Alison G. Freifeld,
Daniel R. Kaul
SUMMARY OF KEY POINTS
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INTRODUCTION
Numerous disease-related and chemotherapy-induced factors render the patient with cancer at increased risk for infection. [1] [2] These include the type of cancer (solid tumor versus a lymphoma or acute leukemia), depth and duration of neutropenia, and impairments in cellular function caused by cytotoxic or immunosuppressive drugs; breaches in the integument from surgical procedures, presence of indwelling plastic venous catheters, or mucositis of the gastrointestinal tract secondary to chemotherapy; and comorbid conditions such as malnutrition, deconditioning, or medical problems such as chronic obstructive lung disease or diabetes. In recent years, it has become clear that prevention, diagnosis, and management strategies for infectious complications in patients with cancer are greatly influenced by overall immunosuppression status, as reflected by the cumulative burden of these risk factors. Nonetheless, neutropenia remains a critical risk factor for infection in these patients, and the oncologist must be informed of the most appropriate methods for managing fever and other possible infections during neutropenia.
This chapter addresses current standards for the management of fever during neutropenia and also highlights contemporary guidelines for the prevention and treatment of common infectious complications in patients with cancer.
INFECTION RISK FACTORS
Neutropenia as a Risk Factor for Infection
The association between neutropenia and increased infection risk initially was demonstrated by Bodey and colleagues in 1966 in a study of leukemic patients undergoing cytotoxic therapy.[3] The data show that the frequency of infectious complications is inversely related to the degree and duration of neutropenia ( Fig. 47-1 ). Infection risk starts to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm3 and increases dramatically when it is less than 500 cells/mm3. Fewer than half of the neutropenic patients who become febrile will have an identified infection. In roughly 10% to 20% or more of patients with neutrophil counts less than 100 cells/mm3, a bloodstream infection will develop. More than 50% of all episodes of fever and neutropenia represent fever of undetermined origin (FUO), with no identifiable infection source on physical and radiographic examination and cultures. [3] [4] In addition to the depth of the ANC nadir, the duration of neutropenia also is an important determinant of both infection risk and infection type. Brief durations of neutropenia, particularly for less than 7 days, are associated with a rapid and favorable response to empirical antibiotic therapy. Fever often may be of unknown origin during this early phase of neutropenia, but if a causative pathogen is identified, bacteria and viruses predominate. A neutrophil count persistently less than 500 cells/mm3for more than 7 days is associated with greater risk for infection-related morbidity and mortality and is the setting in which Aspergillus and other invasive fungal infections most often occur. Other pathogens that may cause infection during the course of prolonged neutropenia (i.e., after 7 days) include antibiotic-resistant bacteria, Candida species, and other molds. Deaths during neutropenia usually are due to these subsequent infections. Overall mortality rates during fever and neutropenia are less than 1% for low-risk patients and approximately 5% for those with more prolonged duration of neutropenia. [5] [6] [7] [8] [9]
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Figure 47-1 Relationship between neutrophil count and infection in patients with acute leukemia. |
In addition to cytotoxic chemotherapy, other cases of neutrophil deficiency include bone marrow incompetence occurring as a result of myelodysplastic syndrome, or secondary to crowding out of normal granulocytic precursors by tumor cells. “Functional neutropenia” due to impaired neutrophil microbicidal activity may arise as a consequence of underlying disease such as leukemia or therapies such as steroids. In these instances, ineffective neutrophil killing leaves the patient highly vulnerable to infection despite seemingly normal peripheral white blood cell counts.
Other Risk Factors for Infection
Disruption of integumentary, mucosal, and mucociliary barriers by cytotoxic therapies provides opportunities for invasion by colonizing bacteria on the skin, gastrointestinal tract, or mucous membranes.[10] Shifts in normal colonizing microbial flora at these sites occur as a result of chemotherapy, antibiotic use, and nosocomial exposures, leading to increased colonization with gram-negative and antibiotic-resistant pathogens. Indwelling catheters create a significant breach in host defense, permitting direct access of skin flora and other pathogens to blood or subcutaneous tissue. Tumor growth can disrupt normal anatomic structures, and cancer surgery may result in anatomic alterations and wounds, providing local sites for pathogen entry.
Underlying diseases and cancer therapies also play important roles in infection risk. For example, hypogammaglobulinemia often complicates chronic lymphocytic leukemia (CLL) or multiple myeloma, so that patients are at increased risk for severe pneumococcal infections or Haemophilus influenzae or Neisseria meningitidis infection. In contrast to patients with solid tumors, those with acute leukemias are more likely to have overwhelming sepsis or invasive fungal infections because of prolonged periods of profound neutropenia related to the underlying leukemia. Patients with acute lymphocytic leukemia, Hodgkin's disease, or non-Hodgkin's lymphoma (NHL) typically have defects in cell-mediated immunity that predispose them to development of Pneumocystis jirovecii pneumonia (PCP), cryptococcal disease, or infections with intracellular organisms such as Salmonella or Listeria.
Steroid therapy induces a broad immunosuppressive effect, including impaired chemotaxis and killing by neutrophils, impaired T-cell function, and alterations in skin and mucosal barriers. Long-term or high-dose steroid therapy is a significant risk factor for invasive fungal infections in particular (i.e., Aspergillus and Cryptococcus), as well as P. jiroveci (usually seen with tapering of the steroid regimen). Such therapy also may predispose affected patients to development of bacterial infections and Mycobacterium tuberculosis reactivation. High-dose cytosine arabinoside therapy causes mucositis that may predispose to life-threatening streptococcal bacteremias.[11] Fludarabine and alemtuzumab cause prolonged suppression of CD4+ lymphocytes and attendant susceptibility to infections with Listeria, P. jiroveci, and herpesviruses, as well as bacterial infections. [12] [13] Temazolomide with radiation, given for glioblastoma, also is associated with increased susceptibility to P. jiroveci, as well as profound myelotoxicity.[14]
SOURCES OF INFECTION
Colonization by pathogenic bacteria, fungi, or viruses generally is a prerequisite for infection. Accordingly, endogenous bacterial and fungal flora and latent herpesvirus infections account for a majority of initial infections in the neutropenic patient with cancer. [11] [15] [16] These include skin colonizers such as S. aureus and coagulase-negative staphylococci, viridans streptococci, and herpes simplex from the oropharynx, and gram-positive bacteria as well as enteric gram-negative bacteria from the gut. Candida albicans infections often are derived from the skin or the gastrointestinal or female genital tract. Latent infections that may reactivate during immunosuppression include those due to herpes simplex or varicella-zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), as well as hepatitis B and C viruses, M. tuberculosis, and Toxoplasma gondii.
Exogenous sources of infection often are found in the hospital and home environments. Contaminated blood products, hospital equipment, water sources, and nosocomial spread of organisms from health care workers represent less common, albeit significant sources of infection. Common nosocomially spread infections include those due to C. difficile, respiratory viruses, vancomycin-resistant enterococci, and other multiresistant bacteria. Water sources such as faucets and shower heads have been implicated in the spread of Legionella. Outbreaks of infection related to intravenous solutions have been well documented with Klebsiella and Enterobacter. [17] [18] [19]
Foods can be a potential infection source, particularly unwashed fruits and vegetables. Neutropenic patients generally are advised to avoid raw foods of this type unless measures are taken to peel or thoroughly wash them. Potted plants, mulch, and excavation and building or renovation sites have been identified as sources of Aspergillus and other molds that may cause disease.[20]
APPROACH TO FEVER IN THE NEUTROPENIC PATIENT
Fever often is the only reliable sign of significant underlying infection in the neutropenic patient. No specific clinical features, such as hypotension or chills, or magnitude of the increase in body temperature can accurately distinguish between fever due to an infection and that due to a noninfectious cause. Nor are laboratory tests such as determination of C-reactive protein and procalcitonin considered specific or rapid enough to be relied on.[21] Therefore, all febrile neutropenic patients should receive empirical broad-spectrum antibiotics, ideally within 1 hour of presentation. Although a clinically or microbiologically documented source of fever is not found in most patients with fever and neutropenia, the rapid initiation of empirical antibiotic therapy remains an important standard of care for all patients in this setting. The choice of specific antibiotic regimens, however, depends on an assessment of the patient's infection risk during neutropenia, which is in turn dependent on duration of neutropenia, underlying cancer, and comorbid medical conditions. Conditions and findings that may alter the empirical antibiotic regimen are shown in Table 47-1 .
Table 47-1 -- Approach to Management of Fever and Neutropenia
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History and Physical Findings |
Indicated Modifications in Antimicrobial Coverage or Diagnostic Test |
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Fever during neutropenia |
Empirical antibiotic regimen: See text. |
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If the patient is on antibiotic prophylaxis, then empirical therapy must be based on an agent of a different class from that for prophylaxis (e.g., if the patient is on fluoroquinolone-based prophylaxis, then switch to a beta-lactam–based regimen). |
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Hypotension, signs of sepsis |
Broad-spectrum antimicrobial coverage: A triple-antibiotic regimen (e.g., carbapenem plus vancomycin plus an aminoglycoside) is recommended. |
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If cultures are negative for gram-positive organisms, consider discontinuing vancomycin after 3 days. |
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Fever that is persistent or recrudescent on or after day 5 of antibiotic therapy |
Empirical antifungal therapy: Add amphotericin B product, an echinocandin, or voriconazole if the patient is not already on prophylaxis with a moldactive agent. CT scan of the chest may help identify fungal infection. |
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Consider CT scan of the chest and frequent galactomannan testing during neutropenia to guide preemptive treatment, as an alternative strategy to empirical antifungal treatment. |
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Severe oral or esophageal mucositis |
Send swab for viral (HSV) culture. |
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Add antiviral coverage (if not already being given). |
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Consider antiviral resistance to prophylaxis if esophagitis occurs late in the course of neutropenia. |
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Add antifungal agent for possible Candida esophagitis. |
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Switch streptococcal coverage to vancomycin. |
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Esophagoscopy may be indicated. |
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Catheter exit site or tunnel erythema, tenderness, or discharge or cellulitis at any site |
Culture any discharge. |
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Add vancomycin. |
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For tunnel infection (erythema and tenderness 2 cm above exit site), catheter removal and surgical débridement generally are required. |
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Possible anaerobic infection |
Add metronidazole to broad-spectrum antibiotics. |
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Abdominal pain, especially right lower quadrant, suggestive of neutropenic enterocolitis |
Perform CT scan of affected area. |
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Supportive care: Avoid surgical intervention if possible in a neutropenic patient. |
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Oropharyngeal or neck or soft-tissue swelling |
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New pulmonary infiltrate |
Bronchoscopy (with or without biopsy) is the preferred method for evaluating new infiltrates in the high-risk patient. |
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Nodular: Add mold coverage with voriconazole, posaconazole, or amphotericin B preparation. |
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Alveolar: Broaden gram-negative coverage and add Legionella coverage (quinolone or macrolide). |
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Interstitial: Send specimen for diagnostic studies for both respiratory viruses and herpesviruses, particularly CMV. |
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Review patient history for risk factors for tuberculosis or infection with endemic fungi. |
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Upper respiratory symptoms of coryza, congestion during fall/winter |
Send nasal wash or swab for respiratory virus culture and rapid antigen tests for RSV and influenza virus. |
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Hemorrhagic cystitis |
Indicated studies include urine viral culture and BK virus PCR assay. |
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CMV, cytomegalovirus; CT, computed tomography; HSV, herpes simplex virus; PCR, polymerase chain reaction; RSV, respiratory syncytial virus. |
DEFINITIONS
Guidelines for evaluating antimicrobial therapy for fever and neutropenia have been developed by the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN): [2] [22] Fever is defined as a single temperature measurement of 38.3°C (101°F) or greater, in the absence of other obvious causes; a temperature of 38°C or greater for an hour or longer is considered to represent a “febrile state” that also requires prompt evaluation and intervention in the setting of neutropenia. [2] [22] Neutropenia is defined as an absolute neutrophil count (ANC) less than 1000 cells/mm3 in some centers but more often is designated by a neutrophil count of less than 500 cells/mm3, which is a level associated with a much higher risk for infection. For practical purposes, an ANC less than 500 cells/mm3, or a count that is anticipated to fall below that level within 48 hours, constitutes a state of neutropenia.
