HIV, Cytomegalovirus, and Malaria Infections during Pregnancy Lead to Inflammation and Shifts in Memory B Cell Subsets in Kenyan Neonates.

Infections during pregnancy can expose the fetus to microbial Ags, leading to inflammation that affects B cell development. Prenatal fetal immune priming may have an important role in infant acquisition of pathogen-specific immunity. We examined plasma proinflammatory biomarkers, the proportions of various B cell subsets, and fetal priming to tetanus vaccination in cord blood from human United States and Kenyan neonates. United States neonates had no identified prenatal infectious exposures, whereas Kenyan neonates examined had congenital CMV or mothers with prenatal HIV or Plasmodium falciparum or no identified infectious exposures. Kenyan neonates had higher levels of IP-10, TNF-α, CRP, sCD14, and BAFF than United States neonates. Among the Kenyan groups, neonates with prenatal infections/infectious exposures had higher levels of cord blood IFN-γ, IL-7, sTNFR1, and sTNFR2 compared with neonates with no infectious exposures. Kenyan neonates had greater proportions of activated memory B cells (MBC) compared with United States neonates. Among the Kenyan groups, HIV-exposed neonates had greater proportions of atypical MBC compared with the other groups. Although HIV-exposed neonates had altered MBC subset distributions, detection of tetanus-specific MBC from cord blood, indicative of fetal priming with tetanus vaccine given to pregnant women, was comparable in HIV-exposed and non-HIV-exposed neonates. These results indicate that the presence of infections during pregnancy induces fetal immune activation with inflammation and increased activated MBC frequencies in neonates. The immunologic significance and long-term health consequences of these differences warrant further investigation.

Cord Blood Antiparasite Interleukin 10 as a Risk Marker for Compromised Vaccine Immunogenicity in Early Childhood.

Background: Antenatal exposure to parasites can affect infants' subsequent responses to vaccination. The present study investigated how maternal prenatal infections and newborns' antiparasite cytokine profiles relate to immunoglobulin G (IgG) responses to standard vaccination during infancy. Methods: A total of 450 Kenyan women were tested for parasitic infections during pregnancy. Their newborns' responses to Plasmodium falciparum, schistosome, and filaria antigens were assessed in cord blood lymphocytes. Following standard neonatal vaccination, this infant cohort was followed biannually to age 30 months for measurement of circulating IgG levels against Haemophilus influenzae b (Hib), diphtheria toxoid (DT), hepatitis B virus (HBV), and tetanus toxoid. Results: Trajectories of postvaccination IgG levels were classified by functional principal component (PC) analysis to assess each child's response profile. Two main components, PC1, reflecting height of response over time, and PC2, reflecting crossover from high to low responses or from low to high responses, were identified. Cord blood cytokine responses to schistosome and filarial antigens showed a significant association between augmented antihelminth interleukin 10 and reduced antibody levels, particularly to DT and HBV, and a more rapid postvaccination decline in circulating IgG levels against Hib. Conclusion: Antenatal sensitization to schistosomiasis or filariasis and related production of antiparasite interleukin 10 at birth are associated with reduced antivaccine IgG levels in infancy, with possibly impaired protection.

Use of prospective hospital surveillance data to define spatiotemporal heterogeneity of malaria risk in coastal Kenya.

