Neutropenia

Neutropenia remains the most common predisposing factor for infection in cancer patients.⁹ The relationship between neutropenia and infection has been studied most extensively in patients with acute leukemia.¹⁰ Both the degree and the duration of neutropenia influence the development of infection. The currently accepted definition of neutropenia is an absolute neutrophil count of ≤ 500/mm³. Most serious infections, including bacteremias, develop during episodes of severe and prolonged neutropenia, and virtually every patient whose neutrophil count is less than 100/mL for 3 weeks or more will develop an infection, indicating a direct relationship between the risk of infection and the duration of neutropenia (Figure 160-1).

Figure 160-1

Relations between granulocyte count and infection in patients with acute leukemia. Percentage of days spent with infection is inversely related to the level of circulating granulocytes.

Patients undergoing initial remissioninduction therapy for acute leukemia are at great risk for developing infections associated with neutropenia because the duration of neutropenia in such patients is generally 21 to 25 days, with approximately 12 to 15 days at levels below 100/mL. Also, patients undergoing bone marrow or hematopoietic stem cell transplantation have essentially no circulating neutrophils for a period of 3 weeks following transplantation and are at great risk of developing infections until engraftment occurs and the neutrophil count begins to rise. For the majority of solid tumors, therapy usually results in shorter periods of less-severe neutropenia. However, some solid tumors, such as testicular carcinoma, small-cell carcinoma of the lung, and some lymphomas and sarcomas, are being treated with increasingly intensive chemotherapeutic regimens, which produce significant periods of severe neutropenia.

Neutropenic patients often fail to develop the characteristic signs and symptoms of infection, since they are unable to mount an adequate inflammatory response.¹¹ For example, purulent sputum was produced by only 8% of patients with severe neutropenia (less than 100/mL) who developed pneumonia, as compared with 84% of patients with adequate neutrophils (> 1,000/mL). Likewise, only 11% of the former had pyuria during episodes of urinary tract infection, as compared with 97% of the latter. Inflammatory exudates in neutropenic patients may be devoid of neutrophils and may contain only a few lymphocytes and macrophages. Neutropenic patients who develop pneumonia may not have pulmonary infiltrates on chest radiographs or may fail to demonstrate meningismus when they develop meningitis.

Infection can disseminate widely and rapidly in patients with severe neutropenia. Nearly all episodes of bacteremia and disseminated fungal infection complicating neoplastic diseases arise in patients with neutrophil counts of less than 100/mL. An autopsy study of pneumonia in 40 children who died of cancer illustrates the relationship between neutropenia and the development of bacteremia. None of the children with neutrophil counts above 1,000/mL developed bacteremia in association with pneumonia, as compared with 64% of children with less than 1,000 neutrophils/mL and 80% of children with 100 neutrophils/mL or less.

The most common sites of infection in neutropenic patients include the lung, oropharynx, blood, urinary tract, skin, and soft tissues, including the perirectal area. Infections are generally caused by organisms already colonizing the patient, although some of these organisms are acquired after admission to the hospital. These hospital-acquired pathogens are more likely to be resistant to commonly used antimicrobial agents because of the pressure of heavy antibiotic usage.

Patients with adequate levels of circulating neutrophils may be susceptible to infection because of impaired neutrophil function secondary to their disease or its therapy. Inadequate neutrophil function has been described in patients with acute and chronic leukemia and Hodgkin disease. Defects include the inability to migrate to sites of inflammation, impaired phagocytosis, and reduced killing of ingested bacteria. The frequency of infection in acute leukemia is higher among patients whose neutrophils have reduced bactericidal capacity in vitro than among patients whose neutrophils function normally.

Not all neutropenic patients have the same risk for developing infection or for developing complications when they do become febrile. It is now possible to recognize high-, moderate-, and low-risk neutropenic patients by using clinical criteria during the initial phases of their febrile episode.^12,13 Many patients with solid tumors that are responding to antineoplastic therapy and in whom neutropenia is relatively short-lived (≤ 7 days) are considered low risk when they develop their febrile episode while receiving chemotherapy without being hospitalized, particularly if they are hemodynamically stable and do not have comorbidity factors, such as thrombocytopenia with clinical blending, respiratory insufficiency, hypertension, congestive heart failure, hypercalcemia, or central nervous system involvement. These patients have a high response rate (> 95%) to antibacterial therapy and a low complication rate (< 2%). Newer strategies for their management, such as early discharge from hospital and outpatient oral antibiotic therapy, have been developed.^14–16 New strategies for predicting the degree and duration of neutropenia are being developed.¹⁷ These will enhance our ability to differentiate high-risk from low-risk patients.

