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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary 2 Endemic Infectious Diseases Linked to Chronic Diseases: Implications for Developing Countries OVERVIEW Successful disease control efforts in some economically developing countries have increased life expectancy and resulted in changes in demographics from predominantly youthful populations to older and aging ones. Consequently, during the next 20 years, chronic diseases are expected to become increasingly important in economically developing regions and to encompass chronic conditions currently attributed to industrialized nations. Not only will changing economics, demographic shifts with lower childhood mortality, and changing lifestyles affect this trend, but migration from rural to urban areas and into previously uninhabited ecosystems may expose populations to new infectious agents that underlie chronic disease. Both newly identified and well-recognized infectious etiologies of chronic disease, including infections known to enter a chronic state, such as tuberculosis and malaria, will acquire increasing importance to domestic and global health. As such, countries with limited research capacities and health care services will face increasing burdens from both infectious and chronic disease. Richard Guerrant illustrated the wide-ranging nature of the threats from chronic diseases caused by infections, using as an example the long-term consequences of early childhood enteric and parasitic infections. The chronic impact of repeated malnourishing diarrheal illnesses is greater than that of acute deaths from enteric illness, which claims more than 6,000 children each day. Early diarrheal illnesses have significant long-term effects not only on physical fitness, but on growth, cognition, and school performance. Diarrhea appears to be a cofactor with malnutrition in that it reduces nutritional absorption.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Josemir Sander detailed the relationship between epilepsy, the most common serious neurological condition worldwide, and a number of parasites. Epilepsy is a symptom complex, so diagnosis relies on clinical history rather than a specific test. Incidence is higher in developing countries than in the industrialized world, and appears to be higher in rural areas than in urban areas. Furthermore, endemic infections may be responsible for the increased incidence in low-income countries. Maureen Durkin discussed ostensibly preventable or controllable infections that are important causes of childhood cognitive disability, paralysis, epilepsy, blindness, and deafness in developing countries. These infections include congenital disorders, such as syphilis, rubella, and cytomegalovirus, as well as infections occurring during infancy and childhood, such as malaria, meningitis, Japanese viral encephalitis, measles, poliomyelitis, and trachoma. Eduardo Gotuzzo described clinical experience with HTLV-1, a retrovirus that causes adult T-cell leukemia and is endemic in much of Latin America.The virus produces 3 different clinical patterns: cancer, autoimmune disease, and immunosuppression disease. In developing countries, 80 percent of lymphomas are non-Hodgkins lymphoma, and 10 pecent of the non-Hodgkins lymphomas seen by the Peruvian national cancer center are associated with HTLV-1. A second clinical presentation is tropical dysplastic paraparesia (TSP). The third clinical pattern associated with the infection is immunosuppression. Sanaa Kamal described chronic hepatitis C infection with and without schistosomiasis. Patients typically present in their thirties or forties with gastrointestinal bleeding, usually massive, and compromised liver function and status. These patients progress rapidly to end stage disease, usually dying in their forties. Coinfected individuals have significantly higher fibrosis levels and are unable to achieve spontaneous viral clearance. Altaf Lal described interactions between the human immunodeficiency virus (HIV) and malaria to illustrate how different pathogens interact with each other and how they modulate the disease process. Infant mortality is higher in babies born to mothers who are infected with placental malaria and HIV-1, and these infants have lower levels of acquired passive immunity. Concurrent infections also promote pathogen diversity. The interactions, however, are extremely complex. For example, acute measles suppresses HIV replication significantly.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary POTENTIAL LONG-TERM CONSEQUENCES OF EARLY CHILDHOOD ENTERIC AND PARASITIC INFECTIONS* Richard L. Guerrant, M.D.; Aldo A.M. Lima, M.D., Ph.D.; Sean R. Moore, M.S.; Breyette Lorntz, M.S.; and Peter Patrick, Ph.D. Center for Global Health, University of Virginia School of Medicine; and Federal University of Ceara, Fortaleza, Brazil The assessment of the global burden of diseases is increasingly important in recognizing and analyzing their importance as well as the priority of economic investments in their amelioration. In this perspective we recognize the quality of life or years lived with varying degrees of disability in addition to the quantity of life lost to premature mortality, as important outcomes or consequences of all diseases or conditions. Recognizing disability or quality of life is especially important, as mortality from a growing list of acute diseases is reduced, and chronic diseases or long-term consequences of diseases or conditions are now being appreciated. Only such a global view can begin to capture the full human and economic costs of diseases, injuries, or other conditions. Only as these true costs are appreciated, can we affect the necessary investments in their alleviation (Guerrant, 2001; Guerrant and Blackwood, 1999). Importance of Measuring Morbidity as well as Mortality Major advances have been made in understanding the quality and quantity elements of health outcomes and the global burdens of disease. Two of these “quality of life” measures are Quality-Adjusted Life Years (QALYs) and Disability-Adjusted Life Years (DALYs). QALYs have been devised by economists to capture both quality and quantity elements of a health care outcome in a single measure, and have been used primarily in assessing the effectiveness of specific interventions to improve health. However, QALYs suffer problems of subjective value assignments that vary considerably with who makes the choices, and they do not capture wider benefits (externalities) that may accrue to society, family, or friends. DALYs involve not only calculating age-specific mortality (as years of potential life lost [YPLL] to fatal conditions) but also taking into account the quality of life affected by disabilities (by formulating years lost to disability [YLD] with nonfatal conditions, injuries, and diseases) (Murray et al., 1994; Murray and Lopez, 1997). In calculating DALYs, perfect health is weighted as 0 disability with disability weights progressing to 1, the equivalent of death. DALYs have the * Parts of this paper have been published in a perspective article (Guerrant et al, 2002a) and in a review (Guerrant et al., 2002b).
