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    Delta values (follow-up–baseline) of levels of soluble tumor necrosis factor-α receptor II (sTNF-rII) and interleukin-10 (IL-10) according to intervention group and human immunodeficiency virus status. Bars represent means with 95% confidence intervals (CIs). Two-way analysis of variance showed that there was a significant reduction of sTNF-rII in the early intervention groups than in the delayed intervention groups (P = 0.03; mean fold change, follow-up–baseline, early intervention groups: 0.84; 95% CI = 0.78–0.90; delayed intervention groups: 0.93, 95% CI = 0.87–0.99). Similarly, IL-10 levels were reduced more in early intervention groups (P < 0.001; mean fold change, follow-up–baseline, early intervention groups: 0.37, 95% CI = 0.29–0.46; delayed intervention groups: 0.64; 95% CI = 0.51–0.79).

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Schistosomiasis and Infection with Human Immunodeficiency Virus 1 in Rural Zimbabwe: Systemic Inflammation during Co-infection and after Treatment for Schistosomiasis

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  • 1 Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Aarhus, Denmark; Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark; The Centre of Inflammation and Metabolism at the Department of Infectious Diseases, Rigshospitalet, Faculty of Health Sciences, and Cluster of International Health, University of Copenhagen, Denmark; National Institute of Health Research, Harare, Zimbabwe; Department of Immunology, College of Health Sciences, and Department of Medical Microbiology, University of Zimbabwe, Harare, Zimbabwe; Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands; Biomedical Research and Training Institute, Harare, Zimbabwe, London School of Hygiene and Tropical Medicine, London, United Kingdom

We previously reported that treatment for schistosomiasis in persons infected with human immunodeficiency virus 1 (HIV-1) attenuated HIV replication as measured by plasma HIV RNA. We investigated systemic inflammation as measured by plasma levels of soluble tumor necrosis factor-α receptor II (sTNF-rII), interleukin-8, (IL-8), and IL-10 during schistosomiasis and HIV co-infection and after schistosomiasis treatment. The cohort was composed of 378 persons who were or were not infected with HIV-1, Schistosoma haematobium, or S. mansoni. Schistosomiasis-infected persons were randomized to receive praziquantel (40 mg/kg) at baseline or at the three-month follow-up. sTNF-rII and IL-8 were positively associated with schistosomiasis intensity as measured by circulating anodic antigen (CAA), regardless of HIV status. Interleukin-10 was positively associated with CAA in HIV-negative participants. IL-8 levels were higher in S. mansoni-infected individuals. Treatment for schistosomiasis caused a decrease in levels of sTNF-rII (P < 0.05) and IL-10 (P < 0.001). Our results indicate that schistosomiasis treatment may attenuate HIV replication by decreasing systemic inflammation.

INTRODUCTION

In sub-Saharan Africa, 25 million persons are infected with human immunodeficiency virus (HIV) with most living without access to antiretroviral treatment.1 Moreover, an estimated 170 million persons are infected with the chronic helminthic infection known as schistosomiasis.2 The number of persons co-infected with these diseases is not known but in some areas the prevalence of co-infected persons can reach high proportions.3 The impact of schistosomiasis on the progression of HIV in co-infected persons has been questioned, with reports from uncontrolled studies showing no or even negative effects of schistosomiasis treatment.46 However, in a controlled intervention study, we found that treatment for schistosomiasis among HIV-infected persons attenuated an accelerated increase in plasma HIV RNA.7

