ABSTRACT
A total of eighty patients with various malignancies seen between September 2008 and April 2009 at the University of Nigeria Teaching Hospital (UNTH) Ituku-Ozalla Enugu Nigeria had their absolute neutrophil counts and CD4 lymphocyte counts done at Days 0 and 12 of the first cycle of their various chemotherapeutic regimens. They were adult patients who had been diagnosed of various malignancies, consisting of Breast cancer 36 cases (45%), Non-Hodgkin’s lymphoma 8 cases (10%), Hodgkin’s lymphoma 13 cases (16.25%), Colorectal carcinoma 6 cases (7.5%), Multiple myeloma 7 cases (8.75%), Cervical carcinoma 1 case (1.25%) and other malignancies 9 cases (11.25%). Manual counting of absolute neutrophil count was done, while the CD4 lymphocyte count was done using the Partec Cyflow ® 2000 CD4 cell counter.Some other haematological indices; packed cell volume, blood haemoglobin concentration, white blood cell count and platelet count were also determined. The socio -demographic data of the patients were assessed from a questionnaire. There were 27 males (33.75%) and 53 females (66.25%). The age of the patients ranged from 18 to 80 years with a median of 45 years. The mean absolute neutrophil count of the respondents pre- and post-chemotherapy was 3.7 ± 2.1 x
/L and 2.5 ± 1.6 x 10
/L respectively. The mean CD4 lymphocyte count pre-
and post-chemotherapy was observed to be 593.98 ± 357.13 cells/L and 411.63 ± 223.88 cells/L respectively. There were significant differences in both the absolute neutrophil count (p= 0.00) and CD4 lymphocyte counts (p=0.00) after chemotherapy compared to the pre-chemotherapy values. Chemotherapeutic combinations containing Cyclophosphamide and Adriamycin were observed to cause significant reduction in absolute neutrophil and CD4 lymphocyte counts. Haematological parameters which were found to be significantly reduced include; haemoglobin concentration, packed cell volume and white cell count.
CHAPTER ONE
INTRODUCTION
Malignancies as well as cytotoxic chemotherapy are associated with an increased risk of immunosuppression and occurrence of infections. The tendency and severity increase with higher dosage and longer duration of chemotherapy
. Many factors increase the susceptibility of immunosuppressed cancer patients to infection 1,2 . It is a known fact that most anti-cancer drugs induce myelosuppression and that this in effect leads to depletion of both cellular and humoral immune system. Destruction of all the rapidly proliferating cells also occurs with consequent break down of mucosal barriers further predisposing to infections
. The development of lymphoid and myeloid lineages from primordial stem cells in the fetal liver, spleen and bone marrow is guided by interactions with stromal cell (such as fibroblasts) and by cytokines (including stem-cell factor and various colony-stimulating factors)
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. Activation of T cells occur after recognition of specific antigens via cell surface receptors and results in replication and or mediation of one of three functions; cytotoxicity, by direct killing of specific target cells; helper function, by stimulating the immune response of other cells; and suppressor function, by inhibiting the immune response of other cell 4,5 . The cytotoxic and suppressor functions are mediated by cells that express the CD8 (T8) surface antigen, whereas the helper functions are mediated by a subset of T cells that express the CD4 (T4) surface antigen. CD4 T cells are mainly cytokine secreting cells. They can be subdivided into two major types- Type 1 (Th1) Helper cells secrete interleukin – 2, and interferon γ and Type 2 (Th2) Helper cells secrete interleukin – 4, 5, 6 and 10 4,5 . However T lymphocytes have an impact on practically all aspects of the immune system as a consequence of their ability to induce specific immune response in other cells 1, 4, 5 .
Lymphopaenia in general and
CD4 lymphocyte depletion also occurs alongside neutropenia in cancer patients, and have been noted in some studies as a predictor of early death in patients on chemotherapy
. Neutropenia remains the most common predisposing factor to infections in cancer patients 1, 2, 6 . The relationship between neutropenia and infection has been studied most extensively in patients with acute leukaemia and both the duration and degree of neutropenia influence the development of infection. The accepted definition of neutropenia is an absolute neutrophil count < 1.5 x 10
/L
, though in our environment with observed lower absolute neutrophil counts, a value of 1.2 x
/L may be considered, being the lower limit of our reference range 7,8,9,10 . Patients with adequate levels of neutrophils may still be susceptible to infection, due to impaired function secondary to either disease or chemotherapy. Inadequate neutrophil function has been described in patients with acute and chronic leukaemia as well as in Hodgkin’s Lymphoma 1, 2, 6,11 . Anti-tumour chemotherapeutic agents predispose to the development of infections in a variety of ways. Some of these agents are myelosuppressive and produce neutropenia which is a well recognized risk factor for infection. They are also known to interfere with cell-mediated and humoral immunity even when administered in doses that do not generally produce significant myelosuppression. 1,2,6,10 Some newer anti-tumour drugs such as fludarabine have profound deleterious effects on multiple components of host defenses, some of which may persist for more than a year after cessation of therapy
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. Other factors contributing to immunosuppression in cancer patients include local factors such as tumour metastases, which may cause obstruction and operative procedures such as gastrostomy which result in disruption of normal
anatomic barriers
. Damage to mucosal surfaces (particularly the gastro-intestinal mucosa) occurs frequently as a result of anti-neoplastic chemotherapy and provides a portal of entry for infecting organisms
. Radiotherapy, amongst other things results in depletion of cell mediated immunity, which can last for several months. In patients who have undergone splenectomy, antibody production and opsonization are defective thereby further predisposing these patients to infection
. Surgically implanted central venous catheter used often in the management of cancer patients, for frequent vascular access may also become portals of infection 1,6 . The occurrence of immunosuppression and thus infection in cancer patients present additional challenges in management and care of these patients. Standard chemotherapy regimen may need to be altered in dosage or duration to avoid deleterious outcomes. Prophylactic or therapeutic antibiotic regimen may be needed in addition to antifungal and antiviral agents. It is therefore imperative to assess the immune status of every individual before and during each course of chemotherapy. This would detect and avoid severe depletion of the cells of the immune system. Evaluation of the best method of assessing immune status using available and affordable investigations is necessary in discerning which patients will be more predisposed to chemotherapy-induced immune suppression. Despite several studies on neutrophil count and infection in cancer patients subjected to chemotherapy 2,6,11 , most centers have not compared absolute neutrophil count to CD4 + ve lymphocyte count in these patients. This study therefore aims to examine the changes that occur in absolute neutrophil and CD4 +ve lymphocyte count in cancer patients due to disease and or due to chemotherapy. It will also try to compare the changes in these parameters for the
different types of cancers as well as various chemotherapeutic regimens, and possibly detect the most immunotoxic combinations.
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