Infectious Complications/Management

Jennifer M. Cuellar-Rodríguez

Juan C. Gea-Banacloche

Cancer patients have a significantly increased risk of infections (1,2). Risk factors for this increased susceptibility of infection are directly related to the underlying malignancy or to its treatment (Table 37.1) (3,4,5).

RISK FACTORS FOR INFECTIONS IN PATIENTS WITH CANCER

Intrinsic Host Factors

Underlying Malignancy

Some hematologic malignancies are associated with specific immune abnormalities that result in increased frequency of infections even in the absence of treatment (see Table 37.1). For instance, the rate of mycobacterial disease seems to be increased in hairy cell leukemia and Hodgkin’s lymphoma. Encapsulated bacterial infections are common in patients with multiple myeloma and chronic lymphocytic leukemia, due to impaired B-cell immunity. Few studies have looked at the incidence and type of infections in non-neutropenic patients with solid tumors. Some well-recognized risk factors are related to the anatomic location of the tumor, for example, head and neck tumors predispose to serious infections by oral flora and they also increase the risk of aspiration pneumonia. Endobronchial tumors may cause postobstructive pneumonia. Neoplasias of the biliary tract significantly increase the risk of cholangitis, colon cancer increases the risk of sepsis secondary to enteric organisms and of anorectal infections, etc. (6,7). There is also a specific association of colon cancer with bacteremia caused by streptococci, in particular Streptococcus gallolyticus (formerly Streptococcus bovis) and anaerobes like Clostridium septicum. Tumors of the genitourinary tract may predispose to pyelonephritis. Breast tumors increase the risk of mastitis and abscess formation, usually by Staphylococcus aureus. Corticosteroid-producing tumors and corticotrophin hormone-secreting tumors are associated with an increased risk of bacterial and opportunistic infections. Pneumocystis jiroveci (formerly Pneumocystis carinii) and Nocardia infections have been reported in patients with Cushing’s disease.

Other Intrinsic Host Factors

Functional asplenia is present after splenectomy and splenic irradiation and with chronic graft-versus-host disease (GVHD) (8). Functionally, asplenic patients are at risk for overwhelming sepsis by Streptococcus pneumoniae, but other pathogens include Haemophilus influenzae and Neisseria meningitidis. In asplenic patients with a history of exposure to dogs, Capnocytophaga canimorsus should be considered. Other pathogens of concern include Babesia that causes babesiosis, Plasmodium that causes malaria, and Salmonella species.

In addition to the above-mentioned risk factors, other risk factors of particular importance in advanced cancer patients include immobility and poor nutritional status.

Treatment-Related Factors

Neutropenia

Most infections in cancer arise from treatment-induced neutropenia. Lack of granulocytes facilitates bacterial and fungal infections and blunts the inflammatory response allowing infections to progress much faster. The risk of infection is proportional to the degree and duration of neutropenia. There are detailed guidelines for the use of antimicrobial agents in the setting of chemotherapy-induced neutropenic fever (see below) (9).

Mucositis

Chemotherapy and radiation therapy disrupt mucosal integrity. Mucosal linings constitute the first line of host defense against a variety of pathogens, both by providing a physical barrier and by secreting a variety of antimicrobial peptides, including lactoferrin, lysozyme, proteases, phospholipases, and defensins. Chronic GVHD may also compromise mucosal immunity, including defective salivary immunoglobulin secretion. Disruption of the epithelial lining may result in local disease and bloodstream infections by local flora (i.e., aerobic and anaerobic bacteria and yeast). Palifermin, a recombinant human keratinocyte growth factor, may result in decreased infections by reduction in severity of mucositis (10,11,12,13).

Hematopoietic Stem Cell Transplantation (HSCT)

Preparative regimens, GVHD, and GVHD prophylaxis and treatment in HSCT recipients are significant drivers of infection. There are detailed guidelines for the prevention and treatment of infections in this patient population (14).