Infection with HIV induces immune activation with high levels of circulating cytokines, such as tumor necrosis factor-α (TNF)-α, interleukin-6 (IL-6), and IL-10.810 Activated CD4 cells express increased levels of the co-receptors CCR5 and CXCR4 used by HIV to enter and infect host cells.11,12 In vitro, the cytokines TNF-α and IL-6, as well as the chemokine IL-8, can activate the transcription factor nuclear factor (NF)-κB in monocytes or macrophages. In uninfected cells, this leads to cell proliferation and differentiation. However, the HIV provirus carries multiple NF-κB binding sites; thus, the activation of NF-κB in HIV-infected cells results in viral replication.1316 Conversely, the anti-inflammatory cytokine IL-10 downregulates the pro-inflammatory cytokine TNF-α and inhibits HIV replication in vitro in macrophages.17 The persistent loss of CD4 cells characterizing the course of the HIV infection might be ascribed to immune activation, as indicated in the study by Tesselaar and others, who found that generalized activation of CD4 cells by CD27 in mice expressing CD70 led to progressive CD4 cell loss and Pneumocystis carinii infection, a hallmark of late-stage HIV infection in humans.18

Chronic schistosomiasis has also been shown to induce systemic inflammation,19 and Schistosoma mansoni and other helminth infections have been associated with increased numbers of activated CD4 cells, lower levels of naive CD4 cells, and higher levels of CD8 cells.20 Although the initial acute schistosomiasis infection is characterized by production of the type 1 cytokine interferon-γ,21 production of type 2 cytokines and IL-10 predominates in the subsequent chronic phase of the infection.2224

There are few reports regarding levels of circulating cytokines during HIV and schistosomiasis co-infection, but Brown and others reported that circulating IL-10 is reduced after treatment with praziquantel in co-infected persons,5 and production of other cytokines during HIV-infection might also be affected by schistosomiasis co-infection.25,26 We hypothesized that schistosomiasis would induce systemic inflammation and that treatment for schistosomiasis would decrease the level of systemic inflammation. We measured levels of circulating soluble TNF-receptor II (TNF-rII), which reflects pro-inflammatory TNF-α levels but fluctuate less,27,28 as well as the chemokine IL-8 and the anti-inflammatory cytokine IL-10.

METHODS

Study design

The Mupfure Schistosomiasis and HIV cohort has been described in detail elsewhere.3 Briefly, a cross-sectional survey was carried out from October 2001 through November 2002 in the Mupfure and adjacent areas in Shamva District, Mashonaland Central Province in Zimbabwe. During the survey, 2,281 persons were screened for HIV and schistosomiasis and dually infected persons were recruited for the cohort study. Concurrently, three control groups were established: HIV-infected persons, schistosomiasis-infected persons, and uninfected persons. In the survey, the prevalence of schistosomiasis was 43%. Malaria slides were prepared for the first six months (approximately 50% of participants were included during this period) and only one person with parasitemia was identified, although this screening included the peak time of transmission; consequently, the screening was discontinued. If tuberculosis was considered, clinical signs or symptoms led to exclusion. Among HIV-infected persons, 6 were infected with intestinal helminths other than S. mansoni, whereas 17 infections were found among HIV-uninfected persons.

Schistosomiasis-infected participants within HIV-infected and HIV-uninfected groups were randomized at baseline to two equal-sized groups: the early intervention and the delayed intervention groups. Participants in the early intervention groups were treated at baseline with a single oral dose of praziquantel (40 mg/kg). Treatment for the participants in the delayed intervention group was postponed until the three-month follow-up visit. Thus, according to HIV status, schistosomiasis status, and time of intervention, six groups were created, including 378 persons at baseline and 302 persons at the three-month follow-up: 1) HIV-infected, schistosome-infected participants who received early treatment; 2) HIV-infected, schistosome-infected participants who received delayed treatment; 3) HIV-uninfected, schistosome-infected participants who received early treatment; 4) HIV-uninfected, schistosome-infected participants who received delayed treatment; 5) HIV-infected, schistosome-uninfected participants; and 6) HIV and schistosome-uninfected participants. Participants were followed-up with clinical examination and blood sampling three months after baseline.

Ethical considerations

The Medical Research Council of Zimbabwe (MRCZ/A/918) and the Central Medical Scientific Ethics Committee of Denmark (624-01-0031) reviewed and approved the study. Oral and written informed consent was obtained from all participants. There was no public scheme for antiviral therapy in Zimbabwe at the time of the study. It can be assumed that all participants had not received anti-retroviral therapy.