Rarely, a neutropenic patient who is afebrile may exhibit signs or symptoms of infection (e.g., abdominal pain, severe mucositis, perirectal pain) and should be considered to have an active infection. The concomitant administration of corticosteroids also may initially blunt the fever response. With afebrile neutropenic patients who show signs or symptoms suggestive of an infection, empirical antibiotics should be started immediately because of their increased risk for serious invasive infections.
INITIAL EVALUATION
The initial evaluation should be directed toward determining the possible sites of infection and causative organisms and assessing the patient's level of risk for infection-related complications. A thorough site-specific review of systems is essential. Pertinent history includes recent antibiotic therapy, recent surgery or other invasive procedures such as biopsies or catheter placement, and possible exposure to infections from close contacts and household members, foods, animals, or travel.
The physical examination should focus on common potential sites of infection. Worthy of emphasis in this regard is that the manifestations of infection are muted in the absence of inflammatory cells. Careful examination of the oropharynx may reveal ulcers, or plaquelike lesions may be due to herpes or thrush, and specimens for appropriate tests should be sent for evaluation. Catheter sites require careful assessment for erythema, tenderness, or discharge. With bacterial cellulitis of the skin or perirectum, induration and erythema may be minimal; pimples or pustules are uncommon without neutrophils to create pus. Similarly, few respiratory signs or symptoms may be noted, and auscultation of the lungs may reveal few adventitial sounds, but an infiltrate may be seen on radiographs. A urinary tract infection may not be associated with dysuria. Gastrointestinal tract mucositis due to cytotoxic chemotherapy can lead to sore throat, oral ulcers, and diarrhea that are indistinguishable from the signs and symptoms of infection. Abdominal pain in neutropenic patients may signify a wide variety of problems, including intestinal tumor necrosis and neutropenic enterocolitis, both of which can result in intra-abdominal catastrophe or sepsis.
Initial laboratory evaluation should include a complete blood count and differential white cell count to determine the degree of neutropenia, liver and renal function tests, oxygen saturation determination, and urinalysis. Chest radiography should be performed routinely at presentation with fever and neutropenia, but initial findings may be minimal in neutropenic patients with pneumonia. Two blood culture samples, each consisting of 20 to 40 mL of blood, should be obtained from febrile, neutropenic patients.[4] An adequate volume of blood taken for culture will enhance the chances of recovering a pathogen.[23]
The usefulness of taking blood samples from both a vascular catheter and a peripheral vein has been confirmed, and this strategy is now standard practice in evaluation. Dual-site blood cultures may help determine whether the catheter is a source of infection if the differential time to positivity between catheter- and venipuncture-derived cultures is less than 2 hours.[24] One study, however, revealed that in patients with cancer, catheter-drawn blood culures without concomitant peripheral cultures have very good negative predicitve value and fairly good sensitivity (89%) and specificity (95%), albeit with low positive predictive value; accordingly, a positive result—especially for a common contaminant such as coagulase-negative staphylococci—requires careful clinical interpretation.[25] Quantitative blood cultures are rarely used because of their expense.
Cultures of any suggestive sites of infection should be performed: Diarrheal stools should be tested for the presence of C. difficile toxin, specimens from oral or perineal lesions suspected to harbor herpes simplex virus (HSV) should be sent for viral cultures, and nasal wash or swab specimens for culture for respiratory viruses should be obtained in patients with suggestive signs or symptoms during the winter season.
Risk Assessment
Risk assessment should be performed as part of the initial evaluation in an effort to predict the probability that a patient is at high or low risk for serious complications during a febrile episode. [2] [22] [26] [27] [28] [29] [30] [31] [32] [33] The assessment of a patient's risk is driven largely by the duration of neutropenia expected to occur as a consequence of chemotherapy, and by certain historical and physical characteristics of the neutropenic patient who presents with fever ( Table 47-2 ). Clinical features in low-risk patients include neutropenia anticipated to last less than 7 days, absence of serious medical comorbidity, and outpatient status at onset offever. [2] [5] [6] Typically, low-risk patients are those receiving chemotherapy for solid tumors or consolidation therapy for leukemia. These patients may be eligible to receive treatment outside of the traditional hospital setting or receive initial empirical therapy with oral antibiotics. Clinical features in high-risk patients generally include expected duration of neutropenia of 7 days or longer and presence of serious medical comorbidity. These patients may be recent recipients of allogeneic hematopoietic stem cell transplants or patients with acute leukemia not in remission, or with neutropenia secondary to induction therapy or other conditions such as aplastic anemia. Additionally, non-neutropenic patients with graft-versus-host disease (GVHD) treated with significant doses of corticosteroids also are considered to be at high risk for infections, particularly those due to encapsulated bacteria and invasive molds. Recipients of autologous hematopoietic stem cell transplants seem to be at intermediate risk for infections, even though prolonged (longer than 7 days) durations of neutropenia are likely in these patients. Similarly, patients with lymphoma or CLL and recipients of purine analog therapy (e.g., fludarabine) or those undergoing mini-allogeneic transplantation may be considered to be at intermediate risk for severe infection because they tend to have only brief periods of neutropenia, or none at all, but they may acquire significant impairments of cellular immunity that make them susceptible to certain types of infections. Although many clinicians rely on the criteria shown in Table 47-2 , an important point is that these criteria are derived from clinical observations from numerous trials, rather than from a risk assessment algorithm.[2] The Multinational Association of Supportive Care in Cancer (MASCC) has put forth a set of validated clinical prediction rules that can distinguish high- from low-risk patients with substantial accuracy (see Table 47-2 ). [8] [29] This prediction model has recently been validated, and the use of the MASCC prediction criteria is encouraged to distinguish between low- and high-risk patients.[33]
Table 47-2 -- Risk for Infectious Complications after Cytotoxic Chemotherapy: Clinical Features Defining Risk Status and Risk Prediction in Patients with Fever and Neutropenia
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GENERAL CLINICAL FEATURES IN HIGH-VERSUS LOW-RISK PATIENTS |
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High risk
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Low risk
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MASCC PREDICTION TOOL FOR DETERMINING HIGH AND LOW RISK FOR SERIOUS MEDICAL COMPLICATIONS |
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Characteristic |
Weight (No. of Points)[*] |
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Age <60 years |
2 |
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Outpatient status |
3 |
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Clinical status at presentation |
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No severe burden of febrile neutropenia |
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No or only mild symptoms |
5 |
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Moderate symptoms |
3 |
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No hypotension: systolic blood pressure >80 mm Hg |
5 |
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No dehydration requiring parenteral fluids |
3 |
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Medical history, underlying disease, and/or comorbidity |
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No chronic obstructive pulmonary disease |
4 |
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Solid tumor or hematologic malignancy without previous invasive fungal infection |
4 |
Adapted from IDSA Guidelines 2007.
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MASCC, Multinational Association for Supportive Care in Cancer. |
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* |
If relevant, points are added to yield a sum score. If the score is >20, the patient is predicted to be at low risk (<10%) for the development of serious medical complications during the course of febrile neutropenia. |
Once risk categorization has been assigned and after pertinent historical data have been acquired, physical examination and radiographic studies have been performed, and appropriate culture specimens have been obtained, then empirical antibiotics should be started promptly in the patient with fever and neutropenia. Preferably, these tasks should be completed within 1 or 2 hours, at most.
EMPIRICAL ANTIBIOTIC THERAPY: GENERAL PRINCIPLES
Numerous clinical trials over the last 3 decades have failed to demonstrate the clear superiority of one empirical antibiotic therapy regimen over all others. Effective and reliable regimens, however, are characteristically bactericidal for gram-negative pathogens, particularly P. aeruginosa, even in the absence of neutrophils. Several antibiotic approaches are acceptable, but an important point is that the final choice of a specific regimen will depend on the patient's risk factors for infection, the specific sites that may be sources of infection, and the prevailing institutional flora.
Monotherapy with a broad-spectrum antipseudomonal agent such as an extended-spectrum antipseudomonal cephalosporin (e.g., cefepime, ceftazidime), or piperacillin-tazobactam or a carbapenem (e.g., imipenem-cilastatin, meropenem), constitutes a standard approach to the management of fever and neutropenia in patients with cancer. [2] [22] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] The choice of agent should be based on a review of local institutional bacterial susceptibility patterns. Some institutions routinely use combinationt therapy with either (1) an aminoglycoside plus either an extended-spectrum antipseudomonal cephalosporin or piperacillin-tazobactam or (2) ciprofloxacin plus an antipseudomonal penicillin. No clear benefit of combination therapy over montherapy has been demonstrated, and increased renal toxicity has been observed with aminoglycoside use. [39] [40] In an era of increasing bacterial resistance, however, circumstances may arise in which initial empirical antibiotic combinations are advisable.[41] With the possibility of infection due to methicillin-resistant S. aureus, for example, addition of vancomycin is prudent. If a pneumonia is identified at the outset, then adding an antipseudomonal fluoroquinolone (i.e., ciprofloxacin or levofloxacin) ensures a broadened spectrum against potentially resistant gram-negative or atypical pathogens, as well as “atypical” organisms such asLegionella.[42]
INITIAL EMPIRICAL ANTIBIOTIC THERAPY
For patients who have been determined to be at low risk for developing infection-related complications during the course of neutropenia, oral ciprofloxacin plus amoxicillin-clavulanate (or clindamycin for patients who are allergic to penicillin) is an effective alternative to intravenous monotherapy, as indicated by several large randomized studies. [30] [31] [32] High-dose ciprofloxacin or ofloxacin oral monotherapy has been evaluated in small trials, but the evidence does not currently support the routine use of these fluoroquinolones for monotherapy in low-risk patients with fever and neutropenia. [43] [44] [45] [46] Ciprofloxacin as a single agent does not provide adequate coverage for certain gram-positive organisms (e.g., S. aureus, alpha-streptococci), and therefore should never be used without an additional antibiotic directed toward those pathogens. Levofloxacin oral monotherapy has not been adequately studied.
Patients who are assessed as being in a high-risk category for complications during fever and neutropenia should receive intravenous antibiotics, as outlined earlier, in the inpatient setting. The choice of specific regimen is highly dependent on institutional profiles of pathogen susceptibility and on potential infection sites in a specific patient.
Use of Vancomycin or Other Gram-Positive Agents
Vancomycin or another agent with activity against drug-resistant gram-positive pathogens is not routinely recommended for inclusion in the initial empirical regimen, despite a predominance of gram-positive pathogens isolated in febrile neutropenic patients.[47] The dilemma is that a small proportion of infections caused by gram-positive pathogens can be fulminant, so some clinicians are anxious to use these agents. Regardless, a large, prospective, randomized trial from the European Organization for Research and Treatment of Cancer failed to show a clinical advantage for using a vancomycin-containing regimen over one that did not contain vancomycin, in adults with fever and neutropenia.[48] A major concern with widespread routine empirical use and prolonged courses of vancomycin has been the emergence of vancomycin-resistant organisms, especially enterococci, associated with these practices. To limit the spread of vancomycin resistance, the Hospital Infection Control Practices Advisory Committee of the Centers for Disease Control and Prevention has issued guidelines to limit vancomycin use.[49] These guidelines include specific clinical situations that may justify initial use of vancomycin therapy in febrile, neutropenic patients with cancer ( Table 47-3 ). Other agents active against gram-positive pathogens include daptomycin, quinupristin-dalfopristin, and linezolid. The use of these drugs should be similarly limited to distinct indications, rather than broadly applied. Caution is advised with use of these agents because each has significant adverse effects; of note, linezolid may cause myelosuppression when used for a prolonged course.
