
Epidemic dynamics in absence of isolation control (
Citation: Dong-Mei Li, Bing Chai, Yu-Li Fu, Qi Wang. Cytomegalovirus dynamics model with random behavior[J]. AIMS Mathematics, 2020, 5(6): 6373-6394. doi: 10.3934/math.2020410
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Mathematical models of infectious diseases spreading have played a significant role in infection control. On one hand, they have given an important contribution to the biological and epidemiological understanding of disease outbreak patterns; on the other hand, they have helped to determine how and when to apply control measures in order to quickly and most effectively contain epidemics [1]. Research in this field is constantly evolving and ever new challenges are launched from the real world (just think of the ongoing COVID–19 pandemic). One among the many increasingly attractive topics is the mutual influence between the individual behaviours and choices and the disease dynamics [2,30].
In mathematical epidemiology literature a prominent position is occupied by the compartmental epidemic models. They are macroscopic models where the total population is divided into disjoint compartments according to the individual status with respect to the disease, and the switches from a compartment to another follow given transition rules. The size of each compartment represents a state variable of the model, whose rate of change is ruled by a balance differential equation. The milestone of compartmental models is the well–known deterministic Susceptible–Infected–Removed (SIR) model, proposed by Kermack and McKendrick in 1927 [18].
Like any mathematical model, also epidemic models postulate some simplifying assumptions that are needed to make them analytically tractable and/or numerically solvable. Quantifying the impact of such simplifications is extremely important to understand the model reliability and identify its range of application. For example, deterministic compartmental models are valid for large populations. Hence, they can hardly describe situations in which compartments are almost empty (for example at the onset of an epidemic, when the infectious individuals are very few) and, then, stochastic fluctuations cannot be disregarded.
A significant aspect neglected by classical epidemic models is the heterogeneity of disease transmission and progression linked to the viral load of each infected individual. Viral load is defined as a quantitative viral titre (e.g. copy number) [11] and may represent a useful marker for assessing viral kinetics, disease severity and prognosis. Indeed, symptoms and mortality induced by the infection may depend on the individual viral load, like asserted, for example, by studies on seasonal flu [21], measles [28] and COVID–19 disease [14]. The quantity of virus in the organism can also influence the results by screening and diagnostic tests, which are capable of detecting a different quantity of virus per
The mathematical framework of multi–agent systems [27] allows one to introduce a detailed microscopic description of the interactions between individuals, that are generally called agents, within a population. One of the key aspects is that it allows one to recover a statistical description of the system by introducing a probability density function accounting for the statistical distribution of some microscopic traits of the individuals. Its evolution may be described by kinetic equations that also permit to derive macroscopic equations, i.e. macroscopic models, that, thus, inherit a large number of features of the original microscopic dynamics. In particular, the authors in [22] introduced a particle model describing a microscopic dynamics in which agents have a double microscopic state: a discrete label that switches as a consequence of a Markovian process and a microscopic trait that changes as a consequence of binary interactions or interactions with a background. The trait may take into account the individual viral load, while the label denotes the compartment to which the agent belongs. The authors then derived nonconservative kinetic equations describing the evolution of the distribution of the microscopic trait for each label and, eventually, macroscopic equations for the densities and momentum of the microscopic trait of each compartment.
Kinetic equations have been applied to compartmental epidemic models in order to take into account the role of wealth distribution during the spread of infectious diseases, for example in [8,9]. In these works, the authors described in more detail social contacts among the individuals but still relied on an SIR–like structure to model contagion dynamics. To our best knowledge, the only kinetic model taking into account the spread of an infectious disease by means of interactions and including the individuals' viral load is the one proposed in [25], where, however, the authors did not consider epidemiological compartments.
Motivated by the previous arguments, in the present work we propose a microscopic stochastic model allowing one to describe the spread of an infectious disease as a consequence of the interactions among individuals who are characterized by means of their viral load. Once infected, the viral load of the individuals increases up to a maximum peak and then decreases as a consequence of a physiological process. Furthermore, the individuals are labelled in order to indicate their belonging to one of the disjoint epidemiological compartments. Specifically, we consider an SIR–like dynamics with an isolation mechanism that depends on the individual viral load (Section 2). We derive kinetic evolution equations for the distribution functions of the viral load of the individuals in each compartment and, eventually, a macroscopic model for the densities and viral load momentum (Section 3). We perform then a qualitative analysis of the ensuing macroscopic model (Section 4), and we present some numerical tests of both the microscopic and the macroscopic models to show the matching between the aggregate trends obtained from the macroscopic descriptions and the original particle dynamics simulated by a Monte Carlo approach (Section 5). Finally, we draw some conclusions and we briefly sketch possible research developments (Section 6).
