Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Talaromyces marneffei, Coccidioides species, and Paracoccidioides species-a systematic review to inform the World Health Organization priority list of fungal pathogens.

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal pathogen priority list. This systematic review aimed to evaluate the epidemiology and impact of infections caused by Talaromyces marneffei, Coccidioides species, and Paracoccidioides species. PubMed and Web of Sciences databases were searched to identify studies published between 1 January 2011 and 23 February 2021 reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 25, 17, and 6 articles were included for T. marneffei, Coccidioides spp. and Paracoccidioides spp., respectively. Mortality rates were high in those with invasive talaromycosis and paracoccidioidomycosis (up to 21% and 22.7%, respectively). Hospitalization was frequent in those with coccidioidomycosis (up to 84%), and while the duration was short (mean/median 3-7 days), readmission was common (38%). Reduced susceptibility to fluconazole and echinocandins was observed for T. marneffei and Coccidioides spp., whereas >88% of T. marneffei isolates had minimum inhibitory concentration values ≤0.015 µg/ml for itraconazole, posaconazole, and voriconazole. Risk factors for mortality in those with talaromycosis included low CD4 counts (odds ratio 2.90 when CD4 count <200 cells/µl compared with 24.26 when CD4 count <50 cells/µl). Outbreaks of coccidioidomycosis and paracoccidioidomycosis were associated with construction work (relative risk 4.4-210.6 and 5.7-times increase, respectively). In the United States of America, cases of coccidioidomycosis increased between 2014 and 2017 (from 8232 to 14 364/year). National and global surveillance as well as more detailed studies to better define sequelae, risk factors, outcomes, global distribution, and trends are required.

Fusarium species,Scedosporium species, and Lomentospora prolificans: A systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies.

BACKGROUND: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines. METHODS: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021. RESULTS: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001). CONCLUSIONS: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.

Genomic description of human clinical Aspergillus fumigatus isolates, California, 2020.

Aspergillus fumigatus, an environmental mold, causes life-threatening infections. Studies on the phylogenetic structure of human clinical A. fumigatus isolates are limited. Here, we performed whole genome sequencing of 24 A. fumigatus isolates collected from 18 patients in U.S. healthcare facilities in California. Single-nucleotide polymorphism (SNP) differences between patient isolates ranged from 187 to 70 829 SNPs. For five patients with multiple isolates, we calculated the within-host diversities. Three patients had a within-host diversity that ranged from 4 to 10 SNPs and two patients ranged from 2 to 16 977 SNPs. Findings revealed highly diverse A. fumigatus strains among patients and two patterns of diversity for isolates that come from the same patient, low and extremely high diversity.

Aspergillus fumigatus is an environmental mold. It can cause a severe infection called aspergillosis in patients with weakened immune systems. We analyzed A. fumigatus DNA from patients at California hospitals. We described genetic diversity between samples from the same patients and among different patients. Our findings provide insight on using genomic sequencing to investigate aspergillosis in hospitals.

Evaluation of OIDx Histoplasma Urinary Antigen EIA.

A sandwich enzyme immunoassay (EIA) for the detection of Histoplasma antigens (Ag) in urine, developed by Optimum Imaging Diagnostics (OIDx) was evaluated. A verification using a standardized reference panel of urine samples found sensitivity of 92%, specificity of 32% and accuracy of 51%. In this study, the OIDx Histoplasma urinary Ag EIA displayed high sensitivity, however, in non-histoplasmosis cases this EIA displayed false-positive results in 68% of specimens tested.

Implementation of rapid diagnostics assays for detection of histoplasmosis and cryptococcosis in central american people living with HIV.

