selection will favor the propagation of resistant variants of a pathogen. The human body is a rich environment for the growth of large numbers of bacteria and for the interaction of a variety of pathogenic and nonpathogenic bacteria. Thus, there is optimal opportunity for rare mutational and genetic-exchange events.

Other pathogens have more limited options for drug resistance. Strains of pathogens develop that are naturally less susceptible to a particular drug due to a normally occurring mutation. In the face of continuing drug use, this strain rapidly grows out of the population being spread through the usual transmission process. Malaria, a protozoan disease, was successfully treated for many years with chloroquine, a drug that was widely available over the counter in regions where malaria was a problem. In recent decades, Plasmodium strains that are resistant to this drug have appeared and spread throughout Africa, South America, and Southeast Asia.

Emerging and Re-emerging Infectious Diseases

Fifty years ago many people believed the age-old battle of humans against infectious disease was virtually over, with humankind the winners. The events of the past two decades have shown the foolhardiness of that position. At least a dozen "new" diseases have been identified (such as AIDS, Legionnaire disease, and hantavirus pulmonary syndrome), and traditional diseases that appeared to be "on their way out" (such as malaria and tuberculosis) are resurging. Globally, infectious diseases remain the leading cause of death, and they are the third leading cause of death in the United States. Clearly, the battle has not been won.

Emerging infectious diseases are diseases that (1) have not occurred in humans before (this type of emergence is difficult to establish and is probably rare); (2) have occurred previously but affected only small numbers of people in isolated places (AIDS and Ebola hemorrhagic fever are examples); or (3) have occurred throughout human history but have only recently been recognized as distinct diseases due to an infectious agent (Lyme disease and gastric ulcers are examples). Figure 7 lists several examples of infectious diseases that have emerged in the last three decades.

A review of Figure 7 reveals that environmental changes are related to the emergence of many infectious diseases. For example, Lyme disease, hantavirus pulmonary syndrome (HPS), and Lassa fever all emerged when humans began encountering the insect vector (for Lyme disease) or rodent host (for HPS and Lassa fever) of the causative agents in greater numbers than ever before. Factors related to the emergence of infectious diseases such as Legionnaire disease and hemolytic uremic syndrome include changing technologies: air conditioning systems for the former disease and mass food production for the latter.

Figure 7 - Examples of emerging infectious diseases.
Disease Infectious Agent Year Recognized* Contributing Factors
Lassa fever Arenaviridae family (virus) 1969 urbanization and other conditions that favor the rodent host; nosocomial transmission
Ebola hemorrhagic fever Filoviridae family (virus) 1977 unknown natural reservoir; nosocomial transmission
Legionnaire disease Legionella pneumophila (bacterium) 1977 cooling and plumbing systems
hemolytic uremic syndrome Escherichia coli 0157:H7 (bacterium) 1982 mass-food-production systems
Lyme borreliosis Borrelia burgdorferi (bacterium) 1982 conditions favoring the tick vector and deer, such as reforestation near homes
AIDS human immunodeficiency virus 1983 migration to cities, global travel, transfusions, organ transplants, intravenous drug use, multiple sexual partners
gastric ulcers Helicobacter pylori (bacterium) 1983 newly recognized as due to infectious agent
cholera Vibrio cholerae 0139 (bacterium) 1992 evolution of new strain of bacteria combining increased virulence and long-term survival in the environment
hantavirus pulmonary syndrome Bunyaviridae family (virus) 1993 environmental changes favoring contact with rodent hosts
pandemic influenza Orthomyxoviridae family (virus) new viral strains emerge periodically pig-duck agriculture (possibly)

Sources: Morse, S.S. 1995. Factors in the emergence of infectious diseases. Emerging Infectious Diseases [Serial online], 1(1). Available http://www.cdc.gov/ncidod/EID/index.htm. June 1999; Satcher, D. 1995. Emerging infections: Getting ahead of the curve. Emerging Infectious Diseases [Serial online], 1(1). Available http://www.cdc.gov/ncidod/EID/index.htm. June 1999; Morse, S.S. (Ed.). 1993. Examining the origins of emerging viruses. Emerging viruses. New York: Oxford University Press; ProMED. 1994. About ProMED. Available http:// www.fas.org/promed/about/index.html, June 1999.

