RESUMO
Schistosomiasis is associated with undernutrition, but the mechanisms involved remain unknown. We analyzed baseline and follow-up data from a longitudinal treatment-reinfection study in N = 477 Schistosoma japonicum-infected subjects 7-20 years of age from Leyte, the Philippines. After baseline treatment with praziquantel, follow-up visits were scheduled every 3 months for 18 months; stool, venous blood, and anthropometric measurements were collected at each visit. Cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with specific S. japonicum antigens was measured once 4 weeks after treatment. After adjustment for confounders, S. japonicum intensity was associated with decreased serum albumin and Z-scores (all P < 0.05) and with increased serum C-reactive protein (CRP) and interleukin (IL)-6. CRP was associated with decreased albumin and Z-scores (all P < 0.01). Production of IL-1b and tumor necrosis factor (TNF)-alpha in response to worm antigen was associated with decreased albumin (both P < 0.005) and height-for-age Z-score (TNF-alpha only, P = 0.05). S. japonicum-associated undernutrition may, in part, result directly from inflammation.
Assuntos
Proteína C-Reativa/análise , Citocinas/sangue , Desnutrição/etiologia , Esquistossomose Japônica/complicações , Adolescente , Adulto , Animais , Anti-Helmínticos/uso terapêutico , Criança , Fezes/parasitologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Desnutrição/sangue , Desnutrição/imunologia , Avaliação Nutricional , Estado Nutricional , Contagem de Ovos de Parasitas , Praziquantel/uso terapêutico , Estudos Prospectivos , Recidiva , Schistosoma japonicum/crescimento & desenvolvimento , Schistosoma japonicum/imunologia , Esquistossomose Japônica/tratamento farmacológico , Esquistossomose Japônica/imunologia , Albumina Sérica/análiseRESUMO
There is a relationship between schistosomiasis and anemia, although the magnitude and exact mechanisms involved are unclear. In a cohort of 580 Schistosoma japonicum-infected 7- to 30-year-old patients from Leyte, The Philippines, we evaluated the impact of reinfection with S. japonicum after treatment with praziquantel on the mean hemoglobin level, iron-deficiency (IDA) and non-iron-deficiency anemia (NIDA), and inflammatory markers. All participants were treated at baseline and followed up every 3 months for a total of 18 months. At each follow-up, participants provided stools to quantify reinfection and venous blood samples for hemograms and measures of iron status and inflammation. After 18 months, reinfection with S. japonicum was associated with a lower mean hemoglobin level (-0.39 g/dl; 95% confidence interval [95% CI], -0.63 to -0.16) and 1.70 (95% CI, 1.10 to 2.61) times higher odds of all-cause anemia than those without reinfection. Reinfection was associated with IDA for high reinfection intensities only. Conversely, reinfection was associated with NIDA for all infection intensities. Reinfection was associated with serum interleukin-6 responses (P<0.01), and these responses were associated with NIDA (P=0.019) but not with IDA (P=0.29). Our results provide strong evidence for the causal relationship between S. japonicum infection and anemia. Rapidly reinfected individuals did not have the positive treatment effect on hemoglobin seen in nonreinfected individuals. The principle mechanism involved in S. japonicum-associated anemia is that of proinflammatory cytokine-mediated anemia, with iron deficiency playing a role in high-intensity infections. Based on the proposed mechanism, anemia is unlikely to be ameliorated by iron therapy alone.
