Annex A FACT SHEETS FOR CANDIDATE DISEASES FOR ELIMINATION OR ERADICATION

1. Noninfectious Conditions

Spina bifida and anencephaly are among the most common and severe birth defects. Almost all affected persons with spina bifida have lower-body paralysis and significant physical disability. In many countries, spina bifida is the most common cause of infantile paralysis. Anencephaly is a common birth defect that contributes to fetal and infant mortality.

An estimated 50-75% of these birth defects can be prevented by providing adequate intakes of synthetic folic acid (pteroylmonoglutamic acid) before and during the first trimester of pregnancy. Preventing folic-acid-preventable spina bifida and anencephaly presents an outstanding opportunity to improve the health of children throughout the world. Moreover, substantial evidence suggests that, in adults, sub-optimal intake of folic acid is a major factor for increasing the risk of cardiovascular disease.

Each year, 300,000 to 400,000 infants worldwide are born with spina bifida and anencephaly. In China, 100,000 infants are born annually with these two birth defects, which are the leading cause of infant mortality. The rates are also high in Mexico and Central America. Together these conditions contribute significantly to infant morbidity and mortality.

Approximately 75% of spina bifida and anencephaly are folic-acid-preventable, and it is biologically possible to prevent all folic-acid-preventable spina bifida and anencephaly. The prevention impact would be approximately equal to the prevention derived from poliomyelitis vaccines.

The biological feasibility of preventing spina bifida and anencephaly using folic acid-containing vitamin supplements has been demonstrated in randomized controlled trials and other studies. Data from these studies indicate a 50-100% reduction in risk for women taking the supplement before conception and during the first trimester of pregnancy. No randomized controlled studies indicate that dietary changes alone will prevent these birth defects.

The U.S. Public Health Service recommends that all women who could become pregnant should consume 400 ug of folic acid daily to prevent these birth defects. Many other countries have policy statements seeking to increase consumption. The United States Institute of Medicine recommended in April 1998 that all women who could become pregnant should consume 400 ug daily of synthetic folic acid to prevent birth defects.

Folic acid fortification of flour is feasible and inexpensive. In the USA, formal analysis of costs and benefits of fortification of wheat flour and other grains indicate that a fortification strategy would be highly cost-beneficial. Because costs associated with the purchase and distribution of folic-acid-containing supplements would be higher, programmes depending on pill consumption would break even.

Folic acid intake to prevent folic-acid-preventable spina bifida and anencephaly can be increased by fortifying staple foods with folic acid or implementing a programme that increases the consumption of folic-acid-containing supplements, as follows: fortify with synthetic folic acid one or more centrally processed and distributed foods, such as grain products, so that the vast majority of reproductive-aged women consume at least 400 (g of folic acid each day; establish folic acid vitamin pill consumption programmes; add folic acid to iron supplement pill programs; and add folic acid to contraceptive pills.

Cost-effective methods for population assessment of blood folate levels need to be field tested and improved. Such indicators of folate status are needed to provide a reliable means of evaluating the effectiveness of folic acid intervention programmes. Research is needed to develop messages that will motivate women to consume more folic acid.

Although many countries have developed recommendations to increase the consumption of folic acid, more needs to be done to implement these strategies. In the USA, 3 of 4 reproductive-aged women have blood folate levels that place them at risk of having a child with a folic-acid-preventable birth defect. Data from Europe are similar. The USA and China are implementing programmes to increase folic acid intakes. Approximately 20 other countries encourage the use of folic-acid-containing vitamins and the consumption of folate-rich foods. The USA and a few other countries have fortified one or more grain products with folic acid. Fortification concentration levels, however, so far have not been sufficient for complete prevention of these preventable birth defects.

The principal challenges to eliminating folic-acid-preventable birth defects are a lack of awareness of this prevention opportunity by health care providers, policy-makers, and the public; the financial burden and logistical barriers to providing supplements to women; lack of centrally processed and distributed foods to serve as fortification vehicles in some countries; regulations in some countries limiting the amount of folic acid in supplement pills; misinterpretation of data, resulting in recommendation to promote only increased consumption of folate-rich foods rather than an adequate fortification or supplement programme with crystalline folic acid (pteroylmonoglutamic acid); and unwillingness of government to set fortification concentration levels high enough.

Iodine deficiency disorders (IDD) result from insufficient iodine in the environment and inadequate intake of iodine from food. Because development of the central nervous system depends on an adequate supply of thyroid hormone, which requires iodine for biosynthesis, iodine is an essential micronutrient for normal intellectual development and function. Endemic cretinism is the most severe manifestation of the lack of maternal and fetal thyroid hormone caused by severe dietary iodine deficiency; community-based assessments and iodine intervention trials indicate that IDD can leave entire populations with reduced intellectual capacity and impaired motor functions. Mild iodine deficiency can reduce the average population cognitive scores by 10-15%. Goitre, the most obvious clinical manifestation, frequently occurs in iodine-deficient populations.

In 1991, using the most current data, WHO estimated that 20% of people throughout the world lived in areas in which iodine intake was inadequate. Subsequently, data became available that showed major cities in most of the developing world were also affected. In one study, 30-80% of neonates living in Asian cities had elevated TSH levels (greater than 5 mU/l), indicating lack of iodine during the critical phase of brain development. The WHO estimates excluded data from states in the former Soviet Union, where iodized salt is generally unavailable, and where it is now known that the entire population lacks adequate iodine intake.

Since 1990, worldwide production and availability of iodized salt has increased greatly; production of iodized salt has increased from less than 10% to greater than 50% in south-east Asia and India, greater than 70% in China and Africa, and greater than 80% in Latin America. Questions about iodized salt were included in the UNICEF-supported, household surveys conducted in 1996 in 50 countries; these surveys indicate that in 27 developing countries greater than 90% of households use iodized salt, and in 15 countries 75-90% of households use iodized salt. In 1994, a total of 48 developing countries with IDD had no significant salt-iodization programmes; today, most of them have iodized more than half their salt. However, because problems with obtaining and maintaining the optimum level of iodine in salt have been widespread in most countries, iodine levels often are inadequate or, occasionally, too high to afford the best protection.

The global burden of disease (Christopher Murray & Alan Lopez, editors) ranked iodine deficiency in 1990 at 77, with 1 562,000 disability-adjusted life years (DALY); this estimate was based on the 1990 WHO data, which focused on the severe clinical manifestations of iodine deficiency and did not estimate the more widespread impact of reduced intellectual capacity in entire populations. With the success of salt iodization in most countries, the global burden of IDD has greatly decreased. However, further efforts are needed in many countries, and programmes must be maintained if IDD is to be permanently controlled.

Using salt iodization, it is possible to eliminate iodine deficiency as a public health problem and to employ sensitive biological markers to document this success. The principal challenge to elimination is the permanent intervention of adequate dietary iodine intake. In both developed and developing countries, iodine deficiency was eliminated, then recurred because of a lack of vigilance and a breakdown in the continuation of the intervention. Permanent elimination of iodine deficiency requires collaboration among private salt producers and government sectors to promote and monitor the use of iodized salt or other iodine-containing foods.

Few estimates have been published of the costs and benefits. In 1993, the World Bank estimated an attractive US$ 8 DALY cost for iodine elimination through salt fortification. The estimated cost in India in 1994 was US$ 0.02-0.05 per person per year. The cost of salt fortification depends on the type of salt fortified and current practices; in areas with large manufacturers producing high-quality salt, the cost to iodize is less than 5% of production. The greatest cost is in packaging and labelling. If the salt is already packaged and labelled, the costs are insignificant. If the entire process is upgraded, as in China (representing about one-third of the global population), the investment is approximately US$ 100 million. In 1991, UNICEF estimated that US$ 100 million (in addition to the expected investments from national governments and local industry) would be necessary to achieve the mid-decade goal of Universal Salt Iodization. From 1993 through mid-1997, bilateral, multilateral development agencies and Kiwanis have invested approximately US$ 60 million for IDD elimination. Continued investments are necessary to ensure success and sustainability of IDD elimination.

Critical to any national IDD elimination programme requiring salt iodization are policies, laws, and agreements requiring all edible salt to be iodized, effective inspection and enforcement systems, and political advocacy and scientific support from community leaders. Ultimately, consumers need to be aware of the benefits so that the less expensive, unauthorized, noniodized salt does not persist in the market. Inclusion of salt testing and community education through school programmes has been effective in many countries. Because most salt is now produced by large-scale producers, once iodization is adopted and the best manufacturing practices are implemented, the impact can be massive and quality-control maintained. Salt iodization has been most difficult to implement and control in the tens of thousands of small-scale, cottage-industry producers.

Quality control in salt production and iodization is not common practice and is one of the greatest challenges to eliminating IDD. Simply providing salt iodization equipment is not the long-term answer. The development of cooperatives for iodization and use of micro-credit systems have been successful in some cases. Because establishing and maintaining laboratories capable of quality assurance of salt and measuring biological indicators have not been a priority for governments or agencies, long-term facilities for monitoring elimination and ensuring surveillance are widely lacking. Despite substantial achievements towards IDD elimination, the magnitude of iodine deficiency, its devastating impact on intellectual capacity, and the cost-benefit of its elimination are generally not well known beyond a small group of development professionals. Overcoming this communication deficit is probably the most important key in reaching and maintaining the elimination of IDD.

Elimination of iodine deficiency requires 1) developing simple, qualitative tests to verify inexpensively the level of iodine in salt, rather than indicate only its presence or absence; 2) establishing the best practices of small-scale salt iodization, and simplifying and standardizing the process with appropriate quality assurance; 3) evaluating the impact of using iodized salt in food processing (such as pickling or cheese-making or in various types of cooking) to address the common perceptions of its negative qualities in such processes or inordinately high iodine losses; 4) evaluating factors that have led to successful implementation of IDD programmes so that these can be replicated in areas where progress is lagging or be used to model success in other nutrition or public health programmes.

In 1990, following the World Summit for Children, heads of state and governments of over 120 countries committed themselves to virtually eliminate IDD by the year 2000. UNICEF, other United Nations agencies, and bilateral donors agreed to a mid-decade goal of universal salt iodization. In September 1996, Bolivia was the first country to declare that it had achieved the "virtual elimination of IDD".

Although tremendous progress has been made in most developing countries towards producing iodized salt, substantial gaps remain. The most significant is in the countries of the former Soviet Union, where salt was once partially iodized but by the end of 1997 was largely noniodized. Goitre rates in schoolchildren are high, and cretinism is reported to be serious among newborns in the Central Asian Republics. IDD is serious and not addressed in countries/areas where political control or external access is limited (e.g. China (Autonomous Region of Tibet), Sudan, Afghanistan, and Democratic People's Republic of Korea). Ensuring the correct quantity of iodine in each batch or packet of salt remains a significant problem in many places. The overall adequate quality-assurance programmes are generally lacking in most countries. IDD has re-emerged as a continuing concern in western Europe.

Challenges to elimination include 1) raising the level of awareness of the nature and significance of IDD so that governments, salt producers, and others invest in their own protection; 2) ensuring participation by all countries and all regions within countries in the elimination efforts; 3) developing the best manufacturing practices for all salt producers and developing monitoring systems to ensure compliance and eliminate the black market for noniodized salt; 4) developing and maintaining a monitoring system to ensure protection from IDD and employ warning systems to detect breakdowns in salt iodization, or in other protective measures.

Iron is critical to the formation of haemoglobin in red blood cells. Iron deficiency and its adverse health consequences result primarily from a dietary iron intake that is inadequate to meet the relatively high iron requirements of young children and reproductive-aged women. In addition, increased blood loss from conditions such as hookworm infection can contribute to iron deficiency.

Anaemia is the most widely recognized consequence of iron deficiency. Severe anaemia can cause death in young children and pregnant women by hindering sufficient oxygen transport to body tissues. In mild-to-moderate anaemia, the most important consequence for adults is reduced work capacity, which can adversely affect the economic output of both families and countries. For young children, the most important consequence of iron deficiency is reduced mental development and cognitive function, potentially aggravated by an increased tendency to absorb lead. For pregnant women, iron-deficiency anaemia is associated with an increased risk of pre-term births, which in turn affects child survival and development.

Iron deficiency is a global nutritional problem, affecting primarily infants, children, and reproductive-aged women, especially during pregnancy. Using anaemia as an indicator of iron deficiency, an estimated 50-60% of young children, 20-30% of nonpregnant women, and 50-60% of pregnant women in developing countries are iron deficient. In developed countries, approximately 5% of young children and 5-10% of reproductive-aged women are affected.

In a recent review based on 22 studies from Africa and Asia, anaemia accounted for approximately 20% of maternal mortality. In Africa, 30% of childhood mortality also is associated with severe anaemia. The average reduction in cognitive performance related to iron-deficiency anaemia approximates one standard deviation of the scale used to assess intellectual development. For adults who suffer from iron-deficiency anaemia, the reduction in work productivity is approximately 10-15% depending on the severity of anaemia. For populations where 30% of women and 10% of men have significant anaemia, the net loss of productivity approximates 2-3% of the gross domestic product (GDP).

Nutrition education has generally been ineffective in addressing iron deficiency because food from animal sources, which contains more bioavailable iron, is often not affordable by the poor. Iron supplementation for pregnant women is common, but its effectiveness is limited because it requires a functional distribution system and adequate communication to women, which is not feasible in many settings. In many areas where iron-deficiency anaemia is severe, supplementation is not sufficient to meet the high iron requirements of pregnancy. Supplementation for younger children and nonpregnant women can be justified, but the cost and logistics for long-term supplementation make this a difficult proposition.

