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Occasional Articles J Clin Pathol 1992;45:1-5 I Occasional articles Diagnosing fungal infections in J Clin Pathol: first published as 10.1136/jcp.45.1.1 on 1 January 1992. Downloaded from immunocompromised hosts C M Tang, J Cohen Introduction they can be done, and the fact that they do not Systemic fungal infections are increasing in require "invasive" sampling procedures. In incidence and importance, particularly in some cases this approach has been extremely patients with haematological malignancies' and useful-for example, the latex test for cryp- in association with bone marrow and organ tococcal antigen-but it must always be transplantation; 18-50% ofpatients develop an remembered that few ofthese tests are sufficien- invasive fungal infection after bone marrow tly sensitive so as to exclude the diagnosis on transplantation.2" Immunosuppressive treat- the basis of a negative result. Antifungal treat- ment is also being used in an increasing number ment should never be withheld solely on the of conditions, such as colitis, nephritis, and basis of a negative serological test. asthma. Therefore patients with systemic Finally, fungal infection can often be best mycoses are likely to present to doctors work- diagnosed by histological examination of an ing in a wide range of specialties. appropriate biopsy specimen. This need not Mortality from systemic fungal infections in entail undue delay; immediate examination of a the immunocompromised remains depres- "wet prep" or a simple smear stained with singly high, in the order of 80%.' The diag- Giemsa can produce a diagnostic result within nosis is often only made at necropsy, not having a very short time. Glycoproteins from fungal been suspected clinically. Early treatment can cell walls preferentially bind lectins6; if lectins reduce the mortality4 so it is extremely impor- are labelled with fluorescein, fungi in tissue tant to establish the diagnosis promptly. sections could be rapidly identified. The commonest pathogens in the United There is no single "gold standard" for diag- Kingdom are Candida spp, Aspergillus spp, and nosing deep fungal disease, a problem that has Cryptococcus neoformans.5 To make a definitive bedevilled the proper evaluation of fungal http://jcp.bmj.com/ diagnosis of systemic infection with one of disease and its treatment. Each of the approa- these organisms means that those responsible ches we have described (and will discuss in for the care of the patient have to have a high more detail below) have their place, and always index of suspicion. In laboratories three gen- require close consultation between the clinician eral approaches are used. and the laboratory. Isolation of fungi from clinical specimens is not difficult, but does not necessarily indicate Candidosis on October 1, 2021 by guest. Protected copyright. that they are pathogens. In some cases-the Most systemic candidal infections are caused recovery of C neoformans from cerebrospinal by Candida albicans, though many other fluid for instance-the result is unambiguous, species of Candida, such as C tropicalis, C but in others-the isolation of C albicans in the parapsilosis, C glabrata, C pseudotropicalis and sputum-the interpretation depends entirely C krusei, may be pathogenic.7 Colonisation of on the clinical setting. Hence laboratories the gastrointestinal tract with Candida spp should be wary of reporting fungal isolates as occurs frequently, even in the non-immuno- "normal flora" if the patient could be regarded compromised host. This complicates the inter- as being "at risk" of invasive fungal disease. pretation of clinical isolates. The clinical pic- There is perhaps another general point that can ture often provides few clues. Disseminated be made here. Full identification of a fungal candidosis usually presents with a persistent isolate, especially moulds, can take several fever and no diagnostic clinical features.8 Fun- days, time that is precious for the immunocom- doscopy should be performed on all patients Infectious Diseases promised host. It is always worth giving the with suspected candidosis as candidal endo- Unit, Department of Medicine and clinician preliminary information about poten- phthalmitis, although only present in 5% of Bacteriology, Royal tial pathogens, even if the result has to be patients with confirmed invasive disease, is Postgraduate Medical amended later. characteristic and its early recognition and School, Du Cane Road, London The second broad diagnostic approach treatment may save the patient's sight.9 Any W12 ONN available in the laboratory is the detection of an nodular skin eruption of recent origin in a C M Tang immune response to the organism (either febrile, neutropenic patient should be biopsied J Cohen antibody or antigen), or the measurement of as it may represent cutaneous emboli which are Correspondence to: some other marker of its presence, such as a occasionally seen in patients with disseminated Dr J Cohen metabolic product. The attraction of all these candidosis'0 and in some of the less common Accepted for publication 25 April 1991 techniques is the potential speed with which systemic mycoses. 2 Tang, Cohen Blood cultures are part of the routine inves- invasive disease.22 One such antigen is a 48 tigation of febrile neutropenic patients and in kilodalton cytoplasmic protein which was this setting isolates of Candida spp are highly found in the serum of77% ofaffected patients.23 predictive of invasive disease. Unfortunately A much more rapid and convenient way of Candida spp are grown from blood cultures in detecting circulating antigen is to use a latex J Clin Pathol: first published as 10.1136/jcp.45.1.1 on 1 January 1992. Downloaded from only 20% of those with definite disseminated agglutination test. Such a system has been candidosis." The yield can be improved using developed24 and is available commercially biphasic rather than vented blood culture (Cand-Tec, Ramco Laboratories, Texas, media,'2 while the lysis centrifugation system USA). Latex particles are coated with serum often gives an answer a day or two earlier than from a rabbit previously immunised with heat- both these methods, especially in infections killed blastoconidia. The antigen detected by caused by C tropicalis and Cglabrata.'3 It is not this method is a heat-labile glycoprotein that is practicable to use these alternative forms of not mannan. Using a cut-off titre of 1 in 8 as blood cultures routinely, but they can be valu- positive, the test is fairly specific (about 80%) able in at-risk patients when a rapid diagnosis is but not sufficiently sensitive, identifying important, or when other methods of culture antigenaemia in only 19-46% of immuno- have been unsuccessful. The finding of can- suppressed patients with disseminated diduria is harder to assess: many patients disease.2526 The sensitivity of the test is higher without systemic disease, and particularly in those who are not immunosuppressed. those with indwelling urinary catheters, may Candida spp produce a metabolite, D- have urinary tract colonisation with Candida arabinitol, which can be detected using gas- spp. Nevertheless, interpretation ofcandiduria liquid chromatography (GLC).27 Unfortun- remains very difficult. It has been suggested ately D-arabinitol is found in low concentra- that specimens containing more than 104 tions in some healthy people. Concentrations organisms/ml should be regarded as clinically increase in renal impairment as it is cleared by significant,'4 but this has never been properly the kidney at the same rate as creatinine; a D- validated. Similarly, the relevance of pyuria in arabinitol : creatinine ratio can be calculated to association with candiduria has not been compensate for this. This test is highly specific, established; the absence of white cells is not but reported sensitivities vary from only 48- helpful in patients who are neutropenic. Can- 82%.27 28 diduria in immunosuppressed patients should Most of the serological tests aimed at detect- always be reported by the laboratory, although ing antibody, antigen, or fungal metabolites are it is not always an indication for systemic too insensitive to be of clinical use. The publi- antifungal treatment. shed sensitivity data can be improved by test- An alternative approach to isolating the ing serial (often weekly) samples. This is of organism is to study the host's antibody res- little benefit for the patient when an early ponse to the major cytoplasmic proteins of diagnosis is required. Another problem is that Candida spp. Serological studies used to most of the serological tests have been assessed http://jcp.bmj.com/ involve identifying Candida precipitins in in Candida albicans infections alone and will patients' serum; this proved extremely unreli- need to be evaluated for disease caused by the able, with poor specificity and sensitivity." The other species of Candida. The Cand-Tec test, main problem is that immunocompromised however, detects antigenaemia in C tropicalis patients have poor antibody responses and and C parapsilosis infections.24 when sensitive techniques, such as radioim- munoassay (RIA) and enzyme linked Aspergillosis on October 1, 2021 by guest. Protected copyright. immunosorbent assay (ELISA), have been Aspergillus spp are free-living saprophytes used an unacceptable number of false positive which are ubiquitous in the environment, results are obtained in patients colonised with present in the air as conidia. Aspergillus has Candida spp.'6 It has been suggested that the been labelled the "weed ofthe culture room" as presence of circulating antibodies in a patient it often contaminates fungal culture plates. with invasive candidal disease is a good prog- This highlights the difficulty of interpreting nostic sign'7; however, measurement of Can- clinical isolates of Aspergillus, and having to dida antibodies remains of little help in estab- decide if it is present as a contaminant, com- lishing a diagnosis. mensal, or pathogen. Infection is usually via It had been hoped that finding circulating inhalation of airborne spores (size 2-4,m in antigen may be a more accurate indicator of diameter) and is primarily pulmonary.
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