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It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Intracranial fungal granulomas are rare and of the histologically verified granulomas, Aspergillus spp. is the commonest causative fungal pathogen. Most of the reported large series of aspergillus granulomas are from countries with temperate climate like India, Pakistan, Sudan, and Saudi Arabia. In contrast to disseminated aspergillosis that occurs in immunosuppressed individuals, most of the intracranial aspergillus granulomas are reported in immunocompetent individuals. The temperature, humidity, high spore content in the atmosphere during ploughing, and occupation as agricultural worker are implicated in the pathogenesis. The sinocranial spread is the most common route of intracranial extension. Extracerebral firm fibrotic lesions and skull base lesions are common. Extensive fibrosis and large number of multinucleated giant cells are the characteristic histological features and these pathological features have therapeutic relevance.

Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology.

Human lungs are constantly exposed to a large number of Aspergillus spores which are present in ambient air. These spores are usually harmless to immunocompetent subjects but can produce a symptomatic disease in patients with impaired antifungal defense. In a small percentage of patients, the trachea and bronchi may be the main or even the sole site of Aspergillus infection. The clinical entities that may develop in tracheobronchial location include saprophytic, allergic and invasive diseases. Although this review is focused on invasive Aspergillus tracheobronchial infections, some aspects of allergic and saprophytic tracheobronchial diseases are also discussed in order to present the whole spectrum of tracheobronchial aspergillosis. To be consistent with clinical practice, an approach basing on specific conditions predisposing to invasive Aspergillus tracheobronchial infections is used to present the differences in the clinical course and prognosis of these infections. Thus, invasive or potentially invasive Aspergillus airway diseases are discussed separately in three groups of patients: (1) lung transplant recipients, (2) highly immunocompromised patients with hematologic malignancies and/or patients undergoing hematopoietic stem cell transplantation, and (3) the remaining, less severely immunocompromised patients or even immunocompetent subjects.

The mycotoxin, ochratoxin A (OTA), is thought to be responsible for Balkan endemic nephropathy. OTA accumulates in several tissues, especially in the kidneys and liver. The excretion of OTA into urine is thought to be mainly by tubular secretion, presumably via the organic anion transport system. Recently, several families of multispecific organic anion transporters have been identified: organic anion transporters (OATs), organic anion-transporting polypeptides (OATPs), oligopeptide transporters (PEPTs), and ATP-binding cassette (ABC) transporters, such as MRP2 and BCRP. These renal transporters mediate the transmembrane transport of OTA and play a pivotal role in the development of OTA-induced nephrotoxicity.

OBJECTIVE: The purpose of this study was to analyze the clinical presentations and disease courses of invasive aspergillosis (IA) in patients after near-drowning.

METHODS: The clinical data of 3 cases of invasive aspergillosis after near-drowning from Oct. 2005 to Aug. 2010 in this hospital were retrospectively analyzed, and the related literature was reviewed.

RESULTS: There were 1 male and 2 female patients, aged from 18 to 72 years. All of them had been immunocompetent before drowning. Two patients drowned because of traffic accident, and 1 fell in sewage by accident. All of the 3 patients were intubated because of acute respiratory failure, and received broad-spectrum antibiotic therapy. One had transient leucopenia, and 2 patients received glucocorticoid therapy. The condition of the 3 cases deteriorated 9 to 11 days after near-drowning. Aspergillus was isolated from sputum samples of 2 patients at the same time. Thoracic CT findings included multiple nodules, consolidation and cavity formation. Multiple abcesses in cerebral parenchyma were found in 1 patient with invasive cerebral aspergillosis. One patient died, whose lungs, cerebral parenchyma, myocardium and kidney were all infected by aspergillus. The other 2 patients, whose infection limited to the lungs, had a positive prognosis. Using the terms "aspergillosis" and "near-drowning" a PUBMED search yielded 7 articles, published between 1984 and 2010. Using the terms "invasive pulmonary aspergillosis" and "near-drowning", searching Wangfang data and CHED data, encompass 1 article, published in 2009. In all of the 8 articles, there are 5 final diagnosis cases and 3 clinical diagnosis cases.

CONCLUSIONS: IA was very rare in immunocompetent hosts but had been reported in previously healthy individuals after near-drowning. Aspergillosis might develop 1 to 2 weeks after near-drowning, and the prognosis was poor in patients with central nervous system involvement.

