Abstract
A sharp threshold is established that separates disease persistence from the extinction of small disease outbreaks in an S→E→I→R→S type metapopulation model. The travel rates between patches depend on disease prevalence. The threshold is formulated in terms of a basic replacement ratio (disease reproduction number), ℛ0, and, equivalently, in terms of the spectral bound of a transmission and travel matrix. Since frequency-dependent (standard) incidence is assumed, the threshold results do not require knowledge of a disease-free equilibrium. As a trade-off, for ℛ0>1, only uniform weak disease persistence is shown in general, while uniform strong persistence is proved for the special case of constant recruitment of susceptibles into the patch populations. For ℛ0<1, Lyapunov's direct stability method shows that small disease outbreaks do not spread much and eventually die out.
1. Introduction
Many compartmental epidemic models focus on how infectious diseases develop with time and ignore the other category that shapes reality, space. Spatial disease spread can be included with distance as a continuous variable leading to partial differential equation models as in Citation1, Citation7, Citation17, Citation18, to integro-differential equations as in Citation25, Citation26, or to equations of mixed type Citation21. (For the spatial spread of epidemic outbreaks see Citation20, Citation21, Citation31 and the references therein.) Alternatively, space can be included as a discrete variable leading to (spatially explicit) metapopulation models as in Citation24 that consist of a (possibly very large) system of ordinary differential equations (ODEs). The underlying idea is to subdivide the spatial region under consideration into a number of discrete patches, which may represent districts, cities, countries, ponds (for the study of amphibian decline), etc. The disease is carried from one patch to another by individuals traveling between patches. As a simplifying assumption, individuals only change disease status when they are on a patch and not when they travel. (See Citation5 for a model with disease transmission during travel.) Work on S→I→S type models Citation2, 23, Citation33–36 and on models for influenza Citation13, Citation14 indicates that a patchy environment and travel between patches can influence disease spread in a complicated way and, depending on parameters values that include characteristics of the specific disease, can enhance or stifle disease spread.
Our aim is to add to the threshold analysis of the type metapopulation model in Citation23 by discussing dynamic disease persistence and the existence of an endemic equilibrium. We also want to extend the threshold analysis to travel rates that depend on the disease prevalence on the patches and to recruitment rates that depend in addition on the patch population densities (see section 2). The variable travel rates take into account behavioral changes that may occur as individuals adjust to such factors as the severity of the disease or travel restrictions. We prove the existence of a sharp threshold that separates disease persistence (sections 4 and 5) from extinction of small disease outbreaks (section 6). This threshold can be formulated in terms of a basic replacement ratio (basic parasite reproduction number), ℛ0, or, equivalently, in terms of the spectral bound of a transmission and travel matrix (section 3). By contrast with Citation23, our results (except for Theorem 6.3) do not depend on the existence of a disease-free equilibrium because our methods fully exploit the crucial choice that disease transmission is modeled by frequency-dependent (standard) incidence. The threshold condition for density-dependent (mass action) incidence would involve the patch population densities at a unique disease-free equilibrium (see the Discussion). As a trade-off, our approach struggles with the fact that, under frequency-dependent incidence, the disease can drive both host and parasite to extinction if it induces fatalities or reduces fertility Citation9, Citation29, Citation38. This is why, under general recruitment, we can only establish uniform weak persistence of the disease if
(section 4). For the same reason, we formulate disease persistence in terms of the frequencies rather than the densities of the infectives on the patches. So disease persistence does not necessarily imply persistence of the causative agent (parasite, pathogen).
For uniform strong disease persistence, we assume constant recruitment into the patch populations (section 5) as in Citation23. Under this strong assumption, not only the disease but also the host and the parasite persist, and there exists an endemic equilibrium (a question left unanswered in Citation23). Alternatively, the assumption could be made that the disease neither induces fatalities nor reduces fertility as has been done in Citation34, Citation35 for an S→I→S type model.
