Publications by authors named "Dimitrios P Kontoyiannis"

488 Publications

Effect of high-dose posaconazole on serum levels in adult patients with hematologic malignancy.

Antimicrob Agents Chemother 2021 Sep 27:AAC0123021. Epub 2021 Sep 27.

Department of Infectious Diseases and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Posaconazole (POS) appears to have dose-proportional pharmacokinetics, however there is paucity of real-life data. We retrospectively evaluated 67 patients with hematological cancer who had POS dose increase from 300 mg/d to either 400 mg/d (n=52) or 300 mg twice daily (BID; n=15) and POS serum levels measured. Median POS levels were 840 ng/mL, 1625 ng/mL, and 2710 ng/mL on the 300mg/d, 400mg/d and 300mg BID doses respectively. Significant inter-patient variability in serum levels was noted.
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http://dx.doi.org/10.1128/AAC.01230-21DOI Listing
September 2021

COVID-19-associated pulmonary aspergillosis (CAPA): how big a problem is it?

Clin Microbiol Infect 2021 09 27;27(9):1376-1378. Epub 2021 Jun 27.

Infectious Diseases Service and Institute of Microbiology, University Hospital of Lausanne and Lausanne University, Lausanne, Switzerland.

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http://dx.doi.org/10.1016/j.cmi.2021.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275029PMC
September 2021

Aspergillus terreus Species Complex.

Clin Microbiol Rev 2021 Jun 30:e0031120. Epub 2021 Jun 30.

Fungal Biology Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.

Infections due to species are an acute threat to human health; members of the section are the most frequently occurring agents, but depending on the local epidemiology, representatives of section or section are the second or third most important. species complex is of great interest, as it is usually amphotericin B resistant and displays notable differences in immune interactions in comparison to . The latest epidemiological surveys show an increased incidence of as well as an expanding clinical spectrum (chronic infections) and new groups of at-risk patients being affected. Hallmarks of these non- invasive mold infections are high potential for tissue invasion, dissemination, and possible morbidity due to mycotoxin production. We seek to review the microbiology, epidemiology, and pathogenesis of species complex, address clinical characteristics, and highlight the underlying mechanisms of amphotericin B resistance. Selected topics will contrast key elements of with . We provide a comprehensive resource for clinicians dealing with fungal infections and researchers working on pathogenesis, aiming to bridge the emerging translational knowledge and future therapeutic challenges on this opportunistic pathogen.
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http://dx.doi.org/10.1128/CMR.00311-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404697PMC
June 2021

Do Not Forget Daptomycin as a Cause of Eosinophilic Pneumonia!

Chest 2021 04 6;159(4):1687-1688. Epub 2021 Apr 6.

Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX.

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http://dx.doi.org/10.1016/j.chest.2020.10.086DOI Listing
April 2021

Resistance to Antifungal Drugs.

Infect Dis Clin North Am 2021 06;35(2):279-311

Infectious Diseases, University of Texas M D Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA. Electronic address:

Pathogenic fungi have several mechanisms of resistance to antifungal drugs, driven by the genetic plasticity and versatility of their homeostatic responses to stressful environmental cues. We critically review the molecular mechanisms of resistance and cellular adaptations of pathogenic fungi in response to antifungals and discuss the factors contributing to such resistance. We offer suggestions for the translational and clinical research agenda of this rapidly evolving and medically important field. A better understanding of antifungal resistance should assist in developing better detection tools and inform optimal strategies for preventing and treating refractory mycoses in the future.
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http://dx.doi.org/10.1016/j.idc.2021.03.003DOI Listing
June 2021

Epidemiology and organ specific sequelae of post-acute COVID19: A narrative review.

