Fungal Infections Other Than Invasive Aspergillosis in COVID-19 Patients

Invasive fungal disease (IFD) associated with Coronavirus Disease 2019 (COVID-19) has focussed predominantly on invasive pulmonary aspergillosis. However, increasingly emergent are non-Aspergillus fungal infections including candidiasis, mucormycosis, pneumocystosis, cryptococcosis, and endemic mycoses. These infections are associated with poor outcomes, and their management is challenged by delayed diagnosis due to similarities of presentation to aspergillosis or to non-specific features in already critically ill patients. There has been a variability in the incidence of different IFDs often related to heterogeneity in patient populations, diagnostic protocols, and definitions used to classify IFD. Here, we summarise and address knowledge gaps related to the epidemiology, risks, diagnosis, and management of COVID-19-associated fungal infections other than aspergillosis.

COVID-19-associated Invasive Fungal Infection

COVID-19 can become complicated by secondary invasive fungal infections (IFI), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic invasive fungal infection following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis and management of COVID-19-associated fungal infections.

120. An open-label comparative trial of SUBA-itraconazole (SUBA) versus conventional itraconazole (c-itra) for treatment of proven and probable endemic mycoses (MSG-15): a pharmacokinetic (PK) and adverse Event (AE) analysis

Background C-itra is the drug of choice for treatment of most non-CNS, non-life-threatening forms of endemic mycoses (EM), including histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis and talaromycosis. SUBA represents a new formulation of itraconazole that utilizes nanotechnology to improve bioavailability when administered orally. SUBA is formulated as nanoparticles allowing for absorption in the small bowel while not relying on gastric acidity for optimal absorption. MSG-15 is an open-label, comparative clinical trial comparing SUBA to c-itra for the treatment of EM. Herein we report the final PK and AE profiles of these two compounds. Methods Subjects with proven and probable EM were eligible this open-label comparative study. The protocol allowed up to 14 d of prior therapy with any antifungal for this episode of EM. Subjects were randomized to receive either SUBA 130 mg po bid or c-itra 200 mg po bid for up to 6 months. Follow up occurred at 7, 14, 28, 42, 84 and 180 d post-enrollment. PK samples were obtained at 7, 14, and 42 d. Clinical assessment, including symptom assessment, AEs, overall drug tolerance, and quality of life were assessed at each visit. We used descriptive statistics for this analysis. Results 89 subjects with EM entered the trial, including 43 on SUBA and 46 on c-itra. We measured PK serum levels of itra and hydroxyl-itra at days 7, 14, and 42 and these data are depicted in Figures 1-3. There were no significant differences in these levels, including combined itra/hydroxyl-itra levels, among the two study arms. AUC for itra and hydroxyl-itra were similar for both arms. AEs as assessed at each study evaluation were also quite similar among the two study arms. Overall, any AE occurred in 74% vs 85% of SUBA and c-itra recipients, respectively (NS). Drug-related AEs occurred in 35% vs 41% of SUBA and itra recipients, respectively (NS). Most common drug-related AEs included cardiovascular (edema and hypertension), nausea and loss of appetite. Combined Itraconazole and Hydroxy-itraconazole Concentration Over Time Conclusion Compared to c-itra, SUBA demonstrates almost identical serum levels despite being dosed at roughly 60% standard dosing for c-itra (130 mg po bid vs 200 mg po bid). SUBA is slightly better tolerated than c-itra, although the specific AEs are similar. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) George R. R. Thompson III, III, MD, Amplyx (Consultant, Grant/Research Support)Appili (Consultant)Astellas (Consultant, Grant/Research Support)Avir (Grant/Research Support)Cidara (Consultant, Grant/Research Support)F2G (Consultant, Grant/Research Support)Mayne (Consultant, Grant/Research Support)Merck (Scientific Research Study Investigator)Pfizer (Advisor or Review Panel member)

Disseminated sporotrichosis in a person with human immunodeficiency virus disease

