DISEASES, INFECTIOUS

Infectious diseases are caused by microbial agents (e.g., bacteria, fungi, parasites, prions, and viruses) or by their toxic by-products. Infectious diseases have been an inevitable and ubiquitous part of life since humans evolved. Although the contagious nature of many diseases had been observed since early in recorded history, the microbial origin of infectious diseases was not scientifically established until the late nineteenth century, when Robert Koch (1843–1910) demonstrated that the bacterium Bacillus anthracis is the causative agent of anthrax infection. Koch set forth four postulates that must be fulfilled to establish the microbial cause of an infectious disease:

1. Identify a specific organism from a patient with the disease;
2. Obtain a pure culture of that organism;
3. Reproduce the disease in experimental animals using the pure culture; and
4. Recover the organism from the infected animals.

Since Koch's time, causative agents and routes of infection have been described for thousands of infectious diseases of humans and animals. The impact of an infectious disease on an individual or animal can range from trivial to fatal. The impact of an infectious outbreak on a society can range from negligible to devastating.

Infectious diseases are undoubtedly among the most powerful factors that influence human demographics. In some cases, the impact of disease has been widespread, direct, and dramatic, as when epidemics and pandemics of plague, syphilis, cholera, and influenza caused substantial and concentrated morbidity and mortality in the fourteenth to twentieth centuries. At other times, the influences have been less direct, as in the late-nineteenth century when trypanosomiasis (African sleeping sickness) rendered large tracts of Africa uninhabitable until its insect vector, the tsetse fly, was controlled.

Classification Systems of Infectious Diseases

Several unofficial classification systems exist for infectious diseases. Some are based on causative agent and others on route of transmission. The following broad categories by causative agent are generally utilized in academic and microbiologic research institutions:

Bacterial diseases (e.g., salmonellosis, tuberculosis, syphilis);

Viral infections (e.g., West Nile encephalitis, measles, chickenpox, poliomyelitis, HIV);

Fungal infections (e.g., yeast infections, histoplasmosis);

Parasitic protozoan (e.g, cryptosporidiosis, malaria) and metazoan infections (e.g., hookworm, onchocerciasis);

Prion diseases (infectious proteins that are the agents of bovine spongiform encephalopathy or "mad cow disease" and Creutzfeldt-Jacob disease in humans); and

Rickettsial diseases (e.g., typhus and Rocky Mountain spotted fever).

Classification of diseases by route of transmission is typically used in public health and prevention-oriented disease control programs. Categories include:

Diseases transmitted from person-to-person, including respiratory illnesses transmitted by coughing (e.g., influenza and tuberculosis) and systemic diseases transmitted via sexual contact (e.g, HIV, syphilis, and gonorrhea);

Food-borne and waterborne diseases, including illnesses transmitted via the fecal-oral route (e.g., typhoid and hepatitis A) or via contaminated water (e.g., cryptosporidiosis and giardiasis);

Bloodborne infections (e.g., hepatitis B and C); Healthcare-acquired (nosocomial) infections, including surgical wound infections (e.g., staphylococcal infections);

Diseases transmitted by animals or insects, including zoonotic infections (e.g., Escherichia coli H7:O157 and rabies) and vectorborne infections (Lyme disease and yellow fever);

Infections acquired from the environment (Legionnaires' disease, inhaled in water droplets, and coccidioidomycosis, acquired from dust or soil).

Sometimes, vaccine-preventable diseases (such as rubella, mumps, and pertussis–whooping cough), infections of travelers (many diarrheal diseases), and antibiotic-resistant bacterial infections (such as methicillin-resistant Staphylococcus aureus) are regarded as unique categories, as are opportunistic infections (such as Pneumocystis pneumonia and cytomegalovirus retinitis), that are generally restricted to persons with immunodeficiencies. A sad commentary on contemporary society is represented by the category of infectious agents that may be used as biological weapons (including smallpox virus, anthrax spores, and botulinum toxin).

The International Statistical Classification of Diseases and Related Health Problems, issued by the World Health Organization (WHO), is the major official codification of all diseases, conditions, and injuries. The tenth revision (ICD-10) is the latest in a series that began in 1893 as the Bertillon Classification or International List of Causes of Death. The ICD is continually being revised as new conditions, including emerging infections, are described. Every infectious and non-infectious disease of humans is assigned a unique 3-digit number (plus multiple decimal places) in the ICD system. These numbers are used in many medical and public health records, including hospital discharge reports, billing records, and death certificates. The Control of Communicable Diseases Manual, the widely available and standard American Public Health Association handbook of infectious diseases, lists ICD codes for each of the several hundred infectious diseases it describes in its alphabetically arranged entries.

