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  • Tissue reactions to Aspergillus in cases of Hodgkin's disease and leukaemia by Gowing NF, Hamlin IM (1960) Abstract

    Five cases of aspergillosis complicating Hodgkin's disease and leukaemia are reported. The organs involved were: lungs (all five cases), stomach (Case 3); brain and meninges (Case 4); heart, kidneys, spleen, thyroid, and liver (Case 2). Cultures of Aspergillus fumigatus were obtained from the post-mortem tissues of three patients. All the lesions in Case 2 were suppurative. The other four cases had non-suppurative lesions characterized by spreading coagulation necrosis with peripheral hyperaemia, exudation, and haemorrhage. Invasion and occlusion of blood vessels occurred frequently. The various factors that may be responsible for the initiation and progression of the fungal infection are discussed. The available evidence suggests that Aspergillus fumigatus can produce toxic metabolites which are able to cause tissue necrosis and vascular damage. In patients suffering from neoplastic conditions of the lympho-reticular system, especially if steroid hormones or radiomimetic drugs are given, spreading, necrotizing lesions can develop unchecked by antibody or cellular defences.

  • Thyrotoxicosis associated with Aspergillus thyroiditis in chronic granulomatous disease by Halazun JF, Anast CS, Lukens JN (1972) Abstract

    This communication reports the successful treatment of Aspergillus thyroiditis in a boy with chronic granulomatous disease and describes the sequence of alterations in thyroid function produced by the infection. Although the anticipated signs and symptoms of acute suppurative thyroiditis were documented, the abnormalities of thyroid function were those generally considered to be characteristic of subacute thyroiditis.

  • Aspergillomatous abscesses of the brain and thyroid by Lisbona R, Lacourciere Y, Rosenthall L (1973) Abstract

    A case of disseminated aspergillosis with radionuclide documentation of brain and thyroid involvement is presented. The serial nucleographic brain studies exhibited changes that paralleled the clinical course of remission and exacerbation.

  • Invasive aspergillosis. Progress in early diagnosis and treatment by Fisher BD, Armstrong D, Yu B, Gold JW (1981) Abstract

    Ninety-one patients with documented invasive infections due to an Aspergillus species were identified at Memorial Sloan-Kettering Cancer Center from July 1, 1971, through December 31, 1976. Of the 29 patients in whom the diagnosis was made during life, 10 had successful treatment and survived the Aspergillus infection by two to 17 months. An immunodiffusion test was useful in the early diagnosis of invasive aspergillosis, and in 11 patients in whom the diagnosis was supported by seroconversion and who underwent treatment, the survival rate was 64 percent. Cultures of respiratory secretions were not reliable because they often reflected only colonization. In one year, only 9 percent of he patients with Aspergillus species isolated from the sputum had an invasive infection. The lung was the commonest site of involvement, 91 percent of the patients having pulmonary lesions. The most frequently affected extrapulmonary organ was the brain (18.3 percent). Eight patients had nonpulmonary aspergillosis as the only manifestation of this infection. Most of the 91 patients had hematologic neoplasms as the underlying disease, and neutropenia and antibacterial therapy preceded the diagnosis of aspergillosis in the majority of cases.

  • 10 year review of invasive aspergillosis detected at necropsy by Boon AP, O'Brien D, Adams DH (1991) Abstract

    Between 1980 and 1989, 32 cases of invasive aspergillosis were identified out of 2315 consecutive necropsies, an incidence of 1.4%. The incidence in immunosuppressed "high risk" patients was 10.7%. Twenty out of 32 cases showed spread beyond the lungs, with the brain the most common site. There was an increase in cases in the second half of the decade, attributable to the start of a liver transplantation programme. Liver transplant recipients and patients with haematological malignancies were at significantly greater risk of acquiring aspergillosis than kidney transplant recipients or those with solid malignancies treated with chemotherapy. There was also a greater risk of haematogenous dissemination in liver transplant recipients than in all other groups, and this was significantly associated with the use of high dose steroids as anti-rejection treatment. Aspergillus was isolated during life in only eight cases, which indicates a continuing need for and emphasises the value of necropsy.

  • Postmortem analysis of invasive aspergillosis in a tertiary care hospital by Vogeser M, Haas A, Aust D, Ruckdeschel G (1997) Abstract

    To estimate the incidence of fatal invasive aspergillosis in a 1500-bed tertiary-care hospital and to investigate the utility of laboratory diagnostic approaches, necropsy protocols and microbiological data from 1994 and 1995 were reviewed. Among 694 necropsies from 1693 patients who died in these two years, 27 (4%) cases of invasive aspergillosis were identified. Twelve cases of invasive aspergillosis were found after transplantation of solid organs, three after bone marrow transplantation, four in patients with haematological malignancies, and five in patients with solid tumours. In 15 cases (56%) invasive aspergillosis was not suspected before death. In patients in whom serum sampling was performed seven days antemortem, the Aspergillus latex agglutination test had a sensitivity of 53% (9/17). Culture of tracheal secretions or bronchoalveolar lavage fluid from patients with pulmonary aspergillosis yielded Aspergillus fumigatus in 88% (14/16).

  • Thyrotoxicosis induced by thyroid involvement of disseminated Aspergillus fumigatus infection by Hornef MW, Schopohl J, Zietz C, Hallfeldt KK, Roggenkamp A, Gärtner R, Heesemann J (2000) Abstract

    Aspergillus fumigatus is increasingly recognized as an important nosocomial pathogen in severely immunocompromised patients. Infection is difficult to diagnose antemortem and typically has a fatal outcome. Here we report the case of a cardiac transplant recipient with disseminated A. fumigatus infection which clinically presented as thyrotoxicosis due to massive involvement of the thyroid gland.

