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      Think Fungus—Prevention and Control of Fungal Infections

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          Abstract

          Reports of human infections with environmental fungi are on the increase throughout the world. Many of these reports describe infections caused by new agents, as well as by traditional agents with new virulence factors or new mechanisms of infection. Fungal infections historically have been underrecognized and difficult to detect, and treatment options are poor. The reasons for their emergence are likely multifactorial. The advent of medical progress—including the wide use of medical hardware, such as central lines; successful management of immunosuppression in patients with transplanted organs; and immunomodulatory agents for treating underlying diseases from cancer to rheumatoid arthritis—has contributed to the increase in fungal infections in immunocompromised hosts. Risk factors such as changes in land use, seasonal migration, international travel, extreme weather, and natural disasters, and the use of azole antifungal agents in large-scale agriculture are believed to underlie many of the increases in community-acquired fungal infections. Because fungal infections are frequently underrecognized and difficult to detect, one of the largest gaps in our understanding of their epidemiology is determining the incidence of disease. In an article in this issue of Emerging Infectious Diseases, Sondermeyer et al. document the incidence and cost of hospitalizations in California caused by Valley fever (coccidioidomycosis), a fungal infection endemic to the southwestern United States and parts of Latin America ( 1 ). This article reports that during 2000–2011, there were >25,000 Valley fever–associated hospitalizations in California and >$2 billion in hospital costs. The rate of hospitalizations increased over the study period from 2.3 to 5.0 cases/100,000 population, a finding that supports other recent publications documenting the increasing incidence of Valley fever in the United States ( 2 , 3 ). Although the reasons for this increase are not well understood, the practical effect of this increasing incidence has been seen in many settings, including the California state prison system. Recently, a federal court ordered the prison system to move prisoners believed to be at high risk for Valley fever (including Blacks, persons >55 years of age, and persons with preexisting diabetes) out of 2 prisons in the San Joaquin Valley, which is the region in California to which coccidioidomycosis is endemic. Fungal diseases also appear to be emerging beyond their traditionally described borders for reasons that are not entirely understood. One article in this issue reports the incidence of Cryptococcus gattii disease, once believed to be restricted to tropical regions, but which is now found in locations as disparate as Vancouver Island, Canada and parts of the southeastern United States ( 4 ). Although this organism is genetically related to C. neoformans, a cause of meningitis in HIV-infected persons, C. gattii is frequently associated with a different spectrum of disease, prominently pneumonia. In another article in this issue, Nucci et al. report an increase in incidence of community-associated Fusarium spp. infections in a cancer ward in Brazil ( 5 ). In this study, Fusarium spp. caused an increase in invasive infections, which usually started as skin or nail infections, in immunocompetent and immunosuppressed patients. Although the root cause was not determined, speculation has centered on changes in land use patterns and agricultural practices in Brazil. Also in this issue, a novel agent of fungemia, Candida auris, is reported as having been detected in India ( 6 ). All isolates reported in this article were resistant to the antifungal agent fluconazole, which is concerning because fluconazole is frequently the first-line treatment for invasive Candida spp. infections in many countries. Finally, an article by Fong et al. provides serologic evidence that Pneumocystis jirovecii may be transmitted between patients and providers in the health care setting, a finding that could affect future infection control policies ( 7 ). Because most invasive fungal infections have high mortality rates, reducing the incidence of these diseases often relies on rapid and specific diagnostics, effective antifungal drugs, novel immunotherapeutic strategies, and adherence to infection control and sterility practices. Recently, we have seen examples of successes and failures in this area. In regions with high HIV prevalence, use of novel lateral-flow diagnostic tests for cryptococcal disease has opened the door to systematic screening and point-of-care testing in asymptomatic persons with low CD4 cell counts and may result in reduction of deaths caused by this disease ( 8 , 9 ). Conversely, recent contamination of a widely distributed injectable steroid medication with fungal organisms, particularly the black mold Exserohilum rostratum, caused the largest health care–associated outbreak in the United States; as of July 1, 2013, there have been 749 cases of meningitis and related infections among persons in 20 states and 61 deaths ( 10 , 11 ). Swift public health actions, including notification of patients and providers, led to rapid clinical assessments and institution of antifungal therapy among infected persons, thereby reducing the mortality rate and effects of this disease ( 12 ). Broader control of fungal exposures in the community can also be improved by awareness, especially education regarding high-risk practices and activities. Outbreaks of histoplasmosis linked to construction and cleaning activities in places contaminated with bird or bat guano have led to production of educational materials describing how risk can be mitigated ( 13 ). Furthermore, recent advances in whole-genome sequencing are being explored to suggest novel vaccine and diagnostic targets for the agent of Valley fever ( 14 ). Fungal infections remain serious and underappreciated causes of illness and death. Much can be done to prevent the consequences of these infections, although environmental exposure to these agents may not be entirely avoidable in the community. Continued public health efforts toward defining, characterizing, and tracking the emergence of fungal infections can help to focus studies on priority infections and settings. Future translational research is urgently needed to develop novel diagnostics, vaccines, and treatments as more is learned about the pathogenesis of fungal infections and the biology of fungal agents.