J Infect 2021 07 14;83(1):1-16. Epub 2021 May 14.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States. Electronic address:

Objectives: "Long COVID", a term coined by COVID-19 survivors, describes persistent or new symptoms in a subset of patients who have recovered from acute illness. Globally, the population of people infected with SARS-CoV-2 continues to expand rapidly, necessitating the need for a more thorough understanding of the array of potential sequelae of COVID-19. The multisystemic aspects of acute COVID-19 have been the subject of intense investigation, but the long-term complications remain poorly understood. Emerging data from lay press, social media, commentaries, and emerging scientific reports suggest that some COVID-19 survivors experience organ impairment and/or debilitating chronic symptoms, at times protean in nature, which impact their quality of life.

Methods/results: In this review, by addressing separately each body system, we describe the pleiotropic manifestations reported post COVID-19, their putative pathophysiology and risk factors, and attempt to offer guidance regarding work-up, follow-up and management strategies. Long term sequelae involve all systems with a negative impact on mental health, well-being and quality of life, while a subset of patients, report debilitating chronic fatigue, with or without other fluctuating or persistent symptoms, such as pain or cognitive dysfunction. Although the pathogenesis is unclear, residual damage from acute infection, persistent immune activation, mental factors, or unmasking of underlying co-morbidities are considered as drivers. Comparing long COVID with other post viral chronic syndromes may help to contextualize the complex somatic and emotional sequalae of acute COVID-19. The pace of recovery of different aspects of the syndrome remains unclear as the pandemic began only a year ago.

Conclusions: Early recognition of long-term effects and thorough follow-up through dedicated multidisciplinary outpatient clinics with a carefully integrated research agenda are essential for treating COVID-19 survivors holistically.
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http://dx.doi.org/10.1016/j.jinf.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118709PMC
July 2021

COVID-19 Vaccines in Patients With Cancer-A Welcome Addition, but There Is Need for Optimization.

JAMA Oncol 2021 08;7(8):1113-1114

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1001/jamaoncol.2021.1218DOI Listing
August 2021

When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis.

J Fungi (Basel) 2021 Apr 15;7(4). Epub 2021 Apr 15.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Mucormycosis (MCR) has been increasingly described in patients with coronavirus disease 2019 (COVID-19) but the epidemiological factors, presentation, diagnostic certainty, and outcome of such patients are not well described. We review the published COVID-19-associated mucormycosis (CAMCR) cases (total 41) to identify risk factors, clinical features, and outcomes. CAMCR was typically seen in patients with diabetes mellitus (DM) (94%) especially the ones with poorly controlled DM (67%) and severe or critical COVID-19 (95%). Its presentation was typical of MCR seen in diabetic patients (mostly rhino-orbital and rhino-orbital-cerebral presentation). In sharp contrast to reported COVID-associated aspergillosis (CAPA) cases, nearly all CAMCR infections were proven (93%). Treating physicians should have a high suspicion for CAMCR in patients with uncontrolled diabetes mellitus and severe COVID-19 presenting with rhino-orbital or rhino-cerebral syndromes. CAMR is the convergence of two storms, one of DM and the other of COVID-19.
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http://dx.doi.org/10.3390/jof7040298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071133PMC
April 2021

Reply to Day et al.

J Infect Dis 2021 Apr 3. Epub 2021 Apr 3.

Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, Texas, USA.

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http://dx.doi.org/10.1093/infdis/jiab183DOI Listing
April 2021

Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer.

J Fungi (Basel) 2021 Mar 17;7(3). Epub 2021 Mar 17.