Table 47-3 -- Appropriate Use of Gram-Positive–Active Antibiotics in the Neutropenic Cancer Patient
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VANCOMYCIN OR ANOTHER GRAM-POSITIVE–ACTIVE ANTIBIOTIC |
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Clinical situations for which addition of vancomycin or another gram-positive–active antibiotic is recommended include the following:
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OTHER AGENTS FOR USE WITH KNOWN VANCOMYCIN RESISTANCE |
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Linezolid, quinupristin-dalfopristin, or daptomycin may be used in very selected clinical situations in which vancomycin-resistant pathogens (e.g., VRE) are identified or in patients for whom use of vancomycin is not a clinical option. |
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GRAM-POSITIVE–ACTIVE ANTIBIOTICS FOR GRAM-POSITIVE INFECTIONS ONLY |
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Vancomycin or other gram-positive–active antibiotic should be discontinued in 2 to 3 days if no resistant gram-positive infection is identified. |
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TMP-SMX, trimethoprim-sulfamethoxazole; VRE, vancomycin-resistant enterococci. |
Documented serious, clinically apparent infections that are likely to be caused by gram-positive pathogens, such as cellulitis or obvious catheter-related infections, should be treated with vancomycin or another gram-positive–active agent. Many catheter-related bloodstream infections are caused by coagulase-negative staphylococcal isolates, which have high-level beta-lactam antibiotic resistance. Increasingly, Staphylococcus aureus also is being seen as a community-acquired pathogen.[50] If the patient is known to be colonized with methicillin-resistant S. aureus, then vancomycin should be added to the initial regimen until blood and other cultures are proved negative for this organism. Substantial mucosal damage increases risk for infection with viridans streptococci, of which 18% to 29% of are beta-lactam–resistant. [51] [52] [53] [54] [55] High-dose cytarabine or intensive therapy that damages oropharyngeal mucosal barriers has been associated with an increased risk of such overwhelming sepsis due to viridans streptococcal infections. Prophylaxis with ciprofloxacin or trimethoprim-sulfamethoxazole (TMP-SMX) also has been associated with an increased risk of gram-positive infections, particularly those due to viridans streptococci. [51] [52] [53] [54] Viridans streptococcal breakthrough infections also have been observed with levofloxacin prophylaxis. [55] [56]
Presence of hypotension or septic shock in a neutropenic patient necessitates very broad empirical antibiotic coverage, including the use of a gram-positive–active agent, until culture results are available. If a vancomycin (or other gram-positive–active agent) is added initially for empirical coverage, its use should be reassessed in 2 or 3 days. If a drug-resistant gram-positive pathogen cannot be identified, empirical vancomycin therapy should be discontinued.[49]
Initial Empirical Therapy for Patients Who Are Clinically Unstable
Patients who have hypotension when with fever and neutropenia, or those who have a history of P. aeruginosa colonization or invasive disease, should receive multidrug therapy with an antipseudomonal beta-lactam (cephalosporin, carbapenem, or penicillin, depending on local susceptibilities) plus an aminoglycoside or ciprofloxacin, and vancomycin or other gram-positive active agent. Broad coverage is warranted in view of the high mortality rate in neutropenic patients with the systemic inflammatory response syndrome. [2] [22]
Subsequent Modifications of Empirical Antibiotic Regimens
No empirical antibiotic regimen initially administered for fever and neutropenia can be expected to cover all possible infections that may occur during the course of neutropenia. Therefore, modifications of the initial regimen—additions or changes of antimicrobials—sometimes are required. An important consideration in the management of cancer-related infection is that the mean time to defervescence for febrile patients with neutropenia who receive appropriate initial antibiotic therapy ranges from 2 to 7 days. [5] [6] Therefore, at least 3 to 4 days of the initial antibiotic regimen should be given to otherwise stable patients, regardless of continued fever, to determine effectiveness. For patients with a documented infection, it is important to note that tissue-based infections such as pneumonia may take longer to respond to antimicrobial therapy.[7]
Patients with a fever persisting beyond 4 days of initial antimicrobial therapy, and without an identifiable site or source of infection, should undergo reassessment of their initial antimicrobial therapy. Any change in antimicrobials should be based on the patient's clinical status, results of examination and cultures, and also the likelihood of early marrow recovery. Although fever resolution may be slow, persistent fever may suggest a nonbacterial infection, a bacterial infection that is resistant to empirical antibiotics, the emergence of a secondary infection, a closed-space infection, inadequate antimicrobial serum levels, or drug fever. A careful search for these etiologic conditions should be made. Frequent and arbitrary antibiotic changes for persistent fever, in an otherwise stable patient, are to be discouraged, however. The clinically stable patient with persistent fever may be safely watched without altering the initial antibacterial therapy. If vancomycin was started earlier, it should be discontinued if the patient does not meet the criteria for its use.[49] Addition of vancomycin, without specific indications, in a blind effort to suppress persistent fever after empirical antibiotics have been started, has not been shown to be effective.[57] If the fever persists beyond 4 to 7 days, a change in antibiotic regimen or initiation of empirical antifungal therapy should be considered.
For the patient who is persistently febrile and clinically unstable, a change in antibacterial antibiotics may be needed. The addition of increased gram-negative bacillary coverage often is recommended. The addition of vancomycin should be considered if the patient's clinical situation justifies its use, as indicated in Table 47-3 . If fever persists or is recrudescent beyond 4 to 7 days of empirical antibiotic therapy, empirical antifungal therapy probably should be initiated because the risk of invasive fungal disease increases with prolonged neutropenia.
Empirical Antifungal Therapy
Empirical antifungal therapy traditionally is started when neutropenic patients demonstrate continued or recrudescent fever after 4 days or more of an empirical antibacterial regimen. The empirical use of amphotericin B in early studies during the 1970s and 1980s actually failed to demonstrate an effect on defervescence or overall survival; however, a reduction in breakthrough fungal infections was noted.[58] [59] [60] Since then, in an attempt to reduce toxicity, numerous comparative studies have demonstrated that liposomal amphotericin B, amphotericin B lipid complex, itraconazole, and caspofungin are noninferior to, albeit less toxic than, amphotericin B desoxycholate for empirical therapy. [61] [62] [63] [64] [65] [66] [67] It is likely that the other echinocandins (anidulafungin, and micafungin) also are effective in this setting, but they have not been formally studied. In one large randomized trial, voriconazole failed to fulfill criteria for noninferiority in comparison with the comparator amphotericin preparation.[68]Breakthrough fungal infections, however, were less frequent in patients receiving voriconazole. Accordingly, many clinicians accept voriconazole as appropriate for empirical antifungal therapy. Itraconazole has been demonstrated to have efficacy in this setting as well, but concerns about liver and cardiac toxicities have discouraged use of this drug. [61] [67]
Whether all patients with persistent fever require empirical antifungal therapy, and when it should be started, are subjects of longstanding debate. Invasive fungal infections are now relatively infrequent during neutropenia with the advent of more effective antifungal prophylaxis and the use of colony stimulating factors to abbreviate duration of neutropenia. Furthermore, it is clear that fever is a nonspecific surrogate marker for fungal infection. Patients who are not receiving antifungal prophylaxis but who have persistent or recurrent fever after 4 to 7 days of appropriate empirical antibiotics, and without prospect for imminent neutrophil recovery, may be candidates for empirical antifungal therapy. For patients not on antifungal prophylaxis, candidemia is the greatest concern, and persistent fever may be the only manifestation. An amphotericin B preparation, caspofungin, itraconazole, and voriconazole, or even fluconazole, are considered acceptable choices. If the patient is already receiving fluconazole prophylaxis, certain non-albicans species of Candida, including C. glabrata and C. krusei, and mold infections such as invasive aspergillosis must be considered, because fluconazole has reduced activity against these Candida species and lacks activity against molds. At present, no data are available to guide the use of empirical antifungal therapy in patients already receiving antimold prophylaxis, such as with voriconazole, posaconazole, or an echinocandin. In all cases, symptoms and signs of invasive fungal pneumonia or sinusitis should be sought; the workup may include CT scans of chest or sinuses (or both), with follow-up nasal endoscopy or bronchoalveolar lavage as indicated. Biopsy and culture of any suspected lesions should be pursued aggressively in order to make a definitive mycologic diagnosis that can guide therapy.
CT scan of the chest is increasingly used to evaluate the possibility of invasive aspergillosis in patients with prolonged fever and neutropenia; in one study, 90% of those with proven active disease showed radiographic abnormalities by CT.[69] Macronodules with or without a halo sign are characteristic of invasive aspergillosis, the halo sign being an especially important early clue.[70] Other manifestations include nodular, wedge-shaped, peripheral, multiple, and cavitary lesions. An air-crescent sign generally is a late finding. Initiation of antifungals on the basis of finding a halo sign has been associated with significantly better response to therapy and improved survival. [71] [72] In a recent pilot study, Maertens and colleagues used intensive monitoring for clinical symptoms and signs, serial galactomannan testing (see later on), and early CT scanning to identify a group of patients with persistent fever while on fluconazole prophylaxis in whom antimold therapy did not appear to be required.[73] These data, as well as increasing clinical experience, have lead some experts to suggest withholding empirical antifungal therapy if the patient is clinically stable and has no clinical or chest CT scan signs of fungal infection, no Candida or Aspergillus organisms are recovered from any site, and neutrophil recovery is imminent. A high-resolution chest CT scan may be a useful screening tool in patients with persistent fever and neutropenia; any abnormalities should be investigated with nasal endoscopy or bronchoalveolar lavage; biopsy and culture of any suspected lesions should be pursued aggressively in order to make a definitive diagnosis, and an antimold agent should be started.
The serum galactomannan assay specifically detects Aspergillus organisms but not other common fungal pathogens.[74] Sensitivity varies widely in different patient populations. A recent meta-analysis reported sensitivities of 58% to 65% and specificities of 65% to 95% in patients with hematologic malignancies or HSCT.[75] Many conditions affect the performance of the galactomannan assay, especially the use of concomitant piperacillin-tazobactam (false-positive) or antimold antifungal agents (false-negative). Although prospective serial galactomannan monitoring may be useful for pateints at high risk for Aspergillus infections, routine use in low-risk patients is not advised. [74] [75] Furthermore, a single negative test result is of little value in ruling out invasive aspergillosis, although a positive result in concert with abnormalities on the chest CT scan makes the diagnosis highly probable. Galactomannan testing of bronchoalveolar lavage fluid appears to be very sensitive and specific for identifying invasive aspergillosis, as confirmed in early studies. [76] [77]
Duration of Antibiotic Therapy
It generally is recommended that empirical antibiotic therapy continue until recovery of the ANC to more than 500 neutrophilic cells/mm3 on one occasion, so long as the patient is clinically stable. In a stable patient who remains febrile despite return of counts, it usually is safe to discontinue antimicrobials and look for a source of fever. In patients who are afebrile and clinically stable but have continued neutropenia, some clinicians recommend a 2-week course of antibiotics, at a minimum, and then stopping, with close observation. [2] [22]
Documented infections should be treated for a minimum duration of 7 to 14 days with an antibiotic regimen that is narrowed and directed toward any organisms that have been documented microbiologically. Most experts prefer to continue antibiotics at least until the ANC returns to more than 500 cells/mm3. A longer course is given if clinically necessary, regardless of neutrophil recovery.