While allergic bronchopulmonary aspergillosis (ABPA) is well recognized as a fungal complication of asthma, severe asthma with fungal sensitization (SAFS) is not. In ABPA the total immunoglobulin E (IgE) is usually >1,000 IU/mL, whereas in SAFS it is <1,000 IU/mL, and either skin prick tests or fungus-specific IgE tests are positive. ABPA may present with any severity of asthma, and occasionally with no asthma or cystic fibrosis, the other common underlying disease. SAFS is a problem in patients with poorly controlled asthma and occasionally presents in the intensive care unit (ICU). Production of mucous plugs and coughing paroxysms is more common in ABPA. Certain underlying genetic defects seem to underpin these remarkable phenotypic differences. From a management perspective both ABPA and SAFS respond to both high doses of corticosteroids and oral antifungal agents, with ∼60% response rate in both ABPA and SAFS with itraconazole. In 50% of patients itraconazole boosts inhaled corticosteroid exposure, sometimes leading to cushingoid features. Second-line therapy data are scant, but we have shown that 70 to 80% of patients who tolerate either voriconazole or posaconazole also respond. Other useful therapies include nebulized hypertonic saline to aid expectoration of thick sputum and long-term azithromycin for its anti-inflammatory effect on the airways. Omaluzimab is useful in some patients with SAFS and occasionally in ABPA. Complications of ABPA include bronchiectasis, typically central in distribution, and chronic pulmonary aspergillosis. Most patients with ABPA and SAFS can be stabilized for long periods with inhaled corticosteroids and itraconazole or another antifungal agent. Novel immunotherapies are on the horizon.© Thieme Medical Publishers.

Fungal infections are among the most serious complications of lung transplantation. The 1-year cumulative incidence of invasive fungal infections in lung transplant recipients is 6 to 10%, which is higher than most other solid organ transplant recipients. Aspergillus spp. are the most common etiologic agents, but Candida spp., non-Aspergillus mycelial fungi, Cryptococcus, Pneumocystis, and endemic mycoses can cause active infections in this population. Clinical manifestations of fungal infection in lung transplant recipients are protean, and include invasive pulmonary disease, airway and anastomotic infections, posttransplant empyemas, and disseminated infections. Most centers employ either universal or targeted antifungal prophylaxis in some form, but the agents, doses, durations, and monitoring strategies vary widely from one center to another. This review discusses the salient fungal organisms responsible for infection in lung transplant recipients and management strategies for prevention.© Thieme Medical Publishers.

Pharmacokinetic/pharmacodynamic (PK/PD) studies examine the relationships of drug pharmacokinetic properties, in vitro drug potency, and treatment efficacy. Study results are integral to the design of optimal dosing strategies, prevention of toxicity, development and interpretation of susceptibility break points, and prevention and recognition of drug resistance. These principles are increasingly utilized to optimize therapy for pulmonary fungal pathogens such as ASPERGILLUS species, although they have been underutilized for other difficult-to-treat fungal pathogens. Understanding the design and implementation of PK/PD studies facilitates more effective utilization of the available antifungal agents to improve outcomes for many of these life-threatening infections.© Thieme Medical Publishers.

Antifungal treatment in the hematological patient has reached a high complexity with the advent of new antifungals and diagnostic tests, which have resulted in different therapeutic strategies. The use of the most appropriate treatment in each case is essential in infections with such a high mortality. The availability of recommendations as those here reported based on the best evidence and developed by a large panel of 48 specialists aimed to answer when is indicated to treat and which agents should be used, considering different aspects of the patient (risk of fungal infection, clinical manifestations, galactomanann test, chest CT scan and previous prophylaxis) may help clinicians to improve the results.

Earlier reviews

BACKGROUND: Although thought to have common immunopathological processes, concomitant occurrence of allergic bronchopulmonary aspergillosis (ABPA) and allergic Aspergillus sinusitis (AAS) appears to be rarely reported as to date only five detailed case reports are available.

OBJECTIVE: To present a review of seven cases of concomitant ABPA and AAS, three of whom were earlier reported for their unusual presentations.

METHODS: Patients with ABPA with nasal symptoms were evaluated radiologically. Consent was taken for antral wash and/or Caldwell-Luc operation in those with radiological evidence of sinusitis and the material was sent for histopathological and mycological studies.

RESULTS: Of the 95 patients with ABPA, 22 had radiological evidence of sinusitis. Nine consented to surgery, seven of whom were diagnosed as concomitant AAS. Nasal symptoms preceded chest symptoms in two patients, vice versa in one and occurred simultaneously in four. Familial occurrence of ABPA, middle lobe syndrome and collapse with effusion along with an operated aspergilloma were seen in one patient each. Transient pulmonary infiltrates and central bronchiectasis were seen in all patients. Computed tomography of the paranasal sinuses, carried out in six patients, revealed mucosal thickening with hyperdense lesions, without any bony erosion or destruction. All patients had positive skin tests, positive precipitin study and raised total and specific IgE. Allergic mucin was seen in all patients, fungal hyphae in five, and culture grew Aspergillus spp. in four. All patients responded favourably to oral prednisolone.