Assuntos
Anemia/imunologia , Anemia/parasitologia , Anti-Helmínticos/farmacologia , Praziquantel/farmacologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/tratamento farmacológico , Esquistossomose Japônica/imunologia , Adolescente , Adulto , Anemia/patologia , Anemia Ferropriva/imunologia , Anemia Ferropriva/parasitologia , Anemia Ferropriva/patologia , Animais , Anti-Helmínticos/administração & dosagem , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Inflamação/imunologia , Inflamação/parasitologia , Inflamação/patologia , Masculino , Praziquantel/administração & dosagem , Recidiva , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/patologiaRESUMO
BACKGROUND: In communities where Schistosoma species are endemic, the prevalence and intensity of schistosomiasis is disproportionately high among children, compared with adults. This epidemiologic pattern is consistent with either the slow development of resistance or the requirement of host developmental changes for the expression of resistance. METHODS: We enrolled 87 individuals aged 7-18 years who did not have Schistosoma japonicum infection and 641 individuals aged 7-30 years with S. japonicum infection, all of whom reside in 3 villages in Leyte, Philippines. At baseline, S. japonicum infection was assessed by Kato-Katz thick-smear stool examination, and the levels of the pubertal hormone dehydroepiandrosterone sulfate (DHEA-S) in serum were determined. Individuals with S. japonicum infection were treated with praziquantel, after which stool examination and DHEA-S level measurement were performed every 3 months for 18 months. RESULTS: In cross-sectional analyses, the intensity of infection among individuals with high DHEA-S levels was 43% lower (28 eggs per g, n = 243), compared with individuals with low DHEA-S levels (50 eggs per g, n = 242), even after adjusting for age, sex, and village (P = .01). Following praziquantel treatment, increased DHEA-S levels were associated with resistance to reinfection (P = .006). The intensity of reinfection among individuals with high DHEA-S levels was 42% lower, compared with individuals with low DHEA-S levels, even after adjusting for age, baseline intensity of S. japonicum infection, village, sex and water contact (P < .001). CONCLUSIONS: Increased DHEA-S levels in serum, a marker for adrenal development, is associated with reduced S. japonicum infection and reinfection, even after adjusting for age and, by proxy, cumulative exposure. These data suggest that an intrinsic property of host pubertal development mediates, in part, the resistance to infection observed in older individuals.
Assuntos
Puberdade/fisiologia , Esquistossomose Japônica/diagnóstico , Adolescente , Adulto , Envelhecimento , Anti-Helmínticos/uso terapêutico , Criança , Sulfato de Desidroepiandrosterona/sangue , Fezes/parasitologia , Feminino , Humanos , Imunidade Inata , Masculino , Contagem de Ovos de Parasitas , Praziquantel/uso terapêutico , Puberdade/sangue , Esquistossomose Japônica/tratamento farmacológicoRESUMO
BACKGROUND: Observational and interventional evidence supports a relation between human schistosomiasis and anemia; however, the exact causal mechanisms remain unclear. Eggs translocating across the intestinal or bladder wall may result in extracorporeal blood loss with subsequent iron deficiency. Alternatively, anemia may result from cytokine-mediated dyserythropoiesis, as seen in anemia of inflammation. OBJECTIVES: By evaluating the cross-sectional relation between the intensity of Schistosoma japonicum infection, hemoglobin concentration, and iron status in 7-30-y-old persons from S. japonicum-endemic rice-farming villages in the province of Leyte, Philippines, we assessed the relative contribution of iron deficiency and anemia of inflammation to schistosomiasis-associated anemia. DESIGN: We enrolled 627 S. japonicum-infected and 111 S. japonicum-uninfected persons. We obtained stool samples to quantify S. japonicum infection and venous blood samples for hemograms and measures of iron status and inflammation. RESULTS: Intensity of S. japonicum infection was independently associated with hemoglobin (beta = -0.24; 95% CI: -0.31, -0.17). Persons with high-intensity infection had a greater risk of iron deficiency anemia (adjusted prevalence odds ratio: 6.6; 95% CI: 2.9, 14.7), but there was no evidence of this relation in low-intensity infections. In contrast, anemia without iron deficiency was prevalent across all intensities (adjusted prevalence odds ratio: 3.8; 95% CI: 1.5, 9.5). CONCLUSIONS: Storage iron deficiency is a major contributor to anemia in high-intensity S. japonicum infection. A high prevalence of anemia without iron deficiency, exclusion of other mechanisms of anemia, and the evidence of low bioavailable iron suggest that anemia of inflammation contributes to S. japonicum-associated anemia at all infection intensities.
