Invasive Aspergillosis in Cancer Patients

Introduction

Aspergillus species were first described in 1729 as ubiquitous saprophytic filamentous fungi commonly found in the environment.[1,2] The name is derived from the microscopic appearance of the conidia, or spores, of the fungus that radiate from a central structure resembling an aspergillum—a device used for sprinkling holy water. Over 80% of human infections are due to A fumigatus and A flavus. Infections due to A niger, A terreus, and A nidulans constitute an additional 10%, and other less common species, approximately 9%.

Invasive aspergillosis is a life-threatening complication of anticancer therapy. The overall mortality rate associated with this infection has been as high as 100% among untreated patients.[3] In immunocompromised patients, crude mortality rates of 86%, 66%, and 99% have been reported for invasive pulmonary aspergillosis, sinus aspergillosis, and cerebral aspergillosis, respectively.[3] Attributable mortality rates of 65% have been reported among amphotericin B(Drug information on amphotericin b) recipients.[4] The mean crude mortality rates for invasive pulmonary aspergillosis in bone marrow transplant recipients have been 90% (range: 33% to 100%), and for leukemia, neutropenia, and aplastic anemia patients, 77% (range: 13% to 100%).[3]

Increasing Incidence

The last 50 years have seen an increase in the incidence of invasive fungal infection in cancer patients.[5] A survey of autopsies performed since 1919 among patients who died of cancer demonstrated that this increase occurred after 1950 in patients with acute leukemia or lymphoma rather than in those with solid-tissue malignancies.[6,7] This phenomenon was paralleled by the introduction of more effective antineoplastic agents such as nitrogen mustard, the folate antagonists, prednisone(Drug information on prednisone), and mercaptopurine(Drug information on mercaptopurine) (Purinethol) between 1946 and 1952 and broad-spectrum antibacterial agents such as penicillin, streptomycin(Drug information on streptomycin), and the tetracyclines from 1941 to 1948.

More effective anticancer agents allowed patients to survive longer at the cost of increased myelosuppression, immunosuppression, and consequent bacterial infection. In turn, effective antibacterial therapy allowed patients who would have otherwise succumbed to bacterial infection to survive long enough to develop opportunistic fungal infection. Consequently, the incidence of invasive aspergillosis has been rising in the cancer patient population.[7] Factors cited as contributing to this phenomenon include a greater number of patients undergoing hematopoietic stem cell transplantation; use of unrelated stem cell donors which, in turn, is associated with an increased incidence of graft-vs-host disease and corticosteroid therapy; and greater dose intensities of cytotoxic and immunosuppressive regimens administered for a variety of cancers.

Risk Factors

Risk factors for invasive fungal infection include prolonged periods of severe neutropenia (absolute neutrophil count less than 0.5 × 10⁹/L for more than 10 days),[8] treatment for acute myeloid leukemia with cytarabine(Drug information on cytarabine) plus an anthracycline or high-dose cytarabine-based remission induction regimens,[9,10] indwelling venous access devices,[11] delayed engraftment due to low hematopoietic stem cell dose in hematopoietic stem cell transplantation, allogeneic hematopoietic stem cell transplantation,[12] immunosuppressive treatment of graft-vs-host disease,[13] and management of high-risk patients outside of a high-efficiency particulate air-filtered nursing unit.[14,15]

Pathogenesis

A successful approach to the prevention and management of filamentous fungal infection is based on a thorough understanding of the pathogenesis of infection by these microorganisms. Opportunistic filamentous molds such as Aspergillus spp are acquired by inhaling microscopic conidia that are borne on ambient air currents within the environment. Oral inhalation, compared to nasal inhalation, increases the likelihood that the conidia will bypass the protective filtering effect of the upper airways and pass into the periphery of the lower respiratory tree. This is more likely to occur under conditions of low humidity, when the otherwise hygroscopic conidia have the smallest diameter and are able to defeat the filtering effect of the upper airways. Conidia enter the upper or lower airways and come to rest on the respiratory epithelium where they germinate into invasive hyphae forms.

In the absence of an adequate host immune response, the hyphae spread locally in the host tissues and then disseminate to other visceral sites such as the brain, myocardium, liver, spleen, kidneys, or skin. It is not surprising that the majority of infections due to Aspergillus spp typically involve the sinuses and the lungs.[16]

Diagnosis

The diagnosis of invasive aspergillosis is based on an index of suspicion in high-risk patients, the clinical and radiologic findings at anatomic sites most likely to be involved with these fungi, morphologic demonstration of compatible fungal structures in methenamine(Drug information on methenamine) silver-stained tissue biopsies, and the isolation of the pathogen in a microbiological culture from involved tissues (Table 1).[17-19] More recently, non-culture-based techniques that rely on detection of galactomanan cell wall antigens by latex agglutination or enzyme-linked immunosorbent assays[20] or of genomic material by polymerase chain reaction[21,22] in urine, serum, cerebrospinal fluid, and bronchoalveolar lavage fluid have shown promise in establishing the diagnosis of invasive aspergillosis. However, these tests are not routinely available in North America. The Mycoses Study Group of the National Institute of Allergy and Infectious Diseases in the United States and the Invasive Fungal Infections Group of the European Organization for Research and Treatment of Cancer have developed criteria by which the certainty of the diagnoses can be established.[17-19,23]