BACKGROUND: Malaria in coastal Kenya shows spatial heterogeneity and seasonality, which are important factors to account for when planning an effective control system. Routinely collected data at health facilities can be used as a cost-effective method to acquire information on malaria risk for large areas. Here, data collected at one specific hospital in coastal Kenya were used to assess the ability of such passive surveillance to capture spatiotemporal heterogeneity of malaria and effectiveness of an augmented control system. METHODS: Fever cases were tested for malaria at Msambweni sub-County Referral Hospital, Kwale County, Kenya, from October 2012 to March 2015. Remote sensing data were used to classify the development level of each monitored community and to identify the presence of rice fields nearby. An entomological study was performed to acquire data on the seasonality of malaria vectors in the study area. Rainfall data were obtained from a weather station located in proximity of the study area. Spatial analysis was applied to investigate spatial patterns of malarial and non-malarial fever cases. A space-time Bayesian model was performed to evaluate risk factors and identify locations at high malaria risk. Vector seasonality was analysed using a generalized additive mixed model (GAMM). RESULTS: Among the 25,779 tested febrile cases, 28.7 % were positive for Plasmodium infection. Malarial and non-malarial fever cases showed a marked spatial heterogeneity. High risk of malaria was linked to patient age, community development level and presence of rice fields. The peak of malaria prevalence was recorded close to rainy seasons, which correspond to periods of high vector abundance. Results from the Bayesian model identified areas with significantly high malaria risk. The model also showed that the low prevalence of malaria recorded during late 2012 and early 2013 was associated with a large-scale bed net distribution initiative in the study area during mid-2012. CONCLUSIONS: The results indicate that the use of passive surveillance was an effective method to detect spatiotemporal patterns of malaria risk in coastal Kenya. Furthermore, it was possible to estimate the impact of extensive bed net distribution on malaria prevalence among local fever cases over time. Passive surveillance based on georeferenced malaria testing is an important tool that control agencies can use to improve the effectiveness of interventions targeting malaria (and other causes of fever) in such high-risk locations.

Physical condition and maintenance of mosquito bed nets in Kwale County, coastal Kenya.

BACKGROUND: Despite the extensive ownership and use of insecticide-treated nets (ITNs) over the last decade, the effective lifespan of these nets, especially their physical integrity, under true operational conditions is not well-understood. Usefulness of nets declines primarily due to physical damage or loss of insecticidal activity. METHODS: A community based cross-sectional survey was used to determine the physical condition and to identify predictors of poor physical condition for bed nets owned by individuals from communities in Kwale County, coastal Kenya. A proportionate hole index (pHI) was used as a standard measure, and the cut-offs for an 'effective net' (offer substantial protection against mosquito bites) and 'ineffective nets' (offer little or no protection against mosquito bites) were determined (pHI ≤88 (about ≤500 cm2 of holes surface area) and pHI of >88 (≥500 cm2 of holes surface area), respectively). RESULTS: The vast majority (78%) of the surveyed nets had some holes. The median pHI was 92 (range: 1-2,980). Overall, half of the nets were categorized as 'effective nets' or 'serviceable nets'. Physical deterioration of nets was associated with higher use and washing frequency. Young children and older children were found to use ineffective bed nets significantly more often than infants, while the physical integrity of nets owned by pregnant women was similar to those owned by infants. Estuarine environment inhabitants owned nets with the worst physical condition, while nets owned by the coastal slope inhabitants were in fairly good physical condition. The results suggest that bed nets are optimally utilized when they are new and physically intact. Thereafter, bed net utilization decreases gradually with increasing physical deterioration, with most net owners withdrawing physically damaged nets from routine use.This withdrawal commonly happens following 1.5 years of use, making bed net use the most important predictor of physical integrity. On average, the nets were washed twice within six months prior to the survey. Washing frequency was significantly influenced by the bed net colour and bed net age. Lack of knowledge on reasons for net retreatment and the retreatment procedure was evident, while net repair was minimal and did not seem to improve the physical condition of the nets. The "catch-up" bed net distribution strategies are sufficient for ensuring adequate ownership and utilization of 'effective nets' in the targeted groups, but bi-annual mass distribution is necessary to provide similar ownership and utilization for the other groups not targeted by "catch-up" strategies. CONCLUSIONS: Monitoring and maintenance strategies that will deliver locally appropriate education messages on net washing and repair will enhance the effectiveness of malaria control programmes, and further research to assess ineffective nets need is needed.

Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens.

In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child's susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (T(regs)) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4(+)CD25(lo) T cells and CD4(+)CD25(hi) FOXP3(+) cells (T(regs)) were enriched from CBMC. T(reg) frequency and HLA-DR expression on T(regs) were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4(+) T cells cultured with P. falciparum blood-stage Ags induced production of IFN-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of T(regs) to CD4(+)CD25(lo) cells suppressed spontaneous and malaria Ag-driven production of IFN-γ in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, T(regs) only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-ß did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces T(regs) that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T(regs) postnatally could modify a child's susceptibility to malaria infection and disease.

