Convalescent Plasma for Immunocompromised Patients.

COVID-19 convalescent plasma (CCP) is an important therapeutic option for immunocompromised patients with COVID-19. Such patients are at increased risk for serious complications of infection and may also develop a unique syndrome of persistent infection. This article reviews the rationale for CCP utilization in immunocompromised patients and the evidence for its value in immunosuppressed patients with both acute and persistent COVID-19. Both historical precedence and understanding of the mechanisms of action of antibody treatment support this use, as do several lines of evidence derived from case series, comparative studies, randomized trials, and systematic reviews of the literature. A summary of recommendations from multiple practice guidelines is also provided.

COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial.

IMPORTANCE: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

Vaccines and therapeutics for immunocompromised patients with COVID-19.

The COVID-19 pandemic has disproportionately impacted immunocompromised patients. This diverse group is at increased risk for impaired vaccine responses, progression to severe disease, prolonged hospitalizations and deaths. At particular risk are people with deficiencies in lymphocyte number or function such as transplant recipients and those with hematologic malignancies. Such patients' immune responses to vaccination and infection are frequently impaired leaving them more vulnerable to prolonged high viral loads and severe complications of COVID-19. Those in turn, have implications for disease progression and persistence, development of immune escape variants and transmission of infection. Data to guide vaccination and treatment approaches in immunocompromised people are generally lacking and extrapolated from other populations. The large clinical trials leading to authorisation and approval of SARS-CoV-2 vaccines and therapeutics included very few immunocompromised participants. While experience is accumulating, studies focused on the special circumstances of immunocompromised patients are needed to inform prevention and treatment approaches.

Absence of pathogenic viruses in COVID-19 convalescent plasma.

BACKGROUND: It is important to maintain the safety of blood products by avoiding the transfusion of units with known and novel viral pathogens. It is unknown whether COVID-19 convalescent plasma (CCP) may contain pathogenic viruses (either newly acquired or reactivated) that are not routinely screened for by blood centers. METHODS: The DNA virome was characterized in potential CCP donors (n = 30) using viral genome specific PCR primers to identify DNA plasma virome members of the Herpesviridae [Epstein Barr Virus (EBV), cytomegalovirus (CMV), human herpesvirus 6A/B, human herpesvirus 7] and Anelloviridae [Torque teno viruses (TTV), Torque teno mini viruses (TTMV), and Torque teno midi viruses (TTMDV)] families. In addition, the RNA plasma virome was characterized using unbiased metagenomic sequencing. Sequencing was done on a HiSeq2500 using high output mode with a read length of 2X100 bp. The sequencing reads were taxonomically classified using Kraken2. CMV and EBV seroprevalence were evaluated using a chemiluminescent immunoassay. RESULTS: TTV and TTMDV were detected in 12 (40%) and 4 (13%) of the 30 study participants, respectively; TTMDV was always associated with infection with TTV. We did not observe TTMV DNAemia. Despite CMV and EBV seroprevalences of 33.3% and 93.3%, respectively, we did not detect Herpesviridae DNA among the study participants. Metagenomic sequencing did not reveal any human RNA viruses in CCP, including no evidence of circulating SARS-CoV-2. DISCUSSION: There was no evidence of pathogenic viruses, whether newly acquired or reactivated, in CCP despite the presence of non-pathogenic Anelloviridae. These results confirm the growing safety data supporting CCP.

Treatment recommendations for non-HIV associated cryptococcal meningoencephalitis including management of post-infectious inflammatory response syndrome.

Cryptococcal meningoencephalitis (CM) continues to cause major morbidity and mortality in a range of patients such as those immunosuppressed from HIV and with biologic immunosuppressants, including treatments of autoimmunity, malignancies, and conditioning regimens for transplantation. It is currently the most common cause of non-viral meningitis in the United States. Infections in previously healthy patients also develop with autoantibodies to granulocyte-macrophage colony stimulating factor or with monogenetic defects. In all populations, mortality and significant long-term morbidity occur in 30-50% despite therapy, and immune reconstitution and post-infectious inflammatory response syndromes complicate management. To help with these difficult cases, we present here a practical tutorial of the care of a range of patients with CM in the absence of HIV/AIDS.

Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant. Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation. Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall. Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.

EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group.

The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for intensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive candidiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining in the development of definitions applicable in the ICU setting.

Comparative Performance of Five Commercially Available Serologic Assays To Detect Antibodies to SARS-CoV-2 and Identify Individuals with High Neutralizing Titers.