Control of Infectious Diseases in Developed Nations

Rapid progress in control of infectious diseases characterized the late nineteenth and early-twentieth centuries. Deaths from infectious disease declined markedly in the United States during the first half of the twentieth century (see Figure 1). This major demographic change both contributed to, and is reflected in, the sharp drop in infant and child mortality and the more than 30-year average increase in life expectancy at birth achieved over the ensuing years.

In 1900, the three leading causes of death were pneumonia, tuberculosis (TB), and diarrhea and enteritis, which (together with diphtheria) were responsible for one-third of all deaths (see Figure 2). About 40 percent of these deaths were deaths of children below the age of five. Cancer accounted for only 3.7 percent of deaths, because few people lived long enough for it to develop. Coming into the twenty-first century, heart disease and cancers account for almost three-quarters of deaths, with 5 percent due to pneumonia, influenza, and human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).

In 1900, 30.4 percent of children in the United States died before their fifth birthdays; in 1997, the figure was 1.4 percent. Despite this overall progress in the developed world, the twentieth century also witnessed two of the most devastating epidemics in human history. The 1918 influenza pandemic killed more than 20 million people, including 500,000 Americans, in less than a year–more deaths in a comparable time period than in virtually any war or famine. The last decades of the century were marked by the recognition and pandemic spread of HIV, resulting in an estimated 22 million deaths by the year 2000. UNAIDS (the Joint United Nations Programme on HIV/AIDS) projects another 65 million deaths by 2020. These episodes illustrate the volatility of infectious disease death rates and the unpredictability of disease emergence.

Twentieth century landmarks in disease control in the United States included major improvements in sanitation and hygiene, the implementation of universal childhood vaccination programs, control of food-borne diseases, and the introduction of antibiotics.

Sanitation and hygiene. The nineteenth century shift in U.S. population from country to city that accompanied industrialization, along with successive waves of immigration, led to overcrowding and poor housing. The municipal water supplies and rudimentary waste disposal systems that existed at the time were quickly overwhelmed. These conditions favored the emergence and spread of infectious illnesses, including repeated outbreaks of cholera, TB, typhoid fever, influenza, yellow fever, and foodborne illnesses such as shigellosis.

By 1900, however, the incidence of many of these diseases had begun to decline, due to the implementation of public health improvements that continued into the twentieth century. Sanitation departments were established for garbage removal, and outhouses were gradually replaced by indoor plumbing, sewer systems, and public systems for

FIGURE 1

solid waste disposal. The incidence of cholera, which reached its peak between 1830 and 1896, a period during which Eurasia and North America experienced four pandemics, began to fall, as water supplies were insulated from human waste by sanitary disposal systems. Chlorination and other treatments of drinking water began in the early 1900s and became widespread by mid-century, sharply decreasing the incidence of cholera, as well as typhoid fever and other waterborne diseases. The incidence of TB declined, as improvements in housing reduced crowding and TB control programs were put in place. In 1900, TB killed 200 out of every 100,000 Americans, most of them city residents. In 1940 (before the introduction of antibiotic therapy), TB remained a leading killer, but its mortality rate had decreased to 60 per 100,000 persons.

Vaccination programs. The advent of immunization also contributed greatly to the prevention of infectious diseases. Strategic vaccination campaigns virtually eliminated diseases that were common in the United States during the beginning and middle decades of the century–including diphtheria, tetanus, pertussis, polio, smallpox, measles, mumps, rubella, and Haemophilus influenzae type b meningitis. Starting with the licensing of the combined diphtheria-pertussis-tetanus (DPT) vaccine in 1949, state and local health departments began providing childhood vaccinations on a regular basis, primarily to poor children. In 1955, the introduction of the Salk polio vaccine led to the federal appropriation of funds to support childhood vaccination programs initiated by states and local communities. In 1962, a federally coordinated vaccination program was established through the passage of the Vaccination Assistance Act–a landmark piece of legislation that has been continuously renewed and in the early twenty-first century supports the purchase and administration of a full range of childhood vaccines. WHO's Expanded Program on Immunization seeks to extend these benefits globally.

The success of vaccination programs in the United States and Europe gave rise to the twentieth-century concept of disease eradication–the idea that a selected disease could be eliminated from all human populations through global cooperation. In 1980, after an 11-year campaign (1967–1977) involving 33 nations, WHO declared that smallpox had been eradicated worldwide–about a decade after it had been eliminated from the United States

FIGURE 2

and the rest of the Western Hemisphere. Polio and dracunculiasis (also called guinea worm disease, a waterborne, parasitic non-vaccine-preventable illness) were targeted for global eradication in the early twenty-first century, and many other infectious diseases may be targeted in the future, including measles, Haemophilus influenzae type b infections, filariasis, onchocerciasis, rubella, and hepatitis B.

