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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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.
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
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.
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
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)=ΛS−bω∫∞a1v(a)c(a,t)da−(μS+p)S(t)−∫a10β(a)i(a,t)S(t)da−∫∞a1αβ(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<a≤a1∂c(a,t)∂a+∂c(a,t)∂t=Λc(a)−(μc(a)+γ2(a)+θ(a))c(a,t),a1<a<∞R′(t)=ΛR+b(1−ω)+∫a10(1−q(a))γ1(a)i(a,t)da+∫∞a1γ2(a)c(a,t)da−μRR(t)+pS(t), |
with the boundary conditions
i(0,t)=σE(t),c(a1,t)=∫a10q(a)γ1(a)i(a,t)da+bω∫∞a1v(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
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(1−q(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
Symbol | Definition |
rate of recruitment into the susceptible compartment, | |
including unsuccessfully immunized birth and immigration | |
immigration rate into class |
|
age-dependent immigration rate into class |
|
per capital death rate for class |
|
age-dependent death rate for class |
|
birth rate | |
proportion of newborns who are unsuccessfully immunized | |
transfer rate from exposed to acute infection | |
vaccination rate | |
degree of infectiousness of carriers relative to acute infections ( |
|
age-dependent transmission coefficient | |
age-dependent rate of children born to carrier mothers | |
who become HBV carriers | |
age-dependent transfer rate from acute to immunized or carrier class | |
age-dependent transfer rate from carrier to immunized class | |
age-dependent progression from acute infection to carrier class | |
age-dependent HBV-induced death rate |
In order to simplify the analysis, we made the following assumptions.
(H1)
Let
(H2)
(H3)
(H4) The constant parameters
(H5) The initial conditions satisfy
(H6) The supports of
(H7) essential infimum (support(
essential infimum (support(
for
To simplify expressions, we introduce the following notations
π1(a)=e−∫a0(μi(s)+γ1(s))dsa∈[0,a1],π2(a)=e−∫aa1(μc(s)+γ2(s)+θ(s))dsa∈[a1,∞), |
