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Research article

Modeling the cardiac response to hemodynamic changes associated with COVID-19: a computational study


  • Received: 14 January 2021 Accepted: 07 April 2021 Published: 15 April 2021
  • Emerging studies address how COVID-19 infection can impact the human cardiovascular system. This relates particularly to the development of myocardial injury, acute coronary syndrome, myocarditis, arrhythmia, and heart failure. Prospective treatment approach is advised for these patients. To study the interplay between local changes (reduced contractility), global variables (peripheral resistances, heart rate) and the cardiac function, we considered a lumped parameters computational model of the cardiovascular system and a three-dimensional multiphysics model of cardiac electromechanics. Our mathematical model allows to simulate the systemic and pulmonary circulations, the four cardiac valves and the four heart chambers, through equations describing the underlying physical processes. By the assessment of conventionally relevant parameters of cardiac function obtained through our numerical simulations, we propose a computational model to effectively reveal the interactions between the cardiac and pulmonary functions in virtual subjects with normal and impaired cardiac function at baseline affected by mild or severe COVID-19.

    Citation: Luca Dedè, Francesco Regazzoni, Christian Vergara, Paolo Zunino, Marco Guglielmo, Roberto Scrofani, Laura Fusini, Chiara Cogliati, Gianluca Pontone, Alfio Quarteroni. Modeling the cardiac response to hemodynamic changes associated with COVID-19: a computational study[J]. Mathematical Biosciences and Engineering, 2021, 18(4): 3364-3383. doi: 10.3934/mbe.2021168

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    1. Introduction

    Hepatitis B virus infection is a major public-health concern, both in developing countries and immigrant communities in developed countries. An estimated two billion people worldwide are infected with the virus, with about 378 million chronic carriers worldwide and approximately 620, 000 deaths each year [8]. Each year, about 4.5 million new infections occur, of which a quarter progress to liver disease [8]. Approximately 45% of the world's population live in areas with high prevalence of chronic HBV infection [16]. Prevalence ranges between 2% in low-endemic countries and 8% in high-endemic countries [8]. In high-endemic countries, the lifetime risk for HBV infection is greater than 60% [16].

    HBV infection exhibits an acute infection stage and a chronic liver infection, characterized by persistent serum level of HBV surface antigen (HBsAg), IgG anti-core antigen (anti-HBc) and HBV DNA [4]. Acute disease usually occurs when the immune response is well preserved, while patients with an immunodeficiency are more likely to develop a chronic disease, in turn becoming a source for new infections [8]. Chronic infection may later develop into serious disease such as cirrhosis or liver cancer, causing major morbidity and mortality [14].

    Safe and effective HBV vaccines have been commercially available since 1962 [16], being also the first vaccine to protect against cancer [14]. More than 150 countries have HBV vaccine immunization programs, with routine infant vaccination designated a high priority in all countries [16]. However, coverage in developing countries with high endemicity is limited due to high cost and social hurdles [8]. This is despite the cost-effectiveness of the vaccine in both high- and low-endemic countries [14]. In the developed world, the hepatitis B vaccine is one that was targeted by anti-vaccine campaigners, due to the presence of mercury-based thimerosal; however, by March 2001, thimerosal had been removed from all childhood vaccines [10]. An investigation of the literature established that no credible studies demonstrated a link between hepatitis B vaccination and autism [21]. Nevertheless, vaccination in adults in the United States decreased by 2.1% between 2012 and 2013, with 25% of adults 19 years currently vaccinated [25].

    The probability of becoming chronically infected is positively correlated to the age of the infected host [14,6,19,9], while progression of acute-stage and chronic-stage HBV is related to the time since infection. Furthermore, the infectivity of patients varies at different ages during the infectious period. Thus, mathematical models that can examine infection-age structure can be useful in investigating the consequences of infection age on HBV transmission dynamics and disease progression. Continuous age-structured models usually lead to partial differential equation (PDE) formulation. Population migration occurs at regional, national and global scales due to various factors, such as economic development. Labour workers transition from rural regions to large cities in both developing and industrialized countries, while immigrants and refugees migrate from developing countries to immigrant-receiving countries [20].

    Although dynamical analysis of epidemic models with age structures is particularly challenging, there has been recent progress in global analysis [13,22,2,7,15,17,18]. Age-structured models have also been developed to study the epidemiology of HBV infection [6,19,27,29,26]. Medley et al. observed a feedback mechanism that determines the prevalence of HBV infection, using an ODE model to relate the rate of transmission, average age at infection and age-related probability of developing carriage following infection [19]. Based on sero-survey data in China, Zhao et al. [27] constructed an age-structured HBV model to evaluate the long-term effectiveness of vaccination programmes. Zou et al. in [29] proposed a full PDE model that incorporated multiple age structures to study the transmission dynamics of HBV and analyzed the existence and stability of the disease-free and endemic equilibria. In [26], age of infection and nontrivial vertical transmission were incorporated into the model to study the possible effects of variable infectivity on HBV dynamics.

    Brauer and van den Driessche [3] studied an SIS model with a constant flow of infective immigrants into the infectious compartment. Such immigration models do not contain an infection-free equilibrium and consequently have no reproduction number. Guo and Li [11] generalized the immigration model to a high-dimensional SEIR model with constant immigration into each compartment, and the global stability of unique endemic equilibrium was shown by a global Lyapunov function. McCluskey [17,18] proved the global stability of the unique endemic equilibrium by a Lyapunov functional for an SEIR model with age structure consisting of a latent compartment, an infectious compartment and variable-age immigration terms. Guo and Li [12] demonstrated that the immigration inflow is vital to the dynamical behaviour: small variations in the immigration term into infectious compartment and/or latent compartment can profoundly change the resultant dynamics.