Control of food-borne diseases. One of the disease control duties assumed by state and local health departments in the twentieth century was the regulation of food handling practices at food processing plants, restaurants, and retail food stores. The need for such regulation is illustrated by the famous story of Typhoid Mary, an Irish immigrant cook and typhoid carrier who worked at a number of New York restaurants in the 1920s and infected more than a hundred people before the New York City health department placed her under house arrest. The story of Typhoid Mary (who was treated very harshly) illustrates not only the growing expectation among Americans that government should promote public health, but also a tendency (which continues to this day) to associate infectious disease problems with immigrants or minority populations, rather than with specific risk factors or behaviors. During the 1980s, for example, the gay community was unjustly blamed for the AIDS epidemic, and in the early 1990s, the Navajo Nation was stigmatized when an outbreak of hantavirus pulmonary syndrome occurred in their community.

The second half of the twentieth century saw a notable rise in illness caused by nontyphoidal Salmonella species, and an explosion of knowledge made possible by modern molecular techniques resulted in identification of a growing list of previously unrecognized, and in some cases, new food-borne and waterborne agents. These include Escherichia coli O157:H7, Campylobacter spp., Cryptosporidium parvum, Listeria monocytogenes, Legionnella spp., and caliciviruses. A 1999 report estimated an annual incidence of 76 million food-borne illnesses in the United States, with 325,000 hospitalizations and 5,000 fatalities. In 1993, the largest outbreak of waterborne illness in U.S. history occurred when an estimated 400,000 persons in Milwaukee, Wisconsin were infected with the parasite Cryptosporidium.

Factors linked to the continued challenges of food-borne and waterborne illnesses include (1) changing dietary habits that favor foods more likely to transmit infection (e.g., raw seafood, sprouts, unpasteurized milk and juice, and fresh fruits and vegetables that may be inadequately washed); (2) globalization of the food supply; (3) mass production practices; and (4) aging and inadequately maintained water supply systems. Mass food production and distribution, while resulting in an abundant and usually safe food supply, has also increased the potential for large and geographically dispersed outbreaks of illness.

Antibiotics. The discovery of the antibiotic penicillin–and its development into a widely available medical treatment–was a major landmark in the control of infectious diseases. Penicillin and other antibiotics that were subsequently developed allowed quick and complete treatment of previously incurable bacterial illnesses. Discovered fortuitously in 1928, penicillin was not developed for medical use until the 1940s, when it was produced in significant quantities and used by the Allied military in World War II to treat sick or wounded soldiers.

Antibiotics have been in civilian use since the end of World War II, and have saved the lives and health of millions of persons with typhoid fever, diphtheria, bacterial pneumonia, bacterial meningitis, syphilis, gonorrhea, plague, tuberculosis, and streptococcal and staphylococcal infections. Drugs have also been developed to treat viral diseases (e.g., amantadine, ribavirin, zidovudine, and acyclovir); fungal diseases (e.g., nystatin, ketoconazole, and amphotericin B); and parasitic diseases (e.g., chloroquine, mebendazole, and metronidazole).

Unfortunately, these therapeutic advances have been tempered by the emergence of drug resistance in bacteria, parasites, viruses, and fungi. Diseases that have been significantly affected by antibiotic resistance include staphylococcal infections, gonorrhea, tuberculosis, pneumococcal infections, typhoid fever, bacterial dysentery, malaria, and HIV/AIDS. Reasons for the swift development of anti-microbial resistance include the natural tendency of organisms to mutate and share genetic material. However, this process has been facilitated by the following factors: (1) injudicious prescribing of antibiotics by the medical, veterinary, and agricultural industries; (2) unrealistic patient expectations resulting in requests for antibiotic treatment of non-bacterial infections; (3) the economics of pharmaceutical sales; and (4) the growing sophistication of medical interventions, such as transplant surgery and chemotherapy, that require the administration of large quantities of antibiotics. Growing antibiotic resistance poses a substantial threat to the gains in infectious disease control and warrants fresh approaches to promoting wise antibiotic stewardship by prescribers, patients, and industry so that the efficacy of these drugs can be sustained for future generations.

Animal and insect control. The twentieth century witnessed major advances in the control of disease transmission by animal and insect pests. In the United States, nationally sponsored, state-coordinated vaccination and animal control programs eliminated dog-to-dog transmission of rabies. Malaria, which had been endemic throughout the Southeast, was reduced to negligible levels by the late 1940s, through regional mosquito control programs that drained swamps and killed mosquito larvae in bodies of water.