  • A case of disseminated aspergillosis with thyroid involvement by Cornet M, Ugo V, Lefort E, Molina T, James JM, Vekhoff A, Audouin J, Marie JP, Bouvet A (2001) Abstract

    No abstract. First paragraph: Invasive aspergillosis has become the most prevalent life-threatening mold infection. It remains a common opportunistic infection, complicating the clinical course of illness in patients who are severely immunodeficient due to conditions such as hematological malignancy, bone marrow or solid organ transplantation, AIDS or steroid therapy. Invasive pulmonary aspergillosis with respiratory symptoms is the predominant form of the disease. Although thyroid involvement is found frequently at necropsy, it is rarely suspected antemortem. Reported here is a case of disseminated aspergillosis that occurred in a patient with myelodysplasia, who demonstrated symptoms of both thyroid and pulmonary involvement. The literature about this unusual presentation is also reviewed.

  • Fatal airway obstruction caused by invasive aspergillosis of the thyroid gland by Kishi Y, Negishi M, Kami M, Hamaki T, Miyakoshi S, Ueyama J, Morinaga S, Mutou Y (2002) Abstract

    Invasive aspergillosis is a common form of fungal infection in patients with hematological malignancies. Because Aspergillus species have angioinvasive properties, they frequently disseminate from the lung to a variety of organs via hematogenous spread. Extra-pulmonary involvement occurs at an advanced stage of invasive aspergillosis, and represents an ominous sign. However, few reports have been published on extra-pulmonary involvement in cases of aspergillosis. Its clinical features have not been fully clarified. We experienced a patient who developed thyrotoxicosis and fatal airway obstruction caused by invasive aspergillosis of the thyroid. A 26-year-old man was admitted to our hospital for the treatment of non-Hodgkin's lymphoma. During myelosuppression following the chemotherapy, he developed cervical swelling and hyperthyroidism. We suspected lymphoma infiltration to the thyroid, and irradiated it with a total of 26 Gy. However, the cervical lesion enlarged rapidly, and he complained of wheezing and dyspnea. We underwent immediate tracheostomy to secure the airway, but he died. Autopsy findings were striking. Extensive necrosis with diffuse infiltration of Aspergillus hyphae was observed in the thyroid gland. Necrotic tissues of the thyroid protruded into the tracheal lumen, causing airway obstruction. This case demonstrated that invasive aspergillosis of the thyroid can lead to medical emergency.

  • Aspergillus thyroiditis in a living donor liver transplant recipient by Matsui Y, Sugawara Y, Tsukada K, Kishi Y, Shibahara J, Makuuchi M (2006) Abstract

    Aspergillosis is increasingly recognized as an important nosocomial pathogen in immunocompromised patients. Infection is difficult to diagnose and typically has a fatal outcome. We describe a liver transplant patient with fulminant hepatic failure, who had persistent fever of undetected origin postoperatively and an increased (1-3)-beta-d glucan level. Gallium-67 citrate scanning showed abnormal uptake in the thyroid bilaterally. Fine needle biopsy of the thyroid revealed thyroidal invasion of Aspergillosis. Total thyroidectomy was performed and the C reactive protein level decreased to 1.01 mg/dl. The patient died of liver sepsis due to Pseudomonas aeruginosa. (1-3)-beta-d Glucan monitoring and systematic radionuclide images are useful modalities for early diagnosis of Aspergillosis.

  • Intracavitary fungus balls in pulmonary aspergillosis by Saliba A, Pacini L, Beatty OA (1961) Abstract

    No abstract. First paragraph: Mycotic infections continue to play an increasingly important role in the practice of medicine, and often present a challenge in the speciality of pulmonary diseases. Although a relatively new field, one finds reports on the mycoses more frequently in medical literature. An increase in these infections may be the result of an indiscriminate use of antibiotics and increasing use of the corticosteroids.

  • Leukocyte oxidase: defective activity in chronic granulomatous disease by Baehner RL, Nathan DG (1967) Abstract

    The intact leukocytes of two children with chronic granulomatous disease fail to reduce nitroblue tetrazolium during phagocytosis. This is due to defective operation of an oxidase of reduced nicotinamide adenine dinucleotide that is insensitive to cyanide and that indirectly stimulates the oxidation of glucose-6-phosphate in leukocytes. Such leukocytes undergo no increase in oxygen consumption or in activity of the hexose monophosphate shunt during phagocytosis, although lactate production is normal. The addition of nitroblue tetrazolium to a leukocyte suspension appears to provide a sensitive diagnostic screening test for this disease.

  • Intracavitary amphotereicin B in the treatment of symptomatic pulmonary aspergillomas by Hargis JL, Bone RC, Stewart J, Rector N, Hiller FC (1980) Abstract

    The optimal treatment of pulmonary aspergillomas is not established. Surgical resection is often impossible because of severe, underlying pulmonary impairment, and medical treatment has given negative or inconclusive results. Six patients with symptomatic pulmonary aspergillomas were treated with percutaneous instillation of intracavitary amphotericin B. Four patients who received the full course of therapy showed improvement and stabilization or reversal of progressive roentgenographic changes. Also, follow-up serologic studies of Aspergillus spp. precipitins were obtained in three and were negative. One patient did not tolerate this treatment because of repeated systemic reactions. Another patient did not respond clinically or roentgenographically. Intracavitary amphotericin B therapy should be considered in patients with symptomatic pulmonary aspergilloma, particularly when surgical resection is not feasible.

  • "Semi-invasive" pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung by Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT (1981) Abstract

    A chronic cavitary form of pulmonary aspergillosis may occur with mild immunosuppression or underlying lung disease. In this "semi-invasive" type, the fungus is intermediate between a simple saprophyte and an invasive pathogen. Aspergillus may produce extensive lung destruction despite the lack of vascular invasion. The absence of a previous cavity distinguishes such cases from secondary noninvasive mycetomas. Radiographic features include a chronic infiltrate, progressive cavitation, and subsequent mycetoma formation. Biopsy may be helpful; however, marked squamous metaplasia can produce false-positive Class V cytological findings even though malignancy is excluded. This variety of aspergillosis supports the concept that the traditional allergic, saprophytic, and invasive forms may represent a spectrum of disease dependent on host immune status and lung architecture.