where
i(a,t)={i(0,t−a)π1(a)+∫a0Λi(s)π1(a)π1(s)ds,t>a, a∈[0,a1],i0(a−t)π1(a)π1(a−t)+∫aa−tΛi(s)π1(a)π1(s)ds,t≤a, a∈[0,a1], | (2) |
and
{c(a1,a1+t−a)π2(a)+∫aa1Λc(s)π2(a)π2(s)ds,t+a1>a,a∈[a1,∞),c0(a−t−a1)π2(a)π2(a−t−a1)+∫aa−t−a1Λc(s)π2(a)π2(s)ds,t+a1≤a,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
For (2) and (3), it is easy to see that
Y=R2≥0×L1(R≥0,R≥0)×L1(R≥0,R≥0)×R≥0 |
be the state space of system (1). Then
Φt:Y→Y. |
Denote
‖u‖=S+E+∫a10i(a,t)da+∫∞a1c(a,t)da+R. |
Notice that the variable
Let
N(t)=S(t)+E(t)+∫a10i(a,t)da+∫∞a1c(a,t)da+R(t)=‖u‖. |
In the following, we establish that
From (2), we can obtain
∫a10i(a,t)da=∫t0i(a,t)da+∫a1ti(a,t)da=∫t0i(0,t−a)π1(a)da+∫t0∫a0Λi(τ)π1(a)π1(τ)dτda+∫a1ti0(a−t)π1(a)π1(a−t)da+∫a1t∫aa−tΛi(τ)π1(a)π1(τ)dτda. |
Changing the order of integration for two double integrals in the above, we have
∫t0∫a0Λi(τ)π1(a)π1(τ)dτda=∫t0∫tτΛi(τ)π1(a)π1(τ)dadτ,∫a1t∫aa−tΛi(τ)π1(a)π1(τ)dτda=∫t0∫τ+ttΛi(τ)π1(a)π1(τ)dadτ+∫a1t∫τ+tτΛi(τ)π1(a)π1(τ)dadτ−∫a1a1−t∫τ+ta1Λi(τ)π1(a)π1(τ)dadτ. |
Making substitutions
∫a10i(a,t)da=∫t0i(0,τ)π1(t−τ)dτ+∫a1−t0i0(τ)π1(τ+t)π1(τ)dτ+∫a10∫τ+tτΛi(τ)π1(a)π1(τ)dadτ−∫a1a1−t∫τ+ta1Λi(τ)π1(a)π1(τ)dτda. |
Thus differentiating
ddt∫a10i(a,t)da=i(0,t)−i0(a1−t)π1(a1)π1(a1−t)+∫t0i(0,τ)π′1(t−τ)dτ+∫a1−t0i0(τ)π′1(τ+t)π1(τ)dτ+∫a10Λi(τ)π1(τ+t)π1(τ)dτ−ddt∫a1a1−t∫τ+ta1Λi(τ)π1(a)π1(τ)dadτ. |
We have
∫a1−t0i0(τ)π′1(τ+t)π1(τ)dτ=∫a1ti0(a−t)π′1(a)π1(a−t)da |
and
∫t0∫a0Λi(τ)π′1(a)π1(τ)dτda+∫a1t∫aa−tΛi(τ)π′1(a)π1(τ)dτda+∫a1a1−t∫τ+ta1Λi(τ)π′1(a)π1(τ)dadτ=∫a10∫τ+tτΛi(τ)π′1(a)π1(τ)dadτ=∫a10Λi(τ)π1(τ+t)−π1(τ)π1(τ)dτ=∫a10Λi(τ)π1(τ+t)π1(τ)dτ−∫a10Λi(τ)dτ. |
Noticing that
ddt∫a10i(a,t)da=i(0,t)−i0(a1−t)π1(a1)π1(a1−t)+∫t0i(0,τ)π′1(t−τ)dτ+∫a1ti0(a−t)π′1(a)π1(a−t)da+∫t0∫a0Λi(τ)π′1(a)π1(τ)dτda+∫a1t∫aa−tΛi(τ)π′1(a)π1(τ)dτda+∫a10Λi(τ)dτ−∫a1a1−tΛi(τ)π1(τ+t)π1(τ)dτ=i(0,t)−i0(a1−t)π1(a1)π1(a1−t)+˜Λi−∫a1a1−tΛi(τ)π1(τ+t)π1(τ)dτ−∫a10(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+t−τ)dτ+∫∞0c0(τ)π2(t+a1+τ)π2(τ)dτ+∫∞a1∫τ+tτΛc(τ)π2(a)π2(τ)dadτ, |
and hence
