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EDITORIAL 10.1111/1469-0691.12642

Up to date epidemiology, diagnosis and management of invasive fungal infections

I. Oren and M. Paul Infectious Diseases Institute, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion – Israely Institute of Technology, Haifa, Israel E-mail: [email protected]

This issue of Clinical Microbiology and Infection is dedicated to and the presence of GVHD. However, the incidence of invasive fungal infections (IFI) based on the ESCMID confer- invasive is very much dependent on local epide- ence held in Rome on January 2013. The reviews summarize miology and the quality of air control in hemato-oncological the progress achieved in the fields of epidemiology, diagnosis units. Thus, in some settings, invasive aspergillosis is more and management of , Aspergillus and Mucor invasive frequent than invasive [2]. infections. is the second most common invasive mould infection and its incidence increased from 0.7 per million in 1997 to 1.2 per million in 2006 [3]. In addition to immune- Epidemiology suppression, there are some unique host risk factors for mucormycosis such as diabetes keto-acidosis, burns, iron Candida spp. have become important causes of sepsis in overload and, on the other hand, deferoxamine therapy. The hospitals with incidence constantly growing over the last specific clinical syndrome of mucormycosis is associated with 20 years. Candida spp. is now the 4th most common isolate of host risk factors; thus, pulmonary mucormycosis is more bloodstream infections in many countries (and the most common in patients with hematological malignancies, while common IFI), mainly due to the increasing complexity of rhino-cerebral mucormycosis is more common in diabetic medical care [1]. is still the main cause of patients [4]. The aetiologic agents involved in the disease have candidemia in population-based studies worldwide, but its been reclassified in recent years, based on molecular methods relative frequency is decreasing, while the frequency of the establishing taxonomy [4]. Thus, “” was reclassi- other species is increasing. Patients’ characteristics influence fied to either “mucormycosis” or “entomophthoromycosis”. It Candida species distribution; C. glabrata infections are more appears that genera that belong to the subphylum mucormy- common in the elderly, C. krusei in immunocompromised cotina are ubiquitous worldwide and cause severe life-threat- patients, while C. parapsilosis is most common in children and ening infections in immunocompromised patients, while neonates. Risk factors for candidemia include neutropenia, entomophthoromycotina are found in tropical regions and especially during periods of mucositis, broad spectrum cause chronic subcutaneous infections in otherwise healthy antibiotic therapy, abdominal surgery mainly involving the patients. Early identification of mucor spp. to the species level colon, total parenteral nutrition and combination of such risk and advances in epidemiological data will perhaps allow in the factors. future better prediction of patients’ prognosis and tailoring of Invasive aspergillosis is the second most common IFI, with treatment. increasing incidence over the last 20 years along with the advances in the treatment of hematological malignancies. Diagnostics Prolonged neutropenia is the main risk factor. Patients with acute myeloid leukaemia (AML) and those who undergo allogeneic hematopoietic stem cell transplantation (HSCT) Traditional microbiological tests are not sensitive enough for have prolonged durations (more than 10 days) of neutropenia the diagnosis of fungal infections. It has been shown that blood and are at highest risk. In the highest risk group, invasive cultures may fail to diagnose candidemia in up to 50% of the aspergillosis rates can reach 25% [2]. An optimal risk score for cases [5]. In mould infections, the sensitivity of culture is even invasive aspergillosis would have to include fine details on the lower. This led to the development of noncultural serological underlying malignancy and its predicted response to chemo- and molecular tests, for the diagnosis of invasive fungal disease. therapy, regimens, allogeneic transplantation Of the serological tests, the galactomannan antigen for

ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases 2 Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014 CMI

aspergillus and 1-3 beta-D-glucan for fungal infections other mucositis (only recently approved [14]), costs and concerns than and zygomycoses are included in the regarding resistance induction and the lack of treatment diagnostic criteria for IFI [6]. Galactomannan detection in the options for breakthrough infections. Indeed, the downside of BAL fluid has higher sensitivity and specificity for diagnosing any prophylaxis is its potential to increase infections caused invasive pulmonary aspergillosis than serum [7]. PCR-based by resistant strains. Thus, posaconazole and itraconazole have tests have not reached the same level of acceptance, mainly been associated with the appearance of C. glabrata with due to lack of standardization in the type of clinical sample decreased azole susceptibility and fluconazole was associated (serum, plasma, tissue), primer selection (“pan-fungal”, species with the appearance of C. glabrata and C. krusei [15]. Voric- specific) and PCR format (qualitative vs. quantitative, real onazole, itraconazole and have been associated time) [8]. Systematic reviews support the diagnostic potential with appearance of Mucor spp. infections [16,17]. Centres of such tests. Thus, using acceptable diagnostic criteria (other need to define local protocols for prophylaxis than PCR), systematic reviews have summarized that PCR in based on their local epidemiology of candidemias and blood had a sensitivity of 0.88 (95% CI 0.75–0.94) for diagnosis incidence of invasive aspergillosis. The rates of invasive of IA if a single positive sample was required to define aspergillosis without antimould prophylaxis in recent RCTs of positivity and a specificity 0.87 (95% CI 0.78–0.93) if two posaconazole and voriconazole averaged 7–8% of patients at positive samples defined test positivity [9]; PCR in bronchoal- 100 days. Thus, evidence is relevant for settings with similar veolar lavage had a sensitivity and specificity of 0.91 (95% CI incidence. Although RCTs have focused on the main patient 0.79–0.96) and 0.92 (95% CI 0.87–0.96), respectively, for the populations, that is, AML induction, allogeneic transplantation diagnosis of invasive pulmonary aspergillosis [10]; and PCR in with GVHD, prophylaxis might need to be extended to other blood had a sensitivity of 0.95 (95% CI 0.88–0.98) and patients, not specifically examined in RCTs, based on their specificity of 0.92 (95% CI 0.88–0.95) among patients at risk of risk of IFIs. diagnosis of invasive candidiasis [11]. Variability in PCR methods was responsible for some of the heterogeneity in Pre-emptive vs. Empirical Treatment the meta-analyses, but the ability of systematic reviews to identify optimal PCR techniques is limited by the multitude of method components and their interactions. Defining a stan- In 1982, Pizzo et al. showed that empirical antifungal therapy dard methodology should be performed basing the summary with in patients with cancer with prolonged of diagnostic study findings but also relying on expert opinion. fever with granulocytopenia reduce the number of IFIs and The future will probably see the incorporation of molecular fungal deaths [18]. This practice soon became part of the tests in diagnostic algorithms and criteria. guidelines for management of febrile neutropenic patients. With the development of modern imaging and serological/ molecular markers, which allow early detection of IFI, the Prophylaxis “pre-emptive” strategy became optional, where IFIs are actively searched for and antifungal treatment is started when Antifungal prophylaxis has been shown to reduce mortality there is an indication of IFI other than fever (“diagnostic among high-risk hemato-oncological patients [12]. A recent driven” strategy) [19]. The rationale for pre-emptive treat- network meta-analysis of RCTs [13], including direct and ment is to decrease treatment-related toxicity, costs and indirect comparisons, summarized that fluconazole, itraco- resistance emergence and perhaps to improve patient out- nazole solution, voriconazole, posaconazole, low dose comes through more tailored treatment. Currently published liposomal amphotericin B and have the potential RCTs show that the pre-emptive strategy is not necessarily to significantly reduce total IFI rates (compared with no associated with reduced antifungal use (although in 2/3 studies treatment). Posaconazole and voriconazole have been esti- it was) and usually leads to the diagnosis of more IFIs [20–22]. mated as more effective than fluconazole and itraconazole All-cause mortality was not significantly affected in the three capsules (that are poorly absorbed) with regard to IFIs with trials, although only one trial was designed to examine survival more data supporting posaconazole. Itraconazole oral [20]. Compiling or comparing between these studies is suspension has better bioavailability than capsules, but poor difficult because the diagnostic and management pathways of gastrointestinal tolerability hampers its widespread use. empirical and pre-emptive strategies were heterogeneous. Universal adoption of posaconazole is hindered by the Thus, the debate regarding empirical vs. pre-emptive treat- nonavailability of an IV formulation until now for patients ment is open, with a trend favouring the more tailored pre- who cannot take oral treatment during periods of severe emptive strategy in an attempt to improve patients’ manage-

ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4 CMI 3

ment [23]. With effective antimould prophylaxis, the question References is less relevant.

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20. Cordonnier C, Pautas C, Maury S et al. Empirical versus pre- 24. Binder U, Maurer E, Lass-Florl€ C. Mucormycosis - from the pathogens emptive antifungal therapy for high-risk, febrile, neutropenic to the disease. Clin Microbiol Infect 2014; 20 (suppl): 60–66. patients: a randomized, controlled trial. Clin Infect Dis 2009; 48: 25. Ruhnke M. Antifungal stewardship in invasive Candida infections. Clin 1042–1051. Microbiol Infect 2014; 20 (suppl): 11–18. 21. Morrissey CO, Chen SC, Sorrell TC et al. Galactomannan and PCR 26. Cornely OA, Cuenca-Estrella M, Meis JF et al. European Society of versus culture and histology for directing use of antifungal treatment Clinical Microbiology and Infectious Diseases (ESCMID) Fungal for invasive aspergillosis in high-risk haematology patients: a rando- Infection Study Group (EFISG) and European Confederation of Medical mised controlled trial. Lancet Infect Dis 2013; 13: 519–528. Mycology (ECMM) 2013 joint guidelines on diagnosis and management 22. Hebart H, Klingspor L, Klingebiel T et al. A prospective randomized of rare and emerging fungal diseases. Clin Microbiol Infect 2014; 20 controlled trial comparing PCR-based and empirical treatment with (Suppl): 1–4. liposomal amphotericin B in patients after allo-SCT. Bone Marrow 27. Ullmann AJ, Akova M, Herbrecht R et al. ESCMID* guideline for the Transplant 2009; 43: 553–561. diagnosis and management of Candida diseases 2012: adults with 23. Donnelly JP, Maertens J. The end of the road for empirical antifungal haematological malignancies and after haematopoietic stem cell treatment? Lancet Infect Dis 2013; 13: 470–472. transplantation (HCT). Clin Microbiol Infect 2012; 18 (Suppl): 53–67.

ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4