Accurate serological assays to detect antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to characterize the epidemiology of SARS-CoV-2 infection and identify potential candidates for coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) donation. This study compared the performances of commercial enzyme immunoassays (EIAs) with respect to detection of IgG or total antibodies to SARS-CoV-2 and neutralizing antibodies (nAbs). The diagnostic accuracy of five commercially available EIAs (Abbott, Euroimmun, EDI, ImmunoDiagnostics, and Roche) for detection of IgG or total antibodies to SARS-CoV-2 was evaluated using cross-sectional samples from potential CCP donors who had prior molecular confirmation of SARS-CoV-2 infection (n = 214) and samples from prepandemic emergency department patients without SARS-CoV-2 infection (n = 1,099). Of the 214 potential CCP donors, all were sampled >14 days since symptom onset and only a minority (n = 16 [7.5%]) had been hospitalized due to COVID-19; 140 potential CCP donors were tested by all five EIAs and a microneutralization assay. Performed according to the protocols of the manufacturers to detect IgG or total antibodies to SARS-CoV-2, the sensitivity of each EIA ranged from 76.4% to 93.9%, and the specificity of each EIA ranged from 87.0% to 99.6%. Using a nAb titer cutoff value of ≥160 as the reference representing a positive test result (n = 140 CCP donors), the empirical area under the receiver operating curve for each EIA ranged from 0.66 (Roche) to 0.90 (Euroimmun). Commercial EIAs with high diagnostic accuracy to detect SARS-CoV-2 antibodies did not necessarily have high diagnostic accuracy to detect high nAb titers. Some but not all commercial EIAs may be useful in the identification of individuals with high nAb titers among convalescent individuals.

Allogeneic bone marrow transplantation with post-transplant cyclophosphamide for patients with HIV and haematological malignancies: a feasibility study.

BACKGROUND: Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT. METHODS: This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068. FINDINGS: Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log10 reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable. INTERPRETATION: By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption. FUNDING: amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute.

Management of Indwelling Tunneled Pleural Catheters: A Modified Delphi Consensus Statement.

BACKGROUND: The management of recurrent pleural effusions remains a challenging issue for clinicians. Advances in management have led to increased use of indwelling tunneled pleural catheters (IPC) because of their effectiveness and ease of outpatient placement. However, with the increase in IPC placement there have also been increasing reports of complications, including infections. Currently there is minimal guidance in IPC-related management issues after placement. RESEARCH QUESTION: Our objective was to formulate clinical consensus statements related to perioperative and long-term IPC catheter management based on a modified Delphi process from experts in pleural disease management. STUDY DESIGN AND METHODS: Expert panel members used a modified Delphi process to reach consensus on common perioperative and long-term management options related to IPC use. Members were identified from multiple countries, specialties, and practice settings. A series of meetings and anonymous online surveys were completed. Responses were used to formulate consensus statements among panel experts, using a modified Delphi process. Consensus was defined a priori as greater than 80% agreement among panel constituents. RESULTS: A total of 25 physicians participated in this project. The following topics were addressed during the process: definition of an IPC infection, management of IPC-related infectious complications, interventions to prevent IPC infections, IPC-related obstruction/malfunction management, assessment of IPC removal, and instructions regarding IPC management by patients and caregivers. Strong consensus was obtained on 36 statements. No consensus was obtained on 29 statements. INTERPRETATION: The management of recurrent pleural disease with IPC remains complex and challenging. This statement offers statements for care in numerous areas related to IPC management based on expert consensus and identifies areas that lack consensus. Further studies related to long-term management of IPC are warranted.

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.

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

BACKGROUND: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). METHODS: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. RESULTS: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. CONCLUSIONS: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

Angioinvasive, cutaneous infection due to Colletotrichum siamense in a stem cell transplant recipient: Report and review of prior cases.

Colletotrichum is an important fungal plant pathogen, yet an uncommon cause of human disease. Herein we report a case of invasive, cutaneous infection in a stem cell transplant recipient due to Colletotrichum species, with accompanying review of the literature. The infection was successfully treated with a combination of liposomal amphotericin B and voriconazole. Multilocus phylogenetic analysis revealed that the distinct isolate belongs to Colletotrichum siamense, a member of the Colletotrichum gloeosporioides species complex not previously described as a human pathogen. Colletotrichum infection remains in the differential for skin lesions in the immune compromised host.

Emerging fungal infections in solid organ transplant recipients: Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice.

