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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

Cover of The Infectious Etiology of Chronic Diseases

The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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CONTROL OF INFECTIOUS CAUSES OF CHILDHOOD DISABILITY IN DEVELOPING COUNTRIES

, Ph.D., Dr.P.H.

Department of Population Health Sciences and Waisman Center, University of Wisconsin-Madison, Madison, WI

Too often, infectious diseases have been distinguished from chronic diseases, as though these are mutually exclusive categories competing for recognition as a leading public health priority. Nowhere is this view less sustainable than in the field of childhood disability, particularly in developing countries. Worldwide, infections are among the leading causes of chronic, developmental disabilities in children, along with and sometimes interacting with genetic and nutritional causes (Institute of Medicine, 2001). In developing countries today, infections that are ostensibly preventable or controllable continue to be important causes of damage to the developing nervous system resulting in early and long-term cognitive, motor, seizure, hearing, vision, and behavioral disabilities. Infectious causes of developmental disabilities thus take a major and potentially unavoidable toll on the population health and economies of low-income countries today. This paper reviews some of the major infectious causes of developmental disabilities in low-income countries and discusses strategies and inputs needed for their prevention.

Congenital Infections

Numerous prenatal infections can damage the developing nervous system or senses, causing long-term disabilities in children (Levine et al., 2001). The occurrence, nature, and severity of effects vary not only with the type of organism but also often with the timing of the exposure. For example, first or second trimester exposure to toxoplasmosis, cytomegalovirus, and varicella infections may result in a range of impairments recognizable at birth, including microcephaly, hydrocephaly, growth retardation, blindness, seizures, and skin disorders (Remington et al., 1995; Dunn et al., 1999), whereas exposure late in pregnancy or during delivery may result in unapparent infection at birth and onset of developmental delay during infancy or childhood (Koppe et al., 1986).

Congenital Syphilis

The first congenital disability to be linked to an infectious cause (the spirochete Treponema pallidum), congenital syphilis is preventable through routine antenatal screening and treatment with penicillin. As a result, it is now a relatively rare occurrence in developed countries, but in some low-resource settings where routine antenatal care is lacking or where cost barriers prevent access to treatment, recent studies have reported that 4 to 11 percent of births occur to women with positive syphilis tests at delivery (Southwick et al., 2001; Frank and Duke, 2000; Walker and Walker, 2002). The outcomes of congenital syphilis range from fetal and infant death to premature birth, and survival with or without neurological manifestations, which can include deafness, interstitial keratitis, and mental retardation. The most severe outcomes generally result when conception occurs during the early stages of maternal syphilis infection. Outcomes are less severe when conception occurs during the latent state of maternal infection, and clinical manifestations of congenital syphilis are thought to be least severe when onset of maternal infection occurs during the third trimester of pregnancy (Wicher and Wicher, 2001). Animal studies suggest that outcomes may also be modulated by the genetic background of the conceptus (Wicher et al., 1994). Prevention of congenital syphilis requires interventions to reduce the risk of sexual transmission to women of childbearing age, and expansion of antenatal screening and access to treatment. Although the effectiveness and cost-effectiveness of these interventions have been established in developed countries, a recent study in South Africa identified logistical difficulties that prevent timely diagnostic results and access to treatment even when antenatal screening can be accomplished (Beksinska et al., 2002). These difficulties include late presentation for antenatal care, transportation delays that delay access to accurate laboratory results, and lack of record keeping, tracking mechanisms, and counseling services. Considerations such as these have led some to recommend antibiotic treatment of all pregnant women in selected high risk populations (Walker and Walker, 2002).

Congenital Toxoplasmosis

Congenital toxoplasmosis results from transplacental transmission of infection with the protozoan parasite Toxoplasma gondii following an acute episode of maternal infection during pregnancy. The clinical manifestations can include chorioretinitis, intracranial calcification, necrotizing encephalopathy, microcephaly, cranial nerve palsies, spastic hemi- or quadriparesis, seizures, cognitive disability, and death. Clinical signs may be absent at birth, but infants with congenital toxoplasmosis may develop cognitive and vision disabilities by late childhood. While the risk of transplacental transmission has been found to increase with increasing gestational age, approaching 90 percent during the third trimester, the severity of clinical manifestations appears to decrease with increasing gestational age (Jones et al., 2001). Those previously uninfected are susceptible to acute toxoplasmosis infection through ingestion of raw or inadequately cooked infected meat, contaminated unwashed fruits and vegetables, or oocytes from the feces of infected cats. Although little is known about the frequency of congenital toxoplasmosis in low- and middle-income countries generally, a recent study from Brazil reported a prevalence of 1 per 3,000 live births (Neto et al., 2000), more than three times the rate reported in developed countries (Jara et al., 2001). Evidence of the cost-effectiveness and safety of early detection (via prenatal or newborn screening) and treatment of acute infection with antiparasitics is not consistent or conclusive at this time (Jones et al., 2001; Roizen et al., 1995). Thus, prevention of congenital toxoplasmosis in low-income countries requires further research and perhaps more emphasis on educational programs regarding the risks and specific hygienic precautions that can prevent acute infections during pregnancy.

Congenital Rubella

Congenial rubella leads to a range of adverse pregnancy outcomes or birth defects but only when maternal rubella virus infection occurs within the first 18 weeks of pregnancy. Outcomes include fetal death, spontaneous abortion, stillbirth, premature birth and, among surviving infants, sensorineural deafness, cataracts and other visual impairments, mental retardation, autistic features, cardiac defects, and increased susceptibility to juvenile diabetes and other chronic conditions (Peckham and Newell, 2001). The earlier in gestation that the fetus becomes infected, the greater the likelihood of multiple defects. Although congenital rubella has been nearly eliminated in successfully vaccinated populations and with a very high benefit-to-cost ratio (Plotkin et al., 1999), epidemics continue to occur in many developing countries (Lawn et al., 2000). Cutts and Vynnycky have concluded from an extensive review of evidence that “Congenital rubella syndrome is an under-recognized public health problem in many developing countries. There is an urgent need for collection of appropriate data to estimate the cost-effectiveness of a potential global rubella control program” (Cutts and Vynnycky, 1999). A difficulty facing developing countries is that vaccination can prevent congenital rubella only if high coverage is maintained. Incomplete vaccine coverage may actually increase the risk of congenital rubella infection by reducing opportunities for natural immunity and increasing the mean age of infection, thus increasing the susceptibility to infection of women of childbearing age (Panagiotopoulos et al., 1999). The availability of a combined measles and rubella vaccine may increase the feasibility of achieving adequate rubella vaccination and improve opportunities to prevent congenital rubella throughout the world (Banatvala, 1998).

Mother-to-Child Transmission of HIV and Herpes Viruses

This is an emerging cause of developmental disabilities in populations where high HIV prevalence among childbearing women is combined with lack of access to antenatal antiretroviral therapy and cesarean delivery, which in combination are highly effective in preventing vertical transmission of HIV (European Mode of Delivery Collaboration, 1999; International Perinatal HIV Group, 1999). The neurodevelopmental effects of pediatric AIDS include microcephaly and significant delays in cognitive and motor development (Belman, 1990; Macmillan et al., 2001). These effects may be greater when transmission of the virus from mother to child occurs in utero or early in gestation versus during parturition (Smith et al., 2000). In developed countries, improvements in postnatal treatment and survival of children with HIV may be associated with a reduction in adverse neurodevelopmental outcomes. One study of HIV-infected children in the US found no detriment in verbal or performance IQ when compared to controls matched on ethnicity and prenatal drug exposure (Fishkin et al., 2000). Estimates are not available of the prevalence of pediatric HIV-associated neurodevelopmental disorders from low-income countries where few infected children have access to antiretroviral therapy. In addition to direct effects of AIDS on the developing nervous system, the AIDS epidemic may increase children's exposure to social, emotional, and economic deprivation during critical periods of development. Cost-effective and accessible methods of prevention and treatment of HIV in developing countries are needed.

Perinatal transmission of herpes viruses, including cytomegalovirus and Herpes simplex can also result in severe neurodevelopmental disorders (Levine et al., 2001; Peckham et al., 1983), but little is known about their occurrence in developing countries.

Infections Contributing to Perinatal Complications

In addition to infections known to directly damage the developing nervous system or senses, other prenatal and perinatal infections associated with perinatal complications may contribute to developmental disabilities either directly or indirectly (Breslau et al., 1994). Perinatal complications that occur more frequently in the presence of maternal and fetal infections include premature birth, low birth weight, intrauterine growth restriction and asphyxia. For example, maternal malaria infection may result in placental parasitemia and intrauterine growth restriction, as well as maternal anemia and death. Infants born with perinatal complications are often at increased risk for brain and sensory abnormalities and disabilities. For example, retinopathy of prematurity is a leading cause of childhood blindness worldwide (WHO, 2000a), and prematurity is an important risk factor for cerebral palsy and cognitive disabilities in childhood. Yet the role and timing of infections in these disorders are not fully understood (Donders et al., 1993; O'Shea and Dammann, 2000). Many factors may contribute to the elevated frequency of perinatal complications in low-income countries, including the scarcity of resources for obstetrical care and management of complications of labor and delivery, nutritional deficiencies, and increased risk of maternal infections. Research is urgently needed on the role of maternal infections in the etiology of adverse perinatal outcomes; on the causal role of infections in developmental disabilities; and on the impact of infection treatment and control on the prevalence of neurodevelopmental disabilities in low-income countries.

