| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Abstract
One of the most common complications involved in treating patients with hematologic cancer is infection. In many cases there are multiple factors that predispose these patients to infections such as neutropenia induced by therapy or bone marrow involvement, hypogammaglobulinemia, T-cell dysfunction, and mucosal damage. In addition, newer therapies have changed the spectrum of infection that is seen in these patients.
In Section I, Dr. Blijlevens discusses mucosal damage as a major risk factor for complications of cytotoxic chemotherapy. She focuses on mucosal barrier injury (MBI) as manifest in the GI tract and will describe a pathological model to explain MBI, evaluate risk factors for development of this syndrome, explain the relationship between MBI and infection, and discuss treatment and prevention of this injury.
Invasive fungal infections continue to represent a significant problem in patients with hematologic cancer. In Section II, Drs. Anaissie and Mahfouz review the latest developments in the diagnosis, prevention, and management of invasive fungal infections with a focus on a risk-adjusted approach to this problem.
Finally, in Section III, Dr. O’Brien reviews infections associated with newer therapeutic regimens in hematologic cancers. The spectrum of infections has changed with the use of purine analogs and the advent of monoclonal antibodies. The profound T-cell suppression associated with these therapies has led to the emergence of previously rare infections such as cytomegalovirus. An approach to both prophylaxis and management of these infections is discussed.
Nicole M.A. Blijlevens, MD*
Today there are more than 10 million patients worldwide with cancer and this number is expected to increase with an increasingly elderly population. Intensive chemotherapy alone or in combination with radiation therapy is available for a variety of different cancers. Unfortunately, this treatment is often complicated by damage to the integument of the mouth and, to a larger extent, of the gastrointestinal (GI) tract, which results in significant morbidity and a lower quality of life.1 While the severe pain of oral mucositis is often the most obvious and troublesome symptom of patients undergoing intensive cytotoxic therapy, gastrointestinal injury is more life threatening.2 There is some evidence that intensive cytotoxic chemotherapy also damages the mucosa of the upper and lower airways, the bladder, and the vagina. However, the focus of this review is on what has been termed "mucosal barrier injury" (MBI) as manifest in the mouth and GI tract, and will present a pathological model to explain MBI, explore the risk factors involved, highlight the relationship between MBI, infection, and other complications and discuss treatment and prevention.
Defining Mucosal Barrier Injury
Oral mucositis
Each regimen used in anticancer treatment is associated with varying degrees of mucosal damage. Oral mucositis is reported to affect 60% to 100% of hematopoietic stem cell transplant recipients when myeloablative preparative regimens are used. In general, oral mucositis is characterized by functional complaints such as pain and difficulty in swallowing (dysphagia) and anatomical changes such as edema, erythema, ulceration, pseudomembrane formation, alterations in mucus consistency, and changes in saliva production (xerostomia). When severe or protracted, oral mucositis prevents patients from eating and drinking normally. This problem is frequently managed by giving parenteral nutrition. A rational basis for managing oral mucositis is still a distant goal because of the lack of a single, uniform, practical, validated tool to measure oral mucositis. Hence, grading systems like that of the World Health Organization or the National Cancer Institute3 and center-specific systems such as the Daily Mucositis Score4 are widely used although never formally validated. The modified oral mucositis assessment scale (OMAS) was developed and validated to provide a scoring system that would be generally accepted and used for observational studies and in future multicenter clinical trials of prevention and treatment.5 Only time will tell whether the OMAS scheme will become generally accepted. Besides recording the presence of mucositis, the OMAS scheme lends itself to repeated, regular monitoring of oral mucositis, a feature shared with other scoring systems.4,6–8 This, in turn, allows the extent of oral mucositis to be estimated by the area under the oral mucositis curve. Irrespective of the grading system used, oral mucositis is known to begin around a week after starting conditioning and to worsen until a peak is reached after which resolution takes place (Figure 1
).
|
Patient-related risk factors: Patient-related risk factors include age, gender, nutritional status, composition of the oral microflora, salivary function, and the status of oral health and hygiene. The data are sometimes conflicting. For instance, age and gender can either increase or decrease the severity of oral mucositis. General malnutrition, specific deficiencies in vitamins, trace elements and/or antioxidants are thought to exacerbate mucositis.9 Xerostomia that is already present before starting chemotherapy also makes mucositis worse. Contradictory data also exist regarding factors like body mass index, body surface area, or total body nitrogen since these can also adversely influence mucositis. Whether these factors truly indicate the risk of mucositis or simply reflect an altered pharmacodynamic profile of the drugs used for chemotherapy is unclear. Dental care and oral hygiene are also held to be important although randomized studies evaluating the effect of mouth rinses, especially chlorhexidine and oral decontamination regimens, could not show any benefit in reducing mucositis, pain, or oral infection beyond the use of a systematic oral hygiene program.10
Therapy-related risk factors: A large number of cytotoxic agents produce oral mucositis, although specific agents with comparable cytotoxic potential injure the oral mucosa in a wide variety of ways. Antimetabolites and alkylating agents produce a high incidence of oral mucositis. Hematopoietic stem cell transplant (HSCT) recipients treated with regimens containing total body irradiation (TBI) experience more severe mucositis than do patients treated with busulfan containing regimens, although other reports disagree. Addition of idarubicin to the preparative regimen prolongs bone marrow aplasia but also worsens oral mucositis. Wardley and colleagues used multivariate analysis to identify risk factors including age, HSC source, use of myeloid growth factors, and drug regimen and found that the conditioning regimen was the only independent risk factor for oral mucositis.11 Furthermore, high-dose melphalan-based regimens resulted in the highest mean peak mucositis although the onset of mucositis was significantly delayed in comparison with the other regimens (busulfan, busulfan-cyclophosphamide, cyclophosphamide-TBI, cyclophosphamide-carmustine with or without etoposide). In patients undergoing an autologous transplant, prior radiation therapy, a diagnosis of non-Hodgkin’s lymphoma (NHL), and a regimen containing etoposide for the mobilization of progenitor cells was associated with more severe mucositis and a prolonged length of hospital stay. Certain chemotherapeutic agents such as etoposide and methotrexate may also be secreted in the saliva thereby intensifying oral mucositis.