OBJECTIVES: Histoplasmosis and cryptococcosis are important public health problems in people living with HIV (PLHIV) in Central America. Conventional laboratory assays, based on microscopy and culture, are not optimal for the diagnosis of either disease. However, antigen (Ag) assays are rapid and highly accurate for the diagnosis of these infections. METHODS: Laboratory surveillance of PLHIV was carried out in four hospitals in Panama, Honduras and Nicaragua, between 2015 and 2019. Detection of Histoplasma antigens in urine was performed by enzyme immunoassay (EIA), and Cryptococcus antigen detection in sera and cerebrospinal fluid specimens was performed by lateral flow assay (LFA). RESULTS: A total of 4,453 PLHIV with clinical suspicion of histoplasmosis (n = 1,343) or cryptococcosis (n = 3,110; 2,721 sera and 389 CSF) were tested. Of 1,343 patients suspected of having histoplasmosis, 269 (20%) were Histoplasma Ag positive. Of 3,110 patients tested using the Cryptococcus Ag assay, 329 (11%) were positive. Honduras reported the highest positivity rates (32% for Histoplasma Ag, and 16% for Cryptococcus Ag); Panama reported the largest number of patients testing positive using the Histoplasma Ag assay (n = 201); and Nicaragua reported the largest number of patients testing positive using the Cryptococcus Ag assay (n = 170). CONCLUSION: Here, we show how the implementation of rapid diagnostics assays impacted case detection and was useful for the care of people with advanced HIV. Rapid and accurate diagnosis could reduce mortality associated with histoplasmosis and cryptococcosis in PLHIV.

The Changing Epidemiology of Candidemia in the United States: Injection Drug Use as an Increasingly Common Risk Factor-Active Surveillance in Selected Sites, United States, 2014-2017.

BACKGROUND: Injection drug use (IDU) is a known, but infrequent risk factor on candidemia; however, the opioid epidemic and increases in IDU may be changing the epidemiology of candidemia. METHODS: Active population-based surveillance for candidemia was conducted in selected US counties. Cases of candidemia were categorized as IDU cases if IDU was indicated in the medical records in the 12 months prior to the date of initial culture. RESULTS: During 2017, 1191 candidemia cases were identified in patients aged >12 years (incidence: 6.9 per 100 000 population); 128 (10.7%) had IDU history, and this proportion was especially high (34.6%) in patients with candidemia aged 19-44. Patients with candidemia and IDU history were younger than those without (median age, 35 vs 63 years; P < .001). Candidemia cases involving recent IDU were less likely to have typical risk factors including malignancy (7.0% vs 29.4%; relative risk [RR], 0.2 [95% confidence interval {CI}, .1-.5]), abdominal surgery (3.9% vs 17.5%; RR, 0.2 [95% CI, .09-.5]), and total parenteral nutrition (3.9% vs 22.5%; RR, 0.2 [95% CI, .07-.4]). Candidemia cases with IDU occurred more commonly in smokers (68.8% vs 18.5%; RR, 3.7 [95% CI, 3.1-4.4]), those with hepatitis C (54.7% vs 6.4%; RR, 8.5 [95% CI, 6.5-11.3]), and in people who were homeless (13.3% vs 0.8%; RR, 15.7 [95% CI, 7.1-34.5]). CONCLUSIONS: Clinicians should consider injection drug use as a risk factor in patients with candidemia who lack typical candidemia risk factors, especially in those with who are 19-44 years of age and have community-associated candidemia.

Knowledge of Infectious Disease Specialists Regarding Aspergillosis Complicating Influenza, United States.

In an online survey, we found that nearly one fifth of physicians in the United States who responded had seen or heard about a case of invasive pulmonary aspergillosis after severe influenza at their institution. However, <10% routinely used galactomannan testing to test for this fungus in patients with severe influenza.

Evaluation of a Histoplasma antigen lateral flow assay for the rapid diagnosis of progressive disseminated histoplasmosis in Colombian patients with AIDS.