Autologous stem cell transplant may be considered a form of intensive chemotherapy. As such, it is typically associated with a few days or weeks of neutropenia and mucositis, followed by a few weeks or months of defective T-cell-mediated immunity. Allogeneic transplant is a more complex procedure, and there are many variants (i.e., conditioning regimen, degree of human leukocyte antigen
matching, source of stem cells, and GVHD prophylaxis) that result in very different infectious disease risk profiles. Early after HSCT, neutropenia and mucositis are the main host defense defects. Following engraftment, the most important risk factor for infection is the occurrence of severe GVHD and its treatment. Active GVHD is associated with immune dysregulation, may be accompanied by cytomegalovirus (CMV) reactivation or disease, and it is also an independent risk factor for mold infection (15). CMV disease delays immune reconstitution and is associated with an increased risk of bacterial and fungal infections (16).

TABLE 37.1 Selected risk factors for infection in patients with advanced cancer

Risk Factor	Type of Infection
Related to Underlying Malignancy
AML	Bacterial, fungal, and viral
CLL/MM	Encapsulated bacteria
ALL	PCP
Hairy cell leukemia and Hodgkin’s lymphoma	Mycobacterial and viral
ATCL	PCP, Cryptococcus neoformans, viral, and Strongyloides stercoralis
Obstructive pathology from local growth of the tumor	Bacterial
Colon cancer	Enteric bacterial sepsis, in particular Streptococcus gallolyticus and Clostridium septicum
Corticosteroid-producing tumors	PCP and Nocardia sp.
Related to Treatment
Neutropenia	Bacterial (mainly gastrointestinal tract) and fungal
Mucositis	Oral flora, including gram-positive and anaerobic bacteria
Corticosteroid	PCP, bacterial, fungal, and herpes viruses
Nucleoside analogs	PCP, bacterial, fungal, and herpes viruses
Monoclonal Ab	Wide range of infections: bacterial, fungal, viral, parasitic-agent specific
GVHD prophylaxis/treatment	PCP, VZV
Miscellaneous
Immobility	Bacterial-usually related to decubitus ulcers and atelectasis
Nutritional status	Bacterial and yeast infections
Biliary stents, ureteral ostomy tubes, and tracheostomy	Bacterial and yeast
Peripherally inserted central or central venous catheters	Bacterial and yeast
AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; ALL, acute lymphocytic leukemia; PCP, pneumocystic jirovecii pneumonia; ATCL, adult T-cell leukemia/lymphoma; Ab, antibodies; GVHD, graft versus host disease; VZV, varicella zoster virus.

Defects in cell-mediated immunity persist for several months even in uncomplicated allogeneic HSCT, predisposing to opportunistic infections, including candidiasis, P. jiroveci, CMV, and herpes zoster (HZ). Repopulation of specific T-cell subsets occurs at different rates. In addition to low T-cell number, T-cell receptor diversity is reduced (17). In the absence of chronic GVHD, T-cell and B-cell functions are usually reconstituted by 1 to 2 years after engraftment. Chronic GVHD is associated with persistently depressed cell-mediated and humoral immunity.

Defective reconstitution of humoral immunity is a major factor contributing to increased infection susceptibility in the late transplant period. Invasive pneumococcal disease is relatively common, particularly in patients with chronic GVHD (18).

Immunomodulatory Agents and Infectious Risk

Corticosteroids

High-dose corticosteroids have profound effects on the distribution and function of neutrophils, monocytes, and lymphocytes. They blunt fever and local signs of infection. Patients treated with corticosteroids have impaired
phagocytic function and cell-mediated immunity. Infections are a frequent complication of corticosteroid use, and differences in the type and frequency of infections are dependent on the dose and duration of treatment (19). Bacterial infections are most common (20); but opportunistic fungal, viral, and mycobacterial infections are also seen, particularly with high doses and long durations of systemic corticosteroids.

Fludarabine

Fludarabine is a fluorinated analog of adenine that is lymphotoxic, primarily affecting CD4⁺ lymphocytes. Particularly when combined with corticosteroids or cyclophosphamide, fludarabine results in a profound depression of CD4⁺ cells that may persist for several months after completion of therapy, resulting in opportunistic infections like P. jiroveci pneumonia (PCP) or listeriosis, sometimes more than a year after treatment. Mycobacterial and herpes virus infections have also been described.

