Invasive fungal diseases in patients with autoimmune diseases: a case series from the French RESSIF network.

OBJECTIVES: We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality. METHODS: We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP). RESULTS: From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia <1500/mm3 was frequent (132/179, 73.7%) even if CD4+T cell count exceeded 200/mm3 in 56/78 patients (71.8%) (median 472.5/mm3, IQR 160-858). CONCLUSION: IFD associated with AID occurs primarily in RA, AAV and IBD, especially when treated with GCs and immunosuppressants. Mortality is high, especially for patients on high-dose GCs. Lymphopenia may help identify risk of PCP, but normal CD4+T cell count does not rule out the risk. Further studies are needed to assess the individual risk factors for IFD.

Infecciones fúngicas invasivas en niños hospitalizados en un centro de referencia de Uruguay / Invasive fungal infections in children hospitalized at a pediatric reference hospital in Uruguay / Infecções fúngicas invasivas em crianças internadas em um centro hospitalar de referência no Uruguai

Introducción: las infecciones fúngicas invasivas (IFI) son un problema de salud en creciente aumento. Objetivo: describir las características epidemiológicas, microbiológicas y clínicas de los menores de 15 años con IFI hospitalizados en el Hospital Pediátrico, Centro Hospitalario Pereira Rossell entre 2010- 2019. Metodología: estudio retrospectivo, mediante revisión de historias clínicas. Variables: edad, sexo, comorbilidades, factores de riesgo, clínica, patógenos, tratamiento y evolución. Resultados: se registraron 26 casos de IFI en 23 niños. La mediana de edad fue 8 años, de sexo femenino 17, con comorbilidades 17: infección por VIH 5, enfermedad hematooncológica 4. Todos presentaban factores de riesgo para IFI. Las manifestaciones clínicas de sospecha fueron: fiebre en 19, síntomas neurológicos 11, respiratorios 9, gastrointestinales 6, urinarios 2, sepsis/shock en 3. Los agentes identificados fueron: Candida spp en 14, Cryptococcus neoformans complex 8 y Aspergillus fumigatus complex 4. Tratamiento: se indicó fluconazol en 15, asociado a anfotericina B 11. Todas las infecciones por candida fueron sensibles a los azoles. Fallecieron 7 niños, la mediana de edad fue 1 año. En 4 se identificó Candida spp, Aspergillus fumigatus complex 2 y Cryptococcus neoformans complex 1. Conclusiones: las IFI son poco frecuentes, afectan en su mayoría a niños inmunocomprometidos asociando elevada mortalidad. El diagnóstico requiere alto índice de sospecha. Candida spp y Cryptococcus spp fueron los agentes más involucrados. El inicio precoz del tratamiento acorde a la susceptibilidad disponible se asocia a menor mortalidad.

Summary: Introduction: invasive fungal infections (IFI) are an increasing health problem. Objective: describe the epidemiological, microbiological and clinical characteristics of children under 15 years of age with IFI hospitalized at the Pereira Rossell Hospital Center between 2010-2019. Methodology: retrospective study, review of medical records. Variables: age, sex, comorbidities, risk factors, symptoms, pathogens, treatment and evolution. Results: 26 cases of IFI were recorded involving 23 children. Median age 8 years, female 17, comorbidities 17, HIV infection 5, hematological-oncological disease 4. All with risk factors. Suspicion symptoms: fever 19, neurological symptoms 11, respiratory 9, gastrointestinal 6, urinary 2, sepsis / shock 3. Identified agents: Candida spp 14, Cryptococcus neoformans complex 8 and Aspergillus fumigatus complex 4. Treatment: fluconazole 15, associated with amphotericin B 11. All candida infections were sensitive to azoles. 7 died, median age 1 year. In 4, Candida spp was isolated, Aspergillus fumigatus complex in 2 and Cryptococcus neoformans complex in 1. Conclusions: IFI are rare, mostly affecting immunocompromised children, associated with high mortality. The diagnosis requires a high index of suspicion. Candida spp and Cryptococcus spp were the most involved agents. Early treatment according to available susceptibility is associated with lower mortality.

