Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS).

BACKGROUND: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking. METHODS: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists. RESULTS: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and ß-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality. CONCLUSION: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

[Fungal sinusitis]. / Sinusites fongiques.

Although sinusitis affects about 20 % of the population, fungal sinusitis is rare. Aspergillus sp. are most frequently implicated. Fungal sinusitis represents a wide spectrum of disorders, including acute or chronic and invasive or non-invasive forms. Invasive fungal sinusitis may develop in an immunocompromised or diabetic patient, whereas non-invasive fungal sinusitis should be considered in a chronic situation, resistant to antibiotics in immunocompetent patients. Allergic fungal sinusitis is related to hypersensitivity of the host to the fungus. The diagnosis of these infections requires radiological examination and endoscopy with mucosal biopsies examined histologically and mycologically in order to distinguish the different types of sinusitis. In the non-invasive forms, surgical treatment is essential, sometimes combined with antifungal and anti-inflammatory treatment. The invasive forms require antifungal treatment, combined with surgery in some forms, particularly mucormycosis.

Role of a NSAID in the apparent cure of a fungal mycetoma.

UNLABELLED: We report the case of a fungal mycetoma due to Madurella mycetomatis that failed to respond to surgery and antifungal treatment but responded strongly to the addition of a non-steroidal anti-inflammatory drug (NSAID). This African patient was born in Mauritania in 1972. He was a herdsman, living close to the Senegal River. The first nodules appeared on the left foot at the age of 13years (1985). The patient suffered frequent flare-ups with the appearance of black grains and underwent surgery in 1988 and 1992 in Senegal. After remission for several months after surgery, new fistulae occurred. The patient emigrated to France in 1995 and underwent a third surgical intervention in 1996. M. mycetomatis was cultured from the black grains. The patient was otherwise in good health, with no diabetes, and HIV tests were negative. We saw the patient for the first time in 2005, at which time he had flare-ups every two to three months. Imaging disclosed an absence of bone involvement. The patient underwent a fourth operation in October, 2005, and voriconazole treatment was initiated. A new flare-up occurred in February, 2006. CT, MRI, and PET scans revealed calcaneus and tarsal involvement, and posaconazole then replaced voriconazole. Flucytosine was added four months later, due to an absence of improvement. New flares-ups occurred and a fifth surgical intervention was performed in September, 2006. The pain, which had been present for three years, worsened; the patient had to stop working and was no longer able to walk without crutches. Amputation of the foot was considered. Empiric treatment with a NSAID, diclofenac (Voltaren(®); 100mg/day), was added to the antifungal treatment in November 2006, to treat the patient's pain and inflammation. A major improvement was observed within one week. The patient was able to walk without crutches one month later. After two months, clinical examination was normal: no pain, inflammation, nodules or fistulae. Flucytosine was stopped after six months of treatment, in January 2007, diclofenac after 10months, in October 2007, and posaconazole after 18.5months, also in October 2007. No relapse has occurred during the eight years of follow-up since treatment ended. The patient seems to have been cured and has normal CT, MRI, and PET scans. IN SUMMARY: This eumycetoma, which had progressed over 20years despite surgery and antifungal treatments, seems to have been cured by the addition of a NSAID. This observation suggests that inflammation plays a major role in the pathogenesis of fungal mycetoma. Clinical studies of treatments including an NSAID should be conducted to confirm this finding.

Aspergillus spp. invasive external otitis: favourable outcome with a medical approach.

Aspergillus spp. invasive external otitis (IEO) is a rare infection. We performed a seven-year, single-centre retrospective study from 2007 to 2014 including all patients with proven Aspergillus spp. IEO. Twelve patients were identified. All patients had a poorly controlled diabetes mellitus and one underwent solid organ transplant. The most frequently isolated species was Aspergillus flavus (n = 10) and voriconazole was the first-line therapy in all cases, with a median length of treatment of 338.5 days (158-804 days). None of the patients underwent extensive surgery. The clinical outcome was excellent. However, otological sequelae were reported, including hearing impairment (n = 7) and facial palsy (n = 3).

Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis.

BACKGROUND: Mucormycosis incidence is increasing and is associated with a high rate of mortality. Although lipid-based formulations of amphotericin B are the recommended first-line treatment, only one prospective trial in a limited number of patients has been performed to evaluate this regimen. METHODS: Patients with proven or probable mucormycosis were included between June 2007 and March 2011. Patients were scheduled to receive 10 mg/kg/day liposomal amphotericin B (L-AMB) monotherapy for 1 month and surgery was performed when appropriate. The primary outcome was response rate at week 4 or at the end of treatment (EOT) if before week 4, evaluated by an independent committee. ClinicalTrials.gov Identifier: NCT00467883. RESULTS: Forty patients were enrolled. Response was analysed in 33 patients at week 4. Most patients had a haematological malignancy as their primary underlying disease (53%). Seventy-one percent of patients underwent therapeutic surgery. The response rate at week 4 or at EOT was 36%, with 18% partial responses and 18% complete responses. The response rate at week 12 was 45%, with 13% partial responses and 32% complete responses. Overall mortality was 38% at week 12 and 53% at week 24. Serum creatinine doubled in 16 (40%) patients and returned to normal levels within 12 weeks in 10/16 (63%). CONCLUSIONS: High-dose L-AMB for mucormycosis, in combination with surgery in 71% of cases, was associated with an overall response rate of 36% at week 4 and 45% at week 12 and creatinine level doubling in 40% of patients (transient in 63%). These results may serve as the basis for future clinical trials.