Let us consider a large system of interacting individuals in presence of an infectious disease that spreads through social contacts. The total population at time
Being our final aim the proposal of a macroscopic model, we derive as an intermediate stage a statistical description of our multi–agent system through kinetic equations, by which we then derive macroscopic equations. In order to give a statistical description of the multi–agent system, whose total mass is conserved in time, we introduce a distribution function for describing the statistical distribution of the agents characterized by the pair
f(t,x,v)=∑i∈Xδ(x−i)fi(t,v), | (1) |
where
∫10∫Xf(t,x,v)dxdv=∑i∈X∫10fi(t,v)dv=1,∀t≥0. | (2) |
In (1)–(2),
ρi(t)=∫10fi(t,v)dv |
the density of agents in the class
∑i∈Xρi(t)=1,∀t≥0. |
Then, we define the viral load momentum of the
ni(t)=∫10fi(t,v)vdv. |
If
The individuals, labelled with
● susceptible,
● infectious,
● isolated,
● recovered,
Specifically: susceptible individuals have
Epidemic dynamics in absence of isolation control (
● infectious,
● infectious,
Note that new infections enter the class
Also, since our model incorporates birth and death processes, we introduce the following three auxiliary compartments: individuals that enter the susceptible class by newborn or immigration,
Let us now focus on the mathematical modelling of the evolution of an individual viral load
Given an agent labelled with
By interacting with an infectious individual, a susceptible individual may or may not get infected. In the first case his/her viral load after the interaction (say,
v′=Tνβv0, |
where
Infectious, isolated and recovered individuals cannot change their viral load in binary interactions, but the evolution reflects physiological processes. In particular, starting from the initial positive value
In this framework, the microscopic state
v′=v+ν1(1−v). | (3) |
The latter is a prototype rule describing the fact that the viral load may increase up to a certain threshold normalized to 1 by a factor proportional to
Similarly, given an agent
v′=v−ν2v, | (4) |
being the parameter
Let us now define a microscopic stochastic process implementing the modelling assumptions defined so far. Let us consider an agent characterized by the pair of random variables
The two stochastic processes above may be expressed in the following rule describing the variation of
(Xt+Δt,Vt+Δt)=Σ[(1−Θ)(Xt,Vt)+Θ(JvXt,V′Xt)]+Ψ[((1−Ξ)Xt,Vt)+(ΞJXt,Vt)], | (5) |
where
Independent label switch. Let us denote with
●
●
●
●
We remark that, in principle, the probability of dying from the disease,
The frequencies of the Markovian processes describing the switch between the different compartments may, in general, depend on both the departure and the arrival classes. It means that the process of switching from class
●
●
●
●
Simultaneous label switch. In our multi–agent system the first microscopic process causing simultaneously both a label switch and a progression of the viral load is the transition from susceptible (
P(JvXt=I1,V′Xt=v′|Xt=S) |
that is the probability for an agent labelled with
P(JvXt=I1,V′Xt=v′|Xt=S)=P(JvXt=I1,V′Xt=v′)(ρI1(t)+ρI2(t)), |
that can be rewritten as
P(JvXt=I1,V′Xt=v′|Xt=S)=P(JvXt=I1|V′Xt=v′)P(V′Xt=v′)(ρI1(t)+ρI2(t)), |
where
Analogously, we may express the transition probabilities concerning the autonomous process and label switch as
P(JvXt=i,V′Xt=v′|Xt=j,Vt=v)=P(JvXt=i|V′Xt=v′)Pj(v→v′), |
where
Remark 1. If
In our case, the transitions to take into account are:
●
●
●
●
The frequency of these transitions is the frequency of the corresponding microscopic process, i.e.
The kinetic equations describing the evolution of
ddt∫10φ(v)fi(t,v)dv=∫10φ(v)(∑j∈X[λi,jP(j→i)fj(t,v)−λj,iP(i→j)fi(t,v)])dv+∑j∈X∫10∫10[λjφ(v′)P(i,v′|j,v)fj(t,v)−λiφ(v)P(j,v′|i,v)fi(t,v)]dvdv′, | (6) |
From (6), we derive the kinetic equations describing the evolution of the distribution functions
