The World as a Hot Zone: New and Re-Emerging Diseases
Hot zones are not just in the tropics. This military slang identifies any area occupied by deadly infectious organisms, and the diseases they cause exist globally. Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, says, "Despite our best efforts, changes in microbes and our environment will continue to present new health challenges worldwide. Hantavirus, drug-resistant TB and cholera are only a few of the new and re-emerging diseases we see today. NIAID-supported scientists are leaders in efforts to detect, combat and prevent such diseases."
On Tuesday, Feb. 21, John La Montagne, Ph.D., director of the NIAID Division of Microbiology and Infectious Diseases, plans to discuss the institute's research efforts at the annual meeting of the American Association for the Advancement of Science in Atlanta, Ga. Listed below are story ideas selected about NIAID-supported research on emerging diseases. To pursue these or other stories, please call Marion E. Glick in the NIAID Office of Communications at (301) 402-1663. In this tip sheet:
- What Causes a New or Re-emerging Disease?
- Are These Bugs Coming To You?
- Getting Sick in the Hospital: Drug-Resistant Strep
- Seizures in Young Children: Herpesvirus 6
- Bacteria Trigger Guillain-Barre Syndrome?
- Vaccines for Newest Deadly Cholera Strain are Promising
- Scientists Tackle Resistant Herpes
- Stopping Septic Infections
- Severe Liver Disease Stems from Delta Hepatitis
- Tropical Treasures: NIAID International Investigations
NIAID is one of 17 institutes of the National Institutes of Health (NIH), the federal focal point for biomedical research. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.
WHAT CAUSES A NEW OR RE-EMERGING DISEASE?
A new or re-emerging infectious disease is one recently recognized, increasing in humans or threatening to spread to new areas in the near future. The most dramatic example is AIDS, recognized just 15 years ago. Why does this happen? Here are some reasons:
Microbes reinvent themselves.
Viruses and bacteria have few genes compared to humans and one mutation can change an organism's ability to infect, spread or cause disease. Also, microbes transform rapidly because they occur in large numbers and quickly reproduce. This evolutionary advantage often causes the re-emergence of diseases previously controlled by antibiotics and other drugs. Examples include: drug-resistant tuberculosis, malaria and diseases caused by new bacterial strains of Streptococcus pneumoniae and Enterococcus faecalis. These diseases have significant economic impact. In the United States, for example, estimated annual costs associated with hospital-acquired infections caused by resistant bacteria and other organisms range from $100 million to $30 billion.
Climate changes, new housing patterns and imported goods assist in finding new homes for old diseases. Heavy rains and winds after prolonged droughts contributed to an epidemic of valley fever, a fungal disease in the western United States. Hantavirus spread in the southwestern United States in part from a climate that favored increases in rodents. New communities in reforested suburban areas helped foster Lyme disease by increasing human contact with ticks bearing Borrelia burgdorferi bacteria. The arrival of Aedes albopictus mosquito with used tires from Japan in 1986 introduced to the United States a potential new "carrier" that might spread viruses to humans, as it does in Asia.
Public health failures or changes foster disease.
The control of water-borne diseases is especially vulnerable to breakdowns in health controls, such as occurred in Milwaukee, Wis., when Cryptosporidium-contaminated water caused diarrhea in more than 400,000 people in 1993. Feeling safe and complacent can contribute to disease outbreaks as well. For example, measles re-emerged as an U.S. epidemic in 1989 to 1991 primarily because people did not get immunized. Similarly, outbreaks of food-borne diseases have stemmed from inadequate quality control of handling and preparing raw meat.
Faulty immune systems and inappropriate drug use promote disease.
Diseases such as AIDS and therapies for organ or bone marrow transplantation and some cancers impair the immune system's ability fight disease. This suppression allows normally harmless microbes to cause life-threatening illnesses, such as Pneumocystis carinii pneumonia in AIDS patients. Additionally, the extensive and inappropriate use of antibiotics, including broad-spectrum drugs designed to kill many kinds of bacteria at once, has led to the appearance of resistant bacteria. These "super bugs" require physicians to use more expensive drugs and higher doses of older drugs in treatments that are not always effective.
ARE THESE BUGS COMING TO YOU?
Many microbes, including viruses, bacteria, protozoa and fungi, threaten world health. Moreover, many diseases associated with the tropics increasingly cause concern in the United States. Some of the more important emerging, re-emerging and enduring diseases are listed below:
Dengue is common in Southeast Asia, but now causes outbreaks in Puerto Rico, the Caribbean, Central America and South America. Infected mosquitos spread the virus. In Asian countries, 1.5 billion people, including 600 million children, live in areas where the virus is common. Dengue infects 35 to 60 million people and kills up to 20,000 people annually. Mosquitos feeding on infected people traveling within the United States could be potential sources to spread dengue in this country. Herpes viruses cause chickenpox, cold sores and infectious mononucleosis. Other Herpes viruses cause severe and life-threatening diseases, particularly in people with damaged immune systems. Although not new, human Herpes viruses 6 (HHV-6) and HHV-7 recently have been detected and isolated. Both viruses have infected and are carried for life by nearly 90 percent of the U.S. population. The full range of diseases they cause is not yet defined. HHV-6, associated with roseola, is responsible for 11 percent of emergency room visits among children aged six to 12 months.