The threshold condition is sharp as we show that small disease outbreaks do not spread much and eventually die out if
(section 6). Since the disease-free dynamics are unclear, we do not use a linearized stability analysis, but Lyapunov's direct stability method.
The epidemic metapopulation model introduced in Citation24 not only keeps track of the patch where an individual is currently located (as in the model analyzed in this paper) but also of the patch on which an individual is born and usually resides. For m epidemiological classes on n patches such models lead to a system of mn
2 rather than mn ODEs. Under the assumption that travel is independent of disease prevalence, they are analyzed for the S→I→S case in Citation3, for the case in Citation4, and for a model of SARS that includes quarantine in Citation22. An explicit expression for the basic reproduction number is given, and numerical simulations for the S→I→S model indicate that this number acts as a threshold between extinction and persistence of the disease. It remains to be explored whether the methods we develop in this paper will also work for these even more complex models with frequency-dependent incidence.
2. The model
We consider a host metapopulation that is geographically distributed over n patches (districts, countries). The disease divides each patch population into four classes (or compartments): susceptible individuals (represented by letter S), exposed individuals (infected but not yet infective, represented by letter E), infective individuals (represented by letter I), and removed (or recovered) individuals (represented by letter R). We include the possibility that recovered individuals can become susceptible again, so our model will be of type. We assume that disease transmission and transition between disease classes only occurs on patches and not during travel. See Citation5 for a model with disease transmission during travel.
Let denote the respective numbers of susceptible, exposed, infective, and removed individuals and N
i
(t) denote the total population size in patch i at time t (see ). We introduce the following notation for the various epidemiological classes,
Table 1. Model variables.
Table 2. Parameters and parameter functions.
The following assumptions are made throughout the paper.
Assumption 2.1
The functions
are defined for
,
. The functions
,
, are defined for
. These functions are nonnegative and are locally Lipschitz continuous on their respective domains. All parameters are positive with the possible exception of
some or all of which may be 0. Furthermore,
-
(a)
,
-
(b)
,
-
(c) the matrix
is irreducible,
-
(d) the matrix
is irreducible.
All norms are sum-norms, . So ‖J‖ is the total number of non-susceptibles and ‖(S, J)‖ is the size of the total population. S≫0 means that
, i.e. the vector S has all its coordinates positive.
Assumption 2.1 (a) is satisfied, e.g. if all recruitment rates are bounded. Assumption 2.1 (b) guarantees that each local population survives in the absence of the disease. By Assumption 2.1 (c) and (d), every patch can be reached from every other patch by susceptible and infected individuals.
For N
i
=0, we define . The expression
is then a locally Lipschitz continuous function of
. We define the total population size as
Table 3. Vector and other notation.
Theorem 2.2
For all
, there exists a unique solution
, R(t)) of
Equation(2)
with initial data
that is defined for all t≥0 and takes values in
. Further there exists some c>0 such that, for all non-negative solutions of
Equation(2)
,
and
for all t≥0.
Proof
By Theorem [Citation30; Theorem A.4], there exists a unique solution with values in that is defined on some interval [0, b) with
. If b<∞, then
. We add all equations in system Equation(2)
,
3. The basic replacement ratio, ℛ0
To establish a threshold parameter that separates disease persistence from the extinction of small disease outbreaks, the following linear operator B on plays a crucial role: for i=1, …, n,
Let s(B) denote the spectral bound of a linear (bounded) operator B, i.e. the largest real part of its eigenvalues, and let r(B) denote its spectral radius, i.e. the largest absolute value of its eigenvalues. The operators P and Q have the form D−M, where D is represented by a diagonal matrix with all diagonal entries being positive and M is represented by with
for P and
for Q. Thus −P is represented by a quasi-positive matrix. Further, the column sums of −P are negative, which implies that s(P)>0 and r(D
−1
M)<1 (6, Theorem 6.13], [Citation30, Theorem A.44], Citation32). With 𝕀 denoting the identity operator,
Proposition 3.1
With B given by
Equation(8), s(B) and
have the same sign.