● susceptible individuals (
ddt∫10φ(v)fS(t,v)dv=∫10φ(v)(λbbρB(t)fB(t,v)−λμμfS(t,v))dv−λβνβ∫10∫10φ(v′)PS(v′)ρS(t)δ(v−0)(ρI1(t)+ρI2(t))dvdv′, | (7) |
● infectious individuals with increasing viral load (
ddt∫10φ(v)fI1(t,v)dv=−∫10φ(v)(λH1,I1(t)αH(v)fI1(t,v)+λμμfI1(t,v))dv+λβνβ∫10∫10φ(v′)PS(v′)ρS(t)δ(v−0)(ρI1(t)+ρI2(t))dvdv′−λγ∫10∫10φ(v′)η(v′)PI1(v→v′)fI1(t,v)dvdv′+λγ∫10∫10(φ(v′)PI1(v→v′)fI1(t,v)−φ(v)PI1(v→v′)fI1(t,v))dvdv′, | (8) |
● infectious individuals with decreasing viral load (
ddt∫10φ(v)fI2(t,v)dv=−∫10φ(v)(λH2,I2(t)αH(v)fI2(t,v)+λμμfI2(t,v))dv+λγ∫10∫10φ(v′)η(v′)PI1(v→v′)fI1(t,v)dvdv′−λγ∫10∫10φ(v′)γ(v′)PI2(v→v′)fI2(t,v)dvdv′+λγ∫10∫10(φ(v′)PI2(v→v′)fI2(t,v)−φ(v)PI2(v→v′)fI2(t,v))dvdv′, | (9) |
● isolated individuals with increasing viral load (
ddt∫10φ(v)fH1(t,v)dv=∫10φ(v)(λH1,I1(t)αH(v)fI1(t,v)−λddfH1(t,v)−λμμfH1(t,v))dv−λγ∫10∫10φ(v′)η(v′)PH1(v→v′)fH1(t,v)dvdv′+λγ∫10∫10(φ(v′)PH1(v→v′)fH1(t,v)−φ(v)PH1(v→v′)fH1(t,v))dvdv′, | (10) |
● isolated individuals with decreasing viral load (
ddt∫10φ(v)fH2(t,v)dv=∫10φ(v)(λH2,I2(t)αH(v)fI2(t,v)−λddfH2(t,v)−λμμfH2(t,v))dv+λγ∫10∫10φ(v′)η(v′)PH1(v→v′)fH1(t,v)dvdv′−λγ∫10∫10φ(v′)γ(v′)PH2(v→v′)fH2(t,v)dvdv′+λγ∫10∫10(φ(v′)PH2(v→v′)fH2(t,v)−φ(v)PH2(v→v′)fH2(t,v))dvdv′, | (11) |
● recovered individuals (
ddt∫10φ(v)fR(t,v)dv=−λμμ∫10φ(v)fR(t,v)dv+λγ∫10∫10φ(v′)γ(v′)PI2(v→v′)fI2(t,v)dvdv+λγ∫10∫10φ(v′)γ(v′)PH2(v→v′)fH2(t,v)dvdv′+λγ∫10∫10(φ(v′)PR(v→v′)fR(t,v)−φ(v)PR(v→v′)fR(t,v))dvdv′. | (12) |
Equations (7)–(12) have to hold for every
In order to obtain the equations for the macroscopic densities and viral load momentum of each compartment, we set
fi(t,v)=ρi(t)δ(v−ni(t)ρi(t)),i∈X, | (13) |
i.e. we assume that all the agents of the same compartment at a given time
Remark 2. We consider that a monokinetic closure is appropriate in this framework, as the microscopic rules describing the evolution of the viral load (3)–(4) are deterministic, i.e. there is no diffusion related to stochastic fluctuations.
As already observed, if
∫10φ(v)fi(t,v)dv=φ(ni(t)ρi(t))ρi(t). |
Then, we consider test functions such that
φ(ni(t)ρi(t))ρi(t)→0,ifρi(t)→0. | (14) |
When
∫10φ(v)ψ(v)fi(t,v)dv | (15) |
with
φ(nIj(t)ρIj(t))λHj,Ij(t)αH(nIj(t)ρIj(t))ρIj(t),j=1,2. |
Hence, we have to choose the isolation frequency and probability function in such a way that the latter quantity is well defined.
The macroscopic model is given by the following system of non–linear ordinary differential equations:
˙ρS=λbb−λβνβρSρI−λμμρS˙ρI1=λβνβρSρI−λH1,I1(t)αH(nI1ρI1)ρI1−λγν1ρI1−λμμρI1˙ρI2=λγν1ρI1−λH2,I2(t)αH(nI2ρI2)ρI2−λγν2ρI2−λμμρI2˙ρH1=λH1,I1(t)αH(nI1ρI1)ρI1−λγν1ρH1−λddρH1−λμμρH1˙ρH2=λγν1ρH1+λH2,I2(t)αH(nI2ρI2)ρI2−λγν2ρH2−λddρH2−λμμρH2˙ρR=λγν2ρI2+λγν2ρH2−λμμρR˙nI1=λβνβv0ρSρI−λH1,I1(t)αH(nI1ρI1)nI1=−λγν1(nI1+(ν1−1)(ρI1−nI1))−λμμnI1˙nI2=λγν1(nI1+ν1(ρI1−nI1))−λH2,I2(t)αH(nI2ρI2)nI2=−λγν2(2−ν2)nI2−λμμnI2˙nH1=λH1,I1(t)αH(nI1ρI1)nI1−λγν1(nH1+(ν1−1)(ρH1−nH1))=−λddnH1−λμμnH1˙nH2=λγν1(nH1+ν1(ρH1−nH1))+λH2,I2(t)αH(nI2ρI2)nI2=−λγν2(2−ν2)nH2−λddnH2−λμμnH2˙nR=λγν2(1−ν2)nI2+λγν2(1−ν2)nH2−λγν2nR−λμμnR. | (16) |
For convenience of notation, in (16) we have denoted with the upper dot the time derivative and omitted the explicit dependence on time of the state variables.
To model (16) we associate the following generic initial conditions
ρS(0)=ρS,0>0,ρi(0)=ρi,0≥0,ni(0)=ni,0≥0,i∈{I1,I2,H1,H2,R}. | (17) |
Remark 3. We observe that, by assuming
As far as the products
We focus instead on the impact of viral load–sensitivity of tests and frequency of testing activities on the epidemic dynamics and consider the case that:
● the probability for infectious individuals to be isolated,
● the frequencies
With these choices, in system (16), the isolation terms become
λHj,Ij(t)αH(nIjρIj)=λααnIj,j=1,2. | (18) |
Equilibria and stability properties of model (16)–(18) will be investigated in the following section.