  • What happens to patients with pulmonary aspergilloma? Analysis of 23 cases by Rafferty P, Biggs BA, Crompton GK, Grant IW (1983) Abstract

    The problems associated with pulmonary aspergilloma were assessed retrospectively in 23 patients presenting from 1953 to 1982. Haemoptysis occurred in over half the patients and in two it was fatal. Invasive aspergillosis occurred in five patients, a higher proportion than in earlier reports, and two of these died. Amphotericin B in combination with either flucytosine or natamycin and, more recently, ketoconazole have proved useful in the treatment of this condition.

  • Ten-year experience with mycetomas in patients with pulmonary tuberculosis by Butz RO, Zvetina JR, Leininger BJ (1985) Abstract

    We studied 33 consecutive patients with tuberculous pulmonary cavities complicated by fungus balls to evaluate their treatment. Nineteen had surgical resection for massive or recurrent bleeding or possibility of tumor. One patient died of postpneumonectomy empyema (30-day surgical mortality, 5 percent). Fourteen had no surgery. No patient died of hemoptysis. Respiratory failure contributed most often to death. Hepatic complications and other problems of alcoholism were also prominent. Good results can be obtained by resection in these severely ill patients if care is taken to preserve functioning pulmonary tissue and to avoid complications of alcoholic hepatic disease. Within these constraints, tuberculous cavities complicated by mycetomas should be resected for massive or recurrent hemoptysis.

  • Aspergilloma in sarcoid and tuberculosis by Tomlinson JR, Sahn SA (1987) Abstract

    The presentation, treatment, and outcome of 28 patients with aspergilloma and cavitary tuberculosis (14) and sarcoidosis (14) were compared. Patients with tuberculosis had localized disease (12 of 14, 86 percent), whereas patients with sarcoidosis had diffuse disease (1 of 14, 7 percent localized). Results indicated that patients with either sarcoid or tuberculosis who developed an aspergilloma had a poor prognosis over the next decade. Patients with sarcoid appeared to have a worse short-term prognosis; surgical resection in the tuberculosis patients may have contributed to their better short-term survival.

  • Control of hemoptysis: systemic angiography and anastomoses of the internal mammary artery by Jardin M, Remy J (1988) Abstract

    Twenty-three patients with massive and recurrent hemoptysis were examined with angiography. Particular attention was directed to the internal mammary arteries. Specific causes for the bleeding were tuberculosis (n = 9), aspergilloma (n = 8), bronchiectasis (n = 1), primary systemic amyloidosis (n = 1), congenital and acquired pulmonary venous obstruction (n = 2), chronic pulmonary embolism (n = 1), and bilateral congenital pulmonary artery stenosis (n = 1). Eleven of these 23 patients were treated with systemic arterial embolization, and immediate cessation of bleeding occurred in nine. The recognition of the numerous collateral vessels and anastomoses of the internal mammary arteries is essential for successful percutaneous embolization for hemoptysis. The authors outline these various pathways and collateral vessels.

  • Aspergillus colonization of pulmonary rheumatoid nodule by McConnochie K, O'Sullivan M, Khalil JF, Pritchard MH, Gibbs AR (1989) Abstract

    No abstract. First paragraph: Involvement of the lung and pleura in the rheumatoid process is well recognized and can take several forms. These include pleurisy, with or without pleural effusion, diffuse interstitial fibrosis, necrobiotic nodules, obliterative bronchiolitis, follicular bronchiectasis, pulmonary hypertension and pulmonary vasculitis. Nodules occurring in dust exposed individuals who have rheumatoid arthritis constitute Caplan's syndrome.

  • Itraconazole therapy in aspergillosis: study in 49 patients by Dupont B (1990) Abstract

    Itraconazole, 200 to 400 mg once daily, was administered to 49 patients with different types of aspergillosis: pulmonary aspergilloma (14 patients), chronic necrotizing pulmonary aspergillosis (14), and invasive aspergillosis (21). Itraconazole was prescribed alone or in combination or after treatment with amphotericin B and flucytosine. Of 14 aspergilloma patients, 2 were cured and 8 had symptomatic improvement. In chronic necrotizing pulmonary aspergillosis, 7 of 14 patients were cured and 6 improved significantly. In invasive aspergillosis treatment failed in 6 patients and 15 were cured. Itraconazole can be an alternative to amphotericin B in the treatment of invasive aspergillosis and chronic necrotizing pulmonary aspergillosis. In aspergilloma itraconazole may be useful in inoperable cases.

  • Chronic invasive aspergillosis in apparently immunocompetent hosts by Karim M, Alam M, Shah AA, Ahmed R, Sheikh H (1997) Abstract

    Seventeen cases of invasive aspergillosis occurring since 1987 in apparently immunologically normal hosts have been reviewed: 9 of invasive sinus aspergillosis, 2 of isolated brain abscesses, 3 of pneumonia (1 in a patient who developed mediastinitis), 2 of lymph node aspergillosis, and 1 of osteomyelitis of the foot. Two of the 9 patients with sinus aspergillosis died; the rest were stable up to March 1993. They responded initially to combined surgical and medical therapy. Both patients with brain abscesses survived following surgery, but one had neurological sequelae. Both patients with pneumonia were well following therapy with amphotericin B; one also received itraconazole. The patient with mediastinitis died, but this disease was diagnosed late. The patients with lymph node involvement were lost to follow-up, as was the patient with osteomyelitis. Invasive aspergillosis may be common in Pakistan. Greater awareness would allow earlier diagnosis and therapy, thereby improving the outcome.

