hml 308 cancer 2

BACTERIA AS A CAUSE OF CANCER:Bacterial infections traditionally have not been considered major causes of cancer. Recently, however, bacteria have been linked to cancer by two mechanisms: induction of chronic inflammation and production of carcinogenic bacterial metabolites. The most specific example of the inflammatory mechanism of carcinogenesis is Helicobacter pylori infection. H. pylori has been epidemiologically linked to adenocarcinoma of the distal stomach by its propensity to cause lifelong inflammation. This inflammation is in turn thought to cause cancer by inducing cell proliferation and production of mutagenic free radicals and N-nitroso compounds. H. pylori is the first bacterium to be termed a definite cause of cancer in humans by the International Agency for Research on Cancer. Mutagenic bacterial metabolites are also suspected to increase risk for cancer. This model is best exemplified in colon cancer. Bile salt metabolites increase colonic cell proliferation. Exogenous compounds such as rutin may be metabolized into mutagens by resident colonic flora. Moreover, Bacteroides species can produce fecapentaenes, potent in vitro mutagens, in relatively high concentrations. In vivo data on human carcinogenesis by bacterial metabolites, however, are inconsistent. Local bacterial infections may also predispose to nonnodal lymphomas, although the mechanisms for this are unknown. Gastric lymphomas and immunoproliferative small intestinal disease have been most strongly linked to underlying bacterial infection. Because bacterial infections can be cured with antibiotics, identification of bacterial causes of malignancy could have important implications for cancer prevention. C. pneumoniae infection has been found to cause to lung cancer. One meta-analysis of serological data comparing prior C. pneumoniae infection in patients with and without lung cancer found results suggesting prior infection was associated with a slightly increased risk of developing lung cancer. Mycoplasma species also have been found to cause cancer.

BACTERIAL INFECTIONS IN CANCER PATIENTS: Hodgkin lymphoma is a potentially curable lymphoma. There are five types of Hodgkin lymphoma classified by the World Health Organization: nodular sclerosing, mixed cellularity, lymphocyte depleted, lymphocyte rich, and nodular lymphocyte-predominant. Formally known as Hodgkin disease, Hodgkin lymphoma (HL) is a highly curable malignancy. It is a unique neoplasm in which the malignant cell, the Reed-Stenberg cell (RSC), represents only a small proportion of cells constituting the bulk of the tumor. It also has very particular clinical characteristics and distinct biological behavior. Hodgkin lymphoma is a rather rare malignancy in the pediatric population, however, it constitutes approximately 40% of all lymphomas that present during childhood and is the most common malignancy in adolescents and young adults. In all age groups, Hodgkin lymphoma is highly sensitive to chemotherapy and irradiation. In fact, Hodgkin lymphoma was the first cancer to be cured with radiation therapy alone or with a combination of several chemotherapeutic agents

Non-Hodgkin lymphomas (NHLs) are tumors originating from lymphoid tissues, mainly of lymph nodes. These tumors may result from chromosomal translocations, infections, environmental factors, immunodeficiency states, and chronic inflammation. Diffuse large cell lymphoma is the most common lymphoma, representing 31% of the non-Hodgkin lymphomas (NHLs), and it is rapidly fatal if untreated. Treatment recommendations and prognosis vary with different subtypes of the disease. Burkitt lymphoma, or small noncleaved cell lymphoma, is a highly aggressive B-cell non-Hodgkin lymphoma characterized by the translocation and deregulation of thec-myc gene on chromosome 8. Burkitt-like lymphoma (BLL) is considered to be a morphologic variant of Burkitt lymphoma. Follicular lymphoma is a type of non-Hodgkin lymphoma that most commonly presents as a painless, slowly progressive adenopathy. Systemic symptoms, such as fever, night sweats, weight loss in excess of 10%, or asthenia, are infrequent at presentation but can be observed in later stages of the disease. Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can also be observed in the later stages of the disease.

BSc. Medical Lab Sciences Year II I Semester II KU-Main Campus

Lecturer: Shem Peter Mutua Mutuiri. [email protected]

https://en.wikipedia.org/wiki/Serological

https://en.wikipedia.org/wiki/Meta-analysis

https://en.wikipedia.org/wiki/Lung_cancer

Patients with underlying malignancies are at risk for a wide array of infectious diseases that cause significant morbidity and mortality. To develop a clear etiologic understanding of the infectious agents encountered first requires knowledge of the host- and treatment-associated factors that predispose to infection. The astute clinician must also be aware of new and emerging infections in this patient population. As new pathogens are discovered and established pathogens become increasingly drug resistant, they will continue to present challenges for physicians caring for these patients in the years ahead.

