Proven and probable invasive fungal infections in children with acute lymphoblastic leukaemia: results from an university hospital, 2005–2013

Despite improvements in diagnosis and treatment, invasive fungal infections (IFIs) are still a major cause of morbidity and mortality in immunocompromised patients. The data on IFI among children with acute lymphoblastic leukaemia (ALL) are still scarce, and our aim was to estimate the risk, aetiology and outcome of proven and probable IFIs in children with ALL who did not receive primary prophylaxis over an 8‐year period. Between January 2005 and February 2013, 125 children who were treated for ALL at the Pediatric Hematology Department of the Medical School of Ege University were retrospectively reviewed. Proven and probable IFIs were defined according to revised definitions of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. The proven and probable IFI incidence was 30/125 (24%). Profound neutropenia was detected in 18 (60%) patients, and prolonged neutropenia was detected in 16 (53.3%) of the patients. The most isolated agents were non‐albicans Candida spp. The crude and attributable mortality was 20% and 13.3% respectively. Profound neutropenia was associated with mortality (P < 0.05). The younger patients were especially at risk for proven IFI. Prolonged neutropenia, to be in the induction phase of chemotherapy, and profound neutropenia were found to be the most common predisposing factors for IFI episodes.     

Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7‐month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty‐four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty‐two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre‐emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre‐emptively. Twenty‐nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.     

The role of surgery in the treatment of invasive fungal infection in paediatric haematology patients: a retrospective single‐centre survey

Surgery may improve the control of fungal disease and patient survival. The aim of this study was to report a single‐centre experience in using surgery for the treatment of paediatric invasive fungal infection (IFI). From 2001 to 2009, 18 paediatric onco‐haematology patients underwent 24 surgical procedures as treatment of IFI. At surgery, severe thrombocytopenia and neutropenia were present in four and one episodes respectively. Complications were one pleural effusion, one pleural effusion and surgical wound infection, one pneumothorax with wound dehiscence and one wound dehiscence. None of them required repeat surgery. The median duration of hospitalisation for four complicated procedures was 11 days, range 3–16, and 7 days, range 2–13, for the 20 uncomplicated procedures. No surgery‐related deaths occurred. Fourteen patients resumed chemotherapy after a median of 26 days, range 9–77, whereas nine patients underwent hematopoietic stem cell transplantation after a median of 42 days, range 27–110. At 3 months from IFI, 17 patients were alive (94%) and one patient (6%) died from mycosis; the 3‐month overall survival (OS) being 94.4%, CI 66.6–99.2. After a median follow‐up of 7.1 years (CI 2.8–7.5), the OS was 54.5%, CI 29.2–74.2. Surgery is a feasible and valuable option in paediatric patients because it is associated with a low incidence of complications and an acceptable delay in resuming the chemotherapeutic plan.     

Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20‐year autopsy study

Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20‐year period (1989–2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004–2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004–2008 (0.02–0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.     

Chronic pulmonary aspergillosis in a tertiary care centre in Spain: A retrospective,observational study

The aim of this study was to describe the characteristics of patients with chronic pulmonary aspergillosis (CPA) in a tertiary care centre in Spain. Retrospective cohort study of all patients diagnosed with CPA between January 2010 and December 2015. The patients were identified through the Microbiology Registry. Demographic, clinical, laboratory, radiological, microbiological and clinical data were recorded. Patients were followed up for 12 months. Fifty‐three patients were included; median age was 61.5 years. Forty‐seven had a lung condition, 25 suffered from COPD, 19 an active malignancy, 10 had previous pulmonary tuberculosis and 9 lung interstitial disease. Twenty‐eight patients presented with chronic cavitary pulmonary form (CCPA) and 20 with subacute invasive aspergillosis (SAIA). Species identified were A fumigatus (34), A niger (5), A terreus (4) and A flavus (3). All‐cause 1‐year mortality was 56%. Predictors of mortality were cancer history (OR, 9.5; 95% CI, 2.54‐35.51; P < 0.01) and SAIA (OR, 5.49; 95% CI, 1.49‐19.82; P < 0.01). Previous pulmonary tuberculosis, surgery for the treatment of CPA and CCPA were found to be associated with lower mortality (OR, 0.05; 95% CI, <0.01‐0.47; P < 0.01; OR, 0.16; 95% CI, 0.03‐0.88; P = 0.035 and OR 0.2, 95% CI, 0.01‐0.67; P = 0.01, respectively). This is the first study providing an overview of the features of CPA in patients from Spain. CCPA was the most frequent form of CPA and A fumigatus the most frequently isolated species. Patients with cancer history and SAIA had a worse prognosis.     

Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single‐centre study with focus on emerging pathogens

With increased use of expanded‐spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer‐Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post‐IFI mortality. All patients received antifungal prophylaxis. Fifty‐three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n = 31; 50%) and candidaemia (n = 15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n = 6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR) = 6.0], graft‐versus‐host disease (OR = 5.3), central venous catheter use (OR = 5.2) and hypoalbuminaemia (OR = 0.3 g^?1 dl^?1 increase in albumin). The 90‐day mortality rate after IFI was 57%. Non‐cytomegalovirus systemic viral co‐infection (OR = 3.5) and stay in an ICU (OR = 2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging.     

Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008)

Critically ill patients admitted to intensive care units (ICU) are highly susceptible to healthcare-associated infections caused by fungi. A prospective sequential survey of invasive fungal infections was conducted from May 2006 to April 2008 in 38 ICUs of 27 Italian hospitals. A total of 384 fungal infections (318 invasive Candida infections, three cryptococcosis and 63 mould infections) were notified. The median rate of candidaemia was 10.08 per 1000 admissions. In 15% of cases, the infection was already present at the time of admission to ICU. Seventy-seven percent of Candida infections were diagnosed in surgical patients. Candida albicans was isolated in 60% of cases, Candida glabrata and Candida parapsilosis in 13%, each. Candida glabrata had the highest crude mortality rate (60%). Aspergillus infection was diagnosed in 32 medical and 25 surgical patients. The median rate was 6.31 per 1000 admissions. Corticosteroid treatment was the major host factor. Aspergillosis was demonstrated to be more severe than candidiasis as the crude mortality rate was significantly higher (63% vs. 46%), given an equal index of severity, Simplified Acute Physiology Score (SAPS-II). The present large nationwide survey points out the considerable morbidity and mortality of invasive fungal infections in surgical as well as medical patients in ICU.     

Detection of (1→3)‐β‐D‐glucan in same‐day urine and serum samples obtained from patients with haematological malignancies

Serum 1,3‐beta‐d ‐glucan (BDG) testing is an established diagnostic marker for invasive fungal infections (IFI) among patients with haematological malignancies. In contrast limited data exist regarding the application of urine BDG testing. Same‐day midstream urine and serum screening samples were collected in adult patients with underlying haematological malignancies. A total of 80 urine samples from 46 patients were investigated: Twenty‐six had positive corresponding serum BDG >120 pg ml^?1, 27 intermediate (60–80 pg ml^?1), and 27 negative serum BDG (<25 pg ml^?1). A significant positive correlation between BDG in serum and urine samples was observed (P = 0.025; r = 0.252). Sensitivity, specificity, positive predictive value and negative predictive value (compared with same‐day serum results) were: 42%, 76%, 46%, 73% when using an 80 pg ml^?1 urine cut‐off, and 35%, 96%, 82%, 75% for a 250 pg ml^?1 cut‐off. Urine BDG seemed to be higher in samples obtained from patients with probable IFI (n = 13, median 145, IQR 22–253) compared to those from patients without IFI (n = 56, median 24, IQR 15–88) but the difference was not significant (P = 0.069). Overall correlation of same‐day urine BDG and serum BDG was moderate. However, urine BDG testing may warrant further investigation in larger studies, as high‐positive urine results correlated with high‐positive corresponding serum levels and clinical performance was comparable to serum BDG.     

Evolution of procalcitonin,C‐reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis

Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C‐reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D?12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D?12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 μg l^?1, respectively, while CRP was >50, 75 and 100 mg l^?1 in 84%, 70% and 57% and Fib was >4, 5 and 6 g l^?1 in 96%, 80% and 61% of cases respectively (P < 10^?7). The same trends were observed from D1 to D12. Overall, between D?12 and D12, only 6.4% of patients had PCT >1.5 μg l^?1, while CRP >100 mg l^?1 and Fib >6 g l^?1 were observed in 80% and 75% of cases respectively (P < 10^?7). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low.     