Measles causes 45 million cases and 1.2 million deaths a year globally. The disease caused a U.S. epidemic from 1989 to 1991, when 55,000 cases and 130 deaths were recorded. In tropical countries, some 70 million people annually develop measles, of which up to 2 million die. Use of a successful, licensed measles vaccine would substantially reduce these numbers.
Viral hepatitis is a major problem worldwide. Five unrelated viruses cause this liver disease: A, B, C, Delta and E. Infection with either of B, C or Delta can lead to chronic liver disease and recovery is rare. Hepatitis C infects 1 percent of the world's population and appears to be spreading--an estimated 2.5 to 3 million cases occur in the United States and new U.S. infections total 135,000 annually.
Yellow fever is a major problem in Africa, but successful mosquito control programs have limited the virus spread in the Americas. Because the mosquito that carries the virus has reinfested most South American countries, the virus threatens to re-emerge on the continent. From 1986 to 1988, more than 5,300 people worldwide developed the disease and 58 percent died--the most severe three-year outbreak since yellow fever reporting began in 1948. WHO estimates that at least 10 cases occur for each reported case.
Cholera is a global disease. A new strain emerged in India in 1992 and has spread throughout Southeast Asia. In Asia each year, other cholera strains cause life-threatening diarrhea in more than 500,00 people, killing 100,000. Cholera epidemics usually arise where concentrations of malnutrition, poverty and inadequate to nonexistent sanitation occur. The bacteria caused outbreaks in Somalia and among Rwandan refugees in Zaire. Another epidemic has ravaged Central and South America since 1991, affecting more than 1 million people. No safe, effective vaccine exists for this disease. Oral rehydration therapy, developed in part with NIAID support 25 years ago has helped reduce deaths worldwide. Most U.S. cases of cholera not related to international travel are associated with eating raw or undercooked seafood harvested from the U.S. Gulf coast.
Hospital-acquired infections with bacteria resistant to antibiotics are increasing and several are or soon will be untreatable. Some 2 million patients admitted annually to U.S. hospitals acquire an infection during their stay and about 80,000 die. Among the bugs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae. Considerable and inappropriate use of antibiotics, including broad-spectrum antibiotics, contribute to the development of resistant strains.
Lyme disease, caused by Borrelia burgdorferi, is the most common tick-borne U.S. infection. In 1994, 11,144 cases occurred in 48 states. The disease also appears in Europe and Asia. Reforestation of farmlands, building homes near old and new forests and expanding deer populations have led to increases in human contact with the deer tick that carries the Lyme bacteria. Early Lyme disease responds well to therapy, but some patients may develop chronic complications.
Mycobacterium tuberculosis (TB) causes more deaths worldwide than any other infectious disease. The bacteria responsible for TB infect one-third of the world's population, including 10 million Americans, but not all develop active disease. Globally each year, 8 million people are infected, and the number may rise to 12.1 million by 2005. In the 1990s, more than 30 million TB patient deaths are expected. In New York City, TB spiralled 125 percent between 1981 and 1991. TB's future spread depends on the availability of treatments and on limiting transmission. Behind recent U.S. increases: the HIV/AIDS epidemic, immigration from countries where TB is common, poverty, homelessness, alcoholism and drug abuse. Additionally, strains of TB resistant to five to seven drugs have emerged, causing at least 14 U.S. outbreaks. Treatment of patients with these resistant bacteria is difficult, costly and often ineffective.
Cryptosporidia cause diarrhea and inflammation of the digestive system and are a common source of traveler's diarrhea. The parasite caused the largest recorded U.S. outbreak of a water-borne illness: more than 400,000 people became infected in 1993 in Milwaukee, Wis., from contaminated water supplies.
Malaria infects 300 to 500 million people globally, killing up to 3 million each year. Transmitted by infected mosquitos, the parasite easily develops resistance to drugs, making therapy difficult and expensive. Most U.S. cases appear among international travelers. However, cases acquired in the United States have been reported in California and Florida.
Fungal respiratory infections pose significant health problems for healthy people as well as those with suppressed immune systems, such as AIDS patients. For example, Coccidioides immitis, which causes valley fever in California, is found in soils of the southwestern United States and Central and South America. Climate and ecology have contributed to a more than 10-fold increase in cases in these areas. In Kern County, Calif., more than 3,000 people caught the disease in 1992, and related costs grew to more than $30 million from 1991 to 1993.
GETTING SICK IN THE HOSPITAL: DRUG-RESISTANT STREP
Some $4.5 billion is spent on infections acquired by 5 percent of patients staying in U.S. hospitals each year. Among the illnesses that these 2 million people acquire are urinary tract infections that typically increase stays by two days, surgical wound infections that double the post- operative recovery period and bloodstream infections that kill 8.8 percent of these patients.
Increasingly, drug resistance among two species of bacteria, Enterococcus faecalis and E. faecium, contribute to such hospital infections. NIAID-supported investigators have found that both bacterial species may acquire resistance to most commonly prescribed antibiotics, including vancomycin. Vancomycin often is the drug of last resort in treating resistant bacterial infections. The bacteria have clusters of genes responsible for resistance and can readily transfer the genes to other disease-causing bacteria. This sharing makes the appearance of other vancomycin-resistant bacteria a constant threat to successfully treating people with hospital infections.
This research is conducted by scientists at Rockefeller University and the University of Texas at Houston. Sandra Handwerger, M.D., is the principal investigator at Rockefeller and Barbara Murray, M.D., is the principal investigator at Texas.
SEIZURES IN YOUNG CHILDREN: HERPESVIRUS 6
Human Herpesvirus 6 (HHV-6) may account for 12 to 20 percent of emergency room visits for children aged six months to 3 years with high fevers and seizures, according to NIAID-supported investigators. HHV-6, detected and isolated from 1990 to 1993, causes roseola infantum, a mild childhood illness. Other illnesses it could cause are not fully defined.
Recent U.S. studies found that 13 percent of HHV-6 infections occur among children younger than 2 months. These infections developed despite the presence of protective maternal antibodies that fight the virus and are passed to the children during pregnancy. The virus may be transmitted during birth, breast-feeding or other close contact between the mother and child, the scientists suggest, because they detected HHV-6 in blood cells from newborns.
Importantly, the researchers found HHV-6 genetic material in the children's cerebrospinal cord fluid, suggesting that it could affect the central nervous system (CNS). This evidence together with the fevers and seizures associated with some HHV-6 infections suggests to scientists that HHV-6 could play a role in subsequent abnormalities of the CNS.
In addition, children with severe fevers and seizures often undergo extensive and expensive ER tests for sepsis and meningitis. Further HHV-6 studies will define the full burden of infection in children so that rapid and specific tests for viral infection can be created. Such tools would spare the children unnecessary tests.
This research is conducted by scientists at the University of Rochester. Caroline Breese Hall, M.D., is the principal investigator.
BACTERIA TRIGGER GUILLAIN-BARRE SYNDROME?
The common intestinal bacterium Campylobacter jejuni is a prime suspect as a trigger of Guillain-Barre Syndrome (GBS), a severe, usually rapid disease that destroys nerves and weakens muscles. GBS is the most common cause of acute neuromuscular paralysis in the United States, affecting 7 million people each year. The disease's cause is unknown.
Recent NIAID-supported studies show that up to 40 percent of GBS patients may have had C. jejuni infections days to weeks preceding GBS symptoms. The bacteria appear to provoke the stripping of the outer myelin sheath of nerves. Diarrhea precedes GBS in 10 to 30 percent of cases.
GBS treatments include intravenous immune globulin, a naturally occurring antibody that fights bacteria, or transfusions of plasma that contain antibodies. The effectiveness of these therapies indicates that bacterial antibodies likely play important roles in the disease.
This research is conducted by scientists at Vanderbilt University. Martin Blaser, M.D., and Ban Mishu Allos, M.D., are co-principal investigators of this project.
VACCINES FOR NEWEST DEADLY CHOLERA STRAIN ARE PROMISING
Candidate vaccines against the newest form of cholera have protected more than 75 percent of trial participants. The strain, Vibrio cholerae O139, emerged in Bengal in 1992 and has spread through India to Thailand, Nepal, China, Pakistan and Malaysia.
Two separate research teams supported by NIAID have developed the vaccines, which are made with live, altered cholera bacteria. In trials of safety, dosages and effectiveness, the attenuated vaccines protected volunteers against infections from V. cholerae O139. Additional trials are planned to evaluate other vaccines made by further modifying the live bacteria to reduce side effects such as mild diarrhea in the volunteers.
The two research groups also are developing vaccines against a more established strain of cholera, O1 El Tor, found around the world. El Tor caused a large epidemic in South and Central America totaling more than 1 million cholera cases since 1992. El Tor also produced cholera outbreaks among Rwandan refugees residing in Goma, Zaire, during 1994.
This research is conducted by scientists at the University of Maryland and Harvard University. Myron Levine, M.D., is the principal investigator at Maryland and John Mckalanos, Ph.D., is the principal investigator at Harvard.
SCIENTISTS TACKLE RESISTANT HERPES
Infection with herpes simplex viruses (HSVs) resistant to the drug acyclovir (ACV) is a growing problem in patients with AIDS and other immune- suppressing disorders. NIAID-supported investigators are developing drugs that can make an end run around resistant strains.
Most ACV-resistant strains of herpes have a deficient or defective enzyme, thymidine kinase (TK), which ACV needs in order to work within virus-infected cells. TK converts ACV to another form that controls the virus. The scientists prepared compounds the body can process to act like ACV, but without involving TK. Specifically, they found substantial anti-HSV activity in cells infected with ACV-resistant HSV when using the compound ACV diphosphate dimyristoylglycerol (ACVDP-DMG), while ACV virtually was inactive. The researchers are exploring the family of drugs from which ACVDP-DMG comes for use in treating patients with TK-deficient, mutant and naturally occurring HSV strains.
This research is conducted by scientists at the University of California at San Diego. Karl Y. Hostetler, M.D., is the principal investigator.
STOPPING SEPTIC INFECTIONS
Surgical and trauma patients with open wounds in their digestive systems can become infected with Staphylococcus aureus and other bacteria. The bacteria, which have developed some strains resistant to penicillin and methicillin, can spread throughout the body and the bloodstream. Some 25 to 40 percent of patients who develop this septicemia will die.
Gamma interferon, small virus-fighting proteins, restores the protective barrier of the digestive tract, according to results from animal studies supported by NIAID. Specifically, the interferon enhances the immune system's ability to kill the S. aureus.
This research is conducted by scientists at the University of Cincinnati Medical Center in Ohio. J. Wesley Alexander, M.D., Sc.D., is the principal investigator.
SEVERE LIVER DISEASE STEMS FROM DELTA HEPATITIS
The hepatitis delta virus (HDV) exists in three genetically different types: I found worldwide, II in Southeast Asia and III in northern South America. NIAID-supported scientists identified the South American strain, noting it is strongly associated with an unusually severe liver disease.
HDV infections only occur with a preexisting or concurrent infection with hepatitis B virus, mostly commonly transmitted by sex. HDV infections usually occur among people frequently exposed to blood and blood products, such as hemophiliacs and injection drug users who share needles. HDV has a variety of disease manifestations, related to the virus' genes. The scientists found the South American strain is associated with a distinctive alteration of the liver cells, characterized by microscopic fat accumulation.
This research is conducted by scientists at Georgetown University. John L. Gerin, Ph.D., is the principal investigator.
TROPICAL TREASURES: NIAID INTERNATIONAL INVESTIGATIONSNIAID supports four programs to investigate tropical diseases, which can threaten populations around the world.
- Tropical Disease Research Units. Begun in 1980, this program supports four U.S. academic medical centers to foster a multidisciplinary approach to research. Scientists use the latest biotechnology to explore the basic biology of parasites and their interactions with hosts. These studies increase the understanding of disease development and lead to improved methods of diagnosis, new and improved treatments, vaccine development and the control of infectious agents. The units also offer training, ensuring that the United States can maintain a supply of researchers, clinicians and public health experts in tropical diseases. The units are:
- Case Western Reserve University, Cleveland, Ohio
- University of Alabama, Birmingham
- University of Wisconsin, Madison
- Yale University, New Haven, Conn.
- International Collaborations in Infectious Diseases Research. Initiated in 1978, this program includes seven awards to U.S. institutions that collaborate on research in other countries where tropical diseases are common. The major portion of research must be conducted in the foreign country and be relevant to native health problems. The program emphasizes clinical and public-health-related studies including those aimed at understanding transmission and the causes of disease. The seven institutions are:
- Albert Einstein College of Medicine, Bronx, N.Y., with Venezuela
- Brigham Young University, Provo, Utah, with Sudan
- Columbia University, New York, N.Y., with Israel
- Cornell University Medical Center, New York, N.Y., with Brazil
- Harvard University, Boston, Mass., with Brazil
- University of Virginia, Charlottesville, with Brazil
- Vanderbilt University, Nashville, Tenn., with Brazil
- Tropical Medicine Research Centers. Started in 1991, the centers support facilities at three foreign institutions. The centers concentrate on investigations of infectious diseases of major importance to the health of people in the institutions' home countries. The awards provide for research facilities at the institutions, to strengthen their ability to recognize and contain disease outbreaks and to promote the exchange of information between foreign and U.S. scientists.
- Centro Internacional de Entranamiento e Investigaciones Meidcas, Cali, Colombia
- Federal University of Bahia, Salvador, Brazil
- Research Institute for Tropical Medicine, Alabang, Philippines.
- Intramural NIAID Center for International Disease Research. Established in 1991, this center focuses on field and laboratory research in NIAID's Laboratory of Parasitic Diseases in Bethesda, Md.