Four Fungal Horsemen: Emerging Trends in Fungal Disease Epidemiology
New public health perspectives on aspergillosis, sporotrichosis, histoplasmosis, and coccidioidomycosis.
According to conventional wisdom, invasive fungal infections affect limited populations. These diseases tend to be cast as medical zebras even among people at greatest risk, including immunosuppressed patients and those residing in specific geographic areas of the United States. However, fungal disease epidemiology is changing. New risk groups have been identified, zoonotic epidemics with human spillover have taken hold, antifungal resistance has emerged, and previously defined endemic zones are expanding. Here we describe 4 of the most clinically consequential examples of emerging fungal infections. This overview does not cover the multidrug-resistant Candida auris because it has been covered extensively elsewhere.1 Infectious disease specialists have and will continue to act on the front lines as fungal diseases continue to appear in new and curious places.
1. AZOLE-RESISTANT ASPERGILLUS FUMIGATUS
Aspergillus fumigatus is a mold common in the environment, and most people breathe in Aspergillus spores every day without getting sick. It is the most common cause of invasive mold infections in people who are immunocompromised and have lung diseases,2-4 and mortality from invasive aspergillosis is high (>25%).2,4-6 The development of azole antifungal medications such as voriconazole, itraconazole, and posaconazole has greatly improved survival since the late 1990s7; however, infections caused by azole-resistant A fumigatus have emerged.5,8 This resistance was first detected in Europe but has now been found across the globe, including recently in the United States.5,9,10 Azole resistance in A fumigatus is associated with treatment failure and mortality rates greater than 88%.11,12
Of primary concern are azole-resistant A fumigatus strains associated with the use of azole agricultural fungicides.8,13-15 Although not a plant pathogen, A fumigatus can develop resistance during incidental exposure to azole fungicides applied to treat and prevent fungal disease in crops. When these resistant strains cause invasive infections in humans, the efficacy of azole antifungal drugs is reduced. Agricultural azole use has increased in recent decades; in the United States, usage has increased by more than 500% from 2000 (579 metric tons) to 2015 (2940 metric tons).16,17 Environmental fungicide—associated A fumigatus has been found in patients without a history of taking azole medications, supporting the idea that these resistant strains originated in the environment and not during prolonged azole therapy.8,12
The US Centers for Disease Control and Prevention is collecting clinical isolates of A fumigatus to monitor for azole resistance. More information on this program and isolate submission can be found at cdc.gov/fungal/aspergillus-resistance.html. Clinicians should consider azole- resistant aspergillosis in patients who do not respond to antifungal treatment, even in patients who are azole naïve, although other causes of treatment failure exist.
2. INVASIVE PULMONARY ASPERGILLOSIS AND SEVERE INFLUENZA
Invasive pulmonary aspergillosis (IPA) affects primarily patients immunocompromised by stem cell or organ transplantation, chemotherapy, or immunosuppressive medications. However, in the past decade, A fumigatus has emerged as a complication among patients with severe influenza requiring intensive care unit (ICU) admission. Since 2010, several US cases of IPA following severe influenza have been reported.18-23 However, findings from a recent multicenter study in Belgium and the Netherlands suggest that this condition may be more common than anticipated in some regions. The study found that about 20% of 432 ICU patients with severe influenza developed IPA within 3 days of ICU admission.19 About half of those who developed IPA were not immunocompromised. Patients with IPA in severe influenza have developed a rapidly progressive tracheobronchitis, with mortality rates of 46% to 61%.19,20,23 Aspergillus fumigatus may invade lung tissue in the absence of a compromised immune system through disruption of the respiratory epithelium from severe influenza.19,20
The geographic extent of IPA in patients with severe influenza is unknown outside the Netherlands and Belgium; it may be a novel phenomenon or previously present but unrecognized. Until more definitive research and surveillance can answer this question, it is important for clinicians to consider diagnosis and treatment of invasive aspergillosis in patients with severe influenza who are not getting better with treatment, even in those who are not immunocompromised. Fungal culture or galactomannan antigen testing of bronchoalveolar lavage fluid can aid in diagnosis.