    2. Model formulation

    Based on the characteristics of HBV transmission and progression, we divide the population into five classes: susceptible, exposed, acute infection, chronic carriers and immunized. Let S(t), E(t) and R(t) denote the population of susceptible, exposed and immunized individuals, respectively, at time t. Let i(a,t) and c(a,t) denote the densities of acute HBV infections and chronic HBV carriers with infection age a at time t. The acute-infected population is thus I(t)=a10i(a,t)da, while C(t)=a1c(a,t)da represents the total number of chronic HBV carriers at time t. The critical infection age a1 is set at three months, representing the average duration of time in acute infection before the onset of chronic stage.

    Vertical transmission from mother to child is also incorporated into our model. For simplicity, we assume all newborns are vaccinated with the same efficacy and that all the neonates who acquire HBV infection perinatally become chronic carriers, due to the high risk (up to 90%) of becoming chronic for this group. The model flow diagram is shown in Figure 1. Based on the natural history of HBV transmission and the assumptions of infection age, we have the following system of combined ordinary and partial differential equations:

    S(t)=ΛSbωa1v(a)c(a,t)da(μS+p)S(t)a10β(a)i(a,t)S(t)daa1αβ(a)c(a,t)S(t)da,E(t)=ΛE+a10β(a)i(a,t)S(t)da (1)
    +a1αβ(a)c(a,t)S(t)da(μE+σ)E(t),i(a,t)a+i(a,t)t=Λi(a)(μi(a)+γ1(a))i(a,t),0<aa1c(a,t)a+c(a,t)t=Λc(a)(μc(a)+γ2(a)+θ(a))c(a,t),a1<a<R(t)=ΛR+b(1ω)+a10(1q(a))γ1(a)i(a,t)da+a1γ2(a)c(a,t)daμRR(t)+pS(t),
    Figure 1. Flow diagram of the age-structured HBV transmission model (1).

    with the boundary conditions

    i(0,t)=σE(t),c(a1,t)=a10q(a)γ1(a)i(a,t)da+bωa1v(a)c(a,t)da

    and initial conditions

    S(0)=S0,E(0)=E0,i(a,0)=i0(a),c(a,0)=c0(a),R(0)=R0.

    The age-dependent function β(a) describes the rate of infectiousness as disease progresses within an infected individual. The vertical transmission rate is

    V=a1ν(a)c(a,t)da.

    The movement from acute individuals to carriers is given by

    Ic=a10q(a)γ1(a)i(a,t)da.

    The recovery rate is

    IR=a10(1q(a))γ1(a)i(a,t)da.

    The definitions of the other parameters in system (1) are listed in the Table 1. See also Zhang and Xu [26]. Note that unsuccessfully immunized birth is included in ΛS (i.e., ΛS>bω) and the vertical transmission is given by bωV. From the definition of v(a), we have V<1, so it follows that ΛS>bωV.

    Table 1. Definitions of parameters used in model (1).
    SymbolDefinition
    ΛS rate of recruitment into the susceptible compartment,
    including unsuccessfully immunized birth and immigration
    Λk immigration rate into class k (k=E,R)
    Λj(a) age-dependent immigration rate into class j (j=i,c)
    μk per capital death rate for class k (k=S,E,R)
    μj(a) age-dependent death rate for class j (j=i,c)
    b birth rate
    ω proportion of newborns who are unsuccessfully immunized
    σ transfer rate from exposed to acute infection
    p vaccination rate
    α degree of infectiousness of carriers relative to acute infections (α>0)
    β(a) age-dependent transmission coefficient
    v(a) age-dependent rate of children born to carrier mothers
    who become HBV carriers
    γ1(a) age-dependent transfer rate from acute to immunized or carrier class
    γ2(a) age-dependent transfer rate from carrier to immunized class
    q(a) age-dependent progression from acute infection to carrier class
    θ(a) age-dependent HBV-induced death rate
     | Show Table
    DownLoad: CSV

    In order to simplify the analysis, we made the following assumptions.

    (H1) v, β, μi, μc, γ1, γ2, q, θL(R0,R0).

    Let μ_i,μ_c,β_ be the essential infimums of μi,μc,β, respectively, and ˉμi,ˉμc,ˉq,ˉγ1,ˉv be the respective essential supremums of μi,μc,q,γ1 and v.

    (H2) μ_i,μ_c>0 and q,γ1,v are Lipschitz continuous with Lipschitz coefficients Lq,Lγ1 and Lv, respectively.

    (H3) Λi,ΛcL1(R0,R0).

    (H4) The constant parameters ΛS,b,μS,μE,μR,ω,σ,α are positive, and ΛE,ΛR,p are nonnegative.

    (H5) The initial conditions satisfy S00, E00, R00, i0(a),c0(a)L1(R0,R0).

    (H6) The supports of β,qγ1 and Λi+Λc have positive measure. Let ˜Λi=a10Λi(a)da and ˜Λc=a1Λc(a)da, then ˜Λi+˜Λc>0.

    (H7) essential infimum (support(Λi))< essential supremum (support(qγ1)),

    essential infimum (support(Λj))< essential supremum (support(β))

    for j=i or c.

    To simplify expressions, we introduce the following notations

    π1(a)=ea0(μi(s)+γ1(s))dsa[0,a1],π2(a)=eaa1(μc(s)+γ2(s)+θ(s))dsa[a1,),

    where π1(a) is the age-specific survival probability of being acutely infected and π2(a) is the age-specific survival probability of being a chronic carrier. Based on the boundary and initial conditions and methods in [24], integrating i(a,t) and c(a,t) equations in system (1) yields

    i(a,t)={i(0,ta)π1(a)+a0Λi(s)π1(a)π1(s)ds,t>a, a[0,a1],i0(at)π1(a)π1(at)+aatΛi(s)π1(a)π1(s)ds,ta, a[0,a1], (2)

    and c(a,t)=

    {c(a1,a1+ta)π2(a)+aa1Λc(s)π2(a)π2(s)ds,t+a1>a,a[a1,),c0(ata1)π2(a)π2(ata1)+aata1Λc(s)π2(a)π2(s)ds,t+a1a,a[a1,). (3)

    By classical existence and uniqueness results for functional differential equations, there exists a unique solution for the integro-differential system (1) in which i(a,t) and c(a,t) are substituted for the expressions (2) and (3), respectively.