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Although breakthrough mucormycosis (BT-MCR) is known to develop on mold-active antifungals without Mucorales activity, it can also occur while on Mucorales-active antifungals. Herein, we retrospectively compared the characteristics and outcomes of patients with hematologic malignancies (HMs) or hematopoietic stem cell transplant (HSCT) who developed BT-MCR on mold-active antifungals with or without Mucorales activity. Of the patients developing BT-MCR, 16 were on Mucorales-active antifungals (9 isavuconazole, 6 posaconazole, 1 amphotericin B), and 87 were on other mold-active agents (52 voriconazole, 22 echinocandins, 8 itraconazole, 5 echinocandin + voriconazole). Both groups were largely comparable in clinical characteristics. Patients developing BT-MCR while on Mucorales-active antifungals had higher 42-day mortality, from either symptom onset (63% versus 25%, = 0.006) or treatment initiation (69% versus 39%, = 0.028). In multivariate Cox regression analysis, exposure to Mucorales-active antifungals prior to BT-MCR had a hazard ratio of 2.40 ( = 0.015) for 42-day mortality from treatment initiation and 4.63 ( < 0.001) for 42-day mortality from symptom onset. Intensive care unit (ICU) admission and APACHE II score at diagnosis, non-recovered severe neutropenia, active HM, and amphotericin B/caspofungin combination treatment were additional independent predictors of 42-day mortality. In summary, BT-MCR on Mucorales-active antifungals portrays poor prognosis in HM/HSCT patients. Moreover, improvements in early diagnosis and treatment are urgently needed in these patients.
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http://dx.doi.org/10.3390/jof7030217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002622PMC
March 2021

Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia.

Cancer 2021 Jul 1;127(14):2489-2499. Epub 2021 Apr 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia (AML). VEN and HMA treatment can result in prolonged and often profound neutropenia, and this warrants antifungal prophylaxis. Azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism; this results in VEN dose reductions for each concomitant antifungal. Limited clinical data exist on outcomes for patients treated with VEN, an HMA, and various azoles.

Methods: The time to neutrophil recovery (absolute neutrophil count [ANC] > 1000 cells/mm ) and platelet (PLT) recovery (PLT count > 100,000 cells/mm ) in 64 patients with newly diagnosed AML who achieved a response after course 1 of VEN plus an HMA were evaluated. HMA therapy included azacitidine (75 mg/m intravenously/subcutaneously for 7 days) or decitabine (20 mg/m intravenously for 5 or 10 days).

Results: Forty-seven patients (73%) received an azole: posaconazole (n = 17; 27%), voriconazole (n = 9; 14%), isavuconazole (n = 20; 31%), or fluconazole (n = 1; 2%). The median time to ANC recovery were similar for patients who did receive an azole (37 days; 95% confidence interval [CI], 34-38 days) and patients who did not receive an azole (39 days; 95% CI, 30 days to not estimable; P = .8). The median time to PLT recovery was significantly longer for patients receiving azoles (28 vs 22 days; P = .01). The median times to ANC recovery (35 vs 38 days) and PLT recovery (26 vs 32 days) were similar with posaconazole and voriconazole.

Conclusions: VEN plus an HMA resulted in neutropenia and thrombocytopenia, with the latter prolonged in patients receiving concomitant azoles. Concomitant posaconazole or voriconazole and VEN (100 mg) resulted in similar ANC and PLT recovery times, suggesting the safety of these dosage combinations during course 1.
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http://dx.doi.org/10.1002/cncr.33508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249340PMC
July 2021

Navigating the uncertainties of COVID-19 associated aspergillosis (CAPA): A comparison with influenza associated aspergillosis (IAPA).

J Infect Dis 2021 Mar 26. Epub 2021 Mar 26.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit mechanically-ventilated patients. While the association between severe influenza and IPA has been demonstrated, it remains unclear whether SARS-CoV-2 infection represents a specific risk factor for IPA. A variable incidence of such complication has been previously reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA, in the absence of positive serum galactomannan or histopathologic evidence of angio-invasion. Discrimination between Aspergillus airways colonization and CAPA is difficult. Distinct physiopathology and cytokine profiles of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.
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http://dx.doi.org/10.1093/infdis/jiab163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083649PMC
March 2021

EGF-mediated suppression of cell extrusion during mucosal damage attenuates opportunistic fungal invasion.

