Abstract
To date, oncology patients are more dependent on non-cellular host defense against pathogens due to intensive (chemo)therapy-related bone marrow suppression. Since data on complement functionality in oncology patients are limited, we aimed to investigate the innate complement function in relation to the type of malignancy and therapy in a longitudinal cohort of patients. A large single-center, prospective non-intervention study was conducted, in which blood samples were taken from patients before, during, and after treatment with chemotherapy and/or subsequent admittance for (febrile) neutropenia. Analysis of 48 patients showed a high percentage of defects in complement activity of the alternative pathway (19.1%), the classical pathway (4.3%), or both (42.6%). Post hoc analysis of six different treatment protocols with more than three patients each showed distinct effects of specific therapies. Whereas patients treated according to the Ewing, EpSSG-rhabdomyosarcoma, or SIOP CNS germ cell tumor protocol showed no defects, patients treated according to the ALL-11 (leukemia), the EURAMOS I (osteosarcoma), or the ACNS (medulloblastoma) protocols showed an almost universal reduction in complement function. Although we could not explain the reduced complement functionality under all conditions, a strong effect was observed following high-dose methotrexate or ifosfamide. Acquired complement defects were commonly observed in more than 50% of oncology patients, some of which associated with certain chemotherapeutic drugs. Additional studies are needed to determine the clinical and therapeutic context of complement defects and their possible effect on treatment outcome or the increased risk of infection.
Highlights
Infection is the most important cause of treatment-related deaths in oncology and the second most common reason for hospitalization during therapy [1, 2]
Blood was drawn at specific time points (T), when possible, on the day of diagnosis (T = IC), before the start of therapy (T = B), during therapy (T = D), and after therapy (T = A), and thereafter, during episodes of febrile neutropenia (FN; neutropenia
Since mannan-binding lectin (MBL) is a highly variable plasma protein based on genotype and acute phase response reactivity [30] (Appendix B in Supplementary Material), we focused in our subsequent analyses solely on the functionality of the classical pathway (CP) and alternative pathway (AP) cascade of complement activation
Summary
Infection is the most important cause of treatment-related deaths in oncology and the second most common reason for hospitalization during therapy [1, 2]. The risk of infection and inflammation is increased in oncology patients due to treatment-induced neutropenia [3], making them more dependent on their innate, non-cellular immunity. This dependence on innate host defense mechanisms might be more prominent in children because of the relative immaturity of the immune system [4]. Both the intactness of the barriers of skin, pulmonary, and gastrointestinal surface membranes as well as a functional innate immunity provide the most relevant defense against bacterial and fungal pathogens in oncology patients. The formation of a C3-convertase activates the terminal pathway, resulting in the formation of the membrane attack complex and lysis of the target cell [7, 12]
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