Introdução: as infecções fúngicas invasivas (IFI) são um problema de saúde crescente. Objetivo: descrever as características epidemiológicas, microbiológicas e clínicas de crianças menores de 15 anos com IFI internadas no Centro Hospitalar Pereira Rossell entre 2010 e 2019. Metodologia: estudo retrospectivo, revisão de prontuários. Variáveis: idade, sexo, comorbidades, fatores de risco, sintomas, patógenos, tratamento e evolução. Resultados: foram registrados 26 casos de IFI em 23 crianças. Idade mediana 8 anos, sexo feminino 17, comorbidades 17, infecção por HIV 5, doença hemato-oncológica 4. Todos com fatores de risco. Suspeita clínica: febre 19, sintomas neurológicos 11, respiratórios 9, gastrointestinais 6, urinários 2, sepse/choque 3. Agentes identificados: Candida spp 14, Cryptococcus neoformans complexo 8 e Aspergillus fumigatus complexo 4. Tratamento: fluconazol 15, associado à anfotericina B 11. Todas as infecções por cândida foram sensíveis aos azóis. 7 morreram, idade média de 1 ano. Em 4 das crianças Cândida spp foi isolada, Aspergillus fumigatus complexo em 2 e Cryptococcus neoformans complexo em 1. Conclusões: IFIs são raras, afetando principalmente crianças imunocomprometidas, associadas a alta mortalidade. O diagnóstico requer alto índice de suspeita. Cândida spp e Cryptococcus spp são os agentes mais envolvidos. O tratamento precoce de acordo com a suscetibilidade disponível está associado a menor mortalidade.

Invasive aspergillosis is a critical determinant of mortality in cirrhosis: a systematic review with meta-analysis.

Invasive fungal infections pose a severe threat in unconventional immunocompromised hosts such as cirrhosis. Herein we review the impact of invasive aspergillosis (IA) on the prognosis of cirrhosis patients. An electronic search for full-text articles describing IA in cirrhosis was conducted and the disease outcomes and mortality (point-estimate and comparative risk) were pooled on random-effects meta-analysis. Of 4127 articles, 11 studies (9 with good/fair and 2 with poor quality) were included. IA was associated with high disease severity and multi-organ failures in cirrhosis. The pooled-mortality of IA was 81.8% (95% CI: 64.3-91.8, I2 = 59%, P < 0.01). Estimate's-heterogeneity (I2) was explored through sub-groups, meta-regression, and influential diagnostics. Mortality estimates were higher among subgroups of acute-on-chronic liver failure (ACLF, 86.4%) and intensive care unit (ICU)-admitted patients (84.0%). The odds of mortality related to IA were 8.9 times higher than controls and much higher in ACLF (OR: 22.5) and ICU-admitted patients (OR: 36.4). The odds of mortality in IA were 4.1, 12.9, and 48.6 times higher than bacterial, no-fungal infections, and no-infection controls. There was no asymmetry in mortality estimates or odds ratios and mortality in IA was high irrespective of country of origin, site of infection, proven or probable category, and quality of study. Thus, IA is associated with very high mortality in cirrhosis patients, especially in ACLF and ICU-admitted patients. Intensive research is needed for the rapid diagnosis and treatment of IA in cirrhosis. LAY SUMMARY: We report a high mortality rate of 81.8% in patients with liver cirrhosis and invasive aspergillosis. Higher odds (8.9 times) of death, especially in patients with ACLF or ICU admission were seen. Mortality was not affected by the country of study, site of infection, proven or probable nature of infection category, and quality of study.

Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

OBJECTIVES: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality. PATIENTS AND METHODS: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis. RESULTS: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01). CONCLUSIONS: Coinfections are frequent in IA patients and are associated with higher mortality.

Scedosporiosis/lomentosporiosis observational study (SOS): Clinical significance of Scedosporium species identification.

Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain.

Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.

Invasive dermatophyte infection: A systematic review.

