An 81-year-old man prescribed isavuconazole for pulmonary fungal infection developed high serum transaminase levels and biopsy-confirmed hepatic necrosis associated with prolonged high serum isavuconazole levels. Genotyping revealed poor CYP3A5 activity/normal CYP3A4 activity. Older age and slow isavuconazole elimination likely led to isavuconazole-associated hepatic toxicity. This case underscores the importance of isavuconazole therapeutic drug monitoring.

Recent studies suggest coccidioidomycosis can be found outside regions not considered to be endemic for Coccidioides species. We reviewed our experience with coccidioidomycosis at a large quaternary medical center in southeastern Michigan, an area not typically considered to be endemic for this infection. In the last decade, we cared for 18 patients with proven (11) or probable (7) coccidioidomycosis. All patients had a history of travel or prior residence in areas known to be endemic for Coccidioides species; for 16, the presumed source of exposure to Coccidioides was in southern Arizona. The median age was 64 (36-80) years. Thirteen patients had pulmonary coccidioidomycosis; manifestations included multiple lung nodules, consolidated pneumonia, diffuse reticulonodular infiltrates, chronic thick-walled cavitary lesions, and pleural involvement. Five patients had disseminated infection, including two with isolated coccidioidal meningitis, one with osteoarticular coccidioidomycosis, one with extra-thoracic lymphadenopathy in addition to diffuse lung infiltrates, and one with involvement of lung, mediastinal lymph nodes, and skin. Proven coccidioidomycosis was established by growth of Coccidioides species in culture in five patients, histopathological examination in five patients (one of whom also had a positive culture), and positive complement fixation (CF) test for Coccidioides antibody in cerebrospinal fluid for two patients. Probable coccidioidomycosis was documented for seven patients by positive titers for CF antibody to Coccidioides in serum. A careful travel and exposure history remains crucial for patients presenting outside Coccidioides-endemic regions, in which coccidioidomycosis may not be readily suspected and the diagnosis missed.

This article is part of a larger clinical practice guideline on the management of histoplasmosis in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for treatment of mild and moderate acute pulmonary histoplasmosis. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

SUMMARYInvasive fungal diseases cause severe illness and death in immunocompromised patients. Antifungal use is increasingly common, as is fungal diagnostic testing. However, these efforts have not been guided by traditional stewardship efforts akin to those used for bacterial infections. Fungal diagnostic stewardship can have a significant impact on the care of vulnerable patients, including decreasing unnecessary testing while increasing appropriate testing and improving testing strategies to reduce diagnostic errors. In this review, we discuss the most frequently used fungal diagnostic assays for molds and dimorphic fungal infections, their diagnostic performance for these organisms in immunocompromised hosts, and strategies to improve diagnostic stewardship and ultimately patient outcomes.

Background:Histoplasma urine antigen detection, a valuable diagnostic tool, is often used to monitor response to antifungal therapy, but persistently positive antigen values, even when the infection has resolved, often present a clinical conundrum for clinicians. We sought to better define the course of urine antigen values in patients who do not have HIV and to evaluate whether changes correlate with resolution of infection. Methods:Retrospective review of urine antigen tests and time to resolution of histoplasmosis for patients without HIV who were hospitalized between 1 January 2015 and 1 February 2024, and who had >2 sequential urine antigen tests performed. Results:Twenty-seven patients were included: 24 (89%) had disseminated infection and 23 (85%) were immunocompromised. Antigen values were followed for as long as 39 to 58 months in some patients. Changes in antigen values over time roughly fell into 3 groups. For 7 patients, the decrease in antigen corresponded with clinical response. Five patients, whose initial antigen levels were above the assay's level of quantification, had persistence at this high level for up to 15 months after clinical response. For the remaining 15 patients, antigen slowly decreased, sometimes transiently increased, not mirroring the clinical response; 4 patients had persistent antigenuria for as long as 22 to 48 months after all symptoms, signs, and laboratory abnormalities had resolved. Conclusions:These results support the concept that persistently positive Histoplasma urine antigen values, even very high levels, need not be the rationale for continued treatment in patients who have clinically responded and have completed recommended therapy.

