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.

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.

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.

Capítulo 5 - Aspergilose: do diagnóstico ao tratamento / Chapter 5 - Aspergillosis: from diagnosis to treatment

A aspergilose é uma doença multifacetada cujas manifestações clínicas são determinadas pela resposta imune do hospedeiro; podem se apresentar de forma alérgica, saprofítica ou invasiva. A aspergilose broncopulmonar alérgica caracteriza-se por asma corticoide dependente, febre, hemoptise e destruição da via aérea, que pode progredir para fibrose com faveolamento. O tratamento consiste da associação de corticosteroide e itraconazol. A aspergilose pulmonar invasiva requer documentação histopatológica e cultura positiva de material estéril para o diagnóstico. Possui pior prognóstico. O voriconazol apresenta melhor resposta terapêutica, proporcionando maior sobrevida e segurança do que a anfotericina B. A aspergilose pulmonar necrotizante crônica causa destruição progressiva do pulmão em pacientes com doença pulmonar crônica e leve grau de imunossupressão. O tratamento é realizado com itraconazol oral. A aspergilose pulmonar cavitária crônica causa múltiplas cavidades, contendo ou não aspergiloma, associadas a sintomas pulmonares e sistêmicos. O aspergiloma é caracterizado por tosse produtiva crônica e hemoptise em portadores de doença pulmonar crônica, associados a uma cavidade contendo massa arredondada, às vezes móvel, e separada da parede por espaço aéreo. A ressecção cirúrgica é o tratamento definitivo para ambas. Antifúngicos triazólicos promovem beneficio terapêutico a longo prazo com risco mínimo.

Aspergillosis is a multifaceted disease whose clinical manifestations (allergic, saprophytic and invasive forms) are determined by the host immune response. Allergic bronchopulmonary aspergillosis is characterized by corticosteroid-dependent asthma, fever, hemoptysis and destruction of the airways, which can evolve to fibrosis with honeycombing. The treatment consists of the combined use of a corticosteroid and itraconazole. Invasive pulmonary aspergillosis, which has a worse prognosis, is diagnosed based on histopathological documentation and positive culture of a sterile specimen. The treatment response obtained with voriconazole is better, in terms of survival and safety, than that obtained with amphotericin B. In patients with chronic pulmonary disease who are mildly immunocompromised, chronic necrotizing pulmonary aspergillosis causes progressive destruction of the lung. Such patients are treated with oral itraconazole. Chronic cavitary pulmonary aspergillosis causes multiple cavities, with or without aspergilloma, accompanied by pulmonary and systemic symptoms. In patients with chronic pulmonary disease, the aspergilloma is characterized by chronic productive cough and hemoptysis, together with a cavity containing a rounded, sometimes mobile, mass separated from the cavity wall by airspace. Surgical resection is the definitive treatment for both types of aspergillosis. Triazole fungicides provide long-term treatment benefits with minimal risk.

Comparison between referral diagnosis of patients requiring transplantation and pathologic diagnosis of native lungs.

BACKGROUND: The donor organs available for lung transplantation remain far fewer than the number of recipients. Therefore, it is of primary importance to optimize this resource, especially by carefully selecting potential recipients. The diagnosis of end-stage diseases referred for transplantation is mainly based on clinical/radiologic assessment and rarely on histology. METHODS: A clinicopathologic study was performed on 175 patients who underwent lung transplantation over a 12-year period (1995 to 2007). Diagnoses on native lungs were compared with referral diagnoses to assess the presence of discrepancies. In particular, major discrepancies included complete mismatch between referral and pathologic diagnoses and other additional findings likely to affect patient management. RESULTS: Major discrepancies were found in 18 of 175 cases (10%). The highest percentage of discordance was found in diffuse parenchymal lung diseases, more frequently idiopathic pulmonary fibrosis (IPF). In the majority of IPF and other non-IPF idiopathic forms, there was often an imprecise nosographic definition of the diseases. Unsuspected additional findings included Aspergillus and mycobacterial infections, carcinomas and carcinoids. Short-term survival is significantly lower in patients with discrepancies than in those without. CONCLUSIONS: On the basis of the high rate and importance of discrepancies, more accurate and repeated clinicopathologic investigations should be planned in the waiting list period.

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.

Chapter 5--Aspergillosis: from diagnosis to treatment.

Aspergillosis is a multifaceted disease whose clinical manifestations (allergic, saprophytic and invasive forms) are determined by the host immune response. Allergic bronchopulmonary aspergillosis is characterized by corticosteroid-dependent asthma, fever, hemoptysis and destruction of the airways, which can evolve to fibrosis with honeycombing. The treatment consists of the combined use of a corticosteroid and itraconazole. Invasive pulmonary aspergillosis, which has a worse prognosis, is diagnosed based on histopathological documentation and positive culture of a sterile specimen. The treatment response obtained with voriconazole is better, in terms of survival and safety, than that obtained with amphotericin B. In patients with chronic pulmonary disease who are mildly immunocompromised, chronic necrotizing pulmonary aspergillosis causes progressive destruction of the lung. Such patients are treated with oral itraconazole. Chronic cavitary pulmonary aspergillosis causes multiple cavities, with or without aspergilloma, accompanied by pulmonary and systemic symptoms. In patients with chronic pulmonary disease, the aspergilloma is characterized by chronic productive cough and hemoptysis, together with a cavity containing a rounded, sometimes mobile, mass separated from the cavity wall by airspace. Surgical resection is the definitive treatment for both types of aspergillosis. Triazole fungicides provide long-term treatment benefits with minimal risk.