Since in model (16)–(18) the differential equations for
˙ρS=λbb−λβνβρS(ρI1+ρI2)−λμμρS | (19a) |
˙ρI1=λβνβρS(ρI1+ρI2)−λααρI1nI1−λγν1ρI1−λμμρI1 | (19b) |
˙ρI2=λγν1ρI1−λααρI2nI2−λγν2ρI2−λμμρI2 | (19c) |
˙nI1=λβνβv0ρS(ρI1+ρI2)−λααn2I1 |
=−λγν1(nI1+(ν1−1)(ρI1−nI1))−λμμnI1 | (19d) |
˙nI2=λγν1(nI1+ν1(ρI1−nI1))−λααn2I2−λγν2(2−ν2)nI2−λμμnI2. | (19e) |
It is straightforward to verify that the region
D={(ρS,ρI1,ρI2,nI1,nI2)∈[0,1]5|0<ρS+ρI1+ρI2≤λbbλμμ,nI1≤ρI1,nI2≤ρI2} | (20) |
with initial conditions in (17) is positively invariant for model (19), namely any solution of (19) starting in
In the following, we search for model equilibria and derive suitable thresholds ruling their local or global stability.
The model (19) has a unique disease–free equilibrium (DFE), given by
DFE=(λbbλμμ,0,0,0,0). |
It is obtained by setting the r.h.s. of equations (19) to zero and considering the case
Proposition 1. The DFE of system (19) is locally asymptotically stable (LAS) if
R0=λβνβλbbλμμλγν1+λγν2+λμμ(λγν1+λμμ)(λγν2+λμμ). | (21) |
Otherwise, if
Proof. The Jacobian matrix
J(DFE)=(−λμμ−λβνβλbbλμμ−λβνβλbbλμμ000λβνβλbbλμμ−λγν1−λμμλβνβλbbλμμ000λγν1−λγν2−λμμ000λβνβv0λbbλμμ+λγν1(1−ν1)λβνβv0λbbλμμJ400λγν210λγν1(1−ν1)J5), |
with
J4=−λγν1(2−ν1)−λμμ,J5=−λγν2(2−ν2)−λμμ. |
One can immediately get the eigenvalues
ˉJ=(λβνβλbbλμμ−λγν1−λμμλβνβλbbλμμλγν1−λγν2−λμμ). |
From the sign of the entries of
The threshold quantity
As far as the global stability of the DFE, we prove the following theorem.
Theorem 4.1. The DFE of system (19) is globally asymptotically stable if
Proof. Consider the following function
L=λγν1+λγν2+λμμλγν1+λμμρI1+ρI2. |
It is easily seen that the
˙L=λγν1+λγν2+λμμλγν1+λμμ˙ρI1+˙ρI2=λγν1+λγν2+λμμλγν1+λμμ(λβνβρS(ρI1+ρI2)−λααρI1nI1)−λααρI2nI2−(λγν2+λμμ)(ρI1+ρI2)≤(λγν2+λμμ)(λβνβρSλγν1+λγν2+λμμ(λγν1+λμμ)(λγν2+λμμ)−1)(ρI1+ρI2)≤(λγν2+λμμ)(R0−1)(ρI1+ρI2). |
It follows that
As an alternative proof, one may adopt the approach developed by Castillo–Chavez et al. in [3].
Let us denote with
EE=(ρES,ρEI1,ρEI2,nEI1,nEI2) |
the generic endemic equilibrium of model (19), obtained by setting the r.h.s. of equations (19) to zero and considering the case
More precisely, by rearranging equations (19a)–(19b)–(19c)–(19d), one obtains
ρES=λbb−(λααnEI1+λγν1+λμμ)ρEI1λμμρEI1=nEI1λααnEI1+λγν1(2−ν1)+λμμλγν1(1−ν1)+v0(λααnEI1+λγν1+λμμ)ρEI2=λbb−λβνβρESρEI1−λμμρESλβνβρESnEI2=λγν1ρEI1−(λγν2+λμμ)ρEI2λααρEI2. | (22) |
Substituting the expressions (22) into (19e), one gets
λγν1(nEI1+ν1(ρEI1−nEI1))−λαα(nEI2)2−λγν2(2−ν2)nEI2−λμμnEI2=0. | (23) |
Due to the complexity of equation (23), we renounce to get an explicit expression for
To derive a sufficient condition for the occurrence of a transcritical bifurcation at
˙u=Au2+Bλβνβu, |
where
A=z2⋅DxxF(DFE,¯λβνβ)w2≡125∑k,i,j=1zkwiwj∂2Fk(DFE,¯λβνβ)∂xi∂xj | (24) |
and
B=z⋅Dx(λβνβ)F(DFE,¯λβνβ)w≡5∑k,i=1zkwi∂2Fk(DFE,¯λβνβ)∂xi∂(λβνβ). | (25) |
Note that in (24) and (25) the product
Observe that
λβνβ=¯λβνβ=λμμλbb(λγν1+λμμ)(λγν2+λμμ)λγν1+λγν2+λμμ |
so that the disease–free equilibrium is stable if
The direction of the bifurcation occurring at
For our model, we prove the following theorem.
