Browsing by Author "Patterson, Thomas F"

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    Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
    (JAMA, 2023-07) O'Halloran, Jane A; Ko, Emily R; Anstrom, Kevin J; Kedar, Eyal; McCarthy, Matthew W; Panettieri, Reynold A; Maillo, Martin; Nunez, Patricia Segura; Lachiewicz, Anne M; Gonzalez, Cynthia; Smith, P Brian; de Tai, Sabina Mendivil-Tuchia; Khan, Akram; Lora, Alfredo J Mena; Salathe, Matthias; Capo, Gerardo; Gonzalez, Daniel Rodríguez; Patterson, Thomas F; Palma, Christopher; Ariza, Horacio; Lima, Maria Patelli; Blamoun, John; Nannini, Esteban C; Sprinz, Eduardo; Mykietiuk, Analia; Alicic, Radica; Rauseo, Adriana M; Wolfe, Cameron R; Witting, Britta; Wang, Jennifer P; Parra-Rodriguez, Luis; Der, Tatyana; Willsey, Kate; Wen, Jun; Silverstein, Adam; O'Brien, Sean M; Al-Khalidi, Hussein R; Maldonado, Michael A; Melsheimer, Richard; Ferguson, William G; McNulty, Steven E; Zakroysky, Pearl; Halabi, Susan; Benjamin, Daniel K; Butler, Sandra; Atkinson, Jane C; Adam, Stacey J; Chang, Soju; LaVange, Lisa; Proschan, Michael; Bozzette, Samuel A; Powderly, William G; ACTIV-1 IM Study Group Members

    Importance

    Immune dysregulation contributes to poorer outcomes in COVID-19.

    Objective

    To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.

    Design, setting, and participants

    Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.

    Interventions

    Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).

    Main outcomes and measures

    The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.

    Results

    Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.

    Conclusions and relevance

    Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.

    Trial registration

    ClinicalTrials.gov Identifier: NCT04593940.
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    Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.
    (The Lancet. Respiratory medicine, 2022-05-23) Wolfe, Cameron R; Tomashek, Kay M; Patterson, Thomas F; Gomez, Carlos A; Marconi, Vincent C; Jain, Mamta K; Yang, Otto O; Paules, Catharine I; Palacios, Guillermo M Ruiz; Grossberg, Robert; Harkins, Michelle S; Mularski, Richard A; Erdmann, Nathaniel; Sandkovsky, Uriel; Almasri, Eyad; Pineda, Justino Regalado; Dretler, Alexandra W; de Castilla, Diego Lopez; Branche, Angela R; Park, Pauline K; Mehta, Aneesh K; Short, William R; McLellan, Susan LF; Kline, Susan; Iovine, Nicole M; El Sahly, Hana M; Doernberg, Sarah B; Oh, Myoung-Don; Huprikar, Nikhil; Hohmann, Elizabeth; Kelley, Colleen F; Holodniy, Mark; Kim, Eu Suk; Sweeney, Daniel A; Finberg, Robert W; Grimes, Kevin A; Maves, Ryan C; Ko, Emily R; Engemann, John J; Taylor, Barbara S; Ponce, Philip O; Larson, LuAnn; Melendez, Dante Paolo; Seibert, Allan M; Rouphael, Nadine G; Strebe, Joslyn; Clark, Jesse L; Julian, Kathleen G; de Leon, Alfredo Ponce; Cardoso, Anabela; de Bono, Stephanie; Atmar, Robert L; Ganesan, Anuradha; Ferreira, Jennifer L; Green, Michelle; Makowski, Mat; Bonnett, Tyler; Beresnev, Tatiana; Ghazaryan, Varduhi; Dempsey, Walla; Nayak, Seema U; Dodd, Lori E; Beigel, John H; Kalil, Andre C; ACTT-4 Study Group

    Background

    Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.

    Methods

    In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.

    Findings

    Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).

    Interpretation

    In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.

