Novel immunologic classification of aspergillosis in adult cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) demonstrate a wide range of hypersensitivity responses to Aspergillus, beyond allergic bronchopulmonary aspergillosis, which require classification. OBJECTIVE: This study integrated 2 new methods of Aspergillus detection-sputum galactomannan (GM) and real-time PCR-alongside established serologic markers, to reclassify aspergillosis in CF. METHODS: A total of 146 adult patients with CF had serologic tests (ImmunoCap total IgE, specific Aspergillus fumigatus IgE, and specific A fumigatus IgG), sputum real-time Aspergillus PCR, and sputum GM. Patients were classified by using latent class analysis. RESULTS: Both RT-PCR and GM were more sensitive than culture in detecting Aspergillus in sputum (culture 37%, RT-PCR 74%, and GM 46%). Intraassay and interassay reproducibility of PCR and GM was excellent. Latent class analysis of triazole-naive patients identified a nondiseased group and 3 disease classes: class 1 (n = 49, 37.7%) represented patients with or without positive RT-PCR but no immunologic response to A fumigatus and negative GM (nondiseased); class 2 (n = 23, 17.7%) represented patients with positive RT-PCR, elevated total and specific A fumigatus IgE/IgG, and positive GM (serologic allergic bronchopulmonary aspergillosis); class 3 (n = 19, 14.6%) represented patients with or without positive RT-PCR, elevated A fumigatus IgE (not IgG), and negative GM (Aspergillus sensitized); and class 4 (n = 39, 30%) represented patients with positive RT-PCR, elevated A fumigatus IgG (not IgE), and positive GM (Aspergillus bronchitis). CONCLUSIONS: Three distinct classes of aspergillosis in CF were identified by latent class analysis by using serologic, RT-PCR, and GM data. This novel classification will facilitate improved phenotyping, pathogenesis studies, and management evaluations.

Impact of the revised (2008) EORTC/MSG definitions for invasive fungal disease on the rates of diagnosis of invasive aspergillosis.

Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications.

A model for classification of invasive fungal rhinosinusitis by computed tomography.

Our purpose was to classify acute invasive fungal rhinosinusitis (AIFR) caused by Mucor versus Aspergillus species by evaluating computed tomography radiological findings. Two blinded readers retrospectively graded radiological abnormalities of the craniofacial region observed on craniofacial CT examinations obtained during initial evaluation of 38 patients with eventually pathology-proven AIFR (13:25, Mucor:Aspergillus). Binomial logistic regression was used to analyze correlation between variables and type of fungi. Score-based models were implemented for analyzing differences in laterality of findings, including the 'unilateral presence' and 'bilateral mean' models. Binary logistic regression was used, with Score as the only predictor and Group (Mucor vs Aspergillus) as the only outcome. Specificity, sensitivity, positive predictive value, negative predictive value and accuracy were determined for the evaluated models. Given the low predictive value of any single evaluated anatomical site, a 'bilateral mean' score-based model including the nasal cavity, maxillary sinuses, ethmoid air cells, sphenoid sinus and frontal sinuses yielded the highest prediction accuracy, with Mucor induced AIFR correlating with higher prevalence of bilateral findings. The odds ratio for the model while integrating the above anatomical sites was 12.3 (p < 0.001). PPV, NPV, sensitivity, specificity and accuracy were 0.85, 0.82, 0.92, 0.69 and 0.84 respectively. The abnormal radiological findings on craniofacial CT scans of Mucor and Aspergillus induced AIFR could be differentiated based on laterality, with Mucor induced AIFR associated with higher prevalence of bilateral findings.

Spectrum of fungal rhinosinusitis; histopathologist's perspective.