Theorem 4.2. System (19) exhibits a forward bifurcation at DFE and
Proof. From the proof of Proposition 1, one can verify that, when
It can be easily checked that a left and a right eigenvector associated with the zero eigenvalue so that
z=(0,z2,(λγν1+λμμ)(λγν2+λμμ)λγν1(λγν1+λμμ)+(λγν2+λμμ)(λγν1+λγν2+λμμ),0,0),w=(−λγν1+λμμλμμ,1,λγν1λγν2+λμμ,v0(λγν1+λμμ)+λγν1(1−ν1)λγν1(2−ν1)+λμμ,w5)T, |
with
z2=(λγν2+λμμ)(λγν1+λγν2+λμμ)λγν1(λγν1+λμμ)+(λγν2+λμμ)(λγν1+λγν2+λμμ) |
and
w5=λγν1ν1(λγ+λμμ)+v0(1−ν1)(λγν1+λμμ)(λγν1(2−ν1)+λμμ)(λγν2(2−ν2)+λμμ). |
The coefficients
A=z2w1[w2∂2F2(DFE,¯λβνβ)∂ρS∂ρI1+w3∂2F2(DFE,¯λβνβ)∂ρS∂ρI2]=+z2w2w4∂2F2(DFE,¯λβνβ)∂ρI1∂nI1+z3w3w5∂2F3(DFE,¯λβνβ)∂ρI2∂nI2=z2w1(1+w3)¯λβνβ−(z2w2w4+z3w3w5)λαα |
and
B=z2(w2∂2F2(DFE,¯λβνβ)∂ρI1∂(λβνβ)+w3∂2F2(DFE,¯λβνβ)∂ρI2∂(λβνβ))=z2(1+w3)λbbλμμ |
where
In this section, we present and compare some numerical solutions of both the stochastic particle model (5) and the macroscopic model (16).
Our aim is to qualitatively assess the interplay between the evolution of individuals' viral load and the disease spread and isolation control. Hence, demographic and epidemiological parameters values do not address a specific infectious disease and/or spatial area. They refer to a generic epidemic outbreak where control strategies rely on isolation of infectious individuals, as typically happens for new emerging infectious diseases (e.g., 2003–2004 SARS outbreak [31], 2014–2016 Western African Ebola virus epidemic [4], the first phase of the ongoing COVID–19 pandemic [33]).
Numerical simulations are performed in MatlabⓇ [26]. We implement a Monte Carlo algorithm to simulate the stochastic particle model (5) and the 4th order Runge–Kutta method with constant step size for integrating the system (16). Platform–integrated functions are used for getting the plots.
The time span of our numerical simulations is set to
λbb=brˉNNtot, |
where
We assume a population of
For the epidemiological parameters we take the following baseline values:
R0=4,λγ=1/2days−1,ν1=1/(5λγ),ν2=ν1/2,λdd=9.997⋅10−4days−1. |
In particular, the product
λdd=(1−λμμT)CFT, |
where
Initial data are set to the beginning of the epidemic, namely we consider a single infectious individual in a totally susceptible population:
ρS,0=(ˉN−1)/Ntot,ρI1,0=1/Ntot,nI1,0=v0ρI1,0,ρi,0=ni,0=0,i∈{I2,H1,H2,R}. | (26) |
All the parameters of the model as well as their baseline values are reported in Table 1.
List of model parameters with corresponding description and baseline value
.Parameter | Description | Baseline value |
Frequency of new births or immigration | 1 days |
|
Newborns probability parameter | ||
Frequency of natural deaths | 0.01 days |
|
Probability of dying of natural causes | ||
Frequency of binary interactions | 1 days |
|
Transmission probability parameter | 0.29 | |
Initial viral load of infected individuals | 0.01 | |
Frequency of isolation for |
See Section 5.3 | |
Frequency of isolation for |
See Section 5.3 | |
Probability for an infectious individual to be isolated | See Section 5.3 | |
Frequency of viral load evolution | 0.50 days |
|
Factor of increase of the viral load | 0.40 | |
Factor of decay of the viral load | 0.20 | |
Probability of having passed the viral load peak | ||
Probability of recovering | ||
Frequency of disease–induced deaths | 0.01 days |
|
Probability of dying from the disease | 0.10 |
First, we numerically investigate the impact of the epidemiological parameters on the basic reproduction number
Contour plot of the basic reproduction number
Let us now set the basic reproduction number to the baseline value
Here, we introduce the isolation control in the epidemic model and assess how the frequency of testing and the viral load–sensitivity of tests can affect epidemic dynamics. To this aim, we compare the following simulation scenarios:
S1 viral load–dependent isolation, as studied here:
S2 constant isolation, as in classical epidemic models:
In order to make the two scenarios properly comparable, we make the following considerations. In the case S2, the product
λαα|S1=λαα|S2M, |
where
M=ˉnI1+ˉnI22, |
where
ˉnIj=1tf∫tf0nuncIj(t)dt,j=1,2. |
The numerical value for
Figs. 3 and 4 display the numerical simulations in scenarios S1 (grey scale colour) and S2 (blue scale colour). Specifically, solid lines refer to the solutions of the macroscopic model (16) and markers to those of the stochastic particle model (5). As far as the match between the two approaches is concerned, we note that in the case of constant control S2 considerations similar to those made in Section 5.2 apply. Instead, in the case of viral load–dependent control S1, solutions by particle and macroscopic models are qualitatively similar but quantitatively different. This is an expected result because the derivation of the macroscopic model relies on an approximation through the monokinetic closure (13), which acts by levelling the viral loads of all agents belonging to a given class to their average value. However, notwithstanding the postulated monokinetic closure, the matching is quite good, as the peak given by the macroscopic model is only mildly underestimated. Again, we remark that the macroscopic model may not well reproduce the compartment mean viral loads as predicted by the stochastic model (Fig. 4). This happens at the beginning and at the end of the time horizon when some compartments are almost empty (e.g., those of infectious and isolated individuals). In such cases, the law of large numbers does not apply and the concept of theoretical mean departs consistently from that of empirical mean.