Monitoring malaria vector control interventions: effectiveness of five different adult mosquito sampling methods.

Long-term success of ongoing malaria control efforts based on mosquito bed nets (long-lasting insecticidal net) and indoor residual spraying is dependent on continuous monitoring of mosquito vectors, and thus on effective mosquito sampling tools. The objective of our study was to identify the most efficient mosquito sampling tool(s) for routine vector surveillance for malaria and lymphatic filariasis transmission in coastal Kenya. We evaluated relative efficacy of five collection methods--light traps associated with a person sleeping under a net, pyrethrum spray catches, Prokopack aspirator, clay pots, and urine-baited traps--in four villages representing three ecological settings along the south coast of Kenya. Of the five methods, light traps were the most efficient for collecting female Anopheles gambiae s.l. (Giles) (Diptera: Culicidae) and Anopheles funestus (Giles) (Diptera: Culicidae) mosquitoes, whereas the Prokopack aspirator was most efficient in collecting Culex quinquefasciatus (Say) (Diptera: Culicidae) and other culicines. With the low vector densities here, and across much of sub-Saharan Africa, wherever malaria interventions, long-lasting insecticidal nets, and/or indoor residual spraying are in place, the use of a single mosquito collection method will not be sufficient to achieve a representative sample of mosquito population structure. Light traps will remain a relevant tool for host-seeking mosquitoes, especially in the absence of human landing catches. For a fair representation of the indoor mosquito population, light traps will have to be supplemented with aspirator use, which has potential for routine monitoring of indoor resting mosquitoes, and can substitute the more labor-intensive and intrusive pyrethrum spray catches. There are still no sufficiently efficient mosquito collection methods for sampling outdoor mosquitoes, particularly those that are bloodfed.

A 14-year follow-up of ultrasound-detected urinary tract pathology associated with urogenital schistosomiasis in women living in the Msambweni region of coastal Kenya.

BACKGROUND: Complications of urogenital schistosomiasis include acute inflammatory and chronic fibrotic changes within the urogenital tract. Disease burden of this neglected tropical disease is often underestimated, as only active, urine egg-patent Schistosoma infection is formally considered. Previous studies have focussed on short-term effects of praziquantel treatment on urinary tract pathology, demonstrating that acute inflammation is reversible. However, the reversibility of chronic changes is less well studied. METHODS: Our study compared, at two time points 14 y apart, urine egg-patent infection and urinary tract pathology in a cohort of women living in a highly endemic area having intermittent praziquantel treatment(s). In 2014 we matched 93 women to their findings in a previous study in 2000. RESULTS: Between 2000 and 2014 the rate of egg-patent infection decreased from 34% (95% confidence interval [CI] 25 to 44) to 9% (95% CI 3 to 14). However, urinary tract pathology increased from 15% (95% CI 8 to 22) to 19% (95% CI 11 to 27), with the greatest increase seen in bladder thickening and shape abnormality. CONCLUSIONS: Despite praziquantel treatment, fibrosis from chronic schistosomiasis outlasts the presence of active infection, continuing to cause lasting morbidity. We suggest that future efforts to eliminate persistent morbidity attributable to schistosomiasis should include intensified disease management.

Impact of insecticide-treated bed nets on malaria transmission indices on the south coast of Kenya.

