Emerging infections

Emerging Infections are newly identified and previously unknown infectious diseases. Since 1970 there have been over 30 emerging infections identified, causing diseases ranging from diarrheal disease among children, hepatitis, and AIDS to Ebola hemorrhagic fever. 

I. A 25-YEAR PERSPECTIVE 

In the Democratic Republic of the Congo (DRC, formerly Zaire), the decrease in smallpox vaccination coverage, poverty, and civil unrest causing humans to penetrate deep into the tropical rain forest in search of food may have resulted in breeches in the species barrier between humans and animals, causing an extended and continuing outbreak of human monkeypox. During the 1970s and 1980s, when this zoonotic disease was the subject of extensive studies, it was shown that the monkeypox virus infected humans, but that person-to-person transmission beyond three generations was rare. The outbreak of human monkeypox in 1996–1997, and continuing intermittently since then, is a clear example of the ability of infectious diseases to exploit weaknesses in our defenses against them. Numerous infectious diseases have found weakened entry points into human populations and emerged or re-emerged since the 1970s (see Table 32.1). In the early to mid 1970s, for example, classic dengue fever had just begun to reappear in Latin American after it had been almost eliminated as a result of mosquito control efforts in the 1950s and 1960s. Today, dengue is hyperendemic in most of Latin America. In 2001 alone, Latin America reported over 609,000 cases of dengue, of which 15,000 were of the hemorrhagic form. These figures represent more than a doubling of cases reported for the same region in 1995. Outbreaks are also becoming more explosive. An outbreak in Brazil in 2002 caused over 500,000 cases in one of the largest outbreaks ever recorded. A pandemic in 1998, in which 1.2 million cases of dengue fever and dengue haemorrhagic fever were reported from 56 countries, was unprecedented. In 1991, cholera, which had not been reported in Latin America for over 100 years, re-emerged in Peru with over 320,000 cases and nearly 3000 deaths, and rapidly spread throughout the continent to cause well over 1 million cases in a continuing and widespread epidemic. In North America, Legionella infection was first identified in 1976 in an outbreak among war veterans attending a conference in Philadelphia (US). Legionellosis is now known to occur worldwide and poses a threat to travellers exposed to poorly maintained air conditioning systems. In the Netherlands, in 1999, an outbreak of legionellosis occurred which was subsequently traced to whirlpool baths exhibited at a flower show visited by 80,000 people. Local cooling towers are considered the likely source of a large outbreak of legionellosis, involving 751 cases and two deaths, that occurred in Spain in 2001. During this same 25-year period, a new disease in cattle, bovine spongiform encephalopathy, was identified in the United Kingdom in 1986 and, by 2002, had spread to 19 additional countries around the world. The disease is associated with the appearance in 1996 of a previously unknown variant of the invariably fatal Creutzfeldt–Jakob disease that had occurred in over 100 persons by the beginning of 2002. Within a decade, food-borne infection by E. coli O157, unknown in the 1970s, had become a food-safety concern in Japan, Europe, and in the Americas. Hepatitis C was first identified in 1989 and is now thought to be present in at least 3% of the world’s population, while hepatitis B has reached levels exceeding 90% in populations at high risk from the tropics to eastern Europe. Tuberculosis, including multidrug-resistant forms, took advantage of weakened infrastructures in the countries of the former Soviet Union and re-emerged, with cases more than doubling in less than 7 years and with over 20% of patients in prison settings infected with multidrug-resistant strains in 2001. In the Hong Kong Special Administrative Region of China, 18 cases of human infection with influenza A virus sub-type H5N1, previously confined to birds, occurred in 1997, causing six deaths and raising considerable alarm. Human African trypanosomiasis, which had been virtually eliminated in the 1960s, resurged in an epidemic that is currently thought to infect from 300,000 to 500,000 people. In 1976, the Ebola virus was identified for the first time as causing a disease that has come to symbolize emerging diseases and their potential impact on populations without previous immunological experience. The largest recorded outbreak, which began in Uganda in 2001, caused 425 confirmed cases and 224 deaths. Altogether, Ebola has caused just under 2000 cases and around 1250 deaths since its identification in simultaneous outbreaks in Zaire and Sudan. In 1976, at the time of the first Ebola outbreak in Zaire, HIV seroprevalence was already almost 1% in some rural parts of Zaire, as shown retrospectively in blood that had been drawn from persons living in communities around the site of the 1976 outbreak, and HIV has since become a preoccupying problem in public health worldwide. 

II. MISPLACED OPTIMISM 

In this same 25-year period the eradication of smallpox was achieved. This unparalleled public health accomplishment resulted in immeasurable savings in human suffering, death, and money, and stimulated other eradication initiatives. However, recent concerns about the possible deliberate use of variola virus as a biological weapon prompted some countries to consider introduction of population-wide preemptive vaccination, but after close deliberation WHO recommendations of October 2001 were accepted by most countries. The WHO is currently leading international initiatives to eradicate poliomylitis and dracunculiasis and to eliminate African trypanosomiasis, Chagas disease, leprosy, lymphatic filariasis, onchocerciasis, and blinding trauchoma. Since the global polio eradication initiative was launched in 1988, three regions have been certified as free of the disease: the Americas in 1994, the Western Pacific in 2000, and Europe in 2002. Reported cases of polio have dropped from an estimated 350,000 cases in 125 countries in 1988 to 480 cases reported to WHO in 2001 from 10 endemic countries. Reported cases of dracunculiasis have decreased from over 900,000 in 1989 to less than 64,000 in 2001, with the majority of cases in one endemic country. Of the several diseases targeted for elimination, goals have been reached for the original onchocerciasis programme in West Africa and for leprosy, where global elimination was declared in 2001. Chagas disease, likewise, continues its downward trend towards elimination. The eradication of smallpox boosted an already growing optimism that infectious diseases were no longer a threat, at least to industrialized countries. This optimism had prevailed in many industrialized countries since the 1950s, a period that saw an unprecedented development of new vaccines and antimicrobial agents and encouraged a transfer of resources and public health specialists away from infectious disease control. Optimism is now being replaced by an understanding that the infrastructure for infectious disease surveillance and control has suffered and in some cases become ineffective. A combination of population shifts and movements with changes in environment and human behavior has created weaknesses in the defense systems against infectious diseases in both industrialized and developing countries. These weaknesses have recently come into sharp focus as countries consider preparedness plans for responding to the possible deliberate use of biological agents and recognize the importance of strong public health systems as the first line of defense for infectious disease outbreaks, no matter what their origin. 

III. WEAKNESSES FACILITATING EMERGENCE AND RE-EMERGENCE 

The weakening of the public health infrastructure for infectious disease control is evidenced by failures such as in mosquito control in Latin America and Asia with the re-emergence of dengue now causing major epidemics; in the vaccination programs in eastern Europe during the 1990s, which contributed to the re-emergence of epidemic diphtheria and polio; and in yellow fever vaccination, facilitating yellow fever outbreaks in Latin America and sub-Saharan Africa, including a large urban outbreak that occurred in Coˆte d’Ivoire in 2001. It is also clearly demonstrated by the high levels of hepatitis B and the nosocomial transmission of other pathogens such as HIV in the former USSR and Romania, and the nosocomial amplification of outbreaks of Ebola in Zaire, where syringes and failed barrier nursing drove outbreaks into major epidemics. Population increases and rapid urbanization during this 25-year period have resulted in a breakdown of sanitation and water systems in large coastal cities in Latin America, Asia, and Africa, promoting the transmission of cholera and shigellosis. In 1950, there were only two urban areas in the world with populations greater than 7 million, but by 1990 this number had risen to 23, with increasing populations in and around all major cities, challenging the capacity of existing sanitary systems. Anthropogenic or natural effects on the environment also contribute to the emergence and re-emergence of infectious diseases. The effects range from global warming and the consequent extension of vectorborne diseases, to ecological changes due to deforestation that increase contact between humans and animals, and also the possibility that microorganisms will breach the species barrier. These changes have occurred on almost every continent. They are exemplified by zoonotic diseases such as Lassa fever first identified in West Africa in 1969 and now known to be transmitted to humans from human food supplies contaminated with the urine of rats that were in search of food, as their natural habitat could no longer support their needs. In Latin America, Chagas disease emerged as an important human disease after mismanagement of deforested land caused triatomine populations to move from their wild natural hosts to involve human beings and domestic animals in the transmission cycle, eventually transforming the disease into an urban infection that can be transmitted by blood transfusion. Other zoonotic diseases include Lyme borreliosis in Europe and North America, transmitted to humans who come into contact with ticks that normally feed on rodents and deer, the reservoir of Borrelia burgdorferi in nature; and the Hantavirus pulmonary syndrome in North America. The narrow band of desert in sub-Saharan Africa, in which epidemic Neisseria meningitidis infections traditionally occur, has enlarged as drought spread south, so that Uganda and Tanzania experience epidemic meningitis, while outbreaks of malaria and other vectorborne diseases have been linked to the cutting of the rainforests. A 1998 outbreak of Japanese encephalitis in Papua New Guinea has been linked to an extensive drought, which led to increased mosquito breeding as rivers dried into stagnant pools. The virus is now widespread in Papua New Guinea and threatening to move farther east. Buruli ulcer, a poorly understood mycobacterial disease that has emerged dramatically over the past decade, has erupted following significant environmental disturbances, and some evidence suggests that recent explosive increases in flooding, or to the construction of dams and irrigation systems. And finally, human behavior has played a role in the emergence and re-emergence of infectious diseases, best exemplified by the increase in gonorrhea and syphilis during the late 1970s, and the emergence and amplification of HIV worldwide, which are directly linked to unsafe sexual practices. 

