1. Introduction
Chimeric antigen receptor-T (CAR-T) immunotherapy has revolutionized the management of patients with relapsed/refractory (R/R) B cell malignancies and has become the standard of care [1]. Up to date, four CAR-T cell products have been approved for the treatment of B cell lymphomas and B-acute lymphoblastic leukemia (B-ALL): axicabtagene ciloleucel for diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), and follicular lymphoma (FL); brexucabtagene autoleucel for R/R mantle cell lymphoma (MCL) and B-ALL; lisocabtagene maraleucel for DLBCL, PMBCL, and FL; and tisagenlecleucel for DLBCL and B-ALL [2]. Moreover, two CAR-T cell products are available for patients with R/R multiple myeloma (M/M): idecabtagene vicleucel and ciltacabtegene autoleucel [3]. Despite the therapeutic efficacy of this treatment approach, various complications are observed in the post-infusion period [4].
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are considered among the major toxicities developed in CAR-T cell recipients early (within 10 days) after the CAR-T cell immunotherapy administration [5,6]. Endothelial injury and immune dysregulation are implicated in the pathogenesis of these syndromes [7,8]. Tocilizumab, a monoclonal antibody targeting interleukin 6 (IL-6), and corticosteroids are used for the management of patients who develop CRS [9,10]. Prolonged hematological toxicity (anemia, thrombocytopenia, and neutropenia) can also be observed in the post-infusion period [11]. Various scores have been developed and validated for the prediction of CAR-T cell-related toxicity onset and outcomes in these patients [12].
Prolonged neutropenia and lymphopenia, prior chemotherapy, history of hematopoietic cell transplantation (HCT), coexisting comorbidities, and administration of corticosteroids and tocilizumab result in a net state of immunosuppression [13]. Infections in CAR-T cell patients are mainly observed within 30 days after the infusion and are attributed to bacterial and viral species [14,15,16]. Additionally, invasive fungal disease (IFD) can be observed in these patients, leading to increased mortality and morbidity [17,18]. Data regarding epidemiology, risk factors, management, and outcomes of IFDs in CAR-T cell recipients are scarce. Moreover, a lack of large real-world studies about the incidence of IFDs in these patients has been recognized.
In the current literature review, we searched the recent literature, and the published data regarding the pathogenesis-risk factors, diagnosis, epidemiology, management, and outcomes of IFDs in pediatric and adult patients who receive CAR-T cell immunotherapy are summarized. Moreover, the role of antifungal prophylaxis in these patients is examined. In the era of precision medicine and novel therapeutics, more data regarding IFDs in the post-CAR-T cell infusion period are essential.
2. Pathogenesis-Risk Factors
2.1. Pre-Infusion Factors: Underlying Hematological Malignancies and Previous Treatments
Various factors, including diagnosis of B-ALL, history of allogeneic HCT (allo-HCT), history of IFD prior to CAR-T cell therapy, and increased number of previous treatment lines, have been recognized as infection risk factors in CAR-T cell recipients [19,20,21,22,23,24]. Specifically, previous allo-HCT is a well-established risk factor for IFD development, which is more common in patients with R/R B-ALL in comparison to those with lymphomas or MM [25,26]. In patients who receive CAR-T cell immunotherapy, and who have also undergone allo-HCT, a history of graft-versus-host disease diagnosis results in increased risk for IFDs [27]. Furthermore, the administration of targeted therapeutic agents, such as ibrutinib, rituximab (B cell-depleting agent), and alemtuzumab, often leading to impaired cell mediated immunity, before CAR-T cell therapy might increase the IFD risk in these patients [20,28,29]. More real-world data are of paramount importance in understanding the role of these agents in IFD development post-CAR-T cell infusion. In addition to the above, patients’ comorbidities might increase the risk for IFDs. For example, uncontrolled diabetes mellitus has been recognized as a risk factor for mucormycosis [30,31,32].
2.2. CRS and ICANS
CRS and ICANS are the main toxicities developed in the post-infusion period [33]. These complications and the use of corticosteroids for their management are included in the risk factors for infectious complications in CAR-T cell recipients. Interestingly, CRS grade has been associated with the severity of infections in the post-infusion period [34]. Endothelial injury, immune dysregulation, and mucositis are implicated in CRS pathogenesis, which may lead to IFD susceptibility [35]. In addition to corticosteroids, other immunosuppressive agents, such as tocilizumab, and invasive measures (mechanical ventilation, central venous catheterization, hospitalization in intensive care unit [ICU]) are included in the management of these toxicities, increasing the risk for IFDs [36]. High doses of corticosteroids used for the treatment of severe CRS forms, such as hemophagocytic lymphohistiocytosis, have been recognized as a risk for factor IFD development in these patients [32,37,38]. Data regarding the association of IFDs and tocilizumab in CAR-T cell recipients are lacking; however, tocilizumab use in patients with severe coronavirus disease 2019 (COVID-19) infection has been associated with increased prevalence of fungal infections [39,40,41,42]. Future research on the impact of immunosuppressive agents used for CRS and ICANS treatment in the incidence of IFDs is essential.
2.3. Hematological Toxicity: Neutropenia
Severe neutropenia (absolute neutrophil count (ANC) < 500 cells/μL) is frequently observed in CAR-T patients after the administration of lymphodepleting chemotherapy with median duration below 10 days [43,44,45]. CRS and systematic inflammation are implicated in CAR-T-related neutropenia development [46]. Biphasic neutropenia is also common in these patients: within 3 weeks post-infusion is observed an intermittent recovery in ANC (phase I), while in 2 months, approximately, a second decrease is evident (phase II) [47]. CRS and systematic inflammation are implicated in CAR-T-related phase I neutropenia development [46]. The second neutropenic phase is attributed to suppression of bone marrow neutrophil production, and immune-mediated mechanisms have an important role [48]. Prolonged and severe neutropenia are well-established drivers of IFDs in patients with hematological malignancies [49,50]. Cases of IFDs have been described in patients with refractory and severe neutropenia post-CAR-T cell infusion [33,51].
2.4. Hematological Toxicity Beyond Neutropenia
CAR-T-related prolonged hematotoxicity is the most common late-onset adverse event (after the first month of CAR-T infusion) in real-world clinical settings [52]. Hematotoxicity leads to severe infections, hemorrhagic events, longer hospitalization, and more frequent follow-ups [53]. Beyond neutropenia, CD4+ T cell-mediated immunity has been described as impaired in these patients [54]. Persisting lymphopenia has been recognized as a risk factor for late-onset (>3 months post-infusion) IFD development and mainly for Pneumocystis jirovecii pneumonia (PJP). In the study of Little et al., 280 CAR-T cell recipients were studied and PJP was observed in 3 patients with lymphopenia. The median time of PJP onset was 390 days (range: 115–441) [55]. Moreover, PJP infections in the cohort of Baird et al. occurred in patients with CD4+ T cell count below 200 cells/μL [56]. B cell aplasia, hypogammaglobinemia, and antibody deficiency, observed in these patients, might lead to increased IFD risk due to their indirect impact on T cell-mediated immunity [56,57]. Zahid et al. described a case of disseminated coccidioidomycosis after CAR-T cell immunotherapy, which was attributed, among other factors, to an IgG subclass deficiency, as a result of B cell depletion [58]. Predictive score systems, incorporating pre- and post-infusion variables, should be developed to predict IFD onset in these patients [59]. In Figure 1, the risk factors implicated in IFD pathogenesis in CAR-T cell patients are summarized.
3. Diagnosis of IFD in CAR-T Cell Setting
Although major improvements have been made in the diagnosis of IFDs, their differentiation from non-fungal infections and non-infectious complications, such as CRS, still remains challenging and often eludes clinical suspicion. The cornerstones of diagnosis are histopathological examination of infected tissue, chest computed tomography (CT) scans, and microbiological tests, both culture-based and non-culture-based, with serological testing, polymerase chain reaction (PCR), and mass spectrometry being steadily integrated into laboratory protocols [60]. Diagnosis can be classified as proven, probable, and possible, based on the revised and updated version of the consensus definitions of IFDs published by EORTC/MSGERC [61]. Proven diagnosis requires the detection of pathogenic fungi through histopathological or culture methods from sterile sites. For a probable diagnosis, all three of the following criteria must be met: (i) host factors (immunosuppression, neutropenia, etc.), (ii) relevant clinical signs and symptoms, and (iii) mycological evidence, such as positive imaging or molecular testing. A possible diagnosis requires two of the three aforementioned criteria to be present [61]. Histopathological examination is the most certain way to establish a proven diagnosis; however, the invasiveness of biopsy should always be taken into consideration, especially for recipients of CAR-T cell therapy who are immunocompromised and might also suffer from insufficient blood coagulation.
The methods of choice for the identification of fungal pathogens are culture and direct microscopy of biological fluids including blood serum, bronchoalveolar lavage (BAL), sputum, cerebrospinal fluid (CSF), and others, owning to their minimal risk to patient safety and proven specificity. Additionally, fungal culture allows for the determination of antifungal susceptibility, as well as the identification of fungal species. Culture remains the gold standard diagnostic method for invasive candidiasis. However, it also presents some considerable drawbacks, such as the long turn-around time (2 to 5 days for yeast and yeast-like fungi and 7 to 10 days for filamentous fungi), possible contamination with irrelevant microorganisms, and low sensitivity values [62].
As for serological testing, major advancements have paved the way for the inclusion of practices such as the Aspergillus galactomannan (GM) antigen test and the (1,3)-β-d-glucan (BDG) test in laboratory routine. The GM antigen test is measured by a sandwich enzyme immunoassay which detects galactomannan, a polysaccharide cell wall component that is mainly released by Aspergillus during growth in infected blood, bronchial, and other body fluids [63]. It has been proven useful in the diagnosis of aspergillosis in CAR-T cell therapy recipients, and its values have been associated with clinical outcomes [19]. However, it cannot give a proven diagnosis, since false positive and false negative results are not uncommon. False positive results have been associated with MM and the intake of semi-synthetic β-lactam antibiotics and probiotic supplements, all of which are common in CAR-T cell immunotherapy recipients. False negative results have been associated with concomitant use of mold-active antifungal agents [60]. Therefore, the GM antigen test should be used in conjunction with other microbiological methods, notably culture and/or PCR.
The same is true for the BDG test, which detects a cell wall polysaccharide, (1-3)-β-d-glucan, in patient serum, a component present in most fungi, including Candida spp., Fusarium spp., and P. jirovecii. It is notably absent from cryptococci, the Mucormycetes, and Blastomyces dermatitidis [64]. It has been proven as a useful tool in the diagnosis of IFD and fungemia [65]. Similar to the Aspergillus galactomannan antigen test, a tendency for false positive results has been noticed in patients receiving semi-synthetic β-lactam antibiotics and those suffering from bacterial bloodstream infections (e.g., Pseudomonas aeruginosa), while false negative results have been observed in patients under concomitant use of antifungal agents. CAR-T cell therapy recipients who receive multiple prophylactic antifungal agents (fluconazole, posaconazole, and oral trimethoprim/sulfamethoxazole) could belong to the aforementioned categories. Furthermore, we have to underline that the use of BDG detection in pediatric patients is limited due to a high proportion of false positive results. An exception could be PJP with out-of-scale BDG in the presence of the right clinical condition, but this needs further validation [66].
PJP is a rare but documented infectious complication of CAR-T cell therapy [13]. It mostly occurs in later stages following the infusion (from 50 up to 250 days later) and is linked to the observable long-term B cell aplasia and subsequent hypogammaglobulinemia. Since it can manifest so long after the infusion, it is often underappreciated, but nevertheless life threatening. In the case of clinical suspicion of PJP, the recommended method for identification is immunofluorescent microscopy or molecular techniques, which have been found to exhibit higher sensitivity [67].