    For (2) and (3), it is easy to see that i(a,t) and c(a,t) remain nonnegative for any nonnegative initial value. Furthermore, if there exists a t such that S(t)=0 and S(t)>0 for 0<t<t, then, from the S equation of (1), we have S(t)=ΛSbωa1v(a)c(a,t)da>0, which implies that S(t)0 for all t0, noting that unsuccessfully immunized birth bω is included in ΛS. Similarly, it can be shown that E(t)0 for all t0 and all nonnegative initial values. Let

    Y=R20×L1(R0,R0)×L1(R0,R0)×R0

    be the state space of system (1). Then Y is positively invariant and there is a continuous semiflow defined by

    Φt:YY.

    Denote u(t)=(S(t),E(t),i(.,t),c(.,t),R(t))Y, which is endowed with the following norm:

    u=S+E+a10i(a,t)da+a1c(a,t)da+R.

    Notice that the variable R does not appear in other equations in (1); thus the equation of R can be ignored when studying the model dynamics, and the reduced system has the same dynamical behavior as the original system.


    3. Boundedness

    Let N(t) denote the total population size at time t. Then we have

    N(t)=S(t)+E(t)+a10i(a,t)da+a1c(a,t)da+R(t)=u.

    In the following, we establish that N(t) is bounded and the generated semiflow Φt is point dissipative.

    From (2), we can obtain

    a10i(a,t)da=t0i(a,t)da+a1ti(a,t)da=t0i(0,ta)π1(a)da+t0a0Λi(τ)π1(a)π1(τ)dτda+a1ti0(at)π1(a)π1(at)da+a1taatΛi(τ)π1(a)π1(τ)dτda.

    Changing the order of integration for two double integrals in the above, we have

    t0a0Λi(τ)π1(a)π1(τ)dτda=t0tτΛi(τ)π1(a)π1(τ)dadτ,a1taatΛi(τ)π1(a)π1(τ)dτda=t0τ+ttΛi(τ)π1(a)π1(τ)dadτ+a1tτ+tτΛi(τ)π1(a)π1(τ)dadτa1a1tτ+ta1Λi(τ)π1(a)π1(τ)dadτ.

    Making substitutions τ=ta and τ=at in the remaining two integrals gives

    a10i(a,t)da=t0i(0,τ)π1(tτ)dτ+a1t0i0(τ)π1(τ+t)π1(τ)dτ+a10τ+tτΛi(τ)π1(a)π1(τ)dadτa1a1tτ+ta1Λi(τ)π1(a)π1(τ)dτda.

    Thus differentiating a10i(a,t)da with respect to t leads to

    ddta10i(a,t)da=i(0,t)i0(a1t)π1(a1)π1(a1t)+t0i(0,τ)π1(tτ)dτ+a1t0i0(τ)π1(τ+t)π1(τ)dτ+a10Λi(τ)π1(τ+t)π1(τ)dτddta1a1tτ+ta1Λi(τ)π1(a)π1(τ)dadτ.

    We have

    a1t0i0(τ)π1(τ+t)π1(τ)dτ=a1ti0(at)π1(a)π1(at)da

    and

    t0a0Λi(τ)π1(a)π1(τ)dτda+a1taatΛi(τ)π1(a)π1(τ)dτda+a1a1tτ+ta1Λi(τ)π1(a)π1(τ)dadτ=a10τ+tτΛi(τ)π1(a)π1(τ)dadτ=a10Λi(τ)π1(τ+t)π1(τ)π1(τ)dτ=a10Λi(τ)π1(τ+t)π1(τ)dτa10Λi(τ)dτ.

    Noticing that π1(a)=(μi(a)+γ1(a))π1(a), it follows that

    ddta10i(a,t)da=i(0,t)i0(a1t)π1(a1)π1(a1t)+t0i(0,τ)π1(tτ)dτ+a1ti0(at)π1(a)π1(at)da+t0a0Λi(τ)π1(a)π1(τ)dτda+a1taatΛi(τ)π1(a)π1(τ)dτda+a10Λi(τ)dτa1a1tΛi(τ)π1(τ+t)π1(τ)dτ=i(0,t)i0(a1t)π1(a1)π1(a1t)+˜Λia1a1tΛi(τ)π1(τ+t)π1(τ)dτa10(μi(a)+γ1(a))i(a,t)da. (4)

    A similar calculation for (3) yields

    a1c(a,t)da=a1+ta1c(a,t)da+a1+tc(a,t)da=t0c(a1,τ)π2(a1+tτ)dτ+0c0(τ)π2(t+a1+τ)π2(τ)dτ+a1τ+tτΛc(τ)π2(a)π2(τ)dadτ,

    and hence

    ddta1c(a,t)da=c(a1,t)+a1+ta1c(a1,a1+ta)π2(a)da+a1+tc0(ata1)π2(a)π2(ata1)da+a1+ta1aa1Λc(τ)π2(a)π2(τ)dτda+a1+taata1Λc(τ)π2(a)π2(τ)dτda+a1Λc(τ)dτ=c(a1,t)a1(μc(a)+γ2(a)+θ(a))c(a,t)da+˜Λc. (5)