The most viable approach to control iron-deficiency anaemia is through fortification of major food commodities. This is particularly feasible in areas where cereal products, such as wheat flour, are centrally processed and where the food to be fortified is frequently consumed. Up to 60 mg of iron can be added to each kg of wheat or corn flour, and can provide up to 30% of the daily iron requirement in areas where consumption of the fortified food item is high. In countries where fortification of commonly consumed foods is feasible, iron deficiency can be eliminated or substantially reduced, particularly among people with relatively low iron requirements, such as schoolaged children and nonpregnant women. The recent experience with iron fortification in Venezuela provides an example.

For pregnant women, fortification per se is not sufficient, and supplementation is still needed to prevent maternal anaemia. Because their diet often differs from that of adults, infants and young children may benefit little from a general fortification programme, unless their diet is specifically fortified with iron. The effectiveness of targeted fortification was demonstrated in Chile, where fortification of government-distributed milk powder for infants resulted in the elimination of iron-deficiency anaemia. Through such measures, a substantial reduction in iron-deficiency anaemia is feasible, but virtual elimination is difficult to achieve among those with high iron requirements, such as pregnant women. In tropical areas where hookworm infection is common and intense, periodic deworming of older children and adults is essential to reduce the burden of severe anaemia related to iron deficiency. Deworming is feasible through school-based programmes and, for pregnant women, through maternal and child health services.

In general, the cost of fortification is very low. For areas with high consumption of wheat flour (e.g. 50 kg per person per year), the cost of added iron is about US$ 0.05 per person per year, and there is no additional cost to deliver the iron to the consumer. For practical purposes the cost of iron fortification of major commodities is low -- less than 0.3% of the cost of the wheat flour. Such costs can easily be absorbed by the consumer without input from the public sector. In the case of iron supplements for pregnant women, the cost of a 120-day supply of iron tablets is only about US$ 0.40, but there are substantial costs to the health system for distribution and communication. On a population basis, an overall average cost of US$ 0.20 per person per year would provide for fortification of infant diets, targeted supplementation, fortification of one or more major food commodities, and deworming for older children and reproductive-aged women through schools, work sites, and family planning systems.

A comprehensive programme of this type could reduce iron-deficiency anaemia by up to 80%. The net savings from improved work productivity could be US$ 10 per capita for a country with a per capita GDP of US$ 500, representing 2% of GDP; this gives a cost-effectiveness ratio of 50. However, the benefit of an 80% reduction of iron-deficiency anaemia would include better child development and learning capacity, less morbidity and mortality, and thus reduced direct health-care costs. Even though these human resources are difficult to estimate, it is not unreasonable to assume that taking these additional benefits could double the cost-effectiveness ratio from 50 to 100. The World Bank recently estimated the ratio at 500. Even if the cost-effectiveness ratio is conservatively estimated at 100, the elimination of iron deficiency is still a bargain.

A comprehensive approach is needed to address iron deficiency as outlined below.

• For infants, a feasible means to improve the quality of complementary feeding needs to be defined. The consumption of foods from animal sources also needs to be increased. This approach can be considered in some settings because the amounts required for infants are relatively small, and hence are potentially affordable. Explore the possible fortification of common food items in the infant diet that are industrially processed, and in the absence of a dietary approach, consider supplementation of infants with iron from 6 to 12 months.
• For schoolchildren and women of reproductive age, consider iron fortification of a common staple food, such as wheat flour or fish sauce. Implement deworming in areas where hookworm is a significant burden. Implement periodic, supervised supplementation in settings where this is feasible, such as schools.
• For pregnant women, improve the supplementation programme by assuring the availability of iron tablets. Provide for adequate education and communication to both health workers and women on the indications for iron supplements to prevent anaemia.
• For all target groups, include other micro-nutrients. In developing countries, iron deficiency is usually not an isolated nutritional deficit. Low intake of food from animal sources also results in deficiencies in zinc, calcium, riboflavin, and vitamin A. Some of these deficiencies, such as vitamin A deficiency, also contribute to anaemia. For this reason, fortification or supplementation efforts to improve iron status should not be restricted to iron.

• Develop a low-cost micronutrient additive in the form of sprinkles or drops for complementary foods for infants which can be added to food prepared at home. This strategy could be considered for areas that have no means to improve the infant diet using local or centrally processed fortified foods.
• Develop a low-cost iron complex for supplementation or fortification instead of using the more reactive iron salt. Currently available iron complexes are expensive for large-scale applications, although the amounts required are less and increased market opportunities for such compounds would probably decrease the costs.
• Support the development of cereal grains that have greater bioavailability of iron.

Progress in eliminating iron deficiency has been limited. In 1990 the World Summit for Children called for a one-third reduction in maternal anaemia by the year 2000. However, only in the last 2 years has the importance of preventing iron-deficiency anaemia for young children become an issue, especially through the efforts of UNICEF and USAID. Greatest progress has been made in South and Central America, where several countries have initiated iron fortification of wheat flour. In Asia and Africa, the effort is lagging. Thus far, the USA and Chile are the only countries to have documented the near elimination of childhood iron-deficiency anaemia resulting from widespread use of iron-fortified milk powder or formula. This is likely to be the case for many European countries, but data are lacking to assess whether childhood iron-deficiency anaemia has been eliminated.

• To address effectively the problem of maternal anaemia, methods must be found to provide improved baseline iron status to women before pregnancy. Because current interventions are overly focused within the health sector, nutrition and health experts need to communicate effectively with the private sector and the food industry because fortification is necessarily an industry-based approach.
• Preventing iron-deficiency anaemia during late infancy and early childhood needs to be addressed. In many settings, this means improving complementary feeding practices. Efforts to address iron deficiency must include control of other micronutrient deficiencies because poor diets cause multiple deficiencies that affect the health of children.
• Policy-makers must be willing to accept solutions or approaches that do not necessarily target all groups or all segments of the population simultaneously, because a single strategy is unlikely to prevent iron deficiency in all populations at risk. Although interventions should be part of a comprehensive strategy, simultaneous implementation of all aspects of the strategy might not be feasible.

Vitamin A deficiency is defined by tissue concentrations of vitamin A low enough to have adverse health consequences even if there is no evidence of clinical deficiency (xerophthalmia). Subclinical deficiency is defined by serum retinol levels less than 0.70 umol/l, which are considered of moderate and severe public health significance when the prevalence in a population is greater than 10% and greater than 20%, respectively. The consequences of subclinical deficiency are increased risk of mortality from common childhood infections, such as diarrhoea and measles, and recent studies suggest increased risk of maternal mortality. Xerophthalmia occurs when ocular signs are present, including night blindness, Bitot's spots with conjunctival xerosis, and corneal xerosis (which are potentially reversible signs), and keratomalacia, which can result in partial or total irreversible blindness.

Approximately 3 million children develop xerophthalmia annually, 250,000 to 500,000 of whom become blind, and at least 60% die within one year. Estimates of subclinical deficiency among preschool-aged children range from 75 million to 250 million. Recently reported studies from Nepal suggest that in South Asia alone, 1-2 million pregnant women may be at risk from subclinical vitamin A deficiency.

Eliminating vitamin A deficiency and all its consequences, including blindness, as a public health problem is feasible if dietary intake is increased to the recommended levels through natural foods, fortified foods, and/or supplements, and if the burden of other infectious diseases, which exacerbate vitamin A deficiency and lower serum retinol levels, is reduced. It is unlikely that vitamin A deficiency will be eradicated because it is caused by an inadequate dietary intake for economic, social, or cultural reasons, some of which are based on individual human behaviour and choice. However, elimination can be monitored by the prevalence of low serum levels.

The cost of elimination depends on the mix of intervention strategies selected for implementation. After the initial capital investment costs, fortification of a staple food is a long-term low-cost intervention. Vitamin A supplements are inexpensive -- less than US$ 0.03 per capsule -- but costs for delivery may be high depending on the infrastructures used. Semiannual campaigns have proven cost-effective and achieved broad coverage. Similarly, linking the distribution of capsules to vaccination delivery systems has reduced delivery costs. Dietary modification to increase the quantity and quality of menus depends on physical and economic access to food sources and educational/social marketing to guide food choice behaviours. Expected societal benefits include reduced costs for use of medical resources by reduced disease severity and individual benefits of reduced risk of death.

A combination of strategies addressing short- and long-term needs is usually required for sustainable control and elimination. These strategies include direct measures to increase intake of vitamin A through food, such as dietary modification in terms of quantity and quality, fortification, and supplementation; and indirect measures through public health strategies to control disease; income-generating activities to increase buying power; and the empowerment of women through the use of strategies such as literacy and education programmes. The emphasis given to each of the strategies depends on the severity of the problem. Also, increased political and public awareness of the problem, its consequences, and potential solutions is essential to obtain the needed commitment to elimination from national to community levels. Because preschool-aged children and pregnant and lactating women are those who are the most vulnerable to deficiency consequences, strategies should focus first on meeting their short-term needs, perhaps through supplementation, while the longer-term control measures -- dietary modification and fortification -- are concurrently being established.

Research is needed to develop a reliable, low-cost, field-applicable indicator or methodologies for diagnosing subclinical deficiency and monitoring control strategies (this is a priority because serum retinol values are expensive, subject to confounding, and not a reliable index of vitamin A status of individuals except at extremes); assess the bioavailability of carotenoids from typical menus eaten by children in areas with endemic deficiency; conduct operational research to determine the safety and feasibility of community-controlled frequent distribution of low-dose supplements to young children and pregnant women; and develop simple, community-based technology for fortification programmes, either with vitamin A fortificants or through food-to-food combinations using concentrated food sources added to common low-vitamin-A diets of children and pregnant women (e.g. dried mangoes, dark green leafy vegetables or yellow squash added to complementary and post-weaning paps and cereals).

In the past decade, great strides have been made in identifying populations at risk of deficiency, reducing the prevalence of xerophthalmia, and planning and implementing intervention strategies. Baseline information is available for most countries with a problem. It is too soon after implementation to evaluate fully the impact of various intervention strategies on a global basis. Where this has been possible on a national or subnational basis, horticulture, fortification, and supplementation strategies are all effective when coverage of the vulnerable population is high. Public health measures and other indirect measures contribute to making direct intake strategies more effective and efficient. In addition, more political awareness exists of the problem and commitment to its elimination is more widespread than in any previous period.

The principal challenges include the following:

• sustaining global and national commitment to elimination;
• embedding successful control strategies into community systems so that they are sustained;
• increasing dietary intakes of young children and fertile women to adequate levels; and
• educating the medical profession and general public, especially mothers, about the need for vitamin A and its locally available sources for menu planning.

2. Bacterial Diseases

Congenital syphilis results from infection of the fetus by Treponema pallidum, the causative agent of syphilis. During the first 4 years after acquiring syphilis, an untreated pregnant woman has a greater than 70% probability of transmitting the infection to her fetus. About 40% of pregnancies in women with untreated early syphilis end in perinatal death. Infected live-born infants can develop acute systemic illness, bone deformities, developmental disabilities, blindness, or deafness. Only about 50% of infected neonates will immediately manifest these serious problems, with others developing them later in life. Congenital syphilis can be prevented if infected pregnant women are treated with penicillin. However, the painless genital sores of primary syphilis frequently go unnoticed by women, and they do not seek care. In areas where coverage of prenatal care is low, women do not receive routine syphilis testing during pregnancy. Furthermore, increasingly strong evidence indicates that syphilis, like other causes of genital ulcers, greatly enhances HIV transmission, making prevention of syphilis in women additionally important for control of HIV infection. The occurrence of congenital syphilis represents a failure in the basic systems of sexually transmitted disease (STD) control and prenatal care.

Congenital syphilis remains one of the most severe, preventable adverse pregnancy outcomes throughout the world. The World Bank ranks syphilis fifth globally in disability-adjusted life days (DALDs) lost per capita per year, after measles, HIV infection, malaria, and gastroenteritis. Syphilis results in an estimated loss of 16 DALDs per capita per year in the developing world, and to the extent that syphilis enhances HIV transmission, an additional 61 DALDs per capita per year. Estimated syphilis-associated disability-adjusted life years (DALYs) lost among children aged less than 5 years are 500,000 per year; additional DALYs are lost for older children and adults from persistent physical and developmental disabilities.

In 1995, WHO estimated that the worldwide annual incidence of sexually acquired syphilis was 0.4% (12 million cases) and that prevalence was 1% (28 million cases). Given the estimated 6 million incident syphilis infections among women annually, that 90% of these are among women of reproductive age, and that the fertility rate is 20% per year, approximately 900,000 gestations occur annually among infected women. An estimated 40% of these pregnancies (360,000) end in fetal or perinatal death, and 50% of the remaining neonates (270,000) suffer significant physical, developmental, and sensory impairments.

Syphilis elimination is biologically feasible because no naturally occurring non-human host exists for the disease, serological tests for diagnosis are relatively accurate (greater than 95% sensitive and specific), and curative treatment is available -- early syphilis can be treated with a single injection of penicillin. The biological feasibility of syphilis elimination (including the elimination of congenital syphilis) has been demonstrated in most of the developed world. For example, in the USA, the widespread availability of penicillin in the mid-1940s and the targeted control efforts of the U.S. Public Health Service resulted in a 93% decline in primary and secondary syphilis over 10 years, from a rate of 60 per 100,000 population in 1945 to only 4 per 100,000 population in 1955. Congenital syphilis has also declined dramatically in the USA, United Kingdom, and other developed countries during the past 50 years, as a result of prenatal syphilis screening and treatment.