*Year infectious agent was identified.

 

Re-emerging infectious diseases are diseases that once were major health problems globally or in a particular country, and then declined dramatically, but are again becoming health problems for a significant proportion of the population (malaria and tuberculosis are examples). Many specialists in infectious diseases include re-emerging diseases as a subcategory of emerging diseases. Figure 8 lists examples of re-emerging infectious diseases.

A review of Figure 8 reveals some explanations for the re-emergence of infectious diseases. Tuberculosis has re-emerged due to evolution of the causative bacteria. The pathogen has acquired resistance to the antibiotics used to treat tuberculosis (either through mutation or genetic exchange), and the long-term use of antibiotics (both within one individual and across the population) has selected for the pathogen's proliferation. Malaria has also become drug resistant, and the vector mosquito has acquired resistance to pesticides as well. The re-emergence of diseases such as diphtheria and whooping cough (pertussis) is related to inadequate vaccination of the population. When the proportion of immune individuals in a population drops below a particular threshold, introduction of the pathogen into the population leads to an outbreak of the disease.

Figure 8 - Examples of re-emerging infectious diseases.
Disease Infectious Agent Contributing Factors
cryptosporidiosis Cryptosporidium parvum (protozoan) inadequate control in water supply; international travel; increased use of childcare facilities
diphtheria Corynebacterium diptheriae (bacterium) interruption of immunization program due to political changes
malaria Plasmodium species (protozoan) drug resistance; favorable conditions for mosquito vector
meningitis, necrotizing fasciitis (flesh-eating disease), toxic-shock syndrome, and other diseases Group A Streptococcus (bacterium) uncertain
pertussis (whooping cough) Bordetella pertussis (bacterium) refusal to vaccinate based on fears the vaccine is not safe; other possible factors: decreased vaccine efficacy or waning immunity among vaccinated adults
rabies Rhabdovirus group (virus) breakdown in public health measures; changes in land use; travel
rubeola (measles)* Morbillivirus genus (virus) failure to vaccinate; failure to receive second dose of vaccine
schistosomiasis Schistosoma species (helminth) dam construction; ecological changes favoring snail host
tuberculosis Mycobacterium tuberculosis (bacterium) antibiotic-resistant pathogens; immunocompromised populations (malnourished, HIV-infected, poverty-stricken)
yellow fever Flavivirus group (virus) insecticide resistance; urbanization; civil strife

Sources: Krause, R.M. 1992. The origin of plagues: Old and new. Science, 257: 1073-1078; Measles—United States, 1997. April 17, 1998. Morbidity and Mortality Weekly Report, 47(14): 273-276; Pertussis vaccination: Use of acellular pertussis vaccines among infants and young children. 1997, March 28. Morbidity and Mortality Weekly Report, 46(RR-7); ProMED. 1994. About ProMED. Available from http://www.fas.org/promed/about/index.html. June 1999.

*Following the initial decline of measles cases after the licensing of the vaccine in 1963, there was a resurgence of measles—to some 50,000 cases—from 1989 to 1991. Since then, the incidence of measles has declined again, to an all-time low of 138 cases in 1997.

Despite the challenges of emerging and re-emerging infectious diseases, the results of basic research, such as that sponsored by NIH, show that there is reason for hope. AIDS was first described in 1981, and it took two years to identify the retrovirus that causes AIDS, which was named the human immunodeficiency virus. In contrast, less than four months elapsed between the description of hantavirus pulmonary syndrome (HPS) in 1993 and the identification of the previously unknown viral agent, now called Sin Nombre virus. One difference between these two cases is that the years that intervened between the advent of AIDS and the advent of HPS saw the development of polymerase chain reaction, a powerful new research technique that allows rapid identification of causative agents. Recommendations for avoiding and/or treating new infectious diseases become possible when new techniques, developed through basic research, are applied to the problem of disease emergence.

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