Apart from culture, microscopy, serological tests, and histopathological examination, three more methods have been proven useful for rapid fungal identification. Those include imaging techniques, PCR, and mass spectrometry. Regarding imaging techniques, the preferred method for fungal identification is high-resolution computed scanning. Nodules or infiltrates with or without a halo sign, found in CT scans, remain a useful and rapid find for the identification of invasive pulmonary aspergillosis (IPA), especially in neutropenic patients, such as those receiving CAR-T cell immunotherapy [68]. Following neutrophil recovery, an air crescent sign may develop, though it remains a nonspecific and rather late find [61].
PCR-based methods have also been developed. For a long time, they lacked standardization and there were only a few commercially available PCR assays. However, over the past decade, major progress has been made in standardizing the available protocols by the European Aspergillus PCR Initiative (EAPCRI) [69]. With extensive evaluation of the assays, the specificity and sensitivity for plasma Aspergillus PCR reached 83.3% and 94.7%, respectively. Those results make the PCR-based methods comparable to the more widespread GM antigen and BDG tests, and they can be used to verify previous results.
Finally, the latest innovation to find application in mycological diagnostic procedures is matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) [70]. This novel technology was launched around 2010 and has lately found great success in the identification of filamentous and yeast-like fungi, utilizing raw samples taken directly from the culture or blood cultures [71]. Although it has yet to find mainstream use due to its initial high acquisition cost and the newly founded fungal databases, many studies indicate its effectiveness in the identification of cryptic and newly emerging fungal species which often tend to display higher minimum inhibitory concentrations (MIC) to antifungal agents. Such strains are often opportunistic or nosocomial and therefore are more dangerous to immunocompromised patients, such as hematological patients. MALDI-TOF MS has the potential to revolutionize phenotypical fungal identification, but until the databases provided with the equipment are up to date with the increasing number of emerging fungal species, it cannot be solely trusted for a proven diagnosis. Therefore, it is advised that it must be used in combination with other identification techniques [72].
4. Epidemiology of IFDs Post-CAR-T Immunotherapy
4.1. Epidemiology of IFDs in Adult Patients
The prevalence of IFDs in adult CAR-T product recipients varies between studies from 0–12%. In several patient cohorts, no IFDs have been identified. In a study of 26 individuals with R/R MM, no fungal infection was developed, with a median follow-up period of 8.9 (3.1–18.1) months; in this patient cohort, 9 out of 26 (34.5%) patients developed CRS, while anti-mold and anti-yeast prophylaxis was administered as well [73]. Additionally, zero IFDs are reported in the first 30 days post-CAR-T therapy in 72 individuals with ALL and non Hodgkin lymphoma (NHL) [22]. No IFDs were reported, moreover, in a cohort of 41 patients with DLBCL (treated with agenlecleucel and oraxicabtagene ciloleucel) in the course of a 30-day follow-up period [74]. In the study of Wittmann Dayagi et al., the prevalence of IFDs was 1.5% and notably no antifungal prophylaxis was administered [75]. Two phase 2 clinical trials, CARTITUDE-1 and CRB-401, did not report any IFDs nor any fungal disease. CARTITUDE-1 was a multicenter trial (16 centers in the USA) with 97 MM patients between July 2018 and October 2019 [76]. CRB-401 was conducted in 33 patients with R/R MM between 2016 and April 2018 [77]. A low prevalence of IFDs was reported in TRANSCEND, a multicenter, multicohort, prospective study at 14 cancer centers in the USA [78]. In a study developed by our group, none of the 19 CAR-T cell recipients developed an IFD [79].
In a single-center retrospective study by Mikkilineni and colleagues, the prevalence of IFDs was 3.3% (2 of 162 patients), and fatal events were reported in a follow-up period of one month [22]. In a different cohort of 99 patients, 3 developed IFDs (2 invasive pulmonary aspergillosis and 1 proven Candida peritonitis) between the first and 100th day after CAR-T cell therapy, while no fungal infections developed after 100 days of follow-up [80]. Additionally, 1 case of fatal aspergillosis (in a patient with hemophagocytic lymphohistiocytosis) was reported among 99 individuals. Data from the JULIET trial showed that 167 patients with DLBCL presented 3 IFDs (2 Candida and 1 Aspergillus), but no data on the clinical outcomes of the infections are available [81]. In the Zuma-1 study (a multicenter trial with patients from the USA and Israel), 108 individuals with DLBCL received axicabtagene ciloleucel [82]. Among those 108, 3 developed IFDs (2 Candida and 1 Aspergillus).
IFD prevalence was 6% (n = 2) in a cohort of 32 patients with R/R MM, while in this study an increased cumulative incidence of IFDs was reported during days 150–180 after the CAR-T cell therapy [83]. Similar data are presented in the results of two retrospective studies of 52 and 55 individuals with R/R MM (prevalence 5.7% and 6%, respectively) [84,85]. Additionally, in the study by Kambhampati et al., the IFDs were observed 120–150 days after CAR-T cell therapy, and the majority of IFDs identified were attributed to Aspergillus fumigatus (in 2 of 3 patients) [85].
The prevalence of IFDs in patient cohorts with ALL varies. In the study of Wang et al., 3 among 76 CAR-T cell recipients developed IFDs [44]. Vora and colleagues conducted a study on 83 young adults (aged ≥ 18 and < 25 years old) and children [24]. In this cohort, 1 IFD (proven pulmonary infection with Cunninghamella) was reported on day 21 post-therapy. In a single-center retrospective study by Czapka et al., 5 among 73 patients with predominantly NHL (97%) developed an IFD, 4 attributed to invasive yeast infections (Candida species) and 1 to an invasive mold infection (pulmonary aspergillosis) [86]. The prevalence was higher in the first 30 days after CAR-T cell therapy, and it was zero one year after the therapy, in a multicenter retrospective analysis of 248 patients with NHL who received CAR-T cell therapies; 24 developed IFDs, and 3 of these patients deceased. The IFDs were predominantly present in patients with high CAR-HEMATOTOX (HT) scores [47]. Baird and colleagues investigated the development of infective complications in 41 patients with DLBCL who received axicabtagene ciloleucel therapy [56]. In this single-center study, 6 IFDs (mostly from Candida species) developed, and the cumulative incidence of these was calculated to be 8.9% in the follow-up period (12 months). The retrospective study developed by Zhu et al. reported a similar prevalence (8.7%) of IFDs in a population of 92 individuals, but in this cohort of patients, the majority were observed during the first 180 days after the CAR-T cellular therapy [87]. In specific patient cohorts, the mortality in patients with IFDs is high (up to 50%), while the majority of the deaths are observed in patients with rapid disease progression [88]. Not all IFDs are presented in the initial 180 days after the CAR-T therapy. For instance, in a patient cohort at Memorial Sloan Kettering Cancer Center the 1-year cumulative incidence was 4.0 (95% CI, 7.0–12.3) vs. 1.7 (95% CI, 0.1–7.9) at 3 months of follow-up [89].
In a population of 39 adults and children (mean age 52) with R/R ALL or NHL, two presented IFDS, one patient presented Candida fungemia, and one patient presented a skin and soft tissue fungal infection due to Aspergillus and Rhizopus [90]. Hill et al. reported 6 IFDs in 4 adults post-CAR-T therapy; all individuals who presented an IFD had severe grade CRS (≥3) [21]. In this study, the IFDs predominantly occurred in the first 28 days after the CAR-T cell therapy (risk ratio (RR) 0.56; 95% confidence interval (CI), 0.33–0.93; P 5.02). Garner et al. reported a 10% prevalence of fungal infections among 103 patients; additionally, 2 out of 10 patients with an IFD deceased due to the infection [51]. In a different cohort of 280 adult patients with NHL, 8 out of 280 developed an IFD [55]. A fact that should not be disregarded is that patients in this retrospective study did not receive any antifungal prophylaxis. Data from NCT04531046 report 2 fatal cases of IFDs: 1 pulmonary mucormycosis in a 74-year-old male with grade 4 CRS and grade 4 ICANS (63 days post-infusion), and 1 bronchopulmonary aspergillosis in a 66-year-old male with grade 1 CRS and grade 3 ICANS (107 post-infusion) [91]. Park et al. reported a 7.5% prevalence of IFDs in a population of 53 individuals with B-ALL, and the onset of the infection was at 23 days post-CAR-T injection (interquartile range (IQR) 20–29 days) [15]. In the retrospective study of Wudhikarn et al., in which 60 patients who underwent CAR-T cell therapy were enrolled, 2 cases of IFDs were reported, with 1-year cumulative incidence of 4.0 (95% CI: 7.0–12.3) [92]. A study by Munshi of 128 patients with MM who received idecabtagene vicleucel reported 11 fungal infections [93]. In a retrospective observational study conducted by Cordeiro et al., the majority of IFDs were late infections (persisted and/or occurred ≥90 days after the therapy) and involved Aspergillus (n = 2), Candida (n = 1), and Coccidioides (n = 1) species [94].
A case series of Haidar and colleagues reported two cases of IFDs [33]. The first patient was a 23-year-old woman with refractory ALL, and she presented with left maxillary invasive fungal sinusitis caused by Fusarium solani. Liposomal amphotericin B, voriconazole, terbinafine, and amphotericin B nasal irrigations were administered, and surgical management was implemented in this patient’s case. The second was a 56-year-old patient with hairy cell leukemia (HCL) left orbital cellulitis and left sphenoid invasive fungal sinusitis caused by invasive mucormycosis with negative cultures; the patient received liposomal amphotericin B, caspofungin, and posaconazole and underwent surgical therapy for the IFD as well. The patient deceased due to the relapse of the HCL. Cheok et al. presented a case of invasive mucormycosis in a 54-year-old patient with relapsed primary central nervous system lymphoma and steroid-induced diabetes [32]. Rhizopus microspores were identified on the microscopy of surgical specimens; the patient received dual antifungal therapy (liposomal amphotericin-B and intravenous isavuconazole), underwent surgical operations, and survived. The findings of the above studies are summarized in Table 1.
Aspergillus spp., Candida spp., and Pneumocystis jirovecii are the cause of almost 90% of IFDs following CAR-T cell therapy, as indicated by large scale database analysis conducted by Sassine J. et al., where 256 patients from a sample of 2256 (11.4%) presented a fungal infection [95]. Amongst those were 175 with a Candida infection, 46 with an Aspergillus infection, and 28 with a Pneumocystis infection. The rest (23) had other infections, caused by Histoplasma (16), Mucormycetes (5), and Cryptococcus (2).
4.2. Epidemiology of IFDs in Pediatric Patients
IFDs have also been recognized as an important infectious complication in pediatric patients who receive CAR-T cell immunotherapy, with a notable impact on morbidity and mortality [96,97]. The risk factors for IFDs in these patients are similar to those in adult populations. Specifically, previous treatment lines of chemotherapy or radiotherapy for the underlying malignancy lead to immunosuppression [98,99]. Especially in children who receive targeted therapies, possible IFDs require individualized clinical monitoring, along with frequent laboratory testing and antifungal prophylaxis in selected cases [29,100]. As confirmed in most studies in pediatric settings, fungal pathogens that cause IFDs can vary. In the most common pathogen species, Candida spp., causing candidemia or invasive candidiasis infections (ICIs) (yeast infections), and Aspergillus spp., causing invasive aspergillosis infections (IAIs) (mold infections), are included [100,101]. ICIs are more frequently reported in pediatric ICUs, while IAIs are mostly observed in children with underlying malignancies [101].