Cellular Immune Dysfunction

Those aspects of the immune response that are regulated by T lymphocytes or mononuclear phagocytes are collectively referred to as cell-mediated immunity. Activation of T cells occurs 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 responses of other cells; and suppressor function, by inhibiting the immune responses of other cells. 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.¹⁸ The mononuclear phagocyte system includes bone marrow precursors (promonocytes) and their end products, the circulating monocytes, and macrophages. The growth and maturation of promonocytes in the bone marrow is governed by specific colony-stimulating factors (CSFs). Monocytes are released into blood within 24 h of maturation and migrate into tissues after circulating in the blood for 1 to 4 days. In the tissues, they differentiate into macrophages and persist primarily in the spleen, liver, lungs, and connective tissue. Their activation is dependent upon T4 helper cell-derived lymphokines.

Defects in the T lymphocyte and/or mononuclear phagocytic system result in an increased susceptibility to infection. Cell-mediated immunity plays a primary role in protecting against intracellular pathogens.¹⁹ However, T4 lymphocytes have an impact on practically all aspects of immunity as a consequence of their ability to induce specific immune responses in other cells. Thus, the functions of B lymphocytes, which are primarily involved with maintaining humoral immunity, and granulocytes, which engulf and kill microorganisms, are regulated by T4 helper cells.

T-lymphocyte function is impaired in a variety of disorders. The human immunodeficiency virus (HIV) selectively ablates the T4 cell, which results in severe immune deficiency. Patients with Hodgkin disease also have evidence of impaired cell-mediated immunity, and, to a lesser degree, so do patients with chronic and acute lymphocytic leukemia. Defects in the mononuclear phagocytic system have been described in patients with monocytic leukemia. Immunosuppressive therapy with agents such as cyclosporine, tacrolimus azathioprine, corticosteroids, certain cytotoxic agents (fludarabine), and irradiation produces dysfunction in cellular immunity. These patients are especially susceptible to infection with intracellular organisms such as those listed in Table 160-2.

Table 160-2

Common Infectious Agents in Patients with Cancer.

Humoral Immune Dysfunction

The immune response that is mediated by antibodies, which are immunoglobulins with a binding specificity for microbial antigens, is referred to as humoral immunity. B lymphocytes are responsible for antibody production. Activation of B lymphocytes occurs in response to stimulation by specific antigens. This is followed by a proliferative phase and differentiation of activated cells into nondividing plasma cells that produce large quantities of immunoglobulins. Immunoglobulins promote phagocytosis and destruction of microorganisms by various mechanisms, such as opsonization of organisms for destruction by phagocytic cells, neutralization of toxins, and lysis of susceptible organisms.²⁰ Immunoglobulins also have the capacity to block the adherence of certain bacteria to mucosal surfaces, thereby reducing the potential of such organisms to produce disease.

In disorders such as multiple myeloma, Waldenström macroglobulinemia, and the various “heavy-chain diseases,” overproduction of a specific subcomponent of an immunoglobulin occurs as a consequence of malignant proliferation of plasma cells or their precursors. As this pool of malignant plasma cells expands, it does so at the expense of normal cells, resulting in low levels of normal immunoglobulins. Hypogammaglobulinemia is also present in 30% to 40% of patients with chronic lymphocytic leukemia, and infection occurs in nearly 90% of these patients, as compared with only 15% in patients with normal gamma-globulin levels. Infection is the cause of death in approximately 60% of patients with multiple myeloma. Patients with multiple myeloma and chronic lymphocytic leukemia are especially susceptible to infections caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae because specific opsonizing antibodies that play a major role in the defense against such pathogens are greatly reduced. Infections caused by gram-negative bacilli are also frequent in these patients because they develop chemotherapy-induced neutropenia.

Bone Marrow Transplantation

Infection is one of the major complications associated with bone marrow and/or hematopoietic stem cell transplantation. During the initial period of neutropenia, which lasts from approximately 1 week before infusion to about 3 weeks after transplantation, patients are at risk of developing bacterial infections. Fungal infections caused by Candida spp and Aspergillus spp also occur during this period. The risk of these infections decreases after recovery of the neutrophil count, but neutrophil and macrophage function remain abnormal. Patients undergoing allogeneic transplantation also have suppressed cell-mediated immunity. As a consequence, infections with herpes viruses (herpes simplex virus [HSV], varicella-zoster virus [VZV], cytomegalovirus [CMV], Epstein-Barr virus [EBV], respiratory syncytial virus [RSV], and adenoviruses), protozoan organisms (such as Pneumocystis carinii and Toxoplasma gondii), bacteria (such as Legionella spp, and S. pneumoniae) and mold infections (aspergillosis) are common. These infections generally occur after the initial period of neutropenia has elapsed, and patients remain at risk until the regenerating immune system matures and restores normal immunity. This depends a great deal on whether or not graftversus-host disease (GVHD) can be prevented or controlled. Multiple (polymicrobial) infections are not uncommon in this setting.