The country-specific costs of effective congenital syphilis elimination campaigns depend on the prevalence of syphilis in the population, the coverage and quality of prenatal care, and basic public health measures for STD control. In countries with a 1% syphilis prevalence, the estimated costs of antenatal screening and treatment programmes are US$ 0.42 per pregnant woman, and of averting each syphilis-associated adverse pregnancy outcome, US$ 70; in countries with a 15% prevalence, estimated costs are US$ 0.70 and US$ 9.28, respectively. PAHO estimates that an elimination programme in the Region of the Americas would cost US$ 400,000 each year to coordinate, with an additional $100,000 needed in each Member State. The cost of an elimination programme may be substantially higher in sub-Saharan Africa, where the prevalence of syphilis is higher and the coverage of prenatal and STD services is less.

Congenital syphilis contributes to as many as 29% of perinatal and infant deaths, 26% of stillbirths, 11% of neonatal deaths, and 5% of postneonatal deaths. In addition to preventing this morbidity, an elimination programme that implements the strategies described below would confer far-reaching collateral benefits by supporting improvements in prenatal care and HIV-prevention programmes. Even without considering the impact on HIV transmission, cure or prevention of a single case of syphilis saves 161 DALYs; when the contribution of syphilis to HIV transmission is also considered, 396 DALYs per cured or prevented case are saved.

Strategies for eliminating congenital syphilis (adapted from PAHO) include the following:

• strengthening surveillance;
• improving procedures for syphilis testing of pregnant women by using simple and rapid serological tests that are already available; and
• enhancing the capacity of prenatal care services to identify and manage cases of maternal syphilis.

These should be complemented by strategies that would improve the control of syphilis (and other STDs) in high-risk populations and by syndromic management of genital ulcers, as advocated by WHO and UNAIDS. In countries with high rates of syphilis, congenital syphilis elimination will require that syphilis rates are reduced (but not necessarily eliminated) in high-prevalence populations. A programme of congenital syphilis elimination that includes targeted efforts for high prevalence populations will also prevent HIV infection. Strategies that result in strong partnerships with both the reproductive health and the HIV prevention communities have the best chances for success.

In each country, operations research will be needed to develop new paradigms for the transition from syphilis control to elimination, to determine the optimal balance among the different strategies described, and to identify approaches to implement these strategies and to overcome obstacles. For example, in some countries it may be necessary to identify physical, social and cultural barriers to prenatal care. When barriers are identified, further studies may be needed to evaluate practical interventions. The cost-effectiveness of congenital syphilis prevention in traditional and non-traditional health care settings (i.e. in prenatal clinics versus rural areas with lay caregivers) should also be evaluated. Finally, research is needed to evaluate potential one-dose oral treatments and rapid, non-invasive syphilis tests; fingerstick testing methods and one-step strip testing using T. pallidum-specific recombinant antigens are available, but further field testing is needed to develop quality control methods and assess their usefulness.

In 1995, all PAHO Member States resolved to eliminate congenital syphilis in the Americas. Their goal is to reduce congenital syphilis to less than or equal to 0.5 cases per 1000 births by detecting and treating over 95% of infected pregnant women and reducing the overall prevalence of syphilis during pregnancy to less than 1%. Since this resolution, systematic efforts towards elimination, including the development of comprehensive plans have taken place in several Member States, including Argentina, Bolivia, Brazil, and Colombia. Mothercare, a USAID-funded organization, has developed a training package for syphilis prevention and control in maternal and child-health programmes, which has been field-tested in Latin America and Africa and provided to more than 30 countries. Recently, progress in programme development has been reported from Nairobi, Kenya, where syphilis screening of pregnant women increased from 60% to 100% and treatment from 9% to 85%. A programme in Lusaka, Zambia, documented a 50% reduction in adverse pregnancy outcomes over several years by increasing maternal syphilis screening and maternal and partner treatment.

Despite the impact of congenital syphilis on maternal and infant health, and the demonstrated biological feasibility of elimination, it was not until PAHO developed its elimination programme in 1995 that this condition began to receive increasing recognition by governments and donor agencies. Among the principal challenges to the elimination of congenital syphilis are the lack of awareness and understanding of the problem by persons involved in maternal and child health programmes and in HIV prevention programmes. Building support among the many organizations and public health professionals working in these areas will be critical if we are to mount a global effort to eliminate this disease.

Before the development of a vaccine, diphtheria was a major cause of morbidity and mortality among children in temperate climates, especially in crowded urban areas, even after the introduction of an antitoxin in the 1890s reduced the mortality for severe cases from 25-50% to 5-10%.

Diphtheria is caused by toxigenic strains of Corynebacterium diphtheriae; these strains carry a phage coding for the toxin and are transmitted from human to human primarily by infected secretions from the respiratory tract and skin lesions. Absorption of the toxin causes severe tissue damage locally in the respiratory tract, heart, and peripheral nerves, resulting in fatalities due to obstruction of the airway, myocarditis, and diffuse polyneuritis.

Almost complete elimination of diphtheria has been noted in developed countries after childhood vaccination coverage against diphtheria reached 70-80%. Many European countries have not reported cases in more than a decade; almost all the rare cases in others are linked to known importation. In the USA during 1980-95, only 41 cases were reported, and all except one of the culture-proven cases since 1990 were linked to known importation. Low incidence and lack of epidemics persist in these countries despite the gradual accumulation of large numbers of adults who are susceptible because of waning vaccine-induced immunity.

Many developing countries do not have reliable incidence data on diphtheria because of the need for laboratory diagnosis and good surveillance systems. However, the disease burden appears much smaller for diphtheria than for measles or diarrhoeal disease. Cases reported from developing countries have decreased dramatically as coverage with three doses of DPT (DPT3) increased (from 46% in 1985 to 79% in 1992), accounting for most of the global decrease during the 1970s and 1980s (77,040 cases in 1974 and 23,557 in 1988).

However, during the 1990s, diphtheria has resurged in both developed and developing countries where it had been well controlled. An epidemic that began in 1990 in the Newly Independent States (NIS) of the former USSR caused almost 150,000 reported cases and 5000 deaths by the end of 1996. Before aggressive vaccination campaigns during the epidemic, coverage of DPT3 was less than 80% among infants and less than 25% for receipt of a booster dose among adults. Overall, most reported cases and fatalities occurred in adults. Control has been achieved in most NIS by achieving unprecedented levels of adult immunization in addition to intensifying childhood immunization. Developing countries, such as Ecuador (approximately 400 cases in 1993-94) and Algeria (approximately 1000 cases in 1992-96), have also reported outbreaks after periods of good control following implementation of childhood immunization programmes.

Circulation of toxigenic strains of C. diphtheriae persists in parts of both developed and developing countries where diphtheria is not being reported. For example, a focus of toxigenic C. diphtheriae was found in South Dakota in 1996 with molecular analysis of strains suggesting local persistence since the 1970s; and a recent serological study in rural Kenya showed high diphtheria immunity among unvaccinated persons, suggesting continued circulation.

Eradication is not currently feasible because preliminary evidence suggests that circulation of toxigenic C. diphtheriae might persist, even in populations with fairly high childhood immunization coverage, and might be difficult to detect; and sustainable reservoirs for the toxin gene might exist in nonhuman mammals. Future feasibility depends on understanding prevention of continued circulation and evidence that circulation of the toxin gene in the animal reservoirs is not sustained indefinitely.

Four factors favour eradication: humans are the only known sustained reservoir; an inexpensive and safe toxoid vaccine exists; high coverage with this vaccine appears to reduce circulation of toxigenic strains of C. diphtheriae in the human population and to prevent disease; and seasonality exists for both respiratory and cutaneous diphtheria, making transmission of toxigenic strains more vulnerable to interruption.

Seven factors could hinder eradication: the phage carrying the toxin gene can occasionally be found in nondiphtheria Corynebacterium species infecting animals (this may represent an ineradicable reservoir for reintroduction of toxin gene into non-toxigenic C. diphtheriae strains); infection with a toxigenic strain can either be direct or in situ by a phage carrying the toxin gene, infecting a commensal non-toxigenic C. diphtheriae strain; an asymptomatic carrier state exists, even among immune persons, and circulation appears to be able to continue under some settings, even in populations with fairly high childhood immunization rates; immunity to diphtheria is not life-long (a minimum of three doses is required for effective primary immunization, and periodic booster doses are required throughout adult life to maintain protective titres -- in addition, immune persons are not distinguishable from susceptible persons except by serological or Schick testing; in countries with low incidence, both the clinician and the laboratory can easily miss the diagnosis of diphtheria, and empirical antibiotic treatment can prevent recovery of the organism; limited epidemiological, clinical, and laboratory expertise is available on diphtheria; and political will may be lacking because the disease burden is low in developed countries and is perceived to be relatively low in developing countries.

Near elimination could be achieved with full implementation of EPI. Benefits of diphtheria elimination are difficult to estimate in the absence of good data on disease burden in many developing countries. Developed countries would have fewer imported cases. The benefits of full implementation of EPI would extend to the other childhood diseases. Because an effective strategy for eradication is unknown, costs have not yet been calculated.

For elimination, implementation of the EPI programme (greater than 90% coverage with DPT3), coupled with childhood boosters, might allow near elimination of the disease. Maintenance of the disease-free state could require some level of coverage of the adult population (as suggested by the recent epidemic in the NIS).

For eradication, high coverage and high socioeconomic standards in many temperate-zone countries appear to have interrupted circulation of toxigenic C. diphtheriae. It is unclear whether this strategy is applicable to developing countries, especially those with lower socioeconomic conditions.

For elimination, knowledge is needed of the level of vaccine-induced immunity among both children and adults which is sufficient to prevent circulation of toxigenic strains in the population and to provide herd immunity in both developed and developing countries. In addition, knowledge is needed of the epidemiological effect of widespread vaccination in developing countries.

For eradication, knowledge is needed about whether carriage of the toxin gene among zoonotic Corynebacterium strains is stable enough to make eradication impossible and the factors that allow persistent circulation of toxigenic strains despite fairly high levels of childhood vaccination.

Implementation of EPI has achieved remarkable progress in decreasing the burden of disease in countries where reliable data are collected.

The principal challenges to elimination are lack of adequate data about the schedule of childhood and adult boosters which can prevent the disease reliably, and difficulties in global implementation of EPI and the necessary booster schedules.

The principal challenges to eradication are lack of data that toxigenic C. diphtheriae can be eradicated with the current vaccine under the present socioeconomic conditions in which much of the global population lives, and lack of consensus that diphtheria is an important problem globally.

Haemophilus influenzae type b (Hib) is a bacterium that causes meningitis, pneumonia, septicaemia, and other severe, invasive infections. Meningitis is characterized by infection of the spinal fluid and the meninges, a membrane that surrounds the brain. In the USA and other developed countries, approximately 5% of patients with meningitis die, and up to 30% of survivors have long-term disabilities ranging from hearing loss to severe mental retardation. In developing countries, up to 50% of Hib patients die in some settings.

In the absence of vaccination, Hib was consistently identified as the leading cause of bacterial meningitis among under-5-year-olds in developed countries. Before vaccination in the USA, an estimated 1 of every 200 children had an invasive Hib infection before the age 5 years. In developing countries, Hib is the leading cause of bacterial meningitis-associated deaths and the second leading cause of bacterial pneumonia deaths. Globally, Hib meningitis and pneumonia cause 380,000-500,000 deaths among under-5-year-olds each year. Accurate Hib disease incidence data are lacking for many parts of Asia and the Pacific Rim.

The biological feasibility of Hib eradication is difficult to determine, but several aspects of Hib disease and Hib vaccines make elimination possible. Hib is a uniquely human pathogen with no known reservoir in the environment. Hib polysaccharide-protein conjugate vaccines are highly effective (efficacy of 90-100%) in preventing disease, and should provide long-lasting protection. Hib conjugate vaccines also can interrupt transmission by preventing asymptomatic carriage and are thereby able to protect unvaccinated persons through herd immunity. At the practical level, Hib conjugate vaccines are still too expensive for many countries to use, they require more than one dose to provide substantial protection, and not all countries may be able to achieve the levels of vaccination coverage needed for elimination. Thus, programmatic obstacles are the major barriers to elimination.

The feasibility of eradicating Hib is more difficult to determine. At the molecular level, eliminating the genetic material that codes for the type b capsule is more difficult than eliminating the apparent occurrence of type b infections. With more research into the molecular biology of Hib and further experience with the vaccines, it may be possible to determine more accurately the feasibility of eradication.

Although economic analyses of programmes to eliminate/eradicate Hib have not been carried out, a recent analysis of the cost-effectiveness of routine Hib vaccination globally determined that, at current vaccination coverage rates, such a programme could prevent 58-83% of all Hib-related deaths and Hib-related disability-adjusted life years (DALY) lost at a cost of US$ 35-53 per DALY saved. This cost-per-DALY saved compares favourably with other new immunizations and with other life-saving interventions. The analysis, however, assumed that vaccine could be purchased at US$ 1 per dose, a price that should be attainable but is still lower than the current price.

Routine vaccination through national programmes is the cornerstone of control of Hib disease. Efforts to maintain high coverage and timely vaccination will improve the effectiveness of this control strategy. Ensuring a steady, affordable supply of Hib vaccine for developing countries will be essential. Efforts to eliminate Hib in countries with moderate-to-poor vaccination coverage will depend on the ability of the Hib vaccination programme to interrupt transmission and thereby provide herd immunity. Whether routine Hib vaccination will result in herd immunity in developing countries is still unclear. Further experience with Hib vaccines in developing countries may provide insights to novel strategies for maximizing the herd immunity effects of vaccination. Surveillance for Hib disease, including laboratory identification of the bacterium, will be required to monitor the impact of vaccination.