Few studies examining the prevalence and risk factors of IFDs following CAR-T cell infusion in pediatric patients alone have been published. In the clinical trial of Ghorashian et al., 14 patients with ALL were included, and 2 cases of chest IFDs were described [102]. In the aforementioned study of Vora et al., including both pediatric and young adult patients, 1 case of IFD was reported among 83 CAR-T cell recipients with a median age of 12 years (range: 1–25) [24]. In the clinical trial of Maude and colleagues, 75 children were treated with tisagenlecleucel for B-ALL, and a case of fatal mucormycosis was described [103]. In a retrospective study of 79 pediatric patients with B-ALL who received CAR-T cell therapy, 1 fungal infection case was reported (a urinary tract infection caused by Trichosporon asahii) [104]. Maron et al. described two IFD cases among 38 CAR-T cell patients with a median age of 9.06 years (range: 1.8–23.6) [105]. In this study, antifungal prophylaxis with intravenous micafungin, followed by oral voriconazole until neutrophil recovery (ANC ≥ 500 cells/µL for at least 3 consecutive measurements), was given. Diamond et al., in their study, reported 1 case of probable pulmonary aspergillosis out of 27 children who underwent CAR-T cell immunotherapy for B-ALL [106]. Future studies examining the epidemiology of IFDs in pediatric CAR-T patients are of paramount importance, given the lack of data in this population.
The timing of IFDs can vary, given that invasive yeast infections, such as candidiasis, present in the first 30 days after CAR-T therapy, while invasive mold infections can also develop after this period [13]. For the diagnosis of such infections, the classification of proven, probable, and possible cases, as in adult patients, can be used [61]. Nowadays, novel diagnostic tools, such as molecular testing and fungal serum biomarkers, have been found helpful in the diagnosis of IFD cases [99]. The high rates of IFD mortality underline the need for early detection, prompt diagnosis, and immediate management of infections with antifungal agents [99].
5. Antifungal Prophylaxis in CAR-T Cell Recipients
Antifungal prophylaxis, as a strategy, aims to avoid further adverse effects, delays, and/or complications of the underlying disease [107]. Antifungal prophylaxis constitutes a widely used option during and after CAR-T immunotherapy to mitigate the high morbidity and mortality rates that are associated with IFDs, especially in patients with prolonged neutropenia [13,108]. The choice of prophylaxis is still debated, and so antifungals are frequently recommended to be administered after the therapy, depending on the patient’s condition, individualized for each one [33,57,109].
In the determination of this prophylactic strategy, several factors are assessed before the final selection of certain agents. Their safety and efficacy are evaluated and taken into account, always individualized for each patient [33]. Azoles are the antifungal agents with the widest usage both in adult and pediatric populations [60]. Fluconazole represents the first option against yeast infections, like those caused by Candida species, and is administered during periods of neutropenia, while voriconazole and posaconazole are recommended to prevent Aspergillus species [109]. Nowadays, isavuconazole is also suggested as a possible choice and, compared to others, provides several advantages [110]. The adjustment of the dosages is based on the condition of each patient, along with the body weight, mostly in children. Echinocandins are the drugs of second choice for patients unable to tolerate azoles, along with liposomal amphotericin B (LAMB) [111].
Recently published data in patients with hematological malignancies recommended the use of prophylaxis in periods of neutropenia and especially long-lasting neutropenia, independent of the underlying disease [109,112]. However, patients like CAR-T recipients, with a shorter expected duration of neutropenia (ANC < 500 cells/μL for ≤7 days), are not at increased risk of a fungal infection and should not be classified under prophylaxis [109]. In 2022, Little et al. presented their data regarding 280 patients who did not receive prophylaxis after CAR-T cell immunotherapy, and only 8 cases of fungal infections (2.9% of the population) were reported [55]. Of those, 5 patients developed early IFDs (3 IMIs, 2 IYIs) and 3 patients developed late infections with PJP; 4 of these patients died (1.4% of the study population) [55]. In the review of Kampouri et al., published in 2023, the existing guidelines for infection prevention in CAR-T cell therapy recipients were summarized [113]. As antifungal prophylaxis, the European Society for Blood and Marrow Transplantation (EBTM), the European Haematology Association (EHA), and the Société de Greffe de Moelle et de Thérapie cellulaire (SFGM-TC) recommend fluconazole, posaconazole, or micafungin if severe or prolonged neutropenia has a duration of more than 14 days, and/or long-term or high-dose (>3 days) steroids, in post-allo-HCT [113]. Fred Hutch (United States), CHUV Lausanne (Switzerland), and the Spanish group (Spain) suggest the use of fluconazole during neutropenia, while Dana Farber (United States) and LMU Munich (Germany) are against antifungal prophylaxis [113]. Regarding prophylaxis against PJP, all current guidelines from international societies mentioned above consider the administration of trimethoprim–sulfamethoxazole (TMP-SMX) twice daily for 3 days per week or a single dose every day. PJP prophylaxis has to be initiated at lymphodepleting chemotherapy and continue for 1 year until CD4 > 200 cells/mm3 [13,113].
Guidelines about antifungal exposure during CAR-T therapy exist mainly for adult patients since pediatric research is more limited and just characterizes the appropriate use of prophylaxis against viral, bacterial, and fungal pathogens [114]. As a general principle, antifungal prophylaxis is recommended in high-risk patients, but usually pediatric cases follow the guidelines that already exist for adults with several risks, given that there is no specific proof about the safe use of antifungal prophylaxis on this population. Further research into pediatric CAR-T recipients, with a focused interest in the role of antifungal prophylaxis, is needed. In general, for both adult and pediatric settings, research should emphasize individualized recommendations after an initial classification of the patients, based on their epidemiological characteristics, their condition, their risk factors, and treatment endpoints [13,33,57].
6. Management of IFDs in CAR-T Cell Recipients
According to the 8th edition of the EBMT Handbook for Haematopoietic Cell Transplantation and Cellular Therapies, three main strategies are considered when treating an IFD [60]. The first among those is referred to as empirical antifungal therapy and consists of administering broad-spectrum antifungals to neutropenic patients who experience fever for 5 to 7 days after adequate antibacterial coverage. Although this practice is not entirely supported by scientific evidence and most likely leads to increased toxicity and costs, it is favored by centers with limited access to mycological and radiological diagnostic tools. More specifically, the European Conference on Infections in Leukemia (ECIL) recommends the use of caspofungin (50 mg/day following 70 mg on day 1) or liposomal amphotericin B (3 mg/kg).
The second approach, the diagnostic-driven or pre-emptive approach, aims to begin antifungal therapy in high-risk patients upon early positive markers of fungal infection, such as a positive PCR, GM antigen, or BDG test and even indications during CT scanning [115]. A recent study by Maertens et al. illustrates the differences between empirical and diagnostic-driven approaches [116]. The results show that the overall survival for either one of the groups at day 42 and day 84 showed no significant statistical difference. However, there was a significant reduction in the usage of antifungals among the participants of the diagnostic-driven therapy, highlighting its financial benefits over the empirical approach. Lastly, the third approach relies upon the proven or probable diagnosis of IFD and is tailored towards each respective fungi identified.
Regarding IPA, the Infectious Diseases Society of America strongly recommends primary treatment with voriconazole, while equally effective alternative therapies include isavuconazole and liposomal amphotericin B (AmB), see Table 2 [117]. Those should be considered in the case of voriconazole intolerance, drug interactions (such as cyclosporine, tacrolimus, and sirolimus, and other CYP3A4 substrates such as tyrosine kinase inhibitors), prior exposure to broad-spectrum azoles (e.g., prophylaxis), or documented azole resistance. As of the last few years, isavuconazole is considered an equally effective alternative to voriconazole, following the 2017 ECIL recommendations, since it presents similar performance while exhibiting better tolerance and fewer drug interactions [118]. The use of echinocandins and the combination of antifungals as first-line treatment are not recommended. Additionally, the elimination of immunosuppressants (if possible) is recommended in anti-aspergillus therapy, as well as the reduction of corticosteroids, since azoles have been found to increase their levels. Other treatment methods include surgical debridement in easily accessible areas (e.g., in invasive fungal sinusitis or localized cutaneous disease) and granulocyte transfusions for severely neutropenic patients or IPA unlikely to respond to standard therapy. Lastly, therapy should last for at least 6 to 12 months and continue long after the dissipation of initial symptoms. According to the ECIL-6 guidelines, therapeutic drug monitoring for voriconazole (plasma target 1–6 mg/L), isavuconazole (target 2–4 mg/L), and posaconazole (plasma target > 1 mg/L) is strongly recommended, while the testing of Aspergillus GM antigen is a helpful indicator of response to therapy [118].
ICIs and/or candidemia are primarily treated using echinocandins (caspofungin, micafungin, or anidulafungin), as shown in Table 2 [60,118]. Fluconazole is an alternative initial treatment in patients who are not critically ill when fluconazole resistance is considered unlikely. Other treatments include voriconazole and amphotericin B formulations. Following species identification and antifungal susceptibility testing, a step-down approach is recommended and treatment should generally continue for at least two weeks after clearance of Candida and resolution of symptoms. Intravenous catheter removal can be considered for neutropenic patients.
For patients with documented PJP, high doses of trimethoprim/sulfamethoxazole are recommended (Table 2) [119]. The combination of primaquine plus clindamycin is the preferred alternative for patients with documented intolerance to the recommended regimen. Treatment success should be first evaluated after 1 week, and in case of clinical non-response, pulmonary CT scan and bronchoalveolar lavage should be repeated to look for secondary or co-infections. Treatment duration typically is 3 weeks and secondary anti-PCP prophylaxis is indicated in all patients thereafter.
Finally, although mucormycosis is rare in CAR-T cell recipients, it is an infection characterized by its highly destructive nature and rapid development, and therefore treatment should begin immediately upon the confirmation of the disease, following the initial symptoms. The guidelines of the European Confederation of Medical Mycology (ECMM) published in 2019 indicate that surgical debridement with clean margins should be initiated immediately, even if proven destructive to surrounding tissue [120]. Following the debridement, drug treatment should also begin without delay with daily doses of liposomal amphotericin B ranging from 5 mg/kg per day to 10 mg/kg per day. Recipients of increased doses tend to have increased response rates. Alternatives include isavuconazole and posaconazole but should be mostly conserved for salvage treatment. The duration of the therapy has high variability ranging from weeks to months and, in the meantime, antifungal susceptibility testing is recommended to improve the dosage.
7. Conclusions
In the current review the epidemiology of IFDs in CAR-T cell recipients was investigated. IFIDs are regarded as the third most prevalent factor leading to post-immunotherapy infections, with bacterial and viral infections being first and second, respectively. Although bacterial and viral pathogens are much more common than fungi, IFDs are associated with increased mortality and morbidity, especially in cases when diagnosis and treatment are delayed. The prevalence of IFDs has been reported to be low (0–10%) in both pediatric and adult populations. Studies should use the diagnostic criteria of EORTC/MSGERC for the diagnosis and classification of IFDs, to better understand the actual prevalence of these complications. Moreover, more real-world data regarding the role of antifungal prophylaxis in these patients are of paramount importance. Future work should also focus on the estimation of the frequency and cumulative risk of IFDs after CAR-T cell immunotherapy based on the results of published studies.
Conceptualization, P.E. and E.G.; methodology, P.E.; investigation, K.T; writing—original draft preparation, P.E., K.T., A.V. and N.E.; writing—review and editing, P.K., T.-A.V., A.T., M.K. and E.G; visualization, P.E.; supervision, E.G.; project administration, E.G. All authors have read and agreed to the published version of the manuscript.
The authors declare no conflicts of interest.