Interleukin-2

High-dose interleukin-2 (IL-2), sometimes used for metastatic melanoma, is a significant risk factor for bacterial infections, possibly due to a profound but reversible defect in neutrophil chemotaxis. S. aureus and coagulase-negative staphylococci are common pathogens, and prophylactic oxacillin can lead to a reduction in central venous catheter-associated staphylococcal bacteremia (21).

Alemtuzumab

Alemtuzumab (Campath-1H) is a humanized monoclonal antibody that targets CD52, a glycoprotein abundantly expressed on most B and T lymphocytes, macrophages, and natural killer cells. Alemtuzumab treatment results in prolonged and severe lymphopenia, and it can also cause neutropenia in up to one-third of patients. Infections, both opportunistic and non-opportunistic, have been reported in a significant fraction of patients receiving alemtuzumab (22). Bacterial, viral, fungal, mycobacterial, and P. jiroveci infections are observed. CMV reactivation is seen in up to two-thirds of alemtuzumab recipients, although CMV disease seems to be uncommon.

Rituximab

Rituximab is a chimeric human/murine monoclonal antibody directed against the B-cell marker CD20. The increased risk of infection with rituximab seems to be low and related to repeated administration (23) and host co-factors (e.g., advanced HIV disease, HSCT, and specific chemotherapeutic regimen) (24). Hepatitis B virus (HBV) reactivation occurs with rituximab treatment. There have been reports of fulminant hepatitis and even death in patients that experienced hepatitis B flare. Also a “reverse seroconversion” phenomenon has been described, with loss of protective HBV surface antibodies and reactivation (25,26). Rarely, rituximab treatment for malignant and non-malignant conditions can be complicated by progressive multifocal leukoencephalopathy, a chronic encephalitis caused by the John Cunningham (JC) virus (27). There have been several reports of PCP following rituximab, but most patients received other immunosuppressants. Other rare infections that have been described in the setting of rituximab use are enteroviral meningoencephalitis, CMV disease, disseminated varicella zoster virus, refractory babesiosis, parvovirus B19, and nocardiosis (24).

Immunosuppressive Agents for the Prevention and Treatment of GVHD

Immunosuppressive agents to prevent and treat GVHD all involve suppression of T-cell activation to inhibit donor alloreactive T-cell responses. The calcineurin inhibitors (cyclosporine A and tacrolimus), mycophenolate mofetil, sirolimus, and methotrexate are commonly used and are associated with an increased risk of common bacterial and opportunistic infections. Corticosteroids are the mainstay of therapy for GVHD. More intensive immunosuppressive therapy is used in steroid-refractory GVHD, resulting in very high risk for common and opportunistic bacterial, viral, and fungal diseases.

Lymphocyte-depleting antibodies cause severe suppression of cellular immunity. Visilizumab (a humanized anti-CD3 monoclonal antibody) is associated with a high frequency of Epstein-Barr virus reactivation and lymphoproliferative disease (28). Anti-cytokine antibodies include the IL-2 receptor antagonist, daclizumab, and tumor necrosis factor (TNF)-α inhibiting agents, infliximab, etanercept, and adalimumab. Daclizumab in steroid-refractory GVHD is associated with a significant risk of bacterial sepsis. TNF-α is a principal mediator of neutrophil and monocyte activation and inflammation. In patients with autoimmune diseases, agents that deplete TNF-α or inhibit TNF-α signaling are principally associated with an increased risk of tuberculosis and histoplasmosis. In HSCT recipients with refractory GVHD, infliximab was associated with an increased risk of invasive molds (29).

Additional Risk Factors for Infection in Advanced Cancer Patients

Although there are only scarce data on the risk factors for infection in advanced cancer patients that require palliative care (30,31,32), some recognized risk factors include long-term use of invasive devices such as peripherally inserted or central venous catheters, indwelling urinary catheters, ostomy tubes, biliary stents, and ureteral stents. Other risk factors include immobility, poor nutritional status, and palliative chemotherapy.