Viral load–dependent vs. constant isolation control. Numerical solutions as predicted by the model (16) (solid lines) and by the particle model (5) (markers) in scenarios S1 (grey scale colour) and S2 (blue scale colour). Panel (a): compartment size of infectious individuals with increasing viral load,
Viral load–dependent vs. constant isolation control. Numerical solutions as predicted by the model (16) (solid lines) and by the particle model (5) (markers) in scenarios S1 (grey scale colour) and S2 (blue scale colour). Panel (a): mean viral load of infectious individuals with increasing viral load,
As far as the comparison between scenarios S1 and S2 is concerned, from Fig. 3 we note that in the first case (grey scale colour) the epidemic outbreak occurs earlier and with a lower peak w.r.t. the second case (blue scale colour), but the tails of the infected curves are longer. In order to investigate these differences more deeply, we consider the solutions by the macroscopic model (16) and report in Table 2 some relevant epidemiological quantities, including the value of infectious prevalence peak and the time it occurs, and the endemic value of infectious prevalence,
ρEI1|S2=λbb(λαα+λγν1+λμμ)−λμμ(λαα+λγν2+λμμ)λβνβ(λαα+λγν1+λγν2+λμμ)ρEI2|S2=λγν1λαα+λγν2+λμμρEI1|S2. |
Relevant quantities as predicted by the model (16) in the case of viral load–dependent isolation S1 (first column) and in the case of constant isolation S2 (second column). First line: infectious prevalence peak,
Scenario S1 | Scenario S2 | |
arg |
55.08 days | 90.62 days |
CI |
||
CH |
||
CD |
||
289.35 | 75.92 |
We also compute the value at the final time
CI(t)=Ntot∫t0λβνβρS(τ)(ρI1(τ)+ρI2(τ))dτ,CH(t)=Ntot∫t0(λH1,I1(τ)αH(nI1(τ)ρI1(τ))ρI1(τ)+λH2,I2(τ)αH(nI2(τ)ρI2(τ))ρI2(τ))dτ,CD(t)=Ntot∫t0λdd(ρH1(τ)+ρH2(τ))dτ. |
From Table 2, we note that the epidemic peak in scenario S1 is almost halved compared to the scenario S2 and occurs 36 days before. By contrast, the endemic infectious prevalence is much greater in scenario S1 w.r.t. S2: 289 vs. 76. Interestingly, the differences in the cumulative quantities CI
The viral load–dependent isolation function reflects the assumption that an infectious individual with high viral load is more likely to be identified: it may represent the efficiency of the test that, according to its sensitivity, is capable of detecting different concentrations of virus particles per
One of the advantages of a particle model is the possibility to track the trends of all the agents of the system. Here, we are interested in tracking the evolution of individuals' viral load during the simulation time span. To this aim, we consider the particle model (5) with viral load–dependent isolation control (scenario S1) and retrieve the viral load evolution of every single agent. In Fig. 5, we report the temporal dynamics of
Viral load evolution from the time of infection exposure to the final time
In this work, we have proposed a microscopic stochastic model allowing one to describe the spread of an infectious disease through social contacts. Each individual is identified by the epidemiological compartment to which he/she belongs and by his/her viral load. Binary interactions between susceptible and infectious individuals may cause the susceptible to acquire a positive viral load
We have derived from the stochastic particle model a kinetic description by means of evolution equations of the distribution of the viral load in each compartment. Finally, by making use of a monokinetic closure, we have obtained a macroscopic description. The ensuing macroscopic model is a system of non–linear ordinary differential equations for the macroscopic densities and viral load momentum of the compartments. We have performed a qualitative analysis allowing to state that our system has a unique disease–free equilibrium (DFE) that is globally asymptotically stable if
Our numerical tests have allowed us to compare the predictions yielded by the particle and the macroscopic models. In particular, concerning the densities of the compartments, the numerical tests have confirmed the matching between the two approaches in the case that the probability of being isolated,
Deliberately, we have not tried to match real scenarios by calibrating or comparing the results of our models with empirical data. In fact, our aim was first to propose a simple compartmental model including the viral load as microscopic variable. As a consequence, we wanted to explore prototypical scenarios and to compare them to those predicted by classical epidemic models, by focusing on the impact of having a viral load–dependent isolation in place of a constant isolation rate. We have seen that in the case of a viral load–dependent isolation the epidemic outbreak occurs earlier and with a lower peak (almost halved) w.r.t. to the constant isolation case. However, the cumulative disease–related quantities one year after the onset of the epidemic are comparable, while the endemic infectious prevalence is much greater in the viral load–dependent isolation scenario. This may be explained in terms of the viral load–sensitivity and frequency of the testing activities that are embodied in the choice of the functions
In the proposed framework, the description of the microscopic mechanisms and the heterogeneity of the viral load at the microscopic level allows one to derive a macroscopic model (more amenable, of course, to analytical and numerical investigations), that provides for a richer description of the disease spreading in the host population. Here we only considered the explicit influence of the viral load on the isolation mechanism, but, in principle, other switches of individuals between compartments may depend on the viral load at the microscopic level, and on the viral load mean at the macroscopic level. Therefore, more complex situations, such as super–spreading events, that have been proved to be of the utmost importance for example during the COVID–19 pandemic [15], could be addressed. The heterogeneity of transmission could be included by making the disease transmission rate from infectious to susceptible individuals dependent on the viral load. Also, in such a way, different initial viral loads of the infectious individual first introduced in the community may give rise to different epidemic scenarios.