The following abbreviations are used in this manuscript:
| allo-HCT | Allogeneic HCT |
| AmB liposomal | Amphotericin B |
| ANC | Absolute neutrophil count |
| BAL | Bronchoalveolar lavage |
| B-ALL | B-acute lymphoblastic leukemia |
| BDG | 1,3-β-d-glucan |
| CAR-T | Chimeric antigen receptor-T |
| COVID-19 | Coronavirus disease 2019 |
| CRS | Cytokine release syndrome |
| CSF | Cerebrospinal fluid |
| CT | Computed tomography |
| DLBCL | Diffuse large B cell lymphoma |
| EAPCRI | European Aspergillus PCR Initiative |
| EBMT | European Society for Blood and Marrow Transplantation |
| ECIL | European Conference on Infections in Leukemia |
| EHA | European Haematology Association |
| EORTC/MSGERC | European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium |
| FL | Follicular lymphoma |
| GM | Galactomannan antigen |
| HCT | Hematopoietic cell transplantation |
| HT | |
| IAIs | invasive aspergillosis infections |
| ICANS | Immune effector cell-associated neurotoxicity syndrome |
| ICIs | invasive candidiasis infections |
| ICU | intensive care unit |
| IFD | Invasive fungal disease |
| IL-6 | Interleukin 6 |
| IPA | Invasive Pulmonary Aspergillosis |
| MALDI-TOF MS | Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry |
| MCL | Mantle cell lymphoma |
| MIC | Minimum inhibitory concentrations |
| MM | Multiple myeloma |
| NHL | Non Hodgkin lymphoma |
| PCR | Positive polymerase chain reaction |
| PJP | Pneumocystis jirovecii pneumonia |
| PMBCL | Primary mediastinal large B cell lymphoma |
| R/R | Relapsed/refractory |
| SFGM-TC | Société de Greffe de Moelle et de Thérapie cellulaire |
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Enlarge this image.Figure 1. Risk factors implicated in IFD pathogenesis in CAR-T cell recipients. IFD: invasive fungal disease, CAR-T: chimeric antigen receptor-T, B-ALL: b-acute lymphoblastic leukemia, HCT: hematopoietic cell transplantation, GvHD: graft-versus-host disease, allo-HCT: allogeneic hematopoietic cell transplantation; ICU: intensive care unit, CVC: central venous catheter.
Studies examining the epidemiology of invasive fungal disease in CAR-T cell recipients.
| Reference | Number of Patients (CAR-T Recipients) | Study Design | Study Period | Malignancy, | CRS, | Prevalence of IFDs, N (%) | Mortality, N (%) | Follow-Up Period | Prophylaxis |
|---|---|---|---|---|---|---|---|---|---|
| Gavriilaki et al., 2023 [ | 19 | Retrospective study | 2013 to 2022 | ALL | NR | 0 (0) | Not develpoed IFDs | NR | NR |
| Mohan et al., 2021 [ | 26 | Retrospective study | January 2019 to June 2021 | R/R MM | 9 (34.5) | 0 (0) | 0(0) | 8.9 (3.1–18.1) | Yes |
| Josyula et al., 2022 [ | 32 | Retrospective study | January 2018 to February 2020 | R/R MM | 27 (84.4) | 2 (6) | 1 (33.3) | 180 days | Patients with severe neutropenia received fluconazole |
| Tran et al., 2020 [ | 39 (Adult + peadiatric) | Retrospective study | NR | ALL | 33 (85) | 2 (5.2) | NR | 180 days | Yes |
| Baird et al., 2021 [ | 41 | Retrospective study | September 2017 to March 2019 | DLBCL | Severe CRS (2.4) | 6 (14.6) | 0 (0) | Minimum 1 year | If patient has severe mucositis |
| Logue et al., 2022 [ | 52 | Multicenter retrospective study | May 2021 to December 2021 | R/R MM | 44 (84.7) | 3 (6) | 0 (0) | 90 days | Fluconazole |
| Park et al., 2018 [ | 53 | Phase I clinical trial | May 2010 to August 2016 | R/R B-ALL | 45 (84.9) | 4 (7.5) | 1 (25) | As long as MSKCC lasted | Micagungin |
| Kambhampati et al., 2022 [ | 55 | Retrospective study | 2018 to 2020 | R/R MM | 48 (87) | 3 (6%) | 2 (66%) | Mean 6.0 months (95% CI 4.7–7.4) | In patients with ANC < 500/mm3 |
| Beyar-Katz et al., 2022 [ | 60 | Retrospective study | April 2019 to December 2020 | DLBCL | 44 (73) | 0(0) | 0(0) | 30 days | Fluconazole at ANC < 500/mm3 |
| Wudhikarn et al., 2020 [ | 60 | Retrospective study | January 2018–June 2019 | DLBCL | 48 (80) | 2 (4) | 0(0) | 1 year | Fluconazole |
| Garner et al., 2020 [ | 60 | Retrospective study | July 2017 to May 2021 | NHL | 44 (73) | 10 (10) | 2 (20) | Minimum 6 months | NR |
| Houot et al., 2023 [ | 62 | Open-label, phase 2 clinical trial | March 2021 to May 2022 | DLBCL | 58 (93.5) | NR | 2 | Median 12 months (2.1–17.9 | NR |
| Mikkilineni et al., 2021, | 72 | Retrospective study | 2012 to 2018 | ALL | 129 (79.6) | 0 (0) | 0 (0) | 30 days | Micafungin |
| Czapka et al., 2023 [ | 73 | Retrospective study | Patients received CAR-T prior September 2021 | NHL | 65 (89) | 5 (6.8) | NR | Up to 2 years | Fluconazole or micafungin |
| Wang et al., 2021, | 76 | Retrospective study | April 2015 to September 2020 | ALL | 62 (81.6%) | 3 (8) | NR | NR | NR |
| Vora et al., 2020 [ | 83 | Retrospective study | 2014 to 2017 | ALL | 74 (89) | 1 (1.2) | 0 (0) | 90 days | Fluconazole |
| Logue et al., 2021 [ | 85 | Retrospective study | February 2016 to February | DLBCL | 79 (92.4) | 4 (4.7) | 2 (50) | 360 days | Fluconazole |
| Cordeiro et al., 2020 [ | 86 | Retrospective study | July 2013 to February 2017 | ALL | NR | 4 (4.6) | NR | Median 34 months (18–44) | NR |
| Wittmann Dayagi et al., 2021 [ | 88 | Retrospective study | July 2016 to May 2019 | ALL | 65 (74) | 1 (1.2) | 0 (0) | 60 days | No prophylaxis was administered |
| Zhu et al., 2021 [ | 92 | Retrospective study | July | ALL | 61 (66.3) | 8 (8.7) | NR | Up to 2 years | NR |
| Little et al., 2023 [ | 99 | Retrospective study | November 2016 to May 2022 | R/R MM | 85 (85.9) | 3 (3) | 1 (33.3) | 1 year | Micafungin only for patients with >4 days of neutropenic fever |
| Locke et al., 2021 [ | 108 | Μulticenter, open-label, single-arm, phase 1 and 2 trial | May 2015 to September 2016 | DLBCL | 95 (88) | 3 (2.8) | NR | 40·3 months (IQR 37.8–43.8) | NR |
| Hill et al., 2018 [ | 133 | Phase 1/2 open-label clinical trial | Before September 2016 | ALL | 93 (69.9) | 6 IFDS | 2 (33.3) 1 | Up to 90 days | Fluconazole at ANC < 500/mm3 |
| Mikkilineni et al., 2021 [ | 162 | Single-center retrospective study | 2012 to 2018 | ALL | 129 (79.6) | 2 (3.3) | 0 (0) | 30 days | Yes |
| Schuster et al., 2021 [ | 167 | Μulticenter, open-label, single-arm, phase 2 trial | July 2015 to November 2017 | DLBCL | 66 (39.5) | 3 (1.8) | NR | 40·3 months (IQR 37.8–43.8) | NR |
| Rejeski et al., 2022 [ | 248 | Multicenter retrospective study | May 2018 to June 2021 | NHL | 209 | 24 (96.7) | 3 (12.5%) | 90 days | Fluconazole |
| Abramson et al., 2020 [ | 269 | Multicenter prospective study | January 2016 to July 2019 | DLBCL | 127 (47) | 2 (1) | NR | Median 18.8 (15.0–19.3) months | NR |
| Little et al., 2022 [ | 280 | Retrospective study | December 2017 to September 2021 | NHL | 239 | 8 (2.9) | 1 (12.5) | Median 259 days (7–1340) | No |
CAR-T: Chimeric antigen receptor-T, CRS: Cytokine release syndrome, ICANS: Immune effector cell associated neurotoxicity syndrome, IFD: Invasive fungal infections, R/R: Relapsed/refractory, MM: Multiple myeloma, N/R: Not referred, ALL: Acute lymphoblastic leukemia, NHL: Non-Hodgkin lymphoma, OS/NB: Osteosarcoma/Neuroblastoma, ANC: Absolute neutrophil count, DLBCL: Diffuse large B cell lymphoma, IQR: Interquartile range, CI: Confidence interval. All medians are presented as Median (min-max) and means as Mean (95% CI). 1 Infection was the primary cause of death in a patient with CLL who deceased of pulmonary hemorrhage due to an IFD caused by Aspergillus ustus 90 days post-CAR–T cell infusion. Infection was a contributing factor to death in a neutropenic patient with ALL who had fatal CRS and concurrent severe Clostridium difficile infection.
Antifungal agents for the management of IFDs in patients with hematological malignancies.
| IFD | Antifungal Agent |
|---|---|
| IPA | Voriconazole, Isavuconazole, Liposomal Amphotericin B |
| ICIs and candidemia | Echinocandins, Fluconazole, Voriconazole, Amphotericin B |
| PJP | Trimethoprim/sulfamethoxazole, Primaquine plus clindamycin |
IFD: invasive fungal disease, IPA: invasive pulmonary aspergillosis, ICIs: invasive Candida infections, PJP: Pneumocystis jirovecii pneumonia.