Assuntos
Anemia Ferropriva/epidemiologia , Anemia/epidemiologia , Hemoglobinas/análise , Esquistossomose Japônica/complicações , Adolescente , Adulto , Anemia/sangue , Anemia/parasitologia , Anemia Ferropriva/sangue , Anemia Ferropriva/parasitologia , Criança , Intervalos de Confiança , Estudos Transversais , Doenças Endêmicas , Fezes/parasitologia , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Razão de Chances , Contagem de Ovos de Parasitas , Filipinas/epidemiologia , Receptores da Transferrina/sangue , Fatores de Risco , Esquistossomose Japônica/sangue , Estudos Soroepidemiológicos , Índice de Gravidade de Doença , Classe SocialRESUMO
Although schistosomiasis is effectively treated with Praziquantel, rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Using a longitudinal treatment-reinfection study design with 616 participants 7 to 30 years of age, we evaluated the relationship between cytokine responses to Schistosoma japonicum soluble adult worm extract (SWAP), Sj97, Sj22.6, and Sj67, measured 4 weeks after treatment with Praziquantel, and resistance to reinfection in a population from Leyte, The Philippines, where S. japonicum is endemic. S. japonicum transmission was high: 54.8% and 91.1% were reinfected within 6 and 18 months, respectively. A Th2 bias in the following cytokine ratios, interleukin-4 (IL-4)/IL-12, IL-5/IL-12, IL-13/IL-12, IL-4/gamma-IFN (IFN-gamma), IL-5/IFN-gamma, and IL-13/IFN-gamma, in response to SWAP predicted a 1.4- to 2.9-month longer time to reinfection (P < 0.05) and a 27 to 55% lower intensity of reinfection (P < 0.05). Similarly, a Th2 bias in response to Sj97 predicted a 1.6- to 2.2-month longer time to reinfection (P < 0.05) and a 30 to 41% lower intensity of reinfection (P < 0.05). Only a high IL-5/IL-10 ratio in response to Sj22.6 predicted a 3.0-month-longer time to reinfection (P = 0.03). Cytokine responses to Sj67 were not associated with protection. In a large population-based treatment-reinfection study we found that Th2 responses to SWAP and Sj97 consistently predicted resistance to reinfection. These findings underscore Th2-type immune responses as central in human resistance to S. japonicum and support Sj97 as a leading vaccine candidate for this parasite.
Assuntos
Citocinas/metabolismo , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Adolescente , Adulto , Animais , Criança , Feminino , Humanos , Imunidade Inata , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Esquistossomose Japônica/tratamento farmacológico , Esquistossomose Japônica/epidemiologia , Extratos de Tecidos , ÁguaRESUMO
In a cross-sectional study of 641 Schistosoma japonicum-infected individuals in Leyte, Philippines, who were 7-30 years old, we determined the grade of hepatic fibrosis (HF) by ultrasound and used anthropometric measurements and hemoglobin levels to assess nutritional status. Serum levels of interleukin (IL)-1, IL-6, and IL-10; tumor-necrosis factor (TNF)-alpha; soluble TNF- alpha receptor I; and C-reactive protein (CRP) were measured to examine the association between these markers of inflammation and HF grade. HF was present in 8.9% of the cohort; the majority of cases were mild (grade I), and severe (grade II or grade III) cases occurred only in male individuals. Compared with individuals without HF, those with severe HF--and, to a lesser degree, those with mild HF--had a significantly lower body-mass index (BMI) and BMI z-score, a higher prevalence of anemia, and a higher level of CRP and were more likely to produce IL-6; furthermore, those with severe HF had a significantly higher level of IL-1, compared with those either without HF or with mild HF. These findings suggest that even mild HF is associated with nutritional morbidity and underscore the importance of early recognition and treatment. In addition, our data are consistent with the hypothesis that, by systemically increasing the levels of the proinflammatory cytokines IL-1 and IL-6, HF causes undernutrition and anemia.
Assuntos
Citocinas/sangue , Cirrose Hepática/parasitologia , Estado Nutricional , Esquistossomose Japônica/fisiopatologia , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Hemoglobinas/metabolismo , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Masculino , Filipinas , Esquistossomose Japônica/sangue , Esquistossomose Japônica/complicações , Esquistossomose Japônica/imunologiaRESUMO
The objectives of this study were 1) to provide more accurate estimates of the relationship between Schistosoma japonicum infection and both protein energy malnutrition (PEM) and anemia through better adjustment for potential confounders such as socioeconomic status (SES) and geo-helminth infections and 2) to assess the role of occult blood loss in mediating S. japonicum-associated anemia. We examined cross-sectionally 729 individuals (86.7% S. japonicum-infected and 13.3% S. japonicum-uninfected) aged 7-30 years in Leyte, The Philippines. The main outcome measures were height-for-age Z-score (HAZ), body-mass-index Z-score (BMIZ), triceps skinfold Z-score, hemoglobin, and fecal occult blood loss. Multivariate models were created to assess the relationship between S. japonicum infection and nutritional status after adjusting for age, gender, other helminths, and SES. After controlling for confounders, intensity of S. japonicum infection was inversely related to hemoglobin in all age groups (P < 0.0001) and HAZ among children = 12 years (P = 0.03), but not to BMIZ (P = 0.52) or triceps skinfold Z-score (P = 0.11). Individuals with high-intensity S. japonicum infection were 3.5 times more likely to have occult blood in the stool. Adjustment for occult blood did not attenuate the relationship between S. japonicum and hemoglobin, suggesting other mechanisms are involved. Adjustment for SES allows more accurate assessment of the relationship between S. japonicum and both PEM and anemia. Exploration of the mechanisms of S. japonicum-associated anemia suggests that processes other than extracorporeal blood loss, such as anemia or inflammation, may be involved.