    Combining the equations gives

    N(t)=ΛS+ΛE+˜Λi+˜Λc+ΛR+b(1ω)i0(a1t)π1(a1)π1(a1t)a1a1tΛi(τ)π1(τ+t)π1(τ)dτμSS(t)μEE(t)μRR(t)a10μi(a)i(a,t)daa1(μc(a)+θ(a))c(a,t)daΛμN(t),

    where Λ=ΛS+ΛE+˜Λi+˜Λc+ΛR+b(1ω) and μ=min{μS,μE,μR,μ_i,μ_c}. Letting N=Λμ, we have

    lim suptN(t)N

    which implies that all solutions of system (1) are ultimately bounded. Moreover, when N(t)>Nμ, we have dN(t)dt<0, which implies that all solutions are uniformly bounded. Therefore, the solution semiflow Φt:YY is point dissipative. It follows that the set

    Ω={u(t)=(S(t),E(t),i(.,t),c(.,t),R(t))Y:umax{N,N(0)}}

    is positively invariant and absorbing under the semiflow Φt on Y.

    Lemma 3.1. The unique solution semiflow Φt of system (1) is uniformly bounded and point dissipative in Y.

    Lemma 3.2. There exists T,δ>0 such that i(0,t),c(a1,t)>δ for all t>T.

    Proof. First, since limtsupN(t)N, then, for any ϵ>0, there exists t10 such that a10i(a,t)da<N+ϵ and a1c(a,t)da<N+ϵ for all tt1. Thus, for sufficiently large t, from (1), we have

    S(t)ΛSbωa1v(a)c(a,t)daˉβS(t)(a10i(a,t)da+αa1c(a,t)da)(μS+p)S(t)ΛSbωa1v(a)c(a,t)daS(t)[ˉβ(N+ϵ)(1+α)+(μS+p)],

    from which it follows that

    lim inftS(t)ΛSbωa1v(a)c(a,t)daˉβ(N+ϵ)(1+α)+μS+pMS.

    Next we have

    E(t)ΛE+β_S(t)(a10i(a,t)da+αa1c(a,t)da)(μE+σ)E(t)ΛE+β_MS(a10i(a,t)da+αa1c(a,t)da)(μE+σ)E(t),

    which implies

    lim inftE(t)ΛE+β_MS(a10i(a,t)da+αa1c(a,t)da)μE+σME.

    Therefore there exists t2>t1 such that

    i(0,t)=σE(t)σME2 (6)

    for all tt2. Note that (H7) implies that there exist Tt2 and δ>0 such that

    t0a0q(a)γ1(a)Λi(τ)π1(a)π1(τ)dτdaδ

    for all t>T, so it follows that

    c(a1,t)a10q(a)γ1(a)i(a,t)dat0a0q(a)γ1(a)Λi(τ)π1(a)π1(τ)dτdaδ. (7)

    Then, when tT, the result follows from (6) and (7).


    4. Smoothness and attractiveness

    Lemma 4.1. The semi-flow Φ:R0×YY is asymptotically smooth if there are maps Θ,Ψ:R0×YY such that

    Φ(t,u)=Θ(t,u)+Ψ(t,u)

    and, for any bounded closed set CY that is forward invariant under Φ, the following holds:

    (a) limtdiamΘ(t,C)=0,

    (b) there exists tC0 such that Ψ(t,C) has compact closure for each ttC.

    This is a special case of Theorem 2.46 in [23]. Note that Φt=Φ(t,u0)=(S(t),E(t),i(.,t),c(.,t),R(t)), where u(0)=(S0,E0,i0(a),c0(a),R0). Then, for t0, we define two flows Ψ and Θ on Y so that Φ=Ψ+Θ. Let Ψ(t,u0)=(S(t),E(t),˜i(.,t),˜c(.,t),R(t)) and Θ(t,u0)=(0,0,˜i0(.,t),˜c0(.,t),0), where

    ˜i(a,t)={i(0,ta)π1(a),t>a,a[0,a1],0,ta,a[0,a1],˜c(a,t)={c(a1,a1+ta)π2(a),t+a1>a,a[a1,),0,t+a1a,a[a1,),˜i0(a,t)={a0Λi(s)π1(a)π1(s)ds,t>a,a[0,a1],i0(at)π1(a)π1(at)+aatΛi(s)π1(a)π1(s)ds,ta,a[0,a1],˜c0(a,t)={aa1Λc(s)π2(a)π2(s)ds,t+a1>a,c0(ata1)π2(a)π2(ata1)+aata1Λc(s)π2(a)π2(s)ds,t+a1a,

    for a[a1,). Let CY be bounded, with bound K>N. For j=1,2, denote uj0=(Sj0,Ej0,ij0,cj0,Rj0)C, with corresponding solutions

    Φ(t,uj0)=(Sj(t),Ej(t),ij(.,t),cj(.,t),Rj(t)).

    In the following, we evaluate the distance between Θ(t,u10) and Θ(t,u20), which corresponds to condition (a) in Lemma 4.1.

    Noting that ij0(a),cj0(a)L1(R0,R0) for j=1,2, let .1 denote the standard norm on L1. Since

    ˜i10(a,t)˜i20(a,t)={0,t>a,a[0,a1],(i10(at)i20(at))π1(a)π1(at)ta,a[0,a1],

    then

    ˜i10(a,t)˜i20(a,t)1=a1t|i10(at)i20(at)|π1(a)π1(at)da=a1t0|i10(τ)i20(τ)|π1(τ+t)π1(τ)dτ=a1t0|i10(τ)i20(τ)|eτ+tτ(μi(s)+γ1(s))dsdτeμ_ita10|i10(τ)i20(τ)|dτeμ_it(i101+i201)2Keμ_it,

    which approaches zero as t.

    Similarly, ˜c10(a,t)˜c20(a,t)12Keμ_ct, which leads to

    Θ(t,u10)Θ(t,u20)2K(eμ_it+eμ_ct)

    for all t0. Since uj0 is chosen arbitrarily in C, it follows that

    diamΘ(t,C)2K(eμ_it+eμ_ct)

    so condition (a) in Lemma 4.1 is satisfied.