Cell Rep 2021 03;34(12):108896

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. Electronic address:

Severe and often fatal opportunistic fungal infections arise frequently following mucosal damage caused by trauma or cytotoxic chemotherapy. Interaction of fungal pathogens with epithelial cells that comprise mucosae is a key early event associated with invasion, and, therefore, enhancing epithelial defense mechanisms may mitigate infection. Here, we establish a model of mold and yeast infection mediated by inducible epithelial cell loss in larval zebrafish. Epithelial cell loss by extrusion promotes exposure of laminin associated with increased fungal attachment, invasion, and larval lethality, whereas fungi defective in adherence or filamentation have reduced virulence. Transcriptional profiling identifies significant upregulation of the epidermal growth factor receptor ligand epigen (EPGN) upon mucosal damage. Treatment with recombinant human EPGN suppresses epithelial cell extrusion, leading to reduced fungal invasion and significantly enhanced survival. These data support the concept of augmenting epithelial restorative capacity to attenuate pathogenic invasion of fungi associated with human disease.
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http://dx.doi.org/10.1016/j.celrep.2021.108896DOI Listing
March 2021

Environmental Candida auris and the Global Warming Emergence Hypothesis.

mBio 2021 03 16;12(2). Epub 2021 Mar 16.

Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands.

Global warming was proposed to be a contributing cause for the nearly simultaneous emergence of different clades of as a nosocomial pathogen in different continents. The global warming emergence hypothesis posits that existed in the environment prior to its clinical recognition and became pathogenic for humans because of thermal adaptation in response to climate change. The isolation of from two sites in the remote Andaman Islands establishes it as an environmental organism, a necessary condition for the hypothesis. The observation that one environmental isolate grew slower at mammalian temperatures than clinical strains is consistent with the notion that their ancestor recently adapted to higher temperatures. The knowledge that can be recovered from the environment should prompt additional searches to define its ecological niches, and the analysis of future environmental isolates will provide evidence for validating or refuting the global warming emergence hypothesis.
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http://dx.doi.org/10.1128/mBio.00360-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092241PMC
March 2021

Molecular Techniques for Genus and Species Determination of Fungi From Fresh and Paraffin-Embedded Formalin-Fixed Tissue in the Revised EORTC/MSGERC Definitions of Invasive Fungal Infection.

Clin Infect Dis 2021 03;72(Suppl 2):S109-S113

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

The EORTC/MSGERC have revised the definitions for proven, probable, and possible fungal diseases. The tissue diagnosis subcommittee was tasked with determining how and when species can be determined from tissue in the absence of culture. The subcommittee reached a consensus decision that polymerase chain reaction (PCR) from tissue, but not immunohistochemistry or in situ hybridization, can be used for genus or species determination under the new EORTC/MSGERC guidelines, but only when fungal elements are identified by histology. Fungal elements seen in tissue samples by histopathology and identified by PCR followed by sequencing should fulfill the definition of a proven fungal infection, identified to genus/species, even in the absence of culture. This summary discusses the issues that were deliberated by the subcommittee to reach the consensus decision and outlines the criteria a laboratory should follow in order to produce data that meet the EORTC/MSGERC definitions.
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http://dx.doi.org/10.1093/cid/ciaa1836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952508PMC
March 2021

A 77-Year-Old Man with Multiple Myeloma and a Lytic Bone Lesion.

Am J Med 2021 07 21;134(7):860-862. Epub 2021 Feb 21.

Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.01.032DOI Listing
July 2021

Distinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications.

Front Immunol 2020 21;11:590494. Epub 2021 Jan 21.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ IL-17 CD8 T and CXCR3 CCR6 Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.
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http://dx.doi.org/10.3389/fimmu.2020.590494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859512PMC
July 2021

Are All Patients with Cancer at Heightened Risk for Severe Coronavirus Disease 2019 (COVID-19)?

Clin Infect Dis 2021 01;72(2):351-356

Department of Infectious Diseases, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.

