Stability of a Mathematical Model of Malaria Transmission with Relapse

A more realistic mathematical model of malaria is introduced, in which we not only consider the recovered humans return to the susceptible class, but also consider the recovered humans return to the infectious class. The basic reproduction number is calculated by next generation matrix method. It is shown that the disease-free equilibrium is globally asymptotically stable if , and the system is uniformly persistence if . Some numerical simulations are also given to explain our analytical results. Our results show that to control and eradicate the malaria, it is very necessary for the government to decrease the relapse rate and increase the recovery rate.


Introduction
Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes. Approximately half of the world's population is at risk of malaria. Most malaria cases and deaths occur in Sub-Saharan Africa. In 2011, 99 countries and territories had ongoing malaria transmission [1]. Recently, the incidence of malaria has been rising due to drug resistance. Various control strategies have been taken to reduce malaria transmissions.
Many epidemic models have been analyzed mathematically and applied to specific diseases [2,3]. Since the first mathematical model of malaria transmission is introduced by Ross [4], quite a few mathematical models have been formulated to investigate the transmission dynamics of malaria [5][6][7][8][9][10][11][12]. Ngwa and Shu [5] analyze a deterministic differential equation model for endemic malaria involving variable human and mosquito populations. Ngwa [6] also analyzes a mathematical model for endemic malaria involving variable human and mosquito populations and uses a perturbation analysis to approximate the endemic equilibrium in the important case where the disease related death rate is nonzero, small but significant. Furthermore, in quasistationarity, the stochastic process undergoes oscillations about a mean population whose size can be approximated by the stable endemic deterministic equilibrium. Chitnis et al. [7,8] study a model that both human and vector species follow a logistic population, and human have immigration and disease-induced death. They present a bifurcation analysis and analyze a periodically-forced difference equation model for malaria in mosquitoes that captures the effects of seasonality and allows the mosquitoes to feed on a heterogeneous population of hosts. Chamchod and Britton [9] incorporate a vector-bias term into a malaria transmission model to account for the greater attractiveness of infectious humans to mosquitoes in terms of differing probabilities that a mosquito arriving at a human depending on whether he is infectious or susceptible. To take account of the incubation periods of parasites within the human and the mosquito, a delayed Ross-Macdonald model is taken by Ruan et al. [10]. Further, Xiao and Zou [11] use mathematical models to explored a natural concern of possible epidemics caused by multiple species of malaria parasites in one region. They find that epidemics involving both species in a single region are possible. Li [12] provides a basic analysis for the stage-structured malaria model and shows that both the baseline and the stage-structured malaria models undergo backward bifurcations.
Recently, Li et al. [13] consider a fast and slow dynamics of malaria model with relapse, and analyse the global dynamics  by using the geometric singular perturbation theory. They find that a treatment should be given to symptomatic patients completely and adequately rather than asymptomatic infection. On the other hand, for the asymptomatic patients, their results strongly suggest that to control and eradicate the malaria, it is very necessary for the government to control the relapse rate strictly. Nadjm and Behrens [14] state that relapse is when symptoms reappear after the parasites had been eliminated from blood but persist as dormant hypnozoites in liver cells. This commonly occurs between 8-24 weeks and is commonly seen with P. vivax and P. ovale infections. Other papers also consider the inluence of relapse in giving up smoking or quitting drinking, please see [15,16] and references cited therein.
Chitnis et al. [7] assume that the recovered humans have some immunity to the disease and do not get clinically ill, but they still harbor low levels of parasite in their blood streams and can pass the infection to mosquitoes. After some period of time, they lose their immunity and return to the susceptible class. Unfortunately, they do not consider that the recovered humans will return to their infectious state because of incomplete treatment. Li et al. [13] consider the relapse but not that the recovered humans may return to the susceptible class.
Motivated by these works, in this paper, we propose a more realistic mathematical model of malaria, in which we assume that the recovered humans return to the susceptible class and relapse. The basic reproductive number 0 is calculated and the persistence theory is used to analyze the uniformly persistence of the system. The organization of this paper is as follows. In the next section, a mathematical model of malaria with relapse is formulated. In Section 3, the basic reproduction number and the stability of disease-free equilibria are investigated. The existence of endemic equilibrium and uniformly persistence are proved in Section 4, and some numerical simulations are given in Section 5. In the last section, we give some brief discussions.