Dermatophyte infections usually present as various types of superficial cutaneous mycoses; on very rare occasions, dermatophytes enter deep into the dermis and cause invasive infections. In this study, we aimed to perform a systematic review of all reported invasive dermatophytosis cases over the past 20 years. We performed systematic searches in PubMed/Medline, EMBASE and Web of Science and identified 123 papers reporting 160 individual cases of invasive dermatophytosis between 2000 and 2020. Our study included 103 (64.4%) males, and the mean age at diagnosis was 43.0 years (range: 3-87 years). The most common predisposing factor was superficial dermatophytosis (56.9%), followed by solid organ transplantation (26.9%), the use of topical immunosuppressants (15.6%), gene mutations (14.4%), diabetes (14.4%) and trauma (6.9%). Trichophyton (T.) rubrum was the most prevalent pathogen (53.1%) responsible for invasive dermatophytosis, followed by T. mentagrophytes (7.5%), Microsporum canis (6.9%), T. tonsurans (5.6%), T. interdigitale (5.0%) and T. violaceum (3.8%). Patients with CARD9 or STAT3 mutations were prone to have mixed infection of two or more dermatophytes, present with eosinophilia and high IgE, and develop disseminated infections. Overall mortality was 7.9%, and the mortality in patients with and without gene mutations was 17.4% and 5.5%, respectively. Most of the normal host patients responded well to oral antifungal agents, while gene-deficient patients usually required lifelong treatment to stabilise their infection status. Our review indicated the importance of preventive treatment of superficial tinea in patients with immunosuppression and gene deficiencies to avoid the development of invasive dermatophytosis.

Low rates of invasive fungal disease in patients with multiple myeloma managed with new generation therapies: Results from a multi-centre cohort study.

INTRODUCTION: A multi-centre study to determine the outcomes and risks for invasive fungal disease (IFD) in myeloma (MM) patients treated with second-generation immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies was conducted. METHODS: Clinical and microbiology records were reviewed to capture patient demographics, disease characteristics, treatment, IFD episodes and outcomes. Categorical and continuous variables between patients with IFD and without IFD were compared using chi-square test, Fisher's exact test and Mann-Whitney rank sum test, respectively, with P-value < .05 considered statistically significant. RESULTS: Five out of 148 (3.4%) MM patients were diagnosed with five episodes of IFI: 3 were proven, 1 probable and 1 possible. Median time from commencement of new generation therapy to IFD diagnosis was 4.0 months (Interquartile range [IQR]: 3.4-5.7). In patients with IFD, median cumulative steroid dose over 60 days was 1119 mg (IQR: 1066-1333 mg). None of the patients with IFD had prolonged neutropenia (neutrophil count < 0.5 × 109 /L for more than 10 days). Common sites of infection were the respiratory tract (40.0%) and bloodstream (40.0%). Cryptococcus neoformans (n = 2) and Candida krusei (n = 1) were the fungal pathogens isolated in the three proven cases. 30-day mortality rate was 40.0%. Patients with IFD were younger (median 58 versus 68 years, P = .52) and treated with more lines of therapy (median 5 vs 3, P = .04). CONCLUSION: IFD rate is low in heavily treated MM patients treated with second-generation therapy including monoclonal antibodies. Patients do not appear to have traditional risk factors such as prolonged neutropenia.

Invasive fungal disease in humans: are we aware of the real impact?

Despite the medical advances and interventions to improve the quality of life of those in intensive care, people with cancer or severely immunocompromised or other susceptible hosts, invasive fungal diseases (IFD) remain severe and underappreciated causes of illness and death worldwide. Therefore, IFD continue to be a public health threat and a major hindrance to the success of otherwise life-saving treatments and procedures. Globally, hundreds of thousands of people are affected every year with Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Pneumocystis jirovecii, endemic dimorphic fungi and Mucormycetes, the most common fungal species causing invasive diseases in humans. These infections result in morbidity and mortality rates that are unacceptable and represent a considerable socioeconomic burden. Raising the general awareness of the significance and impact of IFD in human health, in both the hospital and the community, is hence critical to understand the scale of the problem and to raise interest to help fighting these devastating diseases.