Cancer patients are traditionally considered at high risk for complicated respiratory viral infections, due to their underlying immunosuppression. In line with this notion, early case series reported high mortality rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with malignancy. However, subsequent large, prospective, epidemiological surveys indicate that the risk for severe coronavirus disease 2019 (COVID-19) may be largely attributed to the multiple confounders operating in this highly heterogeneous population of patients, rather than the cancer or its treatment per se. We critically discuss the conundrums of SARS-CoV-2 infection in cancer patients and underscore mechanistic insights on the outcome of COVID-19 as it relates to cancer therapy and the type and status of the underlying malignancy. Not all cancer patients are similarly at risk for a complicated COVID-19 course. A roadmap is needed for translational and clinical research on COVID-19 in this challenging group of patients.
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http://dx.doi.org/10.1093/cid/ciaa1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454377PMC
January 2021

Disseminated cryptococcosis and anti-granulocyte-macrophage colony-stimulating factor autoantibodies: An underappreciated association.

Mycoses 2021 Jun 5;64(6):576-582. Epub 2021 Feb 5.

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T-cell function. Recently, patients with anti-cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26-year-old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti-GM-CSF autoantibodies. Clinicians should have a heightened awareness of anti-cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.
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http://dx.doi.org/10.1111/myc.13247DOI Listing
June 2021

Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: is there an excess risk for infection?

Lancet Haematol 2021 Mar 15;8(3):e216-e228. Epub 2021 Jan 15.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Therapy with genetically engineered chimeric antigen receptor (CAR) T cells targeting the CD19 antigen is promising for a number of refractory or relapsed B-cell malignancies. Information on the infectious complications of this immunotherapeutic strategy is scarce and difficult to interpret, as many factors influence infection incidence and outcomes. CAR T-cell therapy is usually given to patients with haematological cancers who have been heavily pretreated and are severely immunosuppressed. Moreover, the risk of infection is increased by the administration of lymphodepleting chemotherapy before CAR T-cell infusion, and by the development of complications such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, which are managed with anti-interleukin-6 antibodies, or corticosteroids, or both. On-target, off-tumour toxicities, such as B-cell aplasia, hypogammaglobulinaemia, and persistent or biphasic cytopenia, are common. In this Review, we evaluate the reported infectious complications of CAR T-cell therapy and associated risk factors and offer perspectives on its infection risk.
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http://dx.doi.org/10.1016/S2352-3026(20)30376-8DOI Listing
March 2021

Superficial Thrombophlebitis From Intravenous Pentamidine in Hematopoietic Cell Transplantation Recipient.

Mayo Clin Proc 2021 01;96(1):257-258

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston.

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http://dx.doi.org/10.1016/j.mayocp.2020.10.023DOI Listing
January 2021

Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections.

J Fungi (Basel) 2020 Dec 30;7(1). Epub 2020 Dec 30.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among and spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non- spp. (notably emerging ). For spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among . For non- molds (e.g., , or spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice.
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http://dx.doi.org/10.3390/jof7010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823995PMC
December 2020

How I perform hematopoietic stem cell transplantation on patients with a history of invasive fungal disease.

Blood 2020 12;136(24):2741-2753

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX.

Hematopoietic transplantation is the preferred treatment for many patients with hematologic malignancies. Some patients may develop invasive fungal diseases (IFDs) during initial chemotherapy, which need to be considered when assessing patients for transplantation and treatment posttransplantation. Given the associated high risk of relapse and mortality in the post-hematopoietic stem cell transplantation (HSCT) period, IFDs, especially invasive mold diseases, were historically considered a contraindication for HSCT. Over the last 3 decades, advances in antifungal drugs and early diagnosis have improved IFD outcomes, and HSCT in patients with a recent IFD has become increasingly common. However, an organized approach for performing transplantation in patients with a prior IFD is scarce, and decisions are highly individualized. Patient-, malignancy-, transplantation procedure-, antifungal treatment-, and fungus-specific issues affect the risk of IFD relapse. Effective surveillance to detect IFD relapse post-HSCT and careful drug selection for antifungal prophylaxis are of paramount importance. Antifungal drugs have their own toxicities and interact with immunosuppressive drugs such as calcineurin inhibitors. Immune adjunct cytokine or cellular therapy and surgery can be considered in selected cases. In this review, we critically evaluate these factors and provide guidance for the complex decision making involved in the peri-HSCT management of these patients.
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http://dx.doi.org/10.1182/blood.2020005884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731790PMC
December 2020

Knowledge gaps in candidaemia/invasive candidiasis in haematological cancer patients.

J Antimicrob Chemother 2021 02;76(3):543-546

Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

As neutropenic patients with haematological cancer are not typically included in randomized controlled trials (RCTs) of candidaemia, there is low quality of evidence regarding the management of this common opportunistic mycosis in this patient population, which is at high risk for poor outcomes. Herein we identify the gaps in knowledge that are not addressed by the modern RCTs and candidaemia guidelines, and outline some considerations for the future clinical research agenda in candidaemia/invasive candidiasis in haematological patients.
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http://dx.doi.org/10.1093/jac/dkaa446DOI Listing
February 2021

Live imaging and quantitative analysis of growth and morphology during inter-microbial interaction with .

Virulence 2020 12;11(1):1329-1336

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA.

(PA) and (AF) chronically colonize the airways of patients with cystic fibrosis or chronic immunosuppression and mutually affect each other's pathogenesis. Here, we evaluated IncuCyte time-lapse imaging and NeuroTrack (NT) analysis (Wurster et al., 2019, mBio) as a toolbox to study mycelial expansion and morphogenesis of AF during interaction with PA. Co-incubation of AF with supernatant filtrates of wild-type (WT) PA strains strongly inhibited hyphal growth and branching. Consonant with prior metabolic studies, pyoverdine-deficient PA mutants had significantly attenuated inhibitory capacity. Accordingly, purified PA products pyoverdine and pyocyanin suppressed mycelial expansion of AF in a concentration-dependent way. Using fluorescence-guided tracking of GFP-AF293 mycelia during co-culture with live WT PA cells, we found significant inoculum-dependent mycelial growth inhibition and robust precision of the NT algorithm. Collectively, our experiments position IncuCyte NT as an efficient platform for longitudinal analysis of fungal growth and morphogenesis during bacterial co-infection.
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http://dx.doi.org/10.1080/21505594.2020.1827885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549912PMC
December 2020

Risk factors for the development of invasive aspergillosis after kidney transplantation: Systematic review and meta-analysis.

Am J Transplant 2021 02 4;21(2):703-716. Epub 2020 Sep 4.

Unit of Infectious Diseases, Department of Internal Medicine, University Hospital 12 de Octubre, Madrid, Spain.

To investigate risk factors for invasive aspergillosis (IA) after kidney transplantation (KT), we conducted a systematic search in PubMed and EMBASE to identify studies published until June 2020. We included case-control or cohort design studies comprising KT recipients with a diagnosis of IA, defined according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria, and assessed risk factors for the development of IA. Random-effect models meta-analysis served to pool data. We identified eleven case-control studies (319 IA cases and 835 controls). There was an increased risk of IA among recipients with underlying chronic lung diseases (odds ratio [OR] = 7.26; 95% confidence interval [CI] = 1.05-50.06) and among those with diabetic nephropathy (OR = 1.65; 95% CI = 1.10-2.48). Requiring posttransplant hemodialysis (OR = 3.69; 95% CI = 2.13-6.37) or surgical reintervention (OR = 6.28; 95% CI = 1.67-23.66) were also associated with an increased risk. Moreover, a positive link was identified between IA and posttransplant bacterial infection (OR = 7.51; 95% CI = 4.37-12.91), respiratory tract viral infection (OR = 7.75; 95% CI = 1.60-37.57), cytomegalovirus infection or disease (OR = 2.67; 95% CI = 1.12-6.32), and acute graft rejection (OR = 3.01; 95% CI = 1.78-5.09). In contrast, receiving a kidney from a living donor was associated with a reduced risk (OR = 0.65; 95% CI = 0.46-0.93). KT recipients that accumulate several of these conditions should be closely monitored and a low threshold of suspicion for IA should be maintained. Future studies should explore the benefit of mold-active prophylaxis to this subgroup of KT recipients at highest risk.
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http://dx.doi.org/10.1111/ajt.16248DOI Listing
February 2021

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.