BACKGROUND: Besides significantly reducing malaria vector densities, prolonged usage of bed nets has been linked to decline of Anopheles gambiae s.s. relative to Anopheles arabiensis, changes in host feeding preference of malaria vectors, and behavioural shifts to exophagy (outdoor biting) for the two important malaria vectors in Africa, An. gambiae s.l. and Anopheles funestus. In southern coastal Kenya, bed net use was negligible in 1997-1998 when Anopheles funestus and An. gambiae s.s. were the primary malaria vectors, with An. arabiensis and Anopheles merus playing a secondary role. Since 2001, bed net use has increased progressively and reached high levels by 2009-2010 with corresponding decline in malaria transmission. METHODS: To evaluate the impact of the substantial increase in household bed net use within this area on vector density, vector composition, and human-vector contact, indoor and outdoor resting mosquitoes were collected in the same region during 2009-2010 using pyrethrum spray catches and clay pots for indoor and outdoor collections respectively. Information on bed net use per sleeping spaces and factors influencing mosquito density were determined in the same houses using Poisson regression analysis. Species distribution was determined, and number of mosquitoes per house, human-biting rates (HBR), and entomological inoculation rate (EIR) were compared to those reported for the same area during 1997-1998, when bed net coverage had been minimal. RESULTS: Compared to 1997-1998, a significant decline in the relative proportion of An. gambiae s.s. among collected mosquitoes was noted, coupled with a proportionate increase of An. arabiensis. Following > 5 years of 60-86% coverage with bed nets, the density, human biting rate and EIR of indoor resting mosquitoes were reduced by more than 92% for An. funestus and by 75% for An. gambiae s.l. In addition, the host feeding choice of both vectors shifted more toward non-human vertebrates. Besides bed net use, malaria vector abundance was also influenced by type of house construction and according to whether one sleeps on a bed or a mat (both of these are associated with household wealth). Mosquito density was positively associated with presence of domestic animals. CONCLUSIONS: These entomological indices indicate a much reduced human biting rate and a diminishing role of An. gambiae s.s. in malaria transmission following high bed net coverage. While increasing bed net coverage beyond the current levels may not significantly reduce the transmission potential of An. arabiensis, it is anticipated that increasing or at least sustaining high bed net coverage will result in a diminished role for An. funestus in malaria transmission.

Fetal immune activation to malaria antigens enhances susceptibility to in vitro HIV infection in cord blood mononuclear cells.

Mother-to-child-transmission (MTCT) of human immunodeficiency virus (HIV) remains a significant cause of new HIV infections in many countries. To examine whether fetal immune activation as a consequence of prenatal exposure to parasitic antigens increases the risk of MTCT, cord blood mononuclear cells (CBMCs) from Kenyan and North American newborns were examined for relative susceptibility to HIV infection in vitro. Kenyan CBMCs were 3-fold more likely to be infected with HIV than were North American CBMCs (P=.03). Kenyan CBMCs with recall responses to malaria antigens demonstrated enhanced susceptibility to HIV when compared with Kenyan CBMCs lacking recall responses to malaria (P=.03). CD4(+) T cells from malaria-sensitized newborns expressed higher levels of CD25 and human leukocyte antigen DR ex vivo, which is consistent with increased immune activation. CD4(+) T cells were the primary reservoir of infection at day 4 after virus exposure. Thus, prenatal exposure and in utero priming to malaria may increase the risk of MTCT.

Can prenatal malaria exposure produce an immune tolerant phenotype? A prospective birth cohort study in Kenya.

BACKGROUND: Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections. METHODS AND FINDINGS: We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNgamma, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNgamma, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf-, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10-2.43; p = 0.024) and 1.34 (95% CI 0.95-1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97-2.07, p = 0.074) and 1.39 (95%CI 0.99-2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNgamma and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage-specific IgG antibody levels were similar among the three groups. CONCLUSIONS: These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas.

Rift Valley Fever Seroprevalence in Coastal Kenya.

Rift Valley fever virus (RVFV) causes severe disease in both animals and humans, resulting in significant economic and public health damages. The objective of this study was to measure RVFV seroprevalence in six coastal Kenyan villages between 2009 and 2011, and characterize individual-, household-, and community-level risk factors for prior RVFV exposure. Sera were tested for anti-RVFV IgG via enzyme-linked immunosorbent assay. Overall, 51 (1.8%; confidence interval [CI95] 1.3-2.3) of 2,871 samples were seropositive for RVFV. Seroprevalence differed significantly among villages, and was highest in Jego Village (18/300; 6.0%; CI95 3.6-9.3) and lowest in Magodzoni (0/248). Adults were more likely to be seropositive than children (P < 0.001). Seropositive subjects were less likely to own land or a motor vehicle (P < 0.01), suggesting exposure is associated with lower socioeconomic standing (P = 0.03). RVFV exposure appears to be low in coastal Kenya, although with some variability among villages.

Dengue and West Nile Virus Transmission in Children and Adults in Coastal Kenya.