3. ZOONOTIC SPOROTRICHOSIS
Sporothrix brasiliensis behaves quite differently from sporotrichosis caused by the better-known Sporothrix schenckii. Although the symptoms of S brasiliensis infection in humans often resemble those of S schenckii infection, classically a localized skin ulceration with spreading lymphangitis, S brasiliensis infections appear more virulent, with up to 20% of cases progressing to disseminated disease.24-26 Additionally, these infections may fail to respond to antifungal therapy.27,28 However, the major difference between these Sporothrix species is in how these infections are acquired. Sporotrichosis from S schenckii is also known as rose gardener’s disease because it is frequently caused by traumatic inoculation from plants, whereas cats are the main reservoir and source of transmission of S brasiliensis, making this an emerging zoonotic disease.29
In cats, S brasiliensis causes primarily facial ulcerations (Figure 130), typically after the cat is scratched or bitten by an infected or colonized cat.27 Feline-to-human transmission similarly occurs through scratches, bites, or contact with lesions of infected cats.27 Before 1990, S brasiliensis was found only in the southeast region of Brazil, around São Paulo and Rio de Janeiro. Since then, it has spread throughout much of southern Brazil, with thousands of cases in humans and cats reported at a single center in Rio de Janeiro since 1998.25
Given the close contact cats often have with people, and the tens of millions of stray cats in the United States and elsewhere,31 there is concern that this outbreak could spread to other areas as it has within Brazil.29 Clinicians, particularly infectious disease physicians, dermatologists, and veterinarians, should be aware of this emerging disease, as early identification will be key in minimizing spread of this fungus.
4. US ENDEMIC MYCOSES: COCCIDIOIDOMYCOSIS AND HISTOPLASMOSIS
Many physicians have been trained to associate endemic fungal diseases with specific geographic areas. However, a growing body of evidence suggests that for the fungi that cause these diseases, classical endemic ranges have expanded.
In the United States, coccidioidomycosis (commonly called valley fever), caused by Coccidioides, occurs mainly in Arizona and Southern California (Figure 2).32-34 Histoplasmosis is normally thought to exist in areas around the Mississippi and Ohio river valleys.35,36 However, these observations are based on half-century-old studies.32,35 Outside these ranges, physicians may not consider these illnesses in the differential diagnosis for many patients. For example, both fungal infections may be clinically indistinguishable from bacterial community acquired pneumonia,37 and both can cause lung nodules that mimic lung cancer,38 leading to unnecessary treatments and delays in appropriate therapy.
Locally acquired coccidioidomycosis cases have been recorded as far north as Washington State,39 and soil samples linked to these cases tested positive for Coccidioides.40 Similarly, histoplasmosis can cause infections far outside its classical range, as suggested by animal cases as far away as Alaska41 and human cases reported to public health departments north of the endemic areas identified in the 1950s, specifically in Michigan, Minnesota, and Wisconsin.42
Some have hypothesized that climate change and human activities are contributing to expanding geographic ranges, although increased detection capacity or other factors may be involved.41,43 Increasing periods of drought and higher temperatures in the West interspersed with high rainfall are thought to be conducive to Coccidioides growth in the soil and airborne dispersal under the “grow and blow” hypothesis.44,45 Likewise, climate and land-use changes could be contributing to a widening of the regions with soils that are well suited for Histoplasma.36 Whatever the reason for the apparent spread of these endemic fungi, practitioners outside these regions should consider these infections as possible causes of illness.
Fungi grow in vastly diverse environments, which occasionally include the bodies of humans and animals. Although the ecological factors associated with fungal disease are complex and poorly understood, the 4 examples described here highlight the need for vigilance as new fungal diseases emerge and familiar ones morph in range and risk groups. As epidemiologists aim to quantify the burden and longitudinal trends in fungal disease, our surveillance systems need to keep pace with the changing fungal world. Among the 4 fungal diseases discussed, only 1 (coccidioidomycosis) is nationally notifiable.46 Improved public health surveillance for these diseases could serve clinical and public health practices alike, by informing patient care and public health policy.
Kelly is an Oak Ridge Institute for Science and Education fellow in the Mycotic Diseases Branch at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, working on invasive mold infection surveillance.Henry is a fourth-year medical student at Columbia University who plans on specializing in emergency medicine. He recently completed the CDC Epidemiology Elective Program with the Mycotic Diseases Branch.Jackson is the lead of the CDC’s Fungal Epidemiology Team, which is devoted to tracking and preventing a wide range of invasive fungal diseases, both established and emerging.Beer is an epidemiologist in the Mycotic Diseases Branch at the CDC, with special interests in invasive mold infections.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
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