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary advantages that they can also help assess effectiveness of interventions as well as the burden of disease and are standardized to permit age weighting and comparability across studies. All conditions affecting health as well as interventions that prevent or reverse the adverse effects of these conditions are measured in economic as well as human terms. These include, in addition to the causes of death and the YPLL due to premature mortality, the morbidity costs or YLD from conditions that impair the ability of individuals to reach their full human and economic potential or productivity. As causes of premature mortality are brought under control worldwide, the morbidity costs are becoming increasingly recognized and their quantitation is increasingly important. Thus, in addition to diseases or conditions like meningitis, AIDS, or automobile accidents that are often fatal at young ages and are thus responsible for disproportionately greater years of life lost, we must also weigh the burden of chronic diseases, like arthritis or depression, that often disable much more than they kill. Both YPLL and YLD are included in the DALYs that are being used to assess the burdens of all diseases or conditions that threaten healthy life worldwide, as well as the “cost-effectiveness” of interventions designed for their amelioration. Both mortality (YPLL) and morbidity (YLD) pose profound economic costs, whether a young, productive working parent dies with AIDS or violence, or whether a child with repeated bouts of diarrhea, parasitic infection, or malnutrition fails to develop normally to meet his or her full human and economic potential. It is just such an analysis that has brought appropriate attention to conditions like neuropsychiatric diseases or depression that kill few but disable many. Likewise, from placebo-controlled prospective studies of albendazole treatment of helminthic infections in Kenyan and Jamaican schoolchildren, intestinal helminths have been found to impair growth, fitness, and even cognitive function (Adams et al., 1994; Nokes et al., 1992a,b; Nokes and Bundy, 1992; Stephenson et al., 1993). Such studies have enabled Chan and Bundy to suggest potential recalculation of the long-term impact of childhood helminthic infections on DALYs to essentially double their previous values (Chan et al., 1994; Guerrant and Blackwood, 1999). Indeed, the disability component of the DALY calculations for malnutrition and the “tropical cluster” (trypanosomiasis, Chagas’ disease, schistosomiasis, and leishmaniasis), like neuropsychiatric conditions, chronic obstructive lung disease, and rheumatoid arthritis, outweigh their mortality components (Guerrant and Blackwood, 1999; Murray and Lopez, 1997). However, the initially calculated DALY for diarrheal diseases, from a 1997 assessment (Murray and Lopez, 1997), initially comprised 95 percent mortality (YPLL) and only 5 percent disability (YLD, from the transient 10 percent incapacitation during just the overt diarrheal illness [i.e., liquid stools] itself). No long-term disability from repeated dehydrating and malnourishing diarrheal illnesses in the critical formative developmental
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary first 2 years of life is considered, largely because there had been no data to suggest such long-term effects (Guerrant and Blackwood, 1999). Potential Long-Term Morbidity from Diarrheal Disease The challenge is to obtain data implicating specific diseases or conditions with long-term impaired outcomes. Best studied perhaps are nutritional effects that may even involve genetic “imprinting” from the regulation of critical developmental genes at pivotal times by DNA methylation, that might further extend the developmental impact of early childhood illnesses perhaps even beyond 2–3 generations (Golden, 1994). In addition, iron deficiency has a well recognized impact on cognitive development (Basta et al., 1979; Soewondo et al., 1989). Nevertheless, despite the lack of a specific single drug (like albendazole for intestinal helminths) to control diarrheal diseases, long-term cohort studies are now enabling associations to be made of heavy early childhood disease burdens with later functional as well as nutritional outcomes. The growing evidence for lasting disability consequences of early childhood diarrhea and specific parasitic infections (including cryptosporidiosis and intestinal helminthic infections in the first 6–24 months of life) is presented in Table 2-1. Perhaps one of the greatest of all overlooked costs of the diseases of poverty, such as diarrhea and intestinal parasitic infections, are the increasingly recognized, long-term developmental impact of early childhood illnesses, so common in developing areas. For example, we are now learning that the 4–8 dehydrating, malnourishing diarrheal illnesses that often occur each year in the critically formative first two years of life may have profound, lasting consequences for impaired fitness, growth, cognitive development, and school performance several years later. Initial studies in Northeast Brazil show reduced fitness 4 to 6 years later associated with early childhood diarrhea, and specifically with cryptosporidial infections in the first 2 years of life, independent of respiratory illnesses, anthropometry, anemia, and intestinal helminths (Guerrant and Blackwood, 1999). The fitness deficits alone that associate with the median diarrhea burdens in the first 2 years of life in these studies in Northeast Brazil are comparable to that associated with a 17 percent decrement in work productivity in Zimbabwe sugarcane workers (Guerrant et al., 1999; Ndamba et al., 1993). Furthermore, these early childhood diarrheal illnesses and intestinal helminthic infections in the first 2 years of life independently and additively associate with substantial long-term linear growth shortfalls that continue beyond six years of age (totaling an average of 8.2 cm [3 1/4 inches] growth shortfall at 7 years old, 3.6 cm with diarrhea alone after controlling for early childhood intestinal helminthic infections) (Moore et al., 2001). In addition, longitudinal studies in Peru (Checkley et al., 1997, 1998) have also shown that cryptosporidial infections (even without overt diarrhea) in young or stunted children predispose to an average 1 cm growth shortfall 1 year after infection.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary TABLE 2-1 Evidence for Lasting Disability Effects from Early Childhood Diarrhea Disease Outcome References Growth shortfalls Cryptosporidial infections and persistent diarrhea Increased diarrhea morbidity and nutritional shortfalls for up to 18 months Agnew et al., 1998 Lima et al., 2000 Newman et al., 1999 Cryptosporidial infections at < 6 months of age and in stunted children 0.95–1.05 cm growth deficits at 1 year later Checkley et al., 1998 Early childhood diarrhea (0–2 y.o.) Lasting growth shortfalls, persisting at 3.6 cm at 7 y.o. (additive to 8.2 cm with intestinal helminths at 0–2 y.o.) Moore et al., 2001 Fitness impairment Early childhood diarrhea (0–2 y.o.) Impaired fitness scores (assessed by the Harvard Step Test, HST) 4–7 years later (by 4–8.2 percent for median and high diarrhea burdens, respectively; for comparison, fitness scores improved 6.9 percent 4 months after albendazole treatment of schoolboys in Kenya and a 4.3 percent increase in HST scores correlated with a 16.6 percent increase in work productivity in sugarcane cutters in Zimbabwe Stephenson et al., 1993 Guerrant et al., 1999 Ndamba et al., 1993 Cognitive impairment Early childhood diarrhea (0–2 y.o.) Impaired cognitive function at 6–9 y.o. by McCarthy Draw-A-Design (p = 0.017 when controlling for early childhood helminthic infections), and WISC coding and reverse digit span testing (p = 0.045) Guerrant et al., 1999 We also find significant associations of early childhood diarrhea with long-term cognitive deficits (by standard “Test of Nonverbal Intelligence” [TONI]) even when controlling for maternal education, breast feeding duration, and early helminthic infections (Niehaus et al., 2002). Furthermore, WISC (Wechsler Intelligence Scale for Children; The Psychological Corp, San Antonio, TX) coding and digit span scores were lower in children with persistent diarrheal illnesses in their first 2 years of life, even when controlling for helminths and maternal education (Niehaus et al., 2002). And these effects are seen in a “best case” scenario in which we have documented substantial improvements in disease rates and in nutritional status over the several years in which we have conducted close, long-term surveillance of this population (Moore et al., 2000), effects that we have subsequently not found in other nearby shantytown communities that had not