For low-risk patients who typically have brief periods of neutropenia, some groups of investigators have examined stopping antibiotics before the ANC reaches 500 cells/mm3. With a clear and steady increase in the ANC or, alternatively, in the absolute phagocyte count (APC = PMNs + bands + monocytes), it appears that discontinuing antibiotics before a count of 500 neutrophilic cells/mm3 is achievedgenerally is safe so long as no complicating comorbid conditions are present. [78] [79] [80] [81] [82] [83]
ADJUNCTIVE THERAPIES
Hematopoietic Growth Factors
Prophylactic use of hemopoietic growth factors is common in the setting of intensive chemotherapy regimens such as stem cell transplantation. Treatment of fever or infection with growth factors, however, is not standard practice. No consistent benefit has been demonstrated in terms of morbidity (duration of fever and use of antimicrobial) or mortality among several randomized controlled trials of growth factors added to antibiotics at the time of fever during neutropenia. [84] [85] [86] Both the IDSA[22] and the American Society of Clinical Oncology (ASCO)[86] guidelines do not recommend the routine use of growth factors in treatment for febrile neutropenic patients. Therapy with colony stimulating factors, however, could be considered for severely neutropenic patients who have serious uncontrolled infections such as bacterial sepsis, pneumonia, severe cellulitis or sinusitis, systemic fungal infections, hypotensive episodes, or multiorgan dysfunction secondary to sepsis.
Granulocyte Transfusions
Granulocyte transfusion may potentially increase the response to antimicrobial therapy in selected cases of uncontrolled fungal or gram-negative infection during prolonged neutropenia. Granulocyte colony stimulating factor use in donors has increased the granulocyte yield approximately fourfold. Multiple recent studies have shown that granulocyte transfusions can be helpful in controlling severe infections progressing despite the use of appropriate antibiotics, with a response rate of 40% to 80%.[87] Variability in results is a consequence of patient characteristics. This benefit is limited to a limited patient population, because the incidence of prolonged yet reversible neutropenia is relatively low. Rare adverse events associated with granulocyte transfusions include transmission of CMV, alloimmunization associated with fever, graft-versus-host reactions if granulocytes are not irradiated, and progressive platelet refractoriness.
INFECTIONS IN THE PATIENT WITH CANCER
Bacteremia
Bloodstream infections occur in about 10% to 20% of febrile patients during neutropenia, most often when neutrophil counts are less than 100/mm3. [4] [5] [6] [7] The risk of bacteremia is related to the depth of neutropenia, the presence of gastrointestinal mucositis or of an indwelling catheter, or the concomitant presence of a specific site of infection such as pneumonia or soft-tissue process. A majority of bacteremias are due to gram-positive organisms, with coagulase-negative staphylococci and streptococci predominating. Gram-negative pathogens, including Escherichia coli, Enterobacter, Klebsiella, andPseudomonas aeruginosa, are important albeit less frequent pathogens (see Table 47-3 ).
A classification system for bacteremias in febrile neutropenic patients has been developed by Elting and colleagues, based on size and presence of associated tissue involvement.[7] Complex bacteremias were those associated with deep-tissue infections of the lung, the liver or spleen, the kidney, the colon, bone and joints, veins and heart, meninges, soft tissues with necrosis, or affected skin or soft tissue, wound, or cellulitis greater than 5cm in diameter. Simple bacteremias were associated with less tissue involvement (bacteruria, otitis, pharyngitis, affected area of soft tissue less than 5cm in diameter). The prognostic significance of complex infection associated with bacteremia on survival was dramatic. At 21 days, 20% of patients with complex infections were dead, compared with only 5% of patients with simple bacteremias (P < 0.0001). Profoundly neutropenic patients with simple bacteremias had a much higher response rate to antibiotics than that noted in patients with complex bacteremias (94% versus 70%; P < 0.0001). The median time to defervescence for patients with simple bacteremias was half that observed for patients with complex bacteremias (2.5 days versus 5.3 days; P < 0.0001).
With increasing incidence of MRSA in hospitals and the community, it is recommended that vancomycin be added to standard empirical antibiotic coverage if gram-positive cocci in clusters are isolated from a blood culture, pending identification. [15] [41] [50] Vancomycin-resistant enterococcus (VRE) also is common in high-risk cancer patients at some institutions. If gram-positive cocci in chains are identified in blood cultures in settings where VRE is prevalent, then empirical addition of an antimicrobial active against VRE (e.g., linezolid, daptomycin) is prudent, pending definite identification and susceptibility profile. Gram-negative bacteremias in the neutropenic patient are associated with high mortality unless treated promptly and with appropriate antibiotics. [88] [89] [90] A variety of resistance mechansims are evolving among gram-negative organisms. Therefore, if gram-negative rods are isolated in blood cultures during fever and neutropenia, an aminoglycoside or a fluoroquinolone should be added to empirical therapy regimens to ensure coverage of resistant strains until a full susceptibility report is available.
Pulmonary Infections
Pulmonary infections are associated with the greatest morbidity and mortality, even when a specific pathogen is not identified. Approximately 25% of all febrile episodes in the neutropenic patient, and 50% of documented infections, are pneumonias. [91] [92] [93] Numerous infectious and noninfectious causes of pulmonary infiltrates are found in cancer patient with cancer who has fever and neutropenia.[87]Noninfectious causes include the underlying disease itself, radiation therapy, drug toxicity, pulmonary hemorrhage, and leukostasis. Infectious involvement of the lungs may be caused by bacteria (pneumococci, members of Enterobacteriaceae, Pseudomonas spp., Legionella spp.), fungi (Candida, Aspergillus, Fusarium spp.), viruses (influenza virus, parainfluenza virus, respiratory syncytial virus [RSV], CMV, HSV), and protozoa (Toxoplasma, Cryptococcus, Strongyloides).
Auscultatory abnormalities in the chest may be minimal or absent, and the chest radiograph appears normal at the onset of clinical manifestations in 30% of neutropenic patients with subsequently identified pneumonia.[92] A CT scan of the chest is essential to better define a pulmonary process. Neutropenia will decrease the diagnostic advantage normally provided by the sputum examination, because purulent sputum production is rare in this setting. Bronchoalveolar lavage will increase the diagnostic yield, especially for P. jiroveci, viruses, and bacteria. The yield for molds such as Aspergillus with this procedure has been mostly in the range of 50% for suspected cases, so a negative result on bronchoalveolar lavage sampling does not rule out an invasive fungal process. Polymerase chain reaction (PCR) assay or galactomannan testing of lavage fluid may increase these yields, although these tests are not currently available commercially. [76] [77] If the clinical picture, radiographic appearance, and findings on lavage fluid analysis are nondiagnostic, a thoracoscopic or CT-guided lung biopsy should be considered if the patient's platelet count is adequate.
The radiograph appearance of a pulmonary infiltrate may give clues to the etiology ( Table 47-4 ).[93] Focal lesions are suggestive of bacterial etiology and should be treated accordingly with broad-spectrum antibiotics. Nodular lesions, particularly those with surrounding areas with a ground-glass appearance (i.e., halo lesions), are suggestive of mold infection—such as with Aspergillus. This is of particular concern in the two patient groups that are at particularly high risk for mold infection: patients with GVHD on high-dose steroids and patients with prolonged neutropenia, such as those undergoing induction treatment for acute myelogenous leukemia. In these types of patients, even minimal symptoms of low-grade fever, pleuritic chest pain, or nasal stuffiness should prompt an immediate CT scan of the chest and sinuses to look for signs of invasive aspergillosis.
Table 47-4 -- Pulmonary Infiltrates and Their Association with Specific Infectious and Noninfectious Disorders
|
Radiologic Sign |
Potential Etiologic Disorder(s) |
|
Interstitial infiltrates |
Pulmonary edema |
|
Diffuse alveolar damage |
Idiopathic pneumonia syndrome |
|
|
Respiratory virus infection: RSV, parainfluenza virus, influenza virus, adenovirus, enterovirus |
|
|
Herpesvirus infection: CMV, HSV, VZV, HHV-6 |
|
|
Pneumocystis pneumonia |
|
Focal airspace disease |
Bacterial pneumonia |
|
|
Fungal pneumonia |
|
Nodules |
Fungal pneumonia (aspergillosis) |
|
|
Nocardia infection |
|
|
Legionella infection |
|
|
Septic bacterial emboli |
|
|
Mycobacterial infection (with cavitation) |
|
|
EBV lymphoproliferative disorder |
|
|
Relapsed malignancy |
|
|
Pulmonary embolism (pleura-based) |
|
Halo sign or air-crescent sign |
Aspergillosis |
|
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella-zoster virus. |
A diffuse interstitial picture is suggestive of a noninfectious etiology such as pulmonary edema or diffuse alveolar damage; or it may represent an atypical pneumonia, such as that due to Legionella, community respiratory viruses (e.g., parainfluenza virus, RSV, influenza virus), or Mycoplasma, or opportunistic infections such as P. jiroveci and CMV infection in the susceptible host (see later). Addition of a fluoroquinolone or a macrolide will cover most atypical bacterial pathogens. For PCP, TMP-SMX at high doses (15 to 20 mg/kg per day) is standard treatment. CMV pneumonia requires initial treatment with intravenous ganciclovir plus administration of intravenous immunoglobulin as an adjuvant treatment.[94]
Pneumonia in a patient undergoing treatment for cancer is considered a health care-associated process. Accordingly, the empirical antimicrobial regimen is directed toward a range of pathogens. Current guidelines from the American Thoracic Society specify a combination of an antipseudomonal beta-lactam agent (cefepime, ceftazidime, a carbapenem, or piperacillin-tazobactam) plus vancomycin or linezolid plus an antipseudomonal fluoroquinolone or aminoglycoside.[95]
Fungal Infections
Fungal infections are due to yeast or mold pathogens. Candida organisms typically may colonize the gastointestinal tract and are the most common yeast pathogens in cancer patients. The spectrum of disease caused by Candida spp. ranges from mild mucocutaneous lesions (e.g., thrush) to disseminated deep tissue involvement (e.g., hepatosplenic candidiasis). An episode of candidemia probably precedes all tissue-invasive infections. Not all candidemias are clinically or microbiologically detected, however, and end-organ disease may be the first manifestation of invasive candidiasis. Blood cultures lack sensitivity for Candida and are positive in only approximately half of the patients with invasive disease.[96]
Neutropenia, the presence of an indwelling venous catheter, and chemotherapy-associated gastrointestinal mucosal injury are important risk factors for invasive candidiasis, rendering patients with cancer at especially high risk. Candida-related mortality rates of 33% to 75% are reported in these patients.[97] Because of the difficulty in diagnosing this infection and the associated high mortality, any blood culture found to grow even a single colony of Candida must be regarded as a sign of true infection, and the patient should receive therapy. Clinical signs of candidemia may range from fever alone to fulminant sepsis. Approximately 15% of neutropenic patients will have pustular skin lesions. C. albicans accounts for about half of the cases, but non-albicans species, especially C. glabrata and C. krusei, are increasing in incidence. Of note, these species are somewhat resistant and fully resistant, respectively, to fluconazole.