Because experience with Hib conjugate vaccines is relatively limited (about 10 years), continued assessment is needed of the long-term impact on immunity and on carriage rates. The mechanism for interrupting Hib transmission is still unknown. Continued efforts on new and improved Hib vaccines, which may be less expensive or provide immunity with fewer doses, are warranted. Additionally, research is needed to determine if it is possible to eradicate the gene for the type b capsule from populations of H. influenzae bacteria.

Because an accurate surveillance programme with relatively simple diagnostic methods would be critical during an eradication campaign, a noninvasive test for confirmation of Hib meningitis should be developed. Such a sentinel test should be supplemented with a standardized protocol to quantify the associated impact on Hib carriage.

In many countries, particularly in Asia, the burden of Hib disease remains largely undefined. Because the political will to pursue vaccination will depend in large part on the magnitude of the Hib disease burden locally, additional efforts are needed to quantify the burden of Hib disease where it remains undefined.

The widespread use of Hib conjugate vaccines for routine vaccination of infants and young children has dramatically reduced the incidence of the disease and the transmission of Hib organisms in several developed countries. In the Nordic countries (Finland, Iceland, Sweden, Norway, and Denmark) routine vaccination has essentially eliminated Hib disease, and in Finland and Iceland carriage in young children is no longer detected. In the USA, the impact of Hib vaccination has been equally dramatic: the incidence of Hib disease in young children has declined by greater than 95%, and good evidence exists that Hib vaccination has interrupted transmission and protected unvaccinated children by herd immunity. In developing countries, however, where the epidemiology of Hib disease differs substantially from the epidemiology in the USA and Europe, the impact of widespread vaccination is still unclear.

The current price of Hib conjugate vaccines is the principal obstacle to the wider control of Hib disease globally. Efforts to ensure access to a steady, inexpensive supply of vaccine will be needed. Hib vaccines combined with other newer vaccines having a broader impact on meningitis and acute respiratory infections may be more acceptable. A lack of information on the burden of disease in some regions also limits the vaccine's uptake in some regions that can afford it. Elimination of Hib invasive disease may be possible in the future, but additional experience with the use of Hib conjugate vaccines for control of Hib disease in nonindustrialized countries will be needed before the feasibility of eradication can be evaluated adequately.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It usually affects the skin and peripheral nerves but has a wide range of possible clinical manifestations. The disease is classified as paucibacillary or multibacillary leprosy (i.e. tuberculoid or lepromatous leprosy, respectively). Paucibacillary leprosy is a milder disease characterized by one or more hypopigmented, hypoaesthic skin lesions. Multibacillary leprosy is associated with symmetric skin lesions, nodules, plaques, thickened dermis, and frequent involvement of the nasal mucosa resulting in nasal congestion and epistaxis, and of peripheral nerve trunks resulting in deformities of the limbs, eyes and face.

The mode of transmission of leprosy remains uncertain but most investigators believe M. leprae is usually spread from person to person primarily as a nasal droplet infection. The incubation period is unusually long for a bacterial disease, generally 5-7 years, with the shortest period being 2-3 years and the longest up to 40 years. Peak age of onset is young adulthood, usually 20-30 years of age; disease is rarely seen in children under 5 years of age.

Leprosy is usually diagnosed by its clinical manifestations, which are characterized by anaesthetic skin lesions and inflammation of peripheral nerve trunks. The diagnosis is confirmed by skin biopsy and acid-fast staining, which are also used to stage disease and judge the response to therapy. Since 1982, WHO has advocated use of multidrug therapy (MDT) regimens to treat paucibacillary leprosy (6 months) and multibacillary leprosy (12 months). This regimen has served as the cornerstone for elimination efforts.

In 1985, WHO estimated 10-12 million leprosy cases worldwide; 5.4 million of these were registered in a leprosy programme. At the beginning of 1998, WHO reported that 883 340 were registered and being treated. Another 1-2 million people are permanently disabled as a result of leprosy but are considered free of active infection.

Each year, an estimated 500,000 new leprosy cases are identified. Most come from 32 countries where the disease continues to be considered a public health problem. At the beginning of 1998, 16 countries -- Bangladesh, Brazil, Cambodia, Democratic Republic of the Congo, Ethiopia, Guinea, India, Indonesia, Madagascar, Mozambique, Myanmar, Nepal, Niger, Nigeria, Philippines, and Sudan -- reported more the 90% of the world's leprosy cases.

Elimination of leprosy may be feasible. Although other animals (e.g. armadillos) carry M. leprae, humans are believed to be the organism's major reservoir, and MDT is curative. However, prolonged incubation of leprosy makes recognition of a disease-free area difficult. Asymptomatic carriers of M. leprae may infect other people, and the frequently chronic and mild symptoms may be difficult to detect without systematic screening of populations.

The estimated cost to identify and treat 2 million leprosy cases per year for the 3 years 1997-2000 is US$ 250 million; drugs account for 10% of the total cost. Prevention of leprosy-associated pain, suffering, ostracism, and disabilities (primarily deformity and blindness) is the primary benefit. In addition, resources now devoted to leprosy treatment and rehabilitation programmes could be directed elsewhere.

The strategy has focused primarily on increasing case-finding and expanding MDT services to all health facilities; ensuring that all existing and new cases are treated appropriately with MDT; encouraging all patients to take treatment regularly and completely; promoting leprosy awareness in the community so that people with suspicious lesions will report voluntarily for diagnosis and treatment; setting targets and time tables for activities and making all efforts to achieve them; and improving surveillance and tracking of patients to monitor progress towards elimination.

BCG vaccine is effective in preventing leprosy in some populations but its role in leprosy elimination programmes has yet to be defined.

• Resistance of M. leprae to rifampicin, when used alone as monotherapy, has been identified. Since rifampicin is a key drug in the MDT programme, this should be carefully monitored.
• New drug regimens requiring shorter treatment times are needed. Trials of ofloxacin, minocycline, and rifampicin in various dosages and time intervals are ongoing.
• Validation of supervised intermittent therapy options are needed. These may be useful when patients are living in remote settings.
• Better means are needed to identify M. leprae infection at the subclinical and early clinical stages, either through direct detection of the organism or indirectly by serological response.
• In the post-elimination phase, surveillance for leprosy will need to be maintained because of its long incubation time.

WHO's year 2000 goal for eliminating leprosy is defined as a reduction in the number of cases to less than 1 case per 10,000 population. Since 1985, the estimated number of leprosy cases has declined from 10-12 million to under 1 million registered cases in 1998. During the past 10 years, more than 10 million patients have been cured using MDT.

The primary challenges to leprosy elimination are: reaching populations that have not yet received MDT services; improving detection of the disease; and providing patients with quality services and drugs free of charge to patients.

Neonatal tetanus (NT) results from Clostridium tetani infection of the umbilical stump at or following delivery of a child born to a mother without sufficient circulating antibodies to protect the infant passively by transplacental transfer. Contamination of the umbilical stump at or following delivery is especially likely in an unattended delivery or a delivery attended by an untrained midwife. In some areas of the world, the cord is cut with an unclean object or the umbilical stump is traditionally covered with contaminated material. In addition, traditional surgeries (e.g. circumcision, uvulectomy) are associated with increased risk, as are mothers with a history of a previously delivered infant with NT.

The average incubation period is 6 days (range: 3-28 days). NT is characterized by generalized stiffness with spasms or convulsions. The case-fatality ratio is greater than or equal to 80%.

NT is a leading cause of childhood mortality in developing countries and is second only to measles among the vaccine-preventable diseases as a cause of childhood mortality. In some developing countries, NT accounts for one fourth of infant mortality and half of neonatal mortality in unimmunized populations. In 1997, an estimated 277 376 neonatal deaths were attributed to NT, with an estimated global mortality rate of 2.1 per 1000 live births.

Because tetanus spores are ubiquitous in the environment, eradication is not biologically feasible. "Elimination" (achieving rates less than 1 per 1000 live births) is feasible only if high levels of coverage with appropriate strategies are achieved (see Status of Elimination Efforts to Date).

Tetanus prevention through vaccination is highly cost-effective. The median estimated cost-effectiveness of tetanus toxoid (TT) vaccination programmes is US$ 89 (range, US$ 27-205) per case prevented for routine strategies, and US$ 0.21 (range, US$ 0.55-1.71) for the cost per dose of TT administered during mass campaign strategies. These costs do not include the need for certification as part of an elimination strategy.

The following are key strategies: achieving and maintaining high vaccination coverage levels for at least two doses of potent TT among reproductive-aged women in high-risk areas; promoting clean delivery, cord-care practices, and other surgical procedures performed on neonates (including the following practices shown to reduce risk: handwashing by the delivery attendant, delivery on a clean surface, use of a sterile or clean cutting tool, and application of a topical antimicrobial to the umbilical stump wound); and targeting women with a history of NT in previous infants.

Studies are needed to determine the following: optimum vaccination schedules for high, long-lasting immunity levels; optimum topical antimicrobial practices; operational approaches to monitor the field effectiveness of TT using data on population coverage and maternal vaccination levels among NT cases; safety of iodine as a topical antimicrobial in newborns and type of iodine to be used; safety and effectiveness of sustained-release TT; duration of protection among girls vaccinated during childhood through EPI; and mechanisms for sensitive surveillance.

An elimination goal (defined as less than 1 case per 1000 live births for all districts) has been established. During 1980-95, the number of developing countries that have eliminated NT increased from 38 to 97.

Challenges to elimination include the following: insufficient resources; coordination of efforts by EPI/MCH to achieve all strategies proposed in Section 5 above; achievement of high coverage levels with two or more doses of potent TT among pregnant women; achievement of high coverage levels with two or more doses of potent TT among women of childbearing age; ensuring that doses of TT meet production and quality requirements; development and delivery of culturally appropriate programmes for promoting vaccination of girls and women and clean-cord and post-surgical care in neonates; development of operational approaches to reach and vaccinate, on a priority basis, women with a history of a previous child with NT; lack of effective surveillance and insufficient political will.

In June 1998 the Scientific Advisory Group of Experts (SAGE) for WHO recommended that TT be replaced with tetanus-diphthesia Td vaccine.

Pertussis, a highly infectious, vaccine-preventable disease lasting many weeks, is caused by infection with Bordetella pertussis, a bacillus first isolated in 1906 by Bordet and Gengou. Pertussis typically manifests as paroxysmal spasms of severe coughing, whooping, and post-tussive vomiting in children. The major complications, including hypoxia, pneumonia, seizures, encephalopathy and malnutrition, are most common among infants and young children. Pertussis is transmitted by direct contact with discharges from respiratory mucous membranes of infected persons and by airborne droplets. Like measles, it is highly contagious, with up to 90% of susceptible household contacts developing clinical disease following exposure to an index case.

Pertussis results in high morbidity and mortality in many countries every year. Worldwide, 206,541 cases were reported in 1994, and 80,606 cases were reported in 1995. However, pertussis cases are substantially underreported in most countries. When this was taken into account, approximately 39 million cases of pertussis and 355,000 pertussis-related deaths occurred in 1995. The estimated number of pertussis cases globally was similar to that of measles cases. The estimated number of pertussis-related deaths is one-third of the estimated number of measles-related deaths and 100,000 fewer than deaths caused by neonatal tetanus.

Pertussis elimination/eradication does not seem feasible for several reasons: whole-cell and acellular pertussis vaccines are most effective in preventing severe disease and may have little impact on acquisition of infection, preventing mild disease, and decreasing transmission to other individuals; pertussis vaccines require multiple doses for protection, hence they require a highly organized vaccine delivery system; immunity following vaccination wanes, and in the absence of booster vaccinations in older children and adults, susceptible adolescents and adults will exist; the true burden of disease is not known because underreporting is a major problem in many countries; and pertussis is difficult to diagnose particularly during the catarrhal stage when it is most contagious (therefore, even aggressive outbreak-control strategies are unlikely to contain it).

Adequate herd immunity to block pertussis transmission in a sustained fashion (greater than 90% level of population immunity may be needed) may not be attainable even with 100% coverage; the efficacy of currently available acellular and whole-cell vaccines is, at best, 90%.

Side-effects associated with whole-cell pertussis vaccines are a major concern among health care providers and parents. Although new acellular pertussis vaccines cause fewer adverse reactions, they are significantly more expensive, especially when resources are limited in many countries.

Because the pathogenesis of B. pertussis and factors related to protection against infection are not well known, development of pertussis vaccines that are effective against infection and laboratory diagnosis of pertussis are challenging.

The following factors favour elimination/eradication: humans are the only reservoir for B. pertussis; whole-cell and acellular pertussis vaccines are highly effective in preventing severe disease (the introduction and widespread use of whole-cell pertussis vaccines, together with improving socioeconomic conditions, has resulted in a marked decline in reported pertussis incidence in many countries); seasonality exists for pertussis epidemics, making transmission more vulnerable to interruption; and long-term carriage is thought not to occur.

The estimated costs to eliminate or eradicate pertussis are unknown because an effective strategy has not yet been planned. Benefits of elimination or eradication are difficult to estimate in the absence of accurate data on the true disease burden in all age groups in many countries. However, eradication would allow cessation of vaccination against pertussis.

Pertussis can be reduced among children with implementation of the EPI programme (greater than 90% coverage with DPT3) and improved surveillance. However, elimination or eradication strategies have not been established because of limitations listed above in Section 3.