Laboratory analyses

Status for HIV was determined by a rapid HIV-1/2 test in the field on a dry blood spot (Determine; Abbott, Tokyo, Japan) and outcome from participants included in the cohort was verified by two enzyme-linked immunosorbent assays (ELISAs) on serum (Recombigen; Cambridge Biotech Ltd., Galway, Ireland and Ortho, Raritan, NJ). There were no disagreements between the initial rapid test result and ELISA results. Testing for HIV was performed confidentially and pre-test and post-test counseling was provided in the native language (Shona) of all participants by qualified personnel. Approximately 50% of participants wished to know their results.

Infection with S. haematobium was diagnosed by microscopic identification and quantification of fixed-volume urine samples filtered on Nytrel filters29 (Vestergaard Frandsen, Kolding, Denmark). For each participant, urine was collected on three consecutive days. Diagnosis of infection with S. mansoni and other helminth eggs or parasites was assessed by the modified formol-ether concentration technique on one gram of stool from each participant.30

CD4 cell counts were measured by flow cytometry at the Department of Hematology, Parirenyatwa Hospital, Harare (FacsCalibur; Becton-Dickinson, San Jose, CA). Plasma HIV RNA was detected at Rigshospitalet, Copenhagen (Roche Amplicor; F. Hoffmann-La Roche, Basel, Switzerland).

Blood was drawn into EDTA-coated tubes and kept cool until separation a maximum of four hours after sampling. Plasma was transferred to cryotubes and stored in liquid nitrogen until shipment on dry ice; in Copenhagen, samples were stored at −80°C until analysis.

Plasma levels of sTNF-rII were assessed by an ELISA (Quantikine; R&D Systems, Minneapolis, MN). Interleukin-8 and IL-10 were measured in plasma by cytometric bead array (CBA) (CBA Human Inflammation Kit; BD Biosciences, San Diego, CA) as described.31 When undetectable, IL-10 was assigned a value of half the lower limit of detection (LLD = 0.94 pg/mL); IL-8 was detectable in all samples. Schistosomiasis intensity was also evaluated by levels of circulating anodic antigen (CAA) and circulating cathodic antigen (CCA), both originating from the parasite gut, measured in serum by ELISA as described by Polman and others.32 When undetectable, they were assigned a value of 1 pg/mL. All ELISA and CBA measurements were run in duplicate and mean concentrations were calculated.

Statistical analysis

Statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Log-transformed values were used when appropriate to approximate normal distribution. Univariate and multivariate linear regressions were performed within each HIV stratum including all participants regardless of schistosomiasis status with inflammation markers as independent variables and CAA, CCA, urine egg count, or fecal egg count as predictors. Schistosomiasis status at baseline was determined by urine and fecal egg counts. However, more individuals were positive for CAA than for egg counts.33 In analyses with CAA and CCA, all participants were included, regardless of schistosomiasis status. In analyses with urine egg counts, only persons infected with S. haematobium were included. Similarly, only S. mansoni-infected persons were included in analyses with fecal egg counts. Regression coefficients and 95% confidence intervals (CIs) were back transformed, thus estimating fold changes of the relevant independent parameter per unit change of the predictor. Levels of IL-10 did not follow a normal distribution because of measurements below the LLD. Therefore, only persons with IL-10 levels above the LLD were included in this analysis. This analysis was then supplemented with a logistic regression with IL-10 coded as above or below the LLD.

Effects of HIV, S. haematobium, and S. mansoni status on levels of sTNF-rII, IL-8, and IL-10 were evaluated by three-way analysis of variance (ANOVA). The ANOVA for IL-10 included only values above the LLD; it was supplemented with a logistic regression.