ddt∫∞a1c(a,t)da=c(a1,t)+∫a1+ta1c(a1,a1+t−a)π′2(a)da+∫∞a1+tc0(a−t−a1)π′2(a)π2(a−t−a1)da+∫a1+ta1∫aa1Λc(τ)π′2(a)π2(τ)dτda+∫∞a1+t∫aa−t−a1Λc(τ)π′2(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(1−ω)−i0(a1−t)π1(a1)π1(a1−t)−∫a1a1−tΛi(τ)π1(τ+t)π1(τ)dτ−μSS(t)−μEE(t)−μRR(t)−∫a10μi(a)i(a,t)da−∫∞a1(μc(a)+θ(a))c(a,t)da≤Λ∗−μ∗N(t), |
where
lim supt→∞N(t)≤N∗ |
which implies that all solutions of system (1) are ultimately bounded. Moreover, when
Ω={u(t)=(S(t),E(t),i(.,t),c(.,t),R(t))∈Y:‖u‖≤max{N∗,N(0)}} |
is positively invariant and absorbing under the semiflow
Lemma 3.1. The unique solution semiflow
Lemma 3.2. There exists
Proof. First, since
S′(t)≥ΛS−bω∫∞a1v(a)c(a,t)da−ˉβS(t)(∫a10i(a,t)da+α∫∞a1c(a,t)da)−(μS+p)S(t)≥ΛS−bω∫∞a1v(a)c(a,t)da−S(t)[ˉβ(N∗+ϵ)(1+α)+(μS+p)], |
from which it follows that
lim inft→∞S(t)≥ΛS−bω∫∞a1v(a)c(a,t)daˉβ(N∗+ϵ)(1+α)+μS+p≡MS. |
Next we have
E′(t)≥ΛE+β_S(t)(∫a10i(a,t)da+α∫∞a1c(a,t)da)−(μE+σ)E(t)≥ΛE+β_MS(∫a10i(a,t)da+α∫∞a1c(a,t)da)−(μE+σ)E(t), |
which implies
lim inft→∞E(t)≥ΛE+β_MS(∫a10i(a,t)da+α∫∞a1c(a,t)da)μE+σ≡ME. |
Therefore there exists
i(0,t)=σE(t)≥σME2 | (6) |
for all
∫t0∫a0q(a)γ1(a)Λi(τ)π1(a)π1(τ)dτda≥δ |
for all
c(a1,t)≥∫a10q(a)γ1(a)i(a,t)da≥∫t0∫a0q(a)γ1(a)Λi(τ)π1(a)π1(τ)dτda≥δ. | (7) |
Then, when
Lemma 4.1. The semi-flow
Φ(t,u)=Θ(t,u)+Ψ(t,u) |
and, for any bounded closed set
This is a special case of Theorem 2.46 in [23]. Note that
˜i(a,t)={i(0,t−a)π1(a),t>a,a∈[0,a1],0,t≤a,a∈[0,a1],˜c(a,t)={c(a1,a1+t−a)π2(a),t+a1>a,a∈[a1,∞),0,t+a1≤a,a∈[a1,∞),˜i0(a,t)={∫a0Λi(s)π1(a)π1(s)ds,t>a,a∈[0,a1],i0(a−t)π1(a)π1(a−t)+∫aa−tΛi(s)π1(a)π1(s)ds,t≤a,a∈[0,a1],˜c0(a,t)={∫aa1Λc(s)π2(a)π2(s)ds,t+a1>a,c0(a−t−a1)π2(a)π2(a−t−a1)+∫aa−t−a1Λc(s)π2(a)π2(s)ds,t+a1≤a, |
for
Φ(t,uj0)=(Sj(t),Ej(t),ij(.,t),cj(.,t),Rj(t)). |
In the following, we evaluate the distance between
Noting that
˜i10(a,t)−˜i20(a,t)={0,t>a,a∈[0,a1],(i10(a−t)−i20(a−t))π1(a)π1(a−t)t≤a,a∈[0,a1], |
then
‖˜i10(a,t)−˜i20(a,t)‖1=∫a1t|i10(a−t)−i20(a−t)|π1(a)π1(a−t)da=∫a1−t0|i10(τ)−i20(τ)|π1(τ+t)π1(τ)dτ=∫a1−t0|i10(τ)−i20(τ)|e−∫τ+tτ(μi(s)+γ1(s))dsdτ≤e−μ_it∫a10|i10(τ)−i20(τ)|dτ≤e−μ_it(‖i10‖1+‖i20‖1)≤2Ke−μ_it, |
which approaches zero as
Similarly,
‖Θ(t,u10)−Θ(t,u20)‖≤2K(e−μ_it+e−μ_ct) |
for all
diamΘ(t,C)≤2K(e−μ_it+e−μ_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
Lemma 4.2.
1.
2.
3.
4.