Proof
Let s(B)>0. By the Perron–Frobenius theory (see, for example 27; A or Citation30, section A.Citation8, there exists an eigenvector (v, w)≫(0, 0) of B with B (v, w)≫(0, 0). By Equation(8),
As in Citation23,
4. Uniform weak disease persistence if ℛ0>1
Since our choice of frequency-dependent incidence makes it possible that the disease drives the host (and the causative disease agent) to extinction Citation9, Citation29, Citation38, we formulate disease persistence in terms of the frequencies rather than the densities of infective individuals on the patches.
Definition 4.1
The disease is said to be uniformly weakly persistent if there exists some ε>0 such that
We will show that the disease is uniformly weakly persistent if . This condition is sharp, as we will show in section 6 that, if
, small disease outbreaks die out. Uniform weak disease persistence is a stronger concept than instability of the disease-free state which is proved in Citation23 for
. In our model, which is more general than the one in Citation23, there is even no clear candidate for the disease-free state.
We will use the following Lemma several times.
Lemma 4.2
There exist
such that the following holds for all nonnegative solutions of
Equation(2)
with ‖S(0)‖>0: If
then
i=1, …, n.
Proof
We obtain the following differential inequality from the first subsystem in Equation(2),
Theorem 4.3
If
the disease is uniformly weakly persistent.
Proof
Suppose the statement is false. Choose an arbitrarily small ε>0. By Definition 4.1, there exists a solution of Equation(2) such that
and S(0)≫0, but
Step 1 There exists some such that
To prove step 1, we obtain the following differential inequality from the second subsystem in Equation(2),
Step 2 There exists some δ2>0 such that , i=1, …, n.
To prove step 2, we derive the following differential inequality from the first subsystem in Equation(2) and Equation(11)
, with
,
Step 3 The contradiction.
Combining step 1 and step 2 and shifting forward in time, we can assume that ,
, and
for i=1, …, n and C=E, I, R. The positive constants
and
do not depend on ε. Then
and, from the second and third subsystem in Equation(2)
,
5. Uniform strong disease persistence and existence of endemic equilibria
Typically, uniform weak implies uniform strong persistence (and the existence of an endemic equilibrium) if the dynamical system has a compact attractor. Unfortunately, Theorem 4.3 has the proviso that S(0)≫0 (see Definition 4.1), which must be built into the state space. So the existence of a compact attractor would imply strong host persistence. However, since our model assumes standard (frequency-dependent) incidence, it is possible that the disease drives the host to extinction Citation9, Citation29, Citation38. A suitable assumption that rules this out can be found in Citation23, namely that all recruitment rates Λ i are positive constants. We adopt it for this section. Under the assumption of constant recruitment, it is easy to see that the host is uniformly strongly persistent.
Lemma 5.1
If all Λ
i
are positive constants, then, for i=1, …, n, S
i
(t)>0 for all t>0, and there exist constants δ
i
>0 such that
for all nonnegative solutions of
Equation(2)
.
Proof
By the first subsystem in Equation(2),
If , the parasite is uniformly strongly persistent as well, at least in total abundance. Since S(t)≫0 for t>0 by Lemma 5.1, the subsequent persistence results do not need the solutions of Equation(2)
to satisfy S(0)≫0.
Theorem 5.2
If
and all Λ
i
are positive constants, there exists some ε>0 such that
Proof
We apply [Citation30; Theorem A.32]. Let
Corollary 5.3
If
and all Λ
i
are positive constants, there exists an equilibrium state of
Equation(2)
with
for C=E, I, R.
Proof
We apply [Citation37; Theorem 1.3.7]. Define X as in the proof of Theorem 5.2 and . Then X
0 is convex and relatively open in X. By Theorems 2.2 and 4.3 and Lemma 5.1, the semiflow induced by the solutions of Equation(2)
is uniformly persistent with respect to
in the language of Citation37. By [Citation37; Theorem 1.3.7], Equation(2)
has an equilibrium in X
0. It easily follows that
not only for C=I, but also for C=E, R. ▪
Under a further irreducibility assumption concerning the migration of exposed or infective individuals, the parasite persists uniformly strongly on each patch.