AIMS: Clinical presentation can provide a clue to the subcategories of fungal rhinosinusitis (FRS); however, tissue examination provides accurate classification. The aim was to analyse the incidence and histopathological spectrum of FRS. METHODS AND RESULTS: A retrospective analysis of all the cases of rhinosinusitis reported in the last 5 years was carried out. Haematoxylin and eosin-stained sections along with special stains such as periodic acid-Schiff and Grocott's were examined. These cases were subclassified based on the presence of allergic mucin, mycelial elements and tissue reaction. Out of a total of 665 cases of rhinosinusitis, 284 (42.7%) were of FRS. On histopathological examination they were broadly categorized as: (i) non-invasive FRS (n = 171, 60.2%), which included 160 cases (56.3%) of allergic fungal rhinosinusitis (AFRS) and eleven (3.9%) of fungal ball; (ii) invasive FRS (n = 101, 35.6%), which included 48 cases (16.9%) of chronic invasive granulomatous FRS, four (1.4%) of chronic invasive FRS and 49 (17.3%) of acute fulminant FRS; and (iii) mixed pattern FRS, comprising 12 cases (4.25%). CONCLUSIONS: AFRS is the most common type of FRS. Cases with mixed reaction pattern suggest that different types of FRS represent a progressive spectrum of disease. An exact histopathological categorization of FRS is important as regards treatment.

Comparison of the use of administrative data and an active system for surveillance of invasive aspergillosis .

BACKGROUND: Administrative data, such as International Classification of Diseases, Ninth Revision (ICD-9) codes, are readily available and are an attractive option for surveillance and quality assessment within a single institution or for interinstitutional comparisons. To understand the usefulness of administrative data for the surveillance of invasive aspergillosis, we compared information obtained from a system based on ICD-9 codes with information obtained from an active, prospective surveillance system, which used more extensive case-finding methods (Transplant Associated Infection Surveillance Network). METHODS: Patients with suspected invasive aspergillosis were identified by aspergillosis-related ICD-9 codes assigned to hematopoietic stem cell transplant recipients and solid organ transplant recipients at a single hospital from April 1, 2001, through January 31, 2005. Suspected cases were classified as proven or probable invasive aspergillosis by medical record review using standard definitions. We calculated the sensitivity and positive predictive value (PPV) of identifying invasive aspergillosis by individual ICD-9 codes and by combinations of codes. RESULTS: The sensitivity of code 117.3 was modest (63% [95% confidence interval {CI}, 38%-84%]), as was the PPV (71% [95% CI, 44%-90%]); the sensitivity of code 117.9 was poor (32% [95% CI, 13%-57%]), as was the PPV (15% [95% CI, 6%-31%]). The sensitivity of codes 117.3 and 117.9 combined was 84% (95% CI, 60%-97%); the PPV of the combined codes was 30% (95% CI, 18%-44%). Overall, ICD-9 codes triggered a review of medical records for 64 medical patients, only 16 (25%) of whom had proven or probable invasive aspergillosis. CONCLUSIONS: A surveillance system that involved multiple ICD-9 codes was sufficiently sensitive to identify most cases of invasive aspergillosis; however, the poor PPV of ICD-9 codes means that this approach is not adequate as the sole tool used to classify cases. Screening ICD-9 codes to trigger a medical record review might be a useful method of surveillance for invasive aspergillosis and quality assessment, although more investigation is needed.

[Aspergillosis for the pulmonologist]. / L'aspergillose en pratique pour le pneumologue.

Aspergillus is involved in various lung illnesses related to type of exposition and immunity host response, local (tracheobronchial) and global. Allergic bronchopulmonary aspergillosis is due to a hypersensitivity response, diagnosis must be considered in presence of severe asthma with radiologic opacities, blood eosinophilia and elevated total serum IgE levels. Bronchial colonization is often accidentally discovered, but needs a monitoring. Pulmonary aspergilloma, often asymptomatic, grows in a preexisting cavity. Aspergillus bronchitis is a prolonged superficious endobronchial infection. Pseudomembranous necrotizing tracheobronchitis is a microinvasive bronchial infection, which prognosis is very bad. Acute invasive pulmonary aspergillosis affects quite always immunocompromised patients, but cases are not exceptional in patients with prior lung disease. Chronic necrotizing pulmonary aspergillosis may be divided in chronic cavitary and chronic fibrosing pulmonary aspergillosis, and subacute invasive aspergillosis according to the course of the disease, radiological outcome first. Management of diseases caused by Aspergillus is evolving with new diagnostic tools (PCR, Aspergillus antigenemia) and with new generation antifungal drugs.