BACKGROUND: Progressive disseminated histoplasmosis (PDH) is an important cause of mortality in persons living with HIV (PLHIV), especially in countries where patients have limited access to antiretroviral therapies and diagnostic testing. OBJECTIVE: A lateral flow assay (LFA) to detect Histoplasma capsulatum antigen in serum developed by MiraVista® was evaluated. METHODS: We tested 75 serum samples: 24 from PLHIV and culture-proven PDH and 51 from PLHIV with other fungal and bacterial infections as well as people without HIV. LFA devices were read manually (read by eye) and by an automated reader. RESULTS: When the LFA was read manually, sensitivity was 96% and specificity was 90%. When an automated reader was used, sensitivity was 92% and specificity was 94%. The Kappa index comparing manual and automated reader was 0.90. Cross-reactions were observed principally in samples from patients with proven diagnosis of paracoccidioidomycosis. CONCLUSIONS: The MiraVista® Diagnostics Histoplasma antigen LFA had high analytical performance and good agreement between manual and automated reader. This LFA allows Histoplasma antigen testing with minimal laboratory equipment and infrastructure requirements.

Bridging the knowledge gap on mycoses in Africa: Setting up a Pan-African Mycology Working Group.

Most African countries have poorly funded and overburdened health systems. Additionally, a high prevalence of HIV in Sub-Saharan Africa contributes to a high burden of opportunistic fungal infections. Data generated by GAFFI from 15 of 57 African countries revealed that an estimated 47 million Africans suffer from fungal diseases, of whom an estimated 1.7 million suffer from a serious fungal infection annually. Almost all African countries lack a surveillance system for fungal infections with the exception of South Africa. South Africa is also the only African country with a national mycology reference laboratory. Across the continent, there is a pervasive picture of inadequate/poor diagnostic capacity, low level of awareness among healthcare workers and policymakers and unavailability and non-accessibility to essential antifungal medications. Recent outreach efforts by the International Society for Human and Animal Mycology (ISHAM) and the European Confederation of Medical Mycology (ECMM) have aimed to increase involvement of African countries and experts in global initiatives such as "One World One Guideline" and also the ECMM Academy. Recently, under the auspices of ISHAM, the African sub-region created a network of mycology experts whose goal is to organise and engage African leaders in the field of medical mycology. The aim of this ISHAM Working Group was to facilitate interaction and synergy among regional leaders in order to develop educational programmes for capacity building to aid in the diagnosis and care of patients with fungal infections in Africa. The working group will also encourage country initiatives to develop clinical guidelines, to support surveys and to support the establishment of reference mycology laboratories.

Case-Case Comparison of Candida auris Versus Other Candida Species Bloodstream Infections: Results of an Outbreak Investigation in Colombia.

BACKGROUND: Candida auris is an emerging multidrug-resistant yeast that causes outbreaks in healthcare settings around the world. In 2016, clinicians and public health officials identified patients with C. auris bloodstream infections (BSI) in Colombian healthcare facilities. To evaluate potential risk factors and outcomes for these infections, we investigated epidemiologic and clinical features of patients with C. auris and other Candida species BSI. METHODS: We performed a retrospective case-case investigation in four Colombian acute care hospitals, defining a case as Candida spp. isolated from blood culture during January 2015-September 2016. C. auris BSI cases were compared to other Candida species BSI cases. Odds ratio (OR), estimated using logistic regression, was used to assess the association between risk factors and outcomes. RESULTS: We analyzed 90 patients with BSI, including 40 with C. auris and 50 with other Candida species. All had been admitted to the intensive care unit (ICU). No significant demographic differences existed between the two groups. The following variables were independently associated with C. auris BSI: ≥ 15 days of pre-infection ICU stay (OR: 5.62, CI: 2.04-15.5), evidence of severe sepsis (OR: 3.70, CI 1.19-11.48), and diabetes mellitus (OR 5.69, CI 1.01-31.9). CONCLUSION: Patients with C. auris BSI had longer lengths of ICU stay than those with other candidemias, suggesting that infections are acquired during hospitalization. This is different from other Candida infections, which are usually thought to result from autoinfection with host flora.

Molecular Epidemiology of Candida auris in Colombia Reveals a Highly Related, Countrywide Colonization With Regional Patterns in Amphotericin B Resistance.

Background: Candida auris is a multidrug-resistant yeast associated with hospital outbreaks worldwide. During 2015-2016, multiple outbreaks were reported in Colombia. We aimed to understand the extent of contamination in healthcare settings and to characterize the molecular epidemiology of C. auris in Colombia. Methods: We sampled patients, patient contacts, healthcare workers, and the environment in 4 hospitals with recent C. auris outbreaks. Using standardized protocols, people were swabbed at different body sites. Patient and procedure rooms were sectioned into 4 zones and surfaces were swabbed. We performed whole-genome sequencing (WGS) and antifungal susceptibility testing (AFST) on all isolates. Results: Seven of the 17 (41%) people swabbed were found to be colonized. Candida auris was isolated from 37 of 322 (11%) environmental samples. These were collected from a variety of items in all 4 zones. WGS and AFST revealed that although isolates were similar throughout the country, isolates from the northern region were genetically distinct and more resistant to amphotericin B (AmB) than the isolates from central Colombia. Four novel nonsynonymous mutations were found to be significantly associated with AmB resistance. Conclusions: Our results show that extensive C. auris contamination can occur and highlight the importance of adherence to appropriate infection control practices and disinfection strategies. Observed genetic diversity supports healthcare transmission and a recent expansion of C. auris within Colombia with divergent AmB susceptibility.

Potential Fifth Clade of Candida auris, Iran, 2018.

Four major clades of Candida auris have been described, and all infections have clustered in these 4 clades. We identified an isolate representative of a potential fifth clade, separated from the other clades by >200,000 single-nucleotide polymorphisms, in a patient in Iran who had never traveled outside the country.

Hospital-Associated Multicenter Outbreak of Emerging Fungus Candida auris, Colombia, 2016.

Candida auris is an emerging multidrug-resistant fungus that causes hospital-associated outbreaks of invasive infections with high death rates. During 2015-2016, health authorities in Colombia detected an outbreak of C. auris. We conducted an investigation to characterize the epidemiology, transmission mechanisms, and reservoirs of this organism. We investigated 4 hospitals with confirmed cases of C. auris candidemia in 3 cities in Colombia. We abstracted medical records and collected swabs from contemporaneously hospitalized patients to assess for skin colonization. We identified 40 cases; median patient age was 23 years (IQR 4 months-56 years). Twelve (30%) patients were <1 year of age, and 24 (60%) were male. The 30-day mortality was 43%. Cases clustered in time and location; axilla and groin were the most commonly colonized sites. Temporal and spatial clustering of cases and skin colonization suggest person-to-person transmission of C. auris. These cases highlight the importance of adherence to infection control recommendations.

Hurricane-Associated Mold Exposures Among Patients at Risk for Invasive Mold Infections After Hurricane Harvey - Houston, Texas, 2017.

In August 2017, Hurricane Harvey caused unprecedented flooding and devastation to the Houston metropolitan area (1). Mold exposure was a serious concern because investigations after Hurricanes Katrina and Rita (2005) had documented extensive mold growth in flood-damaged homes (2,3). Because mold exposure can cause serious illnesses known as invasive mold infections (4,5), and immunosuppressed persons are at high risk for these infections (6,7), several federal agencies recommend that immunosuppressed persons avoid mold-contaminated sites (8,9). To assess the extent of exposure to mold and flood-damaged areas among persons at high risk for invasive mold infections after Hurricane Harvey, CDC and Texas health officials conducted a survey among 103 immunosuppressed residents in Houston. Approximately half of the participants (50) engaged in cleanup of mold and water-damaged areas; these activities included heavy cleanup (23), such as removing furniture or removing drywall, or light cleanup (27), such as wiping down walls or retrieving personal items. Among immunosuppressed persons who performed heavy cleanup, 43% reported wearing a respirator, as did 8% who performed light cleanup. One participant reported wearing all personal protective equipment (PPE) recommended for otherwise healthy persons (i.e., respirator, boots, goggles, and gloves). Immunosuppressed residents who are at high risk for invasive mold infections were exposed to mold and flood-damaged areas after Hurricane Harvey; recommendations from health care providers to avoid exposure to mold and flood-damaged areas could mitigate the risk to immunosuppressed persons.