Infections are major causes of morbidity and mortality in patients with cancer. Although certain cancers are intrinsically associated with immunocompromise, the risk of infection is principally related to the intensity and duration of cytotoxic and immunosuppressive chemotherapy. A patient may have multiple predisposing factors that increase the spectrum of likely pathogens. We have reviewed the major categories of immunologic deficits in persons with cancer and the clinical manifestations of the major pathogens to which they are susceptible. Diagnostic evaluation and management of infections are also discussed.

Certain malignancies are inherently associated with immune deficits. For example, patients with chronic lymphocytic leukemia frequently have hypogammaglobulinemia leading to increased susceptibility to encapsulated bacteria, principally Streptococcus pneumoniae. Such patients may have recurrent sinopulmonary infections and bacteremia. Patients with multiple myeloma also are often functionally hypogammaglobulinemic. A biphasic pattern of infection has been observed. Infections caused by S pneumoniae and Haemophilus influenzae occur early in the disease process and in patients responding to chemotherapy, and infections caused by Staphylococcus aureus and Gram-negative pathogens more commonly occur in advanced disease and during neutropenia.

Factors that predispose to infection are divided into those that are host associated and those that are treatment associated. Host-associated factors include underlying immune deficiencies, medical comorbidities, past infections, poor nutritional status, and psychological stress. Treatment-associated factors include surgery, radiation, immunosuppressant therapies, antimicrobial use, and invasive procedures. Again, clinicians should be aware that in practice, multiple deficiencies are usually encountered simultaneously.

Neutropenia

Neutropenia remains the most common predisposing factor for infection in cancer patients. The relationship between neutropenia and infection has been studied most extensively in patients with acute leukemia. 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.

Patients undergoing initial remission induction 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. 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. 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. New strategies for predicting the degree and duration of neutropenia are being developed. 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. 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. 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

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. 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. BSc. Medical Lab Sciences Year II I Semester II KU-Main Campus


Fungal infections caused by Candida spp andAspergillus 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. 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. 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.

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. 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. The infections commonly seen in such patients are caused by S. pneumoniae, H. influenzae, Neisseria meningitidis, Babesia spp, andCapnocytophaga spp. These infections can be BSc. Medical Lab Sciences Year II I Semester II KU-Main Campus


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.

Treatment-Associated Factors:

Although essential to patient care, no procedure or treatment is without risk. The following treatment-associated factors have all been shown to predispose patients with underlying malignancies to an increased risk of infection.

Surgery

Extensive surgery, especially in the maxillofacial, gastrointestinal, or pelvic regions, increases the risk of infection in cancer patients. Although extensive procedures are often necessary, especially for advanced invasive tumors, they remove large areas of otherwise protective tissue and disrupt anatomical barriers that predispose to leakage of material already containing bacterial flora. The infectious complications following surgery vary depending on the site and extent of the operation and the type of procedure performed; even so, postoperative infections have been shown in one series to be twice as common in cancer versus non-cancer patients. Intra-abdominal procedures such as Hartmann’s operation, which involves sigmoid resection with a diverting colostomy, are frequently complicated by infection in patients with underlying malignancies. Likewise, cancer patients undergoing craniotomy who have previously had a ventriculoatrial shunt placed are at increased risk of meningitis and/or sepsis. Extensive surgery of the paranasal sinuses has also been shown to predispose to Pseudomonas meningitis in these patients. Postoperative cellulitis is frequently reported after breast cancer surgery. The extent of the operation plays a major role in determining infection. As expected, the largest interventions are associated with the maximum risk. Other factors such as obesity and diabetes can also increase the infectious risk in these patients as previously described. Reduced infection rates may be associated with recent advances in minimally invasive surgery and, as previously stated, in patients who receive preoperative immunonutrition.

