I. Introduction

By the mid-1950s, the threat of infectious diseases appeared to be receding in the United States. Deaths from infection, commonplace inour grandparents' time, were no longer a frequent occurrence.American physicians used fast-acting, effective drugs to combatoften fatal bacterial diseases such as meningitis and pneumonia.The incidence of childhood diseases such as polio, whoopingcough, and diphtheria, was declining due to the use of vaccines.Meanwhile, in other parts of the world, chemical pesticides likeDDT were lowering the incidence of malaria, a major killer ofchildren, by controlling populations of parasite-carryingmosquitoes.

As it turned out, our collective -- and quite understandable-- euphoria did not take into account the extraordinary resilienceof microbes, which have a remarkable ability to evolve, adapt,and develop resistance to drugs in an unpredictable and dynamicfashion. Moreover, disease-carrying insects have developedresistance to pesticides in a very short time.

Today, most health professionals agree that new microbial threatsare appearing in significant numbers, while well-known illnessesthought to be under control are re-emerging. Most Americans areaware of the epidemic of the acquired immunodeficiency syndrome(AIDS) and the related increase in tuberculosis (TB) cases in theUnited States. In fact, there has been a general resurgence ofinfectious diseases throughout the world, including significantoutbreaks of cholera, malaria, yellow fever, dengue, anddiphtheria, as well as illnesses caused by antibiotic-resistantbacteria. There has also been a resurgence of fungal infectionsfor which there are very few treatments. Furthermore, theincidence of AIDS is increasing in many countries.

New diseases have also appeared within the United States,including Lyme disease, Legionnaires' disease, and most recently,hantavirus pulmonary syndrome (HPS). HPS was first recognized inthe southwestern United States in 1993 and has since beendetected in more than 20 states and in several other countries inthe Americas. Other new or re-emerging threats in the UnitedStates include multi-drug resistant TB, antibiotic-resistantstaphylococcal, enterococcal, and pneumococcal infections, anddiarrheal diseases caused by the parasite Cryptosporidium parvumand by certain strains of Escherichia coli bacteria. In fact,only one antibiotic remains consistently effective against commonhospital-acquired staphylococcal infections. Meanwhile, thenumber of new antibiotics introduced into the U.S. market hasdeclined; not one new antibiotic was approved in 1994. In therace between drug-resistant bacteria and new drugs, the resilientbacteria are winning.

Smallpox. The economic benefits of the Smallpox Eradication Program have been substantial for all of the countries in the world, as preventive measures and treatment facilities for smallpox are no longer needed. The cost to the United States for the successful 13-year campaign to eradicate smallpox throughout the world was about $30 million. Since smallpox was eradicated in 1977, the total investment has been returned to the United States every 26 days.

Polio. Once a common cause of disabilities or death, polio has been eliminated from the Americas. The current drive towards global eradication is one of the great challenges of our generation. Once the global eradication program is completed (target date: 2000), the United States will save millions of dollars yearly on vaccination costs alone, since there will no longer be a need to immunize newborns. Based on the current rate of progress toward eradication, WHO predicts a global savings of $500 million by the year 2000, increasing to savings of $3 billion annually by the year 2015.

Other Infectious Diseases of Childhood. Health economists estimate that for every dollar spent on the measles/mumps/rubella vaccine, $21 are saved; for the diphtheria/tetanus/pertussis vaccine, $29 are saved; and for the polio vaccine $6 are saved.

Why are infectious diseases re-emerging as major threats to humanhealth?

The reasons for the resurgence of infectious diseases are complexand not fully understood. Contributing factors include populationshifts, increased urbanization and crowding, environmentalchanges, and worldwide commerce and travel. Some specific causesare

• Increased human intrusion into tropical forests (for mining,farming, settlement, and tourism), where people are most likelyto come in contact with infected animals carrying microbes thatcause diseases in humans. For instance, many scientists believethat the human immunodeficiency virus (HIV), which causes AIDS,is a zoonotic pathogen which was transmitted to humans fromnon-human primates.

• Changes in human behaviors which increase the risk ofinfection.

• Population growth and changes in demographics. By someestimates, more than 50% of the population of the world is under15 years of age, and the proportion is increasing. This meansthat there are an enormous number of susceptible people living inpoor and crowded urban areas, where infectious diseases thrive.

• Population shifts within and between countries, due tochanging economic conditions or military conflicts.

• Inadequacy and deterioration of public healthinfrastructures worldwide, including a lack of communicabledisease surveillance and control efforts for food and water-bornediseases and vaccine-preventable diseases.

• Erosion of expertise on diseases such as plague, rabies,malaria, yellow fever, and botulism.

• Misuse of antibiotics or other antimicrobial drugs, whichcan hasten the evolution of resistant microbes. This includesprescribing a drug without proper indications, prescribing thewrong drug or the wrong dose, or having poor patient compliancewith treatment regimens.

• Ecological changes due to irrigation projects ordeforestation. For instance, formerly dry areas may becomeexcellent habitats for parasite-carrying insects as well as forsnails and other animals that serve as parasite hosts.

• Increased trade and expanded markets for imported foods,which occasionally contain bacterial or viral contaminants.Although modern large-scale food technologies generally improvefood safety, when contamination does occur, it may affect largenumbers of people.

• Long- and short-term or cyclical changes in climate andweather that affect infectious microbes and/or the insect vectorsand animal hosts that carry them.

• Continual evolution of pathogenic microorganisms.

Infectious microbes do not recognize national borders

The modern world is a very small place, where any city in theworld is only a plane ride away from any other. Infectiousmicrobes can easily travel across borders with their human oranimal hosts. In fact, diseases that arise in other parts of theworld are repeatedly introduced into the United States, wherethey may threaten our national health and security. Since 1973,more than 30 new pathogenic microbes have been identified andnumerous known diseases have re-emerged (see Table 2 Examples of pathogenic and infectious diseases recognized since 1973 & Table 3 Re-emerging infections during the last two decades and factors contributing to their re-emergence).

Without preventive public health measures in the United Statesand abroad, uncontrolled outbreaks can grow into major epidemics.However, our earlier successes in controlling infections havebred complacency, and the components of the U.S. public healthsystem that protects the public from infectious microbes havebeen neglected, concentrating their resources on a few targeteddiseases.

Nevertheless, the subject of emerging infectious diseases isbeginning to receive sustained public attention. In 1992, theInstitute of Medicine's report, "Emerging Infections: MicrobialThreats to Health in the United States," clarified the issue ofemerging diseases for policymakers in government and in academia.In response, the CDC issued the 1994 report "Addressing EmergingInfectious Disease Threats: A Prevention Strategy for the UnitedStates." Other U.S. Government agencies, including NIH, USAID,and DoD have also examined the issue of U.S. vulnerability toepidemics and re-emerging health problems.

Quite recently, public discussion has been further focused on theglobal issue of emerging diseases by the publication of twobest-selling, non-fiction books, The Hot Zone by Richard Preston,and The Coming Plague by Laurie Garrett, and by popular moviessuch as "Outbreak," starring Dustin Hoffman. Concerns aboutantibiotic-resistant bacteria and food-borne diseases, as well asthe recent plague outbreak in India and the Ebola outbreak inZaire, have been widely discussed in many news magazines, inprint and on television. This media attention has informed theAmerican public of the reasons why it is in our national interestto strengthen disease surveillance and control effortsinternationally.

International health and U.S. foreign policy

A global system for infectious disease surveillance and responsewill help protect the health of American citizens and peoplethroughout the world. In addition, the improvement ofinternational health is a valuable component of the U.S. effortto promote worldwide political stability through sustainableeconomic development. Healthy people are more productive andbetter able to contribute to their countries' welfare. Also, aglobal disease surveillance and response network will enable theUnited States to respond quickly and effectively in the event ofan attack involving biological or chemical warfare, as theexperience gained in controlling naturally occurring microbeswill enhance our ability to cope with a biological warfare agent,should the need arise. The release of nerve gas in the Tokyosubway system in March 1995 has underscored our need to be wellprepared to counteract deliberate attempts to undermine humanhealth.