Conditions 1, 2 and 4 are easy to show, since
0≤˜i(a,t)={i(0,t−a)π1(a),t>a,a∈[0,a1]0,t≤a,a∈[0,a1]}≤σKe−μ_ia |
and
{c(a1,a1+t−a)π2(a)t+a1>a,a∈[a1,∞)0,t+a1≤a,a∈[a1,∞)}≤(ˉqˉγ1+bωˉv)Ke−μ_ca. |
Next we show that Condition 3 is also satisfied. As
∫a10|˜i(a+h,t)−˜i(a,t)|da=∫t−h0|i(0,t−a−h)π1(a+h)−i(0,t−a)π1(a)|da +∫tt−h|0−i(0,t−a)π1(a)|da ≤∫t−h0|i(0,t−a−h)π1(a+h)−i(0,t−a)π1(a)|da+σKh ≤σKh+∫t−h0i(0,t−a−h)|π1(a+h)−π1(a)|da +∫t−h0|i(0,t−a−h)−i(0,t−a)|π1(a)da ≤σKh+σK∫t−h0|π1(a+h)−π1(a)|da +∫t−h0|i(0,t−a−h)−i(0,t−a)|π1(a)da. | (8) |
Noting that
|i(0,t−a−h)−i(0,t−a)|π1(a)=σ|E(t−a−h)−E(t−a)|π1(a), |
which leads to
∫t−h0|i(0,t−a−h)−i(0,t−a)|π1(a)da≤σLEhμ_i. | (9) |
Note that
∫t−h0|π1(a+h)−π1(a)|=∫t−h0π1(a)da−∫t−h0π1(a+h)da=∫t−h0π1(a)da−∫thπ1(a)da=∫t−h0π1(a)da+∫h0π1(a)da−∫t0π1(a)da=∫h0π1(a)da−∫tt−hπ1(a)da<∫h0π1(a)da≤h. | (10) |
Substituting (9) and (10) into (8), we have
∫a10|˜i(a+h,t)−˜i(a,t)|da≤2σKh+σLEh/μ_i. | (11) |
The constant in (11) is dependent on
Lemma 4.3. Both
Proof. The result for
∫∞a1|˜c(a+h,t)−˜c(a,t)|da=∫a1+t−ha1|c(a1,a1+t−a−h)π2(a+h)−c(a1,a1+t−a)π2(a)|da+∫a1+ta1+t−h|0−c(a1,a1+t−a)π2(a)|da=∫a1+t−ha1c(a1,a1+t−a−h)|π2(a+h)−π2(a)|da+∫a1+t−ha1|c(a1,a1+t−a−h)−c(a1,a1+t−a)|π2(a)da+∫a1+ta1+t−h|0−c(a1,a1+t−a)π2(a)|da. | (12) |
Recalling the boundary conditions on
|0−c(a1,a1+t−a)π2(a)|≤(ˉqˉγ1+bωˉv)K. | (13) |
Similar to (10), we have
∫a1+t−ha1c(a1,a1+t−a−h)|π2(a+h)−π2(a)|da≤(ˉqˉγ1+bωˉv)Kh. | (14) |
For the second integral in (12), we have
|c(a1,a1+t−a−h)−c(a1,a1+t−a)|≤∫a10|q(a)γ1(a)i(a,a1+t−a−h)−q(a)γ1(a)i(a,a1+t−a)|da+bω∫∞a1|v(a)c(a,a1+t−a−h)−v(a)c(a,a1+t−a)|da, |
since
∫a10q(a)γ1(a)i(a,t+h)da−∫a10q(a)γ1(a)i(a,t)da=∫h0q(a)γ1(a)i(a,t+h)da+∫a1hq(a)γ1(a)i(a,t+h)da−∫a10q(a)γ1(a)i(a,t)da=∫h0q(a)γ1(a)i(0,t+h−a)π1(a)da+∫h0q(a)γ1(a)∫a0Λi(τ)π1(a)π1(τ)dτda+∫a1hq(a)γ1(a)i(a,t+h)da−∫a10q(a)γ1(a)i(a,t)da≤ˉqˉγ1σKh+ˉqˉγ1˜Λih+∫a1−h0q(τ+h)γ1(τ+h)i(τ+h,t+h)dτ−∫a10q(a)γ1(a)i(a,t)da=ˉqˉγ1(σK+˜Λi)h+∫a1−h0q(τ+h)γ1(τ+h)i(τ,t)π1(τ+h)π1(τ)dτ+∫a1−h0q(τ+h)γ1(τ+h)∫τ+hτΛi(s)π1(τ+h)π1(s)dsdτ−∫a10q(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
∫a1−h0q(τ+h)γ1(τ+h)∫τ+hτΛi(s)π1(τ+h)π1(s)dsdτ≤ˉqˉγ1∫a1−h0∫τ+hτΛi(s)dsdτ=ˉqˉγ1(∫h0∫s0Λi(s)dτds+∫h0∫a1h∫ss−hΛi(s)dτds)=ˉqˉγ1(∫h0sΛi(s)ds+∫a1hhΛi(s)ds) |
≤ˉqˉγ1h∫a10Λi(s)ds=ˉqˉγ1˜Λih, | (16) |
and
1−ˉμih≤e−ˉμih≤e−∫a+haμi(s)ds≤1 |
for
∫a10|q(a)γ1(a)i(a,t+h)−q(a)γ1(a)i(a,t)|da≤ˉqˉγ1(σK+2˜Λi)h+∫a1−h0|q(a+h)γ1(a+h)π1(a+h)π1(a)−q(a)γ1(a)|i(a,t)da≤ˉqˉγ1(σK+2˜Λi)h+∫a1−h0q(a+h)γ1(a+h)|e−∫a+haμi(s)ds−1|i(a,t)da +∫a1−h0|q(a+h)γ1(a+h)−q(a)γ1(a)|i(a,t)da≤ˉqˉγ1(σK+2˜Λi+ˉμiK)h+Lqγ1Kh. | (17) |
Here
∫∞a1|v(a)c(a,t+h)−v(a)c(a,t)|da≤ˉv(K+2˜Λc+ˉμcK)h+LvKh. | (18) |
Substituting (13)-(18) into (12) gives
∫∞a1|˜c(a+h,t)−˜c(a,t)|da≤Lh, |
where
Consequently,
Theorem 4.4. The solution semiflow
This result is implied by Lemma 3.1, Theorem 4.4 and Theorem 1.1.3 in [28].
