A comprehensive dynamic model of cyclic neuropenia

Abstract

Neutropenia is a hematological disorder that is defined as having a low level of neutrophils in the bloodstream. Low levels of absolute neutrophil counts leave the body defenseless against and vulnerable to infections. Cyclic neutropenia is a type of neutropenia that is described as the oscillations observed in the level of blood neutrophils. The disorder is mostly treated with a cytokine named recombinant granulocyte colony– stimulating factor, rG–CSF, which is administered via injection. A delicate injection schedule is called for because the treatment procedure is costly. However, treatment experiments on an actual patient require frequent sampling from bone marrow and blood, which simply cannot be allowed as it can be detrimental to the health of the patient. Therefore, modeling is a must to carry out treatment experiments. Accordingly, the main motivation in this thesis is to construct a comprehensive dynamic model of cyclic neutropenia. As human physiology is rich in dynamic complexities, system dynamics is selected as the primary methodology. We first construct a model that represents the regulatory structures of neutrophil production for a healthy person. After validating the model, the neutrophil dynamics of a cyclic neutropenia patient is obtained by simply changing the parameter values, but without changing the model structure. Neutrophil production deficiency is the most mentioned cause of cyclic neutropenia in the literature, which is also confirmed in our study. According to our simulation results, the clearance of the apoptotic neutrophils of CN patients takes longer than normal and apoptotic neutrophils can suppress both the production and effects of G– CSF. As a result of experiments with pathogens, we claim that the oscillatory behavior is a characteristic of the neutrophil–GCSF–pathogen system even for a healthy person. This may shed some light on the periodic symptoms observed in patients with diseases caused by an overactive immune system. We experiment with rG–CSF injections too.