Aspergilosis sinusal no invasiva por Aspergillus parasiticus en niño inmunocomprometido / Non invasive sinusal aspergillosis by Aspergillus parasiticus in an immunecompromised child

El presente trabajo tiene la finalidad de exponer un caso clínico de un niño inmunosuprimido con antecedentes de hospitalización previa, a los 6 años de edad con múltiples síntomas y signos (poliadenopatías, desnutrición, sepsis en cavidad bucal y foco pulmonar, además de pancitopenia). Permaneció en terapia intermedia durante 38 días, cumpliendo varios esquemas antibióticos sin buena respuesta a los mismos. Fue derivado al Hospital Ricardo Gutiérrez (Buenos Aires) desconociéndose la terapéutica seguida en esa oportunidad. Cinco años después (2007) es ingresado nuevamente a nuestro hospital por cuadro de epistaxis cefaléa, compromiso del estado general y neutropenia febril, por lo que se inicia tratamiento antibiótico, además de estudio con mielograma confirmándose el diagnóstico de leucemia linfocítica aguda. Cinco días después de su ingreso expulsa espontáneamente, desde las fosas nasales material granulomatoso el cual fue enviado a estudio micológico (examen directo y cultivo), detectándose alta presencia de Aspergillus parasiticus en ambos exámenes, lo cual fue ratificado por histopatología como una aspergilosis sinusal no invasiva. El paciente fue remitido a la Sala de Inmunodeprimidos donde recibió tratamiento intravenoso con 350 mg/día de anfotericina B-complejo lipídico y terapia específica para LLA. Presentó una evolución tórpida y al 12º día el paciente falleció por su mal estado general y progresión terminal de su enfermedad de base.

This present paper is meant to reveal the clinical case of an immunesuppressed boy having been previously in a hospital, when he was 6, showing multiple symptoms and signs (polyadenopaties, malnutrition, buccal sepsis and pulmonary focus, in addition to pancitopia). He stayed under intermediate therapy for 38 day being submitted to varied antibiotic schemes, though yielding no satisfactory responses to them. Later on he was derived to the Hospital Ricardo Gutiérrez (Buenos Aires), yet therapeutics used at that place being unknown. Five years later (2007), he is admitted again in our hospital because of cephalea epistaxis, a compromised health condition and fevered neutropenia, so he is given an antibiotic treatment in addition to a mielographic studyyet it is confirmed the diagnosis of an acute lymphocytic leukemia. Five days after his admittance, he discharges granulomatous matter from his nasal cavities which was sent for a mycological study. Direct exam and culture, detecting high presence of Aspergillus parasiticus on both exams which was ratified by histopathology as a non invasive sinusal aspergillosis. The patient was sent to the Immunedepressed Ward where he received intravenous treatment with 350mg/day anfotericina Blipidic complex and a specific therapy for LLA. He had a torpid evolution and on the 12nd day the patient died as a result of his very bad health condition as well as the terminal progression of his base disease.

[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.

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.

[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.

Development of a ligand-directed approach to study the pathogenesis of invasive aspergillosis.

Invasive aspergillosis is a leading cause of infectious death in immunosuppressed patients. Here, we adapted a phage display library-based selection to screen and identify binding peptides to the surface of Aspergillus fumigatus conidia and hyphae. We identified a peptide (sequence CGGRLGPFC) that reliably binds to the surface of Aspergillus fumigatus hyphae. Binding was not Aspergillus strain specific, as it was also observed in hyphae of other Aspergillus clinical isolates. Furthermore, CGGRLGPFC-displaying phage targets Aspergillus fumigatus hyphae on formalin-fixed paraffin-embedded histopathology sections of lung tissue recovered from mice with invasive pulmonary aspergillosis. This approach may yield reagents such as peptidomimetics for novel diagnostic and therapeutic interventions in invasive aspergillosis.

The invasive and saprophytic syndromes due to Aspergillus spp.

Aspergillus spp. produce a wide range of invasive and sapropytic syndromes which may involve any tissue. Within a given tissue or organ the pathology and pathogenesis varies enormously, ranging from angioinvasive disease to noninvasive saprophytic disease. The individual invasive and saprophytic syndromes in which a causative role can be attributed to Aspergillus spp. are detailed specifically with reference to the underlying pathology and pathogenesis, the clinical setting and features, and the manner in which a diagnosis can be established.

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.