Catheter-related candidemia should be treated with antifungal therapy, and the catheter should be removed in most cases.[24] Determining if candidemia arises from a central venous catheter or the gut in a patient with neutropenia or gastrointestinal GVHD can be challenging. For a patient who has candidemia and a tunneled central venous catheter infection, the decision about its removal should be based on the likelihood of catheter-related candidemia. Factors indicating catheter-related candidemia include (1) isolation of Candida parapsilosis from blood samples; (2) quantitative blood cultures showing, in blood drawn through the catheter, five times the number of colonies isolated from blood drawn from a peripheral vein; (3) differential time to positivity (longer than 2 hours) for blood samples drawn from a percutaneous site, compared with that for samples drawn through the catheter; (4) candidemia in a patient who is receiving hyperalimentation through the catheter; and (5) persistent candidemia while receiving systemic antifungal therapy.[93] Catheter removal is strongly encouraged under any of these circumstances. [24] [98] [99] [100]
The availablity of echinocandins (e.g., caspofungin, micafungin, anidulafungin) and newer-generation triazoles (posaconazole and voriconazole), combined with increasing prophylactic use of antifungals in certain populations (e.g., those with acute leukemia or GVHD) and the emergence of resistant Candida species in some institutions, has changed the treatment paradigm for candidemia. Some non-albicansspecies (e.g., C. glabrata) may have reduced susceptibility to fluconazole. In institutions with higher rates of these organisms, empirical treatment with an echinocandin (e.g., caspofungin, micafungin, anidulafungin) or a later-generation triazole (e.g., voriconazole or posaconazole) is appropriate pending identification when a yeast is identified in the blood. Candidemia that develops during prophylaxis with an azole should be treated with an echinocandin or a amphotericin B preparation. Complications of fungemia may include endocarditis, endophthalmitis, vertebral osteomyelitis, and hepatosplenic candidiasis.[101]
Aspergillus spp. are the most common mold pathogens in patients with cancer, but they are seen almost exclusively in two specific settings: during periods of prolonged neutropenia or in patients with GVHD after allogeneic transplantation. As discussed earlier (under Pulmonary Infections), the vast majority of Aspergillus and other mold infections occur in the lung, whereas fewer organisms disseminate to sinuses, skin, or abdominal organs. [102] [103] Dissemination to brain occurs in approximately 5% of patients. Unfortunately, the sensitivity of diagnostic tests used to diagnose invasive aspergillosis remains very poor, and delay in diagnosis is all too common, contributing to poor outcome.[104] The CT scan has become an essential diagnostic tool for earlier diagnosis of invasive aspergillosis, with characteristic lesions such as nodules, the halo sign and the crescent sign having high predictive value for the diseasee. [69] [70] [71] [72] Despite some improvements in antifungal therapy in recent years, invasive aspergillosis is still associated with an at least 50% mortality rate in patients with cancer. [102] [103] Voriconazole has been shown to be superior to amphotericin B for for the treatment of proven or probable invasive aspergillosis, and it is now the agent of choice.[105] The use of combination therapy for invasive Aspergillus infections is an attractive approach that has scientific merit in that combinations of echinocandins with azoles or amphotericin B formulations have produced positive results both in vitro and in aspergillosis animal models. [106] [107]
On the basis of a few small retrospective studies, combination antifungal treatment appears to be safe and has promising efficacy. [106] [108] One recent open-label trial suggested that oral posacon azole was associated with a 42% response rate in patients who are refractory to or intolerant of conventional therapy for Aspergillus infection, although this is not better than results seen with voriconazole.[109] The enhanced efficacy of two- or three-drug antifungal combinations for invasive aspergillosis remains unproved, pending a prospective comparative clinical trial. Many clinicians, however, are anxious to employ combination therapy in an effort to improve the dismal outcomes for invasive aspergillosis.
Fusarium is notable for causing tender, red skin nodules and positive blood cultures for mold in approximately half of the cases.[110] Infection with any of the zygomycetes (Mucor, Rhizopus, Rhizomucor) is characterized by later onset (after day 90 of transplant) and a longer median duration of survival. Sinus disease with erosion through tissue planes is a feature of zygomycete infections but also may occur with Aspergillus infection. The mortality rate is approximately 80% for transplant recipients with proven infection. In up to 60% of those colonized, progression to invasive infection will occur.[111] Other, less common molds, including Fusarium, Scedospoarium/Pseudaollescheria, and Trichosporon, appear to be more susceptible to voriconazole than to amphotericin B. Of note, however, one report recently indicated successful treatment of Fusarium infection with a combination of both agents.[112]
An increased incidence of infection with voriconazole-resistant molds such as Rhizopus or Mucor species has recently been described. This increase is hypothesized to be related to more frequent use of voriconazole prophylaxis in high-risk cancer patients. [113] [114] Use of amphotericin B products has been standard therapy for infections due to these pathogens, but the recently approved triazole posaconazole has potent in vitro activity against the zygomycetes and has quickly become an important drug in battling infections with these molds. Furthermore, it is available in an oral formulation and has less toxicity than that observed with amphotericin products. Posaconazole has not been evaluated as a first-line agent for treatment of zygomycoses, but reports of its use in salvage therapy are promising.[100] Patients in whom pulmonary lesions with radiologic characteristics suggestive of mold infection (e.g., halo sign, as noted earlier) develop despite voriconazole prophylaxis should receive treatment for zygomycoses with amphotericin B or posaconazole pending microbiologic or histologic diagnosis. Aggressive and repeated surgical débridement is a critically important adjunct to the treatment of zygomycoses of the sinuses.[111]
Hepatosplenic candidiasis is a form of chronic disseminated candidiasis that almost exclusively affects patients undergoing leukemia induction or stem cell transplantation.[101] It generally manifests only on recovery from neutropenia, as persistent fevers unresponsive to antibacterial agents. Patients may have right upper quadrant tenderness and demonstrate a variety of other gastrointestinal signs and symptoms. Consistent laboratory findings include marked elevation of alkaline phosphatase, with normal or mildly elevated bilirubin and transaminases, and a rebound leukocytosis after neutrophil recovery. Blood cultures are almost always negative for fungal growth, as are liver biopsy specimens. Suspected hepatosplenic candidiasis is confirmed by the presence of multiple characteristic well-defined lesions in the liver or spleen, and occasionally in the kidneys on CT scan or ultrasound examination. A prolonged course of therapy, initially with amphotericin B or a lipid formulation and then with fluconazole for a number of months, has been advocated. Echinocandins also may be effective.[100] For patients with acute leukemia and hepatosplenic candidiasis, repeated cycles of chemotherapy may be given once the infection is stabilized, and the antifungals are continued through the courses of cytotoxic therapy.
Gastrointestinal Infections
Upper Gastrointestinal Tract
Mucositis of the oral cavity and alimentary mucosa is a common consequence of cytotoxic cancer therapies. Disruption of the gastrointestinal mucosa causes erosions and inflammation that can provide a portal of entry for colonizing organisms. Esophageal symptoms of odynophagia, dysphagia, and retrosternal or epigastric discomfort do not point to a specific etiology, and it often is difficult to discriminate between drug-induced and infection-induced mucositis. The most common organisms causing local oral or esophageal infection are herpes simplex virus and Candida spp., although gram-negative and anaerobic bacteria rarely are responsible. The treatment of presumed esophagitis during a period of neutropenia often is based on the empirical administration of antacids or systemic antifungal or antiviral therapy with acyclovir. For patients who do not respond to empirical therapy with these agents, careful upper endoscopy may be considered to obtain a more precise diagnosis based on direct visualization of the lesions, as well as on tissue biopsy for histopathologic and microbiologic examination. Of note, esophageal endoscopy may be associated with substantial morbidity in patients who are profoundly neutropenic or thrombocytopenic, and it often is advisable to wait until counts recover before proceeding.
Lower Gastrointestinal Tract
Enteritis, clinically manifested by diarrhea, is common in cancer patients. Diarrhea may be due to chemotherapy-induced mucositis or infection-induced. C. difficile is the most common pathogen to cause diarrhea in the cancer patient. Over the past few years, the emergence of an epidemic strain of C. difficile has resulted in a dramatic increase in the incidence and severity of C. difficile infection at many centers. [115] [116] The epidemic strain is resistant to fluoroquinolones, and use of this class of antibiotics has been implicated as a risk factor in institutional outbreaks.[117] Because of an increased rate of failure of oral metronidazole noted in recent studies, some experts recommend oral vancomycin for patients with evidence of severe disease (e.g., white blood cell count above 20,000 cell/mL, shock, renal failure, need for transfer to the intensive care unit),[115] and some advocate the addition of metronidazole. For patients unable to tolerate oral therapy (because of ileus or toxic megacolon, for example), intravenous metronidazole and vancomycin adminstered by nasogastric tube or by enema should be considered. Colectomy may be necessary in seriously ill, nonresponding patients. Relapse rates are high.[118] Although no proven approach is recognized, a slowly tapering course of oral vancomycin or metronidazole over 6 weeks often is used for patients with multiple relapses. Outpatients must be alerted to the possibility of recurrence so that retreatment can be instituted quickly.
Other bacterial causes of diarrhea are uncommon in patients with cancer unless exposure to such pathogens has occurred. CMV infection can cause protracted or hemorrhagic diarrhea, especially in children or in patients undergoing allogeneic HSCT. Adenovirus may cause severe diarrhea in allogeneic transplant recipients, and stool culture techniques and plasma PCR assay aid in diagnosis.
Typhlitis, also known as neutropenic enterocolitis, is a unique and potentially life-threatening syndrome occurring in febrile neutropenic patients, particularly those with leukemia or who have had intensive cytotoxic therapy. [119] [120] [121] [122] Abodominal pain, especially in the right lower quadrant, often with attendant rebound tenderness, and decreased bowel sounds, fever, and diarrhea are typical presenting features. Typhlitis may be limited to the cecum but can involve the entire intestine. CT scan is the diagnostic study of choice and usually demonstrates thickening of the bowel wall, sometimes with pneumatosis coli.[122] C. septicum, P. aeruginosa, enteric gram-negative organisms, and anaerobes are the most common pathogens associated with this syndrome. C. difficile occasionally is associated with typhlitis, so treatment for C. difficile infection (i.e., with oral vancomycin or metronidazole) should be included in the initial antibiotic regimen for typhlitis, along with a broad-spectrum intravenous antimicrobial cocktail. Severe sepsis, bowel perforation, and hemorrhage may accompany or follow typhlitis. Therapy consists of nasogastric suction, bowel rest, intravenous fluids, and broad-spectrum antibiot ics to cover gram-negative organisms and anaerobes (e.g., piperacillin/tazobactam, a carbapenem). Antifungal agents also should be part of the initial treatment regimen for typhlitis. In approximately 5% of patients with typhlitis, complications develop that require surgical intervention, including uncontrolled sepsis, lower gastrointestinal tract bleeding, and perforation.[121]
Perirectal infection occurs primarily in patients with acute leukemia and especially among those with monocytic and myelomonocytic leukemia, although it is relatively uncommon. The usual symptoms are fever, pain on defecation, and persistent rectal discomfort. Although anaerobes are thought to play a role in these infections, the associated bacteremias are most likely to be caused by P. aeruginosa, E. coli, and other enteric gram-negative bacteria. Therapy consists of broad-spectrum antibiotics, warm compresses, and stool softeners. Although few abscesses develop in the absence of neutrophils, some patients will benefit from surgical incision and drainage.
Central Nervous System Infections
In the patient with cancer who demonstrates new mental status changes, focal neurologic signs, or neck stiffness, evaluation for central nervous system (CNS) infection is necessary, because infection is a common cause of neurologic complications.[123] The initial evaluation begins with cerebral magnetic resonance imaging (MRI) or contrast-enhanced CT, followed immediately by lumbar puncture. Empirical treatment with antibacterials with adequate CNS penetration, such as cefepime or meropenem at high doses, is indicated. Of note, neutropenic patients may have few white cells in the cerebrospinal fluid (CSF), even in the setting of meningitis. Impaired T-cell function (e.g., corticosteroids, purine analogs, GVHD, alemtuzamab) but not neutropenia is a risk factor for Listeria meningitis. Ampicillin should be added if Listeria infection is suspected in a patient with T-cell impairment. Patients with varicella-zoster virus (VZV) or HSV meningoencephalitis may have suggestive skin lesions; if such infection is suspected, then acyclovir 10 mg/kg every 8 hours should be added and a CSF sample sent for PCR testing for both viruses. Cryptococcal meningitis often manifests with subtle mental status changes over several days, and very low CSF cell counts often are seen; serum and CSF crytococcal antigens are senstive diagnostic tests. False-positive test results at low titers may occur in patients with plasma cell dyscrasias. Treatment is with amphotericin B preparations combined with 5-fluorocytosine (monitor for thrombocytopenia, leucopenia, and diarrhea) initially. A repeat spinal fluid examination must be done after 2 weeks of therapy to determine if the CSF is culture-negative; if it is, then the patient may be switched to oral fluconazole. Heavily immunosuppressed patients (e.g., recent recipients of allogeneic HSCT, patients with chronic extensive GVHD) are at risk for meningoencephalitis from reactivation of pathogens such as HHV-6, EBV, or T. gondii, although such cases are very rare. CSF PCR assay for these specific herpesviruses or Toxoplasma is used to make the diagnosis; CSF culture typically is negative. Ganciclovir or foscarnet generally is used to treat HHV-6 infection. T. gondii reactivations often are rapidly fatal despite combination therapy with pyrimethamine and sulfadiazine or clindamycin treatment.[124]
Patients with ring-enhancing CNS lesions may have infection with bacteria, Toxoplasma, Nocardia, mycobacteria, or fungal organisms, including cryptococci. Post-transplantation lymphoproliferative disorder (PTLD) and other malignancies also may manifest as mass lesions. Typically, a brain biopsy is required to make the diagnosis if obvious concurrent infection at a more accessible site is not present (e.g., Nocardia growth from blood cultures or conincident diagnosis of pulmonary invasive Aspergillus infection). First-line therapy for CNS nocardiosis includes high-dose TMP-SMX (15 to 20 mg/kg daily) given in three or four divided doses, usually in combination with a second agent such as meropenem. Sensitivity testing should be performed to further refine therapy.
Treatment of CNS mold infections (other than those due to with zygomycetes) should include voriconazole, which attains CSF and brain tissue levels of approximately 22% and 100%, respectively (as indicated by data for a small number of samples).[125] The alternative treatment for CNS mold infection (intraventricular amphotericin accompanied by systemic amphotericin) is very toxic and very rarely used. Limited information suggests that posaconazole may be an effective agent for treatment of CNS fungal infections caused by Cryptococcus neoformans and invasive molds.[126]
Vascular Access Devices
Indwelling venous access devices are commonly required in cancer patients for the administration of chemotherapy, blood products, and parenteral nutrition, as well as for withdrawal of blood for therapy monitoring and microbiologic evaluation. Infection is a common complication of venous access devices. The risk of infection varies with the device used, duration of placement, and extent of the patient's immunosuppression. Local signs and symptoms, such as erythema and tenderness, are unreliable indicators of catheter infection even in the immunocompetent patient. The evolution of these signs over time, however, is suggestive of infection. Venous access device infections are categorized as entry site infections, tunnel or pocket infections, and catheter-associated bloodstream infections. [24] [127]
Entry-site infections can be treated effectively with appropriate antimicrobial therapy, without the need for catheter removal. Tunnel (i.e., erythema, induration or tenderness beyond 2cm from the entry site) and pocket infections necessitate catheter removal, as well as the immediate initiation of an empirical antimicrobial therapy that includes vancomycin to cover methicillin-resistant S. aureus, until culture results are available.
It often is difficult to determine whether a bloodstream infection is related to the venous access device because frequently, no evidence of local catheter inflammation is seen. Recently, however, the concept of “differential time to positivity” has been used to distinguish venous access device–related infections from other types of infection, as follows: If the times at which blood cultures become positive (by machine detection in the clinical microbiology laboratory) are more than 2 hours apart for simultaneously obtained catheter and peripheral vein blood cultures, the catheter is then strongly implicated as the source of infection.[127] Although this differentiation may help determine whether a catheter can be retained or must be removed, most indwelling catheter-related infections will respond to antimicrobial therapy alone, without catheter removal. Certain exceptions are notable: Catheter removal is advisable for patients with bloodstream infections caused by fungi (yeasts and molds) and nontuberculous mycobacteria (M. chelonae, M. fortuitum, M. abscessus). For other bacteria, the decision concerning the need for catheter removal will depend on the severity of the clinical picture, the degree of immunosuppression, and the availability of an alternative vascular access site in a given patient. S. aureus may cause endocarditis, and the value of the transesophageal echocardiography in the setting of any S. aureus bloodstream infections has been well demonstrated to determine duration of therapy.[128] In general, if blood cultures remain positive despite appropriate antimicrobial therapy for more than 48 hours, or if the patient is clinically unstable, the catheter should be removed independent of the etiology.
Viral Infections
The incidence of herpes simplex virus (HSV) reactivation infections has been reduced with the widespread use of acyclovir prophylaxis. Reactivations not involving the CNS are treated with lower doses of intravenous acyclovir (e.g., 5 mg/kg every 8 hours) or similar drugs given orally, whereas VZV infections are treated with higher doses (e.g., intravenous acyclovir 10 mg/kg every 8 hours or oral valacyclovir 1000 mg every 8 hours). Acyclovir resistance is very uncommon among cancer patients. HSV infections that break through acyclovir prophylaxis, however, should be considered to be acyclovir-resistant until viral sensitivity testing can be performed, and consideration should be given to initiating treatment with foscarnet or cidofovir. Reports of acyclovir-resistant varicella are extremely rare.[129]
Patients at highest risk of CMV reactivation include recipients of allogeneic bone marrow transplants in the early period after engraftement (i.e., days 30 to 100 after transplantation) during which invasive CMV disease will develop in approximately 2% of patients.[130] Also, patients receiving alemtuzumab and those receiving high-dose corticosteroids for GVHD are at high risk. Universal prophylaxis and preemptive strategies using ganciclovir or valganciclovir have markedly reduced the incidence of CMV disease in these patient groups.[131] Asymptomatic CMV viremia or “CMV syndrome” (fever, leukopenia) without end-organ disease is common in the absence of universal prophylaxis, and is often a trigger for starting an antiviral preemptively, as described later.
End-organ CMV disease most commonly involves the lungs, gastrointestinal tract, or liver. [132] [133] Definitive diagnosis requires histopathologic evidence, but compatible clinical findings (e.g., colonic ulcers, interstial pattern on chest radiography) in the setting of CMV viremia diagnosed by PCR or antigen testing is suggestive of invasive disease. CMV treatment is initiated with induction doses of the antiviral agent for at least 2 weeks, followed by a variable course of maintenance dosing, which is one-half the induction dose. The total duration of treatment depends on clinical response, the results of viremia or antigenemia assays that reflect viral replication activity, and the patient's overall state of immunosuppression. Intravenous ganciclovir generally is used for the initial antiviral course (induction dose of 5 mg/kg every 12 hours, maintenance dose of 5 mg/kg once daily) when end-organ disease is documented, although some centers are increasingly using oral valganciclovir in patients who can reliably absorb the drug. The valganciclovir dose in patients with normal renal function is 900 mg twice daily for at least a 2-week induction and then 900 mg once daily to complete 1 to 3 months of treatment. Foscarnet and cidofovir are options, albeit somewhat toxic, for patients who are intolerant of or unresponsive to ganciclovir or valganciclovir.
When the end-organ manifestation of CMV infection is pneumonitis, intravenous immune globulin (IVIG) given at a dose of 500 mg/kg typically is added on an every-other-day basis for the duration of induction. [94] [132] When CMV infection manifests in an end organ other than the lungs, the use of IVIG is not so clearly delineated. For other end-organ manifestations of CMV disease, IVIG can be added if the patient's total immunoglobulin G (IgG) level is below 400 mg/dL. No clear advantage favors CMV hyperimmune globulin over regular IVIG. [94] [132]
HHV-6, a virus acquired by 95% of humans during childhood, reactivates asymptomatically in up to 50% of patients after allogeneic HSCT. [134] [135] Clinical disease is uncommon but may include interstitial penumononitis, encephalitis, rash, cytopenias, and delayed engraftment. [134] [135] PCR assay performed on plasma, tissue biopsy material, or CSF can be useful in suggesting HHV-6–associated disease. HHV-6 has 60% DNA homology with CMV, and treatment of documented infection usually is initiated with induction doses of foscarnet or ganciclovir, although responses are variable and it is unclear which drug is more effective.[136]
Respiratory syncytial virus (RSV) and influenza virus infections generally are seasonal; parainfluenza and adenovirus infections may occur year round. Upper respiratory infections may progress to pneumonia, with mortality rates between 6.6% and 80% in heavily immunosuppressed patients. [137] [138] A neuraminidase inhibitor commonly is used to treat influenza and may prevent progression from upper respiratory infection to pneumonia, but prolonged shedding and the development of resistance may occur.[139] Inhaled ribavirin reduces RSV shedding, but clinical efficacy has not been demonstrated[140]; furthermore, difficulty of administration and occupational exposure issues limit use of this agent.
Adenovirus may cause pneumonia, colitis, hemorrhagic cystitis, hepatitis, or disseminated disease with a sepsis-like presentation in patients undergoing allogeneic HSCT.[141] Asymptomatic reactivaton is common in adults, but rising levels of viremia or isolation from multiple sites has been associated with an increased risk of severe disease. No standard treatment has been validated, but cidofovir (1 mg/kg three times a week or 5 mg/kg weekly) has been associated with a reduction in levels of viremia.[142]
Reactivation of BK virus in the uroepithelium may lead to hemorrhagic cystitis in the allogeneic transplant recipient, and quantitative PCR assay for BK virus in urine and plasma may be helpful both diagnostically and in assessing response to treatment. [143] [144] Low-dose cidofovir (1 mg/kg weekly) has been used for treatment, but its efficacy is unknown.[145]
PREVENTION OF INFECTIONS IN SELECTED RISK GROUPS
General guidelines for prevention of infections are shown in Table 47-5 .