These updated AST-IDCOP guidelines review the epidemiology, diagnosis, and management of emerging fungi after organ transplantation. Infections due to numerous generally innocuous fungi are increasingly recognized in solid organ transplant (SOT) recipients, comprising about 7%-10% of fungal infections in this setting. Such infections are collectively referred to as emerging fungal infections and include Mucormycetes, Fusarium, Scedosporium, and dematiaceous fungi among others. The causative organisms are diverse in their pathophysiology, uncommon in the clinical setting, have evolving nomenclature, and are often resistant to multiple commonly used antifungal agents. In recent years significant advances have been made in understanding of the epidemiology of these emerging fungal infections, with improved diagnosis and expanded treatment options. Still, treatment guidelines are generally informed by and limited to experience from cohorts of patients with hematological malignancies and/or solid and stem cell transplants. While multicenter randomized controlled trials are not feasible for these uncommon infections in SOT recipients, collaborative prospective studies can be valuable in providing information on the epidemiology, clinical manifestations, treatment strategies, and outcomes associated with the more commonly encountered infections.

Outcomes of patients with invasive fusariosis who undergo further immunosuppressive treatments, is there a role for secondary prophylaxis?

BACKGROUND: Patients treated for invasive aspergillosis may relapse during subsequent periods of immunosuppression and should receive secondary prophylaxis. Little is known about the frequency of relapse and practices of secondary prophylaxis for invasive fusariosis (IF). OBJECTIVES: Evaluate practices of secondary prophylaxis and the frequency of relapse in patients who survived IF and were exposed to subsequent periods of immunosuppression. METHODS: Multicentre retrospective study of patients with haematological malignancies who developed IF, survived the initial fungal disease period, and were exposed to subsequent periods of immunosuppression. RESULTS: Among 40 patients, 35 received additional chemotherapy and developed neutropenia (median, 24 days; range, 4-104), and five received glucocorticoids for the treatment of graft-vs-host disease. Overall, 32 patients received secondary prophylaxis (voriconazole in 24) for a median of 112 days (range, 12-468). IF relapsed in five patients (12.5%): 2/8 (25%) not on prophylaxis and 3/32 (9.4%) receiving prophylaxis. Among 28 patients with disseminated IF, relapse occurred in 2/2 (100%) not on prophylaxis and in 3/26 (11.5%) on prophylaxis (P = 0.03). All patients who relapsed IF died. CONCLUSIONS: Patients with IF who survive the initial disease may relapse if exposed to subsequent episodes of immunosuppressive therapies. Secondary prophylaxis should be considered, especially if IF was disseminated.

A Mycoses Study Group International Prospective Study of Phaeohyphomycosis: An Analysis of 99 Proven/Probable Cases.

BACKGROUND: Phaeohyphomycosis is infection caused by dematiaceous, or darkly pigmented, fungi. The spectrum of disease is broad, and optimal therapy remains poorly defined. The Mycoses Study Group established an international case registry of patients with proven/probable phaeohyphomycosis with the goal of improving the recognition and management of these infections. METHODS: Patients from 18 sites in 3 countries were enrolled from 2009-2015. Cases were categorized as local superficial, local deep (pulmonary, sinus, osteoarticular infections), and disseminated infections. End points were clinical response (partial and complete) and all-cause mortality at 30 days and end of follow-up. RESULTS: Of 99 patients, 32 had local superficial infection, 41 had local deep infection, and 26 had disseminated infection. The most common risk factors were corticosteroids, solid organ transplantation, malignancy, and diabetes. Cultures were positive in 98% of cases. All-cause mortality was 16% at 30 days and 33% at end of follow-up, and 18 of 26 (69%) with dissemination died. Itraconazole was most commonly used for local infections, and voriconazole was used for more severe infections, often in combination with terbinafine or amphotericin B. CONCLUSIONS: Phaeohyphomycosis is an increasingly recognized infection. Culture remains the most frequently used diagnostic method. Triazoles are currently the drugs of choice, often combined with other agents. Further studies are needed to develop optimal therapies for disseminated infections.

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection.

BACKGROUND: Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs. METHODS: Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. RESULTS: Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in SOT (P = 0.003). Doses of ganciclovir or valganciclovir were low in 10 (26%) of 39 at some time before switching to foscarnet. Renal dysfunction occurred in 20 (51%) of 39 by end of treatment and in 7 (28%) of 25 after 6 months. CONCLUSIONS: Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents.