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2.6 Infectious agents

2.6
Infectious agents

David Heymann

The infectious disease situation at the end of the twentieth century

Introduction

Emerging and re-emerging infections

Mortality in endemic infectious diseases

Disability in endemic infectious diseases

Infectious diseases and cancer
Causes and consequences of emergence, re-emergence, and spread of infectious diseases

Climate and environmental changes

Health impact of El Niño

Other weather patterns and disease outbreaks

Global warming

Transmission of infectious agents from animals to humans

Poverty, neglect, and the weakening of health infrastructure

Uncontrolled urbanization and population displacement

Human behaviour

Anti-infective drug resistance

Globalization of travel and trade
Solutions to infectious disease problems

Eradication, elimination, and intensified control

Effective use of a core set of interventions

Working across government sectors

Expansion of surveillance and response systems

Strengthening international agreements and regulations

Investment in research

Making better use of existing tools

Diagnostic tests

New drugs

New vaccines
Summary
Further reading

Illness and death from infectious diseases can in most cases be avoided at an affordable cost. It is in the interest of all that these obstacles to development be removed. Because of drug resistance, increased travel and the emergence of new diseases, there may only be a limited time in which to make rapid progress.
Dr Gro Harlem Brundtland, Director-General (WHO 1999)
The infectious disease situation at the end of the twentieth century
Introduction
Throughout history, human populations have experienced major epidemics of infectious diseases, often resulting in large numbers of deaths, panic, disruption of trade, and political instability. At the same time, the majority of infectious disease mortality has been caused by endemic diseases such as malaria, tuberculosis, HIV, acute respiratory infections, acute diarrhoeal diseases, and measles—a phenomenon that continues today. While all infectious diseases have the potential to spread, it is the rapid nature of the spread of those with epidemic potential and their high mortality rate in newly affected populations that attracts the greatest attention.
Infectious diseases are termed endemic when they have a stable pattern of occurrence in a given population. Epidemics are defined as the occurrence of an infectious disease greatly in excess of expectation. Some endemic diseases cause epidemics if they spread to unprotected or previously unexposed populations, witnessed by a recent and highly fatal outbreak of cholera which caused well over 3000 deaths after its reintroduction into Latin America in 1991. Endemic diseases can also become epidemic when the mode of transmission changes, especially in the event of nosocomial outbreaks of initially endemic diseases such as hepatitis B. At the same time, many diseases now labelled endemic in certain populations have begun with severe exponential epidemics, becoming endemic only after the highly susceptible risk populations had become infected, thus leaving future risk populations to perpetuate transmission at a lower rate. The HIV epidemic is an example of an infectious disease that has become endemic in some countries and geographic areas while in others it still reaches and causes epidemics in previously unexposed populations.
International public health movements of the late nineteenth century identified the issues of poverty, overcrowding, and poor sanitation as providing fertile ground for infectious diseases, especially in urban areas. Despite these discoveries, the development of effective treatments and vaccines in the first two-thirds of the twentieth century led to erroneous hopes that most infectious disease mortality would be greatly decreased, if not eradicated. But the interrelationship between poverty, health, and development remains a major factor in the continuing threat of infectious diseases. Up to 45 per cent of deaths in low-income countries during 1998 are thought to have been due to an infectious disease, while worldwide 48 per cent of premature deaths (those under the age of 45 years) are thought to have an infectious aetiology (Fig. 1).

Fig. 1 Premature deaths in low-income countries.

The fight against infectious diseases worldwide is therefore far from won. Since the early 1990s, the international public health community has been warning against a fatal complacency which is costing millions of lives every year (13.3 million out of a worldwide total of almost 54 million deaths in 1998), most among the poorest of the poor. Populations remain permanently at risk of the recurrence of epidemics which can to a certain extent be predicted, but also of new pathogens whose occurrence and impact on human health are not known. A good example is influenza, which is an ever-present threat. The last pandemic (defined as a disease which is epidemic worldwide) of highly virulent influenza is thought to have killed over 20 million people within a year, in 1918 to 1919. Another global pandemic of a highly virulent strain of influenza is foreseen, but its timing cannot be predicted. If it occurs, it will spread more rapidly than before owing to increasing and more rapid international travel, and it will have the potential to kill a larger number of people. A similar scenario cannot be excluded with yellow fever in central and western Africa, or malaria and dengue in areas where the diseases are not yet endemic. At the same time, the potential impact of newly identified infectious agents is a subject of continued epidemiological study.
Emerging and re-emerging infections
Over the past three decades, over 30 emerging infections have been newly identified in humans. They range from the Marburg, Ebola, and nipah viruses to the more common rotavirus, hepatitis C virus, and HIV. During this same time period, known infections such as tuberculosis, diphtheria, cholera, meningitis, dengue, yellow fever, and plague have re-emerged.
The term emerging infection, first widely used in the early 1990s, refers to newly identified and previously unknown infectious agents that cause public health problems either locally or internationally. The term re-emerging infection refers to infectious agents that have been known for some time, had fallen to such low levels that they were no longer considered public health problems, and are now showing upward trends in incidence or prevalence worldwide. The number of emerging and re-emerging infectious agents appears to have increased during the past 30 years, while infectious diseases known for centuries continue to cause a heavy burden of suffering, disability, and death.
Emergence and re-emergence of infectious agents have occurred throughout the world, and there have been dramatic reversals in formerly positive trends in infectious disease control, as well as many unexpected outbreaks (Fig. 2).

Fig. 2 Recent unexpected outbreaks of infectious diseases.

By 1995 the problem of infectious diseases had become so politically important that the World Health Assembly, health ministers representing the 191 member countries of the World Health Organization (WHO), urged all countries to strengthen surveillance of infectious diseases in order to detect re-emerging infectious diseases promptly, to identify emerging infections, and to respond more appropriately to both epidemic and endemic infectious diseases.
Re-emerging infections—reversals in trends
During a 3-year period in the early 1990s, a major epidemic of diphtheria occurred in the newly independent states of Eastern Europe. Whereas in 1980, Europe had accounted for less than 1 per cent of diphtheria cases reported worldwide, it reported almost 90 per cent of cases in 1994. The newly independent states have also reported a dramatic increase in sexually transmitted infections over the past decade, where there has been a 15 to 30 per cent increase in syphilis reported between 1989 and 1995, with rates in the Russian Federation increasing by 40 per cent.
The number of reported cholera cases increased nearly 100 per cent in 1998 as compared with 1997, on all continents. Africa was the most affected, with 72 per cent of the global total and 29 countries reporting cases out of a total of 74 worldwide (Fig. 3). In the Americas, the number of cases had declined up to 1997 after the disease had re-emerged along the Peruvian coastline in 1991, but another resurgence was recorded in 1998. Cholera caused by Vibrio cholerae 01 biotype eltor, a strain which first appeared in Indonesia in 1961, has now spread worldwide, causing major epidemics. In 1992, V. cholerae 0139 was first detected in the Bay of Bengal and has since been identified in 10 other Asian countries.

Fig. 3 Countries/areas reporting cholera in 1998.

Epidemic meningococcal meningitis is highly transmissible and has a high case-fatality rate. The disease is characterized by severe recurring epidemics which devastate communities. While epidemic meningitis strikes people of all ages all over the world, the countries most at risk are in sub-Saharan Africa where the infection primarily affects young children. In 1997 to 1998, over 300 000 cases of meningococcal disease were reported to the WHO from the African meningitis belt, which stretches from Ethiopia to Senegal, and includes all or part of at least 15 countries, with an estimated population of 300 million.
Over the past 40 years, the number of reported cases of dengue/dengue haemorrhagic fever has increased 20-fold to nearly 515 000 in the period 1990 to 1998 when compared with the previous 9-year period (Fig. 4). Regions most affected were Latin America and south-eastern Asia.

Fig. 4 Increase in average number of dengue cases reported annually, 1995 to 1998.

Between 1990 and 1998, 11 countries in Africa (Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Gabon, Ghana, Kenya, Liberia, Nigeria, Senegal, Sierra Leone) reported 9370 cases and 1707 deaths from yellow fever, while 1698 cases and 794 deaths were reported from six countries/areas in Latin America (Bolivia, Brazil, Colombia, Ecuador, French Guiana, and Peru).
Japanese encephalitis is the most important form of viral encephalitis in Asia, thought to cause at least 50 000 cases of clinical disease and 10 000 deaths each year, mostly among children. The high case-fatality rate and frequent neuropsychiatric sequelae in survivors make Japanese encephalitis a considerable public health problem in many Asian countries. Close to 3 billion people are now living in Japanese encephalitis endemic regions. In recent decades, outbreaks of Japanese encephalitis have occurred in several previously non-affected areas, and a small outbreak was recently reported from islands in the Torres Strait off the Australian mainland.
Epidemics of rodent or human plague have continued to occur during the past 30 years. In 1994, for example, human plague reappeared in Malawi, Mozambique, and India—after a 15- to 30-year absence. The total number of human plague cases reported to the WHO by 14 countries in 1997 was 5419, of which 274 were fatal. This represented an increase over 1996, when 3017 cases were notified from these same countries, and considerably exceeded the average annual of 1920 cases, 168 deaths for the previous 10 years. Over the last decade, 72 per cent of cases and 79 per cent of plague deaths were reported from Africa.
During 1996 to 1998, there was an outbreak of epidemic typhus in Burundi with over 100 000 cases reported. The case-fatality rate is difficult to assess, but based on the information available it appears that it ranged between 1 and 20 per cent in this region where typhus epidemics had not been reported since the late 1940s.
Emerging infections—newly identified infectious agents
Hepatitis C, first identified in 1989, had already spread worldwide with an estimated global prevalence of at least 3 per cent in the mid-1990s; while hepatitis B, identified several decades earlier, continues an upward trend in many countries, reaching a prevalence exceeding 90 per cent in populations at high risk in countries ranging from the tropics to Eastern Europe.
In the United States, Legionella infection was first identified in 1976 in an outbreak of fatal respiratory illness among war veterans. Legionellosis is now known to occur worldwide and is a threat to travellers and others exposed to poorly maintained air-conditioning systems. In 1999, 2136 cases and 193 deaths were reported in European residents, with an overall case-fatality rate of 13.1 per cent, compared with a case-fatality rate of 10 per cent in 1997. One outbreak in Belgium and one in The Netherlands, both linked to trade shows, collectively gave rise to almost 300 cases in 1999.
In 1997, FluNet, the WHO global surveillance system for human influenza virus, received reports of an isolated and fatal influenza infection in a 3-year-old child in Hong Kong Special Administrative Region of China. The virus was identified as influenza A (H5N1), and was associated with epidemics of avian influenza with high fatality rates in live poultry markets. By the end of 1997, a total of 18 human infections had been confirmed, 6 (33 per cent) of which were fatal. Twelve of the 18 developed complications of which seven were severe pneumonia. In 1999, FluNet received reports of another new influenza virus, A (H9N2), isolated from two human cases in Hong Kong, and no further spread was known to have occurred.
In 1996, the occurrence in the United Kingdom of 10 cases of an apparently new variant of Creutzfeldt–Jakob disease was linked to the epidemic of bovine spongiform encephalopathy among cattle. As of the end of September 2000, at least 84 people in the United Kingdom, one in Ireland, and three in France have contracted variant Creutzfeldt–Jakob disease. Accurate prediction of the future number of variant Creutzfeldt–Jakob disease cases is not possible, but the possibility of a significant and perhaps geographically diverse epidemic occurring over the next two decades cannot be excluded.
Since first being recognized as a human pathogen in 1982, enterohaemorrhagic Escherichia coli has gained increasing importance as a human pathogen. The best known serotype, E. coli 0157 H7, has been responsible for recent large food-borne outbreaks in Japan, Scotland, and the United States, placing heavy demands on medical and public health response systems while causing major political concern about food safety.
Unquestionably one of the most important emerging infections is HIV. First identified in the early 1980s, it has rapidly spread worldwide, affecting over 33 million people. The epidemic characteristics of HIV at the end of the twentieth century are described below.
The Marburg virus, a member of the filovirus family, was first recognized in 1967 when laboratory workers in Germany were infected by handling monkeys imported from Uganda. Since then, there have been reports of sporadic cases in 1975, 1980, and 1987. The most recent outbreak took place in 1999 amongst gold miners in the Democratic Republic of the Congo. The three confirmed cases were thought to have been infected during their work in the mine. All three confirmed cases died, many more suspect cases were identified, and detailed studies were undertaken to define the limits of the outbreak and to attempt to identify the reservoir.
In 1976, the Ebola virus, another member of the family of filoviruses, was identified for the first time, causing an outbreak that has come to symbolize emerging diseases and their potential impact on populations without previous immunological experience. Ebola has caused at least five severe epidemics and numerous smaller outbreaks since its identification in 1976 during simultaneous outbreaks in Zaire (now the Democratic Republic of the Congo) and southern Sudan. In an outbreak which took place in 1995 there were 315 cases, with a case-fatality rate of 77 per cent, and approximately one-third of those infected were health-care workers who came into contact with the blood or body fluids of infected patients. One patient boarded an airplane, carrying the disease to Kinshasa, the capital, 500 km away with no extension of the outbreak. Two years later, in a smaller outbreak in Gabon, 61 cases occurred with a case-fatality rate of 78 per cent.
The largest outbreak of Ebola haemorrhagic fever occurred in October 2000, in Uganda. By the time the epidemic was declared officially over on 28 February 2001, there had been 428 reported clinical cases and 224 deaths.
Other newly identified viruses include sine nombre (1993), which caused an outbreak of hantavirus pulmonary syndrome in the United States (50 cases, case-fatality rate over 75 per cent), Hendra virus, first identified in Australia in 1994, and nipah virus, first identified in 1999 and responsible for 155 confirmed cases in Malaysia.
Interaction of emerging and known infectious diseases
The interaction of infectious diseases is dynamic and at times synergistic, best exemplified in the interaction of endemic infectious diseases with HIV. The increase in active pulmonary tuberculosis and its role as an HIV-associated infection is a prime example. Another example is leishmaniasis, where dual infection with HIV causes increased visceral dissemination and severity. A further example is an extensive outbreak of human monkeypox in 1996 to 1997 in the Democratic Republic of the Congo. Prior to HIV, vaccination with vaccinia would have been the intervention of choice to prevent a continued epidemic. Vaccinia vaccine is now known to have the potential of causing generalized vaccinia in those who are infected with HIV, and an estimated prevalence of HIV infection of 7 per cent precluded the use of vaccinia vaccine in this population.
Mortality in endemic infectious diseases
By mid-1999, one emerging and one re-emerging infection, AIDS and tuberculosis respectively, had surfaced as two of the six endemic infectious processes that cause the highest burden of mortality worldwide. These leading six diseases, which cause almost 90 per cent of infectious disease deaths, are acute respiratory infections (including pneumonia and influenza), AIDS, diarrhoeal diseases, tuberculosis, malaria, and measles (Fig. 5).

Fig. 5 Leading causes of death from infectious diseases in all ages worldwide, 1998.

Acute respiratory infections
Acute respiratory infections are estimated to have caused approximately 3.5 million deaths in 1998, 99 per cent of which occurred in developing countries, among children aged under 5 years. Pneumonia causes more childhood deaths than any other infectious disease process, mostly in children with low birth weight or those whose immune systems are weakened by other diseases or malnutrition. Exposure to smoke from indoor cooking fires likewise appears to be a major risk factor for pneumonia in children. Leading infectious agents causing childhood pneumonia are Streptococcus pneumoniae and Haemophilus influenzae type B.
There is very little information available on mortality from influenza in developing countries. However, in the United States alone, it is estimated that influenza kills 10 000 to 40 000 people in an average influenza season, mostly infants and adults aged over 60 years. During the 1968 influenza season, over 40 000 influenza deaths were recorded in another industrialized country, France, in the space of 2 months.
AIDS
By the end of 1999, 33.6 million people were living with HIV/AIDS worldwide; during 1999, 5.6 million people (including 570 000 children aged under 15 years) became infected.
By the end of 2000, it was estimated that a total of 21.8 million adults and children (including 3 million in 2000) had died because of HIV/AIDS since the beginning of the epidemic. During 2000, 5.3 million (including 600 000 children aged below 15 years) became infected. HIV infections are now almost equally distributed between men and women, with an estimated 18.2 million men aged 15 to 49 years living with HIV/AIDS. HIV/AIDS continues to spread in all regions of the world. The positive sign of a decrease in new infections in sub-Saharan Africa is offset by the increase in AIDS morbidity and mortality. Many African countries are experiencing the full impact of the epidemic, including its economic and demographic consequences. Epidemics of HIV infections continue to occur among injecting drug users in eastern Europe. An increasing number of HIV-positive people can, however, live longer and healthier lives due to antiretroviral therapies.
Asia continues to have relatively low prevalence rates. There are an estimated 6 million adults and children living with HIV/AIDS in Southeast Asia.
In 1999, Eastern Europe and Central Asia have seen the sharpest increase in HIV infections. Most of the 360 000 people living with HIV/AIDS in these countries have been infected through injecting drug use.
Diarrhoeal diseases
Diarrhoeal diseases are estimated to have caused approximately 2.2 million deaths during 1998, the majority of which took place among children under 5 years of age living in developing countries. The most common cause is infection with rotavirus, often occurring at the time of weaning. Death is a result of dehydration. Other causes of diarrhoeal disease include cholera, shigellosis, salmonellosis, E. coli, yersiniosis, giardiasis, campylobacteriosis, and enteroviruses other than rotavirus. In addition to its high mortality rates, diarrhoeal disease imposes heavy nutritional waste on children under 5 years of age who survive infection, especially in deprived areas where sanitation is poor, hygiene inadequate, and drinking water unsafe.
Tuberculosis
During 1999 there were an estimated 8.4 million new cases of tuberculosis—up from 8 million in 1997—adding to the estimated 2 billion people worldwide with latent tuberculosis infection. This rise is due largely to a 20% increase in incidence in African countries most affected by the HIV/AIDS epidemic (WHO 2001). Tuberculosis accounts for 2.3% of the global burden of disease (WHO 2000), and is among the most common causes of death in young women.
Co-infection with HIV significantly increases the risk of developing tuberculosis (Raviglione et al. 1997). Countries with a high prevalence of HIV, particularly those in sub-Saharan Africa, have witnessed a profound increase in tuberculosis, with reported incidence rates increasing two- or threefold in the 1990s (WHO 2001).
As for other infectious diseases, the poor and marginalized in developing countries are the worst affected: 95 per cent of all cases and 99 per cent of all tuberculosis deaths occur in developing countries, where 75% of cases are in the most economically productive age group (15 to 54 years old).
Malaria
Estimates of malaria mortality for 1998 suggest that approximately 3000 people died each day of the year from malaria, mostly due to Plasmodium falciparum. Three out of four of those who died from malaria were children, who are at great risk of cerebral manifestations. One of the sequels of repeated malaria infections is chronic anaemia, mostly affecting women and children. Of the estimated 1.1 million malaria deaths in 1998, most occurred in sub-Saharan Africa, where malaria accounts for almost one in five of all childhood deaths. Worldwide, over 275 million malaria infections are thought to have occurred in 1998. Women are especially vulnerable to malaria infection during pregnancy when infection is associated with an increase in spontaneous abortions, stillbirths, and low-birth-weight babies.
Measles
The measles virus is among the most infectious pathogens known. Although great progress has been made in measles prevention because of a vaccine with an over 95 per cent efficacy, it remains a major cause of childhood mortality in developing countries, where it is thought to have caused approximately 900 000 deaths during 1998. Most at risk are young children who are protected during the first 9 to 12 months of life by placentally passed measles antibody, but who rapidly become susceptible to infection after its disappearance.
The high mortality from these six infectious diseases is an obstacle to economic development. Factors related to these diseases are also obstacles to development. The AIDS epidemic alone has left over 8 million orphans who must often depend on society for support. Families risk high debt through lost earnings and high health-care costs, trapping them in a vicious circle of poverty and ill health. One tuberculosis case alone has been shown to lead to a 30 per cent loss of household income, while recent studies in six African countries and one in Asia have shown that the average number of days of work lost because of an acute episode of malaria ranges from 2 to 6 days (Fig. 6).

Fig. 6 Estimated average number of working days lost by adults for one episode of malaria (best available data).

Disability in endemic infectious diseases
In addition to mortality, the scale of individual pain, suffering, and disability from infectious diseases is immense, and chronic protein depletion and anaemia are common sequelae of many infectious diseases. At any one time, hundreds of millions of people—mainly in developing countries—are affected by infectious diseases either directly because of illness associated with acute infection, or indirectly because they are caregivers of those with illness or have severe postinfection disabilities.
For those suffering from infectious diseases associated with severe and long-term disability, there is often discrimination, stigmatization, shame, and anguish. At the same time those who are disabled are often unable to work, and thus are not only unable to provide resources for the family but become a burden to those who consequently become less productive themselves. The main infectious diseases which cause long-term disability are lymphatic filariasis, schistosomiasis, leishmaniasis, trachoma, onchocerciasis (river blindness), African trypanosomiasis (sleeping sickness), leprosy, dracontiasis (guinea-worm disease caused by Dracunculus medinensis), Chagas’ disease, and intestinal parasites.
Lymphatic filariasis is estimated to be the second most important cause of long-term disability worldwide, after mental illness. The prevalence of chronic infection with lymphatic filariasis at the end of 1998 has been estimated at 120 million. Over 40 million (33 per cent) of those infected are estimated to be severely disfigured and disabled by the most visible manifestation of long-term infection, elephantiasis. At least 1 billion people are at risk of filarial infection—one in six of the world’s population.
Schistosomiasis is estimated to infect over 200 million people worldwide and up to three times as many are at risk. Spread by freshwater snails that serve as intermediate hosts, and contracted by contact with stagnant water sources, it is a constant risk of dam-building and irrigation projects where in the presence of the newly introduced intermediate host a non-endemic region can rapidly become hyperendemic, with children and rural workers most at risk. In some of the most affected areas, over 90 per cent of children have become infected simply by wading through infested waters. In endemic areas, schistosomiasis is a major cause of chronic urinary tract disease, cirrhosis of the liver, and urinary bladder cancer.
More than 12 million people worldwide have been infected with leishmaniasis caused by parasites spread by the bite of the sandfly. In its visceral form, infection causes irreversible organ damage, while the dermatological manifestations include skin lesions and mutilation of the mouth and cartilaginous appendages including the nose. In countries such as India and Sudan there has been a sharp increase in visceral leishmaniasis as a result of coinfection with HIV. Leishmania–HIV coinfection also occurs in European countries, mainly among injecting drug users.
An estimated 5.6 million people today have been blinded or visually disabled by the sequelae of trachoma infection, and an additional 154 million are thought to have been chronically infected during 1998—mainly in Africa and Asia. The disease is transmitted by person-to-person contact, and amplified by poor hygiene.
Over 85 million people in Africa, Latin America, and the Arabian peninsula are at risk of infection with onchocerciasis. This parasitic disease is transmitted by the blackfly and causes visual impairment, blindness, and severe unrelenting pruritis due to the presence of microfilaria in the skin. Pruritis can be so intense that it results in open lesions from scratching, often followed by superinfection and suppuration.
In sub-Saharan Africa, 55 million people in 36 countries are at risk of infection with African trypanosomiasis, commonly referred to as sleeping sickness. The Trypanosoma are transmitted from the animal reservoir to humans by the tsetse fly, and chronic infection results in sleeping sickness manifested by debilitating illness and decrease in mental alertness. Without treatment, infection is fatal, and in some of the worst affected countries over half of the inhabitants in some villages are infected.
Infection with Hansen’s bacillus (M. leprae), the cause of leprosy, results in significant disability in many countries in Africa, Latin America, and Southeast Asia. Approximately 800 000 cases of leprosy are detected each year, and current efforts are underway to decrease its prevalence to less than 1 per 10 000 during the coming 5 years.
Dracontiasis, or guinea-worm disease, is caused by a parasite transmitted by drinking infested water in regions where water is scarce and people with infection wade in that water which is also used for other household purposes including drinking. The mature worm, up to 1 m long, emerges through the skin, often in the lower leg, where it causes excruciating pain and disabling infections, and from where it deposits its eggs when in contact with water. The infection also causes severe arthralgia, fever, and vomiting. Over 78 000 cases were reported worldwide in 1998, mainly in Sudan, Nigeria, and Ghana. Efforts to eradicate dracontiasis are underway, with the major burden of disease remaining in southern Sudan.
Chagas’ disease occurs only in Latin America, where it was estimated that up to 18 million people were infected in 1998. Some 120 million people live in areas at risk. Primarily transmitted by the blood-sucking Triatoma bug (family Reduviidae) that is infected with Trypanosoma cruzi, the parasite can also be transmitted by transfusion of contaminated blood and from mother to child at birth. It is estimated that the proportion of blood that is used for transfusion and is infected is over 50 per cent in some cities. Over one-third of those infected develop chronic disease, and about 30 per cent of them have incapacitating cardiac damage. Chagas’ disease is the leading cause of cardiac death among young adults in some parts of South America. Others suffer intestinal and peripheral nerve damage.
Serious disability is also caused by sexually transmitted infections. In 1995, four sexually transmitted infections—gonorrhoea, Chlamydia, syphilis, and Trichomonas—accounted for an estimated 333 million new cases of curable sexually transmitted infections. In addition to acute suffering, syphilis and gonorrhoea result in serious sequelae worldwide. Acute gonorrhoeal infection has been shown to facilitate HIV transmission and infection, and untreated infections can thus prolong the period of increased transmissibility. Untreated gonorrhoeal infections also result in acute peritonitis, salpingitis, and infertility. Sequelae of untreated syphilis, known for centuries, include cardiac damage and aneurysm.
Infectious diseases and cancer
Epidemiological studies have shown that infection with viruses, bacteria, and parasites may be the initiating event in the later development of cancer, and that up to 85 per cent of some types of cancer can be attributed to an earlier infection. It is further estimated that at least 15 per cent of new cancers each year could be avoided if the associated preceding infectious process could be prevented.
According to estimates, mostly based on preliminary studies, approximately 550 000 cases of stomach cancer are attributable to Helicobacter pylori each year, representing approximately 55 per cent of stomach cancer worldwide. Sexually transmitted infection of the cervix with human papilloma virus is thought to be responsible for an estimated 83 per cent of cervical cancers, while approximately 82 per cent of liver cancers are attributable to infection with the hepatitis B and/or C virus. In countries where schistosomiasis is endemic, up to 4 per cent of new cases of bladder cancer have been linked to the presence of eggs of the adult parasite in the urinary bladder.
Causes and consequences of emergence, re-emergence, and spread of infectious diseases
The eradication of smallpox in the late 1970s boosted the already growing optimism that infectious diseases were no longer a threat, at least to developed countries. This optimism had prevailed since the 1950s, a period that saw unprecedented development of new vaccines and anti-infective drugs, and encouraged a transfer of resources and public health specialists away from infectious disease control. Optimism is now being replaced by an understanding that:

(1)
climate and environmental changes result in the spread of infectious agents to new areas;
(2)
transmission of infectious agents from animals to humans is occurring with increasing frequency, especially as humans exploit new ecological zones;
(3)
poverty and the weakening of health infrastructures after political changes, or as a result of natural disasters or civil strife and war, are major causes of the resurgence of infectious diseases;
(4)
uncontrolled urbanization and population displacement lead to concentrations of human populations in conditions that favour major epidemics (for example, urban slums or refugee camps);
(5)
human behaviour can amplify the transmission of infectious agents;
(6)
rapid development of anti-infective drug resistance is greatly facilitated by the misuse of antibiotics;
(7)
globalization of travel and trade has markedly increased the potential for the spread of infectious diseases.