  • The histological spectrum of chronic necrotizing forms of pulmonary aspergillosis by Yousem SA (1997) Abstract

    Chronic necrotizing pulmonary aspergillosis (CNPA) is a rare locally destructive form of chronic aspergillosis that is recognized as a clinical syndrome, but has been poorly defined histologically. In this study, 10 cases of CNPA were evaluated from a morphological perspective. Three distinct forms of CNPA emerged. One form (n = 4) resembled a necrotizing granulomatous pneumonia centered around a central zone of infarct-like necrosis of parenchyma resulting from angioinvasive aspergillus. The second pattern (n = 4) was that of a granulomatous bronchiectatic cavity with a central fungus ball and subtle tongues of necrosis and inflammation extending into and through the fibrous wall of the cavity. A final form (n = 2) had a bronchocentric granulomatosis-like appearance with a necrotizing granulomatous bronchitis/bronchiolitis associated with luminal necrotic debris and replacement of mucosa by a palisaded histiocytic reaction. Despite the varied histomorphology, all patients survived the aspergillus infection after antifungal therapy and surgical resection. The different forms of pulmonary aspergillosis are briefly discussed, and the differential diagnosis, with particular regard to mycetomas and allergic forms of bronchocentric granulomatosis, is highlighted.

  • Mannose-binding lectin gene polymorphisms as a susceptibility factor for chronic necrotizing pulmonary aspergillosis by Crosdale DJ, Poulton KV, Ollier WE, Thomson W, Denning DW (2001) Abstract

    It was investigated whether a deficiency of mannose-binding lectin (MBL), which binds Aspergillus species avidly in vitro, could account for chronic necrotizing pulmonary aspergillosis (CNPA), which is seen most commonly in nonimmunocompromised patients. Blood samples were obtained from 11 patients (10 white) with CNPA and were compared with blood samples from 82 white control subjects. MBL haplotype profiles were determined by polymerase chain reaction, using sequence-specific primers and sequence-specific oligonucleotide probing techniques. Seven of the 10 white patients with CNPA had MBL haplotypes that encode for low levels of the protein, compared with 25.6% of the white control subjects (P=.004). Presence of the codon 52 mutation was particularly common in patients with CNPA (P=.015), which suggests a greater involvement of this mutation.

  • Chronic necrotizing pulmonary aspergillosis in pneumoconiosis: clinical and radiologic findings in 10 patients by Kato T, Usami I, Morita H, Goto M, Hosoda M, Nakamura A, Shima S (2002) Abstract

    STUDY OBJECTIVE: To characterize clinical, radiographic, and CT findings of chronic necrotizing pulmonary aspergillosis (CNPA) in patients with pneumoconiosis. METHODS: We studied 10 patients with pneumoconiosis who were seen at Asahi Rosai Hospital and received a clinical diagnosis of CNPA during a 15-year period, and detailed the long-term clinical and radiologic courses of four cases. RESULTS: All patients were men, ranging in age from 48 to 77 years (mean, 60.1 years). Their occupational histories included pottery making (n = 9) and coal mining (n = 1). Chest radiographic findings by the International Labor Organization profusion grading system were greater than category 2. All patients were symptomatic, with a productive cough, hemoptysis, and dyspnea. Serum findings were positive for the Aspergillus antibody in seven patients. The radiologic findings consisted of parenchymal infiltrates and cavities mostly containing mycetoma, which generally involved the upper lobes. The disease progressed slowly; in one patient, broad destruction of the lung was observed after > 10 years without antifungal administration. Most of the patients experienced clinical and radiologic improvement after receiving antifungal therapy, by oral, inhaled, or intracavitary administration. CONCLUSIONS: Chronic persistent or progressive upper-lobe infiltrates and cavities in patients with pneumoconiosis should raise the possibility of CNPA. Early diagnosis and initiation of effective therapy are recommended to achieve a better outcome.

  • Adverse reactions to voriconazole by Boyd AE, Modi S, Howard SJ, Moore CB, Keevil BG, Denning DW (2004) Abstract

    Voriconazole is a new antifungal agent effective in the treatment of invasive aspergillosis. Interpatient variation in plasma concentrations is considerable--more than 100-fold. We describe 3 patients with diverse manifestations of toxicity (e.g., hallucinations, hypoglycemia, electrolyte disturbance, and pneumonitis) possibly attributable to high voriconazole concentrations. Measurement of plasma concentrations could be helpful in optimizing voriconazole dosages.

  • Chronic necrotizing pulmonary aspergillosis following cryptococcal infection of the lung by Kitazaki T, Osumi M, Miyazaki Y, Kihara C, Kinoshita A, Tsuji H, Itoh M, Soda H, Kohno S (2005) Abstract

    A 64-y-old male with steroid-induced diabetes mellitus was admitted to our hospital because of a nodular shadow found by chest radiography. Pathological examination revealed pulmonary cryptococcosis, and he was positive for serum Cryptococcus antigen. After oral treatment with fluconazole, he experienced clinical and radiographic improvement, but during ensuing observation without antifungal treatment his respiratory symptoms gradually worsened. Chest radiography showed progressive infiltration around the cavity, and Aspergillus mold was isolated by transbronchial lung biopsy from the lesion where previous cryptococcal infection was present. In addition, serum antibodies to Aspergillus antigens were demonstrated by immunodiffusion. Thus, pulmonary aspergillosis was found to complicate a case of pulmonary cryptococcal infection.

  • A patient with ankylosing spondylitis who presented with chronic necrotising aspergillosis: report on one case and review of the literature by Pamuk ON, Harmandar O, Tosun B, Yörük Y, Cakir N (2005) Abstract

    Upper lobe fibrobullous disease is a well-known finding in advanced stages of ankylosing spondylitis (AS). In this report, we present a 57-year-old male patient who was diagnosed with a right apical cavitary lesion after coming to us with the complaint of haemoptysis. The patient underwent upper lobe segmentectomy and an aspergilloma was detected. Histologic findings were in favour of necrotising Aspergillus pneumonia. It was interesting that the patient had not been diagnosed with AS before and presented initially with chronic necrotising Aspergillus pneumonia. In the literature, there are recently published series of pulmonary high-resolution computed tomography (HRCT) in AS which claim that parenchymal abnormalities are quite frequent. Although the clinical significance of these abnormalities is not known with certainty, it has been reported that they might be seen even in early-stage patients. It is suggested that the pulmonary involvement in AS might be affected by mechanical factors related to limitation of motion of the thoracic cage and also by parenchymal inflammation. Here, we review the series of pulmonary HRCT in AS patients.

