Re-emerging Infectious Diseases
Re-emerging Infectious Diseases
History and Scientific Foundations
Introduction
In the mid-twentieth century, the development of highly effective antibiotics and implementation of successful disease prevention and global vaccination programs led to the control or eradication of serious diseases such as polio and smallpox. At the time, it was widely assumed that infectious disease would ultimately become a minor problem. However, both newly emergent and re-emergent infectious diseases now present a growing public health threat worldwide.
According to the World Health Organization (WHO), infectious and parasitic diseases constitute the second most lethal cause of mortality (death) globally after cardiovascular diseases, implicated in 26% of deaths in 2002. Re-emergent infections have gained renewed virulence (the degree to which an organism can cause disease) due to other emerging or chronic diseases that impair the immune system (e.g., HIV/AIDS, diabetes, cancer) or the spread of antibiotic, antiviral, and anti-fungal medication resistance. In addition, there is the threat of re-emergent infectious disease that is intentionally spread in connection with bioterrorism, as occurred in the United States in the anthrax attacks of 2001. Although the numbers of people infected and killed were small in these attacks, the potential for widespread targeted assaults make the use of bioterrorism agents especially disturbing to consider.
History and Scientific Foundations
In the United States, the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers for Disease Control and Prevention (CDC) have expanded research funding, information sharing, and clinical support to fight emerging and re-emerging infectious disease. Focusing on re-emerging diseases, the CDC journals Emerging Infectious Disease and the Morbidity and Mortality Weekly Report (MMWR) now feature frequent reports of reemergent infections such as coccidioidomycosis, the incidence of which began to dramatically increase as a consequence of the HIV/AIDS pandemic.
In the past decade, epidemiologists have confronted the re-emergence of West Nile fever, human monkey-pox, dengue, tuberculosis, and malaria, at times in populations for which these diseases had not previously been a problem. Furthermore, certain infections such as Staphylococcus aureus and Mycobacterium tuberculosis have developed increasing resistance to drug agents that were previously effective treatments.
Malaria
The resurgence of the ancient plague of malaria, due to rising rates of resistance to chloroquine and other drugs, currently affects more than 300 million people and results in the deaths of more than one million victims worldwide each year, the majority occurring among children in sub-Saharan Africa. Recently, epidemiologists have discovered a connection between resurgent malaria and the HIV/AIDS epidemic.
According to a study sponsored by the Millennium Fund, HIV has major effects on the incidence of malaria. HIV-induced immunodeficiency may decrease the immune response against malarial infection and the risk of parasitemia, and illness with malaria has been inversely correlated to CD4 cell counts, which are adversely affected by AIDS.
HIV infection in regions where malaria transmission is endemic (naturally occurring) mainly increases the risk of clinical malaria in adults and malarial fever in children. In regions in which malaria transmission is not yet endemic, high HIV prevalence results in considerably higher than expected malaria morbidity and mortality. Infection with HIV also affects the treatment and prophylaxis of malaria. Antimalarial therapy is most effective in individuals with some previous immunity to malaria, so immunosuppression due to HIV infection can decrease antimalarial treatment response.
The failure so far to develop an effective vaccine for malaria has sometimes been ascribed to the low prevalence of the disease among industrialized nations. However, the disease poses formidable scientific and technical hurdles to vaccine development, including issues regarding the appropriateness and accessibility of animal models. Other difficulties are due to the need to develop assays (analyses) for ongoing validation of candidate antigens through process development and scale-up production, as well as assays predictive of protection for assessment of immunogenicity (ability to provoke an immune response) and efficacy in clinical trials. Furthermore, the clinical trials themselves are difficult to design because the ultimate measure of efficacy is the interruption of malaria transmission. In spite of these challenges, pharmaceutical companies are currently beginning clinical development of a variety of vaccine candidates that show promise.
Tuberculosis
Another resurgent disease with connections to the HIV/AIDS epidemic is tuberculosis (TB), which according to the WHO is endemic to regions inhabited by one third of the world's population and results in some eight million new cases and two million deaths annually. Tuberculosis rates are extremely high among the HIV-infected population. The one currently available vaccine for tuberculosis offers some protection, but its effectiveness diminishes over time. Effective pharmaceutical treatment exists, but the treatment regimen is lengthy and it is difficult for patients to maintain adherence, which gives rise to multidrug-resistant TB strains. This in turn has added impetus to programs to develop novel vaccines, some of which are now in the pre-clinical investigation stage.
Although more than a billion people have dormant tuberculosis infections, the disease becomes symptomatic when immune systems are weakened by HIV. TB risk doubles shortly after infection with HIV, and increases further over time. A recent study estimates that 9% of the 8.3 million new adult TB cases worldwide in 2000 were directly attributable to HIV. Furthermore, HIV infection makes treating active TB much more difficult, leading to an increase in TB rates in high-HIV-prevalence areas, particularly sub-Saharan Africa. The spread of HIV in sub-Saharan Africa is primarily responsible for driving the number of active TB cases upward by 6% each year.
In 2005, a virulent strain of tuberculosis killed all but one of 53 infected patients at the Church of Scotland Hospital in South Africa's rural KwaZulu-Natal Province. The strain of TB, named XDR for “extensively drug-resistant,” cannot be treated effectively with most tuberculosis drugs, and may be incurable.
Since the detection of XDR, more cases have been found at other South African hospitals. Some epidemiologists and TB experts argue that XDR TB has probably moved beyond the borders of South Africa into Lesotho, Swaziland, Mozambique, and perhaps to Zimbabwe. At least two in three South African TB sufferers are HIV-positive. If XDR TB becomes established in the HIV-positive population, it could devastate tens of millions of HIV-infected people throughout sub-Saharan Africa.
HIV-negative people have a low probability of contracting tuberculosis, even if they are already infected with the TB bacillus. However, since tuberculosis is spread through the air, people in close contact with an active TB victim have some risk of contracting the disease.
It seems likely that all of the 52 people who died in the initial outbreak of XDR-TB in the South African hamlet of Tugela Ferry in 2005 and early 2006 had AIDS. Most of the patients died within a few weeks of infection with drug-resistant tuberculosis, an unprecedented TB mortality rate according to epidemiologists.
The WHO has requested to establish a program in South Africa to deal with the outbreak, but South African officials insist that they have the capabilities to handle the issue and should maintain control of any such program.
WORDS TO KNOW
ADAPTIVE IMMUNITY: Adaptive immunity is another term for acquired immunity, referring to the resistance to infection that develops through life and is targeted to a specific pathogen. There are two types of adaptive immunity, known as active and passive. Active immunity is either humoral, involving production of antibody molecules against a bacterium or virus, or cell-mediated, where T-cells are mobilized against infected cells. Infection and immunization can both induce acquired immunity. Passive immunity is induced by injection of the serum of a person who is already immune to a particular infection.
EMERGING INFECTIOUS DISEASE: New infectious diseases such as SARS and West Nile virus, as well as previously known diseases such as malaria, tuberculosis, and bacterial pneumonias that are appearing in forms that are resistant to drug treatments, are termed emerging infectious diseases.
ENDEMIC: Present in a particular area or among a particular group of people.
ERADICATION: The process of destroying or eliminating a microorganism or disease.
IMMUNOGENICITY: Immunogenicity is the capacity of a host to produce an immune response to protect itself against infectious disease.
INNATE IMMUNITY: Innate immunity is the resistance against disease that an individual is born with, as distinct from acquired immunity that develops with exposure to infectious agents.
PATHOGEN: A disease causing agent, such as a bacteria, virus, fungus, etc.
VIRULENCE: Virulence is the ability of a disease organism to cause disease: a more virulent organism is more infective and liable to produce more serious disease.
West Nile Virus
West Nile Virus (WNV) has been endemic in Africa, West Asia, Europe, and the Middle East for centuries, but has only re-emerged in the United States since 1999. The first WNV infections occurred in the New York metropolitan area and have continued to spread throughout the United States during the summer season, infecting increasingly larger populations. The inexorable spread of the virus has prompted vaccine and drug therapy development, with some candidates currently showing some prevention or treatment effectiveness in animals. Currently the most immediately promising approach to slowing the spread of WNV is the control of insect vectors. New methods of controlling mosquitoes and countering mosquito resistance to insecticides are under development for use in areas where WNV threatens to become endemic.