    Funding

    National Institute of Allergy and Infectious Diseases.
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    Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2019-01) Schwartz, Ilan S; Wiederhold, Nathan P; Hanson, Kimberly E; Patterson, Thomas F; Sigler, Lynne

    Background

    Blastomyces helicus (formerly Emmonsia helica) is a dimorphic fungus first isolated from a man with fungal encephalitis in Alberta, Canada. The geographic range, epidemiology, and clinical features of disease are unknown.

    Methods

    We reviewed human and veterinary isolates of B. helicus identified among Blastomyces and Emmonsia isolates at the University of Alberta Microfungus Collection and Herbarium, University of Texas Health San Antonio's Fungus Testing Laboratory, and Associated Regional and University Pathologists Laboratories. Isolates were selected based on low Blastomyces dermatitidis DNA probe values and/or atypical morphology. Species identification was confirmed for most isolates by DNA sequence analysis of the internal transcribed spacer with or without D1/D2 ribosomal RNA regions. Epidemiological and clinical data were analyzed.

    Results

    We identified isolates from 10 human and 5 veterinary cases of B. helicus infection; all were referred from western regions of Canada and the United States. Isolates remained sterile in culture, producing neither conidia nor sexual spores in the mycelial phase, but often producing coiled hyphae. Isolates were most frequently cultured from blood and bronchoalveolar lavage in humans and lungs in animals. Most infected persons were immunocompromised. Histopathological findings included pleomorphic, small or variably sized yeast-like cells, with single or multiple budding, sometimes proliferating to form short, branching, hyphal-like elements. Disease carried a high case-fatality rate.

    Conclusions

    Blastomyces helicus causes fatal pulmonary and systemic disease in humans and companion animals. It differs from B. dermatitidis in morphological presentation in culture and in histopathology, by primarily affecting immunocompromised persons, and in a geographic range that includes western regions of North America.
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    Coronavirus Disease 2019-Associated Invasive Fungal Infection.
    (Open forum infectious diseases, 2021-12) Baddley, John W; Thompson, George R; Chen, Sharon C-A; White, P Lewis; Johnson, Melissa D; Nguyen, M Hong; Schwartz, Ilan S; Spec, Andrej; Ostrosky-Zeichner, Luis; Jackson, Brendan R; Patterson, Thomas F; Pappas, Peter G
    Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), 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 IFI 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.
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    Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.
    (The Lancet. Infectious diseases, 2021-06) Koehler, Philipp; Bassetti, Matteo; Chakrabarti, Arunaloke; Chen, Sharon CA; Colombo, Arnaldo Lopes; Hoenigl, Martin; Klimko, Nikolay; Lass-Flörl, Cornelia; Oladele, Rita O; Vinh, Donald C; Zhu, Li-Ping; Böll, Boris; Brüggemann, Roger; Gangneux, Jean-Pierre; Perfect, John R; Patterson, Thomas F; Persigehl, Thorsten; Meis, Jacques F; Ostrosky-Zeichner, Luis; White, P Lewis; Verweij, Paul E; Cornely, Oliver A; European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease Canada
    Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.
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    Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.
    (The Lancet. Respiratory medicine, 2021-12) Kalil, Andre C; Mehta, Aneesh K; Patterson, Thomas F; Erdmann, Nathaniel; Gomez, Carlos A; Jain, Mamta K; Wolfe, Cameron R; Ruiz-Palacios, Guillermo M; Kline, Susan; Regalado Pineda, Justino; Luetkemeyer, Anne F; Harkins, Michelle S; Jackson, Patrick EH; Iovine, Nicole M; Tapson, Victor F; Oh, Myoung-Don; Whitaker, Jennifer A; Mularski, Richard A; Paules, Catharine I; Ince, Dilek; Takasaki, Jin; Sweeney, Daniel A; Sandkovsky, Uriel; Wyles, David L; Hohmann, Elizabeth; Grimes, Kevin A; Grossberg, Robert; Laguio-Vila, Maryrose; Lambert, Allison A; Lopez de Castilla, Diego; Kim, EuSuk; Larson, LuAnn; Wan, Claire R; Traenkner, Jessica J; Ponce, Philip O; Patterson, Jan E; Goepfert, Paul A; Sofarelli, Theresa A; Mocherla, Satish; Ko, Emily R; Ponce de Leon, Alfredo; Doernberg, Sarah B; Atmar, Robert L; Maves, Ryan C; Dangond, Fernando; Ferreira, Jennifer; Green, Michelle; Makowski, Mat; Bonnett, Tyler; Beresnev, Tatiana; Ghazaryan, Varduhi; Dempsey, Walla; Nayak, Seema U; Dodd, Lori; Tomashek, Kay M; Beigel, John H; ACTT-3 study group members