  • Chronic necrotising pulmonary aspergillosis: a rare complication in a case of silicosis by Parakh UK, Sinha R, Bhatnagar AK, Singh P (2005) Abstract

    Chronic necrotising pulmonary aspergillosis (CNPA) is a rare complication of silicosis whose diagnosis requires a high index of suspicion as it mimics tuberculosis. We report a case of a 52-year-old male with a long history of silica dust exposure and progressively increasing dyspnoea for the past eight years, productive cough, fever, weight loss for past three months and hemoptysis for preceding three weeks. Based on the clinical, radiological and microbiological evidence, he was diagnosed to be a case of CNPA with aspergilloma complicating silicosis.

  • Chronic necrotizing pulmonary aspergillosis as a complication of pulmonary Mycobacterium avium complex disease by Kobashi Y, Fukuda M, Yoshida K, Miyashita N, Niki Y, Oka M (2006) Abstract

    OBJECTIVE AND BACKGROUND: To investigate the characteristic clinical features of chronic necrotizing pulmonary aspergillosis (CNPA) as a complication of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: Clinical analysis of nine cases without a history of old pulmonary tuberculosis in whom CNPA was found to be a complication during the follow-up period for MAC disease. RESULTS: The average duration from the diagnosis of pulmonary MAC disease to the diagnosis of CNPA was 36.0 months. Five patients received antituberculous therapy including clarithromycin for pulmonary MAC disease, but this treatment was ineffective in most. A positive culture for Aspergillus spp. from sputum and a bronchoscopic specimen and clinical evidence of a chronic infective process were recognized in all cases at the time of detection of CNPA. Serological fungal examinations for anti-Aspergillus IgG antibody were initially negative and became positive in all cases during the follow-up period of pulmonary MAC disease. The presence of CNPA surrounding the cavity previously caused by MAC was characterized by local thickening of the cavity with a fungus ball and the appearance of an infiltration shadow surrounding the cavity. In most of the cases, CNPA was at first treated with oral itriconazole and then with i.v. infusion of micafungin, but the clinical efficacy was generally poor. CONCLUSION: The results of this study showed that during the long follow-up period of patients with pulmonary MAC disease it is important to not only carry out serological examinations, but also perform radiological examinations using chest CT.

  • Interferon-gamma and granulocyte-macrophage colony stimulating factor therapy in three patients with pulmonary aspergillosis by Bandera A, Trabattoni D, Ferrario G, Cesari M, Franzetti F, Clerici M, Gori A (2008) Abstract

    An immune response mediated by type 2 cytokines is thought to contribute to the development and unfavorable outcome of aspergillosis. Adjuvant therapy with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) was added to antifungal treatment in three nonneutropenic patients (one HIV-positive and two HIV-negative patients) with culture proven aspergillosis refractory to classical antifungal therapy. Clinical improvement was observed concomitantly with an increase in peripheral blood leukocyte proliferation and type 1 cytokines production. Our findings suggest an association between the improvement in type 1 cytokine production observed during IFN-gamma and GM-CSF administration and a better control of Aspergillus infection in patients with progressive disease despite adequate antifungal therapy.

  • Bronchopulmonary aspergilloma: a reappraisal by Chatzimichalis A, Massard G, Kessler R, Barsotti P, Claudon B, Ojard-Chillet J, Wihlm JM (1998) Abstract

    BACKGROUND: Classically, most complications observed after operations for aspergilloma occurred in patients with sequelae of tuberculosis. Because the incidence of tuberculosis has declined over the past two decades, aspergilloma is expected to develop with increasing frequency in patients without previous tuberculosis. Therefore, our hypothesis was that operative outcome should have improved during the most recent years in comparison with our previous experience. METHODS: Operative outcome of 12 recently accrued patients was evaluated and compared with a historic control group of 55 patients, previously reported by the same center. RESULTS: As expected, only 17% of patients of the present series had a history of tuberculosis, compared with 57% in the former series. Postoperatively, there was no mortality. Major morbidity has decreased, although this difference is not statistically significant: bleeding decreased from 44% to 9% of patients; space problems decreased from 47% to 18%; and prolonged hospital stay (>30 days) decreased from 32% to 9%. CONCLUSIONS: Our results support a trend toward improved postoperative outcome of operations for aspergilloma owing to a decreased incidence of aspergilloma growing in tuberculous cavitations.

  • A spreading concern: inhalational health effects of mold by Weinhold B (2007) Abstract

    No abstract. First paragraph: The issue of mold contamination has drawn the national and international spotlight on the heels of publicity about prominent situations, such as a hotly contended link between mold and severe illness - and one death - in 10 Ohio infants in 1993 and 1994; a major 2001 insurance battle over the moldy Dripping Springs, Texas, house of Melinda Ballard and her family; the mushrooming mold infestations indoors and out along the Gulf Coast after Hurricanes Katrina and Rita slammed ashore in 2005; and the mold infestation that helped spur the February 2007 outcry over the treatment given to recuperating soldiers at Walter Reed Army Medical Center. As recently as 25 years ago, inhaled mold was considered primarily as a nuisance, not a serious health threat, but the growing scientific and medical evidence suggests that the threat is widespread and, for some people, quite serious.

