Clinical Utility of Routine Use of Fungal Blood Cultures.

Fungemia, including candidemia, is associated with substantial morbidity and mortality.1Clancy CJ Nguyen MH Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care.Clin Infect Dis. 2013; 56: 1284-1292Crossref PubMed Scopus (451) Google Scholar Certain fungi are relatively slow-growing and are therefore more difficult to detect via standard 5-day incubation on automated blood-culture instruments. Lysis-centrifugation, also known as isolator blood cultures, is utilized for detection of intracellular pathogens such as mycobacteria and dimorphic fungi. In this method, host cells in the blood are lysed to release intracellular pathogens, and the sample is centrifuged to concentrate any organisms which are present. The pellet is then seeded onto appropriate solid media for fungal culture and incubated for up to 4-6 weeks at 30°C.2Dorn GL Burson GG Haynes JR Blood culture technique based on centrifugation: clinical evaluation.J Clin Microbiol. 1976; 3: 258-263Crossref PubMed Google Scholar,3Kiehn TE Wong B Edwards FF Armstrong D Comparative recovery of bacteria and yeasts from lysis-centrifugation and a conventional blood culture system.J Clin Microbiol. 1983; 18: 300-304Crossref PubMed Scopus (73) Google Scholar With different vendor options, solid-media choices, and incubation times, fungal-isolator cultures are not standardized across different laboratories. The purpose of this article is to assess the clinical utility of fungal-isolator blood cultures and to provide informed practical guidance to clinicians regarding their use in clinical practice. Previous work performed by Telenti et al4Telenti A Roberts GD Fungal blood cultures.Eur J Clin Microbiol Infect Dis. 1989; 8: 825-831Crossref PubMed Scopus (45) Google Scholar in 1989 described their single-center experience utilizing lysis-centrifugation for isolation of fungi. At that time, they found that this method improved diagnosis of fungemia, primarily for Candida species, Cryptococcus species, and 2 important dimorphic endemic fungi, Histoplasma capsulatum and Coccidioides immitis. The authors’ recommendations were to increase use of fungal blood cultures when there is a high degree of clinical suspicion for fungemia, especially in postsurgical and immunocompromised populations.4Telenti A Roberts GD Fungal blood cultures.Eur J Clin Microbiol Infect Dis. 1989; 8: 825-831Crossref PubMed Scopus (45) Google Scholar Other studies have similarly demonstrated that this fungal-blood-culture technique allows higher sensitivity in detection of fungal organisms as compared to routine blood cultures but only in controlled laboratory assays outside of clinical practice.5Kosmin AR Fekete T Use of fungal blood cultures in an academic medical center.J Clin Microbiol. 2008; 46: 3800-3801Crossref PubMed Scopus (12) Google Scholar Although isolator systems have remained mostly unchanged over the last 2 decades, routine blood-culture techniques have improved and now allow for faster growth with improved identification algorithms. Modern blood cultures can now detect Candida spp. with approximately 50% sensitivity with a median time to positivity of 2-3 days compared to autopsy-proven infection.1Clancy CJ Nguyen MH Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care.Clin Infect Dis. 2013; 56: 1284-1292Crossref PubMed Scopus (451) Google Scholar This knowledge is useful in addressing the general misconception that Candida spp. are slow-growing. At the present time, routine blood-culture techniques and the previously described lysis-centrifugation method are essentially equivalent in the clinical assessment of suspected candidemia.6Ellepola AN Morrison CJ Laboratory diagnosis of invasive candidiasis.J Microbiol. 2005; 43 (Spec No:65-84)PubMed Google Scholar In modern clinical practice, a clinician might consider ordering fungal blood cultures as part of a comprehensive infectious evaluation for fever or a systemic inflammatory syndrome, often seeking an answer when routine blood cultures do not isolate a causative pathogen by attempting to identify a pathogenic fungus. Another reason that fungal blood cultures might be ordered is for diagnostic evaluation in certain immunocompromised hosts, when Cryptococcus, Histoplasma capsulatum, or other opportunistic molds might cause disease more frequently. However, fungal blood cultures are often ordered without knowledge of the culture process, indications, and limitations when interpreting test results. As described earlier, Candida spp. can be readily identified via routine blood cultures. Other fungal infections such as histoplasmosis and coccidioidomycosis can be diagnosed by utilizing a thorough history and physical examination, laboratory and radiographic findings, targeted advanced diagnostics, such as fungal antigen and serological testing, and, in certain instances, histopathological examination of tissue specimens.1Clancy CJ Nguyen MH Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care.Clin Infect Dis. 2013; 56: 1284-1292Crossref PubMed Scopus (451) Google Scholar For example, H. capsulatum can be diagnosed with the urine antigen test with high sensitivity, and the sensitivity and specificity of the serum Cryptococcus lateral flow assay for antigen detection are both 98%.7Xie LM Lin GL Dong HN et al.Evaluation of lateral flow immunochromatographic assay for diagnostic accuracy of cryptococcosis.BMC Infect Dis. 2020; 20: 650Crossref PubMed Scopus (6) Google Scholar In addition, a negative fungal blood culture can also provide false reassurance during clinical assessment. The test result might be a false negative because the sensitivity is not 100% for detection of invasive fungal infections. Also, for many potential fungal infections, empirical therapy might be warranted long before culture-result data are available. Awaiting results of fungal blood culture might be the incorrect clinical decision for certain patients. Importantly, there are no large randomized controlled trials (RCTs) evaluating the utility of fungal blood cultures in diagnosing suspected disseminated fungal infections. Even prior to development of modern blood-culture techniques, the available data were sparse and less robust in adults compared to pediatric populations. A summary of some available data is shown in the Table. In summary, the yield of positive cultures was low, there were many clinically insignificant positive cultures, and many of the clinically significant fungi were identified via other methods. Improvement in techniques for routine bacterial blood cultures will likely only continue to improve detection of fungal organisms, as it has for detection of Candida spp. Additionally, use of fungal blood cultures can also add unnecessary cost in patient care. Overall, available data suggest that routine use of fungal blood cultures is not needed, and a well-designed RCT with relevant clinical endpoints is likely needed to demonstrate their utility as a part of routine diagnostic evaluation.TableLiterature Review of Clinical Experience With Fungal Blood CulturesStudy Group (Years Evaluated)PopulationTotal Fungal Cultures ObtainedFrequency of Candida Uniquely by Fungal CulturesCrypto-coccusMoldsDimorphic FungiExcess CostCampigotta et al (2003-2013)8Campigotto A Richardson SE Sebert M McElvania TeKippe E Chakravarty A Doern CD Low utility of pediatric isolator blood culture system for detection of fungemia in children: a 10-year review.J Clin Microbiol. 2016; 54: 2284-2287Crossref PubMed Scopus (13) Google ScholarPediatric Population at 2 Academic Centers9,44213/134 (9.7%)09/25 (36%) clinically significant6 filamentous fungi(4 episodes Aspergillus spp.- 1 isolated from lung biopsy1 Bipolaris- isolated from pleural fluid1 Curvularia1 Exherohilum)1 Fusarium oxysporum (also identified on routine blood culture)2 dimorphic fungi(see next column)1 episode Histoplasma capsulatum: (focal liver lesion culture positive and positive Histoplasma antibody) 1 episode Coccidiodes, isolated from bone lesion culture as wellNot CalculatedMess et al (1992-1994)9Mess T Daar ES Utility of fungal blood cultures for patients with AIDS.Clin Infect Dis. 1997; 25: 1350-1353Crossref PubMed Scopus (15) Google ScholarAdvanced HIV at 1 Academic Center1,1620 (out of 5 positive)7 unique episodes, all had positive serologic makers1 dimorphic Fungi1 Coccidiodes immitis (positive serology)Not CalculatedKumar et al (2010-2017)10Kumar M Campos J Hanisch B Clinical utility of anaerobic and fungal blood cultures in the pediatric oncologic population.J Pediatr Hematol Oncol. 2020; 42: 345-349Crossref PubMed Scopus (1) Google ScholarPediatric oncology and stem-cell transplant unit at 1 Academic Center1,9803 (1 colony on 2 different patients)0185 Cladosporium spp., 6 Penicillum spp., 1 Aspergillus spp. (not fumigatus, flavus, or niger), 1 Bipolaris (1 colony), 1 Rhodotorula mucillaginosa 4 unidentified moldsImpression: Most clinically insignificantN/A$182,000, $350,000 adjusted for inflationCreger et al (56 months; unknown study period, published 1998)11Creger RJ Weeman KE Jacobs MR et al.Lack of utility of the lysis-centrifugation blood culture method for detection of fungemia in immunocompromised cancer patients.J Clin Microbiol. 1998; 36: 290-293Crossref PubMed Google ScholarImmunosuppressed patients with cancer at 1 Academic CenterUnknown; 41/42 false positive cultures were from fungal cultures2 Candida parapsilo-sis141 Aspergillus flavus, 1 Aspergillus spp.N/ANot CalculatedMorrell et al (14 months, unknown study period, published 1996)12Morrell Jr., RM Wasilauskas BL Steffee CH Performance of fungal blood cultures by using the Isolator collection system: is it cost-effective?.J Clin Microbiol. 1996; 34: 3040-3043Crossref PubMed Google ScholarAll cultures at 1 Adult Hospital at Academic Center5,196 (1.6%+)10/56 (17.9%)Neoformans: 9 (all identified using other methods and 0 affected therapy)Albidus: 1 which affected therapyUnclear significance2 Aspergillus flavus (1 isolated elsewhere, 0 affected therapy)3 Fusarium (3 isolated elsewhere, 0 affected therapy)2 affected therapy (Rhodotorula rubra, Penicillium spp.)N/A$300,000 annually, >$550,000 adjusted for inflation Open table in a new tab In summary, our recommendations for use of fungal blood cultures in daily clinical practice include the following:1)Avoid use of fungal blood cultures in the evaluation of suspected disseminated yeast infections due to Candida spp. and Cryptococcus spp. These organisms are detectable via routine blood cultures, and there are alternate diagnostic methods with more robust evidence such as the magnetic resonance assay2)Consider risk factors for candidemia and treat empirically with echinocandins if Candida spp. are unable to be isolated via routine blood cultures and there remains persistent clinical concern for invasive candidal infection.3)Carefully consider which specific fungi could be causing a particular clinical syndrome, and evaluate each patient individually based on host risk factors and clinical presentation. Utilize targeted testing, such as serum cryptococcal antigen, serum Aspergillus galactomannan, and urine Histoplasma antigen, or undertake other syndrome-specific evaluation, such as tissue biopsy or bronchoscopy.4)If there is significant clinical concern for a disseminated fungal infection other than one caused by Candida spp. without microbiologic evidence, consultation with an infectious disease practitioner is recommended to assist with assessment, diagnostic evaluation, and empirical treatment.a.Fungal blood cultures could be recommended when evaluating for Fusarium spp., other filamentous fungi, H. capsulatum, and Coccidioides spp. if alternate testing methods are not available or clinically feasible.