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Isavuconazole is a new extended-spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was noninferior to that of voriconazole. An open-label trial that studied primary as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug–drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

Central nervous system infections due to Aspergillus spp and other hyaline molds such as Fusarium and Scedosporium spp are rare but fatal conditions. Invasion of the central nervous system (CNS) tends to occur as a result of hematogenous dissemination among immunocompromised patients, and by local extension or direct inoculation secondary to trauma in immunocompetent hosts. Efforts should be directed to confirm the diagnosis by image-guided stereotactic brain biopsy when feasible. Non-culture methods could be useful to support the diagnosis, but they have not been validated to be performed in cerebral spinal fluid. Treatment of these infections is challenging given the variable susceptibility profile of these pathogens and the penetration of antifungal agents into the brain.

Blastomycosis is caused by a thermally dimorphic fungus that thrives in moist acidic soil. Blastomyces dermatitidis is the species responsible for most infections in North America and is especially common in areas around the Great Lakes, the St. Lawrence Seaway, and in several south-central and southeastern United States. Other Blastomyces species have more recently been discovered to cause disease in distinct geographic regions around the world. Infection almost always occurs following inhalation of conidia produced in the mold phase. Acute pulmonary infection ranges from asymptomatic to typical community-acquired pneumonia; more chronic forms of pulmonary infection can present as mass-like lesions or cavitary pneumonia. Infrequently, pulmonary infection can progress to acute respiratory distress syndrome that is associated with a high mortality rate. After initial pulmonary infection, hematogenous dissemination of the yeast form of Blastomyces is common. Most often this is manifested by cutaneous lesions, but osteoarticular, genitourinary, and central nervous system (CNS) involvement also occurs. The diagnosis of blastomycosis can be made by growth of the mold phase of Blastomyces spp. in culture or by histopathological identification of the distinctive features of the yeast form in tissues. Detection of cell wall antigens of Blastomyces in urine or serum provides a rapid method for a probable diagnosis of blastomycosis, but cross-reactivity with other endemic mycoses commonly occurs. Treatment of severe pulmonary or disseminated blastomycosis and CNS blastomycosis initially is with a lipid formulation of amphotericin B. After improvement, therapy can be changed to an oral azole, almost always itraconazole. With mild to moderate pulmonary or disseminated blastomycosis, oral itraconazole treatment is recommended.

A growing population of immunosuppressed patients has resulted in increasingly frequent diagnoses of invasive fungal infections, including those caused by unusual yeasts. The incidence of non-albicans species of Candida is increasing compared with that of Candida albicans, and several species, such as Candida glabrata and Candida krusei, may be resistant to azole antifungal therapy. Trichosporon species are the second most common cause of fungaemia in patients with haematological malignant disease and are characterised by resistance to amphotericin and echinocandins and poor prognosis. Rhodotorula species belong to the family Cryptococcaceae, and are a cause of catheter-related fungaemia, sepsis, and invasive disease in severely immunosuppressed patients. An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant. Other uncommon yeasts that can cause invasive disease in severely immunosuppressed patients include Geotrichum, Hansenula, Malassezia, and Saccharomyces. Host immune status is a crucial determinant of the type of invasive fungal infection a patient is at risk for. Diagnosis can be challenging and relies heavily on traditional cultures of blood and other sterile sites, although serum (1,3)-β-D-glucan testing might have an adjunctive role. Although rare yeasts are emerging as opportunistic human pathogens, diagnosis remains challenging and treatment suboptimal.

We sought to investigate the role of immunocompromise in patients with newly diagnosed histoplasmosis in an era when AIDS is less prevalent. We performed a retrospective comparison of immunocompromised and non-immunocompromised adults hospitalized at Michigan Medicine from 2015 to 2024. Of 51 patients, 37 (73%) were immunocompromised, 32 from solid organ transplantation or tumor necrosis factor antagonist/disease-modifying anti-rheumatic drugs. Of these 37, 34 had disseminated and 3 had pulmonary histoplasmosis; of the 14 non-immunocompromised patients, 8 had disseminated and 6 had pulmonary histoplasmosis, p = 0.004. Fever was the only symptom/sign that was more common in the immunocompromised cohort (86% vs. 36%, p = 0.003). Laboratory/radiological studies showed no major differences between immunocompromised and non-immunocompromised cohorts. Histoplasma urinary antigen was positive for all immunocompromised vs. 79% non-immunocompromised patients, p = 0.003. Median antigen levels were 17.5 (IQR 6.2–19.7) ng/mL for immunocompromised vs. 1.9 (0.6–19.7) ng/mL for non-immunocompromised patients, p = 0.004. Cultures for Histoplasma were more often positive in the immunocompromised cohort, p = 0.025. All-cause 90-day mortality was 14% in each cohort (five immunocompromised and two non-immunocompromised patients); all deaths occurred in those with disseminated histoplasmosis, and four were in the first week of hospitalization. Disseminated histoplasmosis in both immunocompromised and non-immunocompromised patients continues to be a serious, often fatal infection.