    Background

    Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.

    Methods

    We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.

    Findings

    Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.

    Interpretation

    Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.

    Funding

    The National Institute of Allergy and Infectious Diseases (USA).
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    Factors associated with mortality in transplant patients with invasive aspergillosis.
    (Clin Infect Dis, 2010-06-15) Baddley, John W; Andes, David R; Marr, Kieren A; Kontoyiannis, Dimitrios P; Alexander, Barbara D; Kauffman, Carol A; Oster, Robert A; Anaissie, Elias J; Walsh, Thomas J; Schuster, Mindy G; Wingard, John R; Patterson, Thomas F; Ito, James I; Williams, O Dale; Chiller, Tom; Pappas, Peter G
    BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA. METHODS: Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression. RESULTS: Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death. CONCLUSIONS: There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.
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    Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.
    (Clinical microbiology reviews, 2023-07) Thompson, George R; Jenks, Jeffrey D; Baddley, John W; Lewis, James S; Egger, Matthias; Schwartz, Ilan S; Boyer, Johannes; Patterson, Thomas F; Chen, Sharon C-A; Pappas, Peter G; Hoenigl, Martin
    Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.
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    Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology.
    (The Lancet. Infectious diseases, 2021-08) Hoenigl, Martin; Salmanton-García, Jon; Walsh, Thomas J; Nucci, Marcio; Neoh, Chin Fen; Jenks, Jeffrey D; Lackner, Michaela; Sprute, Rosanne; Al-Hatmi, Abdullah MS; Bassetti, Matteo; Carlesse, Fabianne; Freiberger, Tomas; Koehler, Philipp; Lehrnbecher, Thomas; Kumar, Anil; Prattes, Juergen; Richardson, Malcolm; Revankar, Sanjay; Slavin, Monica A; Stemler, Jannik; Spiess, Birgit; Taj-Aldeen, Saad J; Warris, Adilia; Woo, Patrick CY; Young, Jo-Anne H; Albus, Kerstin; Arenz, Dorothee; Arsic-Arsenijevic, Valentina; Bouchara, Jean-Philippe; Chinniah, Terrence Rohan; Chowdhary, Anuradha; de Hoog, G Sybren; Dimopoulos, George; Duarte, Rafael F; Hamal, Petr; Meis, Jacques F; Mfinanga, Sayoki; Queiroz-Telles, Flavio; Patterson, Thomas F; Rahav, Galia; Rogers, Thomas R; Rotstein, Coleman; Wahyuningsih, Retno; Seidel, Danila; Cornely, Oliver A
    With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.
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    Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19.
    (Open forum infectious diseases, 2020-07) Thompson Iii, George R; Cornely, Oliver A; Pappas, Peter G; Patterson, Thomas F; Hoenigl, Martin; Jenks, Jeffrey D; Clancy, Cornelius J; Nguyen, M Hong
    Pulmonary aspergillosis has been increasingly reported following severe respiratory viral infections. Millions have been infected by SARS-CoV-2, placing large numbers of patients at-risk for COVID-19 associated pulmonary aspergillosis (CAPA). Prompt recognition of this syndrome and is paramount to improve outcomes.
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    Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).
    (Clin Infect Dis, 2010-04-15) Pappas, Peter G; Alexander, Barbara D; Andes, David R; Hadley, Susan; Kauffman, Carol A; Freifeld, Alison; Anaissie, Elias J; Brumble, Lisa M; Herwaldt, Loreen; Ito, James; Kontoyiannis, Dimitrios P; Lyon, G Marshall; Marr, Kieren A; Morrison, Vicki A; Park, Benjamin J; Patterson, Thomas F; Perl, Trish M; Oster, Robert A; Schuster, Mindy G; Walker, Randall; Walsh, Thomas J; Wannemuehler, Kathleen A; Chiller, Tom M
