In cmhoove14/DDNTD: Density Dependence in Neglected Tropical Diseases

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Male-female schistosome details

Lu ... Webster 2018: Single-sex schistosome infections of definitive hosts: implications for epidemiology and disease control in a changing world (and cited studies)

Laboratory studies suggests that single-sex infections are likely due to a number of factors. Male S. mansoni cercariae may be more infective than female cercariae, but male worms may subsequently increase the infectivity of female cercariae once established. Furthermore, unpaired male worms are able to establish and mature, waiting for a female mate, whereas unpaired females may not mature, and may die within 8 weeks due to starvation. r citet(c("10.1371/journal.ppat.1006817", "10.1017/S0031182099006393"))

Other experimental studies with S. japonicum suggest that immature female worms may survive for up to a year. r citet("10.1371/journal.ppat.1006817")

Experimental infection of pigs with S. japonicum cercariae at doses of 100, 500, and 2000 cercariae implies acute phase associated with heavy infection initially in high dose group, followed by low-level chronic infection, similar to the low-dosage groups. Also evidence for non-linear density-dependence in number of worms acquired from dose with highest rate of worm establishment in lowest cercarial dose group. Highest egg shedding across al time points in highest dose group. PARAMETER mean cercarial infectivity (worms/cercaria) is time since exposure and exposure dose dependent, ranges from ~2% to ~10% r citet("10.4269/ajtmh.1998.58.248")

Field studies have also found evidence for single-sex infections. In a field study of wild rats in Guadeloupe, around 40% of rats were infected with S. mansoni. Of these, ~80% had dual-sex infections, 18% had single adult male infections, and only 2% had single adult female infections. Pairing probabilities of adult female worms ranged from ~0.83 - 0.97, in agreement with the probabilities derived analytically by May r citet("10.2307/1939595").

Single-sex S. japonicum infections were also common among sentinel mice used to estimate cercarial concentrations in China. r citet("10.1371/journal.ppat.1006817")

Single-sex infections can remain dormant and successfully mate with acquired worms of the opposite sex at later intervals. r citet(c("10.1371/journal.ppat.1006817", "10.1007/BF01022380", "10.1007/s00436-013-3700-0"))

There is variability in the efficacy of PZQ to unmated and mated worm pairs. Unmated worms of either sex require higher doses of PZQ to die. r citet("10.1016/j.ijpara.2003.12.003") Since mated females reside within the groove of males, females may be shielded from PZQ exposure and survive treatment, a potential explanation for observed variability in cure rates over the course of multiple PZQ administrations. r citet(c("10.1111/eva.12341", "10.1016/S1471-4922(01)02209-7"))

Cure rate may be reduced in Senegal, suggesting potential for resistance. Other explanations include very high initial worm burdens whereby egg shedding rates remain high due to remaining worms and relaxation of negative density dependent crowding effects, intense transmission whereby individuals are rapidly reinfected or are harboring immature worms acquired just before treatment that are less susceptible to PZQ. r citet("10.1016/S1471-4922(01)02209-7")

Boissier & Mone 2000: Experimental observations on the sex ratio of adult S. mansoni

Infectivity between male and female cercariae is equivalent when mice exposed to equal sex ratios. Sex ratios of male/female adult worms not different from sex ratios of male/female cercarial exposure. Infectivity maximized at balanced sex ratios. Male cercariae more infective than female cercariae in single-sex exposures, could suggest that male infection stimulates female infectivity. PARAMETER mean cercarial infectivity (worms/cercarial exposure) is ~0.25. r citet("10.1017/S0031182099006393")

Lamberton, Faust, Webster 2017: PZQ decreases fecundity in S. mansoni adult worms that survive treatment