Experiencia de 10 años en pacientes operados por rinosinusitis fúngica invasiva aguda / 10-year experience in patients operated for acute invasive fungal rinosinusitis

INTRODUCCIÓN: La rinosinusitis fúngica invasiva aguda (RSFIA) es una enfermedad poco frecuente, de alta mortalidad. Se presenta principalmente en pacientes inmunocomprometidos con múltiples comorbilidades, lo que dificulta su manejo. El objetivo de este trabajo es describir una cohorte de pacientes operados por RSFIA, sus características clínicas y mortalidad, los agentes etiológicos y el rendimiento de los métodos de diagnóstico. MATERIAL Y MÉTODO: Estudio prospectivo no concurrente de pacientes operados por RSFIA entre el 2005 y 2015 en nuestro centro. RESULTADOS: Se incluyeron 32 pacientes, 62,5% (20/32) hombres, con una edad promedio de 39,4 años (16-65 años). La mortalidad global fue del 71,9%, correspondiendo un 46,9% a mortalidad en agudo y un 25% a tardía. Las neoplasias hematológicas fueron la enfermedad de base más frecuente, correspondiendo al 84,4% (27/32) de los casos, seguida de la diabetes mellitus en un 9,4% (3/32). El 62,5% (20/32) de los pacientes presentó neutropenia al diagnóstico, y un 80% (16/20) de ellos, neutropenia febril. El síntoma más frecuente fue la fiebre en un 65,6% (21/32), luego dolor facial o cefalea en un 53,1% (17/32). Se identificó Aspergillus en el 37,5% (12/32), seguido por Rhizopus en el 31,3% (10/32). No se encontró asociación entre las variables estudiadas y un mayor riesgo de mortalidad. CONCLUSIONES: La RSFIA es una enfermedad agresiva con una alta mortalidad, siendo fundamental el diagnóstico oportuno. Es necesario optimizar los criterios de sospecha para un diagnóstico precoz que permita mejorar el pronóstico

INTRODUCTION: Acute invasive fungal rhinosinusitis (AIFRS) is rare but has high mortality. It is more frequent in immunocompromised patients with multiple comorbidities, which make their management more difficult. The aim of this study is to describe a cohort of patients operated due to AIFRS, their clinical characteristics, mortality, aetiological agent and efficacy of diagnostic tests. MATERIAL AND METHOD: Non-concurrent prospective study of patients with AIFRS who were operated between 2005 and 2015 in our centre. RESULTS: Thirty-two patients were included, 62.5% (20/32) men, with an average age of 39.4 years (16-65 years). Overall mortality was 71.9%; acute mortality 46.9% and late mortality 25%. Haematological malignancies were the most common underlying disease, present in 84.4% (27/32) of cases, followed by diabetes mellitus in 9.4% (3/32). On diagnosis, 62.5% (20/32) of patients were neutropenic, 80% (16/20) of them with febrile neutropenia. Fever was the most frequent symptom, present in 65.6% (21/32) of patients, followed by facial pain or headache in 53.1% (17/32). Aspergillus was identified in 37.5% (12/32) of cases and Rhizopus in 31.3% (10/32). There was no association between the analysed variables and increased risk of mortality. CONCLUSIONS: AIFRS is an aggressive disease with a high mortality rate, therefore a timely diagnosis is fundamental. It is necessary to optimise suspicion criteria for an early diagnosis in order to improve the prognosis

Hematopoietic stem cell transplantation does not increase the risk of infection-related complications for pediatric patients with Hodgkin and non-Hodgkin lymphomas: A multicenter nationwide study.

BACKGROUND: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. OBJECTIVE: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. PATIENTS AND METHODS: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. RESULTS: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. CONCLUSIONS: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Risk factors for mortality in patients with pulmonary mucormycosis.