Infections During Infancy and Childhood

Infections acquired during infancy and childhood that continue to cause developmental disabilities among children in low-income countries, where access to prophylaxis and treatment is often limited and delayed, include neonatal infections (Wolf et al., 1999; Durkin et al., 2000) as well as bacterial meningitis, viral encephalitis, measles, poliomyelitis, trachoma, and parasitic conditions such as malaria, neurocysticercosis, and other helminth conditions (Institute of Medicine, 2001).

Malaria and Helminthic Diseases

Malaria is a public health problem in many countries and is estimated to cause hundreds of millions of cases and approximately one million deaths in children each year (WHO, 1998). Repeated episodes of malaria are responsible for poor school attendance and childhood anemia. Cerebral malaria occurs in a percentage of affected children, with major clinical manifestations, including convulsions and coma. Measures to prevent malaria infection include use of protective clothing, insect repellents, insecticide-treated bednets, and environmental management to control mosquito vectors. Once infection has occurred, chemoprophylaxis is effective against the development of disease. The cost-effectiveness of malaria prophylaxis and treatment programs is well established in populations where malaria is endemic, even without accounting for the potential for long-term neurological deficits in children who survive cerebral malaria. Other parasitic diseases, such as intestinal helminthic diseases, also affect a large proportion of the world's child population and may adversely affect school performance and cognitive development (Dickson et al., 2000).

Meningitis

Meningitis from major bacterial agents probably occurs more commonly in the developing than in developed countries, though specific data are lacking. Children under age 5 and the elderly are at highest risk. In developing countries, pneumonia is the most common presentation of Haemophilus influenzae Type b meningitis; it has been estimated that this cause of meningitis in developing countries has a case fatality rate of 30 percent and results in permanent nervous system impairment in 20 percent of survivors (WHO, 2001a). Meningococcal meningitis occurs sporadically in developed countries, but major epidemics of the disease occur every several years in sub-Saharan Africa and South America. Case fatality exceeds 50 percent in the absence of early and adequate treatment, and it is estimated that 15 to 20 percent of survivors are left with deafness, seizures, and mental retardation (Levine et al., 1998). Primary prevention of Haemophilus influenzae Type b meningitis can be achieved by means of vaccination of all infants or by chemoprophylaxis following close contact with an affected child. Vaccination is the only practical method of preventing infection on a population level. In developed countries where immunization against this disease during infancy is routine, the incidence of Haemophilus influenzae Type b meningitis has dropped dramatically (Levine et al., 1998). It has been argued that vaccination against Haemophilus influenzae Type b infection is cost-effective in developing countries as well (Levine et al., 1998), but information on the frequency of the disease and its sequelae in developing countries is needed to guide the implementation of control strategies. Epidemics of meningococcal meningitis can be controlled effectively by means of mass immunization campaigns resulting in over 80 percent coverage, while infection in endemic situations can be prevented by chemoprophylaxis administered to close contacts of patients (Levine et al., 1998). Information on the cost-effectiveness of these interventions in developing countries is needed.

Japanese Viral Encephalitis

Japanese viral encephalitis is the leading cause of viral encephalitis in Asia, where it is responsible for at least 50,000 cases of clinical disease each year, primarily among children (Siraprapasiri et al., 1997). Case fatality is as high as 20 percent, and the frequency of neuropsychiatric sequelae among survivors is thought to be high, though specific data are lacking. Following an infectious mosquito bite, the virus replicates in the lymph nodes, spreads to the central nervous system and propagates in the brain, leading to seizures, cognitive and motor disabilities, and progressive coma (Siraprapasiri et al., 1997). Effective vaccines have been developed against the viral agent causing Japanese encephalitis. One is a mouse-brain derived vaccine that has been incorporated effectively into the national childhood vaccination program of Thailand (Siraprapasiri et al., 1997). The high cost of this vaccine and the potential for serious neurological sequelae, however, are barriers to its widespread use in endemic and epidemic situations (Siraprapasiri et al., 1997).

Measles

Measles is an acute viral disease that is still a leading cause of death worldwide, largely because of its occurrence among children under age 5 in developing countries. Rarely (about 1/1,000 cases), measles infection causes encephalitis, which can result in long-term nervous system sequelae among survivors. While Vitamin A deficiency has been shown to increase the severity of measles infection, it is thought the infection can, in turn, exacerbate Vitamin A deficiency and lead to blindness (Strebel, 1998). Vaccination using live, attenuated measles virus produces long-lasting immunity. Eradication of measles is theoretically feasible, given the effectiveness of available vaccines and the likelihood that humans are the only reservoir capable of sustaining transmission of the measles virus. Widespread vaccination has successfully prevented the spread of measles in a number of developing countries, and is considered one of the most cost-effective public health interventions ever undertaken (Strebel, 1998). However, measles continues to be a major contributor to childhood death and disease worldwide. Global eradication of this cause of developmental disability will require sustained efforts.