Prevention

The probability that a susceptible host will encounter a critical innoculum of Aspergillus conidia can be reduced significantly by removing the conidia from the ambient air; that is, by managing the patient during the period of highest risk in nursing units equipped with high-efficiency particulate air filters with or without laminar air flow. Such systems are able to remove particles larger than 0.3 µm in diameter with 99.97% efficiency.[24] Previous studies have demonstrated that this strategy can reduce the incidence of proven invasive pulmonary aspergillosis in bone marrow transplant recipients[15] and the risk of developing clinical pneumonia (pooled weighted odds ratio = 0.41, 95% confidence interval = 0.28 to 0.61, N = 1,019 randomized subjects).[25-35]

The Centers for Disease Control and Prevention recommend the use of a protected environment to prevent invasive aspergillosis in cancer patients with prolonged neutropenia.[36,37] Such environments should be well-sealed and equipped with high-efficiency particulate air filters, directional air flow, positive room-air pressure relative to the corridor outside the room, and high rates of room-air exchange (15 to more than 400 exchanges per hour).[37]

Clinical trials that are evaluating the prophylaxis efficacy of antifungal agents such as itraconazole(Drug information on itraconazole) (Sporanox) or low-dose amphotericin B have not been able to demonstrate a treatment effect.[38]

Treatment Options

Early initiation of antifungal therapy in patients with suspected invasive aspergillosis influences survival. The mortality rate for patients who were or were not treated within 10 days of clinical or radiologic evidence of invasive aspergillosis was 41% and 90%, respectively.[39] Although amphotericin B deoxycholate at doses of 1.0 to 1.5 mg/kg/d remains the standard agent for the treatment of invasive aspergillosis,[23] the high mortality rates among patients receiving such treatment and the drug-related metabolic and infusional toxicities limit enthusiasm for this agent.[40]

The lipid-based formulations of amphotericin B administered in daily doses of 3 to 5 mg/kg have similar efficacy to standard amphotericin B deoxycholate but significantly lower rates of nephrotoxicity and infusional toxicities such as chills or rigors.[41] Some investigators advocate the use of lipid-based formulations of amphotericin B as first-line therapy for life-threatening invasive fungal infection in (1) patients with preexisting renal dysfunction defined by a calculated creatinine clearance of less than 50 mL/min; (2) those at high risk of renal dysfunction defined by the concomitant use of nephrotoxic agents such as cyclosporin, tacrolimus(Drug information on tacrolimus), the aminoglycosides, or platinum analogs; or (3) those with underlying diseases such as diabetes mellitus predisposing to renal damage.[42] This position is supported by pharmacoeconomic analysis, particularly in allogeneic hematopoietic stem cell transplant recipients.[43]

Itraconazole administered in daily doses of ³ 400 mg is the only other agent currently available for both oral and intravenous administration in the treatment of invasive aspergillosis.[17,18] This agent has significant limitations with regard to drug interactions and bioavailability, particularly in the setting of achlorhydria, which is common among cancer patients. Newer azoles including voriconazole(Drug information on voriconazole), posaconazole, and ravuconazole are active against Aspergillus spp; however, their role in clinical disease remains to be elucidated. Furthermore, the newer echinocandin agents that inhibit 1,3-beta-d-glucan synthase in the fungal cell wall appear very promising in the treatment of invasive aspergillosis in animal models.[44]

Duration of Treatment

Treatment is initiated at the point when it is determined that a patient probably has invasive aspergillosis. Evidence supporting this diagnosis may be limited to fever and an imaging result consistent with the diagnosis. Further studies may be needed to substantiate or refute the diagnosis. No standard total dose of amphotericin B has been established.[45] The duration of treatment is based on the extent of the infection, the response to therapy, and the status of the patient’s underlying malignancy.[23] Treatment should continue until all clinical signs and symptoms have abated and imaging studies and microbiological culture-based and non-culture-based studies are negative. Some investigators recommend that treatment be continued throughout subsequent cytotoxic anticancer therapy.[46]

The response rates in patients with invasive aspergillosis treated with conventional amphotericin B deoxycholate have ranged from 30% to 40%.[3,4] Response rates for itraconazole recipients have been reported to range from 39% to 63%.[4,17,18] Surgical excision has been advocated for patients with invasive pulmonary aspergillosis who are at risk of life-threatening hemorrhage.[47]

Conclusions

There is a dearth of data from randomized controlled clinical trials that evaluated treatments for invasive aspergillosis. Accordingly, evidence supporting use of the above approaches is based largely on the opinions of experienced investigators.[23] As the number of cancer patients who are receiving intensive cytotoxic and immunosuppressive therapy rises, so, in turn, does the number of patients at risk for Aspergillus infection. Further clinical trials evaluating the newer treatment modalities are needed.