    In the following, we verify condition (b) in Lemma 4.1, which can be alternatively proved by verifying four conditions in Lemma 4.2 below. This shows that ˜i(a,t) and ˜c(a,t) remain in a subset of L10, which has compact closure and is independent of u0.

    Lemma 4.2. (Theorem B.2 in [23] for the case S=L1(R0,R0)) A set SL1+(0,) has compact closure if and only if the following conditions hold:

    1. supfS0f(a)da<,

    2. limrrf(a)da0 uniformly for fS,

    3. limh0+0|f(a+h)f(a)|da0 uniformly for fS,

    4. limh0+h0f(a)da0 uniformly for fS.

    Conditions 1, 2 and 4 are easy to show, since

    0˜i(a,t)={i(0,ta)π1(a),t>a,a[0,a1]0,ta,a[0,a1]}σKeμ_ia

    and 0˜c(a,t)=

    {c(a1,a1+ta)π2(a)t+a1>a,a[a1,)0,t+a1a,a[a1,)}(ˉqˉγ1+bωˉv)Keμ_ca.

    Next we show that Condition 3 is also satisfied. As h tends to 0+, without loss of generality, we can assume h(0,t). Thus

    a10|˜i(a+h,t)˜i(a,t)|da=th0|i(0,tah)π1(a+h)i(0,ta)π1(a)|da +tth|0i(0,ta)π1(a)|da th0|i(0,tah)π1(a+h)i(0,ta)π1(a)|da+σKh σKh+th0i(0,tah)|π1(a+h)π1(a)|da +th0|i(0,tah)i(0,ta)|π1(a)da σKh+σKth0|π1(a+h)π1(a)|da +th0|i(0,tah)i(0,ta)|π1(a)da. (8)

    Noting that |E(t)| is bounded by LE=ΛE+ˉβK2(1+α)+(μE+σ)K, it follows that E() is Lipschitz for t0 with coefficient LE=LE(K) and

    |i(0,tah)i(0,ta)|π1(a)=σ|E(tah)E(ta)|π1(a),

    which leads to

    th0|i(0,tah)i(0,ta)|π1(a)daσLEhμ_i. (9)

    Note that π1(a) is a positive decreasing function with 1 as its supremum. Thus

    th0|π1(a+h)π1(a)|=th0π1(a)dath0π1(a+h)da=th0π1(a)dathπ1(a)da=th0π1(a)da+h0π1(a)dat0π1(a)da=h0π1(a)datthπ1(a)da<h0π1(a)dah. (10)

    Substituting (9) and (10) into (8), we have

    a10|˜i(a+h,t)˜i(a,t)|da2σKh+σLEh/μ_i. (11)

    The constant in (11) is dependent on K but independent of u0. Thus (11) holds for all u0C, which implies that ˜i(a,t) satisfies Condition 3 in Lemma 4.2. It remains in a pre-compact subset CiK of L10. A similar result can be obtained for ˜c(a,t).

    Lemma 4.3. Both ˜i(a,t) and ˜c(a,t) remain in a pre-compact subset of L10.

    Proof. The result for ˜i(a,t) follows from (11). Note that

    a1|˜c(a+h,t)˜c(a,t)|da=a1+tha1|c(a1,a1+tah)π2(a+h)c(a1,a1+ta)π2(a)|da+a1+ta1+th|0c(a1,a1+ta)π2(a)|da=a1+tha1c(a1,a1+tah)|π2(a+h)π2(a)|da+a1+tha1|c(a1,a1+tah)c(a1,a1+ta)|π2(a)da+a1+ta1+th|0c(a1,a1+ta)π2(a)|da. (12)

    Recalling the boundary conditions on c(a1,t), it follows that

    |0c(a1,a1+ta)π2(a)|(ˉqˉγ1+bωˉv)K. (13)

    Similar to (10), we have

    a1+tha1c(a1,a1+tah)|π2(a+h)π2(a)|da(ˉqˉγ1+bωˉv)Kh. (14)

    For the second integral in (12), we have

    |c(a1,a1+tah)c(a1,a1+ta)|a10|q(a)γ1(a)i(a,a1+tah)q(a)γ1(a)i(a,a1+ta)|da+bωa1|v(a)c(a,a1+tah)v(a)c(a,a1+ta)|da,

    since

    a10q(a)γ1(a)i(a,t+h)daa10q(a)γ1(a)i(a,t)da=h0q(a)γ1(a)i(a,t+h)da+a1hq(a)γ1(a)i(a,t+h)daa10q(a)γ1(a)i(a,t)da=h0q(a)γ1(a)i(0,t+ha)π1(a)da+h0q(a)γ1(a)a0Λi(τ)π1(a)π1(τ)dτda+a1hq(a)γ1(a)i(a,t+h)daa10q(a)γ1(a)i(a,t)daˉqˉγ1σKh+ˉqˉγ1˜Λih+a1h0q(τ+h)γ1(τ+h)i(τ+h,t+h)dτa10q(a)γ1(a)i(a,t)da=ˉqˉγ1(σK+˜Λi)h+a1h0q(τ+h)γ1(τ+h)i(τ,t)π1(τ+h)π1(τ)dτ+a1h0q(τ+h)γ1(τ+h)τ+hτΛi(s)π1(τ+h)π1(s)dsdτa10q(a)γ1(a)i(a,t)da. (15)