Serum Aspergillus galactomannan antigen values strongly correlate with outcome of invasive aspergillosis: a study of 56 patients with hematologic cancer

BACKGROUND: Determining the outcome of patients with aspergillosis can be particularly difficult because patients with aspergillosis are at risk for other conditions that mimic this infection. Galactomannan is an Aspergillus-specific antigen released during invasive aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test. METHODS: Using a kappa correlation coefficient test (KCC), the strength of correlation was determined between GMI and survival outcome of aspergillosis among 56 adults with hematologic cancer (90% had myeloma) who underwent serial GMI monitoring until hospital discharge or death. RESULTS: All 56 patients received antineoplastic therapy (myeloablative followed by stem cell transplantation [autologous in 21 patients and allogeneic in 3 patients] or nonmyeloablative therapy [32 patients]). The overall correlation between survival outcome and GMI was excellent (KCC = 0.8609; 95% confidence interval [95% CI], 0.7093-1.000 [P < .0001]) and was comparable among neutropenic and nonneutropenic patients (KCC = 0.8271; 95% CI, 0.6407-1.000 [P < .0001] and KCC = 1.0; 95% CI, 1-1 [P = .0083], respectively). CONCLUSIONS: The survival outcome of patients with aspergillosis strongly correlated with serum GMI. These findings have important implications for patient care and clinical trials of mold-active antifungal agents.     

Clinical and mycological features of onychomycosis in central Tunisia: a 22 years retrospective study (1986–2007)

Onychomycosis is the most frequently encountered nail disease and may be difficult to diagnose and treat. The objective of this study was to determine the prevalence, the clinical and mycological characteristics of onychomycosis in central Tunisia. It is a retrospective study performed over a 22‐year period (1986–2007). It included 7151 patients (4709 women and 2442 men) with suspected fingernails and/or toenails onychomycosis. The patients were referred to the Mycology‐Parasitology Laboratory of Farhat Hached hospital in Sousse for mycological examination. Both direct microscopy and culture of the nail material were performed to diagnose and identify the causative fungal species. Onychomycosis was confirmed in 78.6% of investigated patients (5624/7151). The positivity rate was higher in women as compared with men. In both men and women, fingernails were most frequently involved than toenails. No significant relation was found between gender and toenails onychomycosis, whereas fingernails were frequently involved in women. As far as aetiological agents are considered, dermatophytes, yeast and moulds were responsible for 49.9%, 47.4% and 2.7% of onyxis cases respectively. In fingernail infections, yeast were the most frequent fungi (83.6%), Candida albicans being the leading species (51.6%). In contrast, in toenail infections, dermatophytes were more frequent (74.1%). Trichophyton rubrum was by far the dominant species (88.1%). Yeast were observed more frequently in women whereas dermatophytes were more common in men. Moulds were involved in 4.2% of cases. The most frequent species were Aspergillus sp. and Chrysosporium sp. Onychomycosis is a frequent disease in central Tunisia. T. rubrum is the predominant agent in toenails infection and yeast, mainly C. albicans, in fingernails onychomycosis.     

Prevalence of the reversed halo sign in neutropenic patients compared with non‐neutropenic patients: Data from a single‐centre study involving 27 patients with pulmonary mucormycosis (2003‐2016)

Pulmonary mucormycosis (PM) is a life‐threatening infection and the diagnosis can be challenging. The objective was to retrospectively explore the value of the RHS in our cohort of 27 patients with mucormycosis and its relation to neutropenia. This was a retrospective study including all patients with a diagnosis of probable or proven invasive PM according to the 2008 EORTC/MSG criteria between September 2003 to April 2016. Fisher's exact test and Mann‐Whitney test, with a P‐value statistically significant under .05 (P<.05), were used to compare neutropenic and non‐neutropenic groups. 27 patients were eligible. The RHS could be identified in 78% of cases in the neutropenic group, and was less common in the non‐neutropenic group (31%) (P<.05). Reticulations inside ground‐glass opacity in case of RHS were present in 13 out of 15 patients (87%). Mucorales DNA detection by PCR on serum provided, a median time to the first PCR‐positive sample of 3 days (?33 to +60 days) before diagnosis was confirmed. Six patients had IPA co‐infection. In conclusion, RHS is more frequent in case of PM in neutropenic patients compare to non‐neutropenic patients. Its presence in immunocompromised patients should be sufficient to promptly start Mucorales‐active antifungal treatment, while its absence especially in non‐neutropenic cases should not be sufficient to exclude the diagnosis.     