Table 47-5 -- Prophylaxis for Selected Risk Categories
|
Risk Category |
Bacterial |
Duration |
Viral[*] |
Duration |
Fungal |
Duration |
PCP[†] |
|
Most solid tumors |
None |
— |
None[‡] |
Neutropenic period |
None |
— |
None |
|
Acute leukemia/MDS |
Fluoroquinolone |
Neutropenic period |
HSV, VZV |
Neutropenic period |
Posaconazole |
Neutropenic period |
Only patients with ALL |
|
Autologous HSCT (neutropenic period) |
None |
— |
HSV, VZV |
Neutropenic period and 30 days after |
Fluconazole |
Neutropenic period |
For 90–180 days after transplantation |
|
Allogeneic HSCT |
Penicillin |
Minimum 1 year after transplantation |
HSV, VZV, CMV |
HSV and VZV during neutropenia, some centers continue for up to 1 year, CMV monitoring to day 100 minimum |
Fluconazole (some centers use moldactive agent) |
75 days after transplantation |
For at least 6 months after transplantation |
|
GVHD |
Penicillin |
Until resolution of GVHD and off immunosuppression |
HSV, VZV, CMV |
Until resolution of GVHD and off immunosuppression |
Posaconazole |
Until off significant immunosuppression |
Until resolution of GVHD |
|
Alemtuzumabs |
None |
None |
HSV, VZV, CMV |
At least 2 months and CD4+ ≥100 cells/μL |
Consider |
None |
At least 2 months and CD 4+ ≥200 cells/μL |
|
Purine analogs[§] |
None |
None |
HSV, VZV |
At least 2 months |
None |
None |
At least 2 months and CD4+ ≥200 cells/μL |
|
ALL, acute lymphoblastic leukemia; CMV, cytomegalovirus; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; MDS, myelodysplastic syndrome; PCP, Pneumocystis pneumonia; VZV, varicella-zoster virus. |
|
* |
HSV or VZV prophylaxis with acyclovir, valacyclovir, or famciclovir; see text (under Prevention of Infections in Selected Risk Groups) for CMV prophylaxis strategy. |
|
† |
Agents used for PCP prophylaxis include trimethoprim-sulfamethoxazole, dapsone, atovaquone, and inhaled pentamidine. |
|
‡ |
HSV prophylaxis for patients with a history of HSV reactivation. |
|
§ |
Fludarabine, cladribine, pentostatin. |
Low-Risk Patients
Patients categorized at low risk for complications during fever and neutropenia include most with solid tumors. These patients are at lower risk for serious infections, so they do not generally require any prophylaxis against bacteria, fungi, or viruses. Although one recent large randomized study demonstrated that levofloxacin prophylaxis led to a statistically significant decrease in febrile episodes, hospitalizations, and possible infections in a group of largely low-risk patients (e.g., those with breast cancer, testicular cancer, or small cell lung cancer), the reductions seen were of marginal clinical significance. Consequently, this practice is discouraged by most experts. [146] [147] [148] The absolute risk reduction for a first febrile episode was only 4.4%, documented infections were rare, and mortality was unaffected by prophylaxis.[147] Concerns for antimicrobial resistance and for increasing incidence of severe C. difficile with widespread fluoroquinolone use are also reasons to limit the use of these agents. Furthermore, because fluoroquinolone-based outpatient treatment of fever during neutropenia is an option for many low-risk patients, routine fluoroquinolone prophylaxis in these patients would eliminate that attractive possibility. Routine fungal or viral prophylaxis also is not required for low-risk patients, with the exception of HSV prophylaxis in patients with a history of HSV reactivation.
Patients who receive autologous transplants may be considered to be at intermediate risk for severe infections in that the associated period of neutropenia is relatively long, often at least 10 days, but they typically experience few complications. The role of prophylaxis in these patients varies with the center and the preparative regimens used; consistent recommendations are lacking.
Patients with Acute Leukemia
Patients undergoing induction or consolidation therapy for acute leukemia have a prolonged period of neutropenia, and the use of routine antibacterial prophylaxis during the period of neutropenia has been controversial. A recent large trial randomized patients with expected duration of neutropenia longer than 7 days to receive either treatment with 500 mg of levofloxacin daily or placebo. Among patients with acute leukemia, a reduction in febrile episodes, microbiologically documented infection, and bacteremia was observed with levofloxacin treatment; however, no mortality benefit was seen.[149] A meta-analysis of clinical trials of fluoroquinolone prophylaxis in high-risk patients did show a survival advantage.[150] The NCCN curently recommends antibacterial prophylaxis with a fluoroquinolone (levofloxacin preferred) for patients with acute leukemia with expected duration of neutropenia of greater than 7 days.[2] Potential problems associated with routine antibacterial prophylaxis include C. difficile colitis, fungal superinfections, and the development of antimicrobial resistance.
Similarly, in patients with acute leukemia, a recent trial suggested a morbidity and mortality benefit with the use of antimold prophylaxis with posaconazole. This trial, conducted in more than 600 patients with acute leukemia or myelodysplastic syndrome, randomized patients to prophylaxis with itraconazole, fluconazole, or posaconazole until recovery from neutropenia and complete remission of disease were obtained.[151] Patients who received treatment with posaconazole experienced significantly fewer invasive mold infections and had a survival benefit. Based on this data, posaconazole should be considered the agent of choice for antifungal prophylaxis in neutropenic patients with acute leukemia. Many centers use voriconazole for this purpose because its activity against Aspergillus spp. also is potent, but no comparative study has been done to show equivalence of voriconazole and posaconazole for this purpose.
HSV reactivations in seropositive cancer patients are frequent after chemotherapy and are associated with increased mucosal damage, resulting in increasing pain, limitation of the patient's ability to maintain oral hydration and nutrition, and an increased risk of bacterial and fungal superinfections. Therefore, HSV prophylaxis with acyclovir, valacyclovir, or famciclovir is recommended during the period of neutropenia for patients with acute leukemia. Although VZV reactivation is less common than HSV reactivation, life-threatening disseminated disease may occur, and the foregoing agents will serve as prophylaxis for this pathogen as well. CMV disease is not common in this population, and no routine preventive strategy is required. With the exception of patients with acute lympocytic leukemia (ALL), routine prophylaxis against PCP is not required.
Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Bacterial infections may cause over 25% fevers in the pre-engraftment phase of allogeneic HSCT, so antibacterial prophylaxis (usually with a newer fluoroquinolone) is often used during this period[152] (Fig. 47-2 ). This practice has been shown to reduce the incidence of infections, particularly those due to gram-negative organisms, in other high-risk groups (see earlier section), but has not been consistently associated with a decrease in mortality. [149] [150] Because of the risk of resistant organisms and C. difficile infection, some centers choose not to use routine prophylaxis for allogeneic transplant recipients.[153] [154] After engraftment, prophylaxis against encapsulated organisms is indicated. Penicillin prophylaxis has decreased the incidence of infection-related morbidity and mortality from S. pneumoniae, H. influenzae type b, and N. meningitidis significantly. Prophylaxis generally is discontinued 1 or 2 years after transplantation, or later if immunosuppression is ongoing at the 2-year point. Prophylaxis with TMP-SMX (or atovaquone, dapsone, or aerosolized pentamidine, if intolerant) for 6 months after transplanation is indicated to prevent PCP.
|
Figure 47-2 Phases of predictable immune suppression with characteristic opportunistic infections among allogeneic hematopoietic stem cell transplant recipients. CMV, cytomegalovirus; GVHD, graft-versus-host disease; HSV, herpes simplex virus; VOD, veno-occlusive disease; VZV, varicella-zoster virus. |
Fluconazole prophylaxis has been clearly demonstrated to prevent candidemia and hepatosplenic candidiasis among allogeneic transplant recipients, with treatment generally continuing to day 75 after transplantation. [155] [156] [157] [158] Fluconazole, however, does not have activity against yeasts such as C. glabrata (some strains) and C. krusei, or molds such as Fusarium, Aspergillus, and the zygomycetes. Some centers use prophylaxis with a moldactive agent such as voriconazole in high-risk patients (i.e, mismatched or matched unrelated donor transplants), and a recent trial demonstrated voriconazole to be equivalent to fluconazole for the prevention of fungal infections when administered for the first 100 days (180 days for those receiving prednisone at a dose of ≥1 mg/kg/day or for recipients of T-cell depleted grafts with CD4+ counts <200 at day 100) after transplant.[159]
Prevention of CMV disease after allogeneic HSCT can be effectively accomplished using either universal prophylaxis or preemptive therapy with ganciclovir or valganciclovir. [160] [161] The preemptive strategy employs weekly or twice-monthly blood antigenemia or PCR viral load monitoring tests to guide initiation of antivirals, whereas universal prophylaxis involves providing the drug to all patients at risk (all but seronegative donors and recipients). A majority of transplant recipients will initially manifest CMV reactivation silently; this typically is detected by the weekly monitoring test before the development symptoms (e.g., fever) or end-organ disease. Severe end-organ disease can occur if subclinical reactivations are not treated. The preemptive strategy is preferred to universal CMV prophylaxis for two reasons: First, it decreases exposure to this marrow-toxic drug, and, second, allowing for some low-level replication of CMV, recovery of CMV-specific immunity may be enhanced. Both strategies, however, appear to shift the timing of CMV reactivations to later (after day 100, when monitoring often stops) in the postengraftment course, after it is discontinued in those transplant recipients at higher risk.[159] Strategies for preemptive therapy vary; typically, intravenous valganciclovir or ganciclovir is administered at induction dosing for 7 to 14 days and then reduced to maintenance dosing if reduction in viremia or antigenemia is observed.[162] Treatment may be continued for 2 to 3 weeks after a negative result on a viremia or antigenemia test, and then weekly monitoring is resumed. In most centers, weekly monitoring is continued for at least 100 days, and longer if immunosuppression for GVHD is needed.
For patients seropositive for HSV and VZV, most centers use antiviral prophylaxis with acyclovir or an equivalent agent (valacyclovir, famciclovir) during the neutropenic period, and some continue for up to a year to prevent VZV reactivation. These agents should be stopped if a patient is receiving ganciclovir or valganciclovir.
Vaccination after allogeneic HSCT should be initiated once cellular immunity is thought to be reconstituted. Typically, this occurs at approximately 1 year after transplantation, provided that the patient is not on continued immunosuppression for GVHD. Table 47-6 shows a standard vaccination schedule for after allogeneic transplantation.
Table 47-6 -- Vaccine Schedule after Hematopoietic Stem Cell Transplantation
|
Vaccine |
12 mo |
14 mo |
24 mo |
|
INACTIVATED-ORGANISMVACCINES |
|||
|
Begin reimmunization at 1-year anniversary visit. |
|
|
|
|
Diphtheria, tetanus, pertussis[*] |
× |
× |
× |
|
Haemophilus influenzae type b conjugate |
× |
× |
× |
|
Hepatitis B |
× |
× |
× |
|
Pneumococcal 23-valent |
× |
|
Optional |
|
Inactivated polio |
× |
× |
× |
|
Influenza |
Seasonal if >6 months after transplantation |
||
|
LIVE-VIRUS VACCINES |
|||
|
Reimmunize at 2-year anniversary visit if no active graft-versus-host disease or immunosuppressive therapy. |
|
|
|
|
Mumps-measles-rubella |
|
|
× |
|
Varicella |
|
|
× |
|
* |
One of these three boosters should be the Tdap tetanus–diphtheria–acellular pertussis vaccine. |
Patients with Graft-versus-Host Disease
GVHD and its treatment result in significant suppression of the cell-mediated immune system and high risk of certain infections. The use of penicillin to prevent infection with encapsulated organisms (e.g.,Streptococcus pneumoniae) is widely accepted, [2] [161] despite the fact that S. pneumoniae is increasingly resistant to this agent.
Although invasive mold infections, particularly invasive aspergillosis, constitute a serious threat during GVHD, few studies have evaluated fungal prophyalxis until recently. A large randomized trial comparing the new triazole posaconazole with fluconazole in patients with grade II or IV acute GVHD or chronic extensive GVHD has now demonstrated a reduction in overall breakthrough invasive fungal infections including invasive Aspergillus infections.[163] No effect on mortality was observed, however. Based on this trial, the NCCN recommended posaconazole prophylaxis in patients who are undergoing immunosuppressive treatment for severe GVHD.[2] Posaconazole currently is available only as an oral suspension that must be taken three times daily with a high-fat meal, which is critical for adquate absorption of the drug. Patients with GVHD of the gut may not be able to tolerate this regimen. Voriconazole and echinocandins are potential alternatives but are not well studied for prophylaxis in this setting.