Local Factors

Local factors, such as tumor metastases, that produce obstruction and operative procedures that result in disruption of normal anatomic barriers play an important role in infections occurring in cancer patients. In an autopsy study of children with metastatic carcinoma, 80% of the cases of pneumonia were associated with pulmonary metastases, aspiration, or tracheostomy. Pneumonia and pulmonary abscesses frequently develop distal to tumors, causing obstruction of major bronchi, and these infections respond poorly to antibiotic therapy, unless adequate drainage is established. Obstruction of the biliary tract secondary to cancer can result in ascending cholangitis, especially in patients with T-tube drainage.²¹ Likewise, urinary tract infections are common in patients with tumors, such as bladder or prostatic carcinoma, that obstruct a ureter or the bladder neck causing retention of residual urine. Hydronephrosis, pyonephrosis, chronic pyelonephritis, and cystitis are not uncommon complications in patients with cancer of the genitourinary tract (Table 160-3). In these situations, the infection is generally caused by one or more of the microorganisms colonizing the site of obstruction. Antibiotics seldom eradicate these infections in the presence of persistent structural abnormalities but do ameliorate the systemic symptoms of acute infection.

Table 160-3

Common Infections in Solid Tumor Patients.

Damage to mucosal surfaces (particularly the gastrointestinal mucosa) occurs frequently as a result of antineoplastic chemotherapy and provides a portal of entry for infecting organisms. Radiation therapy results in depression of cell-mediated immunity, which can last for several months. Radiation also causes local tissue damage, which can predispose to secondary infection. Foreign bodies, such as urinary and venous catheters, also damage or circumvent normal anatomic barriers, thereby facilitating entry of microorganisms into tissues and the bloodstream.

Intravascular Devices

Surgically implanted central venous catheters are used extensively in patients who require frequent vascular access. These catheters (Hickman, Broviac, and long lines) can have up to three lumens, greatly facilitate a variety of functions, including the drawing of blood, and may remain in the same location for prolonged periods, ranging from several weeks to months. Three separate types of device-related infection have been described: infection of the entry site, tunnel infection, and catheter-related bacteremia or fungemia.²² Gram-positive organisms cause these infections most often, but gram-negative bacilli are not infrequent. Fungemia is most often caused by Candida spp. Localized Aspergillus infection has also been described. Infections of shunts, stents, and prosthetic devices are also common.

Splenectomy

Patients who have undergone splenectomy, such as those with Hodgkin disease, are at greater risk of developing infections than are patients with intact spleens because the spleen performs several important host defense functions, including antibody production and the removal of poorly opsonized or unopsonized pathogens.²³ The infections commonly seen in such patients are caused by S. pneumoniae, H. influenzae, Neisseria meningitidis, Babesia spp, and Capnocytophaga spp. These infections can be extremely severe. The syndrome of overwhelming pneumococcal sepsis, for example, is much more common in splenectomized individuals and can be rapidly fatal. The emergence of penicillin-resistant pneumococci made this infection an even more serious problem. The newer fluoroquinolones might have a role instead of penicillin, for chemoprohylaxis. Patients should be given the pneumococcal polyvalent capsular polysaccharide vaccine prior to splenectomy and every 3 years thereafter. Vaccination with H. influenzae type B conjugated polysaccharide vaccine and yearly influenza vaccination are also recommended. Quadrivalent meningococcal vaccination should only be administered during an epidemic of meningococcal infection.

Chemotherapeutic Agents

Chemotherapeutic agents predispose to the development of infections in a variety of ways. Many agents produce severe mucositis, particularly of the gastrointestinal tract, facilitating entry of microorganisms into tissues and the bloodstream.²⁴ Agents that are myelosuppressive produce neutropenia, which is a well-recognized risk factor for infection. Chemotherapeutic agents are also known to interfere with cell-mediated and humoral immunity even when administered in doses that do not generally produce significant myelosuppression. Some of the newer antitumor agents such as fludarabine, have profound effects on multiple components of host defenses, some of which may persist for more than a year after cessation of therapy.