Thus, the effort to build a global surveillance and responsesystem is in accord with the national security and foreign policygoals of the United States. Moreover, leadership in globalinfectious disease surveillance and control is a natural role forthe United States. American business leaders and scientists arein the forefront of the computer communications and biomedicalresearch communities (both public and private sector) thatprovide the technical and scientific underpinning for diseasesurveillance. Furthermore, American scientists and public healthprofessionals have been among the most important contributors tothe international efforts to eradicate smallpox and polio.

The challenge ahead outstrips the means available to any onecountry or to international organizations. The U.S. Governmentmust not only improve its capacity to meet the growing threat ofemerging infectious diseases, but also work in concert with othernations and international bodies. Although international effortsmust be coordinated to prevent global pandemics, diseasesurveillance must be the responsibility of each sovereign nation.However, individual governments may not easily share nationaldisease surveillance information, fearing losses in trade,tourism, and national prestige. Nevertheless, because U.S.experts are often consulted on problems of infectious diseaserecognition and control, the U.S. Government is usually informedabout major disease outbreaks in other countries, although notalways in an official or timely fashion. To ensure that wecontinue to be notified when an unusual outbreak occurs, we mustencourage and support other countries' efforts in nationaldisease surveillance and respond when asked for assistance. Wemust strive to develop a sense of shared responsibility andmutual confidence in the international effort to combatinfectious diseases.

There is much room for optimism. If the United States takes thelead, we can expect that other nations will contribute resourcesto a global surveillance system. Both Canada and the EuropeanUnion have recently decided -- in spite of tight budgets -- toprovide substantial funds ($7 and $10 million per year,respectively) to strengthen infectious disease surveillance andcontrol. It is also absolutely critical that developing nationsbe engaged in an international effort that is in their owninterests. In May 1995, WHO passed a resolution urging memberstates "to strengthen national and local programmes ofsurveillance for infectious diseases, ensuring that outbreaks ofnew, emerging, and re-emerging infectious diseases areidentified." Soon after the resolution was drafted, WHO issued areport urging the strengthening of global disease surveillanceand control, and encouraging greater use of WHO CollaboratingCenters in this endeavor.

Are infectious disease surveillance and control cost-effective?

The direct and indirect costs of infectious disease arestaggering (see Table 1). Clearly, public health measures thatprevent infectious diseases can be extremely cost-effective. In 1994 and 1995 two major U.S. health-care expenses have beenfor the treatment of tuberculosis and AIDS. The Public HealthService budget for fiscal year 1996 includes $343 million tocombat TB and nearly $3 billion to combat AIDS. TB is a very old,well-known disease that has re-emerged sometimes in adrug-resistant or multidrug-resistant form. AIDS, on the otherhand, is a new disease, unrecognized before the 1980s. When thefirst cases of AIDS and drug-resistant TB were detected in theUnited States, control measures were delayed, partly because of alack of surveillance information and incomplete understanding ofthe epidemiology of these diseases.

Table 1 Estimated costs of common infectious diseases in the United States

These costs, combined with dollars spent on AIDS and TB, exceed $120 billion per year.

Tuberculosis

For many years, the United States had in place a surveillancesystem to monitor cases of TB. However, during the 1980s, federaland local spending on infectious disease control declined, and in1986 the surveillance system for multidrug-resistant TB wasdiscontinued. Consequently, there was no warning signal whendrug-resistant TB emerged in the late 1980s. This lack of earlywarning undoubtedly contributed to the more than $700 million indirect costs for TB treatment incurred in 1991 alone.Surveillance of drug-resistant TB was not reinstated until 1993,by which time multidrug-resistant TB had became a public healthcrisis and millions of federal dollars had been appropriated.

AIDS

As mentioned above, AIDS is a new disease that was unknown beforethe 1980s, and thus, was not on any surveillance lists. AIDSweakens the immune system, allowing other infections to takehold. Therefore, it can be difficult to diagnose since itsclinical presentation may involve a variety of symptoms, and itsincubation period (the time between infection and the appearanceof symptoms) can be many years. Nevertheless, long before AIDSwas diagnosed in the United States and Europe, a distinctsyndrome called slim disease (now known to be a form of AIDS)that causes its victims to waste away was recognized by Africandoctors. In fact, an aggressive, slim-associated, generalizedform of Kaposi sarcoma, distinct from the classical form, hasbeen described in Uganda since at least 1962. Some health workersbelieve that if a global surveillance network had been in placein the 1970s, AIDS might have been identified earlier, perhapsbefore it became well established in the United States.Epidemiologists might have gained a head start in learning howAIDS is transmitted and prevented, and many lives might have beensaved. However, other health experts believe that the lack ofdisease surveillance and specimen collection facilities incentral Africa in the 1960s and 1970s make it nearly impossibleto be sure, even in retrospect, if AIDS was present at that time.