Tended to observe an excess of unpaired males, while unpaired female infections were rare. PZQ treatment decreased fecundity of mated adult worms, with important implications for estimation of PZQ efficacy based on egg-diagnostics: if PZQ reduces fecundity, egg-based diagnoses will identify reductions in worm burden they may in fact be due to reductions in fecundity, not reductions in parasite burden. PZQ treatment affected fecundity of adult worms more than their survival, but unclear if reductions (embryostasis) are permanent or temporary (e.g. if surviving worms return to pre-treatment fecundity) r citet("10.1186/s40249-017-0324-0")

Neves, Webster, Walker 2019: Estimating helminth burdens using sibship reconstruction

"Sibship reconstruction is a form of parentage analysis that can be used to identify the number of helminth parental genotypes infecting individual hosts using genetic data on only their offspring". Introduces new statistical technique that could be used to estimate the number of mated adult female worm pairs from miracidial genotype data based on parentage analysis. Suggests this could answer questions re: DD fecundity of adult schistosomes, questions regarding MDA efficacy (whether reductions in worm burden are due to actual reduced parasite burdens, reduced fecundity of worms exposed to PZQ, or something else) r citet("10.1186/s13071-019-3687-1")

Genetic studies

Norton ... Webster: Genetic consequences of mass human chemotherapy for S. mansoni

Allelic richness and heterozygosity decrease, implying significant decrease in genetic diversity following a single PZQ treatment, not only in treated children, but also in other cohorts of children, implying that the entire local population was affected by treatment. Another interesting idea is that treatment with PZQ kills adult parasites and the host immune system is able to develop specific antibodies to the strain(s) of parasite that are killed. This psuedo-vaccination then prevents re-infection with these same strains, but other strains are able to reinfect, therefore post-PZQ genetic diversity is restricted to those strains which were not present previously. r citet("10.4269/ajtmh.2010.10-0283")

Huyse et al: Regular treatments of praziquantel do not impact on the genetic make-up of Schistosoma mansoni in Northern Senegal

No significant change in genetic diversity or population structure of S. mansoni in Nder, a community on the wester side of Lac-de-Guiers, about 30km from Richard Toll with a population of ~500 in Northern Senegal. Children were assessed at baseline, treated with PZQ twice (three weeks apart) and then up to five times total over 13 months. Treatment associated with large, rapid decrease in egg production 6 weeks after treatment that rebounded rapidly to heavy egg shedding 6 months post-treatment citet("10.1016/J.MEEGID.2013.05.007")

Lelo et al: No Apparent Reduction in Schistosome Burden or Genetic Diversity Following Four Years of School-Based Mass Drug Administration in Mwea, Central Kenya, a Heavy Transmission Area

In depth sampling of 15 "phenotypically susceptible"" children who had high egg burdens at baseline and every year of follow-up shows that gene diversity, allelic richness, effective number of breeders, and full sibling families did not change over 4 years of annual school-based MDA, implying no signficicant effects on transmission intensity or parasite population size. citet("10.1371/journal.pntd.0003221")

Barbosa et al: Repeated praziquantel treatments remodel the genetic and spatial landscape of schistosomiasis risk and transmission (in Brazil)

S. mansoni nfection intensity reduced by 57% over three rounds of treatment in 2009, 2012, and 2013. Prevalence reduced from 45% to 24% and then to 16%. Number of eggs transmitted to the environment decreased by 92% (from an estimated 3.28 million eggs shed per day to 0.26 millions eggs/day). Observed sustained reductions in incidence and reinfection with little intervention other than treating infected individuals in 2009, 2012, 2013. This success (compared to results in SSA) attributed to relatively small community size, better sanitation, treatment of all individuals regardless of age. Successful transmission reduction attributed to reductions in egg output to the environment which was due to treatment of individuals >15 years old. Genetic analyses suggest that those who were treated and subsequently found to have infection were indeed reinfected with new parasites, rather than having parasites that persisted through treatment due to resistance or other mechanisms. Allelic frequency and variance effective population size (Ne) both decreased over the treatment rounds, with Ne values approaching those suggested to be associated with extinction due to a lack of genetic diversity. This reduced genetic diversity also suggests lower likelihood of developing PZQ resistance citet("10.1016/J.IJPARA.2016.01.007")