Dengue virus (DENV) and West Nile virus (WNV) are important reemerging arboviruses that are under-recognized in many parts of Africa due to lack of surveillance. As a part of a study on flavivirus, alphavirus, and parasite exposure in coastal Kenya, we measured neutralizing antibody against DENV and, to evaluate assay specificity, WNV in serum samples that tested positive for serum anti-DENV IgG by enzyme-linked immunosorbent assay. Of 830 anti-DENV IgG-positive samples that were tested for neutralizing activity, 488 (58.8%) neutralized DENV and 94 (11.3%) neutralized WNV. Of children ≤ 10 years of age, 23% and 17% had serum neutralizing antibody to DENV and WNV, respectively, indicating that DENV and WNV transmission has occurred in this region within the past decade. The results suggest that ongoing DENV and WNV transmission continues on the coast of Kenya and supports a need for routine arboviral surveillance in the area to detect and respond to future outbreaks.

Spatial and temporal variations in local transmission of Schistosoma haematobium in Msambweni, Kenya.

As part of an extensive study of the eco-epidemiology of urinary schistosomiasis along the southern coast of Kenya, spatial and temporal transmission patterns were associated with various ponds infested with Bulinus snails. The household-level spatial pattern of infection for children of various age groups in 2000 was contrasted with historical data from 1984. Significant local clustering of high and low infection levels among school age children was detected, and the spatial extent of clusters and their direction from specific water sources were measured. High infection levels were clustered around ponds known to contain Bulinus nasutus snails that shed Schistosoma haematobium cercariae, and low infection levels were concentrated near a river where intermediate host snails were rarely found. The spatial patterns of infection varied between 2000 and 1984 and between age groups. High levels of infection were clustered around different transmission foci in the two study periods, and, for younger children in 2000, were clustered nearer to the transmission foci than for the older children. Simultaneous consideration of the effects of different foci on transmission will allow for targeted application of control measures aimed at interrupting S. haematobium transmission at a local level.

Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort.

IgG antibodies to Plasmodium falciparum are transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized to P. falciparum in utero, defined by cord blood lymphocyte recall responses to malaria antigens, acquired antimalarial antibodies at the same rate as those who were not sensitized in utero, indicating that fetal exposure to malaria antigens did not affect subsequent infant antimalarial responses. Infants with detectable serologic antibodies at 12 months of age had an increased risk of P. falciparum infection during the subsequent 24 months. We conclude that serologic measures of antimalarial antibodies in children 36 months of age or younger represent biomarkers of malaria exposure rather than protection and that functional antibodies develop after 36 months of age in this population.

The effects of maternal helminth and malaria infections on mother-to-child HIV transmission.

OBJECTIVE: To investigate the effect of helminth and/or malaria infection on the risk of HIV infection in pregnant women and its transmission to their offspring. DESIGN: A retrospective cohort study of pregnant Kenyan women and their offspring from term, uncomplicated vaginal deliveries (n = 936) with a nested case-control study. METHODS: We determined the presence of HIV, malaria, schistosomiasis, lymphatic filariasis, and intestinal helminthes in mothers and tested for HIV antibodies in 12-24 month-old offspring of HIV-positive women. We related these findings to the presence of cord blood lymphocyte activation and cytokine production in response to helminth antigens. RESULTS: HIV-positive women (n = 83, 8.9% of all women tested) were 2-fold more likely to have peripheral blood and/or placental malaria (P < 0.025) and a 2.1-fold greater likelihood of lymphatic filariasis infection (P < 0.001) compared to location-and-parity matched HIV-negative women. Women with HIV and malaria tended to show an increased risk for mother-to-child-transmission (MTCT) of HIV, although this difference was not significant. MTCT of HIV, however, was significantly higher in women co-infected with one or more helminthes (48%) verses women without helminth infections (10%, P < 0.01; adjusted odds ratio, 7.3; 95% confidence interval, 2.4-33.7). This increased risk for MTCT of HIV correlated with cord blood lymphocytes production of interleukin-5/interleukin-13 in response to helminth antigens (P < 0.001). CONCLUSION: Helminth co-infection is associated with increased risk for MTCT of HIV, possibly by a mechanism in which parasite antigens activates lymphocytes in utero. Treatment of helminthic infections during pregnancy may reduce the risk of MTCT of HIV.

