Diagnosing fungal infections in immunocompromised hosts.

Introduction Systemic fungal infections are increasing in incidence and importance, particularly in patients with haematological malignancies' and in association with bone marrow and organ transplantation; 18-50% ofpatients develop an invasive fungal infection after bone marrow transplantation.2" Immunosuppressive treatment is also being used in an increasing number of conditions, such as colitis, nephritis, and asthma. Therefore patients with systemic mycoses are likely to present to doctors working in a wide range of specialties. Mortality from systemic fungal infections in the immunocompromised remains depressingly high, in the order of 80%.' The diagnosis is often only made at necropsy, not having been suspected clinically. Early treatment can reduce the mortality4 so it is extremely important to establish the diagnosis promptly. The commonest pathogens in the United Kingdom are Candida spp, Aspergillus spp, and Cryptococcus neoformans.5 To make a definitive diagnosis of systemic infection with one of these organisms means that those responsible for the care of the patient have to have a high index of suspicion. In laboratories three general approaches are used. Isolation of fungi from clinical specimens is not difficult, but does not necessarily indicate that they are pathogens. In some cases-the recovery of C neoformans from cerebrospinal fluid for instance-the result is unambiguous, but in others-the isolation of C albicans in the sputum-the interpretation depends entirely on the clinical setting. Hence laboratories should be wary of reporting fungal isolates as "normal flora" if the patient could be regarded as being "at risk" of invasive fungal disease. There is perhaps another general point that can be made here. Full identification of a fungal isolate, especially moulds, can take several days, time that is precious for the immunocompromised host. It is always worth giving the clinician preliminary information about potential pathogens, even if the result has to be amended later. The second broad diagnostic approach available in the laboratory is the detection of an immune response to the organism (either antibody or antigen), or the measurement of some other marker of its presence, such as a metabolic product. The attraction of all these techniques is the potential speed with which they can be done, and the fact that they do not require "invasive" sampling procedures. In some cases this approach has been extremely useful-for example, the latex test for cryptococcal antigen-but it must always be remembered that few ofthese tests are sufficiently sensitive so as to exclude the diagnosis on the basis of a negative result. Antifungal treatment should never be withheld solely on the basis of a negative serological test. Finally, fungal infection can often be best diagnosed by histological examination of an appropriate biopsy specimen. This need not entail undue delay; immediate examination of a "wet prep" or a simple smear stained with Giemsa can produce a diagnostic result within a very short time. Glycoproteins from fungal cell walls preferentially bind lectins6; if lectins are labelled with fluorescein, fungi in tissue sections could be rapidly identified. There is no single "gold standard" for diagnosing deep fungal disease, a problem that has bedevilled the proper evaluation of fungal disease and its treatment. Each of the approaches we have described (and will discuss in more detail below) have their place, and always require close consultation between the clinician and the laboratory.