Defining Opportunistic Invasive Fungal Infections in Immunocompromised Patients with Cancer and Hematopoietic Stem Cell Transplants

Defining Opportunistic Invasive Fungal Infections in Immunocompromised Patients with Cancer and Hematopoietic Stem Cell Transplants: An International Consensus

S. Ascioglu, J. H. Rex, B. de Pauw et al.                                                                                                                                           CID 2002, 34:7-22

On behalf of the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Mycoses Study

BACKGROUND: Opportunistic invasive fungal infections (IFIs) are a major cause of morbidity and mortality in immunocompromised patients. However, there still remains much uncertainty and controversy regarding the best methods for establishing the diagnosis of most IFIs. A series of estimates of probability (e.g., definite, proven, suspected, presumptive, and probable) is also a part of all of these systems, which is also evident from the literature on IFIs (1). Although there are reference standards for diagnosing IFIs, these usually involve use of invasive procedures to obtain tissue specimens for culture and histological examination. Unfortunately, these procedures are not always feasible.
METHODS: A systematic review of the literature for an explicit identification of major problems related to heterogeneity of immunocompromised patients with cancer who have IFIs was undertaken. In brief, the abstracts of 7086 articles published from 1985 through 1997 were screened. Of these, 173 articles were finally selected because they were reports exclusively regarding clinical research on immunocompromised patients with cancer or recipients of hematopoietic stem cell transplants who also had deeptissue fungal infections. The minimum diagnostic criteria used to include patients in the study were extracted from definitions devised by the investigators. Likewise, the criteria used to express different degrees of diagnostic probability were summarized, as were the terms most often used to express these levels of uncertainty.
RESULTS: Definitions for a new classification based on the level of certainty for the diagnosis of IFIs were proposed. This proposal includes both diagnostic criteria for proven IFIs and also classification criteria for probable and possible diseases. Three elements form the basis of the proposed definitions: host factors, clinical manifestations, and mycological results. Host factors, for invasive fungal infections in patients with cancer and recipients of hematopoietic stem cell transplants include: neutropenia (< 500 neutrophils/mm3 for > 10 days), persistent fever for > 96 h refractory to appropriate broad-spectrum antibacterial treatment in high-risk patients, body temperature either > 38°C or < 36°C and any of the following predisposing conditions: prolonged neutropenia (> 10 days) in previous 60 days, recent or current use of significant immunosuppressive agents in previous 30 days, proven or probable invasive fungal infection during previous episode of neutropenia, or coexistence of symptomatic AIDS, signs and symptoms indicating graft-versus-host disease, particularly severe (grade > 2) or chronic extensive disease, prolonged (> 3 weeks) use of corticosteroids in previous 60 days. There are a number of major and minor clinical criteria for lower respiratory tract, sinonasal, CNS and disseminated fungal infections. Proven invasive fungal infections are defined by histopathologic or cytopathologic examination showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage or positive culture results for a sample obtained by sterile procedure from normally sterile and clinically or radiologically abnormal site consistent with infection. The microbiological evidence acquired by means of either direct examination or culture of specimens from sites that may be colonized (e.g., sputum, bronchoalveolar lavage fluid, or sinus aspirate) were thought only to support the diagnosis, not prove it. Probable invasive fungal infections combine at least 1 host factor criterion and 1 microbiological criterion and 1 major (or 2 minor) clinical criteria from the abnormal site consistent with infection. Possible invasive fungal infections combine at least 1 host factor criterion and 1 microbiological or 1 major (or 2 minor) clinical criteria from the abnormal site consistent with infection.
INTERPRETATION: Although the definitions are restricted to patients with cancer and to recipients of hematopoietic stem cell transplants, the criteria for proven IFIs are likely valid for all host groups. This classification allows not only a more rational diagnosis and treatment of fungal infection, but also a tool to define patients’ condition in clinical trials to evaluate new diagnostic methodology and antifungal therapy.