CHAPTER 30. Cytomegalovirus in Patients with Cancer by Morgan Hakki, Per Ljungman, Michael Boeckh

ABSTRACT

Human cytomegalovirus (CMV) is a common opportunistic infection after hematopoietic cell transplant (HCT) and is less frequently encountered among patients undergoing cytotoxic chemotherapy for various malignancies. Both primary infection and reactivation can result in substantial morbidity and mortality in the immunocompromised host. Therefore, the prompt recognition and treatment of CMV infection is critical. This chapter will outline the diagnosis, prevention, and treatment of CMV, focusing on the HCT recipient since it is this population that is at greatest risk for, and bears the largest burden of, CMV infection and disease.

CHAPTER 29. Immunotherapy for difficult to treat invasive fungal diseases by Brahm H. Segal, Amar Safdar, David A. Stevens

ABSTRACT

Opportunistic fungal diseases occur most commonly in highly immunocompromised patients, such as those with prolonged neutropenia or transplant recipients treated with intensive immunosuppression. Significant advances have been made in antifungal agents, which have led to improved therapeutic outcomes as well as a greater emphasis on antifungal prophylaxis targeted to the highly immuncompromised. In addition, we are gaining more knowledge about how our immune system recognizes fungi and protects us from fungal disease, while limiting potentially injurious inflammation and allergy. This knowledge has led to novel experimental approaches for immunotherapy. Progress in paving the way from promising pre-clinical approaches and limited clinical experience to properly conducted clinical trials has been poor – a reflection of invasive fungal diseases being relatively uncommon and the heterogeneity of the patient populations at risk, and insufficient funding for multicenter clinical immunotherapeutic trials. We describe our approaches to immunotherapy for severe and refractory invasive fungal diseases, realizing that important gaps in knowledge exist regarding benefit and toxicity. Future perspectives on immunotherapy are discussed.

CHAPTER 28. Fungal Drug Resistance and Pharmacologic Considerations of Dosing Newer Antifungal Therapies by Russell E. Lewis, David S. Perlin

ABSTRACT

Recent advances in hematopoetic cell transplantation and a broadening array of salvage chemotherapy options have extended the survival of patients with hematological cancers, but can result in prolonged periods of immunosuppression and susceptibility to invasive fungal infections.  Among these high-risk patient populations, systemic antifungal therapy is administered episodically or sometimes continuously for months or even years, increasing concerns for the development of antifungal resistance. As newer triazoles (voriconazole and posaconazole) and echinocandins (anidulafungin, caspofungin, and micafungin) have supplanted amphotericin B formulations as the preferred antifungal therapies for primary and secondary prophylaxis, pharmacokinetic variability inherent to the triazoles as well as emerging patterns of intrinsic and acquired antifungal resistance are becoming increasingly important factors in the long-term management of invasive fungal infections. In this chapter, we review recent data concerning antifungal drug resistance for these newer azoles and echinocandins, as well as key considerations in drug dosing.

CHAPTER 27. Current Controversies in the Treatment of Fungal Infections by Christopher D. Pfeiffer, John R. Perfect, Barbara D. Alexander

ABSTRACT

With improved laboratory techniques and the availability of new antifungal agents, complexity in the treatment of invasive fungal disease has rapidly increased over the past decade, stimulating a debate on the best management strategies.  In this chapter, we address four important areas of current uncertainty, including: 1) the role of therapeutic drug monitoring for voriconazole and posaconazole, 2) the utility of in vitro antifungal susceptibility testing of yeasts and moulds, 3) the optimal treatment of zygomycosis, and 4) the value of combination therapy for invasive aspergillosis.  For each topic, we examine the available evidence surrounding the ambiguity and then offer data-driven recommendations on how to proceed with management.

CHAPTER 26. Cryptococcal Disease and Endemic Mycosis by Johan A. Maertens and Hélène Schoemans

ABSTRACT

Cryptococcus and the endemic fungi (Histoplasma, Blastomyces and Coccidioides) can cause severe, even life-threatening pulmonary and extrapulmonary disease in immunocompromised patients, including cancer patients and transplant recipients. This chapter describes the epidemiology, clinical manifestations, diagnosis and treatment of these infections in patients with prolonged immunodeficiency.