Abstract Background IFI are associated with high morbidity and mortality among LTx patients (pt). Preventive strategies are commonly used, but the optimal AP approach is unclear. Over the last 10 years, our LTx program has transitioned from universal AP with itraconazole (ITR), to targeted AP, and now universal AP with posaconazole (POS). We compared the efficacy of these strategies. Methods All adult LTx pt at U Michigan from 7/1/2014-2/28/2023 were followed for 12 months (mo) post-LTx. Pt were divided into 3 cohorts based on AP regimen: cohort 1 - universal ITR for 6 mo; cohort 2 - targeted voriconazole (VOR) for 3 mo if colonized with Aspergillus or fluconazole (FLU) for 14 days (d) if colonized with Candida; cohort 3 - universal POS for 6 mo. Demographics, LTx characteristics, IFI defined by MSGERC criteria, breakthrough IFI (B-IFI) defined by MSGERC/ECMM criteria, and mortality were noted. Results Of 134 pt, 86 (64%) were men, and 101 (75%) had double-LTx. Pulmonary fibrosis was the most common reason for LTx (47,35%). There were 59 (44%), 29 (22%), and 46 (34%) pt in the universal ITR, universal POS, and targeted cohorts, respectively. A total of 23 proven/probable IFI occurred: 14 invasive pulmonary aspergillosis (IPA), 7 invasive candidiasis (IC), 1 cryptococcal pneumonia (CP) and 1 hyaline mold IFI. IFI occurred at a median of 98 d (range 1–322 d). IFI occurred in 6/59 (10%) receiving universal ITR (all but one of whom had IPA, all B-IFI); 5/29 (17%) receiving universal POS (3 IC and 2 IPA, all B-IFI); and 12/46 (26%) in the targeted AP cohort (7 IPA, 4 IC, 1 CP). Of the 12 pt with IFI in the targeted cohort, 10 did not meet criteria for use of AP and thus were not given VOR or FLU; 7/10 developed IPA and 2/10 IC. No IPA occurred in 5 pt who received VOR AP, but 2 pt on FLU AP developed breakthrough IC. Kaplan-Meier curve showed a trend toward IFI-free survival at 12 mo to be greater among pt receiving universal ITR (0.89) and universal POS (0.83) vs. targeted AP (0.73), p=0.16. All-cause mortality was 10% (14/134) and did not differ among the 3 AP cohorts, p=.49. Only 1 death (IC) was caused by IFI. Conclusion Universal AP using POS or ITR may be a more effective strategy than targeted AP for prevention of IFI post-LTx, but this comes with an increased risk for harder-to-treat B-IFI. Disclosures Marisa H. Miceli, MD, AN2: PI in clinical trial|F2G: PI in clinical trial|Pulmocide: PI in clinical trial|Scynexis: Advisor/Consultant|Scynexis: PI in clinical trial

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.

Blastomycosis is caused primarily by Blastomyces dermatitidis. The fungus is a mold in the environment, causing infection when conidia are dispersed and inhaled. In the lungs, the organism transforms into the yeast phase. Pneumonia is most common, but dissemination to skin, bones, and other organs also occurs. Diagnosis is established by growth in culture, identifying large thick-walled yeast with a single broad-based bud in tissue, and testing for cell wall antigens in urine and serum. Antifungal treatment and duration depend on severity. Mild-to-moderate disease is treated with itraconazole; severe blastomycosis is initially treated with amphotericin B, followed by itraconazole.

Amphotericin B (AmB) has broad fungicidal activity against many fungi, but the high incidence of adverse events, particularly nephrotoxicity, and the need for intravenous administration restrict its use for many patients. MAT2203, an investigational oral AmB formulation available under a compassionate use program, uses a lipid nanocrystal bilayer structure to deliver AmB with lower toxicity. We present a synopsis of clinical characteristics, treatment course, and outcomes for 5 patients who were treated with MAT2203. Outcomes were positive, with cure of infection noted in 4 patients and improvement in 1 patient who remains on therapy. MAT2203 was well tolerated with only modest gastrointestinal adverse effects. This new oral formulation might provide a safer treatment option for patients requiring extended courses of AmB.

The authors discuss the endemic fungal infections coccidioidomycosis and histoplasmosis, including ecologic niches, signs and symptoms, the course of illness, complications, diagnosis, and treatment.

BACKGROUND:Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico. METHODS:After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS. RESULTS:Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1-3)-β-d-glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis. CONCLUSION:Antifungal prophylaxis may be useful in preventing donor-derived infections in recipients of organs from donors that are found to have Fusarium meningitis.

Review of histoplasmosis and blastomycosis antigen testing for 39 patients hospitalized with these diseases found that there were significantly longer turnaround times between the time of specimen collection and receipt of positive test results among those patients who had worse outcomes.

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.

ImportanceCurrent data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders.ObjectiveTo identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection.Design, Setting, and ParticipantsThis secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023.ExposuresComorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment.Main Outcomes and MeasuresCoprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection.ResultsA total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001).Conclusions and RelevanceIn this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities.

We conducted a retrospective review of the infectious complications and outcomes over a 2-year follow-up period of adult patients who received a second allogeneic hematopoietic cell transplant (2nd allo-HCT) during a five-year period at two cancer centers in Michigan. Sixty patients, of whom 44 (73%) had acute leukemia or myelodysplastic syndrome, were studied. The majority (n = 37,62%) received a 2nd allo-HCT because of relapsed leukemia. Infection episodes after the 2nd allo-HCT totaled 112. Bacteria were identified in 76 episodes, the majority of which occurred pre-engraftment. The most common infecting organisms were Enterococcus species and Clostridioides difficile. Viral infections, predominantly cytomegalovirus, accounted for 59 infection episodes and occurred mostly in pre-engraftment and early post-engraftment periods. There were 16 proven/probable fungal infections, of which 9 were invasive aspergillosis or candidiasis. Mortality was 45% (n = 27) at one year and 65% (n = 39) at 2 years after transplant, and 16 deaths (41%) were due to infection. Of those 16 infection deaths, 8 were bacterial, 4 fungal, 2 both bacterial and fungal, and 2 viral. Failure to engraft neutrophils or platelets was significantly associated with decreased survival, p < 0.0001 and p < 0.001, respectively. Infections are common after a 2nd allo-HCT and are associated with a high mortality rate.

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.