The threat of plague epidemics in the United State was also greatly diminished. During the early 1900s, infected rats and fleas were introduced via shipping into port cities along the Pacific and Gulf coasts (e.g., San Francisco, Seattle, New Orleans, Galveston, and Pensacola), as well as into Hawaii, Cuba, and Puerto Rico. The most serious outbreaks occurred in San Francisco from 1900 to 1904 (121 cases/118 deaths) and 1907–1908 (167 cases/89 deaths). The last major rat-associated outbreak of plague in the United States occurred in 1924 and 1925 in Los Angeles. This outbreak, which was characterized by a high percentage of pneumonic plague cases, included the last identified instance in the United States of human-to-human transmission of plague (via inhalation of infectious respiratory droplets from coughing patients).

The introduction of West Nile virus, transmitted from birds to humans via mosquitoes, into North America in 1999 underlined the importance of maintaining insect control programs. In the four years after West Nile virus was first reported in New York City, it had spread to 43 states. Moreover, during the summer of 2002, West Nile virus infections were reported in patients who received organ transplants or blood from infected persons.

Opportunities and Challenges for the Twenty-first Century

Future advances in molecular biology, bioinformatics, and other areas are likely to revolutionize the detection, treatment, control, and prevention of infectious diseases during the twenty-first century. Advances in microbial genomics will enable epidemiologists to identify any microbial species, subtype, or strain within hours or minutes. A detailed understanding of human genetics will help physicians target vaccines and prophylactic drugs to the most susceptible individuals, while improved knowledge of human immunology will stimulate the development of vaccines that not only prevent disease but also boost the immunity of people who are already infected with HIV or other pathogens. Moreover, in-depth knowledge of climatic and environmental factors that influence the emergence of animal-and insect-borne diseases (facilitated by the availability of remote sensing technologies) will inform public health policy and allow public health authorities to predict outbreaks and institute preventive measures months in advance.

Although the impact of technology on the control of infectious diseases has been overwhelmingly positive, certain twentieth-century technological advances have created new niches and modes of transmission for particular pathogens; for example: (1) The bacteria that cause Legionnaire's disease have been spread through modern ventilation systems;(2) HIV and hepatitis B and C viruses have been spread through unscreened blood donations; (3) Food-borne diseases like Salmonellosis and E. coli O157 infections have been spread through centrally processed food products that are distributed simultaneously to many states or countries; and (4) Airplanes have replaced ships as major vehicles of international disease spread. More people are traveling to tropical rain forests and other wilderness habitats that are reservoirs for insects and animals that harbor unknown infectious agents. This incursion is due not only to economic development (e.g., mining, forestry, and agriculture), but also to missionary or other volunteer work and an expanded tourist trade that caters to individuals who wish to visit undeveloped areas.

In the United States, increasing suburbanization, coupled with the reversion of agricultural land to secondary growth forest, has brought people into contact with deer that carry ticks infected with Borrelia burgdorferi, the causative agent of Lyme disease, and has brought household pets into contact with rabies-infected raccoons.

A development with potentially profound implication for disease prevention and treatment is the blurring of the distinction between infectious and chronic diseases. Infectious causes may be found for many chronic cardiovascular, intestinal, and pulmonary diseases. Current research suggests that some chronic diseases formerly attributed to lifestyle or environmental factors are actually caused by or intensified by infectious agents. For example, most peptic ulcers–long thought to be due to stress and diet–are now known to be caused by the bacterium Helicobacter pylori. Several types of cancers, including some liver and cervical cancers, are linked to infectious agents. Chlamydia pneumoniae infection has been proposed as a contributor to coronary artery disease, and enteroviruses appear to be associated with type 1 diabetes mellitus in some children. Thus, in the future it is possible that some forms of cancer, heart disease, and diabetes, may be treated with anti-microbial drugs or prevented by vaccines.

The general success in reducing morbidity and mortality from infectious diseases during the first three-quarters of the twentieth century led many medical and public health experts to become complacent about the need for continued research into treatment and control of infectious microbes. However, subsequent developments–including the appearance of AIDS, the reemergence of tuberculosis (including multidrug-resistant strains), and an overall increase in U.S. infectious disease mortality between 1980 and 1998 (see Figure 1)–have reinforced the realization that as long as microbes can evolve and societies change, new diseases will inevitably arise. Furthermore, infectious diseases continue to be responsible for almost half of mortality in developing countries, where they occur primarily among the poorest people. About half of infectious disease deaths in these countries can be attributed to just three diseases–HIV/AIDS, TB, and malaria. WHO estimates that these three diseases cause over 300 million illnesses and more than 5 million deaths each year.

See also: AIDS; Black Death; Emerging Infectious Disease; Epidemics; Influenza; Tuberculosis.

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Alexandra M. Levitt