Theorem 5.4
Let
and all Λ
i
be positive constants. Further assume that for each
the matrix
is irreducible. Then there exists some ε>0 such that
Proof
Let the state space X be as in Theorem 5.2. Fix and define
by
. By Theorem 2.2 and Lemma 5.1, the compactness condition of [Citation30;Theorem A.34] is satisfied. Notice that every total orbit
of Φ is associated with a solution of Equation(2)
that is defined for all times and takes value in X. By our irreducibility assumption,
whenever
for all
. The claim for C=I now follows from [Citation30; Theorem A.34]. For C∈{E, R}, modify
. For C=S, the statement has already been shown in Lemma 5.1. The existence of an equilibrium in (0, ∞)4n
follows from [Citation37; Theorem 1.3.7]. ▪
6. Extinction of small outbreaks if ℛ0<1
In order to illustrate that the condition is sharp for disease persistence, we show that small disease outbreaks do not spread much and eventually die out if
. Recall that J=(E, I, R) and all norms are sum norms. So ‖J‖ is the total number of individuals that are not susceptible.
Theorem 6.1
If
, the following local stability results hold for nonnegative solutions of
Equation(2)
.
-
For every ε>0 there exists some δ>0 such that
for all t≥0 provided
.
-
Further there exists some δ0>0 such that
as t→∞ whenever
.
Proof
We use Lyapunov's direct stability method. The second and third subsystems of Equation(2) imply the inequalities
The preceding result does not preclude that both parasite and host go extinct, which is a possibility as our model uses standard (frequency-dependent) incidence Citation9, Citation29, Citation38. The next result shows that, if , the disease dies out and the host persists if the initial numbers of exposed, infective or removed individuals are small in comparison to the initial number of susceptible individuals.
Theorem 6.2
If
, there exist
such that the following holds for all nonnegative solutions of
Equation(2)
: for any
there exists some δ>0 such that
Proof
Let η>0 to be chosen later. By Theorem 6.1, there exists some δ>0 such that for all t≥0 whenever
. Let
. We add the first subsystem in Equation(2)
,
We now assume as in section 5 that the recruitment rates Λ
i
are positive constants for i=1, …, n. Then the disease-free system, and
Theorem 6.3
If
and all Λ
i
are positive constants, there exists some
with the following property: for any
there exists some δ>0 such that
Proof
By Theorems 6.1 and 6.2, the first subsystem (the one for S) of system Equation(2) is asymptotically autonomous with limit system Equation(22)
. The claim follows from the global stability of S
⋄ for Equation(22)
and results on asymptotically autonomous systems in Citation15 (or Citation28). ▪
If the travel matrices are independent of J, the disease-free equilibrium
is globally asymptotically stable if
[Citation23; Theorem 2.2].
7. Discussion
The sharp threshold results in this paper that separate disease persistence (if ) from the extinction of small disease outbreaks (if
) crucially depend on modeling disease transmission by frequency-dependent (standard) incidence. If frequency-dependent incidence were replaced by density-dependent (mass action) incidence, ℛ0 would involve the population densities on all patches at a disease-free equilibrium, which would need to be unique and globally attracting for the disease-free population dynamics. As a trade-off, for frequency-dependent incidence, it is possible that the disease drives the host and the causative disease agent to extinction Citation9, Citation29, Citation38 while host persistence is typically automatic for density-dependent incidence. For a complex model like this, it seems very hard to establish a threshold for host persistence unless one makes assumptions such as the one made in section 5 and Citation23, constant recruitment into each patch population, or the one made in Citation34, Citation35, no disease fatalities and no fertility reduction. Strangely enough, this problem also has repercussions for disease persistence: we can only prove uniform weak disease persistence in general, and host persistence is required in order to go from uniform weak to uniform strong disease persistence under the assumptions that we have imposed.
We refer to Citation10, Citation16 and the references therein for the discussion as to whether and when frequency-dependent or density-dependent incidence is more adequate. The choice of one over the other not only has consequences for whether or not the disease can eradicate the host, but also for the occurrences of undamped oscillations: they seem to occur more often for density-dependent incidence than for frequency-dependent incidence Citation8, Citation11, Citation19.
Acknowledgements
The authors thank two anonymous referees for helpful comments. This study was partially supported by NSF grant DMS 0314529 (T.D. and H.R.T.) and by NSERC and MITACS (P.v.d.D).
References
- Allen , L. J.S. , Bolker , B. M. , Lou , Y. and Nevai , A. L. “ Asymptotic profiles of the steady states for an SIS epidemic reaction-diffusion model ” . In Discrete Contin. Dyn. Syst in press
- Allen , L. J.S. , Bolker , B. M. , Lou , Y. and Nevai , A. L. 2007 . Asymptotic profiles of the steady states for an SIS epidemic patch model . SIAM J. Appl. Math. , 67 : 1283 – 1309 .
- Arino , J. and van den Driessche , P. 2003 . A multi-city epidemic model . Math. Popul. Stud. , 10 : 175 – 193 .
- Arino , J. and van den Driessche , P. 2003 . The basic reproduction number in a multi-city compartmental epidemic model , 294 : 135 – 142 . LNCIS
- Cui , J. , Takeuchi , Y. and Saito , Y. 2006 . Spreading disease with transport-related infection . J. Theor. Biol. , 239 : 376 – 390 .
- Diekmann , O. and Heesterbeek , J. A.P. 2000 . “ Mathematical Epidemiology of Infectious Diseases. Model Building, Analysis, and Interpretation ” . Chichester : Wiley .
- Fitzgibbon , W. E. and Langlais , M. 2003 . A diffusive S.I.S. model describing the propagation of F.I.V. . Commun. Appl. Anal. , 7 : 387 – 403 .
- Gao , L. Q. , Mena-Lorca , J. and Hethcote , H. W. 1996 . “ Variations on a theme of SEI endemic models ” . In Differential Equations and Applications to Biology and Industry , Edited by: Martelli , M. , Cooke , C. L. , Cumberbatch , E. , Tang , B. and Thieme , H. R. 191 – 207 . Singapore : World Scientific .
- Greenhalgh , D. and Das , R. 1995 . Modelling epidemics with variable contact rates . Theor. Pop. Biol. , 47 : 129 – 179 .
- Hethcote , H. W. 2000 . The mathematics of infectious diseases . 42 : 597 – 653 . SIAM Rev
- Hethcote , H. W. , Wang , W. and Li , Y. 2005 . Species coexistence and periodicity in host–host–pathogen models . J. Math. Biol. , 51 : 629 – 660 .
- Hirsch , W. M. , Hanisch , H. and Gabriel , J.-P. 1985 . Differential equation models for some parasitic infections: methods for the study of asymptotic behavior . Comm. Pure Appl. Math. , 38 : 733 – 753 .
- Hsieh , Y.-H. , van den Driessche , P. and Wang , L. 2007 . Impact of travel between patches for spatial spread of disease . Bull. Math. Biol. , 69 : 1355 – 1375 .
- Hyman , J. M. and LaForce , T. 2003 . “ Modeling the spread of influenza among cities ” . In Bioterrorism: Mathematical Modeling Applications in Homeland Security Edited by: Banks , H. T. and Castillo-Chavez , C. 211 – 236 . Philadelphia SIAM
- Markus , L. 1956 . “ Asymptotically autonomous differential systems, in Contributions to the Theory of Nonlinear Oscillations III ” . In Ann. Math. Stud. , Edited by: Lefschetz , S. Vol. 36 , 17 – 29 . Princeton : Princeton University Press .
- McCallum , H. , Barlow , N. and Hone , J. 2001 . How should pathogen transmission be modelled? . Trend. Ecol. Evol. , 16 : 295 – 300 .
- Murray , J. D. 1989 . Mathematical Biology , Berlin Heidelberg : Springer .
- Murray , J. D. 2003 . Mathematical Biology II: Spatial Models and Biomedical Application, , 3 , Berlin Heidelberg : Springer .
- Pugliese , A. 1991 . “ An S→E→I epidemic model with varying population size, Differential Equations Models in Biology, Epidemiology and Ecology ” . In Lecture Notes in Biomath , Edited by: Busenberg , S. and Martelli , M. Vol. 92 , 121 – 138 . Berlin Heidelberg : Springer .
- Rass , L. and Radcliffe , J. 2003 . Spatial Deterministic Epidemics . AMS , Providence
- Ruan , S. 2007 . “ Spatial–temporal dynamics in non-local epidemiological models ” . In Mathematics for Life Science and Medicine , Edited by: Takeuchi , Y. , Iwasa , Y. and Sato , K. 97 – 122 . Berlin Heidelberg : Springer .
- Ruan , S. , Wang , W. and Levin , S. A. 2006 . The effect of global travel on the spread of SARS . Math. Biosci. Eng. , 3 : 205 – 218 .
- Salmani , M. and van den Driessche , P. 2006 . A model for disease transmission in a patchy environment . Discrete Contin. Dyn. Syst. Ser. B , 6 : 185 – 202 .
- Sattenspiel , L. and Dietz , K. 1995 . A structured epidemic model incorporating geographic mobility among regions . Math. Biosci , 128 : 71 – 91 .
- Schumacher , K. 1980 . Travelling-front solutions for integro-differential equations . Journal für die reine und angewandte Mathematik , 316 : 54 – 70 .
- Schumacher , K. Travelling-front solutions for integro-differential equations. II . Proceedings Conference, Lecture Notes in Biomath. 1979 , Heidelberg. Biological Growth and Spread: Mathematical Theories and Applications , Edited by: Jäger , W. , Rost , H. and Tautu , P. Vol. 38 , pp. 296 – 309 . Berlin : Springer .
- Smith , H. L. and Waltman , P. 1995 . “ The Theory of the Chemostat. Dynamics of Microbial Competition ” . Cambridge : Cambridge University Press .
- Thieme , H. R. 1992 . Convergence results and a Poincaré–Bendixson trichotomy for asymptotically autonomous differential equations . J. Math. Biol. , 30 : 755 – 763 .
- Thieme , H. R. 1992 . Epidemic and demographic interaction in the spread of potentially fatal diseases in growing populations . Math. Biosci. , 111 : 99 – 130 .
- Thieme , H. R. 2003 . “ Mathematics in Population Biology ” . Princeton : Princeton University Press .
- Thieme , H. R. 2006 . “ Spatial Deterministic Epidemics ” . In Math. Biosci , Edited by: Rass , Linda and Radcliffe , John . Vol. 202 , 218 – 225 . American Mathematical Society 2003 . (book report)
- van den Driessche , P. and Watmough , J. 2002 . Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission . Math. Biosci. , 180 : 29 – 48 .
- Wang , W. 2004 . Population dispersal and disease spread . Discrete Contin. Dyn. Syst. Ser. B , 4 : 797 – 804 .
- Wang , W. 2007 . “ Epidemic models with population dispersal ” . In Mathematics for Life Science and Medicine , Edited by: Takeuchi , Y. , Iwasa , Y. and Sato , K. 67 – 95 . Berlin Heidelberg : Springer .
- Wang , W. and Mulone , G. 2003 . Threshold of disease transmission in a patch environment . Journal of Mathematical Analysis and Applications , 285 : 321 – 335 .
- Wang , W. and Zhao , X.-Q. 2004 . An epidemic model in a patchy environment . Math. Biosci. , 190 : 97 – 112 .
- Zhao , X.-Q. 2003 . “ Dynamical Systems in Population Biology ” . New York : Springer .
- Zhou , J. and Hethcote , H. W. 1994 . Population size dependent incidence in models for diseases without immunity . J. Math. Biol. , 32 : 809 – 834 .