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Disease Outcome References Early childhood diarrhea (0–2 y.o.) Impaired Test of Nonverbal Intelligence (TONI-III) scores at 6–10 y.o., when controlling for maternal education, breast feeding duration, and early helminthic infections; and WISC coding and digit span scores were lower in children who had one or more persistent diarrheal illnesses in their first 2 years of life. Niehaus et al., 2002 School performance (increased age at starting school and age-for-grade) Early childhood diarrhea Delayed age at starting school and older age-for-grade, independent of maternal education, socioeconomic status, other illnesses and of also significant effects (of ECD) on height for age Z scores (i.e., stunting) at 0, 2, or 7 years of age (p < 0.02, N = 77). Late starters also are 2-fold more likely to have experienced cryptosporidial infections in their first 2 years of life. Lorntz et al., 2000 been under such intensive surveillance (Lima, Guerrant et al., unpublished observations). We are now finding that these correlations of early childhood diarrhea are also extending to school performance, with significant associations of diarrhea in the first 2 years of life with delayed age at starting school and age for grade that remain even after controlling for maternal education and (also affected) stature. Late starters are also two-fold more likely to have experienced cryptosporidial infections (Lorntz et al., 2000). A recent report describes the significant associations of stunting in the first 2 years of life and multiple episodes of Giardia infection with impaired intelligence quotients on the WISC-R test among children in Peru (Berkman et al., 2002). This is the setting in which diarrhea is also associated with reduced WISC-R scores albeit not independently of its association with stunting. This is also the
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary setting in which cryptosporidial infections are associated with persistent stunting as well (Checkley et al., 1997, 1998). Most recently we have launched studies of sensitive measures of higher order frontal lobe development and critical “executive” functioning that predict functional recovery from brain injury in children. We conducted semantic and phonetic fluency testing among 74 children who have now reached 6–12 years old from our prospective surveillance population (with their diarrheal illnesses recorded from birth). Early childhood diarrhea, whether measured by total numbers of episodes or as days of diarrhea in the first 2 years of life was a highly significant predictor of total fluency scores at 6–12 years of age (i.e., 4–10 years later). Impressively, early childhood diarrhea remained a significant predictor of fluency even when controlling for maternal education and for household income (p = 0.02; beta = –0.31)1 or when controlling for birth size (p = 0.007; beta = –0.325) or height-for-age Z score (HAZ) at 6.5 years old. Since early childhood diarrhea has such profound effects on TONI III scores and on HAZ at age 2 years old, its association with fluency was not significantly independent of TONI III or HAZ at 2 years old. The persistence of strong associations of early diarrhea with fluency to 6–12 years old and its independence of HAZ at birth and at 6.5 years old (despite persistent associations of diarrhea with HAZ to 6–7 years old) suggests that despite the growth effects recovering in part, the lasting impact of early childhood diarrhea does not recover and is even greater on functional verbal fluency than on growth. We conclude that the higher frontal lobe executive functioning impairment seen at 6–12 years old associated with diarrhea in the first 2 years of life, especially with impaired schooling, growth and cognition, suggest that early childhood diarrhea results in critical neurodevelopmental impairment that greatly magnifies the importance of ameliorating these diarrheal illnesses and their long-term consequences. These potential consequences of early childhood malnourishing and dehydrating diarrheal illnesses should not be a great surprise when one considers the importance of early childhood years in human brain development (Dobbing, 1985; 1990; Dobbing and Sands, 1985; Niehaus et al., 2002). Unlike other species such as monkeys, sheep or opossums, which have most of their brain development in utero, it is during the first 2 years of life in humans that the major brain growth and synapse formation occurs. Furthermore, if impaired at this formative stage, it is apparently difficult if not impossible to compensate or build these synapses later in life. Add to this the recognized potential for genetic imprinting noted above, and the duration of impact of early childhood illnesses may well be lifelong and even extend even to the next generation(s). Thus the disability impact and ultimate societal costs of these early child- 1 The statistical symbol p stands for the probability that the observed difference could have been obtained by chance alone, given random variation and a single test of the null hypothesis.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary hood diarrheal illnesses of poverty is potentially far greater and more critical a global investment than is generally appreciated, i.e., a global “tax” that is paid for the impaired work productivity in the global economy because these largely preventable illnesses continue unabated. Thus, beyond their obvious human toll, the diseases of poverty may well require an economic investment (as they are readily prevented) that we cannot afford not to make. Persistent High Diarrhea Morbidity Despite Improving Mortality The importance of an accurate assessment of the YLD, years lost to disability from early childhood illnesses like diarrheal diseases is further accentuated by the striking relative shift from mortality to morbidity seen over recent decades. Despite clear reductions in diarrhea mortality (from 4.2 to 3.3 to 2.5 million) from 1955 to the present (Bern et al., 1992; Kosek et al., 2003; Snyder and Merson, 1982), the morbidity rates from a third 10-year update review (Kosek et al., 2003) have not decreased; instead, with the fastest growing populations occurring in the poorest areas with the highest disease rates, the total global morbidity from diarrhea has actually substantially increased. The potential impact of these still common early childhood diarrheal illnesses on long-term development or disability only further adds to their morbidity costs. Refining DALYs for Diarrheal Disease As shown in the first row of Table 2-2, following the standard formulas with age-weighting and discounting at 3 percent, and all disability falling into the lowest class (weight of 0.096), the DALY calculations for diarrheal diseases are presented. The morbidity in 0–4 year olds is presented in 5 different scenarios as follows: Scenario 1 applies the original assumptions by Murray and Lopez of 2.27 million attacks of 1 week duration, in which the 1.3 million DALYs from morbidity in 0–4 year olds represents 1 percent of the total of 100.9 million global diarrhea DALYs. Scenario 2 assumes that 17 percent of 0–4 year olds (or 33 percent at half the 9.6 percent disability weight) are at risk of at least 1 diarrheal attack (or a diarrhea burden) which could have life-long disability (with a life expectancy of 81.25 years as used by Murray and Lopez). Scenario 3 assumes that 25 percent of 0–4 year olds (or 50 percent at half the 9.6 percent disability weight) are at life-long risk. Scenario 4 assumes that 10 percent of 0–4 year olds (or 50 percent at 20 percent of the 9.6 percent disability weight, i.e., half experience a 2 percent lifelong disability).
