The study explains why some patients develop a serious infection after chemotherapy, and points to ways to avoid this unwanted phenomenon
Cancer chemotherapy can save lives, but it involves serious complications, including infections. Until now, the main criterion for assessing this risk was the number of blood cells: if the number of white blood cells is lower than a critical threshold value, the risk is considered high. A new model developed by mathematicians from the Weizmann Institute of Science, in collaboration with doctors from the Meir Medical Center in Kfar Saba and the Hoffmann La Roche Research Center in Basel, Switzerland, shows that for risk assessment it is essential to determine not only the quantity of blood cells but also their quality, which varies from person to person .
The research is an important step in the development of the young field of personalized medicine:
It may lead to a more personalized approach to chemotherapy. For example, in high-risk patients, doctors will have to take increased measures to prevent infection. Low-risk patients, on the other hand, will be spared unnecessary preventive treatments.
The study was recently published in the scientific journal Journal of Clinical Investigation, and was carried out by a group of researchers from quite different fields: applied mathematics, electrical engineering, oncology, immunology and pediatrics.
The new model explains how the immune system works under conditions of neutropenia, meaning a low level of white blood cells, mainly of the neutrophil type. In this condition, which often arises after chemotherapy or a bone marrow transplant, but may also be congenital, serious infections may develop if the immune system fails to perform its essential function: ingesting and eliminating bacteria. "Our mathematical model discovered new mechanisms responsible for the differences in the degree of vulnerability to infections between neutropenic patients," says the head of the group, Prof. Verd Rom-Kader, from the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science.
The model shows that in a state of neutropenia it is impossible to explain the power relations between the immune cells and the bacteria using the simple ratio between the number of cells and the number of bacteria, or by determining a minimum threshold value for the amount of immune cells. The reason for this is that when the neutrophil count is low, the patient's immune system enters a state of delicate balance - called, in mathematical terms, "bi-stability". This condition may be dramatically violated by small changes in the concentration of bacteria or the number of neutrophils. Additional factors that may dramatically affect this balance include the degree of efficiency of the neutrophils, or the degree of tissue permeability to bacteria - this may increase due to chemotherapy treatments.
Thus, according to the model, in healthy people it is not very important that the function of neutrophils varies from person to person. In patients with neutropenia, however, these differences may be the difference between life and death. This conclusion is based on a study which was based on tests conducted on the blood of four healthy volunteers. To apply the model in practice, a comprehensive clinical trial must be conducted.
The model has already offered solutions to several medical mysteries. It helps explain, for example, why some cancer patients develop life-threatening infections after chemotherapy, even though they are kept in isolation under sterile conditions. It turns out that if their neutrophils are "weak", a tiny amount of bacteria, such as the one that exists permanently in the intestines, is enough to tilt the delicate balance in favor of the bacteria.
The study also explains why some patients develop severe infection after chemotherapy or a bone marrow transplant, even when their neutrophil count returns to a relatively normal level. As mentioned, the chemotherapy causes not only a reduction in the number of neutrophils and a weakening of their function, but also increases the permeability of the patient's tissues to bacteria. The model shows that as a result, in some patients, the concentration of bacteria increases at such a high speed that even the return of neutrophils to normal values fails to overcome the bacteria - which in the meantime had time to reproduce wildly. In the future, this scenario may also explain the rare cases in which serious infections develop in humans with a normal immune system. According to the model, in these cases the rapid growth of particularly violent bacteria may overwhelm the activity of the neutrophils, even if their number and efficiency are normal.
The model may also help doctors decipher unexplained medical cases. For example, an infant treated at Meir Medical Center for healthy congenital neutropenia, even though his neutrophil count was below 200 cells per microliter of blood. In contrast, an adult cancer patient died when his neutrophil count after chemotherapy was 380. The model explains how clinical parameters, such as poor quality of the neutrophils, could lead to the death of the adult patient despite the numerical superiority of his neutrophils.
In addition, the model may help in understanding the development of severe recurrent infections in certain patients. Doctors from the Meir Medical Center were able to establish a diagnosis in only one third of the thousand patients who were referred to them due to serious infections. The mathematical model of the Weizmann Institute scientists suggests that at least some of the unsolved cases probably resulted from a combination of several immune defects, such as differences in the function of neutrophils and other immune cells.
The research was carried out by researchers who combine fields of specialization in an unusual way. The head of the group, the mathematician Prof. Verd Rom-Kader, specializes in the study of dynamical systems. The first author, Dr. Roy Malka, is an electrical engineer who conducted the research as part of his doctoral studies at the Weizmann Institute, and is currently conducting research in a similar field at Harvard University Medical School. The idea for the research was conceived by Dr. Eliezer Shohat, a senior oncologist, who also holds a doctorate in mathematics from the Weizmann Institute. He now works at a research center for the pharmaceutical company Hoffmann La Roche in Basel, Switzerland.
A group from the Meir Medical Center participated in the study: Prof. Baruch Wallach, head of the laboratory for leukocyte function and head of the pediatric immunology department at the Sackler Faculty of Medicine at Tel Aviv University, and the director of the laboratory Ronit Gabrieli, who performed the experiments.
Prof. Wallach: "The research shows that in order to achieve optimal results in chemotherapy or in the treatment of patients with recurrent infections, it is advisable to also check the quality of the patients' neutrophils and the concentration of bacteria in them. Such tests will help in reducing morbidity and death, as well as in reducing hospitalization expenses and providing expensive drugs. Furthermore, it is possible that in this way it will be possible to reduce the use of antibiotics, and thus it will be possible to reduce the development of drug-resistant bacterial strains."
One response
Very interesting article. I really hope that they will continue to advance with the research in the field until they find significant solutions with reduced side effects. The Weizmann Institute is one of the leading research centers in the world and this is not the first time I have heard about it in the context of scientific breakthroughs. well done!!