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          New Clonal Strain of Candida auris, Delhi, India

          A new clonal strain of Candida auris is an emerging etiologic agent of fungemia in Delhi, India. In 12 patients in 2 hospitals, it was resistant to fluconazole and genotypically distinct from isolates from South Korea and Japan, as revealed by M13 and amplified fragment length polymorphism typing.
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            Fungal infections associated with contaminated methylprednisolone in Tennessee.

            We investigated an outbreak of fungal infections of the central nervous system that occurred among patients who received epidural or paraspinal glucocorticoid injections of preservative-free methylprednisolone acetate prepared by a single compounding pharmacy. Case patients were defined as patients with fungal meningitis, posterior circulation stroke, spinal osteomyelitis, or epidural abscess that developed after epidural or paraspinal glucocorticoid injections. Clinical and procedure data were abstracted. A cohort analysis was performed. The median age of the 66 case patients was 69 years (range, 23 to 91). The median time from the last epidural glucocorticoid injection to symptom onset was 18 days (range, 0 to 56). Patients presented with meningitis alone (73%), the cauda equina syndrome or focal infection (15%), or posterior circulation stroke with or without meningitis (12%). Symptoms and signs included headache (in 73% of the patients), new or worsening back pain (in 50%), neurologic symptoms (in 48%), nausea (in 39%), and stiff neck (in 29%). The median cerebrospinal fluid white-cell count on the first lumbar puncture among patients who presented with meningitis, with or without stroke or focal infection, was 648 per cubic millimeter (range, 6 to 10,140), with 78% granulocytes (range, 0 to 97); the protein level was 114 mg per deciliter (range, 29 to 440); and the glucose concentration was 44 mg per deciliter (range, 12 to 121) (2.5 mmol per liter [range, 0.7 to 6.7]). A total of 22 patients had laboratory confirmation of Exserohilum rostratum infection (21 patients) or Aspergillus fumigatus infection (1 patient). The risk of infection increased with exposure to lot 06292012@26, older vials, higher doses, multiple procedures, and translaminar approach to epidural glucocorticoid injection. Voriconazole was used to treat 61 patients (92%); 35 patients (53%) were also treated with liposomal amphotericin B. Eight patients (12%) died, seven of whom had stroke. We describe an outbreak of fungal meningitis after epidural or paraspinal glucocorticoid injection with methylprednisolone from a single compounding pharmacy. Rapid recognition of illness and prompt initiation of therapy are important to prevent complications. (Funded by the Tennessee Department of Health and the Centers for Disease Control and Prevention.).