To estimate the effect of early versus delayed intervention, Δ values were calculated for each participant who attended the three-month follow-up (log10 follow-up value - log10 base-line value). The Δ values of sTNF-rII, IL-8, and IL-10 were compared between intervention and HIV strata by two-way ANOVA. Interactions between HIV and intervention strata were assessed and cross-products were excluded when insignificant. Results were presented as back-transformed means with 95% CIs for each intervention stratum, representing fold changes between follow-up and baseline within each stratum. To validate the conclusions from the ANOVAs, analyses of covariance (ANCOVA) were performed. Follow-up values of parameters were compared between intervention strata after adjusting for baseline values of the parameters: HIV, S. haematobium, S. mansoni, age, and sex. Results were presented as back-transformed means with CIs representing relative differences between strata. Interactions between covariates were assessed and cross-products removed when insignificant. Pearson’s correlation coefficient was presented for the correlation between Δ values of sTNF-rII and HIV RNA.

RESULTS

Baseline characteristics of the cohort have been described.3 Briefly, 156 schistosomiasis and HIV co-infected persons, 133 infected only with schistosomiasis, 42 infected with only HIV, and 47 uninfected persons were included (mean age = 33 years, range = 18–63 years; 80% females). Of the 289 schistosomiasis-infected persons, 213 (HIV+ = 105) were infected with only S. haematobium, 27 (HIV+ = 17) with only S. mansoni, and 49 (HIV+ = 34) with S. haematobium and S. mansoni.

Baseline

Linear regressions were performed with schistosomiasis parameters as predictors for inflammatory parameters among HIV-infected and HIV-uninfected persons (Table 1). In univariate analysis, sTNF-rII was positively associated with CCA among HIV-infected persons but multivariately CAA was the only significant predictor among HIV-infected and HIV-uninfected persons.

Interleukin-8 correlated positively with CAA and CCA in univariate and multivariate analyses irrespective of HIV status. Only persons with IL-10 levels above the LLD (n = 280) were included in linear regression analyses. No associations between IL-10 and schistosomiasis intensity were found in HIV-infected persons. Among HIV-uninfected participants, CAA and CCA were positively associated with IL-10 in univariate as well as multivariate analyses. To determine if this discrepancy was caused by a difference in the association between IL-10 and CAA/CCA according to HIV status, a linear regression model was fitted that included HIV-infected and HIV-uninfected persons. The dependent variable was IL-10 with predictors HIV status, CAA, and their cross-product. There was tendency to an interaction for CAA (P = 0.10). Similarly, a tendency to an interaction for CCA was found (P = 0.08). This finding indicated a tendency to a steeper positive correlation between IL-10 and CAA/CCA in HIV-uninfected persons than in HIV-infected persons.

Logistic regression with IL-10 coded as above or below the LLD showed similar results. Thus, no association was found between IL-10 and schistosomiasis intensity in HIV-infected volunteers. However, in HIV-uninfected volunteers, the odds ratio of IL-10 > LLD versus < LLD increased with CAA (P < 0.05), CCA (P = 0.05), and urine egg count (P < 0.05).

Baseline cytokine levels were previously compared between HIV and schistosomiasis strata. Higher sTNF-rII and IL-8 levels were found among HIV-infected persons but no effect of schistosomiasis was found when dichotomized.34 However, when schistosomiasis strata were split into S. haematobium and S. mansoni and IL-8 levels were compared between groups, IL-8 levels were higher in S. mansoni-infected persons (mean fold difference of S. mansoni+/S. mansoni- = 1.23; 95% CI = 1.05–1.44, P < 0.05;) with a similar effect of HIV. No interactions were found. No indication of a similar discrepancy between schistosomiasis strata was found for sTNF-rII or IL-10 levels.

Follow-up

Characteristics of the 302 participants who returned for the three-month follow-up have been described elsewhere.7,33 The Δ TNF-rII was compared between groups by two-way ANOVA with early/delayed intervention and HIV-status as classifiers. Early intervention decreased sTNF-rII levels compared with delayed intervention (P = 0.03, Figure 1). There was a positive correlation between the change in HIV RNA and the change in sTNF-rII between baseline and follow-up (Pearson’s r = 0.26, P < 0.001). An ANCOVA comparing follow-up values of sTNF-rII levels between early versus delayed intervention adjusted for baseline sTNF-rII level, HIV, S. haematobium, S. mansoni-status, age, and sex confirmed the results (mean ratio of early/delayed intervention = 0.88; 95% CI = 0.78–0.99, P = 0.03).