References
1. Mitra, A.; Barua, A.; Huang, L.; Ganguly, S.; Feng, Q.; He, B. From Bench to Bedside: The History and Progress of CAR T Cell Therapy. Front. Immunol.; 2023; 14, 1188049. [DOI: https://dx.doi.org/10.3389/fimmu.2023.1188049] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37256141]
2. Goyco Vera, D.; Waghela, H.; Nuh, M.; Pan, J.; Lulla, P. Approved CAR-T Therapies Have Reproducible Efficacy and Safety in Clinical Practice. Hum. Vaccin. Immunother.; 2024; 20, 2378543. [DOI: https://dx.doi.org/10.1080/21645515.2024.2378543] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39104200]
3. Swan, D.; Madduri, D.; Hocking, J. CAR-T Cell Therapy in Multiple Myeloma: Current Status and Future Challenges. Blood Cancer J.; 2024; 14, 206. [DOI: https://dx.doi.org/10.1038/s41408-024-01191-8]
4. Brudno, J.N.; Kochenderfer, J.N. Recent Advances in CAR T-Cell Toxicity: Mechanisms, Manifestations and Management. Blood Rev.; 2019; 34, pp. 45-55. [DOI: https://dx.doi.org/10.1016/j.blre.2018.11.002]
5. Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant.; 2019; 25, pp. 625-638. [DOI: https://dx.doi.org/10.1016/j.bbmt.2018.12.758] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30592986]
6. Strongyli, E.; Evangelidis, P.; Sakellari, I.; Gavriilaki, M.; Gavriilaki, E. Change in Neurocognitive Function in Patients Who Receive CAR-T Cell Therapies: A Steep Hill to Climb. Pharmaceuticals; 2024; 17, 591. [DOI: https://dx.doi.org/10.3390/ph17050591]
7. Gavriilaki, E.; Sakellari, I.; Gavriilaki, M.; Anagnostopoulos, A. A New Era in Endothelial Injury Syndromes: Toxicity of CAR-T Cells and the Role of Immunity. Int. J. Mol. Sci.; 2020; 21, 3886. [DOI: https://dx.doi.org/10.3390/ijms21113886]
8. Gavriilaki, E.; Demosthenous, C.; Evangelidis, P.; Bousiou, Z.; Batsis, I.; Vardi, A.; Mallouri, D.; Koravou, E.-E.; Spyridis, N.; Panteliadou, A. et al. Soluble Urokinase-Type Plasminogen Activator Receptor (SuPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (SC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients. Int. J. Mol. Sci.; 2024; 25, 11028. [DOI: https://dx.doi.org/10.3390/ijms252011028]
9. Gavriilaki, E.; Mallouri, D.; Bousiou, Z.; Demosthenous, C.; Vardi, A.; Dolgyras, P.; Batsis, I.; Stroggyli, E.; Karvouni, P.; Masmanidou, M. et al. Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience. Cancers; 2023; 15, 4253. [DOI: https://dx.doi.org/10.3390/cancers15174253]
10. Kotch, C.; Barrett, D.; Teachey, D.T. Tocilizumab for the Treatment of Chimeric Antigen Receptor T Cell-Induced Cytokine Release Syndrome. Expert Rev. Clin. Immunol.; 2019; 15, pp. 813-822. [DOI: https://dx.doi.org/10.1080/1744666X.2019.1629904]
11. Rejeski, K.; Perez, A.; Sesques, P.; Hoster, E.; Berger, C.; Jentzsch, L.; Mougiakakos, D.; Frölich, L.; Ackermann, J.; Bücklein, V. et al. CAR-HEMATOTOX: A Model for CAR T-Cell-Related Hematologic Toxicity in Relapsed/Refractory Large B-Cell Lymphoma. Blood; 2021; 138, pp. 2499-2513. [DOI: https://dx.doi.org/10.1182/blood.2020010543] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34166502]
12. Gavriilaki, E.; Tzannou, I.; Batsis, I.; Tsonis, I.; Liga, M.; Gkirkas, K.; Ximeri, M.; Dolgyras, P.; Bampali, V.; Evangelidis, P. et al. EASIX and M-EASIX Predict Severe Cytokine Release Syndrome and Overall Survival After CAR T-Cell Therapy. Blood Vessel. Thromb. Hemost.; 2024; 1, 100025. [DOI: https://dx.doi.org/10.1016/j.bvth.2024.100025]
13. Little, J.S.; Kampouri, E.; Friedman, D.Z.; McCarty, T.; Thompson, G.R.; Kontoyiannis, D.P.; Vazquez, J.; Baddley, J.W.; Hammond, S.P. The Burden of Invasive Fungal Disease Following Chimeric Antigen Receptor T-Cell Therapy and Strategies for Prevention. Open Forum Infect. Dis.; 2024; 11, ofae133. [DOI: https://dx.doi.org/10.1093/ofid/ofae133]
14. Fishman, J.A.; Hogan, J.I.; Maus, M. V Inflammatory and Infectious Syndromes Associated with Cancer Immunotherapies. Clin. Infect. Dis.; 2019; 69, pp. 909-920. [DOI: https://dx.doi.org/10.1093/cid/ciy1025]
15. Park, J.H.; Romero, F.A.; Taur, Y.; Sadelain, M.; Brentjens, R.J.; Hohl, T.M.; Seo, S.K. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated with Chimeric Antigen Receptor T Cells. Clin. Infect. Dis.; 2018; 67, pp. 533-540. [DOI: https://dx.doi.org/10.1093/cid/ciy152] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29481659]
16. Haroon, A.; Muhsen, I.N.; Abid, M.B.; Albabtain, A.; Alahmari, A.; Ahmed, S.O.; Fakih, R.E.; Aljurf, M. Infectious Complications and Preventative Strategies Following Chimeric Antigen Receptor T-Cells (CAR-T Cells) Therapy for B-Cell Malignancies. Hematol. Oncol. Stem Cell Ther.; 2022; 15, pp. 153-158. [DOI: https://dx.doi.org/10.56875/2589-0646.1049] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36633965]
17. Kyriakidis, I.; Vasileiou, E.; Rossig, C.; Roilides, E.; Groll, A.H.; Tragiannidis, A. Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies. J. Fungi; 2021; 7, 186. [DOI: https://dx.doi.org/10.3390/jof7030186]
18. Mercadal, S.; Gomez, C.A.; Lee, C.J.; Couriel, D.R. Infectious Complications Following CAR-t Cell Therapy for B Cell Non-Hodgkin Lymphoma: A Single-Center Experience and Review of the Literature. Ann. Hematol.; 2023; 102, pp. 1837-1843. [DOI: https://dx.doi.org/10.1007/s00277-023-05131-7]
19. Garner, W.; Samanta, P.; Haidar, G. Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions. J. Fungi; 2021; 7, 156. [DOI: https://dx.doi.org/10.3390/jof7020156]
20. Bernardes, M.; Hohl, T.M. Fungal Infections Associated with the Use of Novel Immunotherapeutic Agents. Curr. Clin. Microbiol. Rep.; 2020; 7, pp. 142-149. [DOI: https://dx.doi.org/10.1007/s40588-020-00154-4]
21. Hill, J.A.; Li, D.; Hay, K.A.; Green, M.L.; Cherian, S.; Chen, X.; Riddell, S.R.; Maloney, D.G.; Boeckh, M.; Turtle, C.J. Infectious Complications of CD19-Targeted Chimeric Antigen Receptor-Modified T-Cell Immunotherapy. Blood; 2018; 131, pp. 121-130. [DOI: https://dx.doi.org/10.1182/blood-2017-07-793760]
22. Mikkilineni, L.; Yates, B.; Steinberg, S.M.; Shahani, S.A.; Molina, J.C.; Palmore, T.; Lee, D.W.; Kaplan, R.N.; Mackall, C.L.; Fry, T.J. et al. Infectious Complications of CAR T-Cell Therapy across Novel Antigen Targets in the First 30 Days. Blood Adv.; 2021; 5, pp. 5312-5322. [DOI: https://dx.doi.org/10.1182/bloodadvances.2021004896]
23. O’Reilly, M.A.; Neill, L.; Collin, S.M.; Stone, N.; Springell, D.; Mensah, J.; Cheok, K.P.L.; Jalowiec, K.; Benjamin, R.; Kuhnl, A. et al. High Pretreatment Disease Burden as a Risk Factor for Infectious Complications Following CD19 Chimeric Antigen Receptor T-Cell Therapy for Large B-Cell Lymphoma. Hemasphere; 2024; 8, e29. [DOI: https://dx.doi.org/10.1002/hem3.29]
24. Vora, S.B.; Waghmare, A.; Englund, J.A.; Qu, P.; Gardner, R.A.; Hill, J.A. Infectious Complications Following CD19 Chimeric Antigen Receptor T-Cell Therapy for Children, Adolescents, and Young Adults. Open Forum Infect. Dis.; 2020; 7, ofaa121. [DOI: https://dx.doi.org/10.1093/ofid/ofaa121]
25. Pagano, L.; Busca, A.; Candoni, A.; Cattaneo, C.; Cesaro, S.; Fanci, R.; Nadali, G.; Potenza, L.; Russo, D.; Tumbarello, M. et al. Risk Stratification for Invasive Fungal Infections in Patients with Hematological Malignancies: SEIFEM Recommendations. Blood Rev.; 2017; 31, pp. 17-29. [DOI: https://dx.doi.org/10.1016/j.blre.2016.09.002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27682882]
26. Lewis, R.E.; Kontoyiannis, D.P. Chimeric Antigen Receptor T-Cell Immunotherapy and Need for Prophylaxis for Invasive Mold Infections. Clin. Infect. Dis.; 2020; 71, pp. 1802-1803. [DOI: https://dx.doi.org/10.1093/cid/ciaa031]
27. Alexoudi, V.-A.; Gavriilaki, E.; Cheva, A.; Sakellari, I.; Papadopoulou, S.; Paraskevopoulos, K.; Vahtsevanos, K. Graft-Versus-Host Disease: Can Biomarkers Assist in Differential Diagnosis, Prognosis, and Therapeutic Strategy?. Pharmaceuticals; 2024; 17, 298. [DOI: https://dx.doi.org/10.3390/ph17030298] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38543084]
28. Chamilos, G.; Lionakis, M.S.; Kontoyiannis, D.P. Call for Action: Invasive Fungal Infections Associated with Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin. Infect. Dis.; 2018; 66, pp. 140-148. [DOI: https://dx.doi.org/10.1093/cid/cix687]
29. Kyriakidis, I.; Mantadakis, E.; Stiakaki, E.; Groll, A.H.; Tragiannidis, A. Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas. Cancers; 2022; 14, 5022. [DOI: https://dx.doi.org/10.3390/cancers14205022]
30. Chakrabarti, A.; Das, A.; Mandal, J.; Shivaprakash, M.R.; George, V.K.; Tarai, B.; Rao, P.; Panda, N.; Verma, S.C.; Sakhuja, V. The Rising Trend of Invasive Zygomycosis in Patients with Uncontrolled Diabetes Mellitus. Med. Mycol.; 2006; 44, pp. 335-342. [DOI: https://dx.doi.org/10.1080/13693780500464930]
31. Prakash, H.; Chakrabarti, A. Global Epidemiology of Mucormycosis. J. Fungi; 2019; 5, 26. [DOI: https://dx.doi.org/10.3390/jof5010026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30901907]
32. Cheok, K.P.L.; Farrow, A.; Springell, D.; O’Reilly, M.; Morley, S.; Stone, N.; Roddie, C. Mucormycosis after CD19 Chimeric Antigen Receptor T-Cell Therapy: Results of a US Food and Drug Administration Adverse Events Reporting System Analysis and a Review of the Literature. Lancet Infect. Dis.; 2024; 24, pp. e256-e265. [DOI: https://dx.doi.org/10.1016/S1473-3099(23)00563-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38310904]
33. Haidar, G.; Dorritie, K.; Farah, R.; Bogdanovich, T.; Nguyen, M.H.; Samanta, P. Invasive Mold Infections After Chimeric Antigen Receptor–Modified T-Cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis. Clin. Infect. Dis.; 2020; 71, pp. 672-676. [DOI: https://dx.doi.org/10.1093/cid/ciz1127]
34. Gao, Z.; Lian, Y.; Ti, J.; Ren, R.; Ma, L. Therapeutic Efficacy and Infectious Complications of CD19-Targeted Chimeric Antigen Receptor-Modified T Cell Immunotherapy. Anticancer Drugs; 2023; 34, pp. 551-557. [DOI: https://dx.doi.org/10.1097/CAD.0000000000001485]
35. Evangelidis, P.; Evangelidis, N.; Kalmoukos, P.; Kourti, M.; Tragiannidis, A.; Gavriilaki, E. Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill. Curr. Issues Mol. Biol.; 2024; 46, pp. 4787-4802. [DOI: https://dx.doi.org/10.3390/cimb46050288]