    BACKGROUND: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. METHODS: The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. RESULTS: During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. CONCLUSIONS: We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.
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    Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001-2006.
    (Emerging infectious diseases, 2011-10) Park, Benjamin J; Pappas, Peter G; Wannemuehler, Kathleen A; Alexander, Barbara D; Anaissie, Elias J; Andes, David R; Baddley, John W; Brown, Janice M; Brumble, Lisa M; Freifeld, Alison G; Hadley, Susan; Herwaldt, Loreen; Ito, James I; Kauffman, Carol A; Lyon, G Marshall; Marr, Kieren A; Morrison, Vicki A; Papanicolaou, Genovefa; Patterson, Thomas F; Perl, Trish M; Schuster, Mindy G; Walker, Randall; Wingard, John R; Walsh, Thomas J; Kontoyiannis, Dimitrios P
    Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001-2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.
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    Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.
    (Clin Infect Dis, 2010-04-15) Kontoyiannis, Dimitrios P; Marr, Kieren A; Park, Benjamin J; Alexander, Barbara D; Anaissie, Elias J; Walsh, Thomas J; Ito, James; Andes, David R; Baddley, John W; Brown, Janice M; Brumble, Lisa M; Freifeld, Alison G; Hadley, Susan; Herwaldt, Loreen A; Kauffman, Carol A; Knapp, Katherine; Lyon, G Marshall; Morrison, Vicki A; Papanicolaou, Genovefa; Patterson, Thomas F; Perl, Trish M; Schuster, Mindy G; Walker, Randall; Wannemuehler, Kathleen A; Wingard, John R; Chiller, Tom M; Pappas, Peter G
    BACKGROUND: The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS: The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS: We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS: In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.
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    Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-09) Donnelly, J Peter; Chen, Sharon C; Kauffman, Carol A; Steinbach, William J; Baddley, John W; Verweij, Paul E; Clancy, Cornelius J; Wingard, John R; Lockhart, Shawn R; Groll, Andreas H; Sorrell, Tania C; Bassetti, Matteo; Akan, Hamdi; Alexander, Barbara D; Andes, David; Azoulay, Elie; Bialek, Ralf; Bradsher, Robert W; Bretagne, Stephane; Calandra, Thierry; Caliendo, Angela M; Castagnola, Elio; Cruciani, Mario; Cuenca-Estrella, Manuel; Decker, Catherine F; Desai, Sujal R; Fisher, Brian; Harrison, Thomas; Heussel, Claus Peter; Jensen, Henrik E; Kibbler, Christopher C; Kontoyiannis, Dimitrios P; Kullberg, Bart-Jan; Lagrou, Katrien; Lamoth, Frédéric; Lehrnbecher, Thomas; Loeffler, Jurgen; Lortholary, Olivier; Maertens, Johan; Marchetti, Oscar; Marr, Kieren A; Masur, Henry; Meis, Jacques F; Morrisey, C Orla; Nucci, Marcio; Ostrosky-Zeichner, Luis; Pagano, Livio; Patterson, Thomas F; Perfect, John R; Racil, Zdenek; Roilides, Emmanuel; Ruhnke, Marcus; Prokop, Cornelia Schaefer; Shoham, Shmuel; Slavin, Monica A; Stevens, David A; Thompson, George R; Vazquez, Jose A; Viscoli, Claudio; Walsh, Thomas J; Warris, Adilia; Wheat, L Joseph; White, P Lewis; Zaoutis, Theoklis E; Pappas, Peter G

    Background

    Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.

    Methods

    To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.

    Results

    There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.

    Conclusions

    These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.