BACKGROUND: Pulmonary mucormycosis (PM) represents a serious burden in terms of morbidity and mortality in immunocompromised patients. Studies of prognostic factors in patients with PM are limited and have involved small numbers of patients. METHODS: Adult patients diagnosed with proven and probable PM according to the modified definitions of the EORTC/MSG 2008 in a tertiary hospital in Seoul, South Korea, between 2008 and 2019 were retrospectively enrolled. RESULTS: A total of 49 patients including 31 (63%) with proven PM and 18 (37%) with probable PM were enrolled. The 90-day mortality rate was 49% (24/49). Neutropenia, thrombocytopenia, use of voriconazole at clinical suspicion, positivity of non-sterile culture, use of steroid and treatment without surgery were more common in fatal cases than non-fatal cases. Voriconazole use at clinical suspicion for invasive mould pneumonia (OR 6.91, P = .01) and prolonged neutropenia (OR 4.86, P = .03) were independent risk factors for mortality. Voriconazole use at clinical suspicion was associated with positive galactomannan (GM) assay (OR 5.93, P = .02) and history of invasive pulmonary aspergillosis (OR, 6.88, P = .05). CONCLUSION: About half of the patients with PM died within 90 days of diagnosis, and fatal outcomes were common in patients with prolonged neutropenia and empirical voriconazole use. Caution is needed in using voriconazole even in patients with positive GM results and prior histories of invasive pulmonary aspergillosis in whom PM cannot be ruled out by differential diagnosis.

A multi-institutional review of outcomes in biopsy-proven chronic invasive fungal sinusitis.

BACKGROUND: Chronic invasive fungal sinusitis (CIFS) is a rare, life-threatening infection of the nose and sinuses. This study aims to identify factors that impact survival in 1 of the largest cohorts to date. METHODS: Pathology records were reviewed for biopsy-proven CIFS from 3 tertiary academic institutions from 1995 to 2016. Variables were analyzed using log-rank survival analysis. Univariate Cox regression was performed at 1 and 12 months. RESULTS: Thirty-eight patients were included. Hematologic malignancy and diabetes were the most common underlying diseases (32% each). Aspergillus was the most common fungus (63%). Greater than 75% of the patients had an absolute neutrophil count (ANC) >1000 at the time of diagnosis. Overall survival at 1, 6, and 12 months was 89%, 68%, and 48%, respectively. In univariate analysis, factors associated with worse survival included: ANC <500 at 12 months (hazard ratio [HR] 4.8; p = 0.01), ANC <1000 at 12 months (HR 5.8; p = 0.001), and recent chemotherapy (HR 4; p = 0.01). The following factor was associated with improved survival in univariate analysis: ANC as a linear variable in the entire cohort (HR 0.7; p = 0.005). CONCLUSION: We present a multi-institutional case-series of CIFS and long-term follow-up. ANC <1000 at time of diagnosis and recent chemotherapy (within 1 month of diagnosis) are associated with poorer survival, whereas a rising ANC >1000 is associated with improved survival at 12 months. Further prospective studies are needed to further define factors that affect outcomes.

Treatment outcomes in acute invasive fungal rhinosinusitis extending to the extrasinonasal area.

Acute invasive fungal rhinosinusitis (AIFRS) can spread beyond the sinonasal cavity. It is necessary to analyze the association between the specific site involved in the extrasinonasal area and the survival rate to predict patient prognosis. We investigated 50 patients who had extrasinonasal lesions on preoperative gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) scan and underwent wide surgical resection of AIFRS. The specific sites with loss of contrast enhancement (LoCE) on Gd-enhanced MRI were analyzed for AIFRS-specific survival rate. The most common underlying disease was diabetes mellitus followed by hematological malignancy. The most common symptoms were headache and facial pain. Seven patients (14.0%) expired because of AIFRS progression. Poor prognosis was independently associated with LoCE at the skull base on preoperative MRI (HR = 35.846, P = 0.004). In patients with AIFRS extending to the extrasinonasal area, LoCE at the skull base was an independent poor prognostic factor.

Clinical characteristics and outcomes of invasive Lomentospora prolificans infections: Analysis of patients in the FungiScope® registry.

OBJECTIVES: Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan-drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis. RESULTS: The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054). CONCLUSIONS: Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development.

Outcome and characteristics of invasive fungal infections in critically ill burn patients: A multicenter retrospective study.