This work was supported by GNFM (Gruppo Nazionale per la Fisica Matematica) of INdAM (Istituto Nazionale di Alta Matematica) through a 'Progetto Giovani 2020' grant. This work was also partially supported by the Italian Ministry of University and Research (MUR) through the "Dipartimenti di Eccellenza" Programme (2018-2022), Department of Mathematical Sciences "G. L. Lagrange", Politecnico di Torino (CUP: E11G18000350001). This work is also part of the activities of the PRIN 2017 project (No. 2017YBKNCE) "Multiscale phenomena in Continuum Mechanics: singular limits, off–equilibrium and transitions", and of the PRIN 2020 project (No. 2020JLWP23) "Integrated Mathematical Approaches to Socio–Epidemiological Dynamics".
[1] | Q. X. Zeng, J. X. Dong, Y. Meng, et al. Progress in epidemiology of human cytomegalovirus Infection, Shandong medicine, 57 (2017), 1131-1133. |
[2] | F. Chiuppesi, T. Kaltcheva, Z. Meng, et al., Identification of a continuous neutralizing epitope within UL128 of human cytomegalovirus, J. Virol., 91 (2017), 1-16. |
[3] | S. E. Jackson, G. X. Sedikides, G. M. Mason, et al. Human Cytomegalovirus (HCMV)-Specific CD4+ T Cells are polyfunctional and can respond to HCMV-Infected dendritic cells in vitro, J. Virol., 91 (2017), 1-16. |
[4] | D. Song, H. Mei, Research Progress of congenital cytomegalovirus infection in newborns, Medical Recapitulate, 23 (2017), 4453-4457. |
[5] |
D. Zhu, C. Pan, J. Sheng, et al. Human cytomegalovirus reprogrammes haematopoietic progenitor cells into immunosuppressive monocytes to achieve latency, Nat. Microbiol., 3 (2018), 503-513. doi: 10.1038/s41564-018-0131-9
![]() |
[6] | Y. H. Li, Analysis of the correlation between breastfeeding of HCMV infected mothers and HCMV infection of newborns, MA. Thesis, Qingdao University, 2015. |
[7] |
D. C. Moylan, S. K. Pati, S. A. Ross, et al. Breast milk HCMV viral load is associated with the establishment of breast milk CMV-pp65-specific CD8 T cells in Human CMV infected mothers, J. Infect. Dis., 216 (2017), 1176-1179. doi: 10.1093/infdis/jix457
![]() |
[8] | W. F. Wu, Progress in the treatment of CMV infection, Chinese Medical Journal, 38 (2003), 10-12. |
[9] |
K. Wang, W. Wang, S. Song, Dynamics of an HBV model with diffusion and delay, J. Theor. Biol., 253 (2008), 36-44. doi: 10.1016/j.jtbi.2007.11.007
![]() |
[10] | G. Alter, D. Heckerman, A. Schneidewind, et al. HIV-1 adaptation to NK-cell-mediated immune pressure, Nature, 476 (2017), 96-100. |
[11] | W. O. Kermack, A. G. Mckendrick, A contribution to the mathematical theory of epidemics, B. Math. Biol., 53 (1991), 57-87. |
[12] | X. N. Han, The transmission dynamies of SARS, MA. Thesis, PLA Academy of Military Sciences, 2006. |
[13] | R. Zhao, H. Wang, X. Wang, et al. Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis, Osteoporosis International, 28 (2016), 1027-1034. |
[14] | L. F. Zhang, Comparison and parameter estimation between deterministic model and stochastic model of infectious disease transmission, MA. Thesis, Southwest Jiaotong University, 2010. |
[15] | A. Q. Miao, J. Zhang, T. Zhang, et al. Threshold dynamics of a stochastic SIR model with vertical transmission and vaccination, Comput. Math. Method. M., 2017 (2017), 1-10. |
[16] | P. Y. Xia, Dynamic behavior of several random virus models, Ph.D thesis, Northeast Normal University, 2018. |
[17] | C. Y. Ji, Asymptotic behavior of stochastic biological model and infectious disease model, Ph.D thesis, Northeast Normal University, 2011. |
[18] | Y. Asai, C. Tomás, X. Han, et al. A random model for immune response to virus in fluctuating environments, Springer International Publishing, 2016. |
[19] | Y. Wang, J. Liu, Y. Y. Liu, et al. Establishment of mouse brain latent cytomegalovirus activation model, Progress in Modern Biomedicine, 15 (2015), 4414-4418. |
[20] | H. Y. Duan, T. Yu, Diagnosis and treatment progress of cytomegalovirus infection, Chinese Journal of Obstetrics and Gynecology, 6 (2010), 68-71. |
[21] |
M. A. Nowak, C. Bangham, Population dynamics of immune responses to persistent viruses, Science, 272 (1996), 74-79. doi: 10.1126/science.272.5258.74
![]() |
[22] |
M. A. Nowak, S. Bonhoeffer, A. M. Hill, et al. Viral dynamics in hepatitis B virus infection, Proceedings of the National Academy of Sciences, 93 (1996), 4398-4402. doi: 10.1073/pnas.93.9.4398
![]() |
[23] | X. Q. Niu, W. D. Li, G. F. Zhu, et al. Modeling the transmission dynamics of hepatitis B Virus and data assimilation forecasting, Mathematics in Practice and Theory, 45 (2015), 205-211. |