PREVENTION OF INFECTION

Preventing infections is preferable to treating them. In the case of cancer patients receiving palliative care, an acute infection may result in extreme loss of quality of life and in very difficult decisions regarding management, including the need to return to the hospital and the appropriateness of
invasive diagnostic procedures. In this regard, it may be reasonable to continue prophylactic measures that are adequate to the clinical condition (e.g., antibiotics during neutropenia and opportunistic infection prophylaxis in recipients of stem cell transplantation) and administer the immunizations recommended by the American College of Physicians (ACP) to both patients and caregivers (http://www.acponline.org/clinical_information/resources/adult_immunization/).

Regarding immunizations it is important to be aware that the inactivated influenza vaccine is relatively ineffective in the elderly and that the newer, apparently more effective inhaled form is not approved for use in people older than 50 and is contraindicated in patients with a history of reactive airway disease. The zoster vaccine is a higher dose of the attenuated VZV present in the chickenpox vaccine and should be avoided in immunocompromised patients. Both the ACP and the Centers for Disease Control (CDC) (http://www.cdc.gov/vaccines/) offer up to date recommendations and answer to both common and unusual questions.

SPECIAL CONSIDERATIONS FOR ADVANCED CANCER PATIENTS

There are limited data on the incidence of infections, their management, and their effects in advanced cancer patients (30,31,32). Most studies have focused on current practice relating to antibiotic use in terminal cancer (32,33,34,35,36,37,38,39). There are scarce data on the impact on the quality of life of patients who receive treatment of known or suspected infections.

In general, antibiotics are not perceived as aggressive treatment such as cardiopulmonary resuscitation and artificial nutrition. Their use and possible side effects are often trivialized, and therefore there appears to be no great ethical debate on their use or non-use in terminal care patients (39,40,41). However, treatment of infection may indeed be considered a life-sustaining therapy that can serve to prolong life without reversing the underlying medical condition, which at times conflicts with the goals and objectives of palliative care. On the other hand, treatment of defined infections can help control symptoms and in fact be an extremely important palliative intervention. However, it is possible that at some point an acute infection may be considered by the patient and the care providers as a merciful terminal event that should not be treated. In these cases, initiating or interrupting potentially life-prolonging treatment may present a true ethical dilemma (Fig. 37.1). Ideally, before deciding to treat an episode of infection, it is necessary to reassess the goals of treatment (i.e., palliation vs. curative intent), to determine the potential benefits and burdens of treatment, and to determine the availability of alternative and adjunctive treatments that can effectively palliate infection-related symptoms, such as morphine for shortness of breath and antipyretics for fever (42). Once specific antimicrobial treatment is instituted, it is recommended to frequently reassess the effectiveness of the intervention on the control of symptoms. Additionally, new symptoms may develop that may be directly related to the use of antimicrobials and therefore affect the overall quality of life.

Figure 37.1. A patient with terminal multiple myeloma developed sudden respiratory insufficiency while in the hospital. A computed tomography of the chest showed worsening pleural effusions and multiple pulmonary infiltrates. A bronchoscopy with bronchoalveloar lavage was performed and was initially non-diagnostic. The patient received oxygen, morphine, and corticosteroids and her respiratory distress improved. Seventeen days later the bronchoalveolar lavage culture was positive for Mycobacterium tuberculosis. Treatment for tuberculosis was recommended, but the patient and her family decided against it and she remained quarantined until she passed away 1 week later.

Currently there are no guidelines or clinical consensus on the treatment of infections in advanced cancer patients. There are no data on antimicrobial selection, efficacy, and safety profile in this susceptible population of patients, and most recommendations are based on extrapolations from other groups.