  • Purification and characterization of mycoferritin from Aspergillus flavus MTCC 873 by Vakdevi V, Sashidhar RB, Deshpande V (2009) Abstract

    The fungus Aspergillus flavus MTCC 873, a non-toxigenic isolate demonstrated its capability to synthesize mycoferritin (MF) upon induction with iron in yeast extract sucrose (YES) medium. The molecular mass, yield, iron and carbohydrate contents of the MF were 440 kDa, 0.015 mg/g of wet mycelia, 0.8 and 30.4%, respectively. Native gel-electrophoresis revealed a band corresponding to dimeric form of equine spleen ferritin (ESF). Subunit analysis by SDS-PAGE revealed a single protein band with an apparent molecular mass of 24 kDa, suggesting similar sized subunits in the structure of apoferritin shell. Immunological cross-reactivity was observed with the anti-fish liver ferritin. Transmission electron microscopy (TEM) revealed an apparent particle size of 100 A. N-terminal amino acid sequence of MF revealed a sequence of SLPLQDYA, which showed identities with other eukaryotic ferritin sequences. The spectral characteristics (UV/VIS, fluorescence and circular dichroic spectra) were similar to ESF. The fungus, unlike A. parasilicus 255 (non-toxigenic) was incapable of producing allatoxins, when grown in YES media.

  • Biosynthesis of antimicrobial silver nanoparticles by the endophytic fungus Aspergillus clavatus by Verma VC, Kharwar RN, Gange AC (2010) Abstract

    AIM: To induce the biosynthesis of silver nanoparticles (AgNPs) using Aspergillus clavatus and evaluate their antimicrobial potential. MATERIALS & METHODS: Aspergillus clavatus (AzS-275), an endophytic fungus isolated from sterilized stem tissues of Azadirachta indica A. Juss., was challenged with 1 mM AgNO(3) solution. The characterization of the AgNPs was carried out by x-ray diffraction spectrometry, transmission-electron microscopy and atomic force microscopy. RESULTS & DISCUSSION: The synthesized AgNPs were found to be extracellular, polydispersed spherical or hexagonal particles ranging from 10 to 25 nm in size. Antimicrobial activity was performed using a disc-diffusion method against Candida albicans, Pseudomonas fluorescens and Escherichia coli. The results showed an average minimum inhibitory concentration of 5.83 microg ml(-1) and minimum fungicidal concentration of 9.7 microg ml(-1) against C. albicans. CONCLUSIONS: AgNPs can be mycosynthesized extracellularly using A. clavatus as the fungal system, which is highly advantageous over chemical synthesis not only because it can be synthesized on a large scale, but because of the ease of downstream processing and its biomedical application in antimicrobial activity.

  • Genetic isolation among sympatric vegetative compatibility groups of the aflatoxin-producing fungus Aspergillus flavus by Grubisha LC, Cotty PJ (2010) Abstract

    Aspergillus flavus, a fungal pathogen of animals and both wild and economically important plants, is most recognized for producing aflatoxin, a cancer-causing secondary metabolite that contaminates food and animal feed globally. Aspergillus flavus has two self/nonself recognition systems, a sexual compatibility system and a vegetative incompatibility system, and both play a role in directing gene flow in populations. Aspergillus flavus reproduces clonally in wild and agricultural settings, but whether a cryptic sexual stage exists in nature is currently unknown. We investigated the distribution of genetic variation in 243 samples collected over 4 years from three common vegetative compatibility groups (VCGs) in Arizona and Texas from cotton using 24 microsatellite loci and the mating type locus (MAT) to assess population structure and potential gene flow among A. flavus VCGs in sympatric populations. All isolates within a VCG had the same mating type with OD02 having MAT1-2 and both CG136 and MR17 having MAT1-1. Our results support the hypothesis that these three A. flavus VCGs are genetically isolated. We found high levels of genetic differentiation and no evidence of gene flow between VCGs, including VCGs of opposite mating-type. Our results suggest that these VCGs diverged before domestication of agricultural hosts (>10,000 yr bp).

  • A cryptic role of a glycolytic-gluconeogenic enzyme (aldolase) in amino acid transporter turnover in Aspergillus nidulans by Roumelioti K, Vangelatos I, Sophianopoulou V (2009) Abstract

    In Aspergillus nidulans the fbaA1013 mutation results in reduced or total loss of growth on glycolytic and gluconeogenic carbon sources, respectively. It also negatively affects growth on several amino acids (including l-proline, l-glutamate or l-aspartate) that the fungus can use as nitrogen source on glycolytic carbon sources. Complementation of the fbaA1013 mutation using an A. nidulans genomic library resulted in cloning of the fbaA gene, which encodes a putative fructose 1,6-biphosphate aldolase (FBA), an enzyme involved in both glycolysis and gluconeogenesis. The fbaA1013 mutation is a chromosome rearrangement in the 5' regulatory region of the fbaA gene resulting in reduced or total loss of transcription in response to glycolytic and gluconeogenic carbon sources respectively. The fbaA gene is essential for growth. A functional FbaA protein is necessary for plasma membrane localization of the AgtA acidic amino acid (l-glutamate/l-aspartate) transporter, as the fbaA1013 mutation results in targeting to and presumably subsequent degradation of AgtA in the vacuole. Our results support a novel role of the FbaA protein that is, involvement in the regulation of amino acids transporters.

  • Development of an HPTLC-based diagnostic method for invasive aspergillosis by Puri A, Ahmad A, Panda BP (2009) Abstract

    A rapid, sensitive and specific high-performance thin-layer chromatographic (HPTLC) method was developed and validated for determination of gliotoxin in Aspergillus infected immunocompromised patients with invasive aspergillosis (IA). Densitometric analysis of gliotoxin was carried out in the absorbance mode at 254 nm after single-step extraction with chloroform. The method uses TLC aluminum plates pre-coated with silica gel 60F-254 as a stationary phase and toluene-isoamyl alcohol-methanol (10:0.5:0.5, v/v/v) as mobile phase, which gives compact spot of gliotoxin (R(f) = 0.51). The calibration curve was linear (r(2) >/= 0.994) between peak area and concentration in the tested range of 100-1000 ng spot(-1) with minimum detectable range 0.025 ng mu(-1) of serum sample. The mean +/- SD value of slope and intercept of the standard chromatogram of gliotoxin were found to be 523.2 +/- 1.555635 and 915.8 +/- 30.68843, respectively. The developed method is simple, rapid, precise and less costly than earlier diagnostic methods, and different serum samples can be run on a single TLC plate for comparative analysis. The proposed method can be used to analyze gliotoxin in patient serum for easy, rapid and cost-effective diagnosis of IA.