BACKGROUND: Characteristics and outcome of invasive fungal infection (IFI) in critically ill burn patients have been poorly explored. OBJECTIVES: We report the factors associated with 90-day mortality in a multicentre retrospective European study. PATIENTS/METHODS: All burn patients with confirmed IFI admitted between 1 January 2010 to 31 December 2015 in 10 centres in France and Belgium were included. RESULTS: Ninety-four patients were enrolled with 110 cases of IFIs: 79 (71.8%) were yeasts IFI and 31 (28.2%) filamentous IFI. Incidence was 1% among admitted patients. The 90-day mortality was 37.2% for all IFIs combined, 52% for filamentous infection and 31.9% for yeast infection. Patients with more than one IFI had a higher 90-day mortality than patients with only one episode (61.5% vs 33.5% (P = .006)). In multivariate analysis, higher Simplified Acute Physiology Score II (OR = 1.05 (95% CI: 1.02-1.09) P = .003), bacterial co-infection (OR = 3.85 (95% CI: 1.23-12.01), P = .014) and use of skin allografts at the time of IFI diagnosis (OR = 3.87 (95% CI: 1.31-11.42), P = .021) were associated with 90-day mortality. CONCLUSIONS: Although rare, invasive fungal infections remain associated with poor outcome in burn patients. Bacterial co-infection and presence of allograft were potentially modifiable factors independently associated with outcome.

A retrospective cohort of invasive fusariosis in the era of antimould prophylaxis.

Mould-active prophylaxis is affecting the epidemiology of invasive mycoses in the form of a shift toward less common entities such as fusariosis. We analyze the characteristics of invasive fusariosis and its association to antifungal prophylaxis in a retrospective cohort (2004-2017) from a tertiary hospital in Madrid, Spain. Epidemiological, clinical, microbiological, and antifungal consumption data were retrieved. Isolates were identified to molecular level, and antifungal susceptibility was tested. Eight cases of invasive fusariosis were diagnosed. Three periods were identified according to incidence: <2008 (three cases), 2008-2013 (zero cases), >2014 (five cases). All except one case involved breakthrough fusariosis. During the earliest period, the episodes occurred while the patient was taking itraconazole (two) or fluconazole (one); more recently, while on micafungin (three) or posaconazole (one). Early cases involved acute leukemia at induction/consolidation, recent cases relapsed/refractory disease (P = .029). Main risk factor for fusariosis (62.5%) was prolonged neutropenia (median 44 days). Galactomannan and beta-D-glucan were positive in 37.5% and 100% of cases, respectively. All isolates except F. proliferatum presented high minimal inhibitory concentrations (MICs) against the azoles and lower MIC to amphotericin B. Most patients received combined therapy. Mortality at 42 days was 62.5%. Resolution of neutropenia was associated with survival (P = .048). Invasive fusariosis occurs as breakthrough infection in patients with hematologic malignancy, prolonged neutropenia, and positive fungal biomarkers. Recent cases were diagnosed in a period of predominant micafungin use in patients who had more advanced disease and protracted neutropenia and for whom mortality was extremely high. Resolution of neutropenia was a favorable prognostic factor.

Invasive Fungal Disease in Critically Ill Patients at High Risk: Usefulness of Lymphocyte Subtyping.

OBJECTIVES: This study aimed to investigate the distinguishing ability of lymphocyte subtyping for diagnosis and prognosis of invasive fungal disease (IFD). METHODS: We assessed lymphocyte subtyping and evaluated the quantitative changes in key immunological parameters at intensive care unit (ICU) admission in critically ill patients at high risk and their potential influence on diagnosis and outcome of IFD. The primary outcome was 28-day mortality. RESULTS: Among the 124 critically ill patients with mean Candida score 3.89 (0.76), 19 (15.3%) were in the IFD group. CD28+CD8+ T-cell counts (area under the curve [AUC] 0.899, 95% confidence interval [CI], 0.834-0.964, P < .001) had better distinguishing ability than other immune parameters for IFD diagnosis. The cutoff value of CD28+CD8+ T-cell counts at ICU admission for IFD diagnosis was 59.5 cells/mm3, with 83.3% sensitivity and 86.4% specificity. Multivariate logistic regression analysis identified CD28+CD8+ T-cell count <59.5 cells/mm3 (odds ratio 59.7, 95% CI, 7.33-486.9, P < .001) as an independent predictor for IFD diagnosis. CD28+CD8+ T-cell counts could also predict 28-day mortality (AUC 0.656, 95% CI, 0.525-0.788, P = .045). Kaplan-Meier survival analysis provided evidence that natural killer cell count <76.0 cells/mm3 (log-rank test; P = .001), CD8+ T-cell count <321.5 cells/mm3 (log-rank test; P = .04), and CD28+CD8+ T-cell count <129.0 cells/mm3 (log-rank test; P = .02) at ICU admission were associated with lower survival probabilities. CONCLUSION: CD28+CD8+ T-cell counts play an important role in early diagnosis of IFD. Low counts are associated with early mortality in critically ill patients at high risk of IFD. Our findings add evidence to the utility of lymphocyte subtyping in a diagnostic algorithm to better define IFD in critically ill patients at high risk.