Late benefits 10-18 years after drug therapy for infection with Schistosoma haematobium in Kwale District, Coast Province, Kenya.

Late benefits of remote antischistosomal therapy were estimated among long-term residents of an area with high transmission of Schistosoma haematobium (Msambweni, Kenya) by comparing infection and disease prevalence in two local adult cohorts. We compared 132 formerly treated adults (given treatment in childhood or adolescence > or = 10 years previously) compared with 132 age- and sex-matched adults from the same villages who had not received prior treatment. The prevalence of current infection, hematuria, and ultrasound bladder abnormalities were significantly lower among the previously treated group, who were found to be free of severe bladder disease. Nevertheless, heavy infection was equally prevalent (2-3%) in both study groups, and present rates of hydronephrosis were not significantly different. Therapy given in childhood or adolescence appears to improve risk for some but not all manifestations of S. haematobium infection in later adult life. Future prospective studies of continued treatment into adulthood will better define means to obtain optimal, community-based control of S. haematobium-related disease in high-risk locations.

Anemia Among Children Exposed to Polyparasitism in Coastal Kenya.

Anemia represents a substantial problem for children living in areas with limited resources and significant parasite burden. We performed a cross-sectional study of 254 Kenyan preschool- and early school-age children in a setting endemic for multiple chronic parasitic infections to explore mechanisms of their anemia. Complete venous blood cell counts revealed a high prevalence of local childhood anemia (79%). Evaluating the potential links between low hemoglobin and socioeconomic factors, nutritional status, hemoglobinopathy, and/or parasite infection, we identified age < 9 years (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 4.4, 33) and the presence of asymptomatic malaria infection (OR: 6.8, 95% CI: 2.1, 22) as the strongest independent correlates of having anemia. A total of 130/155 (84%) of anemic children with iron studies had evidence of iron-deficiency anemia (IDA), 16% had non-IDA; 50/52 of additionally tested anemic children met soluble transferrin-receptor (sTfR) criteria for combined anemia of inflammation (AI) with IDA. Children in the youngest age group had the greatest odds of iron deficiency (OR: 10.0, 95% CI: 3.9, 26). Although older children aged 9-11 years had less anemia, they had more detectable malaria, Schistosoma infection, hookworm, and proportionately more non-IDA. Anemia in this setting appears multifactorial such that chronic inflammation and iron deficiency need to be addressed together as part of integrated management of childhood anemia.

Effect of antenatal parasitic infections on anti-vaccine IgG levels in children: a prospective birth cohort study in Kenya.

BACKGROUND: Parasitic infections are prevalent among pregnant women in sub-Saharan Africa. We investigated whether prenatal exposure to malaria and/or helminths affects the pattern of infant immune responses to standard vaccinations against Haemophilus influenzae (Hib), diphtheria (DT), hepatitis B (Hep B) and tetanus toxoid (TT). METHODS AND FINDINGS: 450 Kenyan women were tested for malaria, schistosomiasis, lymphatic filariasis (LF), and intestinal helminths during pregnancy. After three standard vaccinations at 6, 10 and 14 weeks, their newborns were followed biannually to age 36 months and tested for absolute levels of IgG against Hib, DT, Hep B, and TT at each time point. Newborns' cord blood (CB) lymphocyte responses to malaria blood-stage antigens, soluble Schistosoma haematobium worm antigen (SWAP), and filaria antigen (BMA) were also assessed. Three immunophenotype categories were compared: i) tolerant (those having Plasmodium-, Schistosoma-, or Wuchereria-infected mothers but lacking respective Th1/Th2-type recall responses at birth to malaria antigens, SWAP, or BMA); ii) sensitized (those with infected/uninfected mothers and detectable Th1/Th2-type CB recall response to respective parasite antigen); or iii) unexposed (no evidence of maternal infection or CB recall response). Overall, 78.9% of mothers were infected with LF (44.7%), schistosomiasis (32.4%), malaria (27.6%) or hookworm (33.8%). Antenatal maternal malaria, LF, and hookworm were independently associated with significantly lower Hib-specific IgG. Presence of multiple maternal infections was associated with lower infant IgG levels against Hib and DT antigens post-vaccination. Post-vaccination IgG levels were also significantly associated with immunophenotype: malaria-tolerized infants had reduced response to DT, whereas filaria-tolerized infants showed reduced response to Hib. CONCLUSIONS: There is an impaired ability to develop IgG antibody responses to key protective antigens of Hib and diphtheria in infants of mothers infected with malaria and/or helminths during pregnancy. These findings highlight the importance of control and prevention of parasitic infections among pregnant women.