    Observing the fact that

    i(τ+h,t+h)=i(τ,t)π1(τ+h)π1(τ)+τ+hτΛi(s)π1(τ+h)π1(s)ds

    and

    a1h0q(τ+h)γ1(τ+h)τ+hτΛi(s)π1(τ+h)π1(s)dsdτˉqˉγ1a1h0τ+hτΛi(s)dsdτ=ˉqˉγ1(h0s0Λi(s)dτds+h0a1hsshΛi(s)dτds)=ˉqˉγ1(h0sΛi(s)ds+a1hhΛi(s)ds)
    ˉqˉγ1ha10Λi(s)ds=ˉqˉγ1˜Λih, (16)

    and

    1ˉμiheˉμihea+haμi(s)ds1

    for h sufficiently small, substituting (16) into (15), we have

    a10|q(a)γ1(a)i(a,t+h)q(a)γ1(a)i(a,t)|daˉqˉγ1(σK+2˜Λi)h+a1h0|q(a+h)γ1(a+h)π1(a+h)π1(a)q(a)γ1(a)|i(a,t)daˉqˉγ1(σK+2˜Λi)h+a1h0q(a+h)γ1(a+h)|ea+haμi(s)ds1|i(a,t)da  +a1h0|q(a+h)γ1(a+h)q(a)γ1(a)|i(a,t)daˉqˉγ1(σK+2˜Λi+ˉμiK)h+Lqγ1Kh. (17)

    Here Lqγ1 is the Lipschitz coefficient of q(a)γ1(a), which is dependent on Lq,Lγ1,ˉq and ˉγ1, since q(a) and γ1(a) are both Lipschitz continuous on [0,a1]. By similar calculations, we can obtain

    a1|v(a)c(a,t+h)v(a)c(a,t)|daˉv(K+2˜Λc+ˉμcK)h+LvKh. (18)

    Substituting (13)-(18) into (12) gives

    a1|˜c(a+h,t)˜c(a,t)|daLh,

    where L=2(ˉqˉγ1+bωˉv)K+ˉqˉγ1(σK+2˜Λi+ˉμiK)+ˉv(K+2˜Λc+ˉμcK)+(Lqγ1+Lv)K is independent of u0. Hence condition (3) of Lemma 4.2 is satisfied for ˜c(a,t). This implies that ˜c(a,t) remains in a pre-compact subset CcK of L10.

    Consequently, Φt(C)[0,K]2×CiK×CcK×[0,K], which has compact closure in Y. It follows that Φt has compact closure. By Lemma 4.1, Lemma 4.2 and Lemma 4.3, we have the following theorem.

    Theorem 4.4. The solution semiflow Φt is asymptotically smooth, and there exists a compact global attractor A for Φt.

    This result is implied by Lemma 3.1, Theorem 4.4 and Theorem 1.1.3 in [28].


    5. Equilibria and global stability

    In this section, we will investigate the existence of the endemic equilibrium and its global stability, in the special case of v(a)=0, using a Lyapunov functional as in [26]. Consider the reduced model

    S(t)=ΛSa10β(a)i(a,t)S(t)daa1αβ(a)c(a,t)S(t)da(μS+p)S,
    E(t)=ΛE+a10β(a)i(a,t)S(t)da+a1αβ(a)c(a,t)S(t)da(μE+σ)E,i(a,t)a+i(a,t)t=Λi(a)(μi(a)+γ1(a))i(a,t),0<aa1c(a,t)a+c(a,t)t=Λc(a)(μc(a)+γ2(a)+θ(a))c(a,t),a1<a< (19)

    with boundary conditions

    i(0,t)=σE(t)c(a1,t)=a10q(a)γ1(a)i(a,t)da

    and initial conditions

    S(0)=S0,E(0)=E0,i(a,0)=i0(a),c(a,0)=c0(a).

    For convenience, denote

    W1=a10β(a)π1(a)da,W2=a10q(a)γ1(a)π1(a)da,W3=a1β(a)π2(a)da,W4=a1v(a)π2(a)da,W5=a10q(a)γ1(a)a0Λi(τ)π1(a)π1(τ)dτda,W6=a1v(a)aa1Λc(τ)π2(a)π2(τ)dτda,W7=a10β(a)a0Λi(τ)π1(a)π1(τ)dτda,W8=a1β(a)aa1Λc(τ)π2(a)π2(τ)dτda,W9(a)=a0Λi(τ)π1(τ)dτ,W10(a)=aa1Λc(τ)π2(τ)dτ

    and

    V1=ΛS+ΛEμS+p,V2=μE+σμS+p,V3=bω(c(a1)W4+W6)μS+p.

    Let P=(S,E,i(a),c(a),R) denote the endemic equilibrium, with S>0,E>0,R>0, where i(a) and c(a) satisfy

    i(a)=σEπ1(a)+W9π1(a),c(a)=c(a1)π2(a)+W10π2(a).

    Substituting i(a) and c(a) into the boundary conditions yields

    c(a1)=σEW2+a10q(a)γ1(a)W9(a)π1(a)da+bωa1v(a)(c(a1)π2(a)+W10(a)π2(a))da.

    It follows that

    c(a1)=σEW2+W5+bωW61bωW4

    Solving the first two equations of system (1) in terms of S and E gives

    S=1μS+p[(ΛS+ΛE)(μE+σ)Ebω(c(a1)W4+W6)]=V1V2EV3.

    Noting that bωW4 is the number of infants infected via vertical transmission, we have 1bωW4>0 and hence c(a1)>0. Thus i(a),c(a) and S can be expressed in terms of E, and are all positive for E(0,ΛS+ΛEbω(c(a1)W4+W6)μE+σ) when they exist.

    Since

      a10β(a)i(a)da+αa1β(a)c(a)da=a10β(a)σEπ1(a)da+a10β(a)W9(a)π1(a)da  +αa1β(a)c(a1)π2(a)da+αa1β(a)W10(a)π2(a)da=σEW1+W7+αc(a1)W3+αW8,

    we have

    (σEW1+W7+αc(a1)W3+αW8)(V1V2EV3)=(μE+σ)EΛE.

