Why Are Periodic Erythrocytic Diseases so Rare in Humans?

Many studies have shown that periodic erythrocytic (red blood cell linked) diseases are extremely rare in humans. To explain this observation, we develop here a simple model of erythropoiesis in mammals and investigate its stability in the parameter space. A bifurcation analysis enables us to sketch stability diagrams in the plane of key parameters. Contrary to some other mammal species such as rabbits, mice or dogs, we show that human-specific parameter values prevent periodic oscillations of red blood cells levels. In other words, human erythropoiesis seems to lie in a region of parameter space where oscillations exclusively concerning red blood cells cannot appear. Further mathematical analysis show that periodic oscillations of red blood cells levels are highly unusual and if exist, might only be due to an abnormally high erythrocytes destruction rate or to an abnormal hematopoietic stem cell commitment into the erythrocytic lineage. We also propose numerical results only for an improved version of our approach in order to give a more realistic but more complex approach of our problem.

Modeling the Relationship Between Antibody-Dependent Enhancement and Disease Severity in Secondary Dengue Infection.

Sequential infections with different dengue serotypes (DENV-1, 4) significantly increase the risk of a severe disease outcome (fever, shock, and hemorrhagic disorders). Two hypotheses have been proposed to explain the severity of the disease: (1) antibody-dependent enhancement (ADE) and (2) original T cell antigenic sin. In this work, we explored the first hypothesis through mathematical modeling. The proposed model reproduces the dynamic of susceptible and infected target cells and dengue virus in scenarios of infection-neutralizing and infection-enhancing antibody competition induced by two distinct serotypes of the dengue virus during secondary infection. The enhancement and neutralization functions are derived from basic concepts of chemical reactions and used to mimic binding to the virus by two distinct populations of antibodies. The analytic study of the model showed the existence of two equilibriums: a disease-free equilibrium and an endemic one. Using the concept of the basic reproduction number [Formula: see text], we performed the asymptotic stability analysis for the two equilibriums. To measure the severity of the disease, we considered the maximum value of infected cells as well as the time when this maximum is reached. We observed that it corresponds to the time when the maximum enhancing activity for the infection occurs. This critical time was calculated from the model to be a few days after the occurrence of the infection, which corresponds to what is observed in the literature. Finally, using as output [Formula: see text], we were able to rank the contribution of each parameter of the model. In particular, we highlighted that the cross-reactive antibody responses may be responsible for the disease enhancement during secondary heterologous dengue infection.

Maternal Passive Immunity and Dengue Hemorrhagic Fever in Infants.

Dengue hemorrhagic fever (DHF) can occur in primary dengue virus infection of infants [Formula: see text] year of age. To understand the presumed role of maternal dengue-specific antibodies received until birth in the development of this primary DHF in infants, we investigated a mathematical model based on a system of nonlinear ordinary differential equations that mimics cells, virus and antibodies interactions. The neutralization and enhancement activities of maternal antibodies against the virus are represented by a function derived from experimental data and knowledge from the medical literature. The analytic study of the model shows the existence of two equilibriums, a disease-free equilibrium and an endemic one. We performed the asymptotic stability analysis for these two equilibriums. The local asymptotic stability of the endemic equilibrium (DHF equilibrium) corresponds to the occurrence of DHF. Numerical results are also presented in order to illustrate the mathematical analysis performed, highlighting the most important parameters that drive model dynamics. We defined the age at which DHF occurs as the time when the infection takes off that means at the inflection point of the curve of infected cell population. We showed that this age corresponds to the one at which maximum enhancing activity for dengue infection appears. This critical time for the occurrence of DHF is calculated from the model to be approximately 2 months after the time for maternal dengue neutralizing antibodies to degrade below a protective level, which corresponds to what is observed in the experimental data from the literature.

Global dynamics of a differential-difference system: a case of Kermack-McKendrick SIR model with age-structured protection phase.

In this paper, we are concerned with an epidemic model of susceptible, infected and recovered (SIR) population dynamic by considering an age-structured phase of protection with limited duration, for instance due to vaccination or drugs with temporary immunity. The model is reduced to a delay differential-difference system, where the delay is the duration of the protection phase. We investigate the local asymptotic stability of the two steady states: disease-free and endemic. We also establish when the endemic steady state exists, the uniform persistence of the disease. We construct quadratic and logarithmic Lyapunov functions to establish the global asymptotic stability of the two steady states. We prove that the global stability is completely determined by the basic reproduction number.

Modelling hematopoiesis mediated by growth factors with applications to periodic hematological diseases.

Hematopoiesis is a complex biological process that leads to the production and regulation of blood cells. It is based upon differentiation of stem cells under the action of growth factors. A mathematical approach of this process is proposed to understand some blood diseases characterized by very long period oscillations in circulating blood cells. A system of three differential equations with delay, corresponding to the cell cycle duration, is proposed and analyzed. The existence of a Hopf bifurcation at a positive steady-state is obtained through the study of an exponential polynomial characteristic equation with delay-dependent coefficients. Numerical simulations show that long-period oscillations can be obtained in this model, corresponding to a destabilization of the feedback regulation between blood cells and growth factors, for reasonable cell cycle durations. These oscillations can be related to observations on some periodic hematological diseases (such as chronic myelogenous leukemia, for example).

Periodic oscillations in leukopoiesis models with two delays.

The term leukopoiesis describes processes leading to the production and regulation of white blood cells. It is based on stem cells differentiation and may exhibit abnormalities resulting in severe diseases, such as cyclical neutropenia and leukemias. We consider a nonlinear system of two equations, describing the evolution of a stem cell population and the resulting white blood cell population. Two delays appear in this model to describe the cell cycle duration of the stem cell population and the time required to produce white blood cells. We establish sufficient conditions for the asymptotic stability of the unique nontrivial positive steady state of the model by analysing roots of a second degree exponential polynomial characteristic equation with delay-dependent coefficients. We also prove the existence of a Hopf bifurcation which leads to periodic solutions. Numerical simulations of the model with parameter values reported in the literature demonstrate that periodic oscillations (with short and long periods) agree with observations of cyclical neutropenia in patients.