IV. FURTHER AMPLIFICATION 

The emergence and re-emergence of infectious diseases are also amplified by two major factors—the continuing and increasing evolution of anti-infective (drug) resistance (see Table 32.2), and dramatic increases in international travel. Anti-infective agents are the basis for the management of important public health problems such as tuberculosis, malaria, sexually transmitted diseases, and lower-respiratory infections. Shortly after penicillin became widely available in 1942, Fleming sounded the first warning of the potential importance of the development of resistance. In 1946, a hospital in the United Kingdom reported that 14% of all Staphylococcus aureus infections were resistant to penicillin, and by 1950 this had increased to 59%. In the 1990s, penicillin-resistant S. aureus had attained levels greater than 80% in both hospitals and the community. Levels of resistance of S. aureus to other anti-infectives, and among other bacteria increased with great rapidity. By 1976, chloroquine resistant Plasmodium falciparum malaria was highly prevalent in southeastern Asia and 20 years later was found worldwide, as was high-level resistance to two back-up drugs, sulfadoxinepyrimethamine and mefloquine. In the early 1970s, Neisseria gonorrhoeae that was resistant to usual doses of penicillin was just being introduced into Europe and the United States from Southeast Asia, where it is thought to have first emerged. By 1996, N. gonorrhoeae resistance to penicillin had become worldwide, and strains resistant to all major families of antibiotics had been identified wherever these antibiotics had been widely used. Countries in the western Pacific, for example, have registered quinolone resistance levels up to 69%. The mechanisms of resistance, a natural defense of microorganisms exposed to anti-infectives, include both spontaneous mutation and genetic transfer. The selection and spread of resistant strains are facilitated by many factors, including human behavior in overprescribing drugs, in poor compliance, and in the unregulated sale by non-health workers. In Thailand, among 307 hospitalized patients, 36% who were treated with anti-infective drugs did not have an infectious disease. The over-prescribing of antiinfectives occurs in most other countries as well. In Canada, it has been estimated of the more than 26 million people treated with anti-infective drugs, 50% were treated inappropriately. Findings from community surveys of Escherichia coli in the stool samples of healthy children in China, Venezuela, and the United States suggest that although multiresistant strains were present in each country, they were more widespread in Venezuela and China, countries where less control is maintained over antibiotic prescribing. Animal husbandry and agriculture use large amounts of anti-infectives, and the selection of resistant strains in animals, which then genetically transfer the resistance factors to human pathogens or infect humans as zoonotic diseases, is a confounding factor that requires better understanding. Direct evidence exists that four multiresistant bacteria infecting humans, Salmonella, Campylobacter, Enterococci, and Escherichia coli, are directly linked to resistant organisms in animals (WHO Conference on the Medical Impact of the Use of Antimicrobial Drugs in Food Animals, Berlin, 13–17 October 1997). Infections with resistant organisms require increased length of treatment with more expensive anti-infective drugs or drug combinations, and a doubling of mortality has been observed in some resistant infections. At the same time, fewer new antibiotics reach the market, possibly in part due to the financial risk of developing a new anti-infective drug that may itself become ineffective before the investment is recovered. 

There is no new class of broad-spectrum antibiotic currently on the horizon. Among the major infectious diseases, the development of resistance to drugs commonly used to treat malaria and tuberculosis is of particular public health concern, as is the emerging resistance to anti-HIV drugs. Even if the pharmaceutical industry were to accelerate efforts to develop new antimicrobials immediately, current trends suggest that some diseases may have very few and, in some cases, no effective therapies within the next 10–20 years. Many important medical and surgical procedures, including cancer chemotherapy, bone marrow and organ transplantation, and hip and other joint replacements, could no longer be undertaken out of fear that the associated compromise of immune function might place patients at risk of acquiring a difficult to treat and ultimately fatal infection. The role of travel in the spread of infectious diseases has been known for centuries. Because a traveller can be in a European or Latin American capital one day and the next day be in the center of Africa or Asia, humans, like mosquitoes, have become important vectors of disease. During the 1990s, over 500 million people travelled by air each year (World Tourism Organization), and contributed to the growing risk of exporting or importing infection or drugresistant organisms. In 1988, a clone of multiresistant Streptococcus pneumoniae first isolated in Spain was later identified in Iceland. Another clone of multiresistant S. pneumoniae, also first identified in Spain, was subsequently found in the United States, Mexico, Portugal, France, Croatia, Republic of Korea, and South Africa. A study conducted by the Ministry of Health of Thailand on 411 exiting tourists showed that 11% had an acute infectious disease, mostly diarrheal, but also respiratory infections, malaria, hepatitis, and gonorrhea (B. Natth, personal communication). Forced migration such as by refugees is also associated with the risk of re-emergence and spread of infectious diseases. 