Introduction. Disseminated sporotrichosis is an incapacitating infection caused by the dimorphic fungus Sporothrix schenckii. Because this condition may mimic the presentation of tuberculosis, syphilis and other bacterial infections, the diagnosis may be missed or delayed. Case Presentation. We describe a case of disseminated sporotrichosis in a patient with poorly controlled human immunodeficiency virus infection. The patient was initially treated for bacterial skin infections. The differential diagnosis also included tuberculosis and syphilis. Only after appropriate specimens had been sent for microbiological and histopathological investigations was the diagnosis of disseminated sporotrichosis made and appropriate treatment started. The patient showed a good clinical response to itraconazole. Conclusion. This report highlights the importance of having a high index of suspicion of endemic mycoses when managing immunocompromised patients. The report also demonstrates that a delay in the diagnosis of sporotrichosis increases morbidity and results in unnecessary and inappropriate treatment with associated costs and adverse effects.

Diagnosis of Histoplasmosis Using the MVista Histoplasma Galactomannan Antigen Qualitative Lateral Flow–Based Immunoassay: A Multicenter Study

Background Accurate and timely methods for the diagnosis of histoplasmosis in resource-limited countries are lacking. Histoplasma antigen detection by enzyme immunoassay (EIA) is widely used in the United States (US) but not in resource-limited countries, leading to missed or delayed diagnoses and poor outcomes. Lateral flow assays (LFAs) can be used in this setting. Methods Frozen urine specimens were submitted to MiraVista diagnostics for antigen testing from 3 medical centers in endemic areas of the US. They were blinded and tested for the MVista Histoplasma LFA. Patients were classified as controls or cases of histoplasmosis. Cases were divided into proven or probable; pulmonary or disseminated; immunocompetent or immunosuppressed; and mild, moderate, or severe. Results Three hundred fifty-two subjects were enrolled, including 66 cases (44 proven, 22 probable) and 286 controls. Most of the cases were immunocompromised (71%), and 46 had disseminated and 20 had pulmonary histoplasmosis. Four cases were mild, 42 moderate, and 20 severe. LFA and EIA were highly concordant (κ = 0.84). Sensitivity and specificity of the LFA were 78.8% and 99.3%, respectively. LFA sensitivity was higher in proven cases (93.2%), patients with disseminated (91.3%), moderate (78.6%), and severe disease (80%), and those with galactomannan levels >1.8 ng/mL (97.8%). Specificity was 99.3% in proven cases, 99.3% in patients with moderate or severe disease, and 96.8% in those with galactomannan levels >1.8 ng/mL. Cross-reactivity was noted with other endemic mycoses. Conclusions The MVista Histoplasma LFA meets the need for accurate rapid diagnosis of histoplasmosis in resource-limited countries, especially in patients with high disease burden, potentially reducing morbidity and mortality.

Diagnosis of Pulmonary Infections Due to Endemic Fungi

Endemic mycoses including Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, and Talaromyces are dimorphic fungi that can cause a variety of clinical manifestations, including respiratory infections. Their pulmonary presentations are variable, and diagnosis is often delayed as they can mimic other infectious and non-infectious causes of pulmonary disease. Delay in diagnosis can lead to unnecessary antibiotic use, repeat hospitalizations, and increased morbidity and mortality. The diagnosis of endemic fungal pulmonary infections often relies on multiple diagnostic tests including culture, tissue histopathology, antigen assays, and antibody assays. Due to the increased use of immunosuppressive agents and the widening geographic ranges where these infections are being found, the prevalence of endemic fungal infections is increasing. Physicians need to be aware of the clinical manifestations of pulmonary infections due to endemic fungal in order to ensure that the proper diagnostic work up is obtained promptly. A high index of suspicion is particularly important in patients with suspected pulmonary infections who have failed to improve despite antibiotics in the appropriate setting. We present a review diagnostic testing for pulmonary infections due to endemic mycoses.