Background. Galactomannan is an Aspergillus-specific polysaccharide released during aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. Preclinical and preliminary clinical reports have suggested a good correlation between GMI and aspergillosis outcome. Methods. We reviewed the literature to assess the strength of correlation between GMI and aspergillosis outcome using the κ correlation coefficient. We included 27 studies that enrolled patients with hematological cancer and proven or probable aspergillosis and that used sequential GMI testing. We examined the 3 following outcomes: survival (survival vs. death), global outcome (survival vs. death [including autopsy findings]), and autopsy outcome (autopsy findings only). Results. Overall, 257 patients fulfilled criteria for proven or probable aspergillosis and were eligible for outcome evaluation. Correlation between GMI (within ≤1 week before outcome) and defined outcomes was excellent, with κ correlation coefficients of 0.8737 (95% confidence interval, 0.8140–0.9333; P<.001) and 0.9123 (95% confidence interval, 0.8617–0.9629; P<.001) for survival and global outcome, respectively. Most importantly, the κ correlation coefficient for autopsy outcome was high (0.8498; 95% confidence interval, 0.5608–1.000; P<.001). Furthermore, the κ correlation coefficient for all outcomes was comparable across age groups (pediatric and adult patients) and treatment modalities, including allogeneic transplantation. This strong correlation is also supported by extensive preclinical data and recent clinical reports. Conclusions. We conclude that serum GMI is a good marker of aspergillosis outcome.

Background: Several newly developed biomarker tests for invasive pulmonary aspergillosis (IPA) have been developed, including the IMMY Aspergillus galactomannan lateral flow assay (Aspergillus GM-LFA) evaluated in this study. Methods: Twenty patients with proven/probable IPA (EORTC/MSGERC criteria) were matched by age and underlying disease with 20 patients without IPA. Bronchoalveolar lavage fluid (BALF) was analyzed in duplicate using the Aspergillus GM-LFA. Results were read visually by two blinded observers, and the optical density index (ODI) was obtained digitally with a cube reader. Results: Using a cutoff of ≥0.5 ODI, the Aspergillus GM-LFA had a sensitivity of 40%, specificity of 80%, positive predictive value (PPV) of 67% and negative predictive value (NPV) of 57%. When the cutoff was increased to ≥1.0 ODI, sensitivity remained at 40%, specificity rose to 95%, PPV was 89%, and NPV was 61%. Excellent agreement was found when duplicate samples were read either visually (κ = 1) or with the cube reader (κ = 0.89). Correlation of results obtained by visual inspection and those obtained using the cube reader was excellent (κ = 0.82). Conclusion: The Aspergillus GM-LFA had poor sensitivity but excellent specificity for proven/probable IPA in BALF. The assay was easy to interpret, and there was high concordance between results obtained visually and with a cube reader.

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

Abstract Background Umbilical cord blood transplant (UCBT) is used for patients who do not have a matched donor, but engraftment often takes longer than with a standard allogeneic transplant, likely increasing the risk for infection. We characterized specific infections and outcomes in adults undergoing UCBT at our 2 centers. Methods All adults who underwent UCBT between January 1, 2006 and December 31, 2015 were included. Infectious episodes from 6 months before to 2 years after UCBT were reviewed. Results Fifty-seven patients underwent UCBT; 47 had neutrophil engraftment. A total of 179 infectious episodes occurred in 55 patients, 73 (41%) within 30 days post-UCBT. Viruses caused 85 (47%) infections. Cytomegalovirus caused 32 infectious episodes and was most common from day 30 to 100. Human herpesvirus 6 occurred in 28 episodes, was most common within 30 days, and caused 1 death. Bacteria were responsible for 82 (46%) infections, most commonly bacteremias due to Staphylococcus spp, Enterococcus spp, and Enterobacteriaceae. Of 11 invasive fungal infections, 9 were aspergillosis, 4 of which were fatal. Overall mortality was 56% in the first year. Thirteen deaths were from infection; 11 occurred in the first 100 days and 7 in the first 30 days post-UCBT. Of 10 patients who never engrafted, 9 died, 6 from infection, within 100 days post-UCBT. Conclusions Infectious complications were common after UCBT, especially in the first 30 days. Deaths from viral infections were fewer than expected. Delayed engraftment and nonengraftment continue to convey increased risk for fatal bacterial and fungal infections post-UCBT.

We evaluated the performance of the (1,3)-β-d-glucan (BDG) assay on bronchoalveolar lavage fluid (BALF) as a possible aid to the diagnosis of Pneumocystis jirovecii pneumonia. BALF samples from 18 patients with well-characterized proven, probable, and possible Pneumocystis pneumonia and 18 well-matched controls were tested. We found that the best test performance was observed with a cut-off value of 128 pg/mL; receiver operating characteristic/area under the curve (ROC/AUC) was 0.70 (95% CI 0.52–0.87). Sensitivity and specificity were 78% and 56%, respectively; positive predictive value was 64%, and negative predictive value was 71%. The low specificity that we noted limits the utility of BALF BDG as a diagnostic tool for Pneumocystis pneumonia.