In 1999, more than 7 million people around the world were newly uprooted. Currently, more than 35 million people are refugees or internally displaced persons. In a refugee population estimated to be between 500,000 and 800,000 in one African country in 1994, an estimated 60,000 developed cholera in the first month after the influx, and an estimated 33,000 died. V. SOLUTIONS Eradication and regulation may contribute to the containment of infectious diseases, but do not replace sound public health practices that prevent the weaknesses through which infectious diseases penetrate. Eradication was successful for smallpox and is advancing for poliomyelitis with virus transmission interrupted in the Americas, the Western Pacific, and Europe. Eradication or elimination applies to very few infectious diseases—those that have no reservoir other than humans, that trigger solid immunity after infection, and for which there exists an affordable and effective intervention. The development of powerful new medicines that are safe, affordable, and suitable for single-dose administration in mass campaigns has made it possible for WHO and the international community to launch recent campaigns to eliminate leprosy, lymphatic filariasis, and onchocerciasis and to consider the elimination of schistosomiasis and soil-transmitted helminthiasis in areas where control programmes have succeeded in achieving low transmission. Attempts at regulation to prevent the spread of infectious diseases were first recorded in 1377 in quarantine legislation to protect the city of Venice from plague-carrying rats on ships from foreign ports. Similar legislation in Europe, and later the Americas and other regions, led to the first international sanitary conference in 1851, which laid down a principle for protection against the international spread of infectious diseases: maximum protection with minimum restriction. 

Uniform quarantine measures were determined at that time, but a full century elapsed, with multiple regional and inter-regional initiatives, before the International Sanitary Regulations were adopted in 1951. These were amended in 1969 to become the International Health Regulations (IHRs), which are implemented by the WHO. The IHRs provide a universal code of practice, which ranges from strong national disease detection systems and measures of prevention and control including vaccination, to disinfection and de-ratting. Currently, the IHRs require the reporting of three infectious diseases—cholera, plague, and yellow fever. But when these diseases are reported, regulations are often misapplied, resulting in the disruption of international travel and trade, and huge economic losses. For example, when the cholera pandemic reached Peru in 1991, it was immediately reported to WHO. In addition to its enormous public health impact, however, misapplication of the regulations caused a severe loss in trade (due to concerns for food safety) and travel, which has been estimated as high as $770 million. In 1994, an outbreak of plague occurred in India with approximately 1000 presumptive cases. The appearance of pneumonic plague resulted in thousands of Indians fleeing from the outbreak area, risking spread of the disease to new areas. Plague did not spread, but the outbreak led to tremendous economic disruption and concern worldwide, compounded by misinterpretation and misapplication of the IHRs. Airports were closed to airplanes arriving from India, exports of foodstuffs were blocked, and in some countries Indian guest workers were forced to return to India even though they had not been in India for several years before the plague epidemic occurred. Estimates of the cost of lost trade and travel are as high as $1700 million. Again, the country suffered negative consequences from reporting an IHRmandated diseases due to the misapplication of the IHRs. A further problem with the IHRs is that many infectious diseases, including those which are new or re-emerging, are not covered even though they have great potential for international spread. These range from relatively infrequent diseases such as viral hemorrhagic fevers to the more common threat of meningococcal meningitis. Because of the problematic application and disease coverage of the IHRs, WHO has undertaken a revision and updating of the IHRs to make them more applicable to infection control in the twenty-first century. Revisions include a considerable broadening of scope to embrace all infectious diseases of international importance, especially new and re-emerging diseases. 

The present obligation on countries is being broadened to include a clear mechanism for confidential collaboration between the affected country and WHO to verify the presence or absence of a suspected outbreak unofficially reported by the press or electronic media. Modifications also introduce provisions for defining what constitutes a “public health emergency of international concern,” thus helping to avoid inappropriate reactions to strictly localized events. It is envisaged that the revised IHRs will become a true global alert and response system to ensure maximum protection against the international spread of diseases with minimum interference with trade and travel. Eradication and elimination cannot substitute for good public health—rebuilding of the weakened public health infrastructure and strengthening water and sanitary systems; minimizing the impact of natural and anthropogenic changes in the environment; effectively communicating information about the prevention of infectious diseases; and using antibiotics appropriately. The challenge in the twenty-first century will be to continue to provide resources to strengthen and ensure more cost-effective infectious disease control while also providing additional resources for other emerging public health problems, such as those related to smoking and aging.