Table 2 Examples of pathogenic microbes and infectious diseasesrecognized since 1973

Table 3 Re-emerging infections during the last two decades andfactors contributing to their re-emergence

In recent years, antimicrobial drug resistance has become aserious problem in the United States and abroad. Antimicrobialresistance occurs when a disease-carrying microbe (bacteria,virus, parasite, or fungus) is no longer affected by a drug thatpreviously was able to kill the microbe or prevent it fromgrowing.

The types of antimicrobial drug resistance include

Antibiotic resistance. Resistance to drugs that kill bacteria orkeep them from growing. Antibiotic resistance is a growingproblem in American hospitals. It affects the treatment ofbacterial pneumonia, TB, ear infections, and many other commonbacterial illnesses.

Antiviral resistance. Resistance to drugs that prevent thereplication of viruses. Antiviral resistance is a serious problemin the treatment of AIDS, which is caused by the HIV retrovirus.For instance, most strains of HIV become resistant over time tothe drug AZT, which is a first-line drug against AIDS.

Antiparasite resistance. Resistance to drugs that kill parasitesor keep them from growing. For example, common medicines andprophylactic treatments for malaria, including chloroquine, areno longer reliably effective because drug resistance is spreadingamong malarial parasites.

Antifungal resistance. Resistance to drugs that kill fungi orkeep them from growing. Drug resistance has developed to thedrugs for the treatment of candida infections which are common inAIDS patients worldwide.

Multidrug resistance. A bacterium, parasite, or fungus which hasdeveloped resistance to several previously potent drugs,sometimes through a non-specific mechanism that allows themicrobe to eject or neutralize drugs of different chemicalstructures. In the United States, multidrug-resistant TB is onthe rise.

Pesticide resistance. A microbe-carrying insect or animal(disease vector) becomes resistant to an agent that previouslywas used to kill it. The most common type of pesticide resistanceis insecticide resistance. Insecticides are used in many parts ofthe world to kill mosquitoes that carry malaria parasites. Otherinsect vectors include tsetse flies (which carry parasites thatcause African sleeping sickness) and reduviid bugs (which carryparasites that cause Chagas' disease, a serious disease prevalentin South America.)

Researchers at CDC's biosafety level-four laboratory in Atlanta,Georgia, confirmed on May 10 that a mysterious disease outbreakin Kikwit, Zaire, was caused by the deadly Ebola virus. On thefollowing day, the Government of Zaire informed its citizens ofthe danger and began to institute quarantine measures. At thegovernment's invitation, WHO investigators arrived in the capitalcity, Kinshasa, on May 10, where a 3-person CDC team joined themon May 11.

A few days earlier, on May 6, the U.S. Embassy in Zaire hadlearned that Kikwit, an area about 350 miles from Kinshasa, wassuffering an outbreak of an unusual hemorrhagic fever.

A medical professor at the University of Kinshasa reported thatthe symptoms of the fever patients were the same as those seen inan earlier Ebola outbreak (in 1976). The Ebola virus, which istransmitted through contact with infected bodily fluids, causes afatal illness in 50-90 percent of its victims, and there is noknown drug treatment or vaccine.

The Government of Zaire has quarantined the Kikwit area andclosed the road leading from Kinshasa to Bandundu State, whereKikwit is located. The U.S. Embassy has declared the outbreak adisaster, and USAID's Office of Foreign Disaster Assistance(OFDA) has authorized the payment of $25,000 to non-governmentalorganizations (NGOs) in the area for the purchase and transportof disposable protective clothing, plasma, body bags, andessential medicines and supplies. OFDA has also requested aDepartment of Defense airlift to transport equipment andsupplies, including plasma, plastic hospital gowns and sterileneedles.