Gut Injury
Signs and symptoms
Much more is known about oral mucositis than its gastrointestinal counterpart. Indeed, there are no reliable data on the incidence of gut injury although bowel symptoms like nausea, vomiting, diarrhea, and abdominal complaints affect almost every HSCT recipient. Moreover, the exact course and severity of gut injury are difficult to ascertain because many patients receive narcotic analgesics to relieve pain associated with oral mucositis thereby masking or dampening gastrointestinal complaints. Measurements like fecal volume according to the National Cancer Institute (NCI)–Common Toxicity Criteria and parameters such as the days of diarrhea and duration in days of parenteral nutrition are commonly used to evaluate gut injury. Use of the latter, although convenient, is heavily influenced by several other factors like oral pain, dysphagia, and the patency of central venous catheters but also by physician preference, department protocol and hospital policy. Whether patient-related risk factors play any role in gut injury remains to be seen. By contrast, treatment-specific risk factors have been reported. Diarrhea is related to specific drugs like 5-fluorouracil, docetaxel, and cytosine arabinoside. The active metabolite of irinotecan (CPT-11), SN-38, can be deconjugated in the gut by bacterial ß-glucuronidase resulting in mucosal damage. When TBI is included in the conditioning regimen, significantly more HSCT recipients experience severe diarrhea12; the duration of parenteral nutrition is prolonged in younger patients, those who receive a bone marrow transplant, and when TBI is included in the regimen.2 Diarrhea that develops following allogeneic HSCT is most likely attributed to acute graft-versus-host disease (GVHD) but this was only true in 72 of the 150 (48%) of the episodes in a prospective study in which biopsies were obtained endoscopically.13 Nausea and vomiting are universal in the first 24 hours after high-dose chemotherapy without antiemetic therapy and a later onset is particularly common with cyclophosphamide. Nausea and vomiting can also persist for 2–8 weeks after autologous HSCT without evident signs of mucositis or obstruction. Gastroparesis appears to play an important role because symptoms of bloating, nausea, and vomiting are consistent with delayed gastric emptying,14 which, in turn, is influenced by the use of opiates but could also be due to autonomic neurologic damage induced by the preparative regimen.
Noninvasive tests
Hence, it is difficult to determine gut toxicity based solely on signs and symptoms. Alternative tests are therefore necessary to describe gut injury. For instance, radionuclide imaging and ultrasound can be used to document the severity or extent of bowel mucositis by measuring bowel wall thickness. Significant bowel thickening > 4 mm was observed almost exclusively in patients having the clinical picture of neutropenic enterocolitis,15 which is considered an extreme manifestation of gut MBI. Permeability tests are noninvasive and generally accepted to be surrogate markers of intestinal disease or damage in patients treated for cancer.16 Alterations in permeability and loss of epithelial surface are the principle features of gut injury. Permeability can be measured in vivo by means of urinary excretion of test substances that have been ingested or by detecting their presence in blood. Various sugars (lactulose, rhamnose, xylose, mannitol), polymers of polyethylene glycol (PEG) or 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA) have been used to determine gut permeability in different populations of patients given different chemotherapy regimens. Permeability increases within 2 days after initial therapy and continues to increase for about another 10 days when it reaches a plateau, which persists for another 1 to 3 weeks.17
The lactulose/rhamnose ratio
The lactulose/rhamnose ratio is commonly used as an index to reflect changes in the permeability and gut surface area following chemotherapy, which assumes that premucosal and postmucosal factors equally affect both sugars. The lactulose/rhamnose ratio will be higher after high-dose chemotherapy due to an increase of lactulose absorption through open tight junctions together with a decrease of rhamnose absorption due to loss of surface area of the gut epithelium18 (Figure 2). However, the permeability test is nonspecific and is also altered when acute GVHD develops after allogeneic HSCT.19 When using a nonmyeloablative regimen for HSCT, intestinal permeability as measured by 51Cr-EDTA is preserved, just as diminished gut complaints would indicate.20 After myeloablative therapy, clinically scored gastrointestinal but not oral toxicity was consistent with a significant increase in permeability, which, nonetheless, could not predict the clinical severity.21 The lactulose/rhamnose ratio is correlated poorly with clinically scored gut toxicity indicating that permeability tests measure another feature of gut injury than do gut complaints.22 The altered permeability reflects damage to the small intestinal mucosa that is associated with an increase of apoptosis in crypts that precedes hypoplastic villous atrophy and loss of enterocyte height as has been documented by biopsies of duodenal tissue after intensive chemotherapy.23
|
released in response to cytotoxic therapy is integrated with the effects upon local immunity and the oral microflora24 (Figure 3). This model has been adapted to the gastrointestinal tract because of major differences in architecture of mucosal tissue between mouth and the other parts of the digestive tract17 (Figure 4).
|
|
Variability in the extent of mucositis
The variability in the extent and degree of mucositis might be explained by genetic differences in the expression of proinflammatory cytokines or proteins that control stem cell apoptosis, for example p53 and bcl-2 along the GI-tract.25 The role of activated transcription factors like nuclear factor-kappa B (NF-
B) by cytototoxic drugs is now the subject of study with respect to inflammation, cell growth, differentiation and apoptosis of epithelial cells (Bea van’t Land, personal communication).
Until recently, pharmacokinetics received little attention. Indeed, the simple question of whether dose determinations of cytostatic drugs should be based upon surface area or actual or ideal weight is still unanswered for many cytotoxic drugs. Variability in the timing of administration of chemotherapeutic agents that act on topoisomerase II has implications for the rate of mucositis because of the circadian rhythm of their expression. Genetic variability in drug response as a result of molecular alterations of drug-metabolizing enzymes, receptors, and transport proteins may be of greater importance and perhaps might predict drug concentrations to optimize the therapeutic effect while minimizing toxicity.26 Genetic polymorphism of the cytochrome P450 enzyme family located in the liver and gut is becoming of interest as reports are being published about interactions between alkylating chemotherapeutic agents and drugs given for other purposes particularly in the transplant setting. For instance, the antifungal, itraconazole, decreases clearance of busulfan. The resultant increase in the area under the curve of busulfan is related with more gastrointestinal toxicity. This might explain the greater incidence of some gut toxicity reported after treatment with itraconazole.27 The interval between busulfan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide.28 The antibacterial fluoroquinolone, ciprofloxacin, also suppresses certain cytochromes P450 at the transcriptional level decreasing clearance of cyclophosphamide.29 A very interesting observation was made 20 years ago but never followed up on; it was observed that a priming injection of cyclophosphamide was shown to reduce gut toxicity in patients receiving high-dose melphalan. This suggests that clearance of cytotoxic drugs is important in the development of MBI. The variability in the pharmacokinetics and pharmacodynamics of anticancer chemotherapy is also influenced by the presence of an inflammatory response to conditions such as infections, cancer, and, of course, mucosal injury.30
Clinical Consequences of Mucosal Damage
Damaged mucosa leads to significant morbidity and impaired quality of life, especially in the setting of HSCT. The extent and severity of oral mucositis is significantly correlated with days of fever, parenteral narcotic use, total parenteral nutrition, antibiotic therapy, and the total number of days in hospital. The risk of significant infections and mortality was higher in those transplant recipients who had ulcerative mucositis with total hospital charges that were almost $43,000 higher.1 An increased risk of bacterial infection and mortality has been associated with more severe mucositis.2 Oral viridans streptococcal (OVS) infections are related to MBI of the upper part of the digestive tract, particularly the oral cavity, whereas enteric Gram-negative bacillary infections and neutropenic enterocolitis are related to the lower part of the digestive tract.
Gram-positive infections—oral viridans streptococci
Although infection can originate from exogenous sources, the majority of organisms responsible for infection arise from the patient’s own endogenous microflora, particularly from those residing on the mucosal surfaces of the mouth and gastrointestinal tract. There has been a shift from Gram-negative bacilli to Gram-positive cocci which now account for 3 of every 4 bacteremic isolates in patients with hematological malignancies (SCOPE project).31 Recipients of autologous HSCT with oral ulcerative mucositis were found to be 3 times more likely to develop OVS bacteremia than those without mucositis and OVS bacteria were isolated from the blood at a median of 6 days (range 2–8 days) after transplant.32 Drug-induced achlorhydria and the use of antimicrobial prophylaxis with fluoroquinolones contribute toward the development of OVS bacteremia.33 One particular group of OVS, the mitis group which comprises the species S mitis and S oralis, is reported to be associated with more serious complications like sepsis and adult respiratory distress syndrome particularly following chemotherapy with high-dose cytarabine. These complications are associated with a high mortality (80%) and occur within a few days of the onset of bacteremia. Recently, a simple scoring system for predicting streptococcal infection was proposed.34
Gram-positive infections—coagulase-negative staphylococci
Coagulase-negative staphylococci (CoNS) were the most frequently isolated microorganisms of the SCOPE project.31 CoNS bacteremia is frequently related to the use of central venous catheters, as CoNS are predominant members of the skin microflora. However, CoNS are also present in the endogenous flora of the mucosa of mouth and gastrointestinal tract of neutropenic patients. Plasmid pattern analysis on CoNS bloodstream isolates revealed that the mucosa was the origin in 70% of hematology patients. CoNS bacteremia mostly occurred within the first 2 weeks after transplant when gut integrity was markedly disturbed.35
Gram-negative bacillary infections
Escherichia coli and Klebsiella species remain the most common causes of Gram-negative bacillary bacteremia, although Pseudomonas aeruginosa accounted for 14% of the isolates and was associated with the highest mortality (40%) amongst HSCT recipients despite adequate empiric antibiotic therapy. Unusual but more resistant pathogens, such as Acinetobacter species, Stenotrophomonas maltophilia and Capnocytophaga species are occasionally isolated and are related to either gastrointestinal or oral mucositis.36
Anaerobic infections
The severity of mucosal damage was an independent predictor of anaerobic bloodstream infections, which occurred in 23 of 611 transplants with a rate of 4 infections per 100 HSCT procedures. Fusobacterium nucleatum was the most frequently isolated pathogen a week after transplant.
Neutropenic enterocolitis
Neutropenic enterocolitis (NE) or typhlitis is the most severe example of cytotoxic therapy-induced mucosal damage of the gut and cannot be diagnosed by clinical signs of fever, abdominal pain, and diarrhea alone. Mortality rates vary between 40% and 90% depending on the selection criteria.37 Patients fitting the clinical picture of NE undergoing ultrasonography can be graded by their bowel wall thickness as a bowel wall of more than 10 mm indicates poorer outcome. This serious complication illustrates how the delicate balance between host and microflora can be totally disturbed by MBI in the setting of prolonged exposure to antibiotics prophylaxis. Necrosis of the mucosal surfaces provides a portal of entry for several toxin-producing bacteria like Staphylococcus aureus, Pseudomonas aeruginosa, and Clostridium species. Not surprisingly, fungal pathogens were cultured as new microorganisms at autopsy in more than 50% of patients who died with NE. Interestingly, xylose malabsorption occurred earlier after remisson-induction chemotherapy among patients who developed NE.
Candida infections
Candida species are commensal yeast that normally reside on the mucosal surfaces of the digestive tract and vagina. Adherence to these surfaces appears to be a prerequisite for local mucosal infection and subsequent invasive disease since regular surveillance cultures of hematological patients have shown that colonization invariably precedes infection.38 The local oral infection with Candida species on top of mucositis increases local discomfort and pain and reduces oral intake. Mucosal damage is a risk factor for invasive candidiasis (candidemia and/or hepatosplenic candidiasis) among the patients receiving antineoplastic therapy. Patients treated for AML who developed invasive candidiasis had significantly lower serum D-xylose levels with the maximum difference noted at week 2 after start than patients without invasive disease. Candidemia is also correlated with NE.39 HSCT recipients prepared with regimens composed of TBI and patients treated with remission-induction regimens containing either high-dose cytarabine or an anthracycline, have an increased risk of developing invasive disease.
These data support the contention that mucosal damage provides a portal of entry to the systemic circulation for commensal oral and gastrointestinal microorganisms (Figure 3
). Thus, the ability to treat or prevent severe MBI is an important step toward decreasing the infectious complications experienced by patients given intensive chemotherapy.
Acute graft-versus-host disease
MBI induced by cytotoxic chemotherapy and GVHD of the gut present with similar signs and symptoms and even permeability tests are unable to distinguish these entities. Hence only histology can confirm the diagnosis. Tissue damage of the gut caused by conditioning regimens plays a role in triggering acute GVHD. The epithelial cells and immune cells of the GALT release proinflammatory cytokines, which upregulate expression of adhesion molecules and histocompatibility proteins. Donor T-lymphocytes recognize unregulated host mucosal antigens and macrophages of acceptor and donor are further activated by translocated endotoxin leading to mucosal damage of the gut by acute GVHD (aGVHD). The gut is not only a major target organ of aGVHD but also a critical amplifier of systemic GVHD.40 Intensification of conditioning may also result in more mucositis and correlate with more severe GVHD directly as a result of toxicity or indirectly as a result of inadequate GVHD prophylaxis.41–43 Prior animal and clinical studies of monoclonal antibodies to TNF-, soluble IL-1 receptor, and IL-1 receptor antagonist (IL-1RA) suggested that specific inhibition might be effective in preventing GVHD. However, a double-blind randomized trial of recombinant human IL-1 receptor antagonist given to 186 HSCT recipients failed to show any reduction in GVHD or toxicity, including mucositis.44 Polymorphisms of the IL-1 genes might have influenced severity or TNF- is the dominant cytokine in mediating GVHD and its production is stimulated by translocated endotoxin (which is a constituent of Gram-negative bacilli of the normal commensal bowel flora). Mice given an allogeneic HSCT with LPS-resistant bone marrow had significantly less TNF- production and less severe GVHD.45 Decontamination of the gut reduces clinical GVHD although there are several other bacterial products, besides endotoxin, that might play a role in triggering GVHD.46
Systemic inflammatory response syndrome
Patients who develop severe complications after HSCT tend to have significantly higher levels of cytokines around the time of transplant with an excess of proinflammatory cytokines. This results in vascular endothelial damage and is known as the systemic inflammatory response syndrome (SIRS). Major complications such as GVHD, acute respiratory distress syndrome (ARDS), thrombotic microangiopathy, veno-occlusive disease, and central nervous system disorders can be considered manifestations of SIRS.47 The MBI that occurs following conditioning therapy is accompanied by the release of proinflammatory cytokines—the first manifestation of SIRS. Mucosal damage could therefore be used as a marker of systemic toxicity and damage to other organs. However, unlike C-reactive protein, which is easy to measure, the detection of cytokines is not straightforward. Regular monitoring of CRP after transplant can be used to identify patients at risk of severe transplant-related complications and even mortality.48 As mentioned previously, inflammation influences the pharmacokinetics and pharmacodynamics of drugs. Exposure of intestinal epithelial cells to proinflammatory cytokines decreases the mRNA expression of CYP3A4 and increases the multidrug resistance by increasing Pgp expression. The functional linkage in the enterocytes of CYP3A4 and Pgp will therefore limit bioavailability, even when oral intake of medication is successful.
Malnutrition
Metabolism in patients undergoing intensive cytotoxic treatment changes over time with the highest energy expenditure occurring about 14 days after transplant. At that time, oral intake is negligible and malnutrition together with severe weight loss would occur without total parenteral nutrition (TPN). However, even with TPN, there will still be a profound loss of fluid and electrolytes together with malabsorption and the hypoproteinemia associated with protein-losing enteropathy.
Summary and Treatment Options
MBI is a risk factor for severe infectious complications but is more than just a toxicological side effect of anticancer treatment (Table 1). The intact mucosa not only form a line of first defense against systemic infections but also play an active role in the crucial balance between host and environment, particularly in the setting of an allogeneic HSC transplant. The therapeutic potential of allogeneic transplant is related to the graft-versus-malignancy effect and protection of the mucosa could lessen any immunostimulatory effects of MBI and reduce GVHD.
|
). Trials of oral or parenteral glutamine supplementation yield conflicting results showing either no effect on mucositis or a decrease of infections. Allogeneic transplant recipients seemed to benefit the most, especially when TBI is used. Topical or systemically administrated granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) met a similar fate. The first clinical randomized Phase 1 trial of recombinant human keratinocyte growth factor indicated that patients treated with this agent had a lower rate of WHO grade 2–4 mucositis.49 IL-11 ameliorates thrombocytopenia following myelosuppresive chemotherapy, increases proliferation of mucosal basal cell layer, and partially suppresses apoptosis. In experimental studies, IL-11 almost completely prevented GvHD of the gut and reduced serum endotoxin levels after HSCT. However, a randomized placebo-controlled dose-finding study of IL-11 among patients given high-dose chemotherapy found no difference in the rate of WHO grade 3 or 4 mucositis between the active treatment group and the placebo group although incidence of bacteremia was decreased.50 Another double-blind randomized trial in which 40 patients underwent intensive chemotherapy demonstrated a reduction in bacteremia together with more normal lactulose/rhamnose ratios in the group given IL-11.51 This agent might therefore offer a new approach toward managing infectious complications occurring in patients with MBI.
|
II. INVASIVE FUNGAL INFECTIONS: NEW DEVELOPMENTS IN PREVENTION, DIAGNOSIS AND MANAGEMENT
Tahsine H. Mahfouz, MD,* and Elias J. Anaissie, MD*
Invasive fungal infections (IFIs) continue to represent a significant problem for patients with hematologic cancer. In this manuscript, we present an update on the newest developments in the diagnosis, prevention and management of IFIs in this patient population with a focus on a risk-adjusted approach and the practical implications for clinicians.
