Defining Invasive Fungal Infections — More Than the Sum of the Individual Elements?
Defining Invasive Fungal Infections—More Than the Sum of the Individual Elements?
Abstract & Commentary
Synopsis: A set of proposals for defining invasive fungal infections in patients with cancer and those undergoing a hematopoietic stem cell (HSC) transplant has been put forward by an international panel.
Source: Ascioglu S, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants. Clin Infect Dis. 2002;34:7-14
The steady rise in the incidence of invasive fungal infections (IFIs), the wider choice of antifungal agents, and development of new approaches to diagnosis has finally forced the issue about just how one should diagnose IFI, especially for the purposes of clinical trial. A review of the literature revealed a wide variety of different definitions, most of which attempted to assign a degree of certainty to the classification of IFIs. Hence, the IFICG took the initiative and set out to create a set of definitions based on published information that were clinically applicable by experienced researchers as well as practical within the context of the sort of objectively verifiable data generated in daily clinical practice. The MSG joined the group later and the committee as a whole approved the final result.
The definitions comprise 3 elements: host factors, clinical features, and mycology (see Figure 1). In the first instance, the committee decided to restrict the definitions to only patients with cancer and those receiving an HSC transplant. This is not unreasonable since most research on the diagnosis and treatment of IFI is conducted among these risk groups and new broad-spectrum antifungal drug products are tested for their efficacy and safety. The host factors described are readily discernible and should present few problems. Similarly, the clinical features listed to characterize the various mycological disease entities are familiar and commonly used. However, more weight has been assigned to imaging techniques which help visualize a diseased organ or body system and only one of these major criteria needs to be met. By contrast, at least 2 minor clinical symptoms and signs need to be present. The newest departure from convention concerns mycology since indirect evidence based on the detection of antigen in blood and other body fluids is now included alongside the results of microscopy and culture of specimens. Nucleic acid techniques were excluded because none have been developed sufficiently; but, the principle of using indirect tests for evidence has been firmly established, so it is only a matter of time before tests based on PCR and the like find their place in the definitions.
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The definitions are simple to apply. Proven IFI is dependent upon the quality and nature of the specimen obtained for mycological examination (see Figure 1). Any fungi found in tissue from a site associated with infection or recovered from blood cultures is considered sufficient evidence of proven IFI. For endemic fungal infections the recovery of Blastomyces, Coccidioides, Paracoccidioides, or Histoplasma from blood or a specimen from the affected site (usually the lungs) is sufficient proof. No real difference here. The important breakthrough arises from now being able to distinguish possible from probable IFI. A disease process is considered to be probable IFI if the level of proof is not sufficient to meet the criteria for proven disease but each of the 3 elements is present (see Figure 2). By contrast, IFI is deemed possible if a host factor is present accompanied by either at least one clinical feature or one mycological criterion but not both.
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Comment by J. Peter Donnelly, PhD
These definitions are not comprehensive and will need validating in practice and, when necessary, adjusted to incorporate new information. For instance, some solid organ transplants—liver transplants—are associated with higher incidences of IFI than are found among cancer patients and recipients of an HSCT. Patients with AIDS are also not catered to nor are a wide range of other immunocompromised hosts such as those in the ICU. Also, there will be occasions when investigators will want to regard a clinical entity as most likely due to IFI even though it has been defined as only possible IFI. One example would be an HSC transplant recipient being treated with corticosteroids for graft-versus-host disease with a halo-sign seen on CT of the lungs. Few would regard this as anything else other than likely aspergillosis despite what the definitions declare. Notwithstanding these potential shortcomings, the definitions as presented provide an elegant framework of 3 separate elements any of which can be altered or supplemented as and when the need arises. They should also prove both practical and scientifically useful in meeting a wide range of needs from the simple exchange of information to selecting candidates for therapeutic trials. Last but not least, they will help foster a clearer climate for better understanding of the problem facing increasing numbers of patients and their careers.
Dr. Donnelly, Clinical Microbiologist, University Hospital, Nijmegen, The Netherlands, is Associate Editor of Infectious Disease Alert.
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