MODULE 1: Epidemiology and Risk Factors for Invasive Fungal Infections

Introduction Invasive fungal infections (IFIs) are an important cause of morbidity and mortality, particularly among certain patient populations (eg, chemotherapy, transplants).1-3 Understanding the epidemiology of IFIs and their associated risk factors can improve their detection and provide patients with the lifesaving treatment. The following review summarizes the current trends of four IFIs—invasive candidiasis, invasive aspergillosis, cryptococcal meningitis, and mucormycosis.

Epidemiology Candidiasis Invasive candidiasis is the most common cause of IFIs, accounting for over one-quarter of a million infections and 50,000 deaths worldwide each year.4 In the United States, it is among the top five hospital-acquired bloodstream infections.5 Candidemia is the most common form of invasive candidiasis, associated with mortality rates of approximately 30%.5 Adults aged 65 and older comprise the age group with the highest incidence rates of candidemia.

Candida albicans remains the leading cause of candidemia worldwide, but its relative frequency is decreasing, while the frequency of non-C albicans species is increasing.5 The increase in non- C albicans species shows that some Candida species are becoming resistant or naturally resistant to antifungal therapy, particularly fluconazole and echinocandins.5 Patients’ characteristics influence Candida species distribution. For example, C glabrata infections are more common in elderly patients, and C krusei in immunocompromised patients.

Multiple risk factors for candidemia have been identified and include neutropenia, broad- spectrum antibiotic therapy, abdominal surgery, and total parenteral nutrition, among others.

Aspergillosis Invasive aspergillosis is the second most common IFI, with increasing incidence over the past few two decades.6 The most common species identified is Aspergillus fumigatus.6,7 Because it is not a reportable disease in the United States, the exact incidence of invasive aspergillosis is unknown.8 Local epidemiology and air quality play a role in its incidence. In some settings, invasive aspergillosis is more frequent than invasive candidiasis.6 Invasive aspergillosis is a major cause of death in immunocompromised patients, with mortality rates ranging from 40% to 80% of those with widespread infection.2,3,7 Prospective surveillance among transplant recipients performed during 2001-2006 found that invasive aspergillosis was the most common type of

fungal infection among allogeneic stem cell transplant recipients and the second most common type of fungal infection among solid organ transplant recipients; the 1-year survival rates for these patients were 25% and 59%, respectively.2,3

Cryptococcal meningitis Globally, cryptococcal meningitis causes an estimated 223,000 AIDS-related cases annually and more than 180,000 deaths.9 While the number of AIDS-related cases, hospitalizations, and deaths associated with cryptococcal meningitis have been declining, largely due to earlier initiation of antiretroviral therapy,9 the number of cases in HIV-uninfected individuals has been increasing.10 In addition, studies have shown worse outcomes and a higher mortality rate among HIV-uninfected individuals than those with HIV infection.10,11

Mucormycosis Mucormycosis is a rare but a potentially fatal fungal infection.12,13 Rhizopus oryzae is the most common organism isolated from infected patients, accounting for approximately 70% of all cases.12 The mortality rate for mucormycosis remains above 50% and approaches 100% for patients with disseminated disease or persistent neutropenia.12

In addition to immunosuppression, there are some unique host risk factors for mucormycosis such as diabetes ketoacidosis, trauma/burns, iron overload and deferoxamine therapy.12,14 Mucormycosis can affect any organ system, with rhino-orbital-cerebral and pulmonary infections being the most predominant infection types.15

An analysis of US hospital discharge data from the Healthcare Cost and Utilization Project – Nationwide Inpatient Sample showed that less than 0.01% of all US hospitalizations between 2003 and 2010 were for mucormycosis.13 Although rates remain low, it is becoming an increasingly important fungal infection, more than doubling in incidence in the last decade.12,14,16 Early identification at the species level and epidemiological data will perhaps allow better prediction of patients’ prognosis and tailoring of treatment.15

Recognizing Risk Factors The most common risk factor for invasive fungal disease is immunosuppression, particularly when it is associated with hematological malignancy, solid organ transplant, or allogeneic hematopoietic stem cell transplant. As the incidence of each of these increases, the US Centers for Disease Control and Prevention predicts that the incidence of IFIs will rise.17 To better recognize patients at risk for IFIs, it is important to know which conditions are associated with each type of fungal infection (Table).

Table. Risk Factors for Invasive Fungal Infections

Fungal infection Risk factors

18 Invasive Candidiasis • Immunosuppression • Neutropenia • Advanced age • Deteriorating health • Catheter use • Total parenteral nutrition • Surgical intervention (notably major intra-abdominal procedures) • Prolonged use of broad spectrum antibiotics • Prolonged hospital stay • Corticosteroid use • Pancreatitis • Any type of dialysis Invasive Aspergillosis6,19,20 • Prolonged neutropenia – main risk factor • Allogeneic hematopoietic stem cell transplant • Solid organ transplant • Immunodeficiency • Corticosteroid use • Hematological malignancy • Diabetes • Prolonged ICU stay • Chronic obstructive pulmonary disease • Renal or live dysfunction Mucormycosis12,14 • Uncontrolled diabetes with ketoacidosis • Immunosuppression • Organ transplant • Neutropenia • Trauma and burns • Malignant hematological disorders • Deferoxamine therapy in hemodialysis • Elevated serum iron level • Malnutrition • Renal or liver dysfunction Cryptococcal meningitis11,21 • HIV • Immunosuppression therapy • Corticosteroid use • Chemotherapy • Autoimmune disease • Liver disease HIV, human immunodeficiency virus; ICU, intensive care unit.

Summary Invasive fungal infections are a problem worldwide. This is predominantly driven by the widespread adoption of immunosuppressive therapy among certain patient populations (e.g., recipients of solid organ or hematopoietic stem cell transplantation, patients with hematologic malignancies, and patients receiving intensive care). Although Candida species accounts for a large proportion of IFIs, incidence and epidemiology vary between institutions and regions depending on the type of population risk factors and antifungal use. Of concern is an increase in resistance among certain fungal species. Keeping abreast of local epidemiological trends and resistance patterns is key to prevention and treatment of IFIs. Moreover, knowledge of the risk factors for IFIs can lead to earlier testing and diagnosis.

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