Climate and environmental changes
Alterations to the environment, whether natural or man-made, contribute to the emergence and re-emergence of infectious diseases. They range from localized warming with resultant extension of vector-borne diseases to deforestation that forces animals into closer human contact in search of food, increasing the possibility for infectious agents to breach the species barrier between animals and humans. Such changes have occurred on almost every continent. Most at risk are the over 500 million people who live in poverty and in ecologically fragile regions.
Health impact of El Niño
During the late 1990s, interest grew in the links between El Niño (and other extreme weather events) and human health. The longest single El Niño period on record occurred from 1990 to 1995. El Niño and similar weather disturbances affect human health mainly as a result of the natural disasters they trigger and the related outbreaks of infectious diseases.
The best-documented links exist between weather variations thought to be due to El Niño and the incidence of vector-borne diseases (for example, malaria or Rift Valley fever) and epidemic diarrhoeal diseases, particularly cholera. The resurgence in cholera cases in the Americas in 1998 was primarily attributable to the continuing effects of major disasters caused by the El Niño phenomenon and Hurricane Mitch. The increase in cholera cases on all continents in 1998 is similarly thought to be related to similar changes which have created conditions favourable for cholera outbreaks worldwide. The devastation of water and sanitation systems which has resulted from these naturally occurring phenomena is so severe that it is likely to take decades before the infrastructure and basic services in some of the affected regions regain their previous levels, thus continuing to favour outbreaks of diarrhoeal and other water-borne infectious diseases.
Recent outbreaks of Rift Valley fever, a vector-borne disease that principally infects livestock, have occurred in eastern Africa on almost every occasion that there has been excessive rainfall. Concurrent with the 1997 El Niño, areas of northeastern Kenya and southern Somalia experienced rainfall which was 60 to 100 times heavier than normal—the heaviest recorded rainfall since 1961. The rains are thought to have caused an increase in Rift Valley fever virus-infected eggs of Aedes mosquitos to hatch in the floodwaters. In the outbreak of Rift Valley fever that followed, which inflicted heavy livestock losses, there were an estimated 89 000 human cases with approximately 250 deaths, the largest recent outbreak of this disease.
Other weather patterns and disease outbreaks
The band of desert in sub-Saharan Africa, in which epidemic Neisseria meningitidis subgroup A infections traditionally occur, has enlarged as drought spreads south, so that countries such as Uganda and the United Republic of Tanzania now experience epidemic meningitis.
Current evidence suggests that in tropical and subtropical regions, influenza viruses circulate all year round, and that migrating aquatic birds transport viruses from these regions to the temperate zones during migration. More generally, outbreaks of diseases tend to follow temperature and precipitation patterns which affect the ability of influenza vectors such as birds to survive. New research into the links between specific weather patterns and outbreaks of Ebola haemorrhagic fever are examining the relationship between the clustering of reported outbreaks and climatic factors. Although the animal host of the Ebola virus remains elusive, it is hoped that by pinpointing specific regional and temporal ‘trigger’ weather events, it might be possible to establish the consequent animal behaviour which brings the host species into contact with humans under certain circumstances.
Global warming
Unprecedented changes taking place in the global climate because of greenhouse gas emissions could have even more wide-ranging effects on illness and death from infectious diseases. Global climate change is gradual and complex, and the environmental consequences are difficult to predict. A global mean temperature increase of 1 to 2°C would enable mosquitos to extend their range to new geographical areas, leading to increases in malaria and other mosquito-borne diseases, especially in populations living just outside areas endemic to these diseases. The proportion of the world’s population at risk for malaria, currently estimated at 2.4 billion, could increase from 45 per cent in 1998 to 60 per cent by 2050 if global warming continues at the current estimated rate. The estimated annual number of deaths from malaria would inevitably rise as well, and control measures that might have been affordable and cost-effective at the end of the twentieth century could become impossible to implement. Some of the other vector-borne diseases potentially affected by global climate change include lymphatic filariasis, dengue, leishmaniasis, and Chagas’ disease.
Transmission of infectious agents from animals to humans
Over two-thirds of emerging infections identified during the 1990s are known to have originated from animals—both wild and domestic species. Some are believed to have emerged from animals living in tropical rainforests or elsewhere in close proximity to humans, where micro-organisms have succeeded in crossing the species barrier to humans directly from an animal reservoir, or through an intermediary vector. The origins of some outbreaks of infectious agents, the Marburg and Ebola outbreaks for example, remain a mystery in spite of intensive research, but both are thought to have animal sources somewhere in the cycle of transmission to index cases. One was a single case of Ebola in a scientist working in Côte d’Ivoire who dissected a chimpanzee later known to be infected with the Ebola virus. A recent outbreak of Ebola in Gabon, associated in time and place with the butchering of a chimpanzee by the 19 index cases, adds credibility to this hypothesis.
Emerging influenza infections in humans have been associated with geese, chickens, and pigs. The influenza virus A (H5N1) that was isolated in 1997 from geese and chickens in Hong Kong Special Administrative Region of China was shown to be related to viruses isolated in the early 1990s in ducks in China and chickens in Italy. Likewise, the influenza A (H9N2) virus isolated in China in 1999 was similar to swine viruses isolated in Hong Kong Special Administrative Region of China in 1998. An influenza virus which had hitherto only been isolated in swine, A (H3N2), was detected for the first time in a human in 1999. In each of these instances the viruses were not able to transmit easily from human to human and did not become established in human populations as did others earlier in the century.
The majority (93 per cent) of people infected in the 1999 outbreak of viral encephalitis in Malaysia were people involved directly in the pig farming industry. The outbreak had a double aetiology: the re-emergence of the Japanese encephalitis virus and the emergence of a second, newly identified, neurotropic virus later named nipah.
An outbreak of West Nile like fever which caused five deaths in New York City in 1999 was thought to have been caused by transmission of the virus from birds to humans through mosquitos. Although West Nile virus is commonly found in humans and other vertebrates in Africa, western Asia, and eastern Europe, this was the first time it was detected in the western hemisphere. How the virus reached the area is the topic of great speculation, but its source had not been ascertained by the time of writing.
Animal displacement in search of new sources of food after deforestation or climate change can bring them into closer contact with human settlements and opulations not previously in contact. One example is Lassa fever, first identified in West Africa in 1969, and now known to be transmitted to humans from food supplies contaminated with the urine of rats in search of food away from a natural habitat that can no longer support their needs. An outbreak of sine nombre virus in the United States in 1993 was linked to drought that likewise brought rodents into closer contact with humans, permitting transfer of this animal virus to humans.
Finally, humans themselves penetrate or modify formerly unpopulated regions, and come closer to animal reservoirs or vectors of infectious disease. Outbreaks of malaria, yellow fever, and leishmaniasis continue to be linked to the men who work in the rainforest cutting trees, and recent importation of yellow fever into Switzerland, the United States, and Germany have resulted from tourist excursions deep into the rainforests where yellow fever is enzootic.
Lapses in food production, handling, and processing also result in transmission of infectious agents from animals to humans. Outbreaks of food-borne infections such as salmonellosis and E. coli 0157 are regularly linked to faulty food processing practices, as has been new variant Creutzfeldt–Jakob disease associated with bovine spongiform encephalopathy in the United Kingdom. As lifestyles change, more people eat meals prepared outside the home, and insufficient training in food handling constitutes another major factor responsible for the rise in food-borne disease incidence.
Poverty, neglect, and the weakening of health infrastructure
More than one in four of the world’s population are estimated to be living in poverty—over a billion of them with incomes of less than US$1 a day. Industrialized countries are not free of poverty, and 100 million people in industrialized countries live below the poverty line. These poor populations are a major reservoir of infectious diseases, and a source of continued transmission. In many developing countries poverty leads to malnutrition, a key factor that affects health, and malnutrition in turn increases the severity of infectious diseases such as pneumonia, malaria, measles, and diarrhoeal diseases—the major killers of young children. In 1997 it was estimated that over 160 million children were moderately or severely malnourished, and it is therefore not surprising that malnutrition is an associated factor in over half of all childhood deaths.
A child born in a developing country today has a 1000-fold greater chance of not being vaccinated and dying from measles than a child born in an industrialized country. This is clearly reflected by the fact that children born in Singapore during 1999 were likely to live 40 years longer than children born in Sierra Leone.
Effective public health policies save resources and can be effectively implemented even where poverty predominates. Over the years, cost-effective strategies have been developed for the prevention and control of the major infectious diseases. When implemented effectively, these strategies can decrease death and suffering caused by infectious diseases. Yet many governments fail to ensure that these strategies receive enough funding to succeed. In some cases, this is because health budgets are unrealistically small, and because the advocacy skills needed to increase them are lacking. In other cases, it is because health spending is poorly prioritized, often misplaced in curative rather than preventive infrastructure, and therefore not addressing the most urgent health threats. Finally, it is because some of the technologies available are out of the reach of governments and the majority of those willing to purchase health care with their own resources.
The strategy of integrated management of childhood illnesses, developed over the past 20 years, is a cost-effective means of preventing childhood mortality associated with acute diarrhoeal and respiratory infections and malaria, yet it has only been adopted by 57 of the 120 countries for which it is deemed appropriate. In none of those countries where it has been adopted is it being implemented nationwide. Expansion of integrated management of childhood illnesses and other cost-effective strategies in countries that have adopted them is slowed by weak public health infrastructure resulting in unequal distribution of supplies or difficulties in retaining qualified health workers.
Malaria is a particular risk for women during pregnancy. Pregnant women are more likely to die from malaria—either during pregnancy or the immediate postpartum period. Chronic anaemia resulting from repeated malaria infections is associated with low-birth-weight infants. To prevent this and other sequelae, it is recommended that pregnant women in high-risk malaria areas be treated presumptively for malaria at intervals to decrease parasite loads. Yet fewer than one in five are treated. Lack of funds are often cited as the reason, and failure to develop adequate health delivery systems is the result.
HIV prevention efforts targeted at youth, especially sex education in schools or other settings, has been demonstrated to be effective in preventing HIV infection. But in 171 countries worldwide, sex education of youth is not routinely provided, often because of unfounded fears that it will cause increased sexual activity among them. In countries where it is taught, girls are often not reached because they are excluded from secondary education.
On average, health expenditure in 1994 in low-income countries was US$16 per capita. Some of the poorest countries in the world provide no more than US$7 per capita for health care annually—making it difficult to ensure that even the most basic health needs are met. By comparison, average health expenditure in high-income countries during the same year was more than US$1800 per capita. Low-income countries spend 4 per cent of gross domestic product per capita on health, half the amount spent by wealthier countries. In many poor countries, spending is even lower. In Cameroon, Indonesia, Nigeria, and Sri Lanka, for example, it is less than 2 per cent of gross domestic product.
Some of the poorest countries fail to commit the resources necessary to purchase even the inexpensive vaccines available through the WHO and the United Nation International Children’s Emergency Fund (UNICEF). Hepatitis B vaccine, for example, has now been introduced to childhood vaccination programmes in over 100 countries, but countries in areas where hepatitis B prevalence is highest—sub-Saharan Africa, Southeast Asia, and Eastern and Central Europe—have not yet included hepatitis B vaccine in childhood immunization programmes, even at the preferential price of US$0.50 to 1 per dose. Widespread use of hepatitis B vaccine could, in future generations, markedly decrease the prevalence of people chronically infected with hepatitis B, currently estimated at 350 million worldwide. The result would be decreased prevalence of hepatitis B, and decreased cirrhosis and hepatic carcinoma, two sequelae of chronic hepatitis B infection. At the end of the twentieth century two-thirds of the world’s population still live in areas with high prevalence of hepatitis B, a fully vaccine-preventable infection.
Similarly, yellow fever vaccine has been available since 1937 but is currently not used in some of the countries most at risk. These countries, mainly in sub-Saharan Africa, are also among the world’s poorest, and are those that have seen the steady increase in yellow fever reported since the late 1980s.
Weakening public health infrastructure for infectious disease surveillance and control, the result of under-resourced health ministries, is evidenced by such failures as mosquito control in Latin America and Asia with the re-emergence of dengue, failure of vaccination programmes in eastern Europe which contributed to the re-emergence of epidemic diphtheria and polio, and neglect of yellow fever vaccination which has facilitated the yellow fever outbreaks in Latin America and sub-Saharan Africa. It is also clearly demonstrated by high levels of hepatitis B and nosocomial transmission of other pathogens such as HIV in the former USSR and Romania, and by repeated nosocomial amplification of outbreaks of Ebola in the Democratic Republic of the Congo where needles, syringes, and failed barrier nursing methods drove transmission of Ebola and amplified outbreaks in 1976 and 1995 into major epidemics.
Increased funding for health care, however, does not necessarily decrease the prevalence of infectious diseases. In some developing countries, 60 per cent or more of government health expenditure is devoted to meeting the operating costs of urban hospitals and high-technology equipment that facilitates, but is not required for, patient management. For the cost of a few expensive procedures in such institutions, lives could be spared by preventive or curative interventions for infectious diseases among populations without access to the most basic health care. An outbreak of acute respiratory infection in a mountain area of Afghanistan in 1999, for example, continued for several months before it was reported, but was immediately controlled when adequate medical services were made available. Almost 800 million people worldwide lack access to basic health services.
The interrelationships between poverty, health, and development are so intertwined that it is impossible to address one without the others. Improvements in community health depend on sustainable development. At the same time, health is a minimum requirement for development. Infectious diseases remain a major obstacle to economic development in many countries because of the mortality and disability they cause. Premature deaths among the educated workforce, such as those that are occurring as a result of the AIDS epidemic, can take a generation to compensate. People with such disabilities as elephantiasis resulting from lymphatic filariasis, or trachoma- or onchocerciasis-associated blindness, cost the economy double in terms of both their lack of contribution to the workforce and their demands on the workforce for financial support. Intestinal parasites in women and children continue to cause severe debilitating anaemia in women, resulting in unsafe deliveries and postpartum illness, and decreased verbal fluency and cognitive skills in children.
In addition to the indirect costs associated with premature death and disability, or because of temporary absence from work, the cost of treatment for single or repeated bouts of an infectious disease such as malaria, for example, can be significant. In Nigeria, it has been estimated that subsistence farmers spend as much as 13 per cent of total household expenditure on malaria treatment each year. This economic output for malaria, heavy in itself, is compounded by absence from farming activities, which are most intense during the rainy season when malaria transmission is at its height, or the absence from work of another family member to take care of a child or adult sick with malaria.
The social and psychological impact of disabilities from infectious diseases often lead to marginalization, the destruction of marriages, family, and social relationships, and further obstructing economic development. Disabilities such as elephantiasis and blindness are involved, but in recent history no more important example of marginalization because of an infectious disease has occurred than AIDS. But AIDS has also been associated with other important obstacles to development. AIDS prevention strategies are much more difficult to implement where basic literacy skills are absent. At the same time, efforts to increase literacy have become a difficult struggle in many countries where schoolteachers have been among those at increased risk of HIV infection. In the United Republic of Tanzania, for example, the investments in education required to yield expected standards have been increased substantially because of high AIDS mortality among teachers. Additionally, 20 per cent fewer children attend school because parents are ill or dying with AIDS and therefore unable to pay school fees.
Uncontrolled urbanization and population displacement
The growth of densely populated cities with substandard housing, unsafe water, and poor sanitation place a great burden on public health services. Whereas in 1950 there were only two urban centres in the world with populations greater than 7 million, by 1990 this number had risen to 23, with increasing populations in and around all major cities challenging the capacity of existing sanitary systems and public housing. In Africa, Asia, and Latin America, at least 600 million urban dwellers live in substandard homes or neighbourhoods. People living in these neighbourhoods are at greater risk of infectious disease.
The link between environmental quality and health is critical. Over 10 per cent of all preventable ill health is estimated to be due to poor environmental quality—conditions such as substandard housing, overcrowding, indoor air pollution, poor sanitation, and unsafe water. The breakdown of sanitation systems in large coastal cities in Africa, Asia, and Latin America has facilitated the transmission of cholera, shigellosis, and intestinal parasites, and it is estimated that over a billion people worldwide lack access to safe drinking water—further increasing their vulnerability to diarrhoeal and intestinal parasitic diseases.
Traditional housing and substandard living conditions are likewise important factors leading to acute respiratory infections in children. Approximately 700 million people—mainly women and children in poor rural areas—inhale harmful smoke from burning wood and other fuels each day, and it is among this population that the risk of acute respiratory infections, especially pneumonia, is greatest.
Civil strife and political conflict are also major impediments to public health. In addition to destroying health infrastructures, they result in large numbers of homeless people living in refugee camps or less structured settings. If basic preventive services such as vaccination do not reach these populations, diseases which could easily be controlled become outbreaks. Negotiations with warring parties are sometimes necessary to ensure that national immunization days for polio eradication can be carried out.
The number of refugees and displaced people has increased ninefold over the past two decades. In 1996, it was estimated that as many as 50 million people worldwide had been uprooted from their homes. These refugees and displaced people are especially vulnerable to disease, forced to live in overcrowded insanitary conditions where the risk of outbreaks of water-borne diseases such as cholera and shigellosis are amplified. The movement of people as refugees and displaced people has also been shown to facilitate the spread of infectious diseases to new geographical areas, placing populations living in these regions at risk. In sub-Saharan Africa, for example, HIV is spread by migrant workers who congregate in urban areas where prevention is not promoted, and who then carry infection to their villages when they return home to families, and by lorry drivers who buy sex at or near truck stops on their way across the continent.
Human behaviour
A clear example of the impact of human behaviour in the emergence and re-emergence of infectious diseases is the increase in gonorrhoea and syphilis during the late 1970s, and the emergence and amplification of HIV worldwide—all directly linked to unsafe sexual practices. Other examples of the important relationship of human behaviour to infectious diseases are described throughout this chapter. They are related to lifestyle and include changes in agricultural and food production patterns which permit food-borne infectious agents to enter human populations, increased international travel for business or leisure which exposes humans to infectious diseases to which they ordinarily would not have exposure, and the outdoor activity and residential locations closer to forest and water that increase the risk of human exposure to animals or insect vectors.
Anti-infective drug resistance
Shortly after penicillin became widely available in 1942, Fleming warned of the potential importance of resistance and by 1946 a hospital in the United Kingdom had reported that 14 per cent of all Staphylococcus aureus infections were resistant to penicillin. By 1950 resistance in hospitals had increased to 59 per cent, and by 1990 penicillin-resistant S. aureus had attained a prevalence of greater than 80 per cent in hospitals and the community. At the same time resistance of S. aureus to other antimicrobials occurred with great rapidity, and by 1999 deaths were attributed to multiresistant staphylococcal infection in four children living in the United States. By 1999 it had become clear that bacteria, viruses, and parasites are all capable of rapidly developing or acquiring resistance to anti-infective agents, causing a decrease in the cost-effectiveness of treating most major infectious diseases.
In the early 1970s N. gonorrhoeae resistant to the usual doses of penicillin was introduced into Europe and the United States from Southeast Asia where it is thought to have first emerged. By 1999, N. gonorrhoeae resistance to penicillin had become global, and strains resistant to all major classes of antibiotics had been identified wherever these antibiotics had been widely used, with some countries in the Western Pacific region having registered quinolone resistance levels up to 69 per cent.
During the 1970s chloroquine-resistant P. falciparum malaria became highly prevalent in Southeast Asia, and by 1999 it had spread worldwide, as had high-level resistance to two second-line drugs, sulfadoxine-pyrimethamine and mefloquine.
The dramatic upsurge in the spread of drug-resistant microbes over the past decade is undermining today’s efforts to control infectious diseases. As diseases once thought to be under control become increasingly resistant to the arsenal of available drugs, the spectre of incurable infectious diseases looms large. In addition to requiring increased length of treatment, with more expensive, and in some instances more toxic, anti-infective drugs or drug combinations, a doubling of mortality has been observed in some resistant infections. At the same time fewer new anti-infective drugs reach the market, in part due to the high cost of new drug development, and the risk of developing a new anti-infective drug which may itself become ineffective before investment in its development is recovered. In fact, as the twentieth century came to a close, no new class of antibiotic had been marketed for human use since the 1960s (Fig. 7).

Fig. 7 Antimicrobial resistance, 1997.

Although antimicrobial resistance affects industrialized and developing countries alike, its impact is far greater in developing countries. The switch from normally less expensive first-line drugs to second- or third-line drugs involves a dramatic escalation in the price of treatment. In some of the poorest countries, the cost of lengthy treatment and replacement drugs means that some diseases are too expensive to treat. Gonorrhoea, once easily treated in sub-Saharan Africa by penicillin or tetracycline, now requires more expensive drugs to which government health budgets do not commit. The resultant chronic gonorrhoeal infections lead to increased levels of infertility among young women, and chronic gonorrhoeal infections amplify the HIV epidemic by continuing to facilitate HIV transmission and infection throughout Africa.
In low-income countries, the cost of curing multidrug-resistant tuberculosis is as high as US$1500 to 4000, out of reach of health budgets. In Southeast Asia the cost of treating a child for meningococcal meningitis has been shown to increase from US$20 to 110 when second-line anti-infective drugs are required, while the cost of treating lower respiratory infections—the most frequent cause of childhood death—increases from US$5 to 40 for a course of antibiotics.
Major diseases affected
The effectiveness of anti-infective drugs against five of the six major infectious disease killers—tuberculosis, malaria, pneumonia, bacterial diarrhoeas, cholera, and HIV—is severely compromised by resistance, as is their effectiveness in most other common infections.
Tuberculosis
A 1997 report on antituberculosis drug resistance identified ‘hot zones’ of resistance around the world where over 5 per cent of tuberculosis infections are resistant to the most commonly prescribed drugs. In some countries in Eastern Europe more than 20 per cent of tuberculosis patients were found infected with multidrug-resistant organisms, and among prisoners in the Russia Federation up to 40 per cent of tuberculosis infections were found to be multiresistant.
Malaria
Chloroquine—once the first-line treatment for malaria—is no longer effective in curing malaria infections in over 80 of the 92 countries where malaria is a major public health problem. At the same time, mosquitos worldwide show resistance to the most commonly used insecticides including pyrethroids and dichlorodiphenyltrichloroethane (DDT).
Pneumonia
In some countries, up to half of all pneumococcal infections are resistant to penicillin. With increased treatment failures in children with pneumococcal pneumonia, mortality from this once easily treated infection is increasing.
Bacterial diarrhoeas
In some countries, up to 90 per cent of Shigella infections are resistant to ampicillin and trimethoprim. In central and southern Africa epidemics of bacillary dysentery over the past decade—including those in refugee camps—have shown resistance to quinolones, and in some outbreaks the case-fatality rate has been as high as 15 per cent. Since 1989, 11 countries have identified epidemics of multidrug-resistant salmonellosis, and where effective second-line drugs are not available the case-fatality rate rises to approximately 10 per cent.
Bacterial meningitis
Over 50 per cent of all cases of meningococcal meningitis are resistant to penicillin. Even under optimal treatment, 10 to 30 per cent of patients have permanent neurological sequelae depending on age, and this rate continues to increase with increasing levels of resistance and treatment failure.
Hospital-acquired infection
Up to 60 per cent of hospital infections are caused by drug-resistant microbes worldwide, and in the United States alone it is estimated that approximately 14 000 hospital patients die each year from nosocomially transmitted drug-resistant bacteria.
Causes of resistance
Numerous factors lead to anti-infective resistance by favouring selection of resistant strains of micro-organisms, while at the same time resistant genes can be transferred genetically from one bacterium to another through the spread of resistant plasmids.
Wrong prescribing practices
Widespread misuse of anti-infective drugs in human medicine is a major factor in selection of resistant micro-organisms. Misuse occurs in developing and industrialized countries alike. Overprescribing adds unnecessary anti-infective drugs to the environment, while prescribing anti-infective drugs in doses lower than required helps select out those organisms with resistance that are then passed on to others. In Canada and the United States, studies indicate that approximately half of all outpatient prescriptions for antibiotics are unnecessary, and in a recent study of patients in hospital in Thailand, 36 per cent of patients who received an anti-infective drug had no laboratory-confirmed infection. In a similar study in Vietnam, over 70 per cent of patients with a laboratory-confirmed infection were given antibiotics in doses lower than recommended by national infection treatment guidelines. The lack of simple diagnostic tests suitable for use at peripheral health facilities in most developing countries necessitates treatment of syndromes presumptively rather than based on diagnosis, further increasing anti-infective drug use.
Non-adherence by patients
Where anti-infective drugs are correctly prescribed, patient non-adherence to the correct dosage and/or number of days of treatment often occurs, especially once the symptoms disappear. In addition, antibiotics can be bought without a prescription in many developing countries resulting in self-medication that is often at incorrect dose and duration.
Counterfeit drugs
Counterfeit anti-infective drugs are commonplace in many developing countries; some are bogus and contain no active ingredient, while others contain non-standardized amounts of the active ingredient either due to intentional cost saving or lack of quality control during manufacture. As well as resulting in treatment failure and at times in death, counterfeit anti-infective drugs with reduced and non-standardized amounts of active ingredients contribute to the problem of drug resistance by selecting out resistant strains.
Use of anti-infective drugs in animals and plants
Anti-infective drugs are not only used in humans. They are used in animals for treatment as growth enhancers, non-specifically added to animal feed. They are also used in horticulture in temperate countries, sprayed on fruit trees to prevent blight, and in tropical countries to prevent blight on crops such as rice and orchids. Current estimates are that approximately 50 per cent of all anti-infective drugs are used in animal husbandry including fisheries. Although the full effect of anti-infective drug use in animals on human health is not yet fully known, there is growing evidence that anti-infective drug resistance developing in animals contributes to the problem of resistance in humans. Better understanding is required of the implications of antibiotic pressure and selection of resistant strains in animals, and of the genetic interaction between zoonotic and human pathogens. There is, however, scientific evidence that four multiresistant bacteria infecting humans (Salmonella, Campylobacter, enterococci and E. coli) are directly linked to resistant organisms in animals, and there is growing consensus worldwide that anti-infective drugs used in humans should not be used as growth-enhancement additives to animal feed.
Globalization of travel and trade
In the Middle Ages infectious agents were often the cause of high mortality rates among sailors and their passengers travelling in insanitary and crowded conditions. They were carried by animal vectors such as rats which transported plague from one continent to another on board ships. Today infectious agents travel worldwide by plane—carried by airline passengers in a matter of hours. A passenger can be infected on one continent and travel to another while still asymptomatic to the infectious agent, and then become sick and expose passengers and populations at the destination. As the number of international airline passengers has soared from 2 million a year in 1950 to over 1.4 billion today, the world has been slow to recognize the implications for public health (Fig. 8).

Fig. 8 Most popular air routes between continents (1997) and percentage increase in international arrivals between 1993 and 1997.

In 1988, a clone of multiresistant Streptococcus pneumoniae first isolated in Spain was shortly thereafter identified in Iceland. Another clone of multiresistant S. pneumoniae, also first identified in Spain, was subsequently found in seven different countries on three continents. A study conducted by the Ministry of Health of Thailand of 411 exiting tourists in 1996 showed that 11 per cent had an acute infectious disease, mostly diarrhoeal but also respiratory infections, malaria, hepatitis, and gonorrhoea. Failure to suspect and diagnose an infection such as malaria in a person with fever after returning home is not an uncommon death-provoking event among travellers.
Airborne infections such as pneumonic plague, influenza, and tuberculosis are easily spread in crowded airport lounges, on airplanes or by passengers after arrival at their destination. In the United States in 1977, over 70 per cent of the passengers on board an airliner were infected with influenza by a fellow passenger; in 1978 poliovirus was imported to Canada by Western Europeans who had refused polio vaccination, resulting in an outbreak of paralytic disease with 11 cases. In the early 1990s, a flight attendant with active tuberculosis is thought to have infected up to 23 fellow crew members over the course of several flights, while in 1996, a health worker in South Africa was infected with Ebola by a patient who had entered the country to seek medical care during an outbreak in Gabon.
Malaria infections and deaths regularly occur in Europe and North America following unrecognized infection in blood transfusions and more commonly after a one-off bite from an imported mosquito near international airports. Brussels, Geneva, London, and Oslo have all reported recent cases of such airport malaria, as have the United States and Canada. In 1985, the tiger mosquito—normally found in Asia—slipped unnoticed into the United States inside a shipment of water-logged used tyres from Asia. Within 2 years tiger mosquitos—capable of transmitting yellow fever, dengue, and other diseases—were found in 17 states. In 1991, a ship thought to have carried contaminated water from Asia in its ballast tanks caused the cholera epidemic in Peru that spread rapidly throughout South and Central America resulting in reports of over 11 000 deaths.
Outbreaks and epidemics of infectious diseases have far-reaching economic and political consequences, at times out of reasonable proportion with their true threat to human health.
The response to infectious disease outbreaks requires an immediate investigation and containment activities, at times placing great financial demands on countries at the expense of routine endemic disease prevention and control measures. In recent epidemics of meningococcal meningitis in sub-Saharan Africa vaccine, antibiotic, and logistic support required massive inputs of funding from national governments and international donors. The countries most affected by the epidemic were those who had the greatest difficulty in responding appropriately, and routine health services and other important activities were disrupted as the health system attempted to cope.
Global media coverage of infectious disease outbreaks in remote and distant locations can trigger unjustified fear among populations for whom the threat is negligible. The collective imagination is fuelled by media stories such as those that have recently speculated on the origins of the Ebola virus, or on how West Nile like virus entered North America, and by fear of intentional use of infectious agents in terrorism or war. The resulting economic losses resulting from such reactions are significant indirect costs of infectious diseases, in addition to the direct costs to economies in lost earnings as a result of the disability and death they cause among those of working age.
The consequence of an outbreak with widespread and sensational reporting on trade and tourism is often immediate. In Peru in 1991, reports of a cholera epidemic resulted in a loss of US$770 million, almost one-fifth of normal export earnings in the trade and tourism sectors as countries banned seafood imports and tourism decreased.
Seven years later, when cholera outbreaks were reported from the Horn of Africa, embargoes were again placed on fishery products originating from these countries, with consequential loss of economic revenues estimated as high as US$36 million in one of the countries involved. Yet another infectious disease outbreak, an epidemic of plague in India, resulted in severe economic losses estimated unofficially at US$1.7 billion. Hotel bookings in India fell by 20 to 60 per cent immediately after media reports were published, and one airline reported losses of over US$1 million during the first week after reports. In countries throughout the world airports were closed to aeroplanes arriving from India, imports of foodstuffs were blocked, and in some countries Indian guest workers were forced to return to India even though they had not been there for several years before the plague epidemic occurred (Fig. 9).

Fig. 9 Economic burden of infectious diseases, 1990s.

Globalization of the food supply regularly results in exposure of humans, through foods purchased locally, to pathogens native to remote parts of the world. The risk of V. cholerae transmission associated with trade in certain food products is considered very small; to date there has been no documented outbreak of cholera resulting from commercially imported food from countries where cholera is endemic. But other infectious agents have clear potential to spread internationally in foodstuffs, creating major negative impact on economies. Recent examples include the epidemics of influenza in Hong Kong, nipah virus in Malaysia, and bovine spongiform encephalopathy in the United Kingdom, which resulted in the mass destruction of poultry, pigs, and cattle respectively. Concern occurs over the safety of a range of goods that are prepared from animals or animal products, ranging from cosmetics to biological agents.
Unjustified embargos, protectionism, and other political issues related to infectious diseases can lead to a severe strain on diplomatic relations between countries. A recent example occurred in 1999 when France refused to allow the importation of beef from the United Kingdom on the grounds that available scientific evidence was not sufficient to guarantee consumer safety from the threat of bovine spongiform encephalopathy. The perception of the potential use of the smallpox virus as a bioweapon has recently prevented the destruction of the remaining stocks of variola virus and continues to cause serious tensions between countries that wish destruction and those who do not. The unexplained appearance of a West Nile like virus in New York led to speculation in the media that it might have been released deliberately, again raising uncertainty and fear for national security and providing fertile ground for tensions between countries.
Infectious diseases occur in every country. Old scourges such as tuberculosis and diphtheria have occurred in explosive epidemics in industrialized countries of Eastern Europe during the 1990s. A 1996 outbreak of polio in Albania, Greece, and the Federal Republic of Yugoslavia showed how easily an infectious disease can be reintroduced to countries once free of the disease if immunization coverage is allowed to drop.
It is in the best interest of all countries to support global initiatives to control infectious diseases. Any segment of society that ignores the spread of infections among its neighbours does so at its own peril.
Solutions to infectious disease problems
At the beginning of the twenty-first century it is clear that new infectious agents will continue to emerge. Known infectious agents will continue to be transmitted—in some instances to re-emerge at greater incidence than previously while in others to decrease to lower incidence. Moreover, the effectiveness of existing anti-infective drugs will continue to decrease. At the same time new anti-infective drugs under development offer hope, new vaccines are adding to those that have successfully controlled many childhood infections, and the potential of the genomic research agenda is becoming a reality as information about the genome begins to be applied to further drug and vaccine development.
However, most of the 13 million deaths and untold disabilities estimated to have occurred from infectious diseases in 1998 could have been prevented using the tools we have available today. Vaccines offer solid immunity to infectious agents, and anti-infective drugs can still be effectively applied to most infections. The use of these existing tools has been largely responsible for the advances in the control of infectious diseases made to date (Table 1). But the window of opportunity for their cost-effective use is closing, and they must be applied now to reduce infectious diseases and ensure healthy economic development.

Table 1 Affordable health services for developing countries, 1990s

Based on decades of operational study of existing technologies, it is generally agreed that infectious-disease-related mortality and disability could be greatly decreased if political support were strengthened to exploit fully the following proven strategies for infectious disease control:

(1)
eradication, elimination, and intensified control through global public–private sector partnerships;
(2)
promotion of a core set of interventions that use proven cost-effective strategies and are selected based on national infectious disease priorities;
(3)
working across government sectors to ensure sustainability and synergy in public health activities;
(4)
expansion of surveillance and response systems to alert the world and respond to unexpected outbreaks and emergences of new infectious diseases;
(5)
strengthening international agreements and regulations to ensure maximum international public health security with minimal interference in travel and trade;
(6)
investment in research and development of diagnostic tools, drugs and vaccines to improve prevention and control.

Eradication, elimination, and intensified control
Eradication is the interruption of transmission of an infectious agent and its disappearance from nature. Only one infectious disease—smallpox—has been eradicated. Efforts to eradicate smallpox began in 1966 when ministers of health from around the world resolved in the World Health Assembly to utilize maximally vaccination with the vaccinia vaccine to eradicate smallpox within the coming 10 years. The initial strategy of smallpox eradication was mass vaccination of the entire population. This gradually shifted to a search and containment strategy, with active surveillance to search for and identify cases of smallpox that were then isolated in their homes, which became the central focus for mass vaccination of populations living in households in the near vicinity. In 1966 at the start of the eradication programme, smallpox was endemic in 30 countries, the other countries having eliminated smallpox by routine vaccination. During 1966 alone, smallpox virus was estimated to cause disease in 10 to 15 million worldwide, among whom 1.5 to 2 million were thought to have died, while survivors were left with severe facial scarring, and in some instances corneal scarring with blindness.
However, the eradication of smallpox has raised serious political and scientific issues. In spite of a recommendation made by the World Health Assembly in 1990 that remaining stocks of variola virus be destroyed, the debate continues and the decision as to when destruction will actually occur is still pending consensus within the scientific and political communities.
To eradicate an infectious disease a combination of factors is required. There must be no known animal reservoir, and disease must result in solid life-long immunity with no long-term carrier state. At the same time there can be no subclinical manifestation of infection that could result in continued transmission, and case detection must be relatively simple. Above all a highly effective, stable, and easily administered vaccine or curative drug must be available, which, in the case of the vaccine, must confer long-term protection. Smallpox eradication was certified by the WHO in 1980, and in addition to the morbidity and mortality that have been prevented, savings have been substantial because smallpox vaccination is no longer required. A study in the United States during the immediate posteradication period demonstrated that because the United States no longer needed to vaccinate its population against smallpox, and support those who suffered the rare but severe neurological side-effects associated with the vaccine, an amount equal to its investment in the global smallpox eradication programmes was being saved every 29 days.
At the end of the twentieth century, two more diseases—poliomyelitis and guinea-worm disease—are on the verge of eradication (Fig. 10). In 1988, the World Health Assembly resolved to eradicate polio globally by the year 2000 by calling for maximum use of the trivalent oral polio vaccine which was developed during the 1950s. Substantial progress in implementing the recommended polio eradication strategies was reported from all endemic countries in the subsequent decade, achieving and maintaining high routine coverage with oral poliovirus vaccine, conducting national immunization days to decrease poliovirus circulation rapidly, establishing sensitive surveillance systems for the detection of polio cases and identifying the poliovirus, and carrying out mopping-up vaccination activities to eliminate the last remaining reservoirs of poliovirus transmission.

Fig. 10 Diseases close to eradication/elimination, 1999.

While progress has been dramatic in many countries, significant obstacles remain in the early twenty-first century, particularly in 14 priority countries that represented global poliovirus reservoirs because of insufficient national commitment or political conflict (Fig. 11). At the same time, three geographical regions had eliminated poliovirus or were close to doing so: the Americas had interrupted polio transmission during 1991 and has been polio-free since then, the Western Pacific region has not detected poliovirus since 1997, and poliovirus transmission in Europe was confined to southeastern Turkey.

Fig. 11 Global polio situation, April 1999.

Reaching the global polio eradication goal required the planned acceleration of eradication activities during the year 2000 in the remaining major foci of poliovirus transmission in the densely populated global reservoir countries of southern Asia and Africa—Bangladesh, Democratic Republic of the Congo, Ethiopia, India, Nigeria, and Pakistan.
The World Health Assembly resolved to eradicate dracontiasis (guinea-worm disease) in 1991. Between 1989 and 1998, the number of cases were reduced from almost 900 000 to just under 80 000. Strategies for eradication include filtering of drinking water and education about the infection and its means of transmission, and by 1999 only 15 countries reported cases. By the end of 1999 it appeared that guinea-worm transmission had been interrupted in Asia, and the remaining endemic areas in Africa remained a formidable challenge either because of decreasing government commitment or unstable political situations making operations difficult.
Although there were just two eradication programmes being implemented at the end of 1999, several more infectious diseases were gradually being brought under control worldwide by elimination programmes, or by programmes of intensified control. Elimination is defined as the reduction in incidence or prevalence of an infectious disease to a level which is more manageable within the existing health systems (Fig. 10). Unlike diseases targeted for eradication, once a disease elimination target is reached continued control measures are required. For some of the diseases targeted for elimination the question remains as to whether, once these diseases are brought to low levels, interruption of transmission will occur spontaneously as occurred for several infectious diseases in industrialized countries. Intensified control is similar to elimination, with a resolution of health ministers for increased commitment, but with no elimination target.
The neonatal tetanus elimination strategy was adopted by the World Health Assembly in 1989, with a target for 1993 of less than 1 case per 1000 live births. The estimated global number of neonatal tetanus cases decreased from 510 000 in 1990 to 355 000 in 1997, with a corresponding decrease in mortality, using vaccination of pregnant women with tetanus toxoid and provision of safe delivery services to all pregnant women as the primary strategies. The goal at the end of 1999 was to achieve this targeted incidence in each health district of all countries by 2000.
In 1991, the World Health Assembly resolved to eliminate leprosy as a public health problem by 2000, elimination being defined as prevalence less than 1 case per 10 000 population. By the end of 1999, of the 122 countries which were highly endemic for leprosy in 1985 prior to the WHO resolution, 98 had reached the elimination target at the national level and were working to achieve this target in all health districts by the end of 2000. Leprosy prevalence worldwide has thus been reduced by 85 per cent using an active search strategy to identify people with leprosy who are then provided free treatment with multidrug therapy.
At the end of 1999 the majority of the global leprosy burden was concentrated in 24 countries where the leprosy elimination target had not been reached, within limited and difficult to access geographical areas in these countries as well as in some of those countries that had reached the global target.
In 1997 the World Health Assembly adopted a resolution calling for the global elimination of lymphatic filariasis as a public health problem. The elimination target resolved is 2015, and the elimination strategy uses simple safe inexpensive periodic delivery of albendazole and ivermectin or diethycarbamazole to kill the parasite in populations at risk of infection. By the end of 1999, 10 countries had begun elimination programmes with momentum expected to increase in the early twenty-first century.
In 1991, six countries in Latin America have made a political commitment to interrupt transmission of Chagas’ disease. The strategy for elimination is screening of blood donations and vector control. Transmission was interrupted in Uruguay in 1997 and in Chile in 1999.
In 1989 the World Health Assembly resolved an intensification of prevention activities to reduce measles morbidity and mortality by 90 and 95 per cent, respectively, by 1995 using measles vaccine. During 1997 it was estimated that approximately 31 million measles cases and 1 million associated deaths had occurred worldwide, and by the end of 1997 measles morbidity and mortality worldwide had been reduced by 74 and 85 per cent, respectively, when compared with prevaccine rates (Fig. 12). By 1998 measles mortality was estimated to have decreased from 1 million in 1997 to 800 000, and by the end of 1999 all countries in the Americas and in the western Pacific had reached the morbidity and mortality reduction goals, and Europe had reached the mortality reduction goal. At the end of 1999, 99 per cent of the remaining measles mortality continued to occur in the least developed countries.

Fig. 12 Measles cases and vaccination coverage worldwide, 1986 to 1997.

The onchocerciasis control programme, which began in 11 countries in West Africa in 1974, has protected an estimated 36 million people from infection and sequelae such as severe pruritis and blindness. The programme, which uses strategies for control of the insect vector and mass distribution of the antiparasitic drug ivermectin to populations at risk of infection, was extended in 1996 to an additional 19 African countries where the disease is endemic. In 1991, an onchocerciasis control programme for the Americas was launched in six Latin American countries, with the aim of decreasing severe pathological manifestations and reducing morbidity through the distribution of ivermectin. It is expected that the onchocerciasis control programmes will have maximum public health impact early in the twenty-first century.
In 1998 the World Health Assembly resolved to give high priority to intensifying tuberculosis control, and in 1999 it resolved to intensify malaria control. From these two resolutions, two worldwide partnerships in public health have developed: the Stop Tuberculosis Initiative and Roll Back Malaria. These two global partnerships promote proven prevention and control strategies at the country level, and have the following global functions:

(1)
removing obstacles to expansion of prevention and control strategies;
(2)
composite work planning with partners;
(3)
global level advocacy and social mobilization;
(4)
resource mobilization.

The partnerships for eradication, elimination, and intensified control programmes provide both technical and financial resources to countries. Their strength lies in forging alliances with donor governments, ministries of health in developing countries, international development banks, foundations, the private sector, civil society, United Nations agencies, and non-governmental organizations. Rotary International, a private sector service organization, has raised US$500 million to purchase vaccine for the polio eradication programme and to help to equip a refrigerated cold chain for vaccine transport, and has used its global network of over 28 000 clubs in 155 countries to enlist volunteers to carry out immunization campaigns. Merck provides ivermectin for onchocerciasis elimination, Glaxo SmithKline provides albendazole for the elimination of leprosy, Novartis provides multidrug treatment for leprosy, and Pfizer provides azithramycin for the treatment of trachoma. Loans from the World Bank are strategically aimed at eradication, elimination, and intensified control, while the recent launch of the New Medicines for Malaria Venture—a joint initiative by the public and private sectors to develop new antimalarial drugs—is a visionary example of efforts to harness greater public and private sector collaboration in developing new products for use in developing countries. In this venture, industry provides its technical expertise for research and development while risk-taking is provided through public sector funding, with a goal of developing one new drug for malaria treatment every 5 years.
Effective use of a core set of interventions
Operational study of existing health technologies during the past several decades has identified cost-effective interventions for the prevention and control of infectious diseases. Government commitment to their use, even in areas of extreme poverty, will prevent infectious disease mortality and disability. A core set of these cost-effective interventions, from which a selection must be made to respond to evidence-based national or subnational disease priorities, includes interventions such as those that follow.
Insecticide-impregnated bednets
One in four childhood deaths from malaria could be prevented if children at risk slept under bednets at night to avoid mosquito bites. Bednets dipped in an insecticide cost about US$10 each, and a supply of insecticide to re-treat the net costs between 50 cents and $1 per year. ‘Dip-it-yourself’ kits are now available for re-treating the nets at home, and the pyrethroid insecticides used have been shown to be safe. Social marketing and community participation in bednet programmes serve to create demand for this affordable intervention and ensure its sustainability.
Directly observed treatment, short course
Expansion of directly observed treatment, short course (DOTS) to greater number of people could avert millions of tuberculosis deaths. This highly effective health-care strategy involves detection of tuberculosis cases through low-cost sputum smear tests, followed by 6 to 8 months of treatment with a combination of inexpensive drugs. A key component is regular ongoing support to the patient that includes observation to ensure that treatment is correctly followed and follow-up sputum tests to determine whether treatment has been successful. DOTS can detect and cure disease in up to 95 per cent of infectious patients, even in the poorest countries.
DOTS not only drastically reduces deaths by increasing the cure rate of tuberculosis treatment, it also cuts the transmission of infection and prevents the development of multidrug-resistant forms of the disease. DOTS has been evaluated by the World Bank to be one of the most cost-effective of all health interventions, as an investment of only about US$3 is required per year of healthy life saved, making it one of the best buys available to health and finance ministries. Since the introduction of the DOTS strategy in the early 1990s, the world has witnessed remarkable progress in global tuberculosis control.
Childhood immunization
Higher vaccine coverage rates could prevent 1.6 million deaths a year among children under the age of 5. At very low cost, vaccines are affordable by governments, or are provided at no cost in quantities sufficient to meet needs. Most materials needed for cold conservation of vaccine, and single-use autodestruct syringes and needles, are being made available, yet today one in five children are still not fully immunized against diphtheria, whooping cough, tetanus, polio, and measles. Integrated management of childhood illnesses is a low-cost strategy that has been shown to reduce the 70 per cent of childhood deaths from pneumonia, diarrhoea, malaria, measles, malnutrition, and other infectious diseases such as meningitis. Seriously ill children often suffer from more than one condition at the same time or in rapid sequence, making exact diagnosis difficult. For these children, combined therapy can be life-saving. Treatment may include oral rehydration salts to treat diarrhoea, low-cost antibiotics to treat pneumonia, antimalarial drugs, and vitamin and mineral supplements. Another key focus of the integrated management of childhood illnesses strategy is prevention by promoting immunization, breast feeding, and better child-feeding practices. Correct management of pneumonia and diarrhoeal diseases through integrated management of childhood illnesses could prevent up to 3 million deaths a year.
Promotion of prevention strategies against AIDS
Prevention of AIDS obviates the need for expensive antiretroviral drug therapy that remains beyond the means of most developing countries. Millions of new infections could be prevented through low-cost interventions including access to cheap condoms and, where necessary, safe drug injecting equipment, use of essential drugs to treat other sexually transmitted infections that amplify the risk of subsequent infection with HIV, HIV testing and counselling which can lead to safer sex, counselling and support for HIV-positive pregnant women and mothers along with antiretroviral drugs, counselling on safe alternatives to breast feeding, and sex education at school and beyond. For those who are infected with HIV, well-targeted low-cost care strategies can have a major impact on the suffering and must be better provided.
Increasing availability of essential drugs and vaccines
Increasing drug and vaccine access requires health infrastructure strengthening to the very periphery of the health-care system in order to decrease the current estimate of one-third of the world’s population that lacks regular access to essential life-saving drugs. Drugs may be too expensive for those on the lowest incomes, or they may not be available in countries or health systems. In Africa it is estimated that in the poorest countries less than half the population has access to the basic drugs they need (Fig. 13).

Fig. 13 Population with regular access to essential drugs in 1996 (1997 estimates).

Ways of increasing access to essential drugs and vaccines require strengthening of national health infrastructure, and inadequacy or breakdown of health-care services is one of the main obstacles to ensuring the availability of essential drugs. Resources being spent on health services must not be wasted. Logistics infrastructures which had been built up by the smallpox eradication programme, for example, disappeared with the disease and debate continues about the long-term effect of those resources in strengthening health infrastructure. The logistics and momentum created by global programmes must be used to strengthen routine health systems.
Clear priorities must be set for prevention and control based on epidemiological analysis and feasibility with existing resources and opportunities, and with careful assessment of the cost-effectiveness and potential for sustainability of the proposed interventions.
But increased access to essential drugs and vaccines does not only require strengthening of infrastructure. It also requires more rational use of those drugs that are available so that their maximum effectiveness is achieved. User-friendly packaging of drugs, for example, is a low-cost way of increasing patient adherence to antimalarial drug therapy. Studies in Ghana show that over 80 per cent of patients given a course of antimalarial drugs packaged in a numbered blister pack finished the course of treatment. Of those receiving loose unpackaged drugs—the way they are usually dispensed in developing countries—only 65 per cent completed the treatment. A simple packet of fast-acting drugs made widely available to parents—together with training to recognize malaria symptoms—could save the lives of many children with severe malaria.
Inexpensive vitamin and mineral supplements can also save lives, and by giving children vitamin A supplements along with other preventive services, deaths from measles and diarrhoea can be reduced. Malaria deaths among children can likewise be reduced through the use of iron supplements to treat anaemia. These inexpensive supplements, and life-saving anti-infective drugs, must be made available where they are needed.
Working across government sectors
Many key determinants of health, and the causes of emergence and re-emergence of infectious diseases that result in the increasing incidence and prevalence of endemic infectious diseases—as well as the solutions—lie outside the direct control of the health sector. Other government sectors involved are those dealing with sanitation and water supply, environmental and climate change, education, agriculture, trade, tourism, transport, industrial development, and housing (Fig. 14). Yet many developing, and some industrialized, countries lack the capacity to ensure co-ordinated action among the health sector and key sectors other than health. Failure to take account of the health impact of other sectors adds to the lack of funds and inadequate application of existing cost-effective tools to fight infectious diseases, and unless a broad multisectoral approach to health is ensured, prevention and control remain tenuous.

Fig. 14 Determinants of health: TB, tuberculosis; STIs, sexually transmitted infections; ARI, acute respiratory infections.

The critical need for collaboration between health and other sectors has been highlighted most recently by efforts to prevent AIDS. A few governments have attempted to reduce individual vulnerability to AIDS through a cross-sectoral approach that influences infrastructure development plans, laws, education, labour policies, and the exercise of human rights, for example, in an effort to create an environment that makes it easier for people to avoid AIDS. In some countries the approach has involved providing incentives to enable girls to finish secondary education, boosting job and educational opportunities for women to break the cycle of economic and sexual dependency, and ending the criminalization of marginalized groups such as sex workers and injecting drug users. It has also involved the conduct of impact assessments for development projects to foresee ways in which schemes could fuel the epidemic—through accelerating the pace of urbanization, for example, or splitting up families through creating the need for a migrant labour force.
Expansion of surveillance and response systems
Many networks throughout the world provide information about infectious disease occurrences. These networks include non-governmental organizations such Médecins sans Frontières, electronic discussion groups such as Promed, and search engines for infectious disease information from the World Wide Web such as those maintained by the Global Public Health Information Network. They also include laboratory and epidemiologist networks such as the WHO collaborating centres, the Training in Epidemiology and Intervention Public Health Network, and the Association of South-East Asian Nations. Together these networks are a powerful means of obtaining the information that leads to a co-ordinated international response and enhanced international public health security.
Epidemic intelligence is the constant receipt and validation of information about suspected or confirmed infectious disease outbreaks that is received from these networks worldwide. Once the information has been validated, key public health professionals must be informed of those confirmed and unconfirmed outbreaks that are of potential international public health importance. At the same time active and appropriate response must occur, ranging from local containment measures to an investigation and containment by a highly specialized international team. Recent outbreaks such as the human monkeypox outbreak in the Democratic Republic of the Congo reported by the Médecins sans Frontières network, the outbreak of influenza A (H5N1) in Hong Kong Special Administrative Region reported by the WHO Flunet, and the outbreak of highly fatal respiratory disease in Afghanistan reported by Global Public Health Information Network all led to partnerships of national and international public health experts for co-ordinated investigation and containment. In all three of these outbreaks, and in many more during the past 3 years, detection and response have forged partnerships between scientists in developing and industrialized countries that continue to strengthen and ensure greater public health security (Fig. 15).

Fig. 15 Reported outbreaks of known infectious diseases, 1998 to 1999.

Since infectious disease outbreaks will continue to occur, often in countries without the capacity to respond fully, the challenge is to build national epidemic preparedness before outbreaks occur. Investment must be made now if adequate systems are to be put in place. The metaphor of the fire service is a good illustration—it is impossible to build a fire service while trying to respond to the fire.
Essential tools to ensure epidemic preparedness include surveillance standards and stronger multidisease surveillance systems, preidentified partners for outbreak response, strengthened laboratory capacity, and training in field epidemiology.
Surveillance networks that have been built for one infectious disease must be expanded to include others. Those systems built with eradication or elimination programmes are examples, and are usually well funded so that the vital search for final cases and certification activities are possible. The acute flaccid paralysis surveillance system established for polio eradication in Myanmar, for example, was expanded in 1999 to include surveillance for measles and neonatal tetanus; and the laboratory networks for polio surveillance in sub-Saharan Africa have routinely been expanded to other viral diseases such as yellow fever. In sub-Saharan Africa acute flaccid paralysis surveillance systems are likewise being strengthened by the provision of field epidemiology and public health laboratory training.
Strengthening international agreements and regulations
Attempts at agreement and 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 in 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 Rules were adopted, in 1951. These were amended in 1969 to become the International Health Regulations which are implemented by the WHO.
The International Health Regulations provide a universal code of practice which ranges from strong national disease detection systems and measures of prevention and control including vaccination, to disinfection, disinsection, and deratting of public conveyances, and sanitary norms at ports of entry. Currently the International Health Regulations require reporting of three infectious diseases—cholera, plague, and yellow fever. But when these diseases are reported, the Regulations are often wrongly applied, resulting in disruption of international travel and trade, and huge economic losses.
Many infectious diseases, including those which are new or re-emerging, are not covered by the International Health Regulations even though they have great potential for international spread. Because of the problematic application and disease coverage of the International Health Regulations, the World Health Assembly has requested a revision and updating of the Regulations so that they are better adapted to the control of infectious diseases in the twenty-first century. The revised Regulations are expected to replace reporting of specific diseases (for example cholera) by reporting of disease syndromes with high mortality, such as epidemic haemorrhagic fever. They will have a broader scope to include all infectious diseases of international importance, and will clearly indicate what measures are appropriate internationally, as well as those which are inappropriate. It is envisaged that the revised International Health Regulations will strengthen global alert and response to ensure maximum protection against infectious diseases with minimum restriction on world traffic and trade.
Investment in research
Despite their importance, infectious diseases come low on the global health research and development agenda. In 1992, global spending on health research was US$56 billion—less than 4 per cent of total global expenditure on health. Of that, no more than 10 per cent was allocated to research relating to the health needs of developing countries—mainly infectious diseases.
The combined investment in research and development into acute respiratory infections, diarrhoeal diseases, and tuberculosis—which kill over 7 million people a year—was US$133 million (about 0.2 per cent of global spending on health research and development). Yet these three diseases together account for almost one-fifth of the global disease burden. Malaria, which accounts for 3 per cent of the disease burden globally and almost 10 per cent in sub-Saharan Africa, fared as poorly—attracting about 0.1 per cent of research funds.
In contrast to the limited funds available, the research needs for infectious diseases are vast. Some of the research needed involves cutting-edge science—sequencing the genome of the major disease-causing microbes, for example, or discovering ways of slowing the spread of anti-infective-drug resistance. Other critical research needs include the discovery of new affordable drugs, vaccines, and diagnostic tests. In some cases, these are needed to lower costs, improve compliance, and replace drugs that have been compromised by resistance.
Equally important is the need for research to find ways of making more widespread and better use of existing cost-effective tools such as vaccines, multidrug therapy, bednets, and an integrated approach to childhood illness. Meanwhile, research is also needed to understand better the causes of the disease burden in individual countries, so that health systems can respond effectively to needs in the most cost-effective way. An urgent need is to develop new low-cost anti-infective drugs to replace those that have become ineffective due to resistance (Table 2).

Table 2 New drugs and vaccines under development, 1999

Making better use of existing tools
In the short term, a great deal can be achieved through research into ways of improving the use of existing tools—one of the most neglected areas of research. This includes the need to improve the home management of malaria and other childhood diseases, and to provide clear information about prompt referral for severely ill children. Research is also needed to find ways of ensuring that newer more expensive vaccines such as those against H. influenzae type b and hepatitis B—which have proved successful in the industrialized countries—can now be introduced into developing countries.
Diagnostic tests
Research is needed to develop low-cost rapid diagnostic tests to improve the accuracy of diagnosis and accelerate the start of appropriate treatment. Although rapid diagnostic dipstick tests for malaria are in the final stages of development, they are currently too expensive for widespread use in developing countries. Tests are also needed for tuberculosis, gonorrhoea, and sleeping sickness for use in developing countries.
New diagnostic tests for sexually transmitted infections could help prevent their spread, ensure prompt and more effective treatment, and provide a valuable weapon in the fight against HIV/AIDS. The currently available tests are too expensive for use in developing countries and laboratory analysis is not always available. Simple diagnostic tests are also required for other diseases, including tuberculosis and malaria.
New drugs
It is now urgent to develop new drugs to treat diseases like malaria, tuberculosis, and pneumonia which are rapidly becoming resistant to first-line drugs. Without a new generation of low-cost drugs, some diseases could become serious treatment problems in countries which have not been able to purchase more expensive second-line drugs. Also needed are new combination therapies to treat diseases such as lymphatic filariasis, river blindness, and malaria—using more than one drug to increase effectiveness and lower the risk of developing drug resistance. Other priorities include a new oral drug which could help reduce deaths from visceral leishmaniasis and a new non-injectable quick-acting drug to treat severe cases of malaria. One promising new product (a combination of chlorproguanil and dapsone) is an oral treatment for cases of uncomplicated malaria in Africa. Another is a suppository (artesunate) for malaria sufferers who are too sick to take oral medication. It is fast-acting, easy to administer, and can ‘buy time’ for people with severe malaria living in remote areas who might not survive the journey to hospital.
New low-cost drugs that could improve compliance with drug therapy by shortening the course or simplifying the treatment are also needed. The drop-out rates for DOTS therapy for tuberculosis, for example, could be greatly improved if the multidrug therapy could be combined in a single tablet and the length of treatment reduced from the minimum 24 weeks now required. For leprosy, efforts are being made to develop new drugs which could both increase the effectiveness and shorten the duration of multidrug therapy.
New vaccines
Top of the global priority wish-list in vaccine development are vaccines against acute respiratory infections, diarrhoeal diseases, HIV/AIDS, malaria, tuberculosis, and dengue. Of these, a vaccine against HIV/AIDS is arguably the most important since no cure exists and mortality is high.
Advances in genetic engineering have produced vaccine contenders that should simplify immunization, boost the performance of existing vaccines, and protect children against diseases which are not yet vaccine-preventable. New vaccines against tuberculosis, malaria and acute respiratory infections could provide the first line of defence against drug-resistant microbes. The successful sequencing of the genome of the tuberculosis-causing microbe in 1998 was a major breakthrough that is expected to shed more light on which genes cause tuberculosis and to speed up the development of a more effective vaccine. Meanwhile progress in microbial genetics is also driving the development of new, improved vaccines against meningococcal meningitis, dengue fever, and Japanese encephalitis.
Efforts must also be made to reach the one in five children who are still not immunized each year through national immunization programmes. This includes efforts to lower vaccine delivery costs, simplify the administration of vaccines, and reduce the number of immunization contacts needed. In addition to the need to develop new or improved vaccines, research is under way to simplify the administration of existing vaccines, reduce delivery costs, and boost immunization coverage. This includes research into ways of reducing the number of immunization contacts that are needed through combining several vaccines in a single dose and combining several booster doses in a single slow-release dose. Another priority is the development of new safer ways of delivering vaccines—orally or nasally—that minimize the risk of injection hazards.
Summary
The rapid economic and scientific advances of the twentieth century for controlling infectious diseases can be built upon, and the impact of infectious diseases can be cut dramatically. With the emergence of new infectious agents, the re-emergence of those we know, and the rapid development of anti-infective drug resistance, the windows of opportunity to use these advances cost effectively are closing. Increased commitment is required for their use, and for the research necessary in the future.
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6 comments on “2.6 Infectious agents

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