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary TABLE 2-2 Revised Calculations of Disability-Adjusted Life Years (DALYs) for Diarrheal Diseases Scenario Attack rate/year Proportion disabled Duration of disability DALYS for morbidity in 0–4 year olds (millions) [percentage of total] Total DALYs (millions) 1 3.6 1 0.02 1.3  100.9 2 1 0.17 81.25 351.7  451.3 3 1 0.25 81.25 517.2  616.8 4 1 0.10 81.25 215.2  314.8 5 1 0.05 81.25 107.6  207.2 Scenario 5 assumes that only 5 percent of 0–4 year olds (or half experience a 1 percent life-long disability). Thus, a 1 to 4.8 percent disability affecting one-third to one-half of 0–4-year-old children would increase the total global diarrhea DALYs to 2 to 6-fold the current estimates. Considered differently, for every 5 percent of children affected lifelong, DALYs increase by about 100 million; 25 percent of children affected would increase current DALY estimates by over six-fold; only 5 percent affected lifelong (or 10 percent affected for only 25 years) would more than double the total global diarrhea DALYs (Guerrant et al., 2002a). Add to this the concept that even subclinical enteric infections that may alter critical absorptive function without necessarily producing overt symptoms of liquid stools, like those with Cryptosporidium or enteroaggregative E. coli may impair growth (Checkley et al., 1997, 1998; Steiner et al., 1998), or impede the absorption of (and potentially thus enhance resistance to) key anti-HIV or antituberculosis drugs (Lima et al., 1997; Brantley et al., 2003), and the potential cost of these diseases of poverty, inadequate water, and inadequate sanitation become increasingly unacceptable. Conclusions Critical to understanding and making this case for investing adequate resources in the presentation or amelioration of the diseases of poverty like diarrhea is obtaining solid information about the potential long-term correlates with illness rates and even subclinical infections, controlling to the extent possible the numerous confounding variables, and careful studies of potential interventions that could alter these adverse outcomes. Only improved data and careful, accurate analyses will direct adequate attention to alleviation of these diseases of poverty that are so potentially costly to human and societal development for us all.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary REFERENCES Adams EJ, Stephenson LS, Latham MC, Kinoti SN. 1994. Physical activity and growth of Kenyan school children with hookworm, Trichuris trichiura and Ascaris lumbricoides infections are improved after treatment with albendazole. Journal of Nutrition 124:1199–1206. Agnew DG, Lima AA, Newman RD, Wuhib T, Moore RD, Guerrant RL, Sears CL. 1998. Cryptosporidiosis in northeastern Brazilian children: association with increased diarrhea morbidity. Journal of Infectious Diseases 177:754–760. Basta SS, Soerkirman, D Karyadi, NS Scrimshaw. 1979. Iron deficiency anaemia and the productivity of males in Indonesia. The American Journal of Clinical Nutrition 32: 916–925. Berkman DS, Lescano AG, Gilman RH, Lopez SL, Black MM. 2002. Effects of stunting, diarrhoeal disease, and parasitic infection during infancy on cognition in late childhood: a follow-up study. Lancet 359:564–571. Bern C, Martines J, de Zoysa I, Glass RI. 1992. The magnitude of the global problem of diarrhoeal disease: a ten-year update. Bulletin of the World Health Organization 70:705–714. Brantley RK, Williams KR, Silva TM, Sistrom M, Thielman NM, Ward H, Lima AA, Guerrant RL. 2003. AIDS-associated diarrhea and wasting in Northeast Brazil is associated with subtherapeutic plasma levels of antiretroviral medications and with both bovine and human subtypes of Cryptosporidium parvum. Brazilian Journal of Infectious Diseases 7:16–22. Chan MS, Medley GF, Jamison D, Bundy DA. 1994. The evaluation of potential global morbidity attributable to intestinal nematode infections. Parasitology 109:373–387. Checkley W, Gilman RH, Epstein LD, Suarez M, Diaz JF, Cabrera L, Black RE, Sterling CR. 1997. Asymptomatic and symptomatic cryptosporidiosis: their acute effect on weight gain in Peruvian children. American Journal of Epidemiology 145:156–163. Checkley W, Epstein LD, Gilman RH, Black RE, Cabrera L, Sterling CR. 1998. Effects of Cryptosporidium parvum infection in Peruvian children: growth faltering and subsequent catchup growth. American Journal of Epidemiology 148:497–506. Dobbing J. 1985. Infant nutrition and later achievement. The American Journal of Clinical Nutrition 41:477–484. Dobbing J. 1990. Boyd Orr memorial lecture. Early nutrition and later achievement. Proceedings of the Nutrition Society 49:103–118. Dobbing J and Sands J. 1985. Cell size and cell number in tissue growth and development. An old hypothesis reconsidered. Archives Francaises de Pediatrie 42:199–203. Golden MH. 1994. Is complete catch-up possible for stunted malnourished children? European Journal of Clinical Nutrition 48:S58–S70. Guerrant DI, Moore SR, Lima AA, Patrick PD, Schorling JB, Guerrant RL. 1999. Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil. The American Journal of Tropical Medicine and Hygiene 61:707–713. Guerrant RL. 2001. The unacceptable costs of the diseases of poverty. Current Infectious Disease Reports 3:1–3. Guerrant RL and Blackwood BL. 1999. Threats to global health and survival: the growing crises of tropical infectious diseases—our “unfinished agenda.” Clinical Infectious Diseases 28:966–986. Guerrant RL, Kosek M, Lima AA, Lorntz B, Guyatt HL. 2002a. Updating the DALYs for diarrhoeal disease. Trends in Parasitology 18:191–193. Guerrant RL, Kosek M, Moore S, Lorntz B, Brantley R, Lima AA. 2002b. Magnitude and impact of diarrheal diseases. Archives of Medical Research 33:351–355. Kosek M, Bern C, Guerrant RL. 2003. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bulletin of the World Health Organization 81:197–204.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary We are currently conducting comprehensive and sensitive analysis of HCV-specific CTL and CD4+ responses in PBMCs and liver-infiltrating lymphocytes of patients coinfected with HCV and S. mansoni versus HCV-monoinfected patients. Conclusion In summary, HCV infection is a worldwide problem for which there has been insufficient success with treatment options presently available. The lack of a clear understanding of the immunological events during acute and chronic infection has hampered vaccine development and immunotherapeutic approaches to treatment. From an immunological point of view the interplay between T helper cell responses and CTL has been difficult to assess in humans, and infection with S. mansoni offers the unique situation of studying the impact of an altered response on the outcome and progression of HCV-related liver disease. REFERENCES Abdel Aziz F, Habib M, Mohamed M, Abdel Hamid M, Gamil F, Madkour S, Mikhail N, Thomas D, Fix A, Strickland T, Anwar W, Ismail S. 2000. Hepatitis C virus infection in a community in the Nile Delta: population description and HCV prevalence. Hepatology 32:111–115. Alter MJ. 1997. Epidemiology of hepatitis C. Hepatology 26:62S–65S. Angelico M, Renganathan E, Gandin C, Fathy M, Profili MC, Refai W, De Santis A, Nagi A, Amin G, Capocaccia L, Callea F, Rapicetta M, Badr G, Rocchi G. 1997. Chronic liver disease in Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections. Journal of Hepatology 26:236–243. Bertoletti A, D’Elios MM, Boni C, De Carli M, Zignego AL, Durazzo M, Missale G, Penna A, Fiaccadori F, Del Prete G, Ferrari C. 1997. Different cytokine profiles of intrahepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology 112:193–199. Cerny A and Chisari FV. 1999. Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 30:595–601. Chitsulo L, Engels D, Montresor A, Savioli L. 2000. The global status of schistosomiasis and its control. Acta Tropica 77:41–51. Curry AJ, Else KJ, Jones F, Bancroft A, Grencis RK, Dunn DW. 1995. Evidence that cytokine-mediated immune interactions induced by Schistosoma mansoni alter disease outcome in mice concurrently infected with Trichuris muris. The Journal of Experimental Medicine 181:769–774. Diepolder HM, Zachoval R, Hoffmann RM, Jung MC, Gerlach T, Pape GR. 1996. The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C. Journal of Molecular Medicine 74:583–588. El-Khoby T, Galal N, Fenwick A, Barakat R, El-Hawey A, Nooman Z, Habib M, Abdel Wahab F, Gabr NS, Hammam HM, Hussein MH, Mikhail NN, Cline BL, Strickland GT. 2000. The epidemiology of schistosomiasis in Egypt: summary of findings in nine governorates. The American Journal of Tropical Medicine and Hygiene 62:88–99. Gerlach T, Diepolder H, Jung M, Gruner N, Schraut W, Zachoval R, Hoffman R, Schirren A, Santantonio T, Pape G. 1999. Recurrence of hepatitis C virus after loss of virus specific CD4+ T-cell response in acute hepatitis C. Gastroenterology 117:993–941.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Habib M, Mohamed MK, Abdel-Aziz F, Magder LS, Abdel-Hamid M, Gamil F, Madkour S, Mikhail NN, Anwar W, Strickland GT, Fix AD, Sallam I. 2001. Hepatitis C virus infection in a community in the Nile Delta: risk factors for seropositivity. Hepatology 33:248–253. Hammam HM, Allam FA, Moftah FM, Abdel-Aty MA, Hany AH, Abd-El-Motagaly KF, Nafeh MA, Khalifa R, Mikhail NN, Talaat M, Hussein MH, Strickland GT. 2000. The epidemiology of schistosomiasis in Egypt: Assiut governorate. The American Journal of Tropical Medicine and Hygiene 62:73–79. He XS, Rehermann B, Lopez-Labrador FX, Boisvert J, Cheung R, Mumm J, Wedemeyer H, Berenguer M, Wright TL, Davis MM, Greenberg HB. 1999. Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers. Proceedings of the National Academy of Sciences USA 96:5692–5697. Kamal SM, Madwar MA, Bianchi L, EL Tawil A, Fawzy R, Peters T, Rasenack JW. 2000a. Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with Schistosoma mansoni. Liver 20:281–289. Kamal SM, Madwar MA, Peters T, Fawzy R, Rasenack J. 2000b. Interferon therapy in patients with hepatitis C and schistosomiasis. Journal of Hepatology 32:172–174. Kamal SM, Bianchi L, Al Tawil A, Koziel M, El Sayed Khalifa K, Peter T, Rasenack JW. 2001a. Specific cellular immune response and cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni. The Journal of Infectious Diseases 184:972–982. Kamal SM, Rasenack JW, Bianchi L, Al Tawil A, El Sayed Khalifa K, Peter T, Mansour H, Ezzat W, Koziel M. 2001b. Acute hepatitis C with and without schistosomiasis: correlation with hepatitis C-specific CD4+ T-cell and cytokine response. Gastroenterology 121:646–656. Koziel MJ. 1999. Cytokines in viral hepatitis. Seminars in Liver Disease 19:157–169. Lechner F, Wong D, Dunbar R, Chapman R, Chung R, Dohrenwend P, Robins G, Phillips R, Klenerman P, Walker B. 2000. Analysis of successful immune responses in persons infected with hepatitis C virus. Journal of Experimental Medicine 1499–1512. Lohr HF, Gerken G, Roth M, Weyer S, Schlaak JF, Meyer zum Buschenfelde KH. 1998. The cellular immune responses induced in the follow-up of interferon-alpha treated patients with chronic hepatitis C may determine the therapy outcome. Journal of Hepatology 29:524–532. Pereira LM, Melo MC, Saleh MG, Massarolo P, Koskinas J, Domingues AL, Spinelli, Mies S, Williams R, McFarlane IG. 1995. Hepatitis C virus infection in Schistosomiasis mansoni in Brazil. Journal of Medical Virology 45:423–428. Poynard T, Leroy V, Conhard M. 1996. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 24:278–289. Sabin EA and Pearce EJ. 1995. Early IL-4 production by non-CD4+ cells at the site of antigen deposition predicts the development of a T helper 2 cell response to Schistosoma mansoni eggs. Journal of Immunology 155:4844–4855. Schirren CA, Jung MC, Gerlach JT, Worzfeld T, Baretton G, Mamin M, Hubert Gruener N, Houghton M, Pape GR. 2000. Liver-derived hepatitis C virus (HCV)-specific CD4+ T cells recognize multiple HCV epitopes and produce interferon gamma. Hepatology 32:597–603. Seeff LB. 1997. Natural history of hepatitis C. Hepatology 26:21S–28S. Thevenot T, Rigimbeau C, Ratziu V, Leroy V, Opolon P, Poynard T. 2001. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C in naive patients: 1999 update. Journal of Viral Hepatitis 8:48–62.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary INTERACTIONS OF MULTIPLE INFECTIOUS AGENTS IN MALARIA-ENDEMIC AREAS: CONCURRENT HIV/AIDS AND MALARIA Altaf A. Lal, Ph.D. Division of Parasitic Diseases, National Center for Infectious Diseases Centers for Disease Control and Prevention, Atlanta, GA Establishment of microorganisms in human host populations requires structural, biologic, and molecular compatibilities between the host and pathogen. In situations where multiple infectious organisms coexist in an individual, the resulting polyparasitism could lead to increased infectivity, altered pathogen load, and modulation in pathogenesis. Burkitt’s lymphoma, which is commonly found in areas with malaria transmission, is a good example of coinfections. It has been proposed that malaria-induced immune activation may be associated with the development of these lymphomas (Whittle et al., 1984). The introduction of HIV-1 in the human population has altered the epidemiology of several infectious diseases. A number of these organisms, termed together as opportunistic infectious agents, cause significant morbidity and mortality. HIV-1 is now a firmly established infectious agent and the potential to interact with parasitic, viral, fungal, and bacterial infectious agents is very high. The progression from HIV-1 infection to AIDS is associated with a decline in the CD4 T-cell count and an increase in HIV-1 viral load. Although several factors