Antiviral prophylaxis with acyclovir or an equivalent drug (e.g., valacyclovir, famciclovir) is widely used to prevent HSV- or VZV-related disease. Most centers have adopted a preemptive monitoring approach, as discussed previously (see earlier section, Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation) to decrease the incidence of CMV-related disease. TMP-SMX or an alternative agent for intolerant patients (e.g., dapsone, inhaled pentamidine, atovaquone) is routinely used as prophylaxis against PCP while patients remain on immunosuppression.
Prophylaxis with Other Immunosuppressive Therapies
Alemtuzumab (Campath) has been used with increasing frequency in patients with a variety of lymphoproliferative disorders, with the primary effect being prolonged suppression of cellular immunity. In one study of patients with B-cell CLL, the median time to reach a CD4+ count greater than 100 cells/mL was 4 months, and the median CD4+ count was less than 25% of baseline at 9 months.[164] A high frequency of CMV reactivation and bacterial infections has been reported during alemtuzumab therapy, and opportunistic infections similar to those seen in patients with late-stage AIDS (e.g., PCP, progressive multifocal leukoencephalopathy, cryptococcosis, disseminated histoplasmosis, cerebral toxoplasmosis) also have been described. [165] [166] Prophylaxis against PCP with TMP-SMX or an alternative agent should be given for at least 2 months after completion of alemtuzumab therapy and probably should be continued until the CD4+ count is above 200 cells/μL. Weekly monitoring for CMV infection (i.e., antigenemia or PCR) should be instituted until a CD4+ cell count is greater than 100 cells/mL, and positive results should be treated (see Viral Infections). Acyclovir or an equivalent agent also should be considered throughout the course of cellular immunosuppression to reduce the risk of HSV or VZV reactivation. Although serious bacterial and fungal infections also appear to be increased with alemtuzumab, it is thus far unclear what type of prophylaxis should be undertaken in these patients.[167]
Purine analogs (e.g., fludarabine, cladribine, pentostatin) also cause a depletion of T-cell populations and an increased risk of opportunistic infections compared with traditional therapy with alkylating agents. The rate of opportunistic infection varies considerably, but patients who have received previous therapy, partially or nonresponding patients, and patients receiving other agents (e.g., alkylating agents, corticosteroids) are at higher risk for such infections. [12] [168] Prophylaxis against PCP for 2 months and until the CD4+ count is above 200 cells/μL is recommended. Antiviral prophylaxis with acyclovir or an equivalent drug should be considered in these higher-risk patients. The role of antifungal prophylaxis with fluconazole or a moldactive agent in this population is unclear.
PRETRANSPLANTATION MEASURES TO PREVENT INFECTION
Pretransplantation Serostatus Blood Work
The serostatus of herpesviruses (HSV, VZV, CMV, and EBV) that may be present in latent form in the body should be checked before transplantation to determine if the patient is at risk for reactivation. Current testing of both donor and recipient before the transplant-preparative regimen begins includes not only herpesvirus antibodies but also hepatitis virus panels, human T-cell lymphotrophic virus (HTLV-I and HTLV-II) antibodies and human immunodeficiency virus (HIV), and syphilis serology.
The only test result that could lead to immediate cancellation of the transplantation procedure would be a positive result on HIV testing in a patient not known to be seropositive. If the screening test for HIV is positive from either the donor or the recipient, a Western blot study should be completed to confirm the result before informing the affected person of the screening test result. Any time a positive HIV test result is conveyed to a patient, appropriate counseling must be provided.
Several serostatus test results, if positive, would not constitute an indication to cancel the transplant but would lead to a different action plan.[169] If the indirect screening test for syphilis, such as the rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test, yields a positive result, confirmed by a direct test, the fluorescent treponemal antibody (FTA) test, then the patient should receive high-dose penicillin treatment for 10 to 14 days.
Hepatitis B (core antibody, surface antibody, and surface antigen) and C serologic studies are performed in donor and recipient before transplantation; if results are positive, viral load testing should be performed. Hepatic dysfunction from either hepatitis B or C after transplant can lead to life-threatening liver complications. [170] [171] [172] Hepatitis occurs within months or the first few years after transplantation in approximately 20% of HBsAg recipients, whereas cirrhosis developing over a period of many years usually is due to hepatitis C.[173] A hepatitis virus-infected person may serve as a donor if no alternative donor is available or if the intended recipient is already seropositive. The risk of transmission is lowest when a hepatitis B- or hepatitis C-positive donor has an undetectable viral load. Accordingly, donors found to have high viral loads on testing for hepatitis B or C should receive treatment with appropriate antivirals to reduce viral loads before transplantation and before donation, in conjunction with hepatology consultation. [174] [175] Similarly, transplant recipients with serologic evidence of previous infection with hepatitis B or C, or those who receive cells from a seropositive donor, should have viral load levels monitored before and after transplantation and also may require treatment. Agents with activity against hepatitis B virus include lamivudine, tenofovir, and entecavir. Hepatitis C currently is treated with pegylated (PEG) interferon and ribavirin, with acceptable safety profiles and cure in up to 50% of patients.[176] Regarding hepatitis C, no evident correlation exists between hepatitis C genotype and type or severity of liver disease after transplantation.[177]
CMV, HSV, and VZV serologic studies are routinely performed before transplantation. If either the donor or the recipient is seropositive, a prevention strategy as presented earlier is used. If both the recipient and the donor are CMV-seronegative, seroconversion with blood products is possible, so CMV-seronegative or filtered blood products should be used. [178] [179] Patients seropositive for HSV or VZV (or with a reliable history of chickenpox) receive prophylaxis as discussed. VZV-seronegative patients should receive varicella-zoster immune globulin (VZIG) prophylaxis within 96 hours of significant exposure.[160] If VZIG is not available, most experts would treat with acyclovir or valacyclovir for 3 weeks.
Knowing the EBV serostatus before transplantation is not mandatory because 95% of adult patients can be assumed to be seropositive for this virus. EBV-driven PTLD occurring as a consequence of EBV reactivation is in the differential diagnosis for any space-occupying mass after transplantation, but this usually occurs several months after the neutropenic phase.[180] Major risk factors for the development of PTLD include primary EBV infection after transplantation in a seronegative recipient, the use of antithymocyte globulin or anti-CD3 monoclonal antibodies for immunosuppression, and CMV primary infection or reactivation. [181] [182] [183] Mismatched or unrelated donor stem cell grafts or T-cell–depleted grafts also are associated with an increased risk for PTLD. Although the incidence of PTLD after allogeneic HSCT is as low as 0.5% in patients without major risk factors, it increases to 22% in patients with three or more risk factors. Routine monitoring of EBV viral load appears to be of limited value after transplantation, however.[184]
Historically, 15% of patients receiving transplants in the United States are seropositive for T. gondii, but this percentage may be higher in European centers.[185] The risk of reactivation among seropositive patients is 2%, for an overall incidence of less than 1% of transplant recipients. [185] [186] Because serologies for T. gondi may be unreliable after transplantation, serologies should be obtained prior to transplant because this information can be useful in evaluating patients who later develop syndromes (e.g., CNS mass lesion) compatible with toxoplasmosis. It is likely that low-dose sulfa-based regimens such as those used to prevent PCP also are effective in preventing Toxoplasma infection. [186] [187]
Environmental Measures to Prevent Infection during and after Transplantation
Handwashing or, preferably, the use of alcohol-based hand-rub disinfectant is the mainstay of infection prevention in the hospital or clinic.[188] Persons entering the patient room to perform examination or touch the patient (including visitors as well as health care workers) should wash or disinfect their hands outside the room.[16] During respiratory virus season, infection control teams will often add extra signs to doorways and in other areas of the wards to remind visitors of the importance of handwashing. Staff and visitors without control of body secretions should not be permitted to have direct patient contact. It should be stressed, however, that routine use of gown, gloves, and masks is not required in the presence of a neutropenic patient.
Some infectious situations necessitate use of special isolation procedures.[16] Contact isolation (gloves, gowns) is indicated for encounters with patients with adenovirus, methicillin-resistant S. aureus, or C. difficile infection. Droplet precautions are added to contact precautions for respiratory virus or varicella infection. Carriers of vancomycin-resistant enterococci are placed in contact isolation until they meet federally determined criteria for discontinuation of isolation, including a negative result on culture from the original site of positive culture, if the site is still available for culture (as in wound or urine), plus three consecutive negative results on culture of rectal swabs taken at least 1 week apart.[189]
High-efficiency particulate air (HEPA) filtration has replaced laminar air flow as the means of prevention of infection through ventilation in most transplant centers.[16] With at least 12 air exchanges per hour, HEPA filters are capable of removing particles larger than 0.2 mm in diameter, such as mold spores. In addition, it is recommended that room air pressure be maintained continuously above that of the corridor (i.e., positive-pressure environment). These environmental measures are recommended for allogeneic transplant recipients; it does not appear that autologous transplant recipients require this level of protection. For individual patients, such as those who will receive T-cell–depleted transplants, “upgrade” to a laminar air flow environment may be considered. Not all centers, however, continue to maintain laminar air flow patient rooms, and the use of these facilities remains controversial.[16]
Patients may ask if portable HEPA filters should be purchased for the home or apartment that will be occupied after hospitalization is over. In the broadest sense, this extra measure can be recommended on an individual basis, but if portable HEPA filters are used, then they should be obtained for each of the rooms that the patient will occupy during the day and night, and each unit should be sized for the individual room.
Review of Commonsense Measures That Will Assist in the Prevention of Infection
After transplantation, questions often arise about the infectious potential of diet, travel, exposure to crowds, and pets.[160] Diet should be reviewed so that both provider and patient recognize whether the patient is taking any restricted foods or herbal supplements.[160] Patients may not realize that such supplements fall in the same category with medications, and that most herbal supplements need to be discontinued after transplantation.[190]
Foodborne infections constitute an increasingly difficult problem in the United States. Ground meat products must be cooked thoroughly so that bacteria distributed onto meat in the grinding process, such as E. coli O157:H7, are killed. Any fruits or vegetables that cannot be peeled must be washed thoroughly before being eaten, and patients should be aware that salad bars are associated with occasional transmission of Salmonella, Shigella, and E. coli infections. [191] [192] Food products that inherently contain infectious organisms should be avoided, including undercooked eggs (Salmonella), miso soup (Aspergillus), and soft cheeses or unpasteurized dairy products (Listeria) or blue cheeses (molds). Yogurt containing Lactobacillus has been found to cause lung infection rarely, possibly after aspiration events.[193]
No particular restrictions apply to travel, but strategies to minimize transmission of infectious diseases have been summarized.[160] Some social situations, such as sitting in a crowded movie theater or classroom, increase the risk of acquiring a viral illness. Turning away from people who are coughing or sneezing, or even quickly donning a mask, may be helpful in preventing transmission of infection in the first months after transplantation, until immunosuppression is stopped. Patients should be instructed to practice appropriate infection prevention by handwashing as soon as possible after being close to someone with a cold. In view of recent outbreaks of infection with noroviruses (Norwalk-like viruses) on cruise ships, and other types of outbreaks (e.g., staphylococcal infection) commonly associated with the close living quarters typical with this type of vacation, cruise ships should not be high on the list for vacation choices. [194] [195]
Healthy dogs and cats are considered acceptable pets. The immunosuppressed patient, however, should avoid any contact with used cat litter, including “scooping” the litter box, because of potentialToxoplasma cyst exposure. Similarly, the patient should not play in sandboxes, because these areas may be used by outdoor cats as litter boxes. Because reptiles of many sorts have been reported to be infected with Salmonella, the patient should not touch these animals or the inside or outside of their aquarium homes. The heated water of tropical fish tanks may carry Mycobacterium marinum.Cryptococcus and Chlamydia psittaci can be transmitted from large pet birds.
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