CONCLUSION: Concomitant occurrence of ABPA and AAS seems to be infrequently recognized. Since asthma and sinusitis are often seen by two different specialities, the occurrence of AAS in ABPA and ABPA in AAS may easily be overlooked.

Medical mycology is gradually assuming its proper place in the field of medicine. Its neglect is due to the facts that the fungi are of comparatively little importance in the acute epidemic diseases; exhibit slight pathogenicity; and have an obscure and slow development, and a complicated morphology. Fungous spores abound in the air, and even if found in the tissues are not necessarily significant. We have been interested in collecting some data on the percentage incidence of fungi cultured aseptically from diseased tissues, and in presenting records of our limited survey in the past year, as well as some statistical data from the recent literature. A serious consideration of fungous etiology, primary and secondary, may do its part to reduce the large quantum of undiagnosed disease.

BACKGROUND: Intracranial fungal granulomas are uncommon and their pathogenesis, clinical picture, and effectiveness of therapy remains unclear.

METHODS: Thirty-two cases were studied retrospectively in two groups: (1) Rhinocerebral group (22 cases) had a chronic paranasal sinus (PNS) disease with secondary involvement of skull base, cranial nerves, and/or brain. The granulomas were adherent to dura, firm, avascular, and tough, requiring a knife to cut. (2) Primary intracranial group (10 cases) had no detectable PNS lesion at initial presentation. The granulomas were soft, suckable, and contained pus or necrotic material.

RESULTS: Postoperative and overall mortality were 37.5% and 50%, respectively. Meningoencephalitis was the most common cause of death. Altered sensorium, pus in the granuloma, and/or severe brain edema were poor prognostic factors. All survivors except four have symptomatic residual or recurrent lesions.

CONCLUSION: Early diagnosis with MRI or stereotactic biopsy, radical surgery, and high dose and chronic suppressive chemotherapy may improve overall results in these cases.

In published reports, the incidence of pleuropulmonary involvement in ankylosing spondylitis varies from 0 to 30%. A review of the records of 2,080 patients with ankylosing spondylitis disclosed 28 who had pleuropulmonary manifestations that we believe are typical of those associated with ankylosing spondylitis (an incidence of 1.3%). Among these 28 patients, the most common abnormality was upper lobe fibrobullous lesions. Five had aspergillomas and two had infections-one caused by Mycobacterium kansasii and one by Mycobacterium avium. Three patients had transient pleural effusion of an exudate with normal sugar content. Two had nonspecific pleuritis, found on pleural biopsy. Thoracotomy for aspergilloma was followed by bronchopleural fistula in one of two cases--approximately the ratio found in the literature.

Botanicals are used in many countries for medicinal and general health-promoting purposes. Numerous natural occurrences of mycotoxins in botanicals and dried fruits have been reported. Aflatoxins or ochratoxin A (OTA) have been found in botanicals such as ginseng, ginger, liquorice, turmeric, and kava-kava in the USA, Spain, Argentina, India, and some other countries, while fumonisins have been found in medicinal wild plants in South Africa and in herbal tea and medicinal plants in Turkey. Zearalenone was identified in ginseng root. Dried fruits can be contaminated with aflatoxins, OTA, kojic acid, and, occasionally, with patulin or zearalenone. One main area of concern is aflatoxins in dried figs; bright greenish yellow fluorescence under ultraviolet light is associated with aflatoxin contamination. OTA in dried vine fruits (raisins, sultanas, and currants) is another concern. There are also reports of aflatoxins in raisins and OTA in dried figs, apricots, dried plums (prunes), dates, and quince. Maximum permitted levels in the European Union include 4 microg kg(-1) for total aflatoxins in dried fruit intended for direct consumption and 10 microg kg(-1) for OTA in dried vine fruit. This review discusses the occurrence of mycotoxins in botanicals and dried fruits and analytical issues such as sampling, sample preparation, and methods for analysis. Fungal contamination of these products, the influence of sorting, storage, and processing, and prevention are also considered.

A Nordic External Quality Assessment programme in medical mycology was established in 2005. In order to monitor not 'best practice' but the level of routine diagnostics, specimens were designed to resemble clinical samples and laboratories were asked to handle the samples like routine samples. Five simulated clinical samples were distributed to 59 participating Nordic laboratories of clinical microbiology. The specimens contained the following microorganisms: 1) Candida glabrata and C. albicans in a ratio of 1:20; 2) Cryptococcus neoformans; 3) Aspergillus fumigatus, C. albicans and Enterobacter cloacae; 4) C. tropicalis, Klebsiella pneumonia and Enterococcus faecium; 5) None. 66% of the laboratories failed to detect the C. glabrata isolate in sample no. 1. 34% of the laboratories reporting susceptibility results incorrectly reported the Cryptococcus neoformans isolate as fluconazole susceptible. 24% of the laboratories failed to detect Aspergillus fumigatus in specimen no. 3 despite the accompanying clinical information notifying that it was a BAL sample from a neutropenic patient in an ICU. In conclusion, this distribution of simulated clinical samples illustrates that the traditional quality assessment programmes may give a false sense of satisfactory performance, that mycological diagnosis is difficult, and that there is a need of further improvement and attention.