[Bronchopulmonary aspergillosis infections in the non-immunocompromised patient]. / Infections aspergillaires broncho-pulmonaires du sujet non immunodéprimé.

The definition of broncho-pulmonary aspergillosis infections in non-immunocompromised patients remains vague and a wide range of clinical, radiological and pathological entities have been described with a variety of names, i.e. simple aspergilloma, complex aspergilloma, semi-invasive aspergillosis, chronic necrotizing pulmonary aspergillosis, chronic cavitary and fibrosing pulmonary and pleural aspergillosis, pseudomembranous tracheobronchitis caused by Aspergillus, and invasive aspergillosis. However, these disease entities share common characteristics suggesting that they belong to the same group of pulmonary aspergillosis infectious disorders: 1- a specific diathesis responsible for the deterioration in local or systemic defenses against infection (alcohol, tobacco abuse, or diabetes); 2- an underlying bronchopulmonary disease responsible or not for the presence of a residual pleural or bronchopulmonary cavity (active tuberculosis or tuberculosis sequelae, bronchial dilatation, sarcoidosis, COPD); 3- generally, the prolonged use of low-dose oral or inhaled corticosteroids and 4- little or no vascular invasion, a granulomatous reaction and a low tendency for metastasis. There are no established treatment guidelines for broncho-pulmonary aspergillosis infection in non-immunocompromised patients, except for invasive aspergillosis. Bronchial artery embolization may stop hemoptysis in certain cases. Surgery is generally impossible because of impaired respiratory function or the severity of the comorbidity and when it is possible morbidity and mortality are very high. Numerous clinical cases and short retrospective series have reported the effect over time of the various antifungal agents available. Oral triazoles, i.e. itraconazole, and in particular voriconazole, appear to provide suitable treatment for broncho-pulmonary aspergillosis infections in non-immunocompromised patients.

Malignant Otitis Externa: A Novel Stratification Protocol for Predicting Treatment Outcomes.

OBJECTIVES: 1) Stratify malignant otitis externa into severe and nonsevere disease categories. 2) Predict treatment courses and outcomes based on this stratification. SETTING: Tertiary center. PATIENTS: Retrospective review 2004 to 2014; 28 patients. Inclusion criteria are a diagnosis by senior authors, radiographic evidence of disease, admission for intravenous antibiotics/debridement, minimum 1 year of follow-up. INTERVENTIONS: Severe group stratification if two or more of the following: cranial nerve VII palsy, fungal positive culture, relapse, surgery performed, major radiographic findings. All other patients stratified to nonsevere group. MAIN OUTCOME MEASURES: Cure, alive/refractory disease, death by disease, death by other cause. Secondary measures are antibiotic duration and number of disease-related admissions. RESULTS: Forty-three percent (12 of 28) and 57% (16 of 28) of patients stratified into the severe and nonsevere groups. The severe group had significantly more adverse disease-specific outcomes than the nonsevere group (7 of 12 versus 0 of 16; p = 0.002). Disease-specific mortality was 42% and 0% in the severe and nonsevere groups, respectively. The severe group had longer antibiotic courses (12.8 versus 6.9 wk; p = 0.01) and more disease-related admissions/relapses (1.6 versus 1, p < 0.001). Only four of 12 severe group patients achieved cure. All but two nonsevere patients achieved cure, with those two dying of other causes. CONCLUSION: A subgroup of malignant otitis externa may exist that is not as susceptible to parenteral antibiotics and local debridement. A combination of clinical and radiographic findings may be useful for stratifying patients into severe/nonsevere categories. Patients with severe disease may be more likely to die of their disease and have worse treatment courses such that additional surgical intervention may be indicated.

Calcification in chronic maxillary sinusitis: comparison of CT findings with histopathologic results.