  • Localization and function of calmodulin in live-cells of Aspergillus nidulans by Chen S, Song Y, Cao J, Wang G, Wei H, Xu X, Lu L (2009) Abstract

    Calmodulin (CaM) is a small, eukaryotic protein that reversibly binds Ca(2+). Study of CaM localization in genetically tractable organisms has yielded many insights into CaM function. Here, we described the dynamic localization of Aspergillus nidulans CaM (AnCaM) in live-cells by using recombination strains with homologous, single cross-over insertions at the target gene which placed the GFP fused copy under the inducible alcA promoter and the RFP-CaM integration under the native cam promoter. We found that the localization of CaM fusion was quite dynamic throughout the hypha and was concentrated to the active growing sites during germination, hyphal growth, cytokinesis and conidiation. The depletion of CaM by alcA promoter repression induced the explicit abnormalities of germlings with the swollen germ tubes. In addition, the position of highly concentrated GFP-CaM in the extreme apex seemed to determine the hyphal orientation. These data collectively suggest that CaM is constantly required for new hyphal growth. In contrast to this constant accumulation at the apex, GFP-CaM was only transiently localized at septum sites during cytokinesis. Notably, depletion of CaM caused the defect of septation with a completely blocked septum formation indicating that the transient CaM accumulation at the septum site is essential for septation. Moreover, the normal localization of CaM at a hyphal tip required the presence of the functional actin cytoskeleton and the motor protein KipA, which is indispensable for positioning Spitzenkörper. This is the first report of CaM localization and function in live-cells by the site-specific homologous integration in filamentous fungi.

  • Clinically Driven Diagnostic Antifungal Approach in Neutropenic Patients: A Prospective Feasibility Study by Girmenia C, Micozzi A, Gentile G, Santilli S, Arleo E, Cardarelli L, Capria S, Minotti C, Cartoni C, Brocchieri S, Guerrisi V, Meloni G, Foà R, Martino P (2009) Abstract

    PURPOSE: Preemptive strategies in neutropenic patients based on serum galactomannan (GM) -guided triggering of diagnostic work-up may be time-consuming and expensive when applied to the entire population. We have assessed the feasibility of a clinically driven diagnostic strategy without GM screening. PATIENTS AND METHODS: Patients with neutropenic fever underwent a baseline diagnostic work-up (BDWU; three blood cultures and other examinations as indicated). An intensive diagnostic work-up (IDWU; GM for 3 days, chest computed tomography and other examinations as indicated) was reserved for patients with 4 days of persisting or relapsing fever or with other clinical findings possibly related to an invasive fungal diseaser (IFD). Antifungal therapy was administered to patients diagnosed with IFD and empirically (negative IDWU) only to those with persisting neutropenic fever and worsening clinical conditions. RESULTS: Of 220 neutropenia episodes, fever occurred in 159 cases and recurred in 28 cases. Overall, 49 IFDs were diagnosed (two by BDWU and 47 by IDWU) during 48 episodes (21.8%). Diagnostic-driven therapy was administered to 48 patients with IFDs; one patient with zygomycosis died without treatment. Only one patient received empirical therapy. IDWU was required in 40% of neutropenia episodes, and only 1.4 mean blood samples per neutropenia episode were tested for GM. Our strategy allowed a 43% reduction in antifungal treatments compared with a standard empirical approach. At 3-month follow-up, 63% of patients with IFD survived, and no undetected IFDs were found. CONCLUSION: A clinically driven diagnostic approach in selected neutropenia episodes offered effective antifungal control and reduced the exposure to unnecessary antifungal treatment.

  • Aspergillus fumigatus survival in alkaline and extreme zinc-limiting environments relies on the induction of a zinc-homeostasis system encoded by the zrfC-aspf2 genes by Amich J, Vicentefranqueira R, Leal F, Calera JA (2009) Abstract

    Aspergillus fumigatus has three zinc transporter-encoding genes whose expression is regulated by both pH and the environmental concentration of zinc. We have previously reported that the zrfA and zrfB genes of A. fumigatus are transcribed at higher levels and are required for fungal growth under acidic zinc-limiting conditions, whereas they are dispensable for growth in neutral or alkaline zinc-limiting media. Here we report that the transporter of the zinc uptake system that functions in A. fumigatus growing in neutral or alkaline environments is encoded by zrfC. The transcription of zrfC occurs divergently with respect to the adjacent aspf2 gene, which encodes an immunodominant antigen secreted by A. fumigatus. Both genes - zrfC and aspf2 - are required to different extents for fungal growth in alkaline and extreme zinc-limiting media. Indeed, these environmental conditions induce the simultaneous transcription of both genes mediated by the transcriptional regulators ZafA and PacC. ZafA up-regulates the expression of zrfC and aspf2 under zinc-limiting conditions regardless of the ambient pH, whereas PacC represses the expression of these genes under acidic growth conditions, regardless of zinc availability. Interestingly, the mode of action of PacC on zrfC-aspf2 transcription contrasts with the more widely accepted model for PacC function, according to which under alkaline growth conditions PacC would activate the transcription of alkaline-expressed genes but would repress the transcription of acid-expressed genes. In sum, this study provides a good framework for investigating several important aspects of the biology of Aspergillus, including the repression of alkaline genes by PacC at acidic pH and the interrelationship that must exist between tissue pH, metal availability in the host tissue, and fungal virulence.