Poliomyelitis

Polio was eradicated from the Western Hemisphere, the Western Pacific region, and Eastern Europe following a concerted international initiative (WHO, 2000b). This enteroviral disease, however, continues to threaten children in tropical Africa and to a lesser extent in South and Southeast Asia. Once established in the intestines, poliovirus can enter the blood stream and invade the central nervous system. As it multiplies, the virus destroys motor neurons and leads to irreversible paralysis. Immunization programs have effectively eradicated poliomyelitis from much of the world, but the disease remains endemic in much of sub-Saharan Africa and parts of South and Southeast Asia. Reported immunization coverage with the oral polio vaccine is still low in most African countries (WHO, 2001b). Although worldwide eradication of polio as a cause of childhood paralysis can be achieved by vaccination during infancy, meeting this goal will require major commitments that may be difficult to sustain in the face of the decline of the disease in much of the world (WHO, 2001b).

Trachoma and Leprosy

Trachoma is a bacterial disease of the conjunctiva caused by Chlamydia trachomatis (Cook, 1998). Repeated infections, which often begin in childhood, result in blindness in adulthood. Trachoma is endemic in many impoverished areas of the world where access to clean water is compromised. An estimated 5.9 million people worldwide have become blind or are at immediate risk for blindness as a result of trachoma infection (Cook, 1998). Improvements in hygiene, including access to clean water and education to promote frequent face washing, are highly cost-effective in the prevention of blindness due to trachoma (Helen Keller International, 2001). Leprosy is another neglected disease with neurological effects that continues to affect large numbers of children throughout the developing world (Jain et al., 2002).

Conclusions

Children in developed countries have benefited for decades from interventions such as maternal vaccination to prevent congenital rubella, pediatric vaccinations to prevent potentially brain-damaging childhood infections such as Haemophilus influenza Type b, and early detection and effective management of bacterial infections that can lead to meningitis or hearing loss. In addition, antiretroviral therapies have become available in developed countries to prevent pediatric HIV transmission. Unfortunately, cost and attitudinal and logistical barriers prevent these interventions from reaching children at greatest risk in the developing world. Extension of such interventions to low-income countries is a necessary step toward the reduction of international inequalities in child health.

To effectively respond to the impacts of infectious causes of developmental disabilities worldwide, proven methods of prevention must be implemented and expanded within primary health care systems in low-income countries. Specific interventions should be tailored to local epidemiology and resources and needs, and should include vaccination programs with high coverage to prevent conditions such as congenital rubella, bacterial meningitis and poliomyelitis, development of laboratory facilities and networks to facilitate accurate diagnoses, and commitment of resources to prevent other infectious diseases, such as pediatric AIDS, malaria, neurocysticercosis, leprosy, viral encephalitis, and trachoma. Additional recommendations articulated in the Institute of Medicine report on Neurological, Psychiatric and Developmental Disorders: Meeting the Challenge in the Developing World (Institute of Medicine, 2001) are as follows:

  1. Increase training and expertise at all levels of health care, as well as in the educational and research sectors, in the intersection between infectious disease control and child development.
  2. Develop and maintain Internet cababilities to facilitate international communication among those involved in the implementation of primary prevention and rehabilitation programs for children with developmental disabilities in low-income countries.
  3. In the context of the successes of current primary health care child survival initiatives in low-income countries, it is essential that increased emphasis be placed in low-income countries on prevention and early identification of developmental disabilities within the primary and maternal and child health care systems. Those systems must in turn be linked to and supported by secondary and tertiary medical services, as well as rehabilitation programs.
  4. Develop increased capacity for evidence-based research by establishing regional coordinating centers in low-income countries to enable the conduct of clinical and community trials of the effectiveness of interventions to prevent infectious causes of developmental disabilities.
  5. Support research on factors that are crucial to understanding how to prevent developmental disabilities in low-income countries, such as the etiology and prevention of adverse perinatal outcomes and the impact of maternal education and alleviation of poverty on the prevention of infections resulting in developmental disabilities.
  6. Develop practical methods for surveillance of infections leading to childhood disabilities.
  7. Document nervous system sequelae of cerebral malaria and their prevention.
  8. Determine the cost-effectiveness of methods for the prevention of prevalent infections that result in developmental disabilities.

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