In this section, we will investigate the existence of the endemic equilibrium and its global stability, in the special case of
S′(t)=ΛS−∫a10β(a)i(a,t)S(t)da−∫∞a1αβ(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<a≤a1∂c(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
i∗(a)=σE∗π1(a)+W9π1(a),c∗(a)=c∗(a1)π2(a)+W10π2(a). |
Substituting
c∗(a1)=σE∗W2+∫a10q(a)γ1(a)W9(a)π1(a)da+bω∫∞a1v(a)(c∗(a1)π2(a)+W10(a)π2(a))da. |
It follows that
c∗(a1)=σE∗W2+W5+bωW61−bωW4 |
Solving the first two equations of system (1) in terms of
S∗=1μS+p[(ΛS+ΛE)−(μE+σ)E∗−bω(c∗(a1)W4+W6)]=V1−V2E∗−V3. |
Noting that
Since
∫a10β(a)i∗(a)da+α∫∞a1β(a)c∗(a)da=∫a10β(a)σE∗π1(a)da+∫a10β(a)W9(a)π1(a)da +α∫∞a1β(a)c∗(a1)π2(a)da+α∫∞a1β(a)W10(a)π2(a)da=σE∗W1+W7+αc∗(a1)W3+αW8, |
we have
(σE∗W1+W7+αc∗(a1)W3+αW8)(V1−V2E∗−V3)=(μE+σ)E∗−ΛE. |
Let
f(E∗)=A0(E∗)2+A1E∗+A2. |
Then
A0=−V2(σW1+ασW2W31−bωW4)A1=(V1−V3)(σW1+ασW2W31−bωW4)−V2(αW3(W5+W6)1−bωW4+W7+αW8)−(μE+σ)A2=ΛE+(V1−V3)(W7+αW8). |
Noting that
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
Theorem 5.1. When
Proof. For
G(x,x∗)=x−x∗−x∗lnxx∗ and g(x)=x−1−lnx. |
It is obvious that
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)=α∫∞aβ(s)S∗π2(s)π2(a)ds. |
Noting that
φ(0)=∫a10[β(s)S∗+ψ(a1)q(s)γ1(s)]π1(s)ds, ψ(a1)=α∫∞a1β(s)S∗π2(s)ds=αS∗W3, 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,t−a)+W9(a)i∗(0)+W9(a), |
we have
∫tt−a1φ(t−τ)i∗(t−τ)ddtg(i(t−τ,t)i∗(t−τ))dτ=∫tt−a1φ(t−τ)i∗(t−τ)g′(i(t−τ,t)i∗(t−τ))ddt(i(t−τ,t)i∗(t−τ))dτ=∫tt−a1φ(t−τ)i∗(t−τ)g′(i(t−τ,t)i∗(t−τ))×W′9(t−τ)(i∗(0)+W9(t−τ))−(i(0,τ)+W9(t−τ))W′9(t−τ)(i∗(0)+W9(t−τ))2dτ=∫a10φ(a)i∗(a)g′(i(a,t)i∗(a))W′9(a)(i∗(0)+W9(a))−(i(0,t−a)+W9(a))W′9(a)(i∗(0)+W9(a))2da |
=∫a10φ(a)i∗(a)g′(i(a,t)i∗(a))W′9(a)i∗(0)+W9(a)(1−i(a,t)i∗(a))da=∫a10φ(a)Λi(a)(1−i∗(a)i(a,t))(1−i(a,t)i∗(a))da=∫a10φ(a)Λi(a)(2−i∗(a)i(a,t)−i(a,t)i∗(a))da, | (20) |
and
∫tt−a1φ(t−τ)di∗(t−τ)dtg(i(t−τ,t)i∗(t−τ))dτ=∫tt−a1φ(t−τ)[Λi(t−τ)−(μi(t−τ)+γ1(t−τ))i∗(t−τ)]g(i(t−τ,t)i∗(t−τ))dτ=∫a10φ(a)Λi(a)g(i(a,t)i∗(a))da−∫a10φ(a)(μi(a)+γ1(a))i∗(a)g(i(a,t)i∗(a))da. | (21) |
Combining (20) with (21), we get
∫tt−a1φ(t−τ)[i∗(t−τ)ddtg(i(t−τ,t)i∗(t−τ))+ddt(i∗(t−τ))g(i(t−τ,t)i∗(t−τ))]dτ=∫a10φ(a)Λi(a)[2−i∗(a)i(a,t)−i(a,t)i∗(a)+g(i(a,t)i∗(a))]da−∫a10φ(a)(μi(a)+γ1(a))i∗(a)g(i(a,t)i∗(a))da=∫a10φ(a)Λi(a)(1−i∗(a)i(a,t)+lni∗(a)i(a,t))da−∫a10φ(a)(μi(a)+γ1(a))i∗(a)g(i(a,t)i∗(a))da=−∫a10φ(a)Λi(a)g(i∗(a)i(a,t))da−∫a10φ(a)(μi(a)+γ1(a))i∗(a)g(i(a,t)i∗(a))da≡Ii≤0, | (22) |