Correspondingly, ΔIL-8 values were compared between groups. No effect of early versus delayed intervention was found. In the ANCOVA, we found interaction between early/delayed intervention and S. mansoni status (P < 0.001); the participants were stratified according to S. mansoni status. Among S. mansoni-infected individuals, the early intervention groups had lower follow-up values of IL-8 (mean ratio, early/delayed intervention = 0.40; 95% CI = 0.26–0.59, P < 0.001). Early intervention did not affect IL-8 levels among S. mansoni-uninfected persons (mean ratio of early/delayed intervention = 1.11; 95% CI = 0.90–1.38, P = 0.32). Results were not altered after controlling for schistosomiasis intensity (CAA levels).

The δIL-10 levels were reduced by the praziquantel treatment (P < 0.001, Figure 1); there was no statistically significant effect of HIV status. Levels of IL-10 at follow-up were lower in both early and delayed intervention groups. The ANCOVA was fitted with ΔIL-10 as the dependent variable with the predictors early/delayed intervention, HIV, S. haematobium, S. mansoni status, and age. It supported the treatment induced reduction of IL-10 (mean ratio of early/delayed intervention = 0.67; 95% CI = 0.51–0.89, P < 0.01). The ratio of sTNF-rII to IL-10 did not change with treatment.

DISCUSSION

The purpose of this study was to determine if the level of systemic inflammation as measured by sTNF-rII, IL-8, and IL-10 was influenced by schistosomiasis intensity in HIV-infected and HIV-uninfected persons and to determine if treatment for schistosomiasis could reduce the level of systemic inflammation. We found that schistosomiasis intensity was associated with increased cytokine and cytokine receptor levels. Moreover, levels of sTNF-rII and IL-10 were reduced by treatment for schistosomiasis and IL-8 levels were attenuated among S. mansoni-infected persons after treatment.

We found evidence for a positive association between inflammatory parameters and schistosomiasis intensity. In multivariate analysis, CAA was positively associated with sTNF-rII independently of HIV status. Intreleukin-8 was positively associated with CAA and CCA independently of multivariate adjustments or HIV status. These findings indicate that schistosomiasis increases immune activation and, thus, may accelerate viral replication. Levels of CAA and CCA were positively associated with IL-10 but interestingly, this only applied to HIV-uninfected persons. Although the interaction between HIV and CAA/CCA was not significant, the tendency suggests that IL-10 was not upregulated by schistosomiasis in HIV-infected persons. This finding could be important because IL-10 is a strong anti-inflammatory cytokine and an important modulator of the immune response to schistosomiasis.23

Our most important finding, a reduction of sTNF-rII and IL-10 levels among schistosomiasis-infected persons treated with praziquantel, supports our previous report of attenuation of an accelerated increase in HIV RNA and decrease in CD4 cell count among schistosomiasis co-infected persons.7 Because TNF-α has been linked to activation of NF-κB leading to immune activation, we propose that this reduction of immune activation with lower levels of sTNF-rII resulted in a decrease in viral replication. We found a correlation between the change from baseline to the three-month follow-up in HIV RNA and the change in sTNF-rII. Circulating sTNF-rII levels increase with HIV progression and are attenuated by antiretroviral therapy.35,36 Our findings support schistosomiasis as an important contributor to immune activation. It was previously found that schistosomiasis induces immune activation,19,20 and increased TNF-α production has been linked to S. haematobium-induced urinary tract morbidity.37 Studies in mice with exaggerated type 1 or type 2 responses caused by IL-10 deficiency lead to immunopathologic changes but not clearance of the infection.38,39 Thus, schistosomiasis and HIV may accelerate immune activation. This activation may eventually increase morbidity of HIV or schistosomiasis.

