The Evidence Supporting the Revised EORTC/MSGERC Definitions for Invasive Fungal Infections

Abstract

Invasive fungal infections (IFIs) in much of the developed world are associated with medical progress. In addition to the millions of individuals worldwide living with human immunodeficiency virus who constitute a significant host group, these infections are also common among other immunocompromised individuals as a reflection of technologic and therapeutic advances that have led to an enlarging susceptible host population. Examples include novel chemotherapy and other antineoplastic treatments, the aggressive use of glucocorticosteroids for a variety of underlying conditions, the rapidly expanding use of monoclonal antibodies and other biologic agents for the treatment of autoimmune disorders, and the extensive use of intravascular catheters and other medical devices that can provide a nidus for IFIs in otherwise immunocompetent individuals [1, 2]. With the exception of the endemic mycoses, cryptococcosis, and isolated mold infections, collectively, IFIs were relatively uncommon before 1950. Since that time, IFIs have been increasingly encountered in hospitalized and immunocompromised individuals, burgeoning to a point that these are dominant causes of undifferentiated fever, pulmonary infiltrates, skin lesions, and central nervous system disorders in a significant proportion of these patients. Notably, the accurate diagnosis of IFI has lagged behind that caused by conventional pathogens such as bacteria and viruses. This is, in part, due to poor noninvasive diagnostics for many disorders (eg, invasive aspergillosis, mucormycosis) and the relative insensitivity and slowness of culture-based methods for others (eg, the poor performance of blood cultures in the diagnosis of invasive candidiasis). Given the interest in carefully studying these disorders for epidemiologic and therapeutic purposes, it became increasingly important to accurately describe the diagnosis of the most common IFIs so as to develop greater homogeneity among clinical trial participants. First published in 2002, the genesis of the original EORTC and the Mycoses Study Group (MSG) definitions for IFIs arose from the need to have consensus definitions for proven, probable, and possible infection among patients with cancer and recipients of hematopoietic stem cell transplants [3]. These definitions were established using the combination of host, clinical, and mycologic criteria and were intended for use in epidemiologic and clinical research, but explicitly not day-to-day for clinical decision-making. Despite the admonition that these definitions were not devised to guide clinical practice, they were adopted by the larger practicing community, gradually creeping into the routine practice of clinical medicine to inform decision-making as it related to targeted antifungal therapy [3]. The first revision of these guidelines was published in 2008 [4]. This revision was necessary in order to address shortcomings in the original version of the definitions and to incorporate emerging diagnostic methodologies. A key issue addressed in this revision included the elimination of the “possible” category for IFI, as this allowed many dubious cases to be included in the definitions. The first revision also broadened the host population beyond those with hematologic malignancies and stem cell transplant recipients to include solid organ transplant recipients and patients with primary immunodeficiency. The revision also includes definitions for less common IFIs [4]. In the most recent (2020) iteration of these EORTC/MSG Education and Research Consortium definitions, there have been further refinements to this evolving document [5]. The update focuses on 9 topical areas that pertain to hosts, fungal diagnostics, and pathogens. This version of the definitions is limited to the proven and probable categories, as no consensus was reached about the possible category. The host definition now includes the pediatric age group, innate immunologic disorders, and CD4 lymphopenia, among other conditions. Fungal diagnostics continue to evolve with improved sensitivity and specificity, resulting in more rapid and accurate diagnosis. These diagnostics have greatly enhanced the utility of the definitions. Finally, the document now includes definitions for Pneumocystis jirovecii infection [5]. In the almost 2 decades since publication of the initial document, the EORTC/MSG definitions for IFIs have established a standard toward defining a more homogeneous population for purposes of conducting clinical trials and for epidemiologic investigations. While not specifically designed for use in clinical practice, these definitions are often used to assist in decision-making regarding targeted antifungal therapy. The main purpose of this Clinical Infectious Diseases supplement is to provide much of the supporting data upon which the recently published revised EORTC/MSGERC definitions for IFI are based [5]. Among the 9 sections covered in revised definitions, data from 6 sections are included herein. These include new understanding pertaining to radiologic diagnoses, updated information on Aspergillus galactomannan serologic studies, updated information on Aspergillus polymerase chain reaction (PCR) diagnostics, new insights into the utility of 1,3-β-D glucan as a diagnostic modality, data that support diagnostics directly from tissue specimens, and data that support P. jirovecii diagnosis. Also included are proposed definitions for IFIs among intensive care unit (ICU) patients. This last category was included among the original 10 groups, but it was removed when the group could not arrive at a consensus for what constituted a susceptible host category for all ICU patients. Nevertheless, these are critically important definitions, and we chose to include them in this supplement in order to provide the type of readership exposure that they deserve. Two completely new topical areas in the most recent definitions include the definition of P. jirovecii infection and enhanced tissue-based diagnosis of IFI [5]. The enhanced diagnosis of this entity using P jirovecii PCR in bronchoalveolar lavage specimens has revolutionized the ability to diagnose accurately this infection in the appropriate host. Enhanced diagnosis of fungal infection based on tissue samples is possible through organism-specific immunostaining and PCR-based diagnostics using a variety of techniques for a host of fungal pathogens. There are 3 important sections that are not included in this supplement but were part of the revised EORTC/MSGERC IFI definitions. A section on pediatric fungal infections was included in the revised definitions but it is not included here because of a recent update published as a supplement in the Journal of the Pediatric Infectious Diseases Society [6]. We refer the reader to this excellent supplement. Similarly, we also did not include data that support the updated definitions for cryptococcosis because a review that includes many of the same authors has recently been published in Clinical Infectious Diseases as a major article, and there is little to add to this excellent article [7]. Finally, the endemic fungi are not included in this supplement because there is simply too little new information to justify an additional manuscript. We believe that the reader of this supplement will find that a deeper dive into the data that describe the rationale supporting these modified definitions will lead to a better understanding of both the importance and the difficulty in achieving consensus definitions for so many key fungal pathogens. This is an area of constant change, driven by improved fungal diagnostics, evolving host characteristics, and continually changing immunotherapeutics. The importance of these definitions in achieving more consistency and homogeneity in defining patients for purposes of inclusion into clinical trials and epidemiologic studies should not be underestimated. Supplement sponsorship. This supplement is sponsored by the EORTC/MSGERC. Potential conflicts of interest. P. G. P. reports grants from Merck, Astellas, Gilead, Mayne, Cidara, Scynexis, and Amplyx outside the submitted work. J. P. D. reports consultancy fees from F2G Ltd, Gilead Sciences, and Pfizer and speaker fees from Gilead Sciences outside the submitted work. S. C.-A. C. reports untied educational grants from F2G Ltd and MSD Australia outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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