Update on the Epidemiology of coccidioidomycosis in the United States.

The incidence of reported coccidioidomycosis in the past two decades has increased greatly; monitoring its changing epidemiology is essential for understanding its burden on patients and the healthcare system and for identifying opportunities for prevention and education. We provide an update on recent coccidioidomycosis trends and public health efforts nationally and in Arizona, California, and Washington State. In Arizona, enhanced surveillance shows that coccidioidomycosis continues to be associated with substantial morbidity. California reported its highest yearly number of cases ever in 2016 and has implemented interventions to reduce coccidioidomycosis in the prison population by excluding certain inmates from residing in prisons in high-risk areas. Coccidioidomycosis is emerging in Washington State, where phylogenetic analyses confirm the existence of a unique Coccidioides clade. Additional studies of the molecular epidemiology of Coccidioides will improve understanding its expanding endemic range. Ongoing public health collaborations and future research priorities are focused on characterizing geographic risk, particularly in the context of environmental change; identifying further risk reduction strategies for high-risk groups; and improving reporting of cases to public health agencies.

Approach to the Investigation and Management of Patients With Candida auris, an Emerging Multidrug-Resistant Yeast.

Candida auris is an emerging, multidrug-resistant yeast that can spread in healthcare settings. It can cause invasive infections with high mortality and is difficult to identify using traditional yeast identification methods. Candida auris has been reported in more than a dozen countries, and as of August 2017, 112 clinical cases have been reported in the United States. Candida auris can colonize skin and persist in the healthcare environment, allowing for transmission between patients. Prompt investigation and aggressive interventions, including notification to public health agencies, implementation of contact precautions, thorough environmental cleaning and disinfection, infection control assessments, contact tracing and screening of contacts to assess for colonization, and retrospective review of microbiology records and prospective surveillance for cases at laboratories are all needed to limit the spread of C. auris. This review summarizes the current recommended approach to manage cases and control transmission of C. auris in healthcare facilities.

High Cryptococcal Antigen Titers in Blood Are Predictive of Subclinical Cryptococcal Meningitis Among Human Immunodeficiency Virus-Infected Patients.

Background: High mortality rates among asymptomatic cryptococcal antigen (CrAg)-positive patients identified through CrAg screening, despite preemptive fluconazole treatment, may be due to undiagnosed cryptococcal meningitis. Methods: Symptoms were reviewed in CrAg-positive patients identified by screening 19233 individuals with human immunodeficiency virus infection and CD4 cell counts <100/µL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and at 2 hospitals until June 2016. Cerebrospinal fluid samples from 90 of 254 asymptomatic patients (35%) and 78 of 173 (45%) with headache only were analyzed for cryptococcal meningitis, considered present if Cryptococcus was identified by means of India ink microscopy, culture, or CrAg test. CrAg titers were determined with stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality rate were assessed. Results: Cryptococcal meningitis was confirmed in 34% (95% confidence interval, 25%-43%; 31 of 90) of asymptomatic CrAg-positive patients and 90% (81%-96%; 70 of 78) with headache only. Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (P < .001) and patients with headache only (P = .003). The optimal titer for predicting cryptococcal meningitis was >160 (sensitivity, 88.2%; specificity, 82.1%); the odds ratio for concurrent cryptococcal meningitis was 34.5 (95% confidence interval, 8.3-143.1; P < .001). Conclusions: About a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where it is not possible to perform lumbar punctures in all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis.

Recognition of Azole-Resistant Aspergillosis by Physicians Specializing in Infectious Diseases, United States.

Infections caused by pan-azole-resistant Aspergillus fumigatus strains have emerged in Europe and recently in the United States. Physicians specializing in infectious diseases reported observing pan-azole-resistant infections and low rates of susceptibility testing, suggesting the need for wider-scale testing.