[24] | J. M. Conway, D. Coombs, A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients, PLoS Comput. Biol., 7 (2011), 1-24. |
[25] |
C. Fraser, N. M. Ferguson, R. M. Anderson, et al. The role of antigenic stimulation and cytotoxic T Cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications, Proceedings: Biological Sciences, 268 (2001), 2085-2095. doi: 10.1098/rspb.2001.1777
![]() |
[26] |
C. Fraser, N. M. Ferguson, R. M. Anderson, Quantification of intrinsic residual viral replication in treated HIV-infected patients, Proceedings of the National Academy of Sciences of the United States of America, 98 (2001), 15167-15172. doi: 10.1073/pnas.261283598
![]() |
[27] |
W. Zhang, L. M. Wahl, P. Yu, Viral blips may not need a trigger: how transient viremia can arise in deterministic in-host models, Siam Rev., 56 (2014), 127-155. doi: 10.1137/130937421
![]() |
[28] |
S. Wang, J. Zhang, F. Xu, et al. Dynamics of virus infection models with density‐dependent diffusion, Comput. Math. Appl., 74 (2017), 1-20. doi: 10.1016/j.camwa.2017.05.001
![]() |
[29] | M. Wei, L. Hu, X. Mao, Neutral stochastic functional differential equations with Lévy jumps under the local Lipschitz condition, Advances in Difference Equations, 2017 (1017), 57. |
[30] | R. Khasminskii, Stochastic Stability of Differential Equations, Stochastic stability of differential equations, 1980. |
[31] | X. X. Liao, Theory methods and application of sability, 2nd Edition, Huazhong University of Science and Technology Press, Wuhan, 2010. |
[32] | N. He, W. D. Wang, A. R. Zhou, et al. Dynamics of stochastic HIV model based on saturation incidence rate, Journal of Southwest University (Natural Science Edition), 40 (2018), 123-125. |
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2. | Giacomo Albi, Giulia Bertaglia, Walter Boscheri, Giacomo Dimarco, Lorenzo Pareschi, Giuseppe Toscani, Mattia Zanella, 2022, Chapter 3, 978-3-030-96561-7, 43, 10.1007/978-3-030-96562-4_3 | |
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6. | Marzia Bisi, Silvia Lorenzani, Mathematical Models for the Large Spread of a Contact-Based Infection: A Statistical Mechanics Approach, 2024, 34, 0938-8974, 10.1007/s00332-024-10062-2 | |
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11. | Andrea Medaglia, Mattia Zanella, 2023, Chapter 15, 978-981-19-6461-9, 191, 10.1007/978-981-19-6462-6_15 | |
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List of model parameters with corresponding description and baseline value
.Parameter | Description | Baseline value |
Frequency of new births or immigration | 1 days |
|
Newborns probability parameter | ||
Frequency of natural deaths | 0.01 days |
|
Probability of dying of natural causes | ||
Frequency of binary interactions | 1 days |
|
Transmission probability parameter | 0.29 | |
Initial viral load of infected individuals | 0.01 | |
Frequency of isolation for |
See Section 5.3 | |
Frequency of isolation for |
See Section 5.3 | |
Probability for an infectious individual to be isolated | See Section 5.3 | |
Frequency of viral load evolution | 0.50 days |
|
Factor of increase of the viral load | 0.40 | |
Factor of decay of the viral load | 0.20 | |
Probability of having passed the viral load peak | ||
Probability of recovering | ||
Frequency of disease–induced deaths | 0.01 days |
|
Probability of dying from the disease | 0.10 |
Relevant quantities as predicted by the model (16) in the case of viral load–dependent isolation S1 (first column) and in the case of constant isolation S2 (second column). First line: infectious prevalence peak,
Scenario S1 | Scenario S2 | |
arg |
55.08 days | 90.62 days |
CI |
||
CH |
||
CD |
||
289.35 | 75.92 |
Parameter | Description | Baseline value |
Frequency of new births or immigration | 1 days |
|
Newborns probability parameter | ||
Frequency of natural deaths | 0.01 days |
|
Probability of dying of natural causes | ||
Frequency of binary interactions | 1 days |
|
Transmission probability parameter | 0.29 | |
Initial viral load of infected individuals | 0.01 | |
Frequency of isolation for |
See Section 5.3 | |
Frequency of isolation for |
See Section 5.3 | |
Probability for an infectious individual to be isolated | See Section 5.3 | |
Frequency of viral load evolution | 0.50 days |
|
Factor of increase of the viral load | 0.40 | |
Factor of decay of the viral load | 0.20 | |
Probability of having passed the viral load peak | ||
Probability of recovering | ||
Frequency of disease–induced deaths | 0.01 days |
|
Probability of dying from the disease | 0.10 |
Scenario S1 | Scenario S2 | |
arg |
55.08 days | 90.62 days |
CI |
||
CH |
||
CD |
||
289.35 | 75.92 |