Scientists have developed a mathematical model they claim demonstrates that in order to accurately predict whether a chemotherapy patient is at risk of developing neutropenia-related infections, the quality of their remaining white blood cells as well as the number needs to be evaluated. Developed by Weizmann Institute mathematicians working with physicians at the Meir Medical Center in Israel, and Roche’s research center in Basel, Switzerland, the model demonstrates how the immune system functions under conditions of neutropenia resulting from chemotherapy or bone marrow transplant.
Corroborated by evaluation of healthy individuals, the model indicates that the ability of white blood cells, primarily neutrophils, to tackle bacterial infections doesn’t just depend on absolute cell number, or the bacteria-to-cell ratio, but is affected by factors including neutrophil function and the permeability of tissues to bacteria, which can increase as a result of chemotherapy. Effectively, in neutropenia the immune system is balanced on a knife-edge—described mathematically as bistability—which can go either way as a result of even minor disturbances to the equilibrium.
Vered Rom-Kedar, Ph.D., and colleagues say their studies suggest that, because the immune system of a healthy individual is far more robust, parameters such as how well neutrophils function aren’t an issue with respect to clearing infections. But in patients with neutropenia inter-individual variation in even minor parameters can explain why in some cases an infection takes hold and in others it is eradicated. The model also explains why some chemotherapy patients will contract life-threatening infections even when kept in isolation. If these patients have poorly functioning neutrophils, then even small numbers of infecting bacteria could prove fatal. Similarly, it provides an indication as to why some chemotherapy or bone marrow transplant patients can sometimes develop acute infections even if their neutrophil levels have returned to relatively normal, and possibly why in very rare cases acute bacterial infections can occur in individuals with apparently normal immunological function.
In fact, the researchers claim, the mathematical model helped shed light on why a diagnosis couldn’t be made for about 33% of 1,000 patients admitted to the Meir Medical Center due to severe recurrent infections. Some of these unresolved cases may have been exacerbated by a combination of minor variations in neutrophil or other immune cell function.
The team points out further studies will be needed on much larger numbers of healthy subjects to fine-tune mathematical forms of bistable models for widespread use in a clinical setting. “These experimental and theoretical explorations will generate estimated population parameters and provide their between-subject variability,” they write. “With these estimations at hand, we envision the suggested protocol will provide a diagnostic tool based on a standard objective measure. We hope that the emerging principle—that the combined effect of mild impairments may lead to significant clinical consequences—can contribute to the current practice for treating patients that suffer from repeated infections or undergo chemotherapy treatments.”
The findings could ultimately help clinicians optimize therapeutic regimens for patients with neutropenia, concludes the Meir Medical Center’s Baruch Wolach, M.D. “Our study suggests that to achieve optimal results in applying chemotherapy, and/or in patients with innate neutrophil dysfunction, it is of value to assess the patient’s neutrophils periodically, as well as the bacterial concentration. Such assessments will help reduce the morbidity and the mortality, as well as the cost, associated with unnecessary hospitalizations and the administration of expensive medications. Moreover, by cutting down on the use of antibiotics, these assessments can help in preventing the rise in antibiotic resistance.”
The investigators report on their model and findings in the Journal of Clinical Investigation, in a paper titled “Evidence for bistable bacteria-neutrophil interaction and its clinical implications.”