Assuntos
Fenômenos Fisiológicos da Nutrição Infantil , Estado Nutricional/fisiologia , Esquistossomose Japônica/fisiopatologia , Adolescente , Adulto , Anemia/parasitologia , Criança , Estudos Transversais , Dieta , Fezes/parasitologia , Feminino , Transtornos do Crescimento/parasitologia , Humanos , Masculino , Contagem de Ovos de Parasitas , FilipinasRESUMO
The objective of this study was to examine the independent effect of infection with each of four helminths (Ascaris lumbricoides, Schistosoma japonicum, Necator americanus, and Trichuris trichiura) on cognitive function after adjusting for the potential confounders nutritional status, socioeconomic status (SES), hemoglobin, sex, and the presence of other helminthes. This cross-sectional study was carried out in a rural village in Leyte, The Philippines in 319 children 7-18 years old. Three stools were collected and read in duplicate by the Kato Katz method. Infection intensity was defined by World Health Organization criteria. Cognitive tests were culturally adapted and translated. Learning and memory cognitive domains were each defined by three subscales of the Wide Range Assessment of Memory and Learning, which had an inter-rater reliability >/= 0.92 and test-retest reliabilities ranging from 0.61 to 0.89. A household SES questionnaire was administered. A logistic regression model was used to quantify the association between performance in different cognitive domains (learning, memory, verbal fluency, and the Philippine Non-Verbal Intelligence Test) and helminth infections. After adjusting for age, sex, nutritional status, hemoglobin, and SES, S. japonicum infection was associated with poor performance on tests of learning (odds ratio [OR] = 3.04, 95% confidence interval [CI] = 1.1-6.9), A. lumbricoides infection was associated with poor performance on tests of memory (OR = 2.2, 95% CI = 1.04-4.7), and T. trichiura infection was associated with poor performance on tests of verbal fluency (OR = 4.5, 95% CI = 1.04-30). Helminth infection was associated with lower performance in three of the four cognitive domains examined in this study. These relationships remained after rigorous control for other helminths and important confounding covariates.
Assuntos
Fenômenos Fisiológicos da Nutrição Infantil , Helmintíase/epidemiologia , Helmintíase/fisiopatologia , Deficiências da Aprendizagem/parasitologia , Transtornos da Memória/parasitologia , Distúrbios da Fala/parasitologia , Adolescente , Anemia/parasitologia , Anemia/fisiopatologia , Criança , Dieta , Feminino , Transtornos do Crescimento/parasitologia , Humanos , Masculino , Filipinas/epidemiologia , Fatores SocioeconômicosRESUMO
Schistosoma japonicum has been related to anemia, but the mechanisms mediating this relationship remain unresolved. The primary objective of this study was to assess the role of occult blood loss in mediating S. japonicum-associated anemia after adjusting for age, sex, socioeconomic status (SES), and other helminth infections. The secondary objective was to identify intensity categories of risk for occult blood loss for Trichuris and hookworm after adjustment for the presence of other helminth infections. The role of occult blood loss in mediating S. japonicum-associated anemia was studied cross-sectionally in 729 individuals 8-30 years old in Leyte, The Philippines. Three stool specimens were examined in duplicate for helminth eggs. Hemoglobin, fecal occult blood loss, and anemia were measured and related to the presence and intensity of helminths. Multivariate models were made to adjust for confounding by other helminths and SES. In multivariate models, hemoglobin significantly decreased with increasing infection intensity of S. japonicum, hookworm, and T. trichuria (P < 0.0031, P < 0.0001, and P < 0.0001, respectively). Individuals with higher intensities S. japonicum and T. trichuria were significantly more likely to be fecal occult positive (odds ratio [OR] = 3.54; P = 0.008 and OR = 2.68; P = 0.013, respectively), although this was not true for individuals with hookworm. Additionally, individuals with higher intensities of S. japonicum, hookworm, and T. trichuria were all more likely to be anemic (OR = 3.7, P = 0.0002; OR = 5.3, P = 0.0003; and OR = 1.6, P = 0.021, respectively). It is likely that occult blood loss plays a role only at heavier intensity S. japonicum infections and some other mechanism, such as anemia of inflammation, may be contributing to anemia.