Research is needed to assess the true burden of infection in all age groups; develop and evaluate vaccines that are efficacious and safe for use among adolescents and adults; develop better diagnostic methods that are more sensitive and easy to perform and yield timely results; demonstrate local or regional elimination and the effectiveness of outbreak-control measures; further laboratory research to understand the pathogenesis of B. pertussis and host factors that are associated with protection against infection; and determine transmission patterns and identify critical factors involved in transmission to other persons through epidemiological studies.

Implementation of EPI has achieved remarkable progress in decreasing pertussis incidence in many countries. However, the true burden of disease is difficult to estimate because of problems with diagnosis and reporting of pertussis.

Challenges to eliminating/eradicating pertussis are as follows: current vaccines may not prevent infection and transmission to others, and immunity is not lifelong; effective booster vaccination for adolescents and adults is not available; highly sensitive and specific diagnostic tests that are also easy and quick to perform are not available; knowledge of the true disease burden in all age groups is lacking; and implementation of EPI is difficult.

Trachoma is a bacterial disease of the conjunctiva caused by four serovars of Chlamydia trachomatis. This organism is also responsible for a common reproductive tract infection, but the serovars that infect the genital tract usually do not infect the eye. Trachoma is the major infectious and preventable cause of blindness. Of all causes of blindness, it is second after cataract. Trachoma generally occurs where there is poverty, poor hygiene, and poor access to water. It is a disease of families; if one sibling is infected, more than 50% of others are likely to be infected with or without clinical signs. Blindness occurs after repeated infections and is 2-3 times more common in women than in men.

It is estimated that trachoma affects 146 million persons, and 500 million are at risk of the disease. An estimated 5.9 million people are blind or are at immediate risk for trachoma-associated blindness. Trachoma accounts for 15.5% of the global burden of blindness.

Elimination of blinding trachoma is possible, but eradication of C. trachomatis seems impossible. Trachoma has disappeared from North America and Europe because of improved socioeconomic conditions and hygiene.

Both surgical and nonsurgical interventions for trachoma control are highly cost-effective. Evans & Ransom employ a new measure -- handicap-adjusted life years (HALYs) -- a composite of years lost from both morbidity and mortality. During the 30 years of a trachoma control programme, the costs were US$ 11 per HALY saved for nonsurgical intervention and US$ 59 per HALY saved for surgical intervention.

A new strategy (SAFE) has been developed from past knowledge and new techniques based on recent epidemiologic and control studies, as outlined below.

S:

Surgery to correct lid deformity and prevent blindness. A simple tarsal rotation technique can be performed by eye nurses in 10 minutes.

A:

Antibiotics for acute infections and/or community control -- tetracycline ointment twice a day for 6 weeks or the new macrolide antibiotic, azithromycin, in a single dose. Operational research is required to work out the best regimen.

F:

Facial hygiene. Clean faces are associated with a lower prevalence of trachoma. Behavioural change can be introduced and sustained even in poor areas with little water.

E:

Environmental change -- improved access to water and sanitation and health education.

Because SAFE depends on community development/good public health practice, it involves not only the ministry of health but ministries of agriculture and water and sanitation. Beyond medical intervention, health education and community involvement are central to the success of this strategy.

In addition to SAFE, a new simplified grading scheme has been developed for detecting and grading active infection in communities:

TF:

follicular disease (the presence of five or more follicles in the upper tarsal conjunctiva);

TI:

intense inflammation (pronounced inflammatory thickening of the upper tarsal conjunctiva that obscures more than half of the normal deep tarsal vessels);

TS:

trachomatous scarring (the presence of scarring in the tarsal conjunctiva);

TT:

Trachomatous trichiasis (at least one eyelash rubs on the eyeball);

CO:

corneal opacity (easily visible corneal opacity over the pupil).

WHO has organized an Alliance for Global Elimination of Trachoma by the Year 2020 (GET 2020), including nongovernmental organizations concerned with blindness prevention (Christoffel Blinded Mission, International Eye Foundation, Sight Savers International, Helen Keller International, Swiss Red Cross, The Carter Center, World Vision, etc.), foundations (Edna McConnell Clark, Hilton, and Gulbenkian), bilateral agencies (such as DANIDA), and the private sector (Pfizer Inc.)

In the absence of a vaccine, operational research with regard to the SAFE strategy is needed for the following: testing and validation of rapid community assessment techniques; azithromycin regimens; cost-benefit studies; surveillance/monitoring studies; and barriers to the acceptance of the preventive surgical procedure.

Trachoma decreases and even disappears with improved economic and social conditions and is absent from North America and Europe. Morocco has embarked on a plan to eliminate trachoma from five southern provinces in a programme supported by WHO, the Edna McConnell Clark Foundation, Pfizer Inc., and the World Bank. Pfizer is donating azithromycin to the programme and supporting efforts to advance health education and community participation.

The principal challenge is generating awareness of both the problem within countries and the feasibility of control. The relative simplicity and low technological requirements of the strategy make trachoma elimination feasible, even in the poorest countries where it remains a public health problem.

Tuberculosis (TB) is a bacterial disease caused by organisms of the Mycobacterium tuberculosis complex (M. tuberculosis, M. bovis, and M. africanum). It is transmitted primarily by airborne droplets; infection occurs when susceptible persons inhale infectious droplets produced by the exhalations (coughs and sneezes) of persons with respiratory tract TB. The risk for infection is directly related to the duration and intensity of exposure to air contaminated with these droplets. Most HIV-negative infected persons react to the purified protein derivative (PPD) tuberculin skin test, and 5-10% of HIV-negatives will develop clinically apparent TB. Infection is more likely to progress to clinical disease in the presence of certain risk factors, including time since infection and level of cell-mediated immunity. Of known risk factors, HIV infection may be the most potent, with up to 50% of persons with TB/HIV co-infection developing TB.

TB can be diagnosed presumptively if acid-fast bacilli (AFB) are found in the sputum, body fluids, or tissue, or by a combination of clinical symptoms, chest radiograph abnormality, and positive PPD skin test. However, definitive diagnosis requires isolation and identification of organisms of M. tuberculosis complex from a clinical specimen. Diagnosis of extrapulmonary TB is more difficult because it requires tissue biopsy or body fluids, which usually contain only a few organisms.

Throughout the world tuberculosis causes significant morbidity and mortality, with 2-3 million deaths annually and 8-10 million new cases (half of which are infectious AFB smear-positive pulmonary TB). Moreover, tuberculosis has infected 1-2000 million persons who are at risk of developing active disease. Untreated, it is fatal in up to 50% of cases. However, effective chemotherapy has significantly reduced morbidity and mortality.

In developed countries, TB morbidity has decreased to low levels. In most developing countries, it remains one of the most common causes of morbidity and mortality. The World Bank estimates that over 25% of avoidable adult deaths worldwide are caused by TB. In many countries, case rates have not changed appreciably during the past several decades, and in areas where HIV infection is common, TB cases have increased dramatically.

Control measures are the same for developed and developing countries. However, the quality of these measures and the degree of their application differ greatly.

There are four general strategies for controlling tuberculosis:

• The most important and universally applied strategy is the early identification and treatment of persons with infectious TB. This strategy cures the affected person and renders the patient non-infectious within a few weeks, thus interrupting transmission in the community.
• Identification and treatment of persons with noninfectious TB (e.g. extrapulmonary TB, culture-negative pulmonary TB, primary TB in children, and TB infection without active disease) prevents infectious cases and subsequent TB transmission.
• Use of BCG vaccine which is commonly given to infants and children in developing countries. The vaccine is less commonly used in developed countries. Although BCG vaccine does protect young children against serious and fatal forms of TB, it does not reliably prevent the development of adult pulmonary TB. Consequently, it has no epidemiological impact on transmission of the disease.

Elimination of TB is feasible for the reasons outlined below.

• Infectious TB is relatively easy to identify by AFB smear. TB is treatable and curable, with cure rates approaching 100% when modern short-course therapy is used, and highly effective regimens costing as little as US$ 18 are available. Early diagnosis and effective treatment significantly reduce transmission. An excellent example of the effect of case-finding and treatment on reducing TB transmission was the U.S. Public Health Service (PHS) programme in Alaska where the annual infection rates in young children decreased from 25% to 1% between 1950 and 1960. The provision of short-course therapy with direct supervision to ensure cure is the cornerstone of the WHO "DOTS" (directly observed treatment-short course) strategy.
• Infected persons at increased risk of developing infectious TB can be identified through tuberculin screening of high-risk populations. TB is preventable by the administration of isoniazid preventive therapy (chemoprophylaxis) to those at risk of developing the disease. The efficacy of preventive therapy has been adequately demonstrated by clinical trials conducted by the PHS. More recent studies in developing countries have also found isoniazid-preventive therapy to be effective in HIV-infected persons.
• Humans are the primary reservoir of TB. Except for dairy cattle infected by M. bovis, no other important animal or environmental reservoirs of infection exists. In developed countries, testing of dairy herds and slaughter of infected animals and pasteurization of milk have virtually eliminated this problem. Moreover, in developing countries where M. bovis disease in cattle remains endemic, human disease associated with M. bovis does not appear to be common.
• In developed countries, TB has retreated into focal pockets that can be targeted for intensified control efforts. However, eliminating TB in these countries depends in part on global elimination because of imported cases. Although improved screening and prevention programmes targeting immigrants from countries with high TB rates will reduce the number of imported cases, tuberculosis in foreign-born persons will continue to occur until TB is eliminated globally.
• The World Bank has shown that short-course TB therapy is one of the most cost-effective health interventions available, comparing favourably with measles immunization, oral rehydration, and HIV screening of blood donors.

No accurate costs for global elimination of TB are available. The immediate global task is to control TB. Clearly, for a condition causing 8 million cases and 3 million deaths each year, the costs of disease and temporary disability are enormous. WHO has reported that TB treatment is a very cost-effective intervention, and DOTS is the key treatment strategy. However, WHO estimates that only about 30% of persons with TB worldwide have access to DOTS. Controlling TB in HIV-positive persons will ease the burden on general health services providing care for people with HIV/AIDS and their families and will add to the period of healthy life for people with HIV/AIDS.

WHO estimates that to implement the DOTS strategy in India for 30% of the population will cost US$ 98.6 million. Global control of TB, leading to elimination, will cost over US$ 500 million and require many decades of sustained effort.

The DOTS strategy must be expanded and sustained where it is working well, and made easier to implement in both vertical and horizontal health-care delivery systems. In addition, more efficient methods to ensure the provision of curative treatment need to be identified and tried in demonstration projects.

• The greatest need is for a new, safe, and effective vaccine to prevent the development of TB in already infected persons. Without such a vaccine, global TB elimination will not be realistic. Recent research has produced several types of candidate vaccines that are effective in animal models; clinical (human) trials of one or more vaccines are anticipated within the next several years. According to WHO, a new vaccine for TB will take 15 years to develop, given the most optimistic scenario.
• An inexpensive, rapid, accurate, and easily applied test is needed for diagnosing TB infection and disease. The ideal tests would be more sensitive and easier to perform than the tuberculin skin test and AFB microscopy.
• Research is also needed in the following areas: further shortening of TB therapy, especially with more widely spaced dosing that could be supervised, to improve the outcome of treatment (several promising new drugs are in various stages of investigation); improved methods to identify infected persons at risk of developing TB (this will permit targeting of preventive therapy to those who will benefit the most); alternatives to isoniazid preventive therapy which are shorter, safer, and better accepted; operational research into how to make delivery services more effective; and rapid transfer into practice of new technologies, which must be cost-effective even in poor countries.

Better use of current tools and implementation of new tools are necessary to control TB globally. WHO reports that many cases remain undiagnosed and receive no or inadequate treatment. These patients commonly are persistently infectious, chronically ill, more likely to die, and often carry drug-resistant strains. WHO estimates that if established "targets for case detection and cure could be met by the year 2000, we can expect to avert 70 million cases and 30 million deaths over the next 20 years." "Every year of delay in reaching targets will be responsible for approximately 2.2 million extra cases and one million extra deaths . . ."

Unfortunately, widespread implementation of the WHO DOTS strategy is proceeding slowly. Current WHO estimates are that only 25% of TB patients in developing countries have access to DOTS services.

The following are challenges to TB elimination: obtaining and continuing the political will of governments to support a strong TB-control effort; obtaining and continuing funding assistance for poor countries where most of the TB epidemic is occurring; assuring an ongoing drug supply; demonstrating the good return that investing in TB control and prevention programmes provides; evaluating programmes for successes; and a global strategic plan that would help ensure identification of funding priorities and present a concerted approach to the prevention, control, and eventual elimination of tuberculosis as a public health problem.

3. Parasitic Diseases

Chagas disease, also known as American trypanosomiasis, is caused by the parasitic protozoan Trypanosoma cruzi and is transmitted primarily by triatomine insects; it can also be transmitted by blood transfusion. Neither an effective vaccine nor therapy is available. In approximately 30% of cases, chronic, often severe and life-threatening cardiac or digestive tract disease occurs 20-30 years after initial infection.

The disease is believed to affect 16-18 million people, primarily in Central and South America; an estimated 100 million people are at risk, accounting for approximately 25% of the entire population of this region. Chagas disease accounts for an estimated 45,000 deaths each year and is ranked third behind malaria and schistosomiasis by WHO in terms of global burden as a tropical disease.

WHO has targeted elimination of domestic transmission of Chagas disease. Because it exists as a zoonosis, complete eradication is not feasible; however, control of human transmission is considered achievable by eliminating domestic insect vector populations.

Early estimates suggested that effective control could result in medical and economic benefits exceeding US$ 53 million per year, in the Southern Cone countries alone, compared with an estimated total cost of US$ 190-350 million for the 10-year programme. More recent (1997) estimates suggest that the overall benefits of disease elimination could exceed US$ 3500 million per year.

Elimination efforts focus on domiciliary insecticide applications using residual pyrethroids, improvement of housing conditions, and blood bank surveillance.

Research needs include studies of vector population biology and genetics, evaluation of the impact of current vector-control programmes, tools for more effective blood bank screening, new effective drugs for treatment, and studies on immunopathogenesis.

Through the efforts of the Southern Cone Initiative, the chief regional vector Triatoma infestans has been virtually eliminated from most of Uruguay and Chile, from much of its original distribution in Brazil and Argentina, and from regions of Paraguay and southern Bolivia, resulting in effective interruption of disease transmission in these countries. A 70% reduction of incidence of T. cruzi infection in young age groups has been achieved between 1985 and 1997.

Effective coordination, thoroughness, and long-term sustainability of vector control efforts are the primary challenges to elimination efforts.

Lymphatic filariasis is a tropical disease caused by the parasitic worms Wuchereria bancrofti or Brugia malayi. Infection with these parasites leads to a variety of clinical manifestations, including lymphoedema and elephantiasis of the leg, genital disease (including hydrocele, chylocele, and elephantiasis of the scrotum and penis) and recurrent acute secondary bacterial infections, commonly known as "acute attacks". The majority of infected persons are asymptomatic, but virtually all have subclinical lymphatic damage, and approximately 40% have renal involvement (proteinuria and haematuria). Tropical pulmonary eosinophilia, a rare progressive lung disease, is caused by inflammatory reactions against the parasite in the lungs.

When an infected mosquito takes a blood meal, the larval form of the parasite enters the skin, migrates to the lymphatic vessels, and develops over 6-12 months into adult worms, which cause damage and dilatation of the lymphatic vessels. Fertile adult females, during their 4-6 year life span, release millions of microfilariae into the blood, which are taken up by mosquitos; further development inside the mosquito is required before the parasite larva is again infectious for humans.

Although lymphatic filariasis infrequently causes death, it is a major cause of clinical morbidity and disability. WHO ranks lymphatic filariasis as the second leading cause of disability worldwide. The economic burden of the disease is poorly defined, but the costs to India alone are estimated at US$ 1500 million. In 1990, the estimated burden of disease was 850,000 disability-adjusted life years (DALYs).

Approximately 120 million persons in tropical areas of the world are actually infected with the parasite, but those at-risk are estimated at 1100 million. Of these infections, 90% are caused by W. bancrofti; B. malayi (10%) is limited to Asia and parts of the South Pacific. An estimated 25 million men suffer from genital disease (most commonly hydrocele); an estimated 15 million persons, the majority of whom are women, have lymphoedema or elephantiasis of the leg. The devastating social and psychological impact of these disfiguring conditions is only beginning to be understood.

The International Task Force for Disease Eradication considers lymphatic filariasis to be one of only six "eradicable or potentially eradicable" diseases. Factors favouring eradication include inefficient transmission (several hundred infective mosquito bites are required to produce a fertile adult worm pair) and, at least for W. bancrofti, the absence of a nonhuman reservoir. Because new drugs and drug combinations are now available that profoundly suppress microfilaria levels in the blood for greater than or equal to 12 months after a single dose, elimination is possible with annual single-dose mass treatment. In 1997, the World Health Assembly called for global elimination of lymphatic filariasis as a public health problem. Lymphatic filariasis has already been eliminated from several countries, both as a result of targeted programmes (e.g. Japan and parts of China) and improved sanitation (e.g. the USA where W. bancrofti was endemic in South Carolina until the 1930s).

Annual costs for mass treatment with available drug combinations are approximately US$ 0.05-0.10 per person. These efforts may have to be sustained for 5 years or longer to assure interruption of transmission. Benefits would include prevention of tremendous social and psychological suffering from chronic disease and improved economic productivity. If the estimated costs of lymphatic filariasis in India (US$ 1500 million) are similar to those in the rest of the world, the global economic benefit of lymphatic filariasis elimination could approach $4000 million per year.

Global elimination of lymphatic filariasis means interrupting transmission of infection, and reducing the suffering of persons with chronic disease, including appropriate treatment of lymphoedema and elephantiasis. The main strategy recommended for interruption of transmission is annual mass treatment of at-risk populations in endemic areas with single doses of albendazole in combination with either ivermectin or DEC; ancillary vector control can be helpful but is not required. To alleviate the suffering, the principal strategy is health education and training so that affected individuals learn the importance of scrupulous hygiene and other measures and the techniques necessary to achieve them.

Diagnostic and therapeutic tools are already available for global elimination of lymphatic filariasis. Additional research is needed to identify and evaluate techniques for rapid assessment and mapping of the disease, to develop mechanisms for surveillance and for monitoring the effectiveness of interventions, to identify optimal drug-delivery systems, and to assess the cost-effectiveness of intervention strategies. Research is also needed to optimize the effectiveness of drugs and drug combinations in killing the adult stage of the parasite.

Recognizing the availability of these new tools and a proven strategy for using them, the World Health Assembly in 1997 defined an international political will for this initiative by resolving to eliminate lymphatic filariasis as a public health problem globally. By November 1997, 13 countries in Asia, South America, and Africa had announced national plans for elimination of lymphatic filariasis, and seven of these countries had already begun implementing these plans. For example, in India alone, 40 million people have been targeted to receive a single dose of DEC on "National Filariasis Day."

Challenges include: developing and sustaining the global, regional, and national will required for filariasis elimination; and developing accurate and efficient methods to certify elimination.

Onchocerca volvulus infection (i.e. "river blindness"), which is caused by filariid parasites that are long-lived (8-15 years), is characterized by chronic skin and eye lesions. It is transmitted by Simulium blackflies that breed in rapidly flowing rivers and streams. The embryonic stage (microfilaria), released by female worms, causes most of the pathology. Human infection occurs from the bite of a blackfly that harbours one or more infectious (third-stage) O. volvulus larvae. Male and female worms gather in groups of five or six, intertwined and encased in a fibrous capsule that forms a palpable nodule. The female worms produce thousands of microfilariae (each about the size of a period on this page), which leave the nodule and migrate into the host's skin, eyes, and other organs. Persons with many fertilized female worms can harbour as many as 200 million microfilariae. The microfilariae live for 9-18 months but cannot develop into adult worms without first passing through the Simulium blackfly vector. In these insects, the microfilariae transform in the course of 6-12 days into the third-stage larvae that are infective to humans. There is no known animal reservoir for O. volvulus.

Several aspects of this life-cycle affect potential eradicability. First, only the few microfilariae that succeed in passing through both human and blackfly hosts reach adulthood. Second, the blackfly must bite at least twice to transmit the infection: once to acquire microfilariae from an infected person, and again to transmit the infectious larvae to another person. Finally, rarely do more than 5% of blackflies harbour infectious larvae at a given time, and most of these flies have only one or two such larvae ready to inoculate. Therefore, the transmission cycle has only one point of amplification (through humans) and is relatively susceptible to interruption.

Onchocerciasis is known to be endemic in 37 countries. In 1995, the WHO Expert Committee on Onchocerciasis estimated that 123 million persons were at risk of contracting the disease, and 17-18 million were infected, of whom about 270,000 were blind and another 500,000 severely visually impaired. About 95% of infected persons reside in Africa, where the disease is most severe along the major rivers in 30 countries in a belt spanning the northern and central part of the continent. Outside Africa, onchocerciasis occurs in Mexico, Guatemala, Ecuador, Colombia, Venezuela, and Brazil in the Americas, and in Yemen in Asia.

In 1993, the International Task Force for Disease Elimination did not list onchocerciasis as one of the six diseases suitable for eradication. However, onchocerciasis was listed as a disease, one aspect of which (blindness) could be eliminated. The difficulties in eradication include: the long life-span of the adult worms: the occurrence of reinfections; and lack of vaccines and acceptable drugs to kill the adult worms (macrofilaricide).

However, reconsideration of these difficulties is now appropriate, given the considerable progress made towards elimination of all morbidity from onchocerciasis in the Onchocerciasis Control Programme (OCP) areas in West Africa and in the Americas. Using vector control, the OCP has been very successful in interrupting transmission of this disease. After 20 years, onchocerciasis is no longer a public health problem in the original OCP area. Whereas infection rates in the programme's most severely affected country, Burkina Faso, were 80-90% when the programme began, the highest rates in 1995 were less than 2%. All 30 million persons at risk in the 11 countries of the OCP are being protected, and 125,000 to 200,000 have been prevented from becoming blind. About 10 million children born since the programme began are free from onchocerciasis, and 25 million hectares of land -- enough to support 17 million persons -- along West African rivers are now available for resettlement. In the Americas, data strongly suggest that semiannual mass distribution of ivermectin, without vector control, has interrupted transmission in 7 of 14 known foci, including those in Colombia and Ecuador, where one of the most efficient vectors in the world (Simulium exiguum) exists. If transmission can be interrupted with a free and easily deliverable medicine, the disease could potentially be eradicable. Furthermore, computer models and observations suggest that repeated ivermectin treatment might affect the fecundity of adult females or longevity of adult males, thus reducing the duration of mass treatment programmes to less than the life span of the adult parasites (8-15 years). Nongovernmental development organizations (NGDOs), bilateral and multilateral institutions, and national governments are providing the international momentum behind major programmes, and industry (Merck & Co.) is donating the drug. Finally, the problem is, unlike lymphatic filariasis, restricted to rural Africa and Latin America. Thus, onchocerciasis may now be eligible to be included on the list of diseases for potential eradication.

In African communities with severe (hyperendemic) onchocerciasis of the savanna type, 15% of the population can be blind and up to 40% of adults can be visually impaired. Visual impairment is a major occupational and social obstacle and reduces the life span of affected persons by an average of 10 years. Agricultural production decreases, young children are forced to care for their parents, and adolescents emigrate because of the fear of becoming blind. Ultimately, the village is further impoverished or completely abandoned. In areas where blinding onchocerciasis is rare, onchocercal skin disease occurs in up to 30% of the population; 8 million persons suffer from troublesome itching associated with dermal onchocerciasis, making it difficult for them to work, study, or interact socially. The unsightly skin changes may result in poor self-esteem and social ostracism. Intensive research is under way on the economic impact of onchocercal skin disease.

The OCP, which began in seven countries in 1974, used a strategy of interrupting transmission via vector control. The programme comprised aerial larviciding, supplemented by ground and water-based handspraying of blackfly breeding sites in rivers over a vast area of West Africa. In 1986, operations were extended to parts of four other countries to prevent reinvasion of the core area by blackflies. Replication of the OCP was not practical for 87% of the onchocerciasis-affected population living outside the OCP area.

In 1987, the introduction of ivermectin (Mectizan) resulted in a new strategy that enabled assistance to be extended to other populations. The drug kills Onchocerca microfilariae with almost no serious side-effects, and its effects after one oral dose last for approximately a year. In 1987, Merck & Co. announced its decision to provide the drug without cost in whatever quantities were needed and for as long as necessary to treat and prevent onchocerciasis. Merck also established an independent group of international scientists, the Mectizan Expert Committee, to evaluate applications for supplies of the drug.

The donation by Merck & Co. prompted national and international health workers in the affected countries to develop systems capable of distributing the orally administered drug once or twice a year to persons in remote villages. Many programmes for community-based distribution of Mectizan are assisted by NGDOs, which have demonstrated their flexibility, creativity, and rapid response to the challenge. The NGDOs have used delivery of what has become a popular drug in the communities as an entry point for developing broader health care services. A 10-member NGDO coalition has been established internationally, and national coalitions of NGDOs have been established in some countries.

In December 1995 the World Bank, encouraged by these successes, launched another regional programme -- the African Programme for Onchocerciasis Control (APOC) -- for the remaining areas of Africa. The primary goal of APOC is to eliminate onchocerciasis as a public health problem in these areas of Africa by the year 2007 by reaching the remaining 50-60 million persons at risk of potentially blinding onchocerciasis and/or severe skin disease. Unlike the OCP, APOC will use annual community-based distribution of Mectizan as its primary control strategy. Similarly, the Onchocerciasis Elimination Program for the Americas (OEPA), established after a Pan American Health Organization resolution in 1991 and aided by the InterAmerican Development Bank, also aims to eliminate onchocerciasis as a public health problem in the Americas by 2007 through Mectizan delivery. On both continents, the strategy entails rapidly determining the severity and distribution of onchocerciasis in remote areas and communities by testing a carefully selected sample of the populations and communities using new microcomputer-based mapping techniques and noninvasive, field-based diagnostic methods. Rapid-assessment field techniques are based on classification of communities by the prevalence of nodules (hyperendemicity is generally defined as rates greater than or equal to 40%). Once the "at-risk" communities are identified, Mectizan is offered annually (or in some countries in the Americas, biannually) for an indefinite period to all healthy persons except mothers who are nursing less than 1-week-old infants.

Research is needed concerning the following: mechanisms of surveillance; GIS (geographic information system) applications; computer-modelling of transmission of the parasite; PCR/DNA probes for infective larvae in blackflies; impact of prolonged ivermectin treatment on onchocercal skin disease; adult worm longevity/fecundity (through antigen detection techniques); monitoring of transmission; aspects of sustainability; economic impact; development of new macrofilaricides; and adapting the programme (without disrupting the current momentum) to other suitable drugs that can be used at the community level to control or eradicate other widespread diseases, such as combination therapy for lymphatic filariasis or praziquantel for schistosomiasis.

The progressive increase in the numbers treated with ivermectin has been impressive -- from 500,000 persons in 1988 to greater than 20 million in 1997. The World Bank signed a declaration of intent to reach the remaining 50-60 million persons at risk of potentially blinding onchocerciasis and/or severe skin disease and eliminate onchocerciasis as a public health problem in Africa by 2007. Similarly, the Onchocerciasis Elimination Program for the Americas aims to eliminate onchocerciasis as a public problem in the Americas by 2007. More than 95% of known hyperendemic communities in the Americas are under treatment. Merck & Co. will provide 410 million tablets of Mectizan, valued at several hundred million US$, during the initiative; over 100-million doses of Mectizan have safely been given since the donation began in 1987.

Challenges to elimination include the following: adequate funding; establishment by APOC and OEPA of effective and lasting partnerships with the coalition participants; continued refinement of the model of sustainable community-based distribution of Mectizan to control onchocerciasis; surveillance mechanisms for "sustainabilty"; management training at the ministry of health level; development of new macrofilaricides; difficulties associated with importing the drug; the relatively short shelf-life (2 years) of ivermectin; and certification criteria that are internationally accepted for elimination of morbidity and transmission.

Schistosomiasis is a tropical disease caused by several species of parasitic worms of the genus Schistosoma that live within human blood vessels. The female worm produces eggs that are fertilized by male worms and deposited in the vessel walls. The eggs either leave the body in the faeces or urine, or remain in the tissues where they cause inflammation and scarring. Symptoms are related to the location and number of eggs. S. mansoni and S. japonicum primarily cause disease of the intestines and liver, including diarrhoea, abdominal pain, fibrosis of the liver and collateral circulation; S. haematobium primarily affects the bladder and urogenital system, causing bloody urine and problems with micturition and fertility. If the eggs reach fresh water, they hatch, and the embryo (miracidium) swims in search of a susceptible intermediate host (snail species). Within the snail, they develop into larvae (cercariae) which are shed into the water and then become infective for humans.

Infection occurs when human skin contacts these fresh-water cercariae, which penetrate the skin, develop into adult worms, and migrate to the veins of the abdominal cavity, where the adult females release millions of eggs. The eggs escape to the lumen of the urinary bladder or intestine and are passed out during micturition or defecation, reach fresh water, and hatch into miracidia which infect the host snails that produce cercariae, and begin new infections.

An estimated 200 million persons in tropical areas of the world are infected with the parasites. Of these, 120 million persons are symptomatic and 20 million have severe disease, with manifestations that include hepatosplenomegaly and portal hypertension for intestinal schistosomiasis. For urinary schistosomiasis the disease manifestations range from haematuria to squamous cell cancer of the bladder. The loss in productivity resulting from schistosomiasis is 4-44 person-days per year.

Humans are the principal reservoir of S. mansoni and S. haematobium. Although other mammals (e.g. baboons) can be permissive hosts and can be infected, they do not contribute significantly to human transmission in most endemic areas. Domestic and other animals can also be infected with S. japonicum and figure significantly in transmission where they share living areas or their faeces are used as fertilizer.

Comprehensive control programmes, including mass treatment with antischistosomal drugs, health education, application of moluscicides, and other measures have reduced the prevalence dramatically in many areas. However, although they often reduce morbidity and mortality, control programmes have not usually led to elimination or eradication of transmission. Examples of the exceptions, in which control programmes have eliminated transmission, include the lesser Antilles Islands of Antigua, Guadeloupe, Martinique, and St. Lucia. In Tunisia, no transmission has occurred since 1984. Schistosomiasis has been eradicated from Japan and Montserrat. Control interventions probably will stop transmission in Indonesia, Islamic Republic of Iran, Morocco, and Saudi Arabia during the next few years.

Benefits of elimination include the following: potential earning of millions of dollars in tourism (e.g. in Malawi); savings in health expenditures for schistosomiasis; reduction in bladder cancer rates; decreases in premature death rates; and increases of approximately 4.5 million disability-adjusted life years worldwide.

A comprehensive approach to elimination is required. This would include mass treatment with praziquantel or other drugs; construction of wells and latrines; community health education to modify water use and sites of defecation/urination; and reduction of the vector snail populations through environmental modification and use of molluscicides.

Research is needed in the following areas: vaccine development; simple field-applicable tools for diagnosis (e.g. a test for circulating antigen in urine or saliva); and continued search for drugs in case widespread resistance develops to praziquantel and oxamniquine.

Although control of schistosomiasis is considered a public health priority in many countries in which it is endemic, serious attempts at elimination/eradication have occurred in relatively few places. Antigua, Guadeloupe, Japan, Martinique, Montserrat, St Lucia, and Tunisia have conducted successful programmes. Large-scale control programmes in Brazil, Egypt, China, Indonesia (Sulawesi), Islamic Republic of Iran, Morocco, the Philippines, and Puerto Rico have achieved varying degrees of success in reducing prevalence and subsequent morbidity.

Challenges include the need for effective treatment and retreatment delivery programmes; rapid, field-applicable tools to assess reinfection; comprehensive programmes, including provision and use of uncontaminated fresh water; a vaccine; and cost-effective methods for snail control. Elimination/eradication is not a feasible goal in sub-Saharan Africa where 80% of transmission is currently taking place and where effective morbidity control should be the aim of all Member States.

4. Viral Diseases

Hepatitis B virus (HBV) is transmitted through percutaneous or permucosal exposure to blood or body fluids, producing an acute or chronic infection. Most acute infections are asymptomatic. Fewer than 10% of children and 33% of adults have acute hepatitis B, which often results in hospitalization and -- in approximately 0.1% of patients -- in acute hepatic failure and death. HBV regularly produces chronic infection in infants (90%) and young children (30-60%) and, less frequently (1-6%), in older children, adolescents, and adults. Among adults, chronic HBV infection can cause death from chronic liver disease (CLD, e.g. cirrhosis) or primary hepatocellular carcinoma (PHC). The risk for a liver-disease-associated death among persons with chronic HBV infection is 25% for those who acquired infection as an infant or young child, and 15% for those who acquired infection as an adolescent or adult. HBV infection also can produce extrahepatic manifestations, including polyarteritis nodosa and membrano-proliferative glomerulonephritis.

The prevalence of chronic HBV infection varies worldwide; it is highly endemic (greater than 8% prevalence) in Africa, the Pacific Islands, parts of South America, and most of Asia, as well as in ethnically defined populations in Australia, New Zealand, and the USA. The high prevalence of infection is sustained by transmission during the perinatal period and early childhood. In populations with intermediate endemicity (2-8% prevalence), perinatal and early childhood transmission accounts for most HBV infection. Endemicity is low (less than 2% prevalence) in Australia, New Zealand, Western Europe, and the USA. Most acute infections occur among adolescents and adults, but perinatal and early childhood infections contribute substantially to the prevalence of chronic infection, and populations in which HBV infection is highly endemic may reside in these areas.

Estimates derived from regional data on prevalence of infection in the general population indicate that 360 million people worldwide have chronic HBV infection: 78% in Asia; 16% in Africa; 3% in South America; and 3% in Europe, North America and Oceania combined. Of these 360 million HBV-infected people, 55-92 million (15-25%) are expected to die at 45-55 years of age from HBV-related CLD. An estimated 1 million people die annually from HBV-related CLD or PHC. Although etiology-specific death rates for CLD are not available in most countries, CLD or PHC is among the five leading causes of death among adults in many developing countries. In countries in which HBV infection is highly endemic, most CLD is HBV-related; in countries in which endemicity is low, such as the USA, 10-15% of CLD is HBV-related.

Immunization with plasma-derived or recombinant hepatitis B vaccine confers a high level of protection against acute and chronic infection. Pre-exposure vaccination prevents greater than 95% of infections, and postexposure vaccination of infants at risk for perinatal infection prevents 90-95% of infections. The initial vaccination series confers protection against chronic infection for at least 15 years, and HBV transmission has been eliminated in populations 10 years after introduction of routine infant vaccination. Most chronically infected persons remain so over their lifetime, but their potential infectivity decreases because of the decline in HBV titre (HBeAg-positivity). The combined effects of immunization and declining infectivity make elimination of HBV infection feasible. Eradication of HBV infection requires sustained elimination of transmission over the number of years needed for persons with chronic infection to be no longer in the population. The increased use of effective antiviral agents to treat chronic HBV infection could hasten its elimination.

Humans are the only known host for HBV. Although experimental infection can be produced in some great apes, they do not appear to be a reservoir. Variants of HBV have been described which appear resistant to vaccine-induced antibody. However, failure of pre-exposure vaccination caused by these variants has not been demonstrated.

Economic analyses have shown routine infant vaccination to be cost-effective in preventing the acute and chronic sequelae of HBV infection in populations in which endemic HBV infection is high or low. In China (Province of Taiwan), the rate of chronic HBV infection and PHC deaths decreased among children within 10 years of a sustained infant hepatitis B vaccination programme. However, because the costs of HBV-related CLD will occur many years in the future, some analyses have not found vaccination to be cost-saving or cost-effective. The economic effects of vaccination programmes to eliminate HBV transmission in populations with differing rates of infection have not been examined.

The basic strategy to eliminate HBV transmission is to integrate hepatitis B vaccine into the routine infant vaccination schedule in a manner that will prevent perinatal and early childhood infection. In populations in which endemic HBV infection is high or intermediate, this generally requires beginning routine vaccination at birth to prevent perinatal transmission. However, using maternal HBsAg screening, any country with the appropriate infrastructure could identify infants who require postexposure vaccination soon after birth and routinely vaccinate all other infants. In countries in which the endemicity of HBV infection is intermediate or low, routine infant vaccination will prevent transmission among adolescents and adults after several decades. Elimination of transmission can be accelerated through catch-up vaccination of young children, adolescents, and high-risk adults.

Country-specific data are needed on HBV infection and the burden of HBV-related disease, development of combination childhood vaccines that include hepatitis B, continued studies to determine the long-term efficacy of infant immunization and the need for booster doses of vaccine, population-based studies of the effectiveness of various vaccination strategies, possible effects of antibody-resistant variants of HBV in elimination of transmission, and the potential for HBV circulation in susceptible animals.

The World Health Assembly has recommended that all countries integrate hepatitis B vaccine into childhood (infant or, where appropriate, adolescent) vaccination schedules by 1997. Thus far, approximately 95 countries have included or are in the process of including hepatitis B vaccine in their childhood vaccination schedules. Population-based evaluation projects (e.g. in China (Province of Taiwan), the Gambia, Shanghai, and Alaska) have been developed to evaluate the effectiveness of various vaccination strategies, and in some, transmission has been eliminated.

HBV is the first chronic infection considered for elimination/eradication. The principle challenges are to eliminate transmission and to maintain elimination for many decades. The primary barrier to elimination of HBV transmission is the cost of hepatitis B vaccine, especially for developing countries. Although the vaccine became available in the early 1980s, the cost appears to be higher relative to other childhood vaccines because it is a new vaccine produced with new technology. Other barriers include lack of knowledge about the relation between chronic HBV infection, CLD, and PHC; lack of local information on the HBV-related disease burden; and continued perception that because HBV-related CLD and PHC occur among adults, prevention of HBV infection is not an appropriate childhood vaccination activity, especially in countries where the endemicity is low.

Measles is an acute disease characterized by fever, cough, coryza, conjunctivitis, and an erythematous maculopapular rash caused by infection with the measles virus (an RNA virus classified as Morbillivirus in the Paramyxoviridae family). Complications such as otitis media, bronchopneumonia, croup, and diarrhoea occur more commonly in young children. Acute encephalitis occurs in approximately one in every 1000 cases. Subacute sclerosing panencephalitis develops rarely (about 1 per 100,000) several years after infection. Measles is more severe in malnourished children in whom it can cause haemorrhagic rash, protein-losing enteropathy, oral sores, diarrhoea with dehydration, and severe skin infections. In children who are borderline nourished, measles often precipitates acute kwashiorkor and exacerbates vitamin A deficiency leading to blindness. In the USA, 1-2 of every 1000 reported cases are fatal. Case-fatality rates in developing countries are 3-5% and can reach 30% in high-risk communities. Case-fatality rates are also high in immunocompromised children, including those with HIV infection and leukaemia; the characteristic rash sometimes does not develop in these patients.

The number of measles cases reported worldwide to WHO declined from 4.4 million in 1980 to 1.3 million in 1990 and 0.8 million in 1996. However, measles reporting is incomplete; the actual burden from measles in 1996 was an estimated 36.5 million cases and 1 million deaths. The Global burden of disease attributes 10% of mortality from all causes among children less than 5 years of age to measles; it is the eighth leading cause of death worldwide, representing 2.7% of disability-adjusted life years in 1990.

Although nonhuman primates can be infected with measles virus, humans are believed to be the only reservoir capable of sustaining transmission of the virus. Acquired immunity after illness is permanent. Live attenuated measles virus, when administered at the recommended ages, produces greater than 85% immunity after one dose and greater than 90% immunity after two doses; and vaccine-induced immunity is long-lasting. Widespread vaccination (mass campaigns and routine vaccination) has resulted in interruption of measles virus transmission in a number of settings (e.g. the Gambia in 1968-69, the English-speaking Caribbean islands, Cuba, Chile, and possibly other countries in Latin America in the 1990s, and the USA over short periods in 1993, 1995, and 1996). However, sustaining elimination in large populations or regions is difficult because of importations of measles virus from endemic areas, which is facilitated by the frequency of air travel. This experience suggests eradication of measles is technically feasible with existing vaccines but will require a coordinated global effort over a relatively short period of time.