since
∫t−a1−∞ψ(t−τ)[c∗(t−τ)ddtg(c(t−τ,t)c∗(t−τ))+ddt(c∗(t−τ))g(c(t−τ,t)c∗(t−τ))]dτ=∫∞a1ψ(a)Λc(a)(1−c∗(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))da−∫∞a1ψ(a)(μc(a)+γ2(a)+θ(a))c∗(a)g(c(a,t)c∗(a))da≡Ic≤0. | (23) |
The terms (22) and (23) are a result of incorporating immigration; compare with the model in [26].
The time derivatives of functions
L′1(t)=−μS+pS(S−S∗)2+S∗(∫a10β(a)i∗(a)da+α∫∞a1β(a)c∗(a)da) +S∗(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da) −S(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da) −(S∗)2S(∫a10β(a)i∗(a)da+α∫∞a1β(a)c∗(a)da),L′2(t)=S(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da) −E∗ES(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da) −(σ+μE)(E−E∗)+ΛE(1−E∗E),L′3(t)=ddt∫a10φ(a)i∗(a)g(i(a,t)i∗(a))da =ddt∫tt−a1φ(t−τ)i∗(t−τ)g(i(t−τ,t)i∗(t−τ))dτ =φ(0)G(i(0,t),i∗(0))+∫a10φ′(a)G(i(a,t),i∗(a))da+Ii, |
and
L′4(t)=ddt∫∞a1ψ(a)c∗(a)g(c(a,t)c∗(a))da =ddt∫t−a1−∞ψ(t−τ)c∗(t−τ)g(c(t−τ,t)c∗(t−τ))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)=L′1(t)+L′2(t)+L′3(t)+L′4(t)≤0. |
Note that
i(0,t)−i∗(0)=σ(E−E∗),c(a1,t)−c∗(a1)=∫a10q(a)γ1(a)[i(a,t)−i∗(a)]da,(σ+μE)E∗−ΛE=∫a10β(a)S∗i∗(a)da+α∫∞a1β(a)S∗c∗(a)da. |
We have
(σ+μE)E∗−ΛE=∫a10β(a)S∗i∗(0)π1(a)da+∫a10β(a)S∗W9(a)π1(a)da +α∫∞a1β(a)S∗π2(a)(c∗(a1)+W10(a))da=∫a10β(a)S∗i∗(0)π1(a)da+∫a10β(a)S∗W9(a)π1(a)da +α∫∞a1β(s)S∗π2(s)∫a10q(a)γ1(a)(i∗(0)+W9(a))π1(a)dads +α∫∞a1β(s)S∗π2(s)W10(s)ds. |
Then
φ(0)i∗(0)lni(0,t)i∗(0)=((σ+μE)E∗−ΛE)lni(0,t)i∗(0)−Wlni(0,t)i∗(0) |
and
φ(0)(i(0,t)−i∗(0))=(σ+μE)(E−E∗)−ΛE(EE∗−1)−W(EE∗−1), |
where
W=∫a10β(a)S∗W9(a)π1(a)da+α∫∞a1β(s)S∗π2(s)∫a10q(a)γ1(a)W9(a)π1(a)dads+α∫∞a1β(s)S∗π2(s)W10(s)ds. |
We also have
∫a10q(a)γ1(a)i∗(a)[1−i(a,t)c∗(a1)i∗(a)c(a1,t)]da=∫a10q(a)γ1(a)i∗(a)da−c∗(a1)c(a1,t)∫a10q(a)γ1(a)i(a,t)da=c∗(a1)−c∗(a1)c(a1,t)c(a1,t)=0 |
and
E∗ES(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da)=i∗(0)i(0,t)S(∫a10β(a)i(a,t)da+α∫∞a1β(a)c(a,t)da)=∫a10β(a)S∗i∗(a)Si∗(0)i(a,t)S∗i(0,t)i∗(a)da+α∫∞a1β(a)S∗c∗(a)Si∗(0)c(a,t)S∗i(0,t)c∗(a)da. |
Combining all these time derivatives of