    Let

    f(E)=A0(E)2+A1E+A2.

    Then f(E)=0 is a quadratic equation in E with coefficients

    A0=V2(σW1+ασW2W31bωW4)A1=(V1V3)(σW1+ασW2W31bωW4)V2(αW3(W5+W6)1bωW4+W7+αW8)(μE+σ)A2=ΛE+(V1V3)(W7+αW8).

    Noting that A0<0 and A2>0 (by assumptions H4 and H7), there exists a unique positive equilibrium P when age-dependant immigration terms have positive measure.

    In the following, based on the techniques used in [26,18], a Lyapunov functional is constructed to prove the global stability of the unique positive equilibrium P when v(a)=0.

    Theorem 5.1. When v(a)=0, ΛS>0, and Λi+Λc have positive measure, system (1) has a unique, globally asympototically stable endemic equilibrium P.

    Proof. For tR, let X(t)=(S(t),E(t),i(,t),c(,t)) be a solution trajectory to the reduced system (19). For x>0,x>0, define

    G(x,x)=xxxlnxx    and    g(x)=x1lnx.

    It is obvious that G(x,x)=xg(xx), and they share the properties g(x)0,g(x)=1x+lnx0 for any x>0. Let

    L1(t)=G(S(t),S),L2(t)=G(E(t),E),L3(t)=a10φ(a)G(i(a,t),i(a))da,L4(t)=a1ψ(a)G(c(a,t),c(a))da,

    where

    φ(a)=a1a[β(s)S+ψ(a1)q(s)γ1(s)]π1(s)π1(a)ds,   ψ(a)=αaβ(s)Sπ2(s)π2(a)ds.

    Noting that

       φ(0)=a10[β(s)S+ψ(a1)q(s)γ1(s)]π1(s)ds,   ψ(a1)=αa1β(s)Sπ2(s)ds=αSW3,   φ(a)=(β(a)S+ψ(a1)q(a)γ1(a))+(μi(a)+γ1(a))φ(a),   ψ(a)=αβ(a)S+(μc(a)+γ2(a)+θ(a))ψ(a),

    and

    di(a)da=Λi(a)(μi(a)+γ1(a))i(a),i(a,t)i(a)=i(0,ta)+W9(a)i(0)+W9(a),

    we have

    tta1φ(tτ)i(tτ)ddtg(i(tτ,t)i(tτ))dτ=tta1φ(tτ)i(tτ)g(i(tτ,t)i(tτ))ddt(i(tτ,t)i(tτ))dτ=tta1φ(tτ)i(tτ)g(i(tτ,t)i(tτ))×W9(tτ)(i(0)+W9(tτ))(i(0,τ)+W9(tτ))W9(tτ)(i(0)+W9(tτ))2dτ=a10φ(a)i(a)g(i(a,t)i(a))W9(a)(i(0)+W9(a))(i(0,ta)+W9(a))W9(a)(i(0)+W9(a))2da
    =a10φ(a)i(a)g(i(a,t)i(a))W9(a)i(0)+W9(a)(1i(a,t)i(a))da=a10φ(a)Λi(a)(1i(a)i(a,t))(1i(a,t)i(a))da=a10φ(a)Λi(a)(2i(a)i(a,t)i(a,t)i(a))da, (20)

    and

       tta1φ(tτ)di(tτ)dtg(i(tτ,t)i(tτ))dτ=tta1φ(tτ)[Λi(tτ)(μi(tτ)+γ1(tτ))i(tτ)]g(i(tτ,t)i(tτ))dτ=a10φ(a)Λi(a)g(i(a,t)i(a))daa10φ(a)(μi(a)+γ1(a))i(a)g(i(a,t)i(a))da. (21)

    Combining (20) with (21), we get

      tta1φ(tτ)[i(tτ)ddtg(i(tτ,t)i(tτ))+ddt(i(tτ))g(i(tτ,t)i(tτ))]dτ=a10φ(a)Λi(a)[2i(a)i(a,t)i(a,t)i(a)+g(i(a,t)i(a))]daa10φ(a)(μi(a)+γ1(a))i(a)g(i(a,t)i(a))da=a10φ(a)Λi(a)(1i(a)i(a,t)+lni(a)i(a,t))daa10φ(a)(μi(a)+γ1(a))i(a)g(i(a,t)i(a))da=a10φ(a)Λi(a)g(i(a)i(a,t))daa10φ(a)(μi(a)+γ1(a))i(a)g(i(a,t)i(a))daIi0, (22)

    since g(x)0 for any x>0. Similarly,

      ta1ψ(tτ)[c(tτ)ddtg(c(tτ,t)c(tτ))+ddt(c(tτ))g(c(tτ,t)c(tτ))]dτ=a1ψ(a)Λc(a)(1c(a)c(a,t)+lnc(a)c(a,t))da  a1ψ(a)(μc(a)+γ2(a)+θ(a))c(a)g(c(a,t)c(a))da=a1ψ(a)Λc(a)g(c(a)c(a,t))daa1ψ(a)(μc(a)+γ2(a)+θ(a))c(a)g(c(a,t)c(a))daIc0. (23)

    The terms (22) and (23) are a result of incorporating immigration; compare with the model in [26].

    The time derivatives of functions L1,L2,L3 and L4 along (1) are

    L1(t)=μS+pS(SS)2+S(a10β(a)i(a)da+αa1β(a)c(a)da)          +S(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)          S(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)          (S)2S(a10β(a)i(a)da+αa1β(a)c(a)da),L2(t)=S(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)          EES(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)          (σ+μE)(EE)+ΛE(1EE),L3(t)=ddta10φ(a)i(a)g(i(a,t)i(a))da       =ddttta1φ(tτ)i(tτ)g(i(tτ,t)i(tτ))dτ       =φ(0)G(i(0,t),i(0))+a10φ(a)G(i(a,t),i(a))da+Ii,

    and

    L4(t)=ddta1ψ(a)c(a)g(c(a,t)c(a))da       =ddtta1ψ(tτ)c(tτ)g(c(tτ,t)c(tτ))dτ       =ψ(a1)G(c(0,t),c(0))+a1ψ(a)G(c(a,t),c(a))da+Ic.