Gower ... Webster: Phenotypic and genotypic monitoring of S. mansoni in tanzanian school children 5 years into a PC national control program

Parentage analysis on miracidia from infected children implies declining adult worm burden, but increasing adult worm fecundity, suggesting relaxation of density-dependent reductions in egg output per adult worm that explain minimal changes in actual infection intensity as measured by egg burden. Genetic diversity as measured by allelic richness and heterozygosity was reduced in 2006 (when compared to 2005), but had returned to similar levels by 2010. In vitro phenotypic monitoring of individual miracidia suggests some reduced susceptibility to PZQ, but not resistance. Furthermore, decreased susceptibility was not clustered with genetic data, implying that the mechanism for reduced susceptibility was not the emergence of a resistant strain r citet("10.1186/s13071-017-2533-6")

China elimination settings

Carlton et al 2011: Evaluation of mammalian and intermediate host surveillance methods for detecting schisto reemergence in SW China

Among 53 villages which had previously achieved transmission control, defined as <1% prevalence among at least 95% of the population surveyed, 35 showed evidence of reemergence, with human prevalence as high as 43%. Acute human schistosomiasis cases reported to NIDRS were a very poor surveillance method for reemergence (identified 1% of villages with reemergence) r citet("10.1371/journal.pntd.0000987")

Spear et al 2011: Challenge of effective surveillance in moving from low transmission ot elimination of schisto in China

Discuss low-level, persistent transmission and reemergence of detectable human infections in the context of transmission dynamics near the breakpoint. Surveillance methods relying on detection of eggs or environmental reservoirs of infection are likely to miss indicators of transmission in these low-level environments. Zoonotic reservoirs of infection (non-Bovine and human hosts of S. japonicum) also become increasingly important in low-transmission settings and can be sufficient to maintain the system above the breakpoint. Draw attention to the need for environmental surveillance methods, which are seriously lagging for schisto when compared to other environmentally mediated infectious diseases like arboviruses, crypto, giardia, polie, etc. r citet("doi:10.1016/j.ijpara.2011.08.002")

Spear, Zhong, Liang 2017: Low transmission to elimination: Rural development as a key determinant of the end-game dynamics of S. japonicum in China

Mention MDA and snail control acting on state variables, while developmental improvements act on parameters that determine. Dramatic reductions in snail habitat in particular suspected to decrease transmission and human infection, but integrated control strategies also focused on improved sanitation via sanitary toilets and biogas digesters. County-by-county comparisons suggest different strategies can be effective in achieving transmission control, with some integrated control efforts more focused on snail habitat mitigation and others more focused on WASH improvements. $R_0$/$R_{eff}$ r citet("doi:10.3390/tropicalmed2030035")

Carlton, Hubbard, Wang, Spear 2013: Repeated S. japonicum infection following treatment in two cohorts: evidence for host susceptibility to helminthiasis?

In two cohorts, one from endemic transmission setting and one in setting with history of transmission control, reinfection with S. japonicum was correlated with previous infection, even when accounting for variability in survey-reported exposure. This suggests imperfect treatment whereby heavily infected individuals retain parasites even after treatment, or a role of individual-level susceptibility whereby some individuals acquire more parasites even given the same exposure as less-susceptible individuals. r citet("doi:10.1371/journal.pntd.0002098")

Wang & Spear 2014: Exploring the impact of infection-induced immunity on the transmission of S. japonicum in hilly and mountainous environments in China

Infection-induced immunity based on assumptions that protective immunity increases as a function of transmission intensity or infection and the rate of increase in immunity is proportional to the current transmission intensity. This leads to "peak-shift" phenomena whereby peak infection intensity occurs in younger individuals in higher transmission intensity settings and is delayed to older individuals in lower transmission intensity settings (also see r citet("10.1038/315491a0") for experiments in mice and epidemiological evidence from r citet("10.1046/j.1365-3024.1997.d01-206.x")). Regression models incorporating age profiles and individual exposure and infection intensities do not support evidence for age-induced immunity (associations between cercarial exposure infection intensity does not vary by age), but rather suggest differential susceptibility as indicated by baseline infection intensity and infection-induced immunity explain patterns of reinfection. PARAMETERS provided for community-mean rates of immunity development and decline as well as an individual-level equation for acquired immunity. Residual immunity can increase the breakpoint in high transmission areas that have recently achieved elimination. r citet("10.1016/j.actatropica.2014.01.005")

Wang & Spear 2015: Exploring the Contribution of Host Susceptibility to Epidemiological Patterns of S. japonicum Infection Using an Individual-Based Model

Using data on water contact activities and estimates of cercarial concentrations, relationships between cercarial exposure, susceptibility, worm acquisition, and egg shedding are derived. Because estimates are derived only for individuals with observable worm burden, an assumtpion is made that they're observing the top ~12% of people in terms of their susceptibility and distributions of the PARAMETER $\alpha_i$ for individual susceptibility are derived based on this assumption. Reinfection found to be highly non-random in the model, even moreso than in epidemiological data. This could be due to residual acquired immunity in the human population that was not accounted for in the IBM. Also concludes that cercarial density and individual susceptibility are definitive determinants of population distributions of infection intensity. r citet("10.4269/ajtmh.14-0691")

Wang & Spear 2016: Exposure versus Susceptibility as Alternative Bases for New Approaches to Surveillance for S. japonicum in Low Transmission Environments

Demonstration of 20/80 rule whereby ~20% of populations that are highly susceptible contribute ~80% of infection into environment, thereby potentially causing infection of other individuals. Argument for biomarker of individual susceptibility to infection is called for. r citet("10.1371/journal.pntd.0004425")

Spear 2012: Internal vs external determinants of S. japonicum transmission in irrigated agricultural villages

Discussion of local ($\approx R_0$) determinants of transmission vs density dependent and external determinants of transmission. Predictions of reinfection based on these equations. Finding that most areas are unable to sustain transmission alone, suggested connectivity is a key determinant of transmission intensity r citet("10.1098/rsif.2011.0285")

Drug resistance

Crellen ... Webster 2016: Reduced Efficacy of Praziquantel Against S. mansoni Is Associated With Multiple Rounds of MDA

Reduced efficacy of PZQ as measured by egg reduction rate (ERR) among children with more PZQ treatments r citet("10.1093/cid/ciw506")

Unclassified

Colley et al 2017: Schistosomiasis is more prevalent than previously thought...

Using point-of-care circulating anodic or cathodic antigen assays that detect evidence of antibodies developed against adult worms, prevalence found to be substantially higher than when using egg-based diagnostic tests such as kato-katz or urine-filtration. These egg-negative, antigen-positive results could suggest very low levels of egg output that egg-detection tests may not be able to detect, temporary cessation of egg-laying by worms harmed, but not killed by PZQ, or single sex infections, all of which may contribute to schistosomiasis persistence r citet("10.1186/s40249-017-0275-5")

Boissier et al: Outbreak of urogenital schistosomiasis in Corsica

Outbreak in Corsica associated with high densities of Bulinus truncatus intermediate host snails and likely introduction of individuals harboring adult parasites from Senegal. First described evidence of potentially purely-zoonotic transmission of S. bovis as miracidia isolated from urine of infected individuals were genotyped as S. bovis and S. haematobium hybrids as well as pure S. bovis. Suggests that breakpoint threshold is very achievable in areas where sufficient snail populations and potential zoonotic transmission are present r citet("10.1016/S1473-3099(16)00175-4")

Harris et al 1984: Review of schistosomiasis in immigrants to Western Australia demonstrating unusual longevity of S. mansoni

Individuals with symptomatic schistomiasis infection had immigrated to Australia >30 years prior, suggesting adult worms may live for three decades r citet("10.1016/0035-9203(84)90129-9")

References

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cmhoove14/DDNTD documentation built on Nov. 23, 2019, 7:04 p.m.