Fungal infections are increasingly common in burn patients. We performed this study to determine the incidence and outcomes of fungal cultures in acutely burned patients. Members of the American Burn Association's Multicenter Trials Group were asked to review patients admitted during 2002-2003 who developed one or more cultures positive for fungal organisms. Data on demographics, site(s), species and number of cultures, and presence of risk factors for fungal infections were collected. Patients were categorized as untreated (including prophylactic topical antifungals therapy), nonsystemic treatment (nonprophylactic topical antifungal therapy, surgery, removal of foreign bodies), or systemic treatment (enteral or parenteral therapy). Fifteen institutions reviewed 6918 patients, of whom 435 (6.3%) had positive fungal cultures. These patients had mean age of 33.2 /- 23.6 years, burn size of 34.8 /- 22.7%TBSA, and 38% had inhalation injuries. Organisms included Candida species (371 patients; 85%), yeast non-Candida (93 patients, 21%), Aspergillus (60 patients, 14%), other mold (39 patients, 9.0%), and others (6 patients, 1.4%). Systemically treated patients were older, had larger burns, more inhalation injuries, more risk factors, a higher incidence of multiple positive cultures, and significantly increased mortality (21.2%), compared with nonsystemic (mortality 5.0%) or untreated patients (mortality 7.8%). In multivariate analysis, increasing age and burn size, number of culture sites, and cultures positive for Aspergillus or other mold correlated with mortality. Positive fungal cultures occur frequently in patients with large burns. The low mortality for untreated patients suggests that appropriate clinical judgment was used in most treatment decisions. Nonetheless, indications for treatment of fungal isolates in burn patients remain unclear, and should be developed.

To update the case-fatality rate (CFR) associated with invasive aspergillosis according to underlying conditions, site of infection, and antifungal therapy, data were systematically reviewed and pooled from clinical trials, cohort or case-control studies, and case series of >/=10 patients with definite or probable aspergillosis. Subjects were 1941 patients described in studies published after 1995 that provided sufficient outcome data; cases included were identified by MEDLINE and EMBASE searches. The main outcome measure was the CFR. Fifty of 222 studies met the inclusion criteria. The overall CFR was 58%, and the CFR was highest for bone marrow transplant recipients (86.7%) and for patients with central nervous system or disseminated aspergillosis (88.1%). Amphotericin B deoxycholate and lipid formulations of amphotericin B failed to prevent death in one-half to two-thirds of patients. Mortality is high despite improvements in diagnosis and despite the advent of newer formulations of amphotericin B. Underlying patient conditions and the site of infection remain important prognostic factors.

Wound infections with Aspergillus are surprisingly rare given the quantity of spores in hospital air. We report the first case of infection of abdominal viscera due to Aspergillus in a patient with a laparostomy for Crohn's disease. Amphotericin B effected a cure. Sampling of air from the patient's environment yielded one isolated of Aspergillus fumigatus that matched the patient's isolates. Other examples of surgical wounds being contaminated by Aspergillus are reviewed.

Otitis externa can take an acute or a chronic form, with the acute form affecting four in 1,000 persons annually and the chronic form affecting 3 to 5 percent of the population. Acute disease commonly results from bacterial (90 percent of cases) or fungal (10 percent of cases) overgrowth in an ear canal subjected to excess moisture or to local trauma. Chronic disease often is part of a more generalized dermatologic or allergic problem. Symptoms of early acute and most chronic disease include pruritus and local discomfort. If left untreated, acute disease can be followed by canal edema, discharge, and pain, and eventually by extra-canal manifestations. Topical application of an acidifying solution is usually adequate in treating early disease. An antimicrobial-containing ototopical is the preferred treatment for later-stage acute disease, and oral antibiotic therapy is reserved for advanced disease or those who are immunocompromised. Preventive measures reduce recurrences and typically involve minimizing ear canal moisture, trauma, or exposure to materials that incite local irritation or contact dermatitis.

(N.B. The Aspergillus website used to maintain a bibliographic database which was compiled from Medline and Web of Science (GRAsp), but as all users now have access to the former free of charge via the NCBI website and most will have access to Web of Science via their own libraries this resource is currently not being updated. It contains papers dating up to 7th October 2002. Search the GRASp Database here.)