Parasitism in Children Aged Three Years and Under: Relationship between Infection and Growth in Rural Coastal Kenya.

BACKGROUND: Parasitic infections, which are among the most common infections worldwide, disproportionately affect children; however, little is known about the impact of parasitic disease on growth in very early childhood. Our objective was to document the prevalence of parasitic infections and examine their association with growth during the first three years of life among children in coastal Kenya. METHODOLOGY/PRINCIPAL FINDINGS: Children enrolled in a maternal-child cohort were tested for soil transmitted helminths (STHs: Ascaris, Trichuris, hookworm, Strongyloides), protozoa (malaria, Entamoeba histolytica and Giardia lamblia), filaria, and Schistosoma infection every six months from birth until age three years. Anthropometrics were measured at each visit. We used generalized estimating equation (GEE) models to examine the relationship between parasitic infections experienced in the first three years of life and growth outcomes (weight, length and head circumference). Of 545 children, STHs were the most common infection with 106 infections (19%) by age three years. Malaria followed in period prevalence with 68 infections (12%) by three years of age. Filaria and Schistosoma infection occurred in 26 (4.8%) and 16 (2.9%) children, respectively. Seven percent were infected with multiple parasites by three years of age. Each infection type (when all STHs were combined) was documented by six months of age. Decreases in growth of weight, length and head circumference during the first 36 months of life were associated with hookworm, Ascaris, E. histolytica, malaria and Schistosoma infection. In a subset analysis of 180 children who followed up at every visit through 24 months, infection with any parasite was associated with decelerations in weight, length and head circumference growth velocity. Multiple infections were associated with greater impairment of linear growth. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate an under-recognized burden of parasitism in the first three years of childhood in rural Kenya. Parasitic infection and polyparasitism were common, and were associated with a range of significant growth impairment in terms of weight, length and/or head circumference.

Age-Stratified Profiles of Serum IL-6, IL-10, and TNF-α Cytokines Among Kenyan Children with Schistosoma haematobium, Plasmodium falciparum, and Other Chronic Parasitic Co-Infections.

In a study of children having polyparasitic infections in a Schistosoma haematobium-endemic area, we examined the hypothesis that S. haematobium-positive children, compared with S. haematobium-negative children (anti-soluble worm antigen preparation [SWAP] negative and egg negative) have increased systemic production of pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α) and decreased down-regulatory IL-10. A total of 804 children, 2-19 years of age, were surveyed between July and December 2009 and tested for S. haematobium, Plasmodium falciparum, filariasis, and soil-transmitted helminth infections. Plasma levels of IL-6, TNF-α, and IL-10 were compared for S. haematobium-positive and S. haematobium-negative children, adjusting for malaria, filaria, and hookworm co-infections, and for nutritional status, age group, sex, and geographic location. IL-10 was significantly elevated among children infected with S. haematobium, showing bimodal peaks in 7-8 and 13-14 years age groups. IL-10 was also higher among children who were acutely malnourished, whereas IL-10 levels were lower in the presence of S. haematobium-filaria co-infection. After adjustment for co-factors, IL-6 was significantly elevated among children of 5-6 years and among those with P. falciparum infection. Lower levels of IL-6 were found in malaria-hookworm co-infection. High levels of TNF-α were found in children aged 11-12 years regardless of infection status. In addition, village of residence was a strong predictor of IL-6 and IL-10 plasma levels. In adolescent children infected with S. haematobium, there is an associated elevation in circulating IL-10 that may reduce the risk of later morbidity. Although we did not find a direct link between S. haematobium infection and circulating pro-inflammatory IL-6 and TNF-α levels, future T-cell stimulation studies may provide more conclusive linkages between infection and cytokine responses in settings that are endemic for multiple parasites and multiple co-infections.