In contrast to our findings, Brown and others found transient increases in HIV RNA one month after praziquantel treatment and sustained decreases of CD4 cell count five months after treatment.5 Nevertheless, they also found a sustainable decrease in serum IL-10 levels, a finding that supports the current results. A decrease in circulating IL-10 levels has been found after initiation of highly active antiretro-viral treatment,10,40 and IL-10 levels are stable in long-term non-progressor HIV-infected individuals as opposed to the increasing levels in progressing patients.10 A reduction in IL-10 levels during HIV-infection therefore appears to be beneficial, but we have recently shown that carriers of a polymorphism in the promoter for the IL-10 gene, IL-10 -1082 A > G, affected HIV-induced mortality.34 Carriers of the IL-10 -1082G allele, linked to production of high levels of IL-10, experienced lower mortality than in low producers. We therefore proposed that the correlation of IL-10 with HIV progression markers might reflect an upregulation in a context of immune activation. Thus, when sTNF-rII decreases, so does IL-10.

It appears that levels of sTNF-rII decrease more in HIV-infected persons whereas IL-10 levels decrease more in the HIV-uninfected persons. This finding was not statistically significant: there was no interaction between treatment and HIV status for either sTNF-rII or IL-10, and there was no change by treatment of the sTNF-rII-to-IL-10 ratio. However, given that IL-10 was found to correlate with CAA and CCA in HIV-negative persons but not in HIV-positive persons, it is compelling to hypothesize that this finding indicates a discrepancy between regulatory activities induced by schistosomiasis in HIV-infected persons compared with HIV-uninfected persons. Helminths have evolved with their hosts and induce regulatory activities to inhibit host inflammatory responses.23,41,42 These regulatory activities may not work in an HIV-infected host. Impaired production of cytokines among HIV-infected persons is associated with advanced disease and increased mortality.43 Similarly, the production of IL-10 was impaired among schistosomiasis- and HIV-infected patients compared with those infected only with schistosomiasis.26 Regulation of IL-10 may be central to understanding the interaction between of HIV and schistosomiasis.

In the delayed intervention groups, we observed lower levels of IL-10 and a tendency to lower levels of sTNF-rII. A possible explanation could be that persons volunteering for the study were prompted by current health issues that resolved before the follow-up, increasing the possibility of a selection bias during follow-up. This bias would furthermore emphasize the importance of the randomized design not used in previous schistosomiasis and HIV co-infection studies. However, we previously performed a thorough analysis of the loss to follow-up, and had found no interaction between randomization group and treatment on the probability of loss to follow-up.7 Additionally, we found no seasonal variation in the levels of IL-10 and sTNF-rII that could explain this finding. The baseline and three-month follow-up samples were collected during more than one year of recruitment. Consequently, there was an overlap in the time of collection of baseline and three-month follow-up samples of more than nine months. The baseline and follow-up samples were stored and handled equally and samples from the same person were always run on the same day/placed side by side on the same ELISA plate. Thus, we did not find any technical explanation for the decrease.

The study combines a cross-sectional design and an openly randomized follow-up study. These designs do have their inherent limitations. Moreover, the time of seroconversion for the HIV-infected participants was not known and the interaction between HIV and schistosomiasis could only be followed within the short time-span of three months. However, it was for obvious ethical reasons not possible to extend this time span. Similarly, the time of schistosomiasis infection was not known and the diagnosis of S. mansoni was based on only one stool sample.

Our results indicate that the immunologic effect of infection with S. mansoni might differ from the effect of infection with S. haematobium. Levels of IL-8 were higher in S. mansoni-participants and treatment with praziquantel only reduced IL-8 levels among S. mansoni-infected participants. This finding may not only depend on the presence of S. mansoni infection but also on the burden of the pathogen, which is generally higher for S. mansoni than for S. haematobium, as indicated by higher egg production and antigen levels in persons infected with S. mansoni.44 Moreover, 62% of S. mansoni-infected persons were co-infected with S. haematobium.

It should also be noted that possible confounding by other chronic infections cannot be ruled out. However, the prevalence of malaria was low in the area and there was no effect of other intestinal helminthic infections on baseline cytokine levels or the response to praziquantel treatment. Signs of tuberculosis led to exclusion. The prevalence of tuberculosis in the area was not precisely known but appeared low as expected in a rural area compared with urban settings.