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              Increase in Reported Coccidioidomycosis — United States, 1998–2011

              Coccidioidomycosis, also known as valley fever, is an infection caused by inhalation of Coccidioides spp. spores. This soil-dwelling fungus is endemic to arid regions of Mexico, Central and South America, and the southwestern United States (1). Symptomatic patients typically experience a self-limited influenza-like illness, but some develop severe or chronic pulmonary disease, and less than 1% of patients experience disseminated disease (1). Coccidioidomycosis can be costly and debilitating, with nearly 75% of patients missing work or school because of their illness, and more than 40% requiring hospitalization (2). Previous publications have reported state-specific increases in coccidioidomycosis in Arizona and California during 1998–2001 and 2000–2007, respectively (3,4). To characterize long-term national trends, CDC analyzed data from the National Notifiable Diseases Surveillance System (NNDSS) for the period 1998–2011. This report describes the results of that analysis, which indicated that the incidence of reported coccidioidomycosis increased substantially during this period, from 5.3 per 100,000 population in the endemic area (Arizona, California, Nevada, New Mexico, and Utah) in 1998 to 42.6 per 100,000 in 2011. Health-care providers should be aware of this increasingly common infection when treating persons with influenza-like illness or pneumonia who live in or have traveled to endemic areas. In collaboration with the Council of State and Territorial Epidemiologists (CSTE), CDC compiles data on selected diseases through NNDSS. Data are reported to CDC from various state and territorial surveillance systems and reporting mechanisms. Coccidioidomycosis has been nationally notifiable since 1995; however, it was not nationally notifiable in 2010. Although the CSTE case definition includes both laboratory and clinical criteria, Arizona uses a laboratory-only case definition because of its large number of cases and the high predictive value of a positive laboratory result (2); since 2008, the laboratory component of the CSTE definition has included cases with a single positive serologic test. California uses the CSTE case definition, requiring both laboratory and clinical evidence of infection, but some counties with large numbers of cases use a laboratory-only definition. State and regional annual incidence rates were calculated by dividing the number of cases by U.S. Census Bureau population estimates for each year. Crude, sex-specific, age-specific, and age-adjusted incidence rates (aIR) were calculated for Arizona, California, and other endemic states where coccidioidomycosis is reportable (Nevada, New Mexico, and Utah, combined). Rates were age adjusted using the 2000 U.S. standard population. Negative binomial regression was performed to assess statistical significance of incidence trends during 1998–2011. This model adjusts for changes in population size and age and sex distribution over time. During 1998–2011, a total of 111,717 coccidioidomycosis cases were reported to CDC from 28 states and the District of Columbia: 66% from Arizona, 31% from California, 1% from other endemic states, and <1% from nonendemic states. In Arizona, California, Nevada, New Mexico, and Utah combined, the number of cases increased from 2,265 in 1998 (aIR: 5.3 per 100,000 population) to 8,806 in 2006 (18.0 per 100,000); a decrease occurred in 2007 and 2008 before an increase in 2009 (12,868 cases; 25.3 per 100,000), which continued into 2010 and 2011 (42.6 per 100,000) (Table 1). Incidence in endemic states increased among all age groups during 1998–2011 (Figure). During this period, incidence typically was highest among the 40–59 year age group in California but was consistently highest among persons aged ≥60 years in Arizona and other endemic states. Incidence during 2011 was 381.1 per 100,000 among persons aged 60–79 years and 385.2 per 100,000 among persons aged ≥80 years in Arizona (Table 2). During 1999–2008, most (56%) Arizona cases occurred among males, but beginning in 2009, a higher proportion (55%) of cases occurred among females. Incidence in 2011 in Arizona was substantially higher among females (286.9 per 100,000) than males (215.7 per 100,000). In contrast, only 35% of California cases occurred among females during 1998–2011, and 2011 incidence among California males (20.5 per 100,000) was more than double that among females (9.7 per 100,000). The increase in the number of Arizona cases, from 1,474 in 1998 to 16,467 in 2011, was statistically significant by negative binomial regression (aIR: 30.5 per 100,000 in 1998; 247.7 per 100,000 in 2011, p<0.001). Adjusting for changes in population demographics, this corresponds to an increase in coccidioidomycosis incidence of approximately 16% each year during the study period. The number of California cases increased from 719 in 1998 (aIR: 2.1 per 100,000) to 5,697 in 2011 (aIR: 14.9 per 100,000) (average annual increase of 13%, p<0.001). The number of cases reported in Nevada, New Mexico, and Utah combined increased from 72 in 1998 (aIR: 1.4 per 100,000) to 237 in 2011 (aIR: 3.1 per 100,000) (p<0.001). Cases reported in nonendemic states increased from six in 1998 to 240 in 2011. Editorial Note This report describes statistically significant increases in the incidence rate of reported coccidioidomycosis in endemic states during 1998–2011 after adjusting for changes in population size and in age and sex distribution. Although the number of cases decreased in Arizona during 2007–2008 and in California during 2007–2009, incidence dramatically increased in 2010 and 2011. In 2011, coccidioidomycosis was the second most commonly reported nationally notifiable condition in Arizona and the fourth most commonly reported in California (5). The reasons for the increases described in this report are unclear. Coccidioides exists in the soil and is sensitive to environmental changes; factors such as drought, rainfall, and temperature might have resulted in increased spore dispersal, and