INCIDENCE AND TYPE OF INFECTIONS IN ADVANCED CANCER PATIENTS

The true incidence of infections in advanced cancer patients is difficult to discern, as many patients treated for suspected infections may not be infected. As an example, the rate of infection was as low as 29% in a study that required a positive culture for the definition of infection, but 83% in a retrospective review of infection based on a clinical diagnosis (30,32). The most common sites of infections are the urinary tract, respiratory tract, bloodstream, and skin and soft tissue. A descriptive review of published reports describing infections in 957 patients with advanced cancer in diverse settings such as palliative care unit, hospice, teaching hospital, hematology/oncology unit, and home found that 42% of terminally ill cancer patients developed infections in the final phase of their care (33). The overall frequencies of infection by organ system were as follows: urinary tract 30.5%, respiratory tract 17.9%, skin 15.7%, and blood 14.4%. The most frequent microbiologic isolates were S. aureus, Escherichia coli, and other Enterobacteriaceae and Pseudomonas aeruginosa. Candida species were the most commonly isolated fungal pathogen in the urinary tract (33).

CLINICAL EVALUATION

Typical signs and symptoms of infection may or may not be present. Fever, the cardinal sign of infection, may be nonspecific in this patient population, or suppressed by advanced age, malnutrition, comorbidities, or the use of corticosteroids. Conversely, fever may be caused by noninfectious processes, including the underlying malignancy, deep venous thrombosis, and drugs. Nonspecific signs of infection may predominate; these include decline in the functional status, confusion, and reduced oral intake. A thorough clinical examination will frequently obviate the need for extensive diagnostic workup.

DIAGNOSTIC TESTS

The use of diagnostic tests for patients with terminal cancer is controversial. A decision to pursue diagnostic workup is usually influenced by the setting in which the patients are been evaluated. Some centers will have limited diagnostic capabilities, as is the case of many palliative care units; however, advanced cancer patients are frequently hospitalized in acute care hospitals (43). A full summary of the diagnostic workup of each possible infection is beyond the scope of this chapter. However, given that the urinary tract, the respiratory tract, and blood are frequent sites of infection, the following initial workup seems reasonable, provided that the resources are available:

A complete blood cell count (CBC) and differential cell counts. The presence of an elevated white blood cell count or a left shift increases the probability of an ongoing bacterial infection. Similarly, the presence of neutropenia significantly increases the risk of bacterial or fungal infection.
Urianalysis, and if abnormal a urine culture. Urine culture should be ordered in patients with unexplained fever, altered mental status, and/or typical signs and symptoms of urinary tract infection such as pyuria, hematuria, dysuria, worsening urinary incontinence, and/or suprapubic pain (43). Asymptomatic bacteriuria does not require treatment. A dipstick urine test with a positive leukocyte esterase, nitrites, and/or pyuria should also prompt a urine culture. Appropriately collected urine culture specimens include a midstream or clean catch urine, or in patients with urethral catheters, cultures should be drawn after the removal of the catheter and insertion of a new one (44).
Blood cultures. When available blood cultures should be drawn in all advanced cancer patients in whom an infection is suspected (2). Although, in general peripherally drawn blood cultures are more reliable, if a catheter is in place, blood for culture should be drawn from the catheter. Blood from peripheral sticks should be obtained in individualized cases in which the suspicion of a catheter-related infection is very high, and positive results would impact the management of the patient.
Pulse oximetry and chest x-ray. To evaluate for pneumonia, heart failure, and pulmonary embolism.

SPECIFIC INFECTIOUS SYNDROMES

Neutropenic Fever

Fever during chemotherapy-induced neutropenia occurs in 10% to 50% of patients with solid tumors and in >80% of those with hematologic malignancies (9). Common sites of infection include the gastrointestinal tract, lung, and skin; bacteremia occurs in up to 25% of patients. Common blood isolates include coagulase-negative staphylococci, Enterobacteriaceae, and non-fermenting gram-negative rods (e.g., P. aeruginosa) (9). Invasive yeast (usually Candida spp.) infections are more commonly seen in patients with severe mucositis and neutropenia. Invasive mold infections (e.g., Aspergillus sp.) typically occur after prolonged neutropenia (>2 wk). The Infectious Diseases Society of America makes available detailed guidelines for the use of antimicrobial agents in the setting of chemotherapy-induced neutropenic fever (9), and these should be consulted for specific questions. The following section discusses the most important principles.

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