BACKGROUND AND PURPOSE: It is important to differentiate fungal from nonfungal sinusitis in order to determine the optimal treatment for chronic sinusitis. The purpose of this study was to describe the CT findings of calcifications in chronic fungal and nonfungal maxillary sinusitis. METHODS: Five hundred ten patients with pathologically proved chronic maxillary sinusitis were studied with unenhanced CT before undergoing sinonasal surgery. In 36 patients, the CT scans were reviewed retrospectively to ascertain the shape and location of intrasinus calcifications. RESULTS: Calcifications were found in 20 (51%) of 39 patients with fungal sinusitis and in 16 (3%) of 471 patients with nonfungal sinusitis. Direct histopathologic correlation was performed in two of 16 patients with nonfungal sinusitis who had intrasinus calcification. The location of intrasinus calcification was central in 95% of the patients with fungal sinusitis and peripheral in 81% of those with nonfungal sinusitis. Although calcifications with a nodular or linear shape were seen in both fungal and nonfungal sinusitis, fine punctate type calcifications were seen only in those with fungal sinusitis (50%) and round or eggshell type calcifications only in those with nonfungal sinusitis (19%). CONCLUSION: Intrasinus calcifications are different in location and shape between fungal and nonfungal maxillary sinusitis. Although intrasinus calcification is uncommon in nonfungal sinusitis, the CT finding of intrasinus calcification may be helpful for differentiating fungal from nonfungal maxillary sinusitis.

Imaging of opportunistic fungal infections in immunocompromised patient.

Opportunistic fungal infection is a common cause of serious morbidity and mortality in the immunocompromised host. Combination of pattern recognition with knowledge of the clinical setting is the best approach to pulmonary infectious processes. The aim of this article is to assess the chest radiographs and CT imaging features of different opportunistic fungal infections in immunocompromised patients.

The spectrum of pulmonary aspergillosis.

Aspergillus species can produce a wide range of pulmonary disorders. Classically, pulmonary aspergillosis has been categorized into invasive, saprophytic, and allergic forms, all of which differ in their manifestations and therapy. More recently, however, other types of infection by this fungus have been recognized that do not fit into these traditional categories; an example is semi-invasive (chronic necrotizing) aspergillosis. In fact, these forms have features that are intermediate between those of the invasive and saprophytic types. The various types of aspergillosis can be regarded as constituting a continuous spectrum, ranging from invasive disease in the severely immunosuppressed patient to hypersensitivity reactions such as allergic bronchopulmonary aspergillosis (and bronchocentric granulomatosis) in the hyperreactive patient. Between these extremes are chronic necrotizing disease seen in midly immunocompromised hosts, and the noninvasive aspergilloma, which is due to saprophytic growth within a previously diseased area of lung in an otherwise normal host. Other intermediate forms may be encountered, their behavior being determined by the host immune status in combination with the underlying lung morphology. The radiographic and clinical features of these various forms of pulmonary aspergillosis are reviewed, including the more recently reported forms of infection such as Aspergillus tracheobronchitis and aspergillosis associated with acquired immunodeficiency syndrome and cystic fibrosis. The proposed concept of a disease spectrum is emphasized.

[Invasive pulmonary aspergillosis in immunocompromized children: diagnosis and classification]. / Aspergillose pulmonaire invasive chez les enfants immunodéprimés: méthodes diagnostiques et classification.

Invasive aspergillosis is an opportunistic infection, with frequent lung involvement. High-risk children are allogenic bone marrow recipients, and those with hematological malignancies, aplastic anemia or chronic granulomatous disease. Profound and prolonged neutropenia, and corticosteroid therapy are the most important predisposing factors. Building and demolition works represent the major environmental risk factor. The diagnosis of invasive aspergillosis remains difficult to establish. Clinical manifestations are non-specific. Early thoracic computed tomographic scan shows halo sign in most cases. Subsequently appears the air crescent sign. Galactomannan research by sandwich ELISA can be useful in serum and in bronchoalveolar lavage fluid. Aspergillus DNA detection by PCR is still not standardized. Culture of the organism allows species identification. Aspergillus hyphae can be found at cytological examination, but a biopsy specimen is usually required to affirm tissue damage. A new classification of invasive fungal infections in immunocompromised patients was recently proposed by experts from the European Organization for Research and Treatment of Cancer and from the Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. On the basis of host linked criteria, microbiological, clinical and radiological features, invasive aspergillosis is classified as proven, probable or possible. These definitions should not be used to guide clinical practice in therapy, but they will improve the quality of epidemiological data, and help the comparison of clinical trial results.

[Cerebral aspergillosis as a cerebral vascular accident].