    We construct the following Lyapunov functional:

    L(t)=L1(t)+L2(t)+L3(t)+L4(t).

    We need to show that the time derivative along the solutions of (1) satisfies

    ddtL(t)=L1(t)+L2(t)+L3(t)+L4(t)0.

    Note that

    i(0,t)i(0)=σ(EE),c(a1,t)c(a1)=a10q(a)γ1(a)[i(a,t)i(a)]da,(σ+μE)EΛE=a10β(a)Si(a)da+αa1β(a)Sc(a)da.

    We have

    (σ+μE)EΛE=a10β(a)Si(0)π1(a)da+a10β(a)SW9(a)π1(a)da  +αa1β(a)Sπ2(a)(c(a1)+W10(a))da=a10β(a)Si(0)π1(a)da+a10β(a)SW9(a)π1(a)da  +αa1β(s)Sπ2(s)a10q(a)γ1(a)(i(0)+W9(a))π1(a)dads  +αa1β(s)Sπ2(s)W10(s)ds.

    Then

    φ(0)i(0)lni(0,t)i(0)=((σ+μE)EΛE)lni(0,t)i(0)Wlni(0,t)i(0)

    and

    φ(0)(i(0,t)i(0))=(σ+μE)(EE)ΛE(EE1)W(EE1),

    where

    W=a10β(a)SW9(a)π1(a)da+αa1β(s)Sπ2(s)a10q(a)γ1(a)W9(a)π1(a)dads+αa1β(s)Sπ2(s)W10(s)ds.

    We also have

      a10q(a)γ1(a)i(a)[1i(a,t)c(a1)i(a)c(a1,t)]da=a10q(a)γ1(a)i(a)dac(a1)c(a1,t)a10q(a)γ1(a)i(a,t)da=c(a1)c(a1)c(a1,t)c(a1,t)=0

    and

      EES(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)=i(0)i(0,t)S(a10β(a)i(a,t)da+αa1β(a)c(a,t)da)=a10β(a)Si(a)Si(0)i(a,t)Si(0,t)i(a)da+αa1β(a)Sc(a)Si(0)c(a,t)Si(0,t)c(a)da.

    Combining all these time derivatives of Li(t) yields

    L(t)=μS+pS(SS)2         +a10β(a)Si(a)[1SS+lnSS+1i(a,t)Si(0)i(a)Si(0,t)+lnSi(0)i(a,t)Si(a)i(0,t)]da         +αa1β(a)Sc(a)[1SS+lnSS+1Sc(a,t)i(0)Sc(a)i(0,t)+lnSc(a,t)i(0)Sc(a)i(0,t)]da         +αSW3a10q(a)γ1(a)i(a)[1i(a,t)c(a1)i(a)c(a1,t)+lni(a,t)c(a1)i(a)c(a1,t)]da         +ΛE(2EEEE)+W(1EE+lni(0,t)i(0))+Ii+Ic.

    Noting that i(0,t)i(0)=EE, we see that L(t)0 and L(t)=0 holds, implying that S(t)=S and

    i(a,t)i(a)=i(0,t)i(0)=c(a,t)c(a)=c(a1,t)c(a1).

    It can be verified that the largest invariant set where L(t)=0 is the singleton {P}. Therefore, by Lyapunov-LaSalle asymptotic stability theorem, the unique endemic equilibrium P is globally asymptotically stable when it exists.


    6. Discussion

    Many epidemiological models assume that all infected individuals are equally infectious during their infectivity period, which is reasonable for some diseases, such as influenza. However, the infection of HBV is a dynamic process characterized by replicative and non-replicative phases based on virus-host interaction so that the infectivity of HBV individuals varies at different age of infection. It follows that age structure of the host population is an important factor for the dynamics of HBV transmission. In general, there are two different age structures in disease models: biological age and infection age. In this paper, according to the characteristics of HBV, we formulated a PDE model incorporating infection-age structure, as well as immigration age, into all compartments, in order to describe the possible effects of variable infectivity and immigration on the transmission dynamics.

    The model studied in this paper is a refined version of the one investigated in [26], with age-dependent immigration into both acute and chronic infection stages. Immigration models do not have infection-free equilibria and hence have no reproduction number [17,18,11,3]. When immigration is introduced into the infectious compartment, the model has a unique globally asymptotically stable equilibrium. Age structure is only applicable to two infectious classes in this paper: the acute and chronic stages. In a more general setting, it can be added to any compartment [29].

    In the case that the perinatal-related parameter v(a) is absent and age-related immigration is measurable, the unique endemic equilibrium is globally stable, and the disease will always persist in the endemic level. Epidemiologically, v(a)>0 indicates vertical transmission of hepatitis B from mother to baby, a complex process where the detailed mechanism remains unclear.

    Relevant simulations in [12] suggest that immigration inflow is vital to the amplitude of the endemic equilibrium: small variations of the rate of immigration to the infectious and/or latent compartments can cause abrupt changes of quantity of endemicity. The feasible epidemiological solution is to screen immigrants with high risk of disease as a first step to control infection from the source. Finally, the scale of the problem and the availability of a safe and effective vaccine means that many more people should be protected from HBV than currently are. Outmoded and ignorant attitudes towards vaccines are costing a great deal of lives that could be saved with the application of evidence-based research.


    Acknowledgments

    For citation purposes, please note that the question mark in "Smith?" is part of his name.




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