Orbital pythiosis: a non-fungal disease mimicking orbital mycotic infections, with a retrospective review of the literature

In the past decade there have been four well-documented cases of orbital pythiosis caused by Pythium insidiosum. All were recorded in apparently healthy children. Although pythiosis seems to be a rare infection in humans, we recently conducted a review of the medical literature to investigate misdiagnosed cases of orbital pythiosis in the past 100 years in children. To track putative cases of orbital pythiosis, we first identified orbital cases initially diagnosed as fungal infections. We were particularly interested in cases (a) involving apparently young healthy hosts, (b) the presence of hyaline, aseptate hyphal elements in the infected tissues, (c) the morphological features of the hyphal elements, (d) the presence of an eosinophilic granulomatous reaction with the Splendore-Hoeppli phenomenon around the mycelial elements, (e) resistance to antifungal therapy, (f) outcome after therapy, if any, and (g) cultural strategies. This study showed that indeed, there had been five other recorded cases of orbital infections, all in young children in the USA, with characteristics consistent with infections caused by P. insidiosum. The reports had described those cases of orbital-cranial-arterial diseases as patients with aspergillosis (one case), penicilliosis infection (one case), and zygomycosis (three cases). We reviewed those anomalous cases and discuss details about their clinical, pathologic, therapeutic, and etiologic evidence used to reclassify them as putative cases of orbital pythiosis.     

Performance of 1,3‐beta‐D‐glucan in the diagnosis and monitoring of invasive fusariosis

Invasive fusariosis (IF) usually presents with high fungal burden at diagnosis, and this may contribute to its high mortality rate. The use 1,3‐beta‐D‐glucan (BDG) may help to establish the diagnosis at an earlier disease stage and to monitor treatment. To evaluate the performance of BDG in the diagnosis of IF and its kinetics in relation to the outcome, we retrospectively tested serum samples of 13 cases of IF, analysed the temporal relationship between the first positive BDG test and the date of the diagnosis of IF, and the kinetics of BDG in relation to patients’ outcome. We selected 13 controls with similar underlying diseases as cases, at least two serum samples stored, and no invasive fungal disease. Twelve patients with IF had at least one positive BDG (median 4, range 1‐16). The test was positive before the diagnosis of IF in 11 of the 12 patients (91.6%), at a median of 10 days (range 1‐32). The median BDG value increased (from 109 to 316 pg/mL, P = 0.04) in patients who died by day 30, and did not change significantly (99‐101 pg/mL, P = 0.60) in survivors. Using two consecutive BDG tests, sensitivity, specificity, and positive and negative predictive values were 85%, 69%, 7% and 99%, respectively. BDG is positive in the majority of patients with IF, usually before the diagnosis, but the low positive predictive value limits its use to diagnose IF earlier. Once therapy is started, decreasing BDG values suggests treatment response.     

Chlorambucil–rituximab as first‐line therapy in patients affected by follicular non‐Hodgkin's lymphoma: a retrospective single‐centre study

Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil–rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m²/day orally for 6 weeks and 375 mg/m² in a standard 4‐weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy‐one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3–4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow‐up of 57 months, 72 patients (96%) are alive. Median event‐free survival (EFS) and median overall survival (OS) were not reached; 5‐year OS rate was 98.4%. The 5‐year EFS was 71.3%. By univariate and multivariate analyses, elevated beta‐2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. Copyright © 2014 John Wiley & Sons, Ltd.     

Defining breakthrough invasive fungal infection–Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology

Breakthrough invasive fungal infections (IFIs) have emerged as a significant problem in patients receiving systemic antifungals; however, consensus criteria for defining breakthrough IFI are missing. This position paper establishes broadly applicable definitions of breakthrough IFI for clinical research. Representatives of the Mycoses Study Group Education and Research Consortium (MSG‐ERC) and the European Confederation of Medical Mycology (ECMM) reviewed the relevant English literature for definitions applied and published through 2018. A draft proposal for definitions was developed and circulated to all members of the two organisations for comment and suggestions. The authors addressed comments received and circulated the updated document for approval. Breakthrough IFI was defined as any IFI occurring during exposure to an antifungal drug, including fungi outside the spectrum of activity of an antifungal. The time of breakthrough IFI was defined as the first attributable clinical sign or symptom, mycological finding or radiological feature. The period defining breakthrough IFI depends on pharmacokinetic properties and extends at least until one dosing interval after drug discontinuation. Persistent IFI describes IFI that is unchanged/stable since treatment initiation with ongoing need for antifungal therapy. It is distinct from refractory IFI, defined as progression of disease and therefore similar to non‐response to treatment. Relapsed IFI occurs after treatment and is caused by the same pathogen at the same site, although dissemination can occur. These proposed definitions are intended to support the design of future clinical trials and epidemiological research in clinical mycology, with the ultimate goal of increasing the comparability of clinical trial results.