Urinary endometriosis: MR imaging appearance with surgical and histological correlations.

OBJECTIVES: The goals of the study were to describe the MR imaging features of endometriosis of the urinary tract and identify those that suggest intrinsic involvement of ureteric wall. MATERIALS AND METHODS: Thirty-five women with proven urinary tract endometriosis and who had preoperative MR imaging between 2001 and 2011 were included retrospectively. MR images were intrepreted by one junior and one senior radiologists. To characterize the intrinsic parietal involvement, the ureteric circumference involved by the lesion of endometriosis was noted. RESULTS: Thirty-eight ureteric and 13 bladder lesions were analyzed. They were found in association in nine women. Ureteric lesions were bilateral in seven women. Of the 38 ureteric lesions, 27 were extrinsic and 11 intrinsic at histopathological analysis. Sixteen women with extrinsic lesions and 10 with intrinsic ones were correctly identified on MR imaging. When the ureter was included less than 360° in the lesion, extrinsic involvement was confirmed in 80% of cases. CONCLUSION: MR imaging appears to be more sensitive (91%vs 82%) but less specific (59% vs 67%) than surgery for the diagnosis of intrinsic form of ureteric location.

Elastography of the thyroid.

Thyroid nodules are very common, while thyroid cancer is rare and has a very good prognosis. Thyroid nodule ultrasound characterization performed by experienced clinicians allows the selection of the tumours to be punctured and guiding fine needle aspiration (FNA). FNA provide cytology information able to differentiate benign tumours from cancer in approximately 80% of cases. However, it remains difficult to identify thyroid cancers with ultrasound imaging, as demonstrated by the very low rate of cancers detected in all of the carried out FNA (approximately 5%). As a majority of thyroid cancers are hard, the stiffness evaluation has become part of nodular characterization. Since 2005, elastography has been used for the evaluation of thyroid nodules; quasi-static elastography was the first technique available and used, at first, an external pressure induced by the probe, which was then replaced by carotid internal excitation allowing improvement in sensitivity. Semi-quantitative analysis allows comparison of tissue elasticities between tissue with elasticity anomalies and normal tissue and provides therefore useful analytic information. Shear wave elastography (SWE) provides a map of the elasticity in a region and allows stiffness quantification of lesions in kilopascals in order to reinforce the predictive value of malignancy. A tumour whose stiffness is greater than 65kPa or for which the stiffness ratio is greater than 3.7 compared to surrounding healthy tissue is highly suspicious. SWE may enable the detection of malignant follicular tumours that currently escape detection by the ultrasound-guided ultrasound/aspiration cytology couple. Lymph node metastasis of papillary thyroid cancer can also be detected by elastography due to its increased stiffness.

Diabetes and mucormycosis: a complex interplay.

Mucormycosis is a life-threatening invasive fungal infection that arises particularly in diabetic patients with or without other underlying conditions such as haematological malignancies or the need for solid-organ transplantation. Rhino-orbito-cerebral involvement is the primary site of mucormycosis, but the paucity of signs may be a cause of delayed diagnosis. Thus, any case of documented non-bacteriological sinusitis in diabetic patients, even without ketoacidosis, should prompt suspicion of a mucormycosis diagnosis. To optimalize information for clinicians in charge of diabetic patients, this extensive review of the literature was carried out to provide an overview of mucormycosis specificities, epidemiology and pathophysiology in the setting of diabetes.

Diagnostic contribution of positron emission tomography with [18F]fluorodeoxyglucose for invasive fungal infections.