J Infect Dis 2020 08;222(Suppl 3):S175-S198

Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, Texas, USA.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.
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http://dx.doi.org/10.1093/infdis/jiaa394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403757PMC
August 2020

Invasive Fungal Infections at Presentation of Untreated Hematologic Malignancies: Rare and Elusive.

Open Forum Infect Dis 2020 Jul 18;7(7):ofaa247. Epub 2020 Jul 18.

Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Invasive fungal infections (IFIs) are a feared complication of hematologic malignancy (HM) treatment. Infrequently, the diagnosis of a new IFI contemporaneously with a new untreated HM has been sporadically described in case reports. We performed a comprehensive search of published literature and reviewed cases describing this synchronous disease phenomenon.
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http://dx.doi.org/10.1093/ofid/ofaa247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368365PMC
July 2020

Pharmacological serum concentrations of epinephrine and norepinephrine do not affect growth rate, morphogenesis, stress tolerance, and virulence of Candida albicans.

Med Mycol 2021 Jan;59(1):102-105

Department of Infectious Diseases, Infection Control and Employee Health; The University of Texas M.D. Anderson Cancer Center; Houston, Texas, USA.

Vasopressors are frequently given in hemodynamically unstable patients with severe Candida sepsis. While catecholamines can aggravate sepsis-induced immune dysfunction and modulate bacterial virulence traits, their impact on fungal pathogenicity is poorly understood. Using IncuCyte time-lapse microscopy and a fruit fly candidiasis model, we studied growth rates, morphogenesis, stress tolerance, and virulence of C. albicans cocultured with epinephrine and norepinephrine. We found that pharmacologically attainable catecholamine serum concentrations caused minimal changes to in vitro growth kinetics, filamentation, and fungal resistance to thermal or oxidative stress. Similarly, exposure of C. albicans to catecholamines did not alter the survival of infected flies.
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http://dx.doi.org/10.1093/mmy/myaa060DOI Listing
January 2021

Serum (1,3)-Beta-d-Glucan has suboptimal performance for the diagnosis of Pneumocystis jirovecii pneumonia in cancer patients and correlates poorly with respiratory burden as measured by quantitative PCR.

J Infect 2020 09 7;81(3):443-451. Epub 2020 Jul 7.

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Objective: Non-HIV immunocompromised patients with Pneumocystis jirovecii pneumonia (PCP) have lower fungal load than those with AIDS, potentially affecting the accuracy of diagnostic biomarkers. Therefore, we investigated the performance of serum (1,3)-Beta-d-Glucan (BDG) in conjunction with quantitative Pneumocystis jirovecii PCR (qPCR) in non-HIV cancer patients.

Methods: We reviewed records of non-HIV cancer patients and classified them as definite, probable, or possible PCP cases, according to clinicoradiological features, microscopy findings, and qPCR results in bronchoscopy specimens. We evaluated the diagnostic performance of serum BDG and its correlation with qPCR results.

Results: We identified 101 PCP patients (73 definite/probable, 28 possible) and 74 controls. Correlation of BDG and qPCR was low among all 101 qPCR-positive patients (Spearman's = 0.38) and in definite/probable PCP cases (Spearman's = 0.18). Considering all qPCR-positive patients, BDG showed consistently low sensitivity at different cutoffs. Among definite/probable cases, the diagnostic accuracy of BDG remained poor, yet slightly improved with high qPCR thresholds (AUC = 0.86 at ≥2000 DNA copies/mL). BDG had a low PPV but excellent NPV across different qPCR and BDG cutoffs.

Conclusions: BDG and qPCR levels correlate poorly in non-HIV cancer patients with PCP. BDG diagnostic performance is suboptimal but a negative test may be useful to rule out PCP in this population.
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http://dx.doi.org/10.1016/j.jinf.2020.07.003DOI Listing
September 2020
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