may be responsible for the variability in HIV-1 disease progression, immune activation appears to be an important determinant. Immune activation leads to up-regulation of viral co-receptors, decreased β chemokine secretion, enhanced viral entry and integration, viral assembly and/or release of the viral particles, changes in the cytokine environment and various degrees of immune dysfunction, hyporesponsiveness, and apoptosis. Because all systemic and/or local concurrent infections cause various degrees of immune activation, it is very likely that they may enhance HIV infection, increase HIV replication and viral load, and even promote progression of the disease. Several studies have focused on the interaction between HIV/AIDS and three major infectious diseases, namely malaria, sexually transmitted diseases (STDs), and tuberculosis (TB) (Bentwich et al., 2000; Chandramohan and Greenwood, 1998). The main impact of STDs has been to facilitate HIV-1 transmission, and the interaction of TB and HIV-1 has been an increase in the burden of an already major cause of morbidity and mortality. As far as malaria is concerned, although early studies did not reveal a definite interaction between malaria and HIV, there is increasing evidence now that suggests these two pathogens interact, thus modifying the pathogenesis of each disease (Bentwich et al., 2000; Chandramohan and Greenwood, 1998; Corbett et al., 2002). This presentation will focus on the interactions between HIV/AIDS and malaria.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Malaria, TB, and HIV/AIDS are important public health problems in sub-Saharan Africa and some parts of Asia. Both HIV and malaria exert their heaviest toll in sub-Saharan Africa, where the progression of HIV-related disease is considered to be most rapid. The interaction between HIV/AIDS and malaria can be viewed in the mechanistic context, where immunomodulation by one organism can impact the natural course of infection of the co-existing pathogen, and in programmatic context, where the treatment for one disease may have beneficial impact on the other disease and/or the treatment for one disease may not be effective in the presence of the co-infecting pathogen. Initial studies of the interactions between HIV and malaria focused on the ability of malaria parasites to act as opportunistic organisms in immunosuppressed HIV-positive persons. As recent reviews demonstrate, most of the earlier studies, conducted primarily in adults, did not show an effect of HIV infection on the prevalence or severity of malaria (Chandramohan and Greenwood, 1998; Corbett et al., 2002). Earlier studies conducted in Zaire, Uganda, Rwanda, and Zambia, showed no or marginal effect of HIV infection on malaria parasitemia (Simooya et al., 1988; Chattopadhya et al., 1991; Greenberg, 1992). However, recent studies conducted in Malawi reported increased prevalence rates of malaria parasitemia and parasite density in HIV-infected pregnant women (Chandramohan and Greenwood, 1998). The higher prevalence of malaria parasitemia was seen in HIV-infected women of all gravidities, indicating that the parity-specific immunity to malaria, which is normally associated with multigravidae, was impaired in HIV-infected women (Chandramohan and Greenwood, 1998). More importantly, these studies revealed that infants born to HIV- and malaria-positive mothers were at a significantly higher risk for low birth weight. Increased prevalence of peripheral parasitemia and placental malaria has also been seen in HIV-positive pregnant women in western Kenya, which has higher rates of malaria transmission than Malawi (Chandramohan and Greenwood, 1998). The increased prevalence of parasitemia in HIV-positive women seemed to be pregnancy associated, because parasitemia in HIV-positive women reduced to the level seen in HIV-negative women 2–6 months postpartum. HIV infection has been shown to induce poor responses to antimalarial treatment with sulfadoxine-pyrimethamine (S/P) in pregnant women. A recent study conducted in western Kenya indicated that although a standard two-dose S/P regimen worked well in controlling peripheral parasitemia and placental malaria during pregnancy in HIV-negative women, it failed to prevent peripheral and placental parasitemia in HIV-infected women. Poor response to S/P antimalarial treatment was also reported in pregnant Malawian women with HIV-1 infection. Because parasitemia was reduced drastically after each treatment and monthly S/ P dosing worked well in both HIV-positive and HIV-negative women, it is possible that the poor treatment response was due to rapid re-infection rather than delayed parasite clearance. No difference in quinine treatment failure was seen
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary between HIV-positive and HIV-negative children with malaria in Kinshasa, Zaire (Chandramohan and Greenwood, 1998; Corbett et al., 2002). Conflicting results have been reported about the effect of HIV infection on malaria antibody responses in Plasmodium falciparum-endemic areas. Earlier studies conducted in Zambia and India showed no differences between HIV-positive and HIV-negative persons in terms of the prevalence of antimalarial antibodies (Simooya et al., 1988; Chattopadhya et al., 1991). Very few HIV-positive persons, however, were involved in these studies, and no attempts were made to compare the titers of antibody response, although one did compare the optical density (OD) (Chattopadhya et al., 1991). In contrast, a study conducted in Uganda demonstrated consistent reduction in mean OD of antibodies to synthetic peptides from the ring-infected erythrocyte surface antigen (RESA) and circumsporozoite protein (CSP) of P. falciparum and CSP of P. malariae. In addition, HIV-positive persons with AIDS had significantly lower antibody levels (mean OD) of RESA antibodies than asymptomatic HIV-positive persons (Wabwire-Mangen et al., 1989). Cellular immune responses to malaria are seemingly also affected by HIV-1 infection. Compared with HIV-negative persons, AIDS patients in Burkina Faso had lower proliferation of PBMCs to stimulation with merozoite surface protein-1 (MSP-1) and parasite culture supernatant. They also had reduced in vitro production of IFN-γ and IL-2. The immune suppression induced by HIV was probably general, because PBMCs of AIDS patients also respond poorly to phytohaemagglutinin, tuberculin purified protein derivative, and lipopolysaccharide (Migot et al., 1996). We have recently evaluated the influence of HIV-1 on malaria antigen specific antibody responses during pregnancy. These studies have revealed that maternal and neonatal antibody levels against blood stage and sporozoite stage antigenic determinants are significantly lower among HIV-infected women compared with HIV-uninfected women. We also observed reduced