disruption of soil by human activity, such as construction, also might be a contributing factor. Changes in surveillance methodology might have resulted in artifactual increases. California transitioned to a laboratory-based reporting system during 2010, which facilitated reporting and might account for the increase in reported cases in 2011. However, some highly endemic counties, such as Kern County, already had been using laboratory-based systems, so this cannot fully explain the recent increase. The observed increase in Arizona might be partially attributable to a 2009 change by a major commercial laboratory to conform its reporting practices to the 2008 CSTE case definition, whereby positive enzyme immunoassay (EIA) results were reported as cases without confirmation by immunodiffusion. One commercially available EIA test (Meridian Bioscience) commonly used to diagnose coccidioidomycosis has been described to have false-positive results in some instances (6), but the contribution of this phenomenon, if any, to the overall increase in cases is unknown. Improved awareness of coccidioidomycosis might have resulted in increased diagnostic testing (and thus reporting) in endemic and nonendemic states. Coccidioides has been found to be the etiologic agent in an estimated 15%–29% of community-acquired pneumonias in highly endemic areas (7). However, a 2006 study demonstrated that only a small proportion (2%–13%) of patients with compatible illness in an endemic area were tested for coccidioidomycosis (7), suggesting that the disease is greatly underreported. Further study is needed to understand if testing practices have changed. Despite the increase in reported cases, overall U.S. coccidioidomycosis mortality rates have remained fairly stable at approximately 0.6 per 1 million person-years during 1990–2008 (8). What is already known on this topic? Coccidioidomycosis is an infection that results from inhalation of Coccidioides spp. fungal spores. It is endemic in the southwestern United States, with the highest number of cases occurring in Arizona and California, and constitutes a substantial public health burden in these areas, particularly among older persons. What is added by this report? Reported coccidioidomycosis cases have increased dramatically in recent years. The age-adjusted incidence was 5.3 cases per 100,000 population in the endemic area in 1998 and 42.6 per 100,000 in 2011. Among persons aged 60–79 years in the endemic area, incidence was 69.1 cases per 100,000 in 2011. What are the implications for public health practice? The number of reported cases of coccidioidomycosis is increasing. Health-care providers should be alert for this infection among persons with influenza-like illnesses who live in or have traveled to endemic areas. Further research on strategies to reduce the morbidity of coccidioidomycosis is needed. The findings in this report are subject to at least four limitations. First, NNDSS data might underrepresent the actual burden of disease because coccidioidomycosis is not reportable in every state, even in known endemic areas such as Texas, and because state reporting of cases to CDC is voluntary. In particular, the number of cases reported in 2010 might underestimate the actual number of infections because coccidioidomycosis was not notifiable in 2010 (but became notifiable again in 2011). Second, minor discrepancies between the findings in this report and those presented in MMWR’s annual Summary of Notifiable Diseases reports likely exist because the summary does not include cases from states where the disease was not reportable. Third, minor discrepancies might exist between this report and state-specific reports because of delays in case reporting. Finally, because nearly 70% of cases were missing race/ethnicity data, incidence rates by race and ethnicity were not calculated. This is an important consideration because high rates among Asians and blacks have been documented previously, and black race has been shown to be an independent risk factor for disseminated coccidioidomycosis (9). Further investigation is needed to determine how much of the observed increase in coccidioidomycosis incidence is artifactual. Nevertheless, health-care providers should be alert for coccidioidomycosis among patients of all ages who live in or have traveled to endemic areas. Persons in endemic areas should consider trying to reduce exposure to dusty air, which might contain Coccidioides spp. spores. However, because there are currently no proven preventive measures for coccidioidomycosis, additional research into strategies that reduce the incidence or morbidity of this infection is warranted. Specifically, the role of antifungal treatment for primary pulmonary disease remains controversial and deserves further exploration (10), although treatment is recommended in certain patient groups, particularly those at high risk for severe disease (1). Because the symptoms of coccidioidomycosis mimic those of other community-acquired respiratory illnesses, patients often experience delays in testing and diagnosis and receive unnecessary antibiotics; however, patients who know about coccidioidomycosis are more likely to request testing and receive a diagnosis sooner than those who are not familiar with the disease (2). Therefore, promoting increased community and health-care provider awareness of this infection continues to be an important role for public health officials.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                October 2013
                : 19
                : 10
                : 1688-1689
                Affiliations
                Centers for Disease Control and Prevention, Atlanta Georgia, USA
                Author notes
                Address for correspondence: Mary E. Brandt, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop G11, Atlanta, GA 30333, USA; email: mbb4@ 123456cdc.gov
                Article
                13-1092
                10.3201/eid1910.131092
                3810766
                24180010
                Categories
                Commentary
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