Measles vaccination is one of the most cost-beneficial public health interventions. A preliminary economic analysis performed by the Children's Vaccine Initiative estimated expenditure of US$ 1100 million in 1995 for treatment of measles disease, and US$ 480 million for implementing the existing vaccination programme. Accelerating measles control, particularly in areas of low vaccination coverage and high disease burden, will probably be highly cost-effective. Cost-benefit and cost-effectiveness analyses for global measles elimination/eradication are under way.

Measles transmission can be interrupted if high population immunity is achieved rapidly through mass vaccination campaigns and/or routine immunization services. The Pan American Health Organization (PAHO) measles-elimination strategies are as follows: conduct a one-time "catch-up" vaccination campaign targeting all children aged 9 months to 14 years; achieve and maintain high routine vaccination coverage; conduct periodic "follow-up" campaigns targeting all children aged 1-4 years; and enhance surveillance for cases with laboratory confirmation of measles virus infection and virus isolation to enable molecular identification of the geographical origin of the virus.

The following areas warrant further investigation and research: the importance of adults in sustaining measles transmission and strategies to prevent adult outbreaks; the effectiveness of PAHO-style elimination strategies in African settings with large urban slums and high HIV-infection rates; the interrelations between HIV infection (or other immunocompromising conditions) and measles disease/vaccination; strategies to improve the safety and ease of administration of measles vaccine in mass campaigns; and monitoring the safety of measles vaccination.

In 1996, the estimated global coverage with one dose of measles vaccine was 81%. Nevertheless, nearly 1 million measles-related deaths occur each year, half of them in Africa. The countries of the Americas are committed to eliminate measles by the year 2000, and the Pacific Island nations are expected to make a similar commitment in the near future. The European Advisory Group on the Expanded Programme on Immunization has recommended that measles be eliminated from Europe by the year 2007. The Regional Committee of the Eastern Mediterranean has adopted an elimination target of 2010. China and several southern African countries have embarked on accelerated measles control/elimination approaches.

Challenges include: perception in developed countries that measles is a minor disease of little consequence; lack of political and financial support; ease of importation of measles virus, particularly through air travel; and need to mobilize global resources and collaboration among partner organizations and focus these over a relatively short period of time (3-5 years).

Rubella usually presents as a mild or asymptomatic infection in adults and children. However, rubella infection in pregnant women, especially during the first trimester, can result in miscarriage, stillbirth, or the constellation of birth defects known as congenital rubella syndrome (CRS). The most commonly described CRS anomalies include nerve deafness, cataracts, cardiac anomalies, and mental retardation.

The global burden of rubella and CRS is undefined. Rubella is endemic in most countries. In a survey conducted by WHO in 1995, 78 of 214 countries (36%) had a national policy of rubella vaccination. Analysis of published serosurveys in several developing countries indicated a wide range of serosusceptibility in reproductive-aged women. Thus, the potential for outbreaks of rubella and subsequent CRS exist. More than 20,000 infants are born with CRS each year in the Americas in the absence of major epidemics. Globally, an estimated 236,000 CRS cases occur every non-epidemic year in developing countries. In countries with endemic rubella in the prevaccine era, the rate of CRS was 1 per 1000 live births.

Use of the established criteria for feasibility of eradication by the International Task force for Disease Eradication indicates that rubella and CRS can be eradicated. Since the introduction of rubella vaccine in the USA in 1969, the incidences of rubella and CRS have decreased by 99%.

The following factors favour elimination/eradication of rubella/CRS: humans are the only reservoir for rubella; rubella vaccine is highly effective in preventing rubella and CRS, and a combination vaccine with measles exists; and because of this combination vaccine, rubella elimination/eradication can be combined with the already existing measles elimination/eradication efforts.

Rubella and CRS prevention is cost-effective. In the USA in 1982, the estimated lifetime cost of caring for a child with CRS was over US$ 200,000. A cost-benefit analysis for rubella vaccine in the USA conducted in 1992 demonstrated a ratio of 11.1 : 1 when considering direct and indirect costs.

The key strategies for countries with no rubella/CRS surveillance or rubella vaccination programme include: establishment of surveillance for rubella and CRS; implementation of a national rubella vaccination programme, particularly ensuring high level protection of reproductive-aged women as a means of direct protection; and prompt outbreak-control measures.

Countries that have an established rubella and CRS surveillance system and national rubella vaccination programme should include maintenance of high vaccination levels in preschool- and school-aged children and young adults (particularly women of childbearing age); intensification of diagnosis of and surveillance for rubella and CRS; and prompt control of rubella outbreaks.

Research needs include development of rapid and non-invasive laboratory tests for diagnosis of rubella/CRS; and determination of the serosusceptibility to rubella among reproductive-aged women in developing countries to monitor the impact of the rubella vaccination programmes.

The USA has targeted a goal of eliminating indigenous rubella and CRS by the year 2000. PAHO has determined it would be premature to establish a hemispheric goal of rubella elimination, but this could be a logical development as progress continues with measles elimination.

Challenges include establishing rubella and CRS as a priority in many developing countries; depending on the vaccination strategy implemented in countries, 30-40 years may be required for eradication/elimination of CRS; and lack of financial resources in many countries to sustain a vaccination programme because of the added cost of the rubella component of the vaccine and the necessity to ensure protection in reproductive-aged women.

Yellow fever (YF) is a multisystem disease of variable severity characterized in most cases by an acute, prostrating, but self-limited generalized febrile illness and, in persons who have the severe form of the disease, by a combination of hepatitis, generalized haemorrhages, proteinuria and myocarditis, and death in 25-50% of cases. The mosquito-borne flaviviral infection occurs naturally only in South America and Africa. In South America, sylvatic YF leads to sporadic cases and small outbreaks. However, following reversal of the gains achieved during the hemispheric campaign to eradicate Aedes aegypti, the principal mosquito vector of urban YF, most tropical and subtropical urban areas of the Americas are now at greater risk of urban epidemics than at any time in the last 50 years. In sub-Saharan Africa YF is a major public health problem occurring in an endemic pattern, with periodic urban epidemics due to interhuman transmission by A. aegypti. With extensive and rapid international air travel, the occurrence of YF outbreaks in either of these regions also increases the risk of introducing the virus into urban areas of the Pacific and Asia, where A. aegypti is also widespread.

Over the period 1986-95, 21,717 cases (5119 fatal) from Africa and 2018 cases (1301 fatal) from South America were reported to WHO, giving an annual average of 2000 and 200 cases, respectively. However, in specific studies, official reports of epidemics have underestimated incidence by factors ranging from 3- to 250-fold. Yellow fever was not included in the recent Global Burden of Disease and Injury Series; however, its reported incidence in sub-Saharan Africa is similar to that of reported Neisseria meningitidis episodes in that region.

Previous national and regional vaccination and A. aegypti eradication programmes have shown the feasibility of significantly reducing or eliminating disease transmission in areas where coverage with the attenuated vaccine was high or the mosquitos were eliminated in urban areas. Over a 15-year period when the vaccine was used consistently in French-speaking Africa, no outbreaks occurred even though epidemic transmission continued in neighbouring English-speaking countries. Although YF can never be eradicated because the virus is maintained in natural animal reservoirs, human disease can be effectively eliminated by vaccination with the proven 17D vaccine, or in urban areas, by mosquito control.

The estimated cost-effectiveness of YF vaccination in Nigeria is US$ 381-763 per case prevented and US$ 1904-3817 per death averted, depending on whether the vaccine was administered during emergency interventions or routinely (under EPI), respectively.

While YF vaccine has recently been administered principally in ad hoc campaigns to contain outbreaks, the above cost-effectiveness analysis showed that routine administration under the EPI was sevenfold more efficient in preventing cases and deaths. In 1988, WHO and UNICEF recommended routine childhood and catch-up YF vaccination in Africa, but coverage rates typically range from less than 1% to 50%. A committed effort by national governments and international agencies to improve and maintain vaccination coverage is needed; administration at the same time as measles vaccine is a strategy to reduce administration costs and to link YF vaccine with a disease that has greater visibility. A. aegypti eradication is not considered feasible in all areas where the disease is endemic. Recent YF cases in unvaccinated Americans and Europeans visiting areas with endemic transmission underscore the underutilization of the vaccine by travellers.

High HIV infection rates overlap areas of Africa where universal YF vaccination is recommended. However, the vaccine's safety in HIV-infected persons remains unresolved. YF vaccine is safe in adults but carries a poorly studied potential for neurological side-effects in infants. Although vaccination is recommended at 9-12 months, the rate of serious neurological side-effects in that age group is unknown. Research is needed to improve vector surveillance methods and to develop practical and more effective vector control methods for emergencies. Although lyophilized YF vaccine is stable at ambient environmental temperatures, immune responses lower than the expected 95% have been reported in recent mass campaigns, underscoring the need to ensure the proper storage and use of reconstituted vaccine. Modifications to improve the stability of reconstituted vaccine would facilitate vaccine implementation in the field.

The inclusion of YF vaccine in the national EPI has been reported, at one time or another, in only 17 of the 34 at-risk African countries and, except for Gambia, coverage rates have ranged from less than 1% to 55%. Nigeria, the site of the largest outbreaks in recent times, has a coverage rate less than 1%. In June 1997, the Executive Committee of the Directing Council of PAHO adopted a resolution urging Member States to include yellow fever vaccine in their national immunization programmes in all areas at risk of transmission of the virus. Five countries in the Americas (Brazil, French Guiana, Panama, Peru, and Trinidad and Tobago) have included the vaccine in the EPI in specified high-risk areas, and others have been encouraged to follow suit.

Although a safe and effective YF vaccine has been available for more than 50 years, the failure to control yellow fever in Africa is due to failure of effective application. Although WHO and UNICEF agreed in 1988 that YF vaccine should be included in the EPI of African countries, implementation of that recommendation has been slow and incomplete. The Global Programme on Vaccines strategic plan outlines needed actions for successful implementation of childhood vaccines, citing the specific roles of national governments, international organizations, the donor assistance community and industry. Those parties should collaborate to examine the obstacles that slowed the implementation plan and to improve its performance within a specified period of time. A similar but more selective initiative is needed in South America.

* Contributed by Godfrey P. Oakley, Jr, Centers for Disease Control and Prevention, Atlanta, GA, USA.

** Contibuted by Glen Maberly, Rollins School of Public Health, Emory University, Atlanta, GA, USA.

*** Contributed by Ray Yip, UNICEF, New York, USA.

**** Contributed by Barbara A. Underwood, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences, Washington, DC 20418, USA.

***** Contributed by Lyn Finelli, Stuart M. Berman, Emilia H. Koumans, and William C. Levine, Centers for Disease Control and Prevention, Atlanta, GA, USA.

****** Contributed by Charles Vitek and Jay Wenger, Centers for Disease Control and Prevention, Atlanta, GA, USA.

******* Contributed by Orin Levine, Jay Wenger, Yand Bradley Perkins, Nancy Rosenstein and Anne Schuchat, Centers for Disease Control and Prevention, Atlanta, GA, USA, and the Global Programme for Vaccines, WHO, Geneva, Switzerland.

******** Contributed by Richard A. Spiegel and Bradley A. Perkins, Centers for Disease Control and Prevention, Atlanta, GA, USA.

********* Contributed by D. Rebecca Prevots, Centers for Disease Control and Prevention, Atlanta, GA, USA.

********** Contributed by Dalya Guris, Peter Strebel and Melinda Wharton, Centers for Disease Control and Prevention, Atlanta, GA, USA.

*********** Contributed by Joseph A. Cook, Program for Tropical Disease Research, The Edna McConnell Clark Foundation, New York, NY, USA

************ Contributed by Bess Miller and Carl Schieffelbein, Division of Tuberculosis Elimination, Centers for Disease Control and Elimination, Atlanta, GA, USA.

************* Contributed by C. Ben Beard, Centers for Disease Control and Prevention, Atlanta, GA, USA; and Chris J. Schofield, London School of Hygiene and Tropical Medicine, London, England, the ECLAT network, and World Health Organization, Geneva, Switzerland.

************** Contributed by David Addiss, Centers for Disease Control and Prevention, Atlanta, GA, USA.

*************** Contributed by Frank O Richards, Centers for Disease Control and Prevention Atlanta, GA, USA; Emanuel Miri, The Carter Center of Emory University, Atlanta, GA, USA; Stefanie Meredith, Task Force for Child Survival and Development, CDC, Atlanta, GA, USA; Ronald Guderian, (formerly) Ecuador Onchocerciasis Control Program, Seattle, WA, USA; Mauricio Sauerbrey, Onchocerciasis Elimination Program of the Americas, Guatemala; Hans Remme, Tropical Disease Research Programme, WHO, Geneva, Switzerland; Randall Packard, Emory University Rollins School of Public Health, Atlanta, GA, USA; Jean-Michel Ndiaye, Africa Regional Advisor in Health/Guinea-worm, UNICEF, Abidjan, C"te d'Ivoire.

**************** Contributed by Daniel G. Colley and David Addiss, Centers for Disease Control and Prevention, Atlanta, GA, USA; and Lester Chitsulo, CTD, World Health Organization, Geneva, Switzerland.

***************** Contributed by Harold S. Margolis, Centers for Disease Control and Prevention, Atlanta, GA, USA.

****************** Contributed by Peter M. Strebel, Centers for Disease Control and Prevention, Atlanta, GA, USA.

******************* Contributed by Susan E. Reef, Centers for Disease Control and Prevention, Atlanta, GA, USA.

******************** Contributed by Theodore F. Tsai, Centers for Disease Control and Prevention, Atlanta, GA, USA.

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