CHAPTER 25. Management of Aspergillosis, Zygomycosis, and Other Clinically Relevant Mold Infections by Konstantinos Leventakos, Dimitrios P. Kontoyiannis  

ABSTRACT

Invasive mold infections (IMIs) are a major cause of morbidity and mortality in severely immunocompromised hematologic malignancy patients and hematopoietic stem cell transplantations recipients. Invasive aspergillosis caused by Aspergillus fumigatus is the most common cause of IMI, but recent advances in the pharmacotherapy of fungal infections and an increase in the number of patients at risk has caused an epidemiologic shift towards infections with resistant non-fumigatus Aspergillus species and non-Aspergillus molds such as Zygomycetes. Patient outcome is a function of immune function recovery, early diagnosis, and multiple interventions, such as with broad-spectrum antifungal therapy and adjunct immunotherapy and surgery in select patients. In this chapter, we review the utility of new diagnostic modalities such as the galactomannan test, the 1,3-beta-D-glucan test, and fungal DNA tests in diagnosing IMIs early. We focus on modern antifungal agents (the lipid formulations of amphotericin B, the broad-spectrum azoles, and the echinocandins) and evaluate them in the context of evolving prophylactic, pre-emptive, and targeted therapies for IMIs.

CHAPTER 24. Invasive Candidiasis by Matteo Bassetti,  Malgorzata Mikulska, Juan Gea-Banacloche, Claudio Viscoli

ABSTRACT

Candida infections are increasing. Non-albicans Candida are now the most commonly isolated species in immunocompromised patients. The determination of serum beta-D-glucan may allow early diagnosis but the best implementation of this new technology as screening or diagnostic test remains to be determined. From the therapeutic standpoint, the echinocandins have changed the management of invasive candidiasis due to their effectiveness and excellent safety and drug interaction profile.

CHAPTER 23. Diagnosis of Invasive Fungal Disease by Dionissios Neofytos, Kieren Marr

ABSTRACT

The diagnosis of invasive fungal infections (IFI) relies on the critical assessment of clinical presentation, associated risk factors, and careful interpretation of the appropriate diagnostic tests.  Frequently, clinicians have to initiate antifungal therapy based on their clinical suspicion and without having made a definitive diagnosis, particularly in cancer or other critically ill patients.  To complicate diagnosis, isolation of fungal organisms does not imply pathogenicity, especially from non-sterile sites, and may not necessitate treatment.  Hence, making the diagnosis of an IFI in clinical practice requires suspicion of disease, depends mostly on the acuity and severity of clinical signs and symptoms, and necessitates careful consideration of findings.  In this chapter we will review the traditional diagnostic modalities (culture, histopathology, and imaging) and recently developed diagnostic tools (BG, PCR, and GM EIA) for the diagnosis of IFIs.  This review will focus on the diagnosis of the most commonly identified IFIs in cancer patients, specifically invasive candidiasis (IC), invasive aspergillosis (IA), and zygomycosis.

CHAPTER 22. Overview of Invasive Fungal Disease in Oncology Patients by Amar Safdar

ABSTRACT

The spectrum of invasive fungal disease has changed considerably in the past two decade. Since late 1980’s triazole prophylaxis has resulted in a significant decline in cases of invasive candidiasis among patients undergoing hematopoietic stem cell transplantation and those with acute leukemia. Recently, reduced rates of invasive mold disease following echinocandin and anti-mold triazoles use during the high risk periods have ushered optimism. This trend in effective drug-mediated prevention has not been without set backs including unexpected toxicity due to drug-drug interaction, and difficult-to-treat breakthrough fungal disease due to previously uncommon yeasts and filamentous fungi. The rise in virulent non-albicans Candida species and non-Aspergillus molds has, to some extent compromise the recent advances in early diagnosis and effective antifungal therapy. As the understanding of hosts’ genetic (polymorphisms) vulnerability to fungal disease improves, next generation of diagnostic assays (DNA proliferation, microarray and other technologies) gain clinical validation, approach towards mitigating underlying immune defects with recombinant cytokines, strategies to restore innate and adaptive immune dysfunction become feasible, and target-specific effective antineoplastic therapy is introduced in the cancer fighting armamentarium; these accomplishments will usher a new era for improved outcomes in cancer patients who are susceptible to invasive fungal disease.

CHAPTER 21. Skin Disorders Difficult to Distinguish from Infection by Sharon Hymes, Susan Chon, Ana Ciurea

ABSTRACT

Dermatologists and infectious disease specialists are often called upon to evaluate skin lesions in cancer patients, especially when an infectious etiology is suspected.  Many different organisms can affect the skin, and these are comprehensively reviewed in other chapters. This section will review some of the non-infectious skin eruptions that mimic cutaneous infections. These non-infectious diagnoses may be suspected after review of the patient history, and are often confirmed by skin evaluation and biopsy as indicated.   The morphology of the primary skin lesion, the one that has not been manipulated or otherwise treated, often provides important diagnostic clues. This chapter is intended to help the clinician generate a differential diagnosis when evaluating cutaneous lesions in cancer patients. Using the morphology of the primary lesion as a starting point, we then list the non-infectious diagnosis that could be considered and the infectious process it mimics.