In this cohort, levels of circulating inflammatory markers increased with schistosomiasis intensity. Our previous report showing attenuation of HIV replication after treatment for schistosomiasis is supported by these results, which demonstrate a decrease in circulating sTNF-rII and IL-10 after treatment with praziquantel. The immunologic interactions between these two systemic infections still require elucidation, and further studies are needed to confirm the possible beneficial effects of treatment for schistosomiasis among HIV-infected persons.

Table 1

Univariate and multivariate regression analysis of human immunodeficiency virus (HIV)–infected or HIV-uninfected participants with schistosomiasis intensity measured by circulating anodic schistosome antigen (CAA), circulating cathodic schistosome antigen (CCA), urine egg count, or fecal egg count as predictors for soluble TNF receptor II (sTNF-rII), interleukin-8 (IL-8), or IL-10*

HIV infectedHIV uninfected
UnivariateMultivariateUnivariateMultivariate
FactorNo.RC95% CIPRC95% CIPNo.RC95% CIPRC95% CIP
* Only persons with IL-10 measurements above the lower limit of detection were included in analyses with IL-10 as the dependent parameter. Analyses with CAA and CCA included all participants regardless of schistosomiasis classification. Analyses with urine egg counts included only persons with positive urine egg counts and was similar for analyses with fecal egg counts. Multivariate analyses were performed with one of the four schistosomiasis intensity measures as the predictor and adjustments for age and sex. Further adjustments for CD4 cell count and plasma HIV RNA were performed among HIV-infected participants. Additionally, urine egg count analyses were adjusted for Schistosoma mansoni infection and fecal egg count analyses were adjusted for S. haematobium infection. For sTNF-rII or IL-8, CD4 cell count and HIV RNA were significant as predictors regardless of additional predictors, indicating that relevant information was provided by both of them. There was no interaction between CD4 cell count and HIV RNA. For IL-10, HIV RNA, but not CD4 cell count, reached significance. Regression coefficients (RCs) and 95% confidence intervals (CIs) have been back transformed; thus, estimating the fold change in the dependent variable with a one unit increase in the predictor.
sTNF-rII
CAA log10, pg/mL1981.040.98–1.100.121.051.00–1.10< 0.051801.081.04–1.13< 0.0011.091.04–1.13< 0.001
CCA log10, pg/mL1981.181.04–1.34< 0.011.110.99–1.240.061801.080.98–1.190.111.090.99–1.200.06
Urine eggs log10, pg/mL1390.930.82–1.050.250.930.83–1.040.251231.070.96–1.200.171.070.95–1.200.20
Fecal eggs log10, pg/mL510.870.63–1.210.411.090.79–1.510.55250.890.45–1.730.721.170.57–2.390.64
IL-8
CAA log10, pg/mL1981.071.00–1.15< 0.051.051.00–1.15< 0.051801.081.01–1.15< 0.051.081.01–1.15< 0.05
CCA log10, pg/mL1981.261.07–1.48< 0.011.201.02–1.42< 0.051801.161.01–1.33< 0.051.161.00–1.33< 0.05
Urine eggs log10, pg/mL1391.090.92–1.280.281.070.90–1.260.391231.181.01–1.38< 0.051.171.00–1.38< 0.05
Fecal eggs log10, pg/mL511.160.75–1.800.481.110.71–1.750.61250.830.25–2.710.740.900.22–3.610.87
IL-10
CAA log10, pg/mL1491.030.94–1.130.491.020.93–1.120.551311.141.04–1.26< 0.011.131.02–1.24< 0.05
CCA log10, pg/mL1490.980.79–1.210.870.940.76–1.160.611311.261.03–1.53< 0.051.241.02–1.51< 0.05
Urine eggs log10, pg/mL1090.910.75–1.110.370.850.69–1.040.12941.220.93–1.580.131.160.89–1.520.26
Fecal eggs log10, pg/mL391.400.93–2.120.091.340.89–2.020.14171.450.58–3.600.410.260.06–1.070.05
Figure 1.
Figure 1.

Delta values (follow-up–baseline) of levels of soluble tumor necrosis factor-α receptor II (sTNF-rII) and interleukin-10 (IL-10) according to intervention group and human immunodeficiency virus status. Bars represent means with 95% confidence intervals (CIs). Two-way analysis of variance showed that there was a significant reduction of sTNF-rII in the early intervention groups than in the delayed intervention groups (P = 0.03; mean fold change, follow-up–baseline, early intervention groups: 0.84; 95% CI = 0.78–0.90; delayed intervention groups: 0.93, 95% CI = 0.87–0.99). Similarly, IL-10 levels were reduced more in early intervention groups (P < 0.001; mean fold change, follow-up–baseline, early intervention groups: 0.37, 95% CI = 0.29–0.46; delayed intervention groups: 0.64; 95% CI = 0.51–0.79).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 3; 10.4269/ajtmh.2008.79.331

*

Address correspondence to Christian Erikstrup, Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. E-mail: christian@erikstrup.org

Authors’ addresses: Christian Erikstrup, Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Brendstrup-gaardsvej 100, DK-8200 Aarhus N, Denmark, Tel: +45-40187491, Fax: +45-35457644, E-mail: Christian@erikstrup.org. Per Kallestrup, Bente Klarlund Pedersen, and Sisse R. Ostrowski, Centre of Inflammation and Metabolism, Department of Infectious Diseases 7641, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark, E-mails: kallestrup@dadlnet.dk, bente.klarlund.pedersen@rh.regionh.dk, and sisse.ostrowski@gmail.com. Rutendo B. L. Zinyama-Gutsire, National Institute of Health Research, Corner Tongogara and Mazoe St, CY 573 Causeway, Harare, Zimbabwe, E-mail: gutsirerbl@yahoo.com. Exnevia Gomo, Research Support Centre, College of Medicine, University of Malawi, P.Bag 360, Chichiri, Blantyre 3, Malawi, E-mail: egomo@rsc.medcol.mw. Govert J. van Dam and André M. Deelder, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands, E-mails: G.J.van_Dam@lumc.nl and a.m.deelder@lumc.nl. Anthony E. Butterworth, Biomedical Research and Training Institute, PO Box CY 1753, Causeway, Harare, Zimbabwe, E-mail: aeb1@ecoweb.co.zw. Jan Gerstoft, Department of Infectious Diseases 5132, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, E-mail: jan.gerstoft@rh.regionh.dk. Henrik Ullum, Department of Clinical Immunology 2031, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark, E-mail: henrik.ullum@rh.regionh.dk.

Acknowledgments: We thank the Mupfure Community; the Village Health Workers; the Environmental Health Technician; the technical team (E. N. Kurewa, N. Taremeredzwa, W. Mashange, C. Mukahiwa, S. Nyandoro, W. Soko, B. Mugwagwa, and E. Mashiri), the Department of Haematology at Parirenyatwa Hospital (R. Mafirakureba, D. Mawire, and B. Mudenge); and the Department of Virology at Rigshospitalet, Copenhagen (M. Luneborg-Nielsen) for their contributions to the study.

Financial support: This study was supported by grants from the Danish AIDS Foundation; Fonden Til Lægevidenskabens Fremme; The Essential National Health Research Fund of the Ministry of Health and Child Welfare of Zimbabwe (P355); The Danish Embassy in Zimbabwe (2001); The DANIDA Health Programme in Zimbabwe (2001); The U.S. Centers for Disease Control and Prevention Program in Zimbabwe; and the Centre of Inflammation and Metabolism (Danish National Research Foundation) (DG 02-512-555).

Disclosure: The authors have no commercial or other association that might pose a conflict of interest.

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Author Notes

Reprint requests: Christian Erikstrup, Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Brendstrup-gaardsvej 100, DK-8200 Aarhus N, Denmark.
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