36. Santomasso, B.D.; Nastoupil, L.J.; Adkins, S.; Lacchetti, C.; Schneider, B.J.; Anadkat, M.; Atkins, M.B.; Brassil, K.J.; Caterino, J.M.; Chau, I. et al. Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. J. Clin. Oncol.; 2021; 39, pp. 3978-3992. [DOI: https://dx.doi.org/10.1200/JCO.21.01992]
37. Major, A.; Collins, J.; Craney, C.; Heitman, A.K.; Bauer, E.; Zerante, E.; Stock, W.; Bishop, M.R.; Jasielec, J. Management of Hemophagocytic Lymphohistiocytosis (HLH) Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy Using Anti-Cytokine Therapy: An Illustrative Case and Review of the Literature. Leuk. Lymphoma; 2021; 62, pp. 1765-1769. [DOI: https://dx.doi.org/10.1080/10428194.2021.1881507]
38. Hines, M.R.; Knight, T.E.; McNerney, K.O.; Leick, M.B.; Jain, T.; Ahmed, S.; Frigault, M.J.; Hill, J.A.; Jain, M.D.; Johnson, W.T. et al. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant. Cell. Ther.; 2023; 29, pp. 438.e1-438.e16. [DOI: https://dx.doi.org/10.1016/j.jtct.2023.03.006]
39. Lamoth, F.; Glampedakis, E.; Boillat-Blanco, N.; Oddo, M.; Pagani, J.-L. Incidence of Invasive Pulmonary Aspergillosis Among Critically Ill COVID-19 Patients. Clin. Microbiol. Infect.; 2020; 26, pp. 1706-1708. [DOI: https://dx.doi.org/10.1016/j.cmi.2020.07.010]
40. Baddley, J.W.; Stephens, J.M.; Ji, X.; Gao, X.; Schlamm, H.T.; Tarallo, M. Aspergillosis in Intensive Care Unit (ICU) Patients: Epidemiology and Economic Outcomes. BMC Infect. Dis.; 2013; 13, 29. [DOI: https://dx.doi.org/10.1186/1471-2334-13-29]
41. Minihan, B.; McAuliffe, E.; Powell, J.; Wong, S.L.; Wilkie, K.; Murphy, C.; Maher, A.; Power, L.; O’Connell, N.H.; Dunne, C.P. Association Between Tocilizumab Treatment of Hyperinflammatory Patients with COVID-19 in a Critical Care Setting and Elevated Incidence of Hospital-Acquired Bacterial and Invasive Fungal Infections. J. Hosp. Infect.; 2022; 126, pp. 29-36. [DOI: https://dx.doi.org/10.1016/j.jhin.2022.04.007] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35472487]
42. Burger, B.J.; Epps, S.M.; Cardenas, V.M.; Jagana, R.; Meena, N.K.; Atchley, W.T. Tocilizumab Is Associated with Increased Risk of Fungal Infections Among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study. Life; 2023; 13, 1752. [DOI: https://dx.doi.org/10.3390/life13081752]
43. Fried, S.; Avigdor, A.; Bielorai, B.; Meir, A.; Besser, M.J.; Schachter, J.; Shimoni, A.; Nagler, A.; Toren, A.; Jacoby, E. Early and Late Hematologic Toxicity Following CD19 CAR-T Cells. Bone Marrow Transplant.; 2019; 54, pp. 1643-1650. [DOI: https://dx.doi.org/10.1038/s41409-019-0487-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30809033]
44. Wang, L.; Hong, R.; Zhou, L.; Ni, F.; Zhang, M.; Zhao, H.; Wu, W.; Wang, Y.; Ding, S.; Chang, A.H. et al. New-Onset Severe Cytopenia After CAR-T Cell Therapy: Analysis of 76 Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia. Front. Oncol.; 2021; 11, 702644. [DOI: https://dx.doi.org/10.3389/fonc.2021.702644] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34277448]
45. Thakkar, A.; Cui, Z.; Peeke, S.Z.; Shah, N.; Pradhan, K.; Lombardo, A.; Khatun, F.; Mustafa, J.; De Castro, A.; Gillick, K. et al. Patterns of Leukocyte Recovery Predict Infectious Complications after CD19 CAR-T Cell Therapy in a Real-World Setting. Stem Cell Investig.; 2021; 8, 18. [DOI: https://dx.doi.org/10.21037/sci-2021-008]
46. Juluri, K.R.; Wu, Q.V.; Voutsinas, J.; Hou, J.; Hirayama, A.V.; Mullane, E.; Miles, N.; Maloney, D.G.; Turtle, C.J.; Bar, M. et al. Severe Cytokine Release Syndrome Is Associated with Hematologic Toxicity Following CD19 CAR T-Cell Therapy. Blood Adv.; 2022; 6, pp. 2055-2068. [DOI: https://dx.doi.org/10.1182/bloodadvances.2020004142]
47. Rejeski, K.; Perez, A.; Iacoboni, G.; Penack, O.; Bücklein, V.; Jentzsch, L.; Mougiakakos, D.; Johnson, G.; Arciola, B.; Carpio, C. et al. The CAR-HEMATOTOX Risk-Stratifies Patients for Severe Infections and Disease Progression after CD19 CAR-T in R/R LBCL. J. Immunother. Cancer; 2022; 10, e004475. [DOI: https://dx.doi.org/10.1136/jitc-2021-004475]
48. Li, X.; Deng, Q.; Henderson, J.; Watson, G.; Deaton, L.; Cain, T.; Fayad, L.; Iyer, S.P.; Hagemeister, F.B.; Nastoupil, L.J. et al. Targetable Cellular Etiology of Prolonged Cytopenia Following CD19 CAR T-Cell Therapy. Blood; 2022; 140, pp. 4502-4503. [DOI: https://dx.doi.org/10.1182/blood-2022-166308]
49. Cornely, O.A.; Maertens, J.; Winston, D.J.; Perfect, J.; Ullmann, A.J.; Walsh, T.J.; Helfgott, D.; Holowiecki, J.; Stockelberg, D.; Goh, Y.-T. et al. Posaconazole vs. Fluconazole or Itraconazole Prophylaxis in Patients with Neutropenia. N. Engl. J. Med.; 2007; 356, pp. 348-359. [DOI: https://dx.doi.org/10.1056/NEJMoa061094]
50. Walsh, T.J.; Gamaletsou, M.N. Treatment of Fungal Disease in the Setting of Neutropenia. Hematol. Am. Soc. Hematol. Educ. Program; 2013; 2013, pp. 423-427. [DOI: https://dx.doi.org/10.1182/asheducation-2013.1.423]
51. Garner, W.; Samanta, P.; Dorritie, K.; Sehgal, A.; Winfield, D.; Agha, M.; Boudreau, R.; Nguyen, M.H.T.; Haidar, G. 1105. The Burden of Infections Prior to Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Predicts Post-CAR T-Cell Infectious Complications. Open Forum Infect. Dis.; 2020; 7, S583. [DOI: https://dx.doi.org/10.1093/ofid/ofaa439.1291]
52. Rejeski, K.; Subklewe, M.; Locke, F.L. Recognizing, Defining, and Managing CAR-T Hematologic Toxicities. Hematol. Am. Soc. Hematol. Educ. Program; 2023; 2023, pp. 198-208. [DOI: https://dx.doi.org/10.1182/hematology.2023000472] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38066881]
53. Rejeski, K.; Jain, M.D.; Shah, N.N.; Perales, M.-A.; Subklewe, M. Immune Effector Cell-Associated Haematotoxicity after CAR T-Cell Therapy: From Mechanism to Management. Lancet Haematol.; 2024; 11, pp. e459-e470. [DOI: https://dx.doi.org/10.1016/S2352-3026(24)00077-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38734026]
54. Jain, T.; Olson, T.S.; Locke, F.L. How I Treat Cytopenias After CAR T-Cell Therapy. Blood; 2023; 141, pp. 2460-2469. [DOI: https://dx.doi.org/10.1182/blood.2022017415]
55. Little, J.S.; Aleissa, M.M.; Beluch, K.; Gonzalez-Bocco, I.H.; Marty, F.M.; Manne-Goehler, J.; Koo, S.; Hammond, S.P.; Jacobson, C.A. Low Incidence of Invasive Fungal Disease Following CD19 Chimeric Antigen Receptor T-Cell Therapy for Non-Hodgkin Lymphoma. Blood Adv.; 2022; 6, pp. 4821-4830. [DOI: https://dx.doi.org/10.1182/bloodadvances.2022007474]
56. Baird, J.H.; Epstein, D.J.; Tamaresis, J.S.; Ehlinger, Z.; Spiegel, J.Y.; Craig, J.; Claire, G.K.; Frank, M.J.; Muffly, L.; Shiraz, P. et al. Immune Reconstitution and Infectious Complications Following Axicabtagene Ciloleucel Therapy for Large B-Cell Lymphoma. Blood Adv.; 2021; 5, pp. 143-155. [DOI: https://dx.doi.org/10.1182/bloodadvances.2020002732]
57. Little, J.S.; Weiss, Z.F.; Hammond, S.P. Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies. J. Fungi; 2021; 7, 1058. [DOI: https://dx.doi.org/10.3390/jof7121058]
58. Zahid, U.; Shaukat, A.-A.; Hassan, N.; Anwer, F. Coccidioidomycosis, Immunoglobulin Deficiency: Safety Challenges with CAR T Cells Therapy for Relapsed Lymphoma. Immunotherapy; 2017; 9, pp. 1061-1066. [DOI: https://dx.doi.org/10.2217/imt-2017-0070]
59. Reynolds, G.; Sim, B.; Anderson, M.A.; Spelman, T.; Teh, B.W.; Slavin, M.A.; Thursky, K.A. Predicting Infections in Patients with Haematological Malignancies Treated with Chimeric Antigen Receptor T-Cell Therapies: A Systematic Scoping Review and Narrative Synthesis. Clin. Microbiol. Infect.; 2023; 29, pp. 1280-1288. [DOI: https://dx.doi.org/10.1016/j.cmi.2023.05.011]
60. Maertens, J.A. Invasive Fungal Diseases. The EBMT Handbook; Springer International Publishing: Cham, Switzerland, 2024; pp. 321-329.
61. Donnelly, J.P.; Chen, S.C.; Kauffman, C.A.; Steinbach, W.J.; Baddley, J.W.; Verweij, P.E.; Clancy, C.J.; Wingard, J.R.; Lockhart, S.R.; Groll, A.H. et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin. Infect. Dis.; 2020; 71, pp. 1367-1376. [DOI: https://dx.doi.org/10.1093/cid/ciz1008]
62. Mendonça, A.; Santos, H.; Franco-Duarte, R.; Sampaio, P. Fungal Infections Diagnosis—Past, Present and Future. Res. Microbiol.; 2022; 173, 103915. [DOI: https://dx.doi.org/10.1016/j.resmic.2021.103915] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34863883]
63. Schuetz, A.N. Invasive Fungal Infections. Clin. Lab. Med.; 2013; 33, pp. 505-525. [DOI: https://dx.doi.org/10.1016/j.cll.2013.03.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23931836]
64. Theel, E.S.; Doern, C.D. β-D-Glucan Testing Is Important for Diagnosis of Invasive Fungal Infections. J. Clin. Microbiol.; 2013; 51, pp. 3478-3483. [DOI: https://dx.doi.org/10.1128/JCM.01737-13]
65. He, S.; Hang, J.-P.; Zhang, L.; Wang, F.; Zhang, D.-C.; Gong, F.-H. A Systematic Review and Meta-Analysis of Diagnostic Accuracy of Serum 1,3-β-d-Glucan for Invasive Fungal Infection: Focus on Cutoff Levels. J. Microbiol. Immunol. Infect.; 2015; 48, pp. 351-361. [DOI: https://dx.doi.org/10.1016/j.jmii.2014.06.009]
66. Ricci, E.; Bartalucci, C.; Russo, C.; Mariani, M.; Saffioti, C.; Massaccesi, E.; Pierri, F.; Brisca, G.; Moscatelli, A.; Caorsi, R. et al. Clinical and Radiological Features of Pneumocystis Jirovecii Pneumonia in Children: A Case Series. J. Fungi; 2024; 10, 276. [DOI: https://dx.doi.org/10.3390/jof10040276]
67. Chotiprasitsakul, D.; Pewloungsawat, P.; Setthaudom, C.; Santanirand, P.; Pornsuriyasak, P. Performance of Real-Time PCR and Immunofluorescence Assay for Diagnosis of Pneumocystis Pneumonia in Real-World Clinical Practice. PLoS ONE; 2020; 15, e0244023. [DOI: https://dx.doi.org/10.1371/journal.pone.0244023]
68. Greene, R. The Radiological Spectrum of Pulmonary Aspergillosis. Med. Mycol.; 2005; 43, pp. 147-154. [DOI: https://dx.doi.org/10.1080/13693780500064771]
69. White, P.L.; Barnes, R.A.; Springer, J.; Klingspor, L.; Cuenca-Estrella, M.; Morton, C.O.; Lagrou, K.; Bretagne, S.; Melchers, W.J.G.; Mengoli, C. et al. Clinical Performance of Aspergillus PCR for Testing Serum and Plasma: A Study by the European Aspergillus PCR Initiative. J. Clin. Microbiol.; 2015; 53, pp. 2832-2837. [DOI: https://dx.doi.org/10.1128/JCM.00905-15]
70. Santos, C.R.; Francisco, E.; Mazza, M.; Padovan, A.C.B.; Colombo, A.; Lima, N. Impact of MALDI-TOF MS in Clinical Mycology; Progress and Barriers in Diagnostics. MALDI-TOF and Tandem MS for Clinical Microbiology; John Wiley & Sons Ltd.: Hoboken, NJ, USA, 2017; pp. 211-230.