The Vice Prime Minister of Zaire, Kamanda Va Kamanda, accompaniedthe WHO and CDC doctors to Kikwit on May 12, where theinternational team set about its primary task of containing theoutbreak of Ebola fever. As part of that effort the team istrying to trace the outbreak's first casualty to gain clues tothe virus's animal or insect host (its "reservoir"). Theinternational team has been joined by additional doctors fromZaire and elsewhere, including government and NGO medical workersfrom Belgium, South Africa, and Sweden.

The different national groups that make up the WHO-ledinternational team bring different resources and types ofexpertise to the cooperative effort. For instance, Belgiandoctors from the organization Medicins Sans Frontieres focus onproviding clinical care and specialize in building and operatingsafe, sanitary, functional hospitals and clinics. Zairian doctorsfrom the University of Kinshasa are familiar with most localhealth problems and take the lead in clinical diagnosis, casemanagement, and clinical work-up. The CDC team provides expertisein filoviruses (the class of virus to which Ebola belongs),experience in disease surveillance and case investigation, andaccess to laboratory diagnosis via the facilities in Atlanta.

Lessons from Kikwit. It is useful to examine the internationalteam's experiences in Zaire for ideas on how to improve U.S.preparedness for controlling infectious diseases outbreaks incountries with poorly developed health and communicationsinfrastructures. One week into the investigation, the three CDCinvestigators report that the team's efforts are hampered bydifficulties with transportation and communication, and by lackof money and personnel. Because the average incubation time (thetime between infection and the appearance of symptoms) for Ebolais 7 days, each week's delay in instituting control measuresmeans that a new generation of the virus has time to spread.

1) Transportation. To investigate suspected Ebola cases, doctorsmust be able to travel quickly from community to community in anarea where there are few paved roads and no publictransportation. The USAID mission to Zaire, which in past yearscould be relied on for assistance with logistics andorganization, was closed in 1994. The U.S. Embassy and OFDA haveprovided some help, as the CDC team did not arrive in Zaire withauthorization to purchase or rent cars or bicycles.

2) Money. The CDC team in Kikwit has no funds at their disposalto obtain radios, cars, bicycles, or additional medical supplies.An initial $20,000 was spent on essential equipment and medicalsupplies. A week into the investigation, the team has requested$781,000 to allow six doctors to work in Zaire for three months.In comparison, the team that responded to the hantavirus outbreakin New Mexico in 1994 involved 24 people working for 18 months ata cost of 4.5 million dollars. (Note: On May 23 OFDA allocated$750,000 for the CDC team and USAID's Bureau of Global ProgramsField Support and Research supplied another $43,000.)

3) Personnel. The Zairian medical authorities have requested thatthe CDC send three additional epidemiologists and oneoperations/logistics manager to provide help with travel,communications, and procurement. In the United States, at CDC'sbiosafety level-four laboratory in Atlanta, additionaltechnicians are needed to process the hundreds of potentiallydangerous clinical samples sent from Zaire. The internationalteam (not only the CDC doctors) are dependent upon the efforts ofthis unique laboratory. (Update: The funds provided by USAID/OFDAon May 23 will be used to support additional personnel in Zaire.)

4) Communication. To prevent the spread of Ebola fever, medicalworkers must report all suspicious fever cases to the nationalhealth authorities so that appropriate follow-up measures can beinstituted. There are very few telephones and no radio station inKikwit, although radio transmissions are received from Kinshasa.The lack of reliable communication has hampered the internationalteam members' initial efforts to coordinate with each other andthe national health authorities of Zaire.
Poor communication has been a problem from the beginning of theoutbreak. Although the first case of Ebola probably occurred asearly as December, 1994, the international community only learnedabout the outbreak in May, after the Ebola virus had nearly 20weeks to spread. This delay reflects the weak health care systemsand the poor state of infectious diseases surveillance in most ofAfrica. Over the last ten years, with the end of thepost-colonial era, the end of the Cold War, and the decline ofWestern interest in tropical medicine, the public healthinfrastructures in many African countries have deteriorated.Infectious disease surveillance is nearly non-existent, andemerging and re-emerging diseases frequently go unreported.

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