(1)
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chapter Overview
Patients with cancer frequently develop immunologic impairment as a result of the underlying malignancy and its treatment. Each immunologic deficit is associated with a specific spectrum of infection, although there is some overlap. Multiple risk factors may be present in the same patient, increasing the risk of and widening the spectrum of infection. Some nonimmunologic factors also play a role in the predisposition to infection. Increased survival durations among patients with solid tumors and hematologic malignancies and those who have undergone hematopoietic stem cell transplantation have resulted in a growing population of patients who remain at risk for the development of serious infections for sustained periods of time. This chapter discusses the immunologic defects commonly encountered in subgroups of cancer patients, focusing on the risk factors, infectious complications, and other features unique to each subgroup. A brief discussion of immune reconstitution in hematopoietic stem cell transplantation recipients is included. The stem cell transplantation specialists at MD Anderson perform more hematopoietic stem cell transplantations than at any other institution in the United States. Finally, the chapter concludes with a brief discussion of antimicrobial stewardship, which has become an important and (in the opinion of the author) mandatory strategy in the overall management of infection in cancer patients, particularly long-term survivors.
Introduction
Infection is a common problem in patients with cancer, both during active treatment and in the survivorship phase. Patients develop significant impairment of host defenses as a result of either the underlying disease or its treatment. Host defense mechanisms can be immunologic or nonimmunologic. Immunologic host defenses, which respond to specific microbial antigens, include phagocytosis (carried out primarily by polymorphonuclear leukocytes and cells of the monocyte-macrophage lineage), cell-mediated immunity (primarily a function of T-cells), humoral immunity and antibody production (primarily a function of B-cells), and the complement system. Nonimmunologic host defenses include anatomic barriers such as the skin and mucous membranes, gastric acid, epithelial ciliary function, tears, and even intestinal peristalsis. This chapter will focus primarily on immunologic host defenses and the infectious complications associated with them.
Neutropenia
Neutropenia, defined as an absolute neutrophil count of ≤500/mm2, is the most common predisposing factor for infections (Rolston and Bodey 2010). Both the degree and the duration of neutropenia influence the development of infection. Bacterial infections are common during the initial phase of neutropenia, and fungal infections are encountered more frequently as neutropenia persists. Fever is the most common, and sometimes the only, manifestation of infection in neutropenic patients. Some patients with adequate numbers of neutrophils may still be susceptible to infection owing to impaired neutrophil function (e.g., neutrophil migration, phagocytosis).
Impaired Cellular Immunity
Defects in the T lymphocyte or mononuclear phagocytic system also result in an increased susceptibility to infection. Cell-mediated immunity plays a primary role in protecting against intracellular pathogens. T-4 lymphocytes, however, can influence all aspects of immunity as a consequence of their ability to induce specific immune responses in other cells. T lymphocyte function is impaired in a variety of disorders, such as Hodgkin disease and chronic or acute lymphocytic leukemia. Immunosuppressive therapy with agents such as corticosteroids and tacrolimus and treatment with purine analogs such as fludarabine and clofarabine, monoclonal antibodies such as alemtuzumab or rituximab, and alkylating agents such as temozolomide also produce lymphocytopenia and prolonged suppression of lymphocyte function (Samonis and Kontoyiannis 2001; Su et al. 2004; Martin et al. 2006).
Impaired Humoral Immunity
The immune response mediated by antibodies is referred to as humoral immunity. B lymphocytes are responsible for antibody production. In disorders such as multiple myeloma, Waldenström macroglobulinemia, and the various “heavy chain diseases,” malignant proliferation of plasma cells or their precursors occurs at the expense of normal plasma cells, resulting in low levels of normal immunoglobulins (Karlsson et al. 2011). Hypogammaglobulinemia is also present in 30–40% of patients with chronic lymphocytic leukemia. Patients with impaired humoral immunity are particularly susceptible to infections caused by encapsulated organisms such as Streptococcus pneumoniae. Common infection-causing organisms associated with the various immunologic deficits are listed in Table 23.1.