71. Identification of Molds Using MALDI-TOF. Available online: https://www.cdc.gov/fungal/hcp/laboratories/identification-of-molds-using-maldi-tof.html (accessed on 4 January 2025).
72. Lau, A.F. Matrix-Assisted Laser Desorption Ionization Time-of-Flight for Fungal Identification. Clin. Lab. Med.; 2021; 41, pp. 267-283. [DOI: https://dx.doi.org/10.1016/j.cll.2021.03.006]
73. Mohan, M.; Nagavally, S.; Dhakal, B.; Radhakrishnan, S.V.; Chhabra, S.; D’Souza, A.; Hari, P. Risk of Infections with B-Cell Maturation Antigen-Directed Immunotherapy in Multiple Myeloma. Blood Adv.; 2022; 6, pp. 2466-2470. [DOI: https://dx.doi.org/10.1182/bloodadvances.2021006178]
74. Beyar-Katz, O.; Kikozashvili, N.; Bar On, Y.; Amit, O.; Perry, C.; Avivi, I.; Gold, R.; Herishanu, Y.; Benyamini, N.; Duek, A. et al. Characteristics and Recognition of Early Infections in Patients Treated with Commercial Anti-CD19 CAR-T Cells. Eur. J. Haematol.; 2022; 108, pp. 52-60. [DOI: https://dx.doi.org/10.1111/ejh.13712] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34564876]
75. Wittmann Dayagi, T.; Sherman, G.; Bielorai, B.; Adam, E.; Besser, M.J.; Shimoni, A.; Nagler, A.; Toren, A.; Jacoby, E.; Avigdor, A. Characteristics and Risk Factors of Infections Following CD28-Based CD19 CAR-T Cells. Leuk. Lymphoma; 2021; 62, pp. 1692-1701. [DOI: https://dx.doi.org/10.1080/10428194.2021.1881506] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33563059]
76. Berdeja, J.G.; Madduri, D.; Usmani, S.Z.; Jakubowiak, A.; Agha, M.; Cohen, A.D.; Stewart, A.K.; Hari, P.; Htut, M.; Lesokhin, A. et al. Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma (CARTITUDE-1): A Phase 1b/2 Open-Label Study. Lancet; 2021; 398, pp. 314-324. [DOI: https://dx.doi.org/10.1016/S0140-6736(21)00933-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34175021]
77. Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A. et al. Anti-BCMA CAR T-Cell Therapy Bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med.; 2019; 380, pp. 1726-1737. [DOI: https://dx.doi.org/10.1056/NEJMoa1817226] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31042825]
78. Abramson, J.S.; Palomba, M.L.; Gordon, L.I.; Lunning, M.A.; Wang, M.; Arnason, J.; Mehta, A.; Purev, E.; Maloney, D.G.; Andreadis, C. et al. Lisocabtagene Maraleucel for Patients with Relapsed or Refractory Large B-Cell Lymphomas (TRANSCEND NHL 001): A Multicentre Seamless Design Study. Lancet; 2020; 396, pp. 839-852. [DOI: https://dx.doi.org/10.1016/S0140-6736(20)31366-0]
79. Gavriilaki, E.; Dolgyras, P.; Dimou-Mpesikli, S.; Poulopoulou, A.; Evangelidis, P.; Evangelidis, N.; Demosthenous, C.; Zachrou, E.; Siasios, P.; Mallouri, D. et al. Risk Factors, Prevalence, and Outcomes of Invasive Fungal Disease Post Hematopoietic Cell Transplantation and Cellular Therapies: A Retrospective Monocenter Real-Life Analysis. Cancers; 2023; 15, 3529. [DOI: https://dx.doi.org/10.3390/cancers15133529]
80. Little, J.S.; Tandon, M.; Hong, J.S.; Nadeem, O.; Sperling, A.S.; Raje, N.; Munshi, N.; Frigault, M.; Barmettler, S.; Hammond, S.P. Respiratory Infections Predominate after Day 100 Following B-Cell Maturation Antigen-Directed CAR T-Cell Therapy. Blood Adv.; 2023; 7, pp. 5485-5495. [DOI: https://dx.doi.org/10.1182/bloodadvances.2023010524]
81. Schuster, S.J.; Tam, C.S.; Borchmann, P.; Worel, N.; McGuirk, J.P.; Holte, H.; Waller, E.K.; Jaglowski, S.; Bishop, M.R.; Damon, L.E. et al. Long-Term Clinical Outcomes of Tisagenlecleucel in Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas (JULIET): A Multicentre, Open-Label, Single-Arm, Phase 2 Study. Lancet Oncol.; 2021; 22, pp. 1403-1415. [DOI: https://dx.doi.org/10.1016/S1470-2045(21)00375-2]
82. Locke, F.L.; Ghobadi, A.; Jacobson, C.A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Braunschweig, I.; Hill, B.T.; Timmerman, J.M. et al. Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma (ZUMA-1): A Single-Arm, Multicentre, Phase 1-2 Trial. Lancet Oncol.; 2019; 20, pp. 31-42. [DOI: https://dx.doi.org/10.1016/S1470-2045(18)30864-7]
83. Josyula, S.; Pont, M.J.; Dasgupta, S.; Song, X.; Thomas, S.; Pepper, G.; Keane-Candib, J.; Stevens-Ayers, T.L.; Ochs, H.D.; Boeckh, M.J. et al. Pathogen-Specific Humoral Immunity and Infections in B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Recipients with Multiple Myeloma. Transplant. Cell. Ther.; 2022; 28, pp. 304.e1-304.e9. [DOI: https://dx.doi.org/10.1016/j.jtct.2022.03.005]
84. Logue, J.M.; Peres, L.C.; Hashmi, H.; Colin-Leitzinger, C.M.; Shrewsbury, A.M.; Hosoya, H.; Gonzalez, R.M.; Copponex, C.; Kottra, K.H.; Hovanky, V. et al. Early Cytopenias and Infections after Standard of Care Idecabtagene Vicleucel in Relapsed or Refractory Multiple Myeloma. Blood Adv.; 2022; 6, pp. 6109-6119. [DOI: https://dx.doi.org/10.1182/bloodadvances.2022008320] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35939783]
85. Kambhampati, S.; Sheng, Y.; Huang, C.-Y.; Bylsma, S.; Lo, M.; Kennedy, V.; Natsuhara, K.; Martin, T.; Wolf, J.; Shah, N. et al. Infectious Complications in Patients with Relapsed Refractory Multiple Myeloma After BCMA CAR T-Cell Therapy. Blood Adv.; 2022; 6, pp. 2045-2054. [DOI: https://dx.doi.org/10.1182/bloodadvances.2020004079] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34543400]
86. Czapka, M.T.; Riedell, P.A.; Pisano, J.C. Infectious Complications of Car T-Cell Therapy: A Longitudinal Risk Model. Transpl. Infect. Dis.; 2023; 25, (Suppl. 1), e14148. [DOI: https://dx.doi.org/10.1111/tid.14148] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37695203]
87. Zhu, F.; Wei, G.; Liu, Y.; Zhou, H.; Wu, W.; Yang, L.; Huang, H.; Hu, Y. Incidence and Risk Factors Associated with Infection after Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory B-Cell Malignancies. Cell Transplant.; 2021; 30, 9636897211025504. [DOI: https://dx.doi.org/10.1177/09636897211025503] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34144648]
88. Logue, J.M.; Zucchetti, E.; Bachmeier, C.A.; Krivenko, G.S.; Larson, V.; Ninh, D.; Grillo, G.; Cao, B.; Kim, J.; Chavez, J.C. et al. Immune Reconstitution and Associated Infections Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma. Haematologica; 2021; 106, pp. 978-986. [DOI: https://dx.doi.org/10.3324/haematol.2019.238634]
89. Wudhikarn, K.; Pennisi, M.; Garcia-Recio, M.; Flynn, J.R.; Afuye, A.; Silverberg, M.L.; Maloy, M.A.; Devlin, S.M.; Batlevi, C.L.; Shah, G.L. et al. DLBCL Patients Treated with CD19 CAR T Cells Experience a High Burden of Organ Toxicities but Low Nonrelapse Mortality. Blood Adv.; 2020; 4, pp. 3024-3033. [DOI: https://dx.doi.org/10.1182/bloodadvances.2020001972]
90. Tran, N.; Eschenauer, G.; Scappaticci, G.; Frame, D.; Miceli, M.H.; Patel, T.S. 578. Infections in Patients Treated with Chimeric Antigen Receptor T-Cells (CAR-T) Therapy. Open Forum Infect. Dis.; 2020; 7, S354. [DOI: https://dx.doi.org/10.1093/ofid/ofaa439.772]
91. Houot, R.; Bachy, E.; Cartron, G.; Gros, F.-X.; Morschhauser, F.; Oberic, L.; Gastinne, T.; Feugier, P.; Duléry, R.; Thieblemont, C. et al. Axicabtagene Ciloleucel as Second-Line Therapy in Large B Cell Lymphoma Ineligible for Autologous Stem Cell Transplantation: A Phase 2 Trial. Nat. Med.; 2023; 29, pp. 2593-2601. [DOI: https://dx.doi.org/10.1038/s41591-023-02572-5]
92. Wudhikarn, K.; Palomba, M.L.; Pennisi, M.; Garcia-Recio, M.; Flynn, J.R.; Devlin, S.M.; Afuye, A.; Silverberg, M.L.; Maloy, M.A.; Shah, G.L. et al. Infection During the First Year in Patients Treated with CD19 CAR T Cells for Diffuse Large B Cell Lymphoma. Blood Cancer J.; 2020; 10, 79. [DOI: https://dx.doi.org/10.1038/s41408-020-00346-7]
93. Munshi, N.C.; Anderson, L.D.; Shah, N.; Madduri, D.; Berdeja, J.; Lonial, S.; Raje, N.; Lin, Y.; Siegel, D.; Oriol, A. et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med.; 2021; 384, pp. 705-716. [DOI: https://dx.doi.org/10.1056/NEJMoa2024850]
94. Cordeiro, A.; Bezerra, E.D.; Hirayama, A.V.; Hill, J.A.; Wu, Q.V.; Voutsinas, J.; Sorror, M.L.; Turtle, C.J.; Maloney, D.G.; Bar, M. Late Events After Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol. Blood Marrow Transplant.; 2020; 26, pp. 26-33. [DOI: https://dx.doi.org/10.1016/j.bbmt.2019.08.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31419568]
95. Sassine, J.; Agudelo Higuita, N.I.; Siegrist, E.A.; Saeedi, A.; Corbisiero, M.F.; Connelly, P.; Bastias, A.G.; Dib, R.W.; Henao-Cordero, J.; Chastain, D.B. et al. Timeline and Outcomes of Viral and Fungal Infections after Chimeric Antigen Receptor T-Cell Therapy: A Large Database Analysis. Clin. Microbiol. Infect.; 2024; in press [DOI: https://dx.doi.org/10.1016/j.cmi.2024.11.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/39528086]