maternal-fetal transplacental antibody transfer in dually infected women. In another recent study conducted in Kenya, we found elevated production of IFN-γ by maternal placental (intervillous blood) mononuclear cells (IVBMC) from multigravidae to be associated with protection against placental malaria (Moore et al., 2000). A protective role for IFN-γ in controlling infection has been demonstrated both in human studies and with animal models. Mechanistically, this cytokine has been proposed to be important in mediating asexual blood-stage parasite clearance, perhaps via its regulatory influence on phagocytic cells. The importance of this cytokine in protection against placental malaria is further supported by our recent finding that IVBMC from HIV-positive women have impaired antigen-specific IFN-γ and IL-4 responses (Moore et al., 2000). Since these cytokines are produced primarily by T-cells, we conclude that this loss of cytokine responsiveness may play a role in the increased susceptibility of HIV-positive women to placental malaria.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary It has been suggested that the progression from HIV-1 infection to AIDS is more rapid in sub-Saharan African patients than in persons living in developed countries (Gilks, 1993; Mulder et al., 1994; Grant et al., 1997). In addition to the lack of access to health care and treatment, chronic immune stimulation from increased exposure to other infectious agents are probable co-factors of immune activation. Earlier investigations of the relationship between HIV-1 and malaria focused mainly on the effect of HIV-1 infection on malaria. Only one study examined the effect of malaria on HIV-1 infection, and failed to detect any effect of malaria infection on HIV-1 progression. No measurements of changes in CD4+ T-cell counts and viral load, which are two current predictors of HIV disease progression, were done in this study. Recent in vitro and in vivo studies, nevertheless, indicate that malaria can potentially affect the course of HIV infection in several aspects. The initial evidence of a possible effect of malaria on HIV-1 infection came from a retrospective analysis of data from a cohort study of mothers and infants in rural Malawi. It was demonstrated that infants born to mothers with both placental malaria and HIV-1 infection had post-neonatal mortality 4.5 times higher than infants born to mothers with only placental malaria, and 2.7–7.7 times higher than infants born to mothers with only HIV-1 infection (Chandramohan and Greenwood, 1998; Corbett et al., 2002). This increased mortality in infants born to mothers with dual HIV and malaria was attributed to the increased transmission of HIV from mothers to infants, although no HIV testing was conducted in these infants. Because immune activation is an important prerequisite for efficient HIV infection and viral replication, we evaluated the effect of malarial antigen stimulation on HIV-1 infection. Stimulation with soluble malarial antigens or malarial pigment from P. falciparum enhanced HIV-1 replication in PBMC from naive donors by 10- to 100-fold. The malarial antigen-upregulated HIV-1 replication was mediated through induction of TNF-α via the activation of long terminal repeat (LTR)-directed viral transcription (Xiao et al., 1998). Preliminary studies conducted with PBMC from HIV-positive individuals residing in western Kenya indicated that recall immune responses induced by soluble malarial antigens can increase HIV-1 replication (Xiao et al., unpublished observation). PBMC from 3 of 10 HIV-1 infected individuals showed active in vitro viral production after the antigen stimulation. These in vitro observations have been confirmed by the result of a recent prospective, cohort study of 47 HIV-positive adults with active falciparum malaria and 42 HIV-positive adults without malaria in Malawi. It was shown that HIV-positive individuals with active malaria had a mean plasma HIV-1 viral load 7-fold higher than HIV-positive individuals without malaria (Hoffman et al., 1999). Plasma HIV-1 RNA concentrations did not correlate significantly with P. falciparum parasite density or the duration of fever. However, antimalarial chemotherapy with S/P resulted in a small (37 percent) but significant reduction in
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary HIV-1 RNA load by week 4 post-treatment in individuals with HIV and malaria coinfection. Another potential interaction between HIV and malaria is at the invasion stage of both pathogens. HIV-1 has been recently shown to bind erythrocytes from Caucasian persons through the Duffy antigen receptor for chemokines (DARC), a receptor that is also used by the invasion of P. vivax merozoites into reticulocytes (Lachgar et al., 1998). It has been proposed that erythrocytes may function as a reservoir for HIV-1, and this binding to CD4 (–) cells via DARC by HIV may be used as a mechanism for the entry of HIV-1 into endothelial cells and neurons (Lachgar et al., 1998). Because P. falciparum-infected erythrocytes adhere to brain endothelial cells and cause brain hemorrhage, it is conceivable that the sequestration of parasitized erythrocytes in the brain with HIV viral particles attached may facilitate the entry of HIV into neurons in individuals that are DARC-positive. This may promote the occurrence of neurologic disorders, which are frequently seen in AIDS patients. Programmatic concerns for interactions between malaria and HIV/AIDS are mainly at the level of diagnosis and treatment. Earlier diagnostic studies showed false positivity of blood samples from malaria-affected individuals during HIV testing (Biggar et al., 1996). This was probably due to nonspecificity of the early HIV diagnostic kits, because antigen cross-reactivity between retroviruses and malaria parasites has been reported (Lal et al., 1994). As far as treatment of uncomplicated and complicated malaria is concerned, blood transfusion for the treatment of severe malarial anemia and presumptive treatment of febrile illness have emerged as two important problems. Recent studies have shown that many of the presumed malarial febrile illnesses were actually the result of primary HIV-1 infection (Nwanyanwu et al., 1997). This problem may be more severe in areas with high prevalence of HIV and malaria, leading to unnecessary use of antimalarials for the treatment of fever. This overuse of antimalarials may contribute to the rapid emergence of drug resistance. As far as the transfusion-related transmission of HIV is concerned, earlier studies clearly revealed that use of unscreened blood for the treatment of severe malarial anemia was a factor in the transmission of HIV. While this paper provides an account of published work on the interaction between malaria and HIV/AIDS, there is compelling evidence of interaction between other microorganisms and HIV/AIDS. It is likely that the interactions between several microorganisms present together in an individual may modulate the pathogenesis and transmission of major infectious agents. From a mechanistic point of view, however, a common thread that seems to tie this interaction together is immune activation induced by infectious agents prevalent in malaria-endemic areas. Therefore, removing risk factors of immune activation (i.e., co-infectious agents) by effective use of drugs, physical interventions to interrupt transmission, such as bednets for malaria, and other prevention methods should have the dual effect of reduced risk of rapid progression of HIV-