System Description.
In this section, we introduce a mathematical model of malaria with relapse. Because hosts might get repeatedly infected due to not acquiring complete immunity so the population is assumed to be described by the SIRS model. Mosquitoes are assumed not to recover from the parasites so the mosquito population can be described by the SI model. The total number of population at time is given by = ℎ ( )+ ℎ ( )+ ℎ ( ) and = ( )+ ( ). The structure of model is shown in Figure 1. The transfer diagram leads to the following system of ordinary differential equations: where ℎ , ℎ , ℎ , , , , and represent the number of susceptible humans, infectious humans, recovered humans, susceptible mosquitoes, infectious mosquitoes, the total size of the human population, and the total size of the mosquitoes population, respectively. is the natural birth and death rate of humans, is the natural birth and death rate of mosquitoes, is from an infectious mosquito to a susceptible human transmission rate in humans, 1 and 2 represent both infectious and recovered human to a susceptible mosquito transmission rate in mosquitoes, is treatment rate, 1 is recovery rate (individuals from recovered class could back to susceptible class again because they had a very small amount of parasites, which would be cleared quickly by their own immune system), 2 is relapse rate, and is the number of mosquitoes per individual. All the parameters can be found in Table 1. In the model, and are constant, so we introduce the new variables in terms of proportion as follows: Abstract and Applied Analysis 3 with ℎ + 1 + 2 = 1, + = 1. Then the system (1) becomes Thus, the total human population and mosquitoes' population are constant. Since the system (3) monitor human population, it is plausible to assume that all its state variables and parameters are nonnegative for all ≥ 0. Further, it can be shown that the region is positively-invariant. Thus, each solution of the system (3), with initial conditions in Ω, remains there for ≥ 0. Therefore, the -limit sets of solutions of the system (3), are contained in Ω. Furthermore, in Ω, the usual existence, uniqueness, and continuation results hold for the system, so that the system (3), is well-posed mathematically and epidemiologically. So we consider dynamics of system (3) on the set Ω in this paper. (3), to ensure the solutions of the system with positive initial conditions remain positive for all > 0, it is necessary to prove that all the state variables are nonnegative, so we have the following lemma.

Positivity of Solutions. For system
In the first case, we have which is a contradiction meaning that 1 ( ) > 0, ≥ 0.
In the second case, we have which is a contradiction meaning that 2 ( ) > 0, ≥ 0.

Analysis of the Model
The model (3) has one disease-free equilibrium 0 and one endemic equilibrium * .

Disease-Free Equilibrium and the Basic Reproduction
Number. The model has a disease-free equilibrium given by In the following, the basic reproduction number of system (3) will be obtained by the next generation matrix method formulated in [17]. Let = ( 1 , 2 , ) , then system (3) can be written as where The Jacobian matrices of F( ) and V( ) at the disease-free equilibrium 0 are, respectively, The model reproduction number denoted by 0 is thus given by Here 0 is associated with disease transmission by infected humans as well as the infection of susceptible humans by infected mosquitoes. Susceptible mosquitoes acquire malaria infection from infected humans in two ways, namely, by infected or recoveries. Susceptible humans acquire infection following effective contacts with infected mosquitoes.

Existence of the Endemic Equilibrium
Proof. It follows from system (3) that From the second equation of (23), we obtain * Substituting * 2 into the third equation of (23), we have * = . (25) Then substituting (24) and (25) into first equation of (23), we get * Hence, if 0 ≤ 1, there is no positive root of (26), while if 0 > 1 there is one positive root.

Uniform Persistence of the Disease.
We using the persistence theory of dynamical system to show the uniform persistence of the disease when 0 > 1. Let be a closed positively invariant subset of Ω, on which a continuous flow F is defined. We denote the restriction F to by F and note that is in general not positively invariant. Let be the maximal invariant set of F on . Suppose is a closed invariant set and there exists a cover { } ∈ of , where is a nonempty index set.
⊂ , ⊂ ⋃ ∈ , and { }( ∈ ) are pairwise disjoint closed invariant sets. Furthermore, we propose the following hypothesis and Lemma. By this lemma, we can show the uniform persistence of disease when 0 > 1, and similar to the proof of Theorem 2.3 in [13], we have the following. Theorem 6. In system (3), assume that 0 > 1, and the disease is initially present, then the disease is uniformly persistent; that is, there is a constant > 0 such that lim inf → +∞ 1 ( ) ≥ , lim inf → +∞ 2 ( ) ≥ , and lim inf → +∞ ( ) ≥ .
Finally, for showing the effect of relapse and recover rate to the basic reproduction number, we give the relation between 0 and 2 (Figure 4), and the relation between 0 and 1 ( Figure 5) in the numerical simulation. From Figures 4 and 5, we know that 0 is increasing with respect to the relapse rate, while it is decreasing with respect to the recovery rate.

Discussion
An ordinary differential equation for the transmission of malaria is formulated in this paper. The model exhibits two equilibria, that is, the disease-free equilibrium and endemic equilibrium. By constructing Lyapunov function and persistence theory of dynamical system, it is shown that if 0 ≤ 1, then the disease-free equilibrium point 0 is globally stable, and if 0 > 1, the disease is uniformly persistent. Some numerical simulations for 0 in terms of relapse rate and recover rate are performed. 0 is increasing with respect to the relapse rate while it is decreasing with respect to the recovery rate. Our results strongly suggest that to control and eradicate the malaria, it is very necessary for the government to decrease the relapse rate and increase the recovery rate.

Conflict of Interests
On behalf of all the authors, Hai-Feng Huo declares that there is no conflict of interests regarding the publication of this paper.