From OncoLog, May 2013, Vol. 58, No. 5
Diagnosis and Treatment of Invasive Fungal Infections in Patients with Hematological Malignancies
By Bryan TuttInvasive fungal infections are important causes of morbidity and death for patients with hematological malignancies. Although much progress has been made in the management of opportunistic fungal infections, their diagnosis and treatment remain a challenge.
Many leukemia and lymphoma patients receive high-dose chemotherapy, sometimes followed by stem cell transplantation, compromising their immune systems. As a result, invasive fungal infections occur in 8%–10% of patients with hematological malignancies. “Because these patients can’t mount an effective immune response, the resulting death rate from many of these infections is over 50%,” said Dimitrios Kontoyiannis, M.D., a professor in the Department of Infectious Diseases at The University of Texas MD Anderson Cancer Center. He added that fungal infections can be a contributing cause of death in patients for whom an infection causes chemotherapy to be attenuated or withheld.
Types of fungal infections
Dr. Kontoyiannis, whose clinical practice and research are focused on the diagnosis and treatment of fungal infections, said the most common invasive fungal infections in patients with hematological malignancies are aspergillosis and candidiasis.
The genus Aspergillus comprises several hundred species that are ubiquitous in the environment but pose little threat to people with healthy immune systems. Immunocompromised patients, however, are more vulnerable to infection by Aspergillus fumigatus or (to a lesser degree) other Aspergillus species.
Invasive candidiasis occurs in immunocompromised patients when Candida yeasts colonizing the body enter the bloodstream. In patients with hematological malignancies, this often occurs in the digestive system, where beneficial bacteria that normally inhibit the growth of yeasts have been destroyed by antibiotics. Candida infections also may occur at catheter insertion sites.
Less common invasive fungal infections, such as cryptococcosis or mucormycosis, also pose a threat to patients with hematological malignancies.
The nonspecific symptoms of invasive fungal infections can impede timely diagnosis. For example, the most common symptom of invasive candidiasis is persistent fever.
Invasive aspergillosis manifests primarily as pneumonia or sinus infections, with symptoms consistent with those conditions, or as relatively asymptomatic lesions in the lung parenchyma. However, invasive aspergillosis can progress rapidly and disseminate hematogenously.
Fungal infections of the airway may be detected by chest radiography or, at an earlier stage, by computed tomography. Because it is not always possible to distinguish between fungal and bacterial infections on imaging studies, bronchoscopy may be used to better visualize the infected area and to obtain tissue samples.
Cultures of tissue, blood, or other fluids are used to make a definitive diagnosis of invasive fungal infections; however, these tests are slow, so treatment may be initiated empirically based on clinical suspicion. Also, comorbid conditions preclude tissue biopsy in some patients with hematological malignancies, and previous treatment with antifungal drugs can make a specific fungal diagnosis difficult.
For these reasons, researchers are developing new diagnostic tests using serum markers. For example, an enzyme-linked immunosorbent assay that detects galactomannan, a component of the Aspergillus cell wall, has been approved by the U.S. Food and Drug Administration for use with serum samples. Serum polymerase chain reaction tests can identify fungal species quickly and accurately, but these tests are not yet routinely used to diagnose fungal infections. Dr. Kontoyiannis is leading two clinical studies of a novel magnetic nanotechnology for the diagnosis of candidiasis at a much earlier stage than is possible with the conventional, blood culture–based tests.
Treatment and prevention
Until the mid-1990s, amphotericin B deoxycholate was the mainstay for treating invasive fungal infections. In the past 2 decades, physicians have witnessed an explosion of effective and less toxic drugs to treat these infections. Specifically, the less nephrotoxic lipid formulations of amphotericin B, the extended-spectrum azoles (such as voriconazole and posaconazole), and the echinocandins (which inhibit fungal cell wall synthesis) are also now commonly used for treatment and prophylaxis.
Antifungal prophylaxis is effective for patients considered at high risk for invasive fungal infections, such as leukemia patients and stem cell transplant recipients; however, guidelines for prophylaxis vary among institutions. New-generation azoles are currently commonly used for prophylaxis, but few head-to-head prospective studies have been done to compare the effectiveness of various antifungal drugs for this purpose.
Empirical antifungal therapy typically is given to patients with neutropenia and fever that persists after 3–7 days of treatment with broad-spectrum antibiotics. Among the drugs commonly used for single-agent empirical therapy are lipid formulations of amphotericin B, echinocandins such as caspofungin, or triazoles such as voriconazole; all of these drugs work against a variety of fungal infections.
Dr. Kontoyiannis said that the selection of agents for primary antifungal therapy is determined by patient-specific characteristics—including the type, location, and severity of the infection; potential for organ toxicity; and possible drug-drug interactions. “The earlier you start therapy for fungal disease, the better the outcome,” he said.
Echinocandins are the main primary therapy for invasive candidiasis, but patients previously treated with azoles or echinocandins may be given liposomal formulations of amphotericin B. Voriconazole is the drug of choice for invasive aspergillosis, although lipid amphotericin B has been used with success. Combinations of voriconazole and other drugs have been studied as primary treatments for invasive aspergillosis, but the data do not support the wide use of combination treatment. Dr. Kontoyiannis said the decision to use combination treatment should be made on a case-by-case basis.
Should the primary antifungal treatment fail, patient characteristics and prior treatments affect the choice of drugs for salvage therapy. Fungal lesions in the lungs that have not responded to antifungal drugs may be removed surgically if the number of lesions and their locations are amenable. Dr. Kontoyiannis said surgery is considered for selected patients with a good performance status who have not yet undergone stem cell transplantation.
Although treatments for invasive fungal infections have improved in the past decade, researchers face obstacles in developing new antifungal drugs. “Fungi and humans are both eukaryotic organisms, which makes it difficult to find a cellular target that can be destroyed without collateral damage to the host,” Dr. Kontoyiannis said. “Not surprisingly, the pipeline for antifungal drug development is currently essentially empty, as pharmaceutical companies are staying away from that relatively small market. Therefore, wise and expert management of our current antifungal armamentarium—with a logical use of antifungals for different indications and in the context of formal guidelines and an antifungal stewardship program—are important.”
Nevertheless, researchers continue to search for new ways to treat or prevent invasive fungal infections in patients with hematological malignancies. Javier Adachi, M.D., an associate professor in the Department of Infectious Diseases, along with Dr. Kontoyiannis and other colleagues, is in the planning stages of a clinical trial of intermittent echinocandin use as prophylaxis against fungal infection in patients with graft-versus-host disease following stem cell transplantation. Also, Issam Raad, M.D., chair of the Department of Infectious Diseases, and colleagues are planning a study of pharmacokinetically improved versions of the triazole posaconazole as a treatment and prophylaxis in patients with hematological malignancies who are at high risk for fungal infections—including patients who have undergone stem cell transplantation.
Finally, immune-enhancing strategies such as the use of growth factors and/or white blood cell transfusions for the prevention and treatment of opportunistic fungal infections in immunocompromised patients remain an important area of investigation.
As researchers work to improve antifungal therapy, accurate early diagnosis and prompt treatment remain the keys to fighting invasive fungal infections in patients with hematological malignancies. “These are relatively uncommon infections that need to be managed in a large center by expert clinical mycologists,” Dr. Kontoyiannis said, “particularly when patients have chronic, complicated, or resistant infections.”
For more information, contact Dr. Dimitrios Kontoyiannis at 713-792-6237.