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary related disease (by elimination or suppression of viral activating factors) and reduced morbidity and mortality by a co-infecting pathogenic organism. The schematics of our current knowledge and the likely outcomes of the interaction between HIV and malaria are shown in Figure 2-1. It is very likely that multiple enteric, respiratory, bloodborne, vectorborne, and waterborne and foodborne agents may induce immunologic changes (even in asymptomatic infections) that promote infection, transmission, and clinical manifestation of illnesses of the co-infectious pathogens. It is therefore important to capture all morbidity data and conduct extensive diagnostic work in future studies so that the analysis can be controlled for the effect of different co-infectious agents. In the context of HIV/AIDS and malaria, the available data should be considered in: Promoting the development of and implementation of intervention guidelines and policies for prompt treatment of malaria with effective antimalarials; treatment would reduce the frequency of malaria-related illness and reduce the risk of rapid progression and transmission of HIV. Incorporating prevention methods, such as the use of insecticide-impregnated bednets and environmental modifications in controlling malaria transmission. Implementing blood screening guidelines in anemia-related blood transfusions. Because of the increasing prevalence of major infectious diseases in many countries, even a small impact of coinfection-mediated increase in pathogenesis and transmission could have unparalleled human health consequences. Therefore, from a global health perspective, there is a need to raise awareness at the national level to the consequences of interactions of multiple infections in malaria-endemic regions of the world. These efforts need to be complemented by political commitment and funding at the national and international level for research and disease control and prevention programs for infectious diseases in malaria-endemic settings. REFERENCES Bentwich Z, Maartens G, Torten D, Lal AA, Lal RB. 2000. Concurrent infections and HIV pathogenesis. AIDS 14:2071–2081. Biggar RJ, Miotti PG, Taha TE, Mtimavalye L, Broadhead R, Justesen A, Yellin F, Liomba G, Miley W, Waters D, Chiphangwi JD, Goedert JJ. 1996. Perinatal intervention trial in Africa: effect of a birth canal cleansing intervention to prevent HIV transmission. Lancet 347:1647–1650. Chandramohan D and Greenwood BM. 1998. Is there an interaction between human immunodeficiency virus and Plasmodium falciparum? International Journal of Epidemiology 27:296–301. Chattopadhya D, Kumari S, Chatterjee R, Verghese T. 1991. Antimalarial antibody in relation to seroreactivity for HIV infection in sera from blood donors. Journal of Communicable Diseases 23:195–198.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary FIGURE 2-1 Current knowledge and likely outcomes of the interaction between HIV and malaria.
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary
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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Corbett EL, Steketee RW, ter Kuile FO, Latif AS, Kamali A, Hayes RJ. 2002. HIV-1/AIDS and the control of other infectious diseases in Africa. Lancet 359:2177–2187. Gilks CF. 1993. The clinical challenge of the HIV epidemic in the developing world. Lancet 342:1037–1039. Grant AD, Djomand G, De Cock KM. 1997. Natural history and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 11:S43–S54. Greenberg AE. 1992. Pp. 143–148 in AIDS in the World, TW Netter, J Mann, DJM Tarantola, eds. Boston: Harvard University Press. Hoffman IF, Jere CS, Taylor TE, Munthali P, Dyer JR, Wirima JJ, Rogerson SJ, Kumwenda N, Eron JJ, Fiscus SA, Chakraborty H, Taha TE, Cohen MS, Molyneux ME. 1999. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 13:487–494. Lachgar A, Jaureguiberry G, Le Buenac H, Bizzini B, Zagury JF, Rappaport J, Zagury D. 1998. Binding of HIV-1 to RBCs involves the Duffy antigen receptors for chemokines (DARC). Biomedicine and Pharmacotherapy 52:436–439. Lal RB, Rudolph D, Alpers MP, Sulzer AJ, Shi YP, Lal AA. 1994. Immunologic cross-reactivity between structural proteins of human T-cell lymphotropic virus type I and the blood stage of Plasmodium falciparum. Clinical and Diagnostic Laboratory Immunology 1:5–10. Migot F, Ouedraogo JB, Diallo J, Zampan H, Dubois B, Scott-Finnigan T, Sanou PT, Deloron P. 1996. Selected P. falciparum specific immune responses are maintained in AIDS adults in Burkina Faso. Parasite Immunology 18:333–339. Moore JM, Ayisi J, Nahlen BL, Misore A, Lal AA, Udhayakumar V. 2000. Immunity to placental malaria. II. Placental antigen-specific cytokine responses are impaired in human immunodeficiency virus-infected women. Journal of Infectious Diseases 182:960–964. Mulder DW, Nunn AJ, Wagner HU, Kamali A, Kengeya-Kayondo JF. 1994. HIV-1 incidence and HIV-1-associated mortality in a rural Ugandan population cohort. AIDS 8:87–92. Nwanyanwu OC, Kumwenda N, Kazembe PN, Jemu S, Ziba C, Nkhoma WC, Redd SC. 1997. Malaria and human immunodeficiency virus infection among male employees of a sugar estate in Malawi. Transactions of the Royal Society of Tropical Medicine and Hygiene 91:567–569. Simooya OO, Mwendapole RM, Siziya S, Fleming AF. 1988. Relation between falciparum malaria and HIV seropositivity in Ndola, Zambia. British Medical Journal 297:30–31. Wabwire-Mangen F, Shiff CJ, Vlahov D, Kline R, Serwadda D, Sewankambo NK, Mugerwa RD, Quinn TC. 1989. Immunological effects of HIV-1 infection on the humoral response to malaria in an African population. The American Journal of Tropical Medicine and Hygiene 41:504–511. Whittle HC, Brown J, Marsh K, Greenwood BM, Seidelin P, Tighe H, Wedderburn L. 1984. T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312:449–450. Xiao L, Owen SM, Rudolph DL, Lal RB, Lal AA. 1998. Plasmodium falciparum antigen-induced human immunodeficiency virus type 1 replication is mediated through induction of tumor necrosis factor-alpha. Journal of Infectious Diseases 177:437–445.
Representative terms from entire chapter: