Research ArticlePARASITOLOGY

Co-infections determine patterns of mortality in a population exposed to parasite infection

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Science Advances  20 Mar 2015:
Vol. 1, no. 2, e1400026
DOI: 10.1126/sciadv.1400026
  • Fig. 1 Map of study area in western Kenya.

    Map shows location of the study area and distinguishes different agroecological zones. Calves were recruited from 20 different sublocations (red), all falling within 45 km from the IDEAL project field laboratory in Busia town.

  • Fig. 2 Age-related variation in risks of T. parva infection, clinical illness, and death from ECF.

    (A) Empirical estimates of (i) hazard of seroconversion to T. parva (18), with censoring of non–T. parva–related deaths and adjusted for a 14-day delay between infection and a detectable antibody response; (ii) case fatality rate (probability of death conditional on infection, CF); (iii) net clinical rate (probability of death or ECF-like illness conditional on infection, CL). In contrast to hazard, CF and CL both decrease with age (Poisson regression: F1,8 = 10.4, P = 0.012 and F1,8 = 57.7, P < 0.001, respectively). (B) Model-predicted estimates for hazard and corresponding predictions for CF and CL with age. Model equations are given in Materials and Methods; parameter estimates are as in Table 3.

  • Fig. 3 Epidemiology of LPT infections and relationships with clinical outcome of T. parva infection.

    (A) Kaplan-Meier plot for calves first infected by T. parva at >16 weeks of age. Observed fractions surviving for those initially exposed (n = 169) and unexposed (n = 141) to LPT are compared. Tick marks indicate censoring (due to non-ECF deaths or end of observation period). A log-rank test indicates a significant difference [χ2(1) = 6.2, P = 0.013]. The change in overall relative risk for the two groups (CF ratio) as the calves age indicates falling levels of protection and is consistent with model predictions (see table S2). (B) Numbers of case and control calves by age class (1 to 4; see Table 1) and detection or nondetection of LPT, having excluded five calves with unknown LPT status. Controlling for age, detection of LPT is significantly protective (odds ratio = 0.11, P = 0.002). (C) Comparison of observed age-related LPT prevalences at time of first detection of T. parva surviving case-control calves (n = 81) in different age classes and overall (with 95% CIs) with expected prevalences averaged over all visits when T. parva was not detected. Expected prevalences in surviving calves from a mathematical model (see main text) are compared.

  • Fig. 4 Sensitivity analysis of mathematical model.

    Sensitivity analysis of model-predicted, age-related changes in the case fatality rate (CF) for different values of the force of infection with LPT (ΛL) and the rate of clearance of LPT infections (σL). ΛL and σL are varied as indicated, baseline and other parameter values as in Table 3, and high ΛL indicates 2× the baseline and low σL corresponds to a value of zero. CF is constant with age in the absence of heterologous protection by LPT.

  • Fig. 5 Modeling the effect of LPT infections on clinical burden due to T. parva.

    (A) Model outputs for scenario A, changing the force of infection for LPT species, ΛL (relative to baseline, scaled to 1 on horizontal axis), but not changing ΛH. Baseline parameter values are as in Table 3. Fraction of calves infected with T. parva before 1 year old (unchanged), high-risk infections only, and overall case fatality rate are shown. (B) Same outputs for scenario B, changing the force of infection for T. parva, ΛH, but not changing ΛL. (C) Same outputs for scenario C, changing both ΛH and ΛL. In contrast to scenario B, there is minimal change in the fraction of calves at high risk over a fourfold change (from 0.5 to 2) in relative forces of infection for this set of parameter values.

  • Table 1 Case-control study.

    Age distribution of ECF deaths (cases) and age-matched, T. parva–exposed but surviving calves (controls). The conditional logistic regression analysis (see Materials and Methods) controls for any imbalance across age classes. The number of deaths by age class predicted by the mathematical model (see Material and Methods) is compared.

    Age
    class
    Age
    (days)
    Observed no. of
    deaths
    Predicted no. of
    deaths
    No. of
    survivors
    115–59710.528
    260–10485.417
    3105–15953.117
    4160+45.119
    All2481
  • Table 3 Parameter definitions and best-fit estimates for mathematical model.
    ParameterDescriptionSource dataCentral estimate (95% CI)
    ΛHForce of infection with T. parvaFraction ever infected with T. parva0.0352 week–1
    (0.0315–0.0388)
    ΛLForce of infection with LPTFraction of T. parva–exposed calves ever infected with LPT0.0685 week–1
    (0.0576–0.0800)
    σHRate of loss of T. parvaFraction of calves with T. parva infection by RLB at 1 year0.335 week–1
    (0.256–0.450)
    σLRate of loss of LPTFraction of calves with LPT infection by RLB at 1 year0.0234 week–1
    (0.0194–0.0278)
    μFraction of high-risk calves that dieScaled to observed no. of acute ECF deaths0.118
    (0.079–0.168)
    ηFraction of high-risk surviving calves with clinical ECFScaled to observed no. of acute ECF deaths + ECF illness0.486
    (0.415–0.556)

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/1/2/e1400026/DC1

    Fig. S1. Relationship of subclinical, clinical, and fatal infections to clinical variables.

    Fig. S2. Relationship between clinical outcome and LPT prevalence.

    Table S1. Conditional logistic regression analyses of clinical predictors.

    Table S2. Impact of setting LPT prevalence at age a, L(a), on subsequent acute ECF death rate.

    References (33, 34)

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. Relationship of subclinical, clinical, and fatal infections to clinical variables.
    • Fig. S2. Relationship between clinical outcome and LPT prevalence.
    • Table S1. Conditional logistic regression analyses of clinical predictors.
    • Table S2. Impact of setting LPT prevalence at age a, L(a), on subsequent acute ECF death rate.
    • References (33, 34)

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