Table 23.1
Common pathogens in patients with cancer
Neutropenia |
Gram-positive bacteria |
Coagulase-negative staphylococci |
Staphylococcus aureus (including MRSA) |
Viridans group streptococci |
Enterococcus species (including VRE) |
Beta-hemolytic streptococci |
Gram-negative bacteria |
Escherichia coli |
Klebsiella species |
Pseudomonas aeruginosa |
Stenotrophomonas maltophilia |
Fungi |
Candida species |
Aspergillus species |
Zygomycetes |
Fusarium species |
Cellular Immune Dysfunction |
Bacteria |
Listeria monocytogenes |
Rhodococcus species |
Salmonella species |
Mycobacteria |
Nocardia species |
Legionella species |
Fungi |
Aspergillus species |
Cryptococcus neoformans |
Histoplasma capsulatum |
Coccidioides immitis |
Pneumocystis jiroveci |
Helminths |
Strongyloides stercoralis |
Humoral Immune Dysfunction |
Streptococcus pneumoniae |
Haemophilus influenzae |
Patients with Hematologic Malignancies
The predominant risk factor for infection in patients with hematologic malignancies is neutropenia (Crawford et al. 2004). Severe and prolonged neutropenia (absolute neutrophil count ≤500/mm3 for >10 days) occurs when normal bone marrow is replaced by malignant cells and as a result of cytotoxic chemotherapy. Bacterial, fungal, and some viral infections are common in neutropenic patients (Table 23.1). Neutropenia, however, is not the only risk factor for infection in patients with hematologic malignancies. Impaired cell-mediated immunity occurs in patients with Hodgkin disease and those treated with corticosteroids. Immunosuppressive drugs such as purine analogs and monoclonal antibodies produce defects in cell-mediated immunity and humoral immunity, and the risk and spectrum of infection may resemble that observed in recipients of allogeneic stem cell transplantation. Additionally, patients with a hematologic malignancy requiring splenectomy develop prolonged impairment of antibody production.
Hematopoietic Stem Cell transplantation Recipients
Recipients of myeloablative hematopoietic stem cell transplantation experience profound and prolonged periods of pancytopenia and immunosuppression. Although the degree of myelosuppression is milder following nonmyeloablative regimens, the degree and duration of lymphodepletion and resultant immunosuppression tends to be similar. Following transplantation, neutrophil recovery occurs first, followed by monocyte, natural killer cell, platelet, and red cell recovery. B-cell recovery generally takes 6–12 months to occur, and patients remain at risk for infections caused by encapsulated bacteria during this time. Humoral immune competence following transplantation can be reliably assessed only by documenting adequate increases in specific antigens following vaccination or infection. T-cells are the last to recover, and their recovery is greatly affected by several factors, including graft-versus-host disease (GVHD), age, other comorbidities, and infectious exposure prior to transplantation. Full immune competence is defined as the ability to safely receive live vaccines. This occurs at approximately 24 months after transplantation in patients who do not have active GVHD and who are not receiving immunosuppressive therapy.
Patients receiving myeloablative preparatory regimens develop infections in three distinct phases (Mir and Battiwalla 2009). Phase I is the pre-engraftment phase, which generally lasts for 15–45 days after the transplantation. During this phase, severe neutropenia and breaches in the mucocutaneous barriers increase the risk for bacterial infections and infections caused by Candida species. As neutropenia persists, infections with Aspergillus species and other molds begin to emerge. Herpes simplex virus reactivation also occurs during this phase. Phase II is the postengraftment phase (30–100 days after the transplantation). During this phase, infections related to impaired cell-mediated immunity predominate. GVHD and immunosuppressive therapy can greatly increase the occurrence of infections during this phase. Infections with herpes viruses (especially cytomegalovirus), Pneumocystis jiroveci, and Aspergillus species are common during this phase. Phase III is the late phase (>100 after the transplantation). Patients with chronic GVHD and alternative donor transplantation recipients remain at risk for infection during this phase. Infections with cytomegalovirus, varicella zoster virus, and encapsulated bacteria, such as Streptococcus pneumoniae, are most common. A detailed description of the clinical features, diagnosis, treatment, and prevention of these various infections is beyond the scope of this chapter (Tomblyn et al. 2009; Freifeld et al. 2011).
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