96. Brissaud, O.; Guichoux, J.; Harambat, J.; Tandonnet, O.; Zaoutis, T. Invasive Fungal Disease in PICU: Epidemiology and Risk Factors. Ann. Intensive Care; 2012; 2, 6. [DOI: https://dx.doi.org/10.1186/2110-5820-2-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22356683]
97. Lehrnbecher, T. Antifungal Prophylaxis in Pediatric Patients Undergoing Therapy for Cancer. Curr. Opin. Infect. Dis.; 2015; 28, pp. 523-531. [DOI: https://dx.doi.org/10.1097/QCO.0000000000000210]
98. Petrikkos, L.; Kourti, M.; Antoniadi, K.; Tziola, T.-S.; Sfetsiori, A.-E.; Antari, V.; Savoukidou, S.; Avgerinou, G.; Filippidou, M.; Papakonstantinou, E. et al. Central Nervous System Fungal Diseases in Children with Malignancies: A 16-Year Study from the Infection Working Group of the Hellenic Society of Pediatric Hematology Oncology. J. Fungi; 2024; 10, 654. [DOI: https://dx.doi.org/10.3390/jof10090654]
99. Tragiannidis, A.; Kattamis, A.; Vyzantiadis, T.-A. Invasive Fungal Infections in Children with Haematological Malignancies: Diagnostic and Therapeutic Challenges. J. Fungi; 2021; 7, 516. [DOI: https://dx.doi.org/10.3390/jof7070516]
100. Hon, K.L.E.; Chan, V.P.; Leung, A.K.; Leung, K.K.Y.; Hui, W.F. Invasive Fungal Infections in Critically Ill Children: Epidemiology, Risk Factors and Antifungal Drugs. Drugs Context; 2024; 13, pp. 1-16. [DOI: https://dx.doi.org/10.7573/dic.2023-9-2]
101. Pana, Z.D.; Roilides, E.; Warris, A.; Groll, A.H.; Zaoutis, T. Epidemiology of Invasive Fungal Disease in Children. J. Pediatric. Infect. Dis. Soc.; 2017; 6, pp. S3-S11. [DOI: https://dx.doi.org/10.1093/jpids/pix046]
102. Ghorashian, S.; Kramer, A.M.; Onuoha, S.; Wright, G.; Bartram, J.; Richardson, R.; Albon, S.J.; Casanovas-Company, J.; Castro, F.; Popova, B. et al. Enhanced CAR T Cell Expansion and Prolonged Persistence in Pediatric Patients with ALL Treated with a Low-Affinity CD19 CAR. Nat. Med.; 2019; 25, pp. 1408-1414. [DOI: https://dx.doi.org/10.1038/s41591-019-0549-5]
103. Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D. et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med.; 2018; 378, pp. 439-448. [DOI: https://dx.doi.org/10.1056/NEJMoa1709866]
104. Wu, X.; Cao, Z.; Chen, Z.; Wang, Y.; He, H.; Xiao, P.; Hu, S.; Lu, J.; Li, B. Infectious Complications in Pediatric Patients Undergoing CD19+CD22+ Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory B-Lymphoblastic Leukemia. Clin. Exp. Med.; 2024; 24, 87. [DOI: https://dx.doi.org/10.1007/s10238-024-01339-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38662121]
105. Maron, G.M.; Hijano, D.R.; Epperly, R.; Su, Y.; Tang, L.; Hayden, R.T.; Naik, S.; Karol, S.E.; Gottschalk, S.; Triplett, B.M. et al. Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy. Front. Oncol.; 2022; 12, 845540. [DOI: https://dx.doi.org/10.3389/fonc.2022.845540] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35356197]
106. Diamond, Y.; Gilsenan, M.; Wang, S.S.; Hanna, D.; Conyers, R.; Cole, T.; Hughes, D.; Fleming, J.; Meyran, D.; Toro, C. et al. Infections in Children Following Chimeric Antigen Receptor T-cell Therapy for B-cell Acute Lymphoblastic Leukemia. Transpl. Infect. Dis.; 2023; 25, e14202. [DOI: https://dx.doi.org/10.1111/tid.14202] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38041799]
107. Young, J.-A.H.; Andes, D.R.; Ardura, M.I.; Arrieta, A.; Bow, E.J.; Chandrasekar, P.H.; Chen, S.C.A.; Hammond, S.P.; Husain, S.; Koo, S. et al. Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies. Open Forum Infect. Dis.; 2024; 11, ofae082. [DOI: https://dx.doi.org/10.1093/ofid/ofae082]
108. Pennese, E.; Salutari, P.; Carriero, L.; Restuccia, F.; De Filippis, A.F.; De Luca, G.; Giancola, R.; Guardalupi, F.; Corradi, G.; Fabi, B. et al. Case Report: Invasive Fungal Infection after Anti-CD19 CAR-T Cell Therapy. Implication for Antifungal Prophylaxis. Front. Immunol.; 2023; 14, 1272798. [DOI: https://dx.doi.org/10.3389/fimmu.2023.1272798]
109. Stemler, J.; Mellinghoff, S.C.; Khodamoradi, Y.; Sprute, R.; Classen, A.Y.; Zapke, S.E.; Hoenigl, M.; Krause, R.; Schmidt-Hieber, M.; Heinz, W.J. et al. Primary Prophylaxis of Invasive Fungal Diseases in Patients with Haematological Malignancies: 2022 Update of the Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). J. Antimicrob. Chemother.; 2023; 78, pp. 1813-1826. [DOI: https://dx.doi.org/10.1093/jac/dkad143]
110. Kato, H.; Hagihara, M.; Asai, N.; Umemura, T.; Hirai, J.; Mori, N.; Yamagishi, Y.; Iwamoto, T.; Mikamo, H. A Systematic Review and Meta-Analysis of Efficacy and Safety of Isavuconazole for the Treatment and Prophylaxis of Invasive Fungal Infections. Mycoses; 2023; 66, pp. 815-824. [DOI: https://dx.doi.org/10.1111/myc.13622]
111. Hou, Z.; Meng, D.; Ruan, M.; Liang, X.; Ni, J.; Jifei, D.; Wu, Z.; Xia, R.; Ge, J.; Long, Z. A Lesson from Fatal Invasive Fungal Infections after CAR-T Cell Therapy: A Case Report and Literature Review. Immunotherapy; 2024; 16, pp. 1021-1027. [DOI: https://dx.doi.org/10.1080/1750743X.2024.2404381]
112. Kansagra, A.J.; Frey, N.V.; Bar, M.; Laetsch, T.W.; Carpenter, P.A.; Savani, B.N.; Heslop, H.E.; Bollard, C.M.; Komanduri, K.V.; Gastineau, D.A. et al. Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy. Biol. Blood Marrow Transplant.; 2019; 25, pp. e76-e85. [DOI: https://dx.doi.org/10.1016/j.bbmt.2018.12.068]
113. Kampouri, E.; Little, J.S.; Rejeski, K.; Manuel, O.; Hammond, S.P.; Hill, J.A. Infections after Chimeric Antigen Receptor (CAR)-T-Cell Therapy for Hematologic Malignancies. Transpl. Infect. Dis.; 2023; 25, (Suppl. 1), e14157. [DOI: https://dx.doi.org/10.1111/tid.14157]
114. Mahadeo, K.M.; Khazal, S.J.; Abdel-Azim, H.; Fitzgerald, J.C.; Taraseviciute, A.; Bollard, C.M.; Tewari, P.; Duncan, C.; Traube, C.; McCall, D. et al. Management Guidelines for Paediatric Patients Receiving Chimeric Antigen Receptor T Cell Therapy. Nat. Rev. Clin. Oncol.; 2019; 16, pp. 45-63. [DOI: https://dx.doi.org/10.1038/s41571-018-0075-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30082906]
115. Santolaya, M.E.; Alvarez, A.M.; Acuña, M.; Avilés, C.L.; Salgado, C.; Tordecilla, J.; Varas, M.; Venegas, M.; Villarroel, M.; Zubieta, M. et al. Efficacy of Pre-Emptive versus Empirical Antifungal Therapy in Children with Cancer and High-Risk Febrile Neutropenia: A Randomized Clinical Trial. J. Antimicrob. Chemother.; 2018; 73, pp. 2860-2866. [DOI: https://dx.doi.org/10.1093/jac/dky244] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30010931]
116. Maertens, J.; Lodewyck, T.; Donnelly, J.P.; Chantepie, S.; Robin, C.; Blijlevens, N.; Turlure, P.; Selleslag, D.; Baron, F.; Aoun, M. et al. Empiric vs. Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer. Clin. Infect. Dis.; 2023; 76, pp. 674-682. [DOI: https://dx.doi.org/10.1093/cid/ciac623]
117. Patterson, T.F.; Thompson, G.R.; Denning, D.W.; Fishman, J.A.; Hadley, S.; Herbrecht, R.; Kontoyiannis, D.P.; Marr, K.A.; Morrison, V.A.; Nguyen, M.H. et al. Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis.; 2016; 63, pp. 433-442. [DOI: https://dx.doi.org/10.1093/cid/ciw444]
118. Tissot, F.; Agrawal, S.; Pagano, L.; Petrikkos, G.; Groll, A.H.; Skiada, A.; Lass-Flörl, C.; Calandra, T.; Viscoli, C.; Herbrecht, R. ECIL-6 Guidelines for the Treatment of Invasive Candidiasis, Aspergillosis and Mucormycosis in Leukemia and Hematopoietic Stem Cell Transplant Patients. Haematologica; 2017; 102, pp. 433-444. [DOI: https://dx.doi.org/10.3324/haematol.2016.152900]
119. Maschmeyer, G.; Helweg-Larsen, J.; Pagano, L.; Robin, C.; Cordonnier, C.; Schellongowski, P. ECIL Guidelines for Treatment of Pneumocystis Jirovecii Pneumonia in Non-HIV-Infected Haematology Patients. J. Antimicrob. Chemother.; 2016; 71, pp. 2405-2413. [DOI: https://dx.doi.org/10.1093/jac/dkw158]
120. Cornely, O.A.; Alastruey-Izquierdo, A.; Arenz, D.; Chen, S.C.A.; Dannaoui, E.; Hochhegger, B.; Hoenigl, M.; Jensen, H.E.; Lagrou, K.; Lewis, R.E. et al. Global Guideline for the Diagnosis and Management of Mucormycosis: An Initiative of the European Confederation of Medical Mycology in Cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect. Dis.; 2019; 19, pp. e405-e421. [DOI: https://dx.doi.org/10.1016/S1473-3099(19)30312-3]
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; Tragiannidis, Konstantinos 2
; Vyzantiadis, Athanasios 3 ; Evangelidis, Nikolaos 1
; Kalmoukos, Panagiotis 1
; Timoleon-Achilleas Vyzantiadis 3
; Tragiannidis, Athanasios 2 ; Kourti, Maria 2
; Gavriilaki, Eleni 4
1 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
2 Children & Adolescent Hematology-Oncology Unit, Second Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
3 Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
4 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;