Outcomes of solid organ transplant recipients with invasive aspergillosis and other mold infections.

OBJECTIVES: To characterize the clinical presentation and outcomes of invasive mold infections (IMI) in solid organ transplant (SOT) recipients. METHODS: Inclusion of all SOT recipients with IMI diagnosed between 2008 and 2016 at a referral center for SOT. Univariable analyses identified factors associated with death at one year, and logistic regression models retained independent predictors. RESULTS: Of the 1739 patients that received a SOT during this period, 68 developed IMI (invasive aspergillosis [IA] in 58). Cumulative incidence of IMI at 1 year ranged from 1.2% to 18.8% (kidney and heart transplantation, respectively). At baseline, compared with other IMI, the need for vasoactive drugs was more frequent in patients with IA. During follow-up, 35 patients (51%) were admitted to the ICU and required mechanical ventilation (n = 27), vasoactive drugs (n = 31), or renal replacement therapy (n = 31). The need for vasoactive drugs (OR 7.34; P = .003) and a positive direct examination (OR 10.1; P = .004) were independently associated with the risk of death at 1 year in patients with IA (n = 33; 57%) CONCLUSIONS: Characteristics of IMI at presentation varied according to the underlying transplanted organ and the mold species. Following IA, one-year mortality may be predicted by the need for hemodynamic support and initial fungal load.

Fosmanogepix (APX001) Is Effective in the Treatment of Immunocompromised Mice Infected with Invasive Pulmonary Scedosporiosis or Disseminated Fusariosis.

There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 µg/ml and ranged from 0.015 to 0.03 µg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an ∼2-log10 reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds.

Invasive Fungal Infections With Good Survival Following Liver Transplant: A Single-Center Experience From a Developing Country.

OBJECTIVES: Invasive fungal infection following liver transplant is considered as one of the important factors influencing morbidity and mortality among liver transplant recipients. The aim of the present study was to describe the prevalence of invasive fungal infections and their predisposing factors in a singlecenter cohort of patients who received liver transplant. MATERIALS AND METHODS: For this study, 250 adult patients undergoing orthotopic liver transplant between March 2010 and March 2015 were enrolled. All patients were followed prospectively for infections. RESULTS: The diagnosis of invasive fungal infection was made in 15 patients (6%). One patient had 2 episodes of fungal infection, and reoperation was performed for 3 patients. Invasive aspergillosis developed in 8 patients (53.3%),followed by Candida species infection in 3 patients (20%) and cryptococcosis in 2 patients (13.3%).The main predisposing factors were renal failure (12/15) and positive history of rejection (11/15). Other risk factors for development of invasive fungal infections were choledochojejunostomy in 3 patients (20%), bile leaks in 3 patients (20%), and pretransplant steroid use in 2 patients (11.8%). Two patients (13.3%) died due to invasive fungal infections. CONCLUSIONS: In this single-center series of liver transplant recipients, the incidence of invasive fungal infections was relatively low, probably due to the universal prophylaxis with fluconazole and limited use of the broad-spectrum antibiotics. Early diagnosis and treatment of invasive fungal infections could lead to a better prognosis for liver transplant recipients with invasive fungal infections.