Pathogens Associated with Invasive Fungal Infections in Patients with Hematologic Cancer
With the introduction of novel antifungal, antiviral and antineoplastic therapies, significant changes in the epidemiology of fungal infections have been noted. These changes include a decrease in candidiasis with C. albicans, C. tropicalis and C. parapsilosis with an emergence of occasional infections by azole-resistant species such as C. glabrata, and C. krusei.1 In addition, an increase in the incidence of mould infections, particularly aspergillosis, has been observed together with an emergence of infections by non-fumigatus Aspergillus spp.2 and other moulds (Fusarium spp., Zygomycetes and others).3
The incidence of IFIs varies widely among patients with hematologic cancers and is highest among those undergoing allogeneic bone marrow transplantation (alloBMT) (Table 3).
|
The incidence and severity of IFIs result from the interaction of three factors (Table 4):
|
Strategy for a Risk-Adjusted Approach to Fungal Infections in Patients with Hematologic Cancer
Determine the risk for fungal infection in specific patient populations
This is best accomplished by evaluating various risk factors (exposure, net state of immunosuppression, and organ damage) (Table 4). For practical purposes, one can distinguish 3 risk groups: high, moderate and low.
High-risk group: 15–30% incidence of IFI. This group includes alloBMT [and peripheral blood stem cell transplant (PBSCT)] recipients who have several of the following risk factors: age > 40 years, malignancy other than chronic myeloid leukemia, mismatched or matched unrelated transplant, graft failure, GVHD or corticosteroid therapy; Patients with acute myeloid leukemia who are > 55 years, receiving gut-damaging cytotoxic therapy (such as high dose cytarabine), and with poor performance status also belong in this high-risk category.
Low-risk group: < 5% incidence of IFI: younger (< 19 years) patients who have none of the risk factors mentioned above, but are undergoing alloBMT/PBSCT or therapy for acute leukemia. Autologous PBSCT patients also belong in this category.
Moderate-risk group: 5–15% incidence of IFI. These are patients who exhibit a small number of the risk factors mentioned under the high-risk group.
Perform radiologic and laboratory evaluation according to risk category
Laboratory and radiological evaluation depend on the risk group.
Cultures: Sputum, nose and bronchoalveolar lavage (BAL) cultures are the most common cultures obtained for invasive aspergillosis. For serious candidal infections, blood cultures remain the standard for diagnosis although serial mucosal cultures have an excellent negative predictive value (NPV) and an acceptable positive predictive value (PPV) for these infections.4
Radiological evaluation: High resolution computed tomography (CT) chest and sinus-CT are both useful at baseline (prior to commencing antineoplastic therapy) and for monitoring high-risk patients. The lung findings in invasive aspergillosis include nodules with an early halo sign during severe neutropenia that may be followed by air-crescent sign with recovery from myelosuppression.5 Of note, an increase in size of pulmonary lesions does not necessarily mean progression of infection as it could be related to the immune recovery.
Serology: Galactomannan antigen test is now FDA-approved for the detection of infection with Aspergillus spp. Surveillance testing of blood specimens is associated with good sensitivity, specificity, PPV and NPV.
False positive results may be observed in patients receiving piperacillin/tazobactam or amoxicillin/clavulanate.6,7 Decreased sensitivity was shown in children, and may also occur in patients with circulating aspergillus antibodies and those receiving antifungal agents active against Aspergillus spp. The cut-off point for true positive Galactomannan antigen test ranges from 0.5 to 1.5 though a consensus may be emerging for a 0.5 cut-off point for positivity.8 The Galactomannan antigen test has several advantages: it is non-invasive, easy to use, quantitative and specific for Aspergillus spp. A negative test may give a false sense of security, as patients may be infected with fungi that are not detected by this test. This test is best reserved for intermediate and high-risk patients.
1-3-beta-D-glucan antigen is a new promising diagnostic test that appears to be useful in detecting all fungal infections (yeasts and moulds) in the bloodstream and is currently undergoing evaluation (not yet approved by the FDA).
Polymerase chain reaction (PCR) is a very sensitive test for detecting aspergillus nucleic acids in various tissues.9 Problems with PCR are related to lack of a commercial product, cost, and risk of false positivity. Real-time PCR has been suggested as a promising diagnostic method for invasive aspergillosis.
Prevent and manage fungal infections according to risk category
In view of the above-mentioned risk stratification, it is critical to develop a practical approach for managing IFIs according to risk in specific patients or patient populations. This approach may utilize antifungal agents for prophylaxis, pre-emptive, or empirical therapy or reserve their use for patients with established fungal infections. A description of these approaches follows:
Therapy of established infection: This approach relies on providing antifungal therapy to patients in whom an IFI has been documented.
Pre-emptive antifungal therapy: Pre-emptive therapy consists of initiating antifungal agents in persistently febrile neutropenic patients who have a probable IFI on the basis of significant colonization, positive serology, clinical, or radiological findings.
Empirical antifungal therapy: Empirical therapy provides antifungal agents to neutropenic patients who have persistent fever despite broad-spectrum antibiotics but do not exhibit the clinical or laboratory findings suggestive of IFI (mentioned above).
Antifungal prophylaxis: Primary prophylaxis provides antifungal agents before any evidence of fungal colonization or infection; it is usually given at initiation of immunosuppression. Secondary prophylaxis provides antifungal agents after recovery from a documented fungal infection and prior to additional immunosuppressive therapy.
Infection control: Sources of Aspergillus spores in hospitals include air, dust, construction area, ventilation system, potted plants, flowers, cereals, nuts, spices and carpets. A newly investigated source is water with secondary aerosolization.10
Measures to reduce exposure of high-risk patients to airborne moulds include:
Measures to reduce hospital-acquired candidal infections in these patients rely on handwashing, an important, simple and inexpensive infection control strategy.
Antifungal Armamentarium
Antifungal agents11
Several antifungal agents are currently available. The properties, in vitro activities and dosing schedules of the available antifungal agents are summarized in Tables 5–9, and Figure 5.
|
|
|
|
|
|
and 6, Figures 5 and 6): Antifungal polyenes have a broad spectrum of activity including most Candida and Aspergillus spp., C. neoformans, and the zygomycetes. Their activity is limited against Fusarium spp., Trichosporon spp. and Scedosporium spp.11
|
Nephrotoxicity is the most important dose-limiting toxicity of AmB-D. It is in general dose-dependent11 and is associated with prolonged hospitalization and increased mortality.
The newer lipid formulations of AmB-D are less nephrotoxic. These agents are, however, significantly more expensive and not necessarily problem-free. The risk of infusion reactions and nephrotoxicity is compound-specific and is in the following order: AmB-D > ABCD > ABLC > LAMB.11
Triazoles: Fluconazole, itraconazole, voriconazole (Tables 5–9, Figure 5): Fluconazole is characterized by water solubility, linear renal excretion, modest drug interactions, and relatively narrow spectrum (mostly yeasts).11 Absorption is generally excellent, and drug interactions are mild to modest. Fluconazole is also as efficacious as amphotericin B in treatment of non-neutropenic patients with candidemia, and is considered the antifungal of choice for prophylaxis aimed at Candida spp. infection.12
Itraconazole is characterized by poor water solubility, variable oral absorption, complex degradation in the liver, and extensive drug interactions. The drug is active against yeasts, and various moulds including Aspergillus species and appears to be effective in preventing invasive aspergillosis in high-risk patients.11,13–15
Itraconazole is available both orally (capsule and solution) and via IV. Itraconazole capsule has an erratic bioavailability; especially in patients with hypochlorhydria (bioavailability improves if the drug is taken with fat-rich food and a cola beverage). Increased and more predictable absorption of itraconazole can be achieved by using the cyclodextrin-based solution, which does not require gastric acidity or fat-rich meals, and is better absorbed away from meals. The IV formulation is most useful for patients with gut dysfunction. Itraconazole suffers from significant drug-drug interaction requiring close monitoring.11 Patients should avoid taking concurrent drugs (antacids, H2 or proton pump blockers) that impair the absorption of the oral capsule or accelerate the metabolism of itraconazole (rifampin, rifabutin, phenytoin, and barbiturates among others) (Table 9). Dosage-adjustment and close monitoring for toxicity is required when agents whose metabolism is affected by itraconazole (cyclosporine A, tacrolimus, benzodiazepines, digoxin, HMG-CoA reductase inhibitors, others) are used concomitantly with this agent (Table 8). Itraconazole is well tolerated. Side effects include nausea, vomiting, diarrhea, and skin rashes. Transient elevations in serum transaminases may occur while fulminant hepatotoxicity and liver failure is extremely rare. Hypertension, edema, and hypokalemia have been reported in patients receiving higher doses of itraconazole. Itraconazole has also been associated with negative inotropic effect, a factor that should be considered in patients receiving cardiotoxic agents such as the anthracyclines or cyclophosphamide.
Voriconazole is available as IV and oral formulation. The drug has good oral bioavailability, and is active against moulds and yeasts. Voriconazole has been shown to be more effective and better tolerated than conventional amphotericin B in patients with invasive pulmonary aspergillosis16 and as effective as Liposomal amphotericin B as empirical treatment of febrile neutropenia.17
All azoles inhibit CYP3A4, the primary oxidative drug-metabolizing enzyme in humans. Voriconazole also inhibits CYP2C9/19. Some agents (Rifampin, long-acting barbiturates and carbamazepine) are con traindicated in patients receiving voriconazole because they greatly reduce voriconazole exposure (Table 9). Patients treated with certain agents (cyclosporine A, tacrolimus, sirolimus, HMG-CoA reductase inhibitors, others) should be closely monitored because the drug concentrations of these drugs are substantially increased by voriconazole (Table 8).18 Voriconazole is generally well tolerated and exhibits the same gut, skin and liver toxicity observed with itraconazole. In addition, voriconazole causes generally mild and transient visual disturbances (brightness, blurring, light sensitivity, or changes in color vision). Typically, these abnormalities are observed in around 30% of patients, starting 30 minutes after the voriconazole dose, and lasting about 30 minutes. Patients should avoid driving at night. Skin photosensitivity has also been observed (~6% of patients), particularly among those receiving longer (> 12 weeks) courses of therapy. Direct exposure to sunlight should be avoided.
Posaconazole is a triazole that is structurally related to itraconazole and possesses a broad spectrum of activity including yeasts and moulds. Among Candida spp., the agent appears to be least active against fluconazole- and itraconazole-resistant strains (C. glabrata, C. krusei, and others).19 Limitations of posaconazole are the lack of IV formulation and the somewhat erratic bioavailability of the drug in the setting of severe mucositis. Posaconazole is currently undergoing Phase III clinical trials.
Ravuconazole is structurally related to fluconazole and voriconazole. The agent possesses broad-spectrum antifungal activity and is formulated as a prodrug thus obviating the need for a solubilizing agent such as a cyclodextrin.19 Ravuconazole is available PO and IV and may be associated with less drug interaction than the other mould-active triazoles. Ravuconazole is currently in Phase II clinical trials.
Flucytosine (Table 5 and Figure 5)11: Flucytosine is the only member of the group of antifungal antimetabolites. The drug is active against most Candida spp., C. neoformans and some of the dematiaceous fungi but should not be used as monotherapy because of the risk of emergence of resistance and should be given in combination. The major toxicities of flucytosine are myelosuppression, gastrointestinal intolerance, and hepatic toxicity and are related to drug accumulation
Echinocandins: Caspofungin (Tables 5 and 6, Figure 5)11: Echinocandins represent a new class of antifungals that inhibit the synthesis of ß 1,3 D-glucan, an essential component of the fungal cell wall. The drug is available only IV. Caspofungin is fungicidal for Candida spp.20 and is most active against Candida albicans, C. tropicalis and C. glabrata. Caspofungin is active against Aspergillus spp. but lacks activity against Cryptococcus neoformans and various moulds.20
Caspofungin decreases the area under the curve (AUC) of tacrolimus requiring monitoring of tacrolimus concentrations. Some drugs may decrease the concentration of caspofungin such as phenytoin, rifampin, and dexamethasone. In patients receiving these agents, the daily maintenance dose of caspofungin should be raised to 70 mg IV.21 Cyclosporine increases the concentration of caspofungin by 30%. Caspofungin is generally well tolerated and may be occasionally associated with fever, skin reactions, rash, infusion site phlebitis and transient increase in liver function tests. Mild-moderate histamine-mediated infusion reactions may occur. In a randomized, double blind study comparing caspofungin and amphotericin B for invasive candidiasis, caspofungin therapy resulted in a higher response rate than amphotericin B and was better tolerated.22 A study of caspofungin as therapy for presumed or probable aspergillosis was conducted in 83 patients with various conditions (including hematologic cancer) who had failed to respond to or tolerate standard antifungal therapy. Response (complete and partial) was observed in 45% of patients.23
Micafungin is an echinocandin with potent in vitro and in vivo activity against a variety of pathogens including Candida spp. and Aspergillus spp. The drug is well tolerated and appears effective. Micafungin has been recently compared to fluconazole in a randomized, double blind trial for prophylaxis of IFIs in patients undergoing allogeneic and autologous BMT/PBSCT. Compared to fluconazole, micafungin significantly reduced the incidence of probable and proven invasive fungal infections (P < .05), was as effective as fluconazole for the prevention of candidiasis with a strong trend toward reduction in invasive aspergillosis (P = .08).24
Anidulafungin is another echinocandin that possesses similar antifungal spectrum and activity and is undergoing Phase II clinical trials.
Cytokines and granulocyte transfusions
Enhancing the patient’s immune status is another approach to managing IFIs in patients with hematologic cancer. Potentially useful approaches include:
Granulocyte colony-stimulating factor (G-CSF): Polymorphonuclear cells (PMNs) from patients treated with G-CSF possess enhanced in vitro activity against A. fumigatus, Rhizopus arrhizus, and C. albicans.25 Data to support the use of G-CSF in preventing IFIs are lacking and G-CSF elicits a Th-2 response, usually associated with poor outcome in patients with serious mycoses.
Granulocyte-macrophage colony-stimulating factor (GM-CSF): GM-CSF stimulates macrophages to release pro-inflammatory cytokines25 and can overcome steroid-mediated suppression of monocytic activity against Aspergillus.26
Gamma interferon (IFN-
): IFN- enhances human neutrophil oxidative burst, and neutrophil and monocyte-mediated damage to A. fumigatus, F. solani hyphae, and C. albicans pseudohyphae.27 and reverses corticosteroid-induced immunosuppression of human neutrophil-induced damage to A. fumigatus hyphae.27 IFN- has been also shown to enhance the antifungal activity of elutriated human monocytes against A. fumigatus hyphae.28 In humans, IFN- enhances the ability of neutrophils to damage Aspergillus hyphae ex vivo,29 accelerates the sterilization of the cerebrospinal fluid in cryptococcal meningitis,30 and has been associated with improved clinical response in patients with acute leukemia and refractory IFIs.31
Granulocyte transfusions: Recent reports have provided encouraging results on the role of granulocyte transfusions, elicited with G-CSF with or without steroids in patients with IFIs.32 Related and or community donors can be utilized.
Granulocyte transfusions should be considered in patients with refractory IFI, who continue to be profoundly neutropenic but whose prospects for recovery from myelosuppression and disease control are good. Mild reactions to the granulocyte transfusion products are common, including fever and chills, and can be reduced if the infusion rate is slowed. Severe side effects, namely hypotension or respiratory distress, are estimated to occur in ~1% of recipients; GVHD is prevented by irradiation of the product pre-infusion with 15–30 Gy.
Risk-Adjusted Recommendations
Primary antifungal prophylaxis (Figure 7)
Antifungal prophylaxis should be provided to patients at high-risk for IFI and should be tailored to the patient population. Those likely to develop hematogenous candidiasis only are best offered oral fluconazole while those at risk for aspergillosis should probably receive itraconazole (voriconazole is also likely to be effective but has not been tested in this setting).14,15,33,34 Itraconazole should be given at maximal tolerated dose (600–800 mg/d), preferably as solution (not capsule) or IV in the presence of significant gut dysfunction. Other options include micafungin (when it becomes available)24 and lipid amphotericin B.
|
Secondary antifungal prophylaxis
Patients with a prior episode of mould infection and who are at risk for relapse when recieving additional immunosuppression should be given secondary antifungal prophylaxis. Following recovery from myelosuppression, these patients can be treated with itraconazole, voriconazole or an IV polyene that is safe for prolonged use (not AmB-D); all residual sites of infections should be resected if possible, and the patient closely monitored with serologic (PCR, Galactomannan antigen) and radiologic tests. Therapy for the primary infection should be continued despite achievement of complete response. Immediately prior to commencing additional immunosuppression, antifungal therapy should be optimized (agent, dose, schedule, and route), and consideration given to utilizing less immunosuppressive antineoplastic agents if possible. Prophylactic GM-CSF and in select patients, pre-emptive granulocyte transfusions to avoid profound neutropenia may be used.
Empirical and pre-emptive therapy (Figure 7)
Empirical/pre-emptive therapy should be utilized in patients at moderate risk for infection when an IFI is suspected (colonization, positive serology, clinical, or radiological findings). Agents effective in this setting include AmB-D, itraconazole, voriconazole, LAMB, and ABCD. Recent metaanalyses support the use of LAMB and itraconazole in pre-emptive/empirical antifungal therapy (Table 10).
|
)) and may cause liver dysfunction.
|
). Therapy should be continued until complete response, resolution of immunosuppression (absolute neutrophil count > 2000, CD 4 count > 400), and cessation of immunosuppressive therapies.
Additional therapeutic measures include reduction or discontinuation of immunosuppressants and resection of infected foci (Figure 9). Consideration should also be given to granulocyte transfusions in the neutropenic patient and to cytokines (IFN- or GM-CSF) in patients with adequate neutrophil counts. Secondary antifungal prophylaxis should always be offered to patients undergoing subsequent immunosuppression.
|
III. MANAGING INFECTIONS ASSOCIATED WITH PURINE ANALOGUES AND MONOCLONAL ANTIBODIES
Susan O’Brien, MD*
Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL).1–7 Up to 50% of patients suffer from recurrent infections. The spectrum of infections in patients with CLL treated with conventional therapy is mainly bacterial.2,6 Infections with Streptococcus pneumoniae, Staphylococcus aureus, and enteric Gram-negative organisms are commonly seen.7–9 Infections predominantly affect the respiratory tract, skin, or urinary tract, with a significant incidence of sepsis.1,7,10–16
Herpes simplex and herpes zoster are also frequently diagnosed in patients with CLL, they are particularly common in advanced disease and after prior therapy.9,16–18 In most cases these infections are localized but disseminated disease may be seen, particularly when there has been a delay in diagnosis. Fungal infections also are more common in patients with advanced disease and therapy or disease-related neutropenia.16,19,20
Opportunistic infections, such as Pneumocystis carinii, are uncommon in patients treated with conventional chemotherapy.21 Other infections, such as tuberculosis, are uncommon due to relative preservation of cellular immunity in early stage CLL. With the use of nucleoside analogs (e.g., fludarabine) or alemtuzumab, particularly in combination with corticosteroids, more unusual infections have been described, including listeriosis and P. carinii pneumonia (PCP).22–24 There is also an increased frequency of invasive mycoses and mycobacterial infections in patients treated with nucleoside analog–containing regimens.22,25,26
Factors Predisposing to Infections in CLL
Hypogammaglobulinemia
Several studies have demonstrated a high incidence of hypogammaglobulinemia in patients with CLL.17,27–33 There is a clear decline in immunoglobulin levels with increasing disease duration.17,28–37 However, the effect of treatment on serum immunoglobulin levels is less clear. The etiology of hypogammaglobulinemia in CLL is poorly understood. Defects in cellular immunity, such as functional abnormalities of T cells resulting in dysregulation of nonclonal CD5- B cells, may be partly responsible.38–39
Various studies have evaluated the frequency of hypogammaglobulinemia, the type of immunoglobulin (Ig) deficiency, and the impact on survival. Deficiencies of IgG, IgA, or IgM were not found to influence survival in a series reported by Ben-Bassat et al.31 In contrast, Rozman et al29 found that the survival of patients with CLL and an immunoglobulin level < 700 mg/dL was significantly shorter than that of patients with levels 
700 mg/dL. Reduced levels of IgG and IgA were associated with reduced probability of survival (P = .027 and P = .014, respectively), whereas low IgM levels had no influence on survival.9,29
The association between low immunoglobulin levels and recurrent infections, usually with encapsulated organisms, has been well described in patients with CLL.2,15,17,18,27–29,39–43 However, patients with a normal serum immunoglobulin level may have recurrent infections, while some patients with severe hypogammaglobulinemia may remain infection-free for prolonged periods of time. Some authors have suggested that the relationship between a deficiency in a specific immunoglobulin class or subclass and the risk of infection may be more important. A recent report emphasized an association between infection and a low serum IgA level.38 Morrison et al44 found that 69% of patients with a low serum IgA concentration had at least four infections, compared with 27% of patients with a normal serum IgA level. Aittoniemi et al. also examined deficiencies of immunoglobulin classes and subclasses in patients with CLL.45 In multivariate analysis, the only independent risk factor for infection was a decreased IgA level. A specific IgG4 deficiency has been associated with severe, recurrent pulmonary infections.46
Copson et al47 reported lower levels of serum IgG3 and IgG4 in patients with CLL compared to those in age- and sex-matched controls. Deficiency of IgG3 may partly explain the increased risk for herpesvirus infections in patients with CLL because IgG3 is a known defense mechanism against these viruses.
Deficiencies in secondary antibody response to common antigens may further explain the increased risk for infection in patients with CLL.2,40 Low levels of pneumococcal antibodies were reported in 23 (39%) of 59 patients with CLL compared to 6 (11%) of 56 controls (P = .005). The association between low levels of antipneumococcal antibodies and hypogammaglobulinemia was not consistent: 12 patients with a low serum IgG level had a normal pneumococcal antibody level, and three patients with a low pneumococcal antibody level had a normal serum IgG level. The majority of patients with severe or multiple infections (13 of 18) had low levels of both total IgG and pneumococcal antibodies.40
Complement system
Several investigators have described abnormalities of the complement system in patients with CLL.43,48,49 Heath and Cheson50 described a defect in binding of the opsonin C3b to bacteria in 15 patients with CLL. Fust et al51 reported a reduction in mean C1 and C4 levels in more than 50% of the samples tested from 46 patients with CLL. No abnormalities of the alternative complement pathway were seen. Others have demonstrated depressed classic complement pathway activity in CLL.52,53 Schlesinger et al examined complement levels in 26 patients with CLL and reported that they were decreased in all of the patients with advanced stage disease and 40% of patients with early stage disease48 Interestingly, the authors also found deficiencies of at least one complement component in 11 first-degree relatives of these patients.
Cellular immunity
Although qualitative and quantitative abnormalities of T lymphocytes have been reported in CLL, the exact cause of these defects is not clear. However, it is likely that these T-cell abnormalities contribute to hypogammaglobulinemia and an increased risk of infection. Increased T-cell numbers with a relative increase of suppressor T cells (CD8) and a decrease of helper T cells (CD4) resulting in a reduced CD4/CD8 ratio is common in CLL.4,30,54,55 This is frequently seen with more advanced stages of disease. Both increased and decreased numbers of the suppressor-inducer phenotype (CD45Ra) have been reported.56,57
Studies of the qualitative function of cellular immunity have been inconclusive; both normal and decreased CD4 cell function have been reported58,59 while excessive, normal, or reduced CD8 cell function has also been described.55,58,60–62 Burton et al63 suggested that T cells obtained from patients with CLL were not inherently dysfunctional but that this was caused by soluble factors elaborated by CLL B cells. Subsequently, Decker et al64 demonstrated no quantitative or qualitative differences in cytokine production or proliferative capacity when purified T cells from patients with CLL were compared with those from normal donors. However, addition of CLL cells as autologous accessory cells resulted in a marked increase in IL-2 production but not induction of IFN- or IL-4. Accessory cells, predominantly monocytes, from normal individuals resulted in a completely different pattern of cytokine stimulation. The authors concluded that T-helper cells from patients with CLL were intrinsically normal but that the predominance of CLL-B cells as accessory cells modulated the immune function of the T cells.
The most obvious clinical indication of impaired cellular immunity is lack of response to recall antigens on skin testing. A diminished response to skin testing for tuberculin, mumps, and Candida in patients with recurrent infections has been shown.43 Chapel and Bunch2 reported anergy to recall skin testing in 48% of 23 patients; the presence of anergy correlated with an increased frequency of infections. Whether the alternations in the T-cell