L′(t)=−μS+pS(S−S∗)2 +∫a10β(a)S∗i∗(a)[1−S∗S+lnS∗S+1−i(a,t)Si∗(0)i∗(a)S∗i(0,t)+lnSi∗(0)i(a,t)S∗i∗(a)i(0,t)]da +α∫∞a1β(a)S∗c∗(a)[1−S∗S+lnS∗S+1−Sc(a,t)i∗(0)S∗c∗(a)i(0,t)+lnSc(a,t)i∗(0)S∗c∗(a)i(0,t)]da +αS∗W3∫a10q(a)γ1(a)i∗(a)[1−i(a,t)c∗(a1)i∗(a)c(a1,t)+lni(a,t)c∗(a1)i∗(a)c(a1,t)]da +ΛE(2−E∗E−EE∗)+W(1−EE∗+lni(0,t)i∗(0))+Ii+Ic. |
Noting that
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
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
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.
For citation purposes, please note that the question mark in "Smith?" is part of his name.
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Symbol | Definition |
rate of recruitment into the susceptible compartment, | |
including unsuccessfully immunized birth and immigration | |
immigration rate into class |
|
age-dependent immigration rate into class |
|
per capital death rate for class |
|
age-dependent death rate for class |
|
birth rate | |
proportion of newborns who are unsuccessfully immunized | |
transfer rate from exposed to acute infection | |
vaccination rate | |
degree of infectiousness of carriers relative to acute infections ( |
|
age-dependent transmission coefficient | |
age-dependent rate of children born to carrier mothers | |
who become HBV carriers | |
age-dependent transfer rate from acute to immunized or carrier class | |
age-dependent transfer rate from carrier to immunized class | |
age-dependent progression from acute infection to carrier class | |
age-dependent HBV-induced death rate |
Symbol | Definition |
rate of recruitment into the susceptible compartment, | |
including unsuccessfully immunized birth and immigration | |
immigration rate into class |
|
age-dependent immigration rate into class |
|
per capital death rate for class |
|
age-dependent death rate for class |
|
birth rate | |
proportion of newborns who are unsuccessfully immunized | |
transfer rate from exposed to acute infection | |
vaccination rate | |
degree of infectiousness of carriers relative to acute infections ( |
|
age-dependent transmission coefficient | |
age-dependent rate of children born to carrier mothers | |
who become HBV carriers | |
age-dependent transfer rate from acute to immunized or carrier class | |
age-dependent transfer rate from carrier to immunized class | |
age-dependent progression from acute infection to carrier class | |
age-dependent HBV-induced death rate |