Optimal staging and evaluation of residual lesions of invasive fungal infections (IFIs) are major challenges in the immunocompromised host. Preliminary data have suggested that [¹8F]fluorodeoxyglucose ([¹8F]FDG) uptake may be observed in the course of active invasive fungal infections. The aim of this study was to assess the role of positron emission tomography with [¹8F]FDG ([¹8F]FDG-PET) in the diagnosis and staging of IFI. A prospective monocentric study evaluating [¹8F]FDG-PET in 30 consecutive adults and children with European Organization for Research and Treatment of Cancer/Mycoses Study Group probable or proven IFI was performed. Twenty males and ten females (median age, 45 years (range 6-7 years)) were enrolled. Twenty-six were immunocompromised, as follows: haematological malignancy (18) with allogeneic stem cell transplantation (16/18), solid tumour (three), solid organ transplantation (two), diabetes mellitus (two) and cystic fibrosis (one). IFIs were acute invasive aspergillosis (ten), chronic disseminated candidiasis (ten), zygomycosis (two), black grains eumycetoma (two), pulmonary Histoplasma capsulatum var. capsulatum histoplasmosis (two), and Phomopsis sp. osteoarthritis, Scedosporium apiospermum and Candida krusei spondylodiscitis, and acute pulmonary coccidioidomycosis in one case each. An increased uptake of [¹8F]FDG was observed in all areas previously identified by computed tomography and/or magnetic resonance imaging to be involved by IFI. In 4/10 chronic disseminated candidiasis cases, [¹8F]FDG-PET revealed small splenic abscesses that were unapparent on the corresponding computed tomography scan. [¹8F]FDG uptake disappeared after 6 months of antifungal therapy in three patients with chronic disseminated candidiasis for whom the [¹8F]FDG-PET was performed to assess the evolution of the disease. [¹8F]FDG-PET could potentially be useful for the initial diagnosis and staging of IFI. Whether or not [¹8F]FDG-PET might be useful for assessing the optimal duration of IFI therapy should now be assessed in a specific prospective study.

Detection of circulating Aspergillus fumigatus DNA by real-time PCR assay of large serum volumes improves early diagnosis of invasive aspergillosis in high-risk adult patients under hematologic surveillance.

Detection of galactomannan antigen (GMA) in serum is the standard assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematological disorders. Detection of Aspergillus DNA in serum has been proposed, but its sensitivity is lower than that of GMA when small serum volumes (SSV) are used. In this study, we investigated whether extraction of DNA from large serum volumes (LSV) improves diagnostic yield. In a 13-month prospective study, we compared the performances of twice-weekly screening of serum for GMA by an enzyme immunoassay and weekly screening for Aspergillus fumigatus DNA by a real-time PCR (RT-PCR) assay of 1.0 ml (LSV) or 100 mul (SSV) of serum. We included 124 patients (138 treatment episodes), with 17 episodes of EORTC (European Organization for Research and Treatment of Cancer)/MSG (Mycoses Study Group)-documented IA. In all, 1,870 samples were screened for GMA. The sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV and NPV, respectively) of GMA for IA were 88.2%, 95.8%, 75%, and 98.3%, respectively. We screened 938 samples for Aspergillus DNA by using LSV; 404 of these samples were also tested with SSV. The Se, Sp, PPV, and NPV of RT-PCR were 100%, 96.7%, 81%, and 100%, respectively, with LSV and 76.5%, 96.7%, 81.3%, and 95.6%, respectively, with SSV. DNA detection gave a positive result when performed on LSV in two cases of IA where the GMA assay result remained negative. Furthermore, in four IA cases, DNA was detected earlier than GMA. The use of LSV for extraction improved the performance of the RT-PCR, which appears highly sensitive and specific for the early diagnosis of IA in high-risk patients with hematological disorders.

Invasive Pasteurella multocida sinusitis in a renal transplant patient.

Pasteurella are commensal gram-negative bacteria isolated from the oral cavity of many domesticated animals. Most human infections occur post animal bite or scratch injury resulting in local cutaneous infection; however, case reports suggest that transmission may occur via animal secretions. Pasteurella species can be associated with serious systemic infections particularly in those with underlying disease and in the immunocompromised. We present a case of invasive Pasteurella multocida sinusitis in an immunocompromised renal transplant patient most likely acquired from a pet dog through direct mucosal inoculation via licking.

Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient.

Immune reconstitution inflammatory syndrome (IRIS) has rarely been described in the course of disseminated cryptococcosis in solid organ transplant recipients. We report here the case of a renal transplant recipient who developed severe cellulitis in the context of Cryptococcus neoformans-associated IRIS while undergoing reduction of his immunosuppressive therapy. IRIS appeared concomitantly with a dramatic increase of blood CD4+ T cells (94-460/mm(3)) and required the administration of a short-term steroid therapy to resolve.

Acute abdominal aortic thrombosis in cancer patients.

We report two cases of acute aortic thrombosis in cancer patients. Aortic thrombosis is rare in the absence of atherosclerosis, dissection, or aneurysm. On the one hand, hypercoagulable state related to cancer is a well-known risk factor for venous thrombosis. On the other hand, arterial thrombosis has been rarely reported in cancer patients. Recognition of aortic thrombosis is important because it is a dangerous condition; furthermore, it exposes at the patient to complications such as peripheral embolism. In addition, anticoagulation can result in resolution of thrombosis.