Radiation Therapy

In addition to surgery, preoperative irradiation increases the risk of infection. In one series, preoperative irradiation given to patients undergoing surgery for breast cancer was associated with a twofold increase in infectious complications. However, postoperative irradiation was not associated with an increased risk. Infection is also the most common complication in patients who receive preoperative irradiation prior to oncologic surgery of the upper respiratory or gastrointestinal tract. This is predominantly due to fistula formation or impaired wound healing and has been well described in patients receiving radiation therapy for rectal cancer. In addition to causing local tissue damage, radiation can result in stenosing lesions, leading to obstruction. Opportunistic infections such as P. jirovecii, Aspergillus terreus, and CMV have been reported following the use of radiation in combination with temozolomide, an alkylating agent, in the treatment for glioblastoma. Radiation of the spleen or lymph nodes can depress cell-mediated immunity and antibody production. Radiation reactions such as radiation enhancement and radiation recall predispose to infection due to local tissue inflammation and breakdown.

Immunosuppressant Therapies:

ChemotherapyBSc. Medical Lab Sciences Year II I Semester II KU-Main Campus


Chemotherapeutic agents predispose to infection in a variety of ways. Many of these agents damage the body’s anatomical barriers. Most notably, they can cause ulceration of the gastrointestinal tract, allowing for erosion and invasion by endogenous microorganisms. Other agents such as bleomycin and methotrexate are associated with skin lesions that can predispose to bacteremia with staphylococci and other skin flora. Agents such as BCNU, Ara-C, and daunorubicin irritate veins, increasing the risk of phlebitis and subsequent bacteremia. Many chemotherapeutic agents cause bone marrow suppression and neutropenia in a doserelated fashion. Some of these drugs can also inhibit neutrophilic migration and chemotaxis. Regimens that include corticosteroids inhibit the bactericidal activity of neutrophils. Humoral immunity is altered by agents such as methotrexate, cyclophosphamide, and 6-mercaptopurine. Deferoxamine, an iron-chelating agent, is associated with increases in bacterial infections and zygomycosis, most likely due to the increased availability of free iron necessary for fungal growth

Biological Response Modifiers

Biological response modifiers (BRMs) are naturally occurring substances often used in conjunction with chemotherapeutic agents that help boost, direct, or restore the body’s immune response to cancer cells. They include interferons, interleukins, hematopoietic growth factors, monoclonal antibodies, components of vaccines and gene therapy, and non-specific immunomodulating agents such as bacillus Calmette– Guerin, used in the treatment for bladder cancer, and levamisole, sometimes used in combination to treat colon cancer. The immunotherapeutic actions of BRMs can be passive or active. The effects of monoclonal antibodies are passive in that they are targeted to antigens or receptor sites on cancer cell surfaces. When the antibody binds to the target, a cascade of events leads to tumor cell death, usually without invoking an immune response. Conversely, other BRMs work by actively evoking either a non-specific immune response to cancer cells as with interferons and interleukins or a specific immune response as with cancer vaccines. Clinicians should be aware that adverse effects of BRMs, especially monoclonal antibodies, interleukins and interferons, can mimic infection as they can precipitate a flu-like reaction with fever, chills, headache, myalgias, and arthralgias. Prolonged symptoms, however, should prompt an evaluation for infection. Monoclonal antibodies such as alemtuzumab, rituximab, and trastuzumab may cause myelosuppression, and, in the case of alemtuzumab, profound and persistent lymphopenia, predisposing to viral and fungal infections.

Antimicrobial Use

A patient’s intact normal flora protects the surfaces of the skin and mucous membranes by competing with non-indigenous organisms for binding sites and by producing substances that inhibit or kill these microorganisms. The use of antimicrobial agents can radically alter host flora, predisposing to infection.



REFERENCES:

1. Inagaki J, Rodriguez V, Bodey GP (1974) Proceedings: causes of death in cancer patients. Cancer 33(2):568–573

2. Viscoli C, Castagnola E (1995) Factors predisposing cancer patients to infection. In: Klastersky K (ed) Infectious complications of cancer. Kluwer Academic, Boston, pp 1–30

3. Freifeld AG, Kaul DR (2008) Infection in the patient with cancer, in Abeloff’s clinical oncology. In: Abeloff MD et al (eds) Churchill Livingstone, Philadelphia, pp 717–738

4. Viscoli C, Castagnola E (2009) Prophylaxis and empirical therapy of infection in cancer patients. In: Mandell GL, Bennett JE, Dolin R (eds) Mandell, Doublas, and Bennett’s principle and practice of infectious diseases. Churchill Livingstone, Philadelphia, pp 3793-3808



hml 308 cancer 2

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