Potential bioterrorism agents
The use of anthrax in terroristic attacks can be seen as a deliberate effort to promote the re-emergence of infectious agents that have otherwise been either eradicated, as in the case of smallpox, or largely controlled, as in the case of anthrax itself. Bioterrorism could also promote the emergence of a pathogen such as the Ebola virus in a setting such as the urban United States that is radically different and distant from the rural African regions in which such infections have occurred to-date. Since a wide variety of dangerous and virulent pathogens could potentially be used as bioweapons, defensive strategies must rely on research at a very broad and basic level in terms of understanding how human immune systems react to them and how infections can be detected, prevented, and treated.
Applications and research
Currently, a wide variety of scientific and industrial biodefense research infrastructure projects are underway in the United States, including the development of Regional Centers of Excellence for Biodefense and Emerging Infectious Disease Research, in addition to the building of secure facilities, including two National Biocontainment Laboratories and nine Regional Biocontainment Laboratories.
Research projects recently completed or underway include the gene sequencing of pathogens considered to be the most potent threats, the screening of chemical compounds that could provide potential treatments, and development of animals to test promising drugs. Immunologists are also investigating ways to boost human innate immunity.
Innate immunity is the immune system's first line of defense and is represented by monocytes and neutrophils (white blood cells), which react to any and all foreign substances and organisms in the body. This innate immune system is distinct from adaptive immunity, the second line of defense represented by T cells and B cells (lymphocytes), which are influenced by the innate immune system to recognize specific pathogens and foreign organisms and destroy them in a focused attack. Finally, as with the other types of re-emergent infections, vaccine development is being fostered under the nation's biodefense program.
Impacts and Issues
Clearly, vaccine development is central to the control of re-emerging infections, particularly development of an effective vaccine for HIV, which is key to preventing the spread of tuberculosis and a number of other infections that otherwise would not have been able to regain virulence after decades of effective treatment and prevention. The HIV epidemic, the rapid growth of international travel and commerce, and the danger of deliberate spread of pathogens into vulnerable new populations will continue to foster or threaten the re-emergence of dangerous pathogens. This threat will pose an ongoing and permanent challenge to public health agencies that must be dealt with by intensified basic biological and clinical research.
The best strategy for dealing with the threat of emerging and re-emerging infections alike is the funding, implementation, and staffing of an excellent global public health infrastructure, which will require international cooperation on an unprecedented scale.
See AlsoEmerging Infectious Diseases; Lyme Disease; Malaria; Pandemic Preparedness; Tuberculosis; War and Infectious Disease; West Nile.
BIBLIOGRAPHY
Books
Brower, Jennifer, and Peter Chalk. The Global Threat of New and Reemerging Infectious Diseases: Reconciling U.S. National Security and Public Health Policy. Santa Monica, CA: Rand, 2003.
Periodicals
Corbett, E., et al. “The Growing Burden of Tuberculosis: Global Trends and Interactions with the HIV Epidemic.” Archives of Internal Medicine 163, 9 (May 12, 2003): 1009–1021.
Hecht, R., et al. “Putting It Together: AIDS and the Millennium Development Goals.” PLoS Medicine 3, 11 (2006).
Kirkland, T.N., and J. Fierer. “Coccidioidomycosis: A Reemerging Infectious Disease.” Emerging Infectious Diseases 2, 3 (July-September 1996).
Web Sites
Fauci, Anthony S. Millbank Memorial Fund. “Emerging and Re-emerging Infectious Diseases: The Perpetual Challenge.” January 2006. <http://www.milbank.org/reports/0601fauci/0601fauci.html> (accessed June 4, 2007).
World Health Organization. “The World Health Report 2004—Changing History.” <http://www.who.int/whr/2004/en/> (accessed June 4, 2007).
Kenneth LaPensee