Cerebral aspergillosis is one of the most common mycotic infections in the central nervous system causing different clinical features such as brain abscess, granuloma, meningitis, and encephalitis. Cerebral aspergillosis, however, may lead to a cerebral vascular accident such as intracranial hemorrhage or cerebral infarction. In this report, we present two patients with cerebral aspergillosis accompanied by intracranial hemorrhage. A total of 124 reported cases of cerebral aspergillosis are reviewed to ascertain the pathogenesis of the associated vascular lesion. The first patient was a 9-year-old girl, who developed drowsiness with a headache during the medical treatment for acute myelocytic leukemia. CT disclosed subarachnoid and intraventricular hemorrhage. The autopsy revealed that the aspergillus arteritis was the cause of repeated hemorrhage. The second patient was a 15-year-old boy with allergic purpura and renal failure, who suddenly developed a stupor with convulsive seizure. CT disclosed an intracerebral hemorrhage in the right parieto-occipital area. The patient gradually deteriorated and died in spite of the surgical removal of the hematoma. The autopsy revealed that the hemorrhage was caused by the aspergillus arteritis. Cerebral aspergillosis has two routes of infection to the central nervous system: hematogenous dissemination from the distant site (usually the lung) and direct extension from the contiguous site (usually the paranasal sinuses or orbit). The primary mechanism of neuropathology is different between these two types. Primary cerebral arteritis is most often seen in patients with the former type, whereas primary basal meningitis occurs in the latter. The incidence of clinico-pathological features is different between hematogenous dissemination type and direct extension type.(ABSTRACT TRUNCATED AT 250 WORDS)

[Aspergillus fumigatus: from saprophytism to virulence. Phenotypic and genotypic biodiversity]. / Aspergillus fumigatus: du saprophytisme à la virulence. Biodiversité phénotypique et génotypique.

During the last two decades, deep changes have arised in aspergillosis. Thus, this fungal infection mainly due Aspergillus fumigatus is becoming a serious public health-hazard in the growing population of immunocompromised patients. From literature and their own experience, the authors present a synthesis of phenomenons promoting this evolution: the host predisposing factors, environment and potential contamination sources, then the fungus itself. Genetic research developed into the disease-causing organism could be of major interest in epidemiology of aspergillosis and to identify new targets of prophylaxis.

Fungal infections of the paranasal sinuses.

Fungal infections can be mainly grouped into four types. The invasive forms are acute sinusitis (fulminant), chronic sinusitis (indolent), whereas the non-invasive forms are mycetoma and allergic fungal sinusitis. From December 1993 to December 1997, 27 cases of fungal sinusitis, 22 of which were noninvasive forms, and 5 of which were invasive forms, were treated and are presented in this study. When we classified the patients with fungal sinusitis, 11 were diagnosed as mycetoma, 9 as allergic fungal sinusitis, 3 as acute fulminant sinusitis and 2 as chronic indolent sinusitis, while 2 patients were not included in our four groups of sinusitis. In all mycetoma cases the active agent was Aspergillus. Patients with non invasive forms of sinusitis were all treated with endoscopic sinus surgery. 2 of the patients with invasive forms of sinusitis underwent maxillectomy and they were given Amphotericin-B. With a mean follow up of 20 months, only 3 recurrences were seen. The infection recurred in 2 patients with allergic fungal sinusitis and 1 patient with chronic invasive sinusitis. However, 2 patients with acute fulminant invasive sinusitis died before they were operated on, and 1 patient died postoperatively.

[Nasal aspergillosis. Apropos of 1 case]. / Aspergilosis nasal. A propósito de un caso.

Rhinosinusal infections due to molds are seldom meet. Those originated by the genus Aspergillus are comparatively more often implicated. The maxillary sinusitis is the customary disease diagnosed, but in spite of the treatment the cure is not attained. Figures of the disease show a mounting tendency in last years because of both antibiotic and immunosuppressor therapies, so that Aspergillosis though less common that the Candidiasis produce higher mortality. Paramount features of the process are: the appearance of the syndrome in prolonged states of neutropenia the recovery paralleling the normalization of the hemogram; and the recurrences with the relapse of the process.