  • Ergot alkaloid biosynthesis in Aspergillus fumigatus: conversion of chanoclavine-I to chanoclavine-I aldehyde catalyzed by a short-chain alcohol dehydrogenase FgaDH by Wallwey C, Matuschek M, Li SM (2010) Abstract

    Ergot alkaloids are toxins and important pharmaceuticals which are produced biotechnologically on an industrial scale. A putative gene fgaDH has been identified in the biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine-type. The deduced gene product FgaDH comprises 261 amino acids with a molecular mass of about 27.8 kDa and contains the conserved motifs of classical short-chain dehydrogenases/reductases (SDRs), but shares no worth mentioning sequence similarity with SDRs and other known proteins. The coding region of fgaDH consisting of two exons was amplified by PCR from a cDNA library of Aspergillus fumigatus, cloned into pQE60 and overexpressed in E. coli. The soluble tetrameric His(6)-FgaDH was purified to apparent homogeneity and characterized biochemically. It has been shown that FgaDH catalyzes the oxidation of chanoclavine-I in the presence of NAD(+) resulting in the formation of chanoclavine-I aldehyde, which was unequivocally identified by NMR and MS analyzes. Therefore, FgaDH functions as a chanoclavine-I dehydrogenase and represents a new group of short-chain dehydrogenases. K (M) values for chanoclavine-I and NAD(+) were determined at 0.27 and 1.1 mM, respectively. The turnover number was 0.38 s(-1).

  • Distinct enzymatic and cellular characteristics of two secretory phospholipases A(2) in the filamentous fungus Aspergillus oryzae by Nakahama T, Nakanishi Y, Viscomi AR, Takaya K, Kitamoto K, Ottonello S, Arioka M (2010) Abstract

    Microbial secretory phospholipases A(2) (sPLA(2)s) are among the last discovered and least known members of this functionally diverse family of enzymes. We analyzed here two sPLA(2)s, named sPlaA and sPlaB, of the filamentous ascomycete Aspergillus oryzae. sPlaA and sPlaB consist of 222 and 160 amino acids, respectively, and share the conserved Cys and catalytic His-Asp residues typical of microbial sPLA(2)s. Two sPLA(2)s differ in pH optimum, Ca(2+) requirement and expression profile. The splaA mRNA was strongly upregulated in response to carbon starvation, oxidative stress and during conidiation, while splaB was constitutively expressed at low levels and was weakly upregulated by heat shock. Experiments with sPLA(2) overexpressing strains demonstrated that two enzymes produce subtly different phospholipid composition variations and also differ in their subcellular localization: sPlaA is most abundant in hyphal tips and secreted to the medium, whereas sPlaB predominantly localizes to the ER-like intracellular compartment. Both sPLA(2) overexpressing strains were defective in conidiation, which was more pronounced for sPlaB overexpressors. Although no major morphological abnormality was detected in either DeltasplaA or DeltasplaB mutants, hyphal growth of DeltasplaB, but not that of DeltasplaA, displayed increased sensitivity to H(2)O(2) treatment. These data indicate that two A. oryzae sPLA(2) enzymes display distinct, presumably non-redundant, physiological functions.

  • Factors affecting fungus-induced larval mortality in Anopheles gambiae and Anopheles stephensi by Tullu Bukhari Anthonieke Middelman Constantianus JM Koenraadt Willem Takken Bart GJ Knols (2010) Abstract

    Background Entomopathogenic fungi have shown great potential for the control of adult malaria vectors. However, their ability to control aquatic stages of anopheline vectors remains largely unexplored. Therefore, how larval characteristics (Anopheles species, age and larval density), fungus (species and concentration) and environmental effects (exposure duration and food availability) influence larval mortality caused by fungus, was studied. Methods Laboratory bioassays were performed on the larval stages of Anopheles gambiae and Anopheles stephensi with spores of two fungus species, Metarhizium anisopliae and Beauveria bassiana. For various larval and fungal characteristics and environmental effects the time to death was determined and survival curves established. These curves were compared by Kaplan Meier and Cox regression analyses. Results Beauveria bassiana and Metarhizium anisopliae caused high mortality of An. gambiae and An. stephensi larvae. However, Beauveria bassiana was less effective (Hazard ratio (HR) <1) compared to Metarhizium anisopliae. Anopheles stephensi and An. gambiae were equally susceptible to each fungus. Older larvae were less likely to die than young larvae (HR < 1). The effect of increase in fungus concentration on larval mortality was influenced by spore clumping. One day exposure to fungal spores was found to be equally effective as seven days exposure. In different exposure time treatments 0 – 4.9 % of the total larvae, exposed to fungus, showed infection at either the pupal or adult stage. Mortality rate increased with increasing larval density and amount of available food. Conclusions This study shows that both fungus species have potential to kill mosquitoes in the larval stage, and that mortality rate depends on fungus species itself, larval stage targeted, larval density and amount of nutrients available to the larvae. Increasing the concentration of fungal spores or reducing the exposure time to spores did not show a proportional increase and decrease in mortality rate, respectively, because the spores clumped together. As a result spores did not provide uniform coverage over space and time. It is, therefore, necessary to develop a formulation that allows the spores to spread over the water surface. Apart from formulation appropriate delivery methods are also necessary to avoid exposing non-target organisms to fungus.

  • A novel method for standardized application of fungal spore coatings for mosquito exposure bioassays by Marit Farenhorst, Bart G J Knols (2010) Abstract

    Background Interest in the use of fungal entomopathogens against malaria vectors is growing. Fungal spores infect insects via the cuticle and can be applied directly on the insect to evaluate infectivity. For flying insects such as mosquitoes, however, application of fungal suspensions on resting surfaces is more realistic and representative of field settings. For this type of exposure, it is essential to apply specific amounts of fungal spores homogeneously over a surface for testing the effects of fungal dose and exposure time. Contemporary methods such as spraying or brushing spore suspensions onto substrates do not produce the uniformity and consistency that standardized laboratory assays require. Two novel fungus application methods using equipment developed in the paint industry are presented and compared. Methods Wired, stainless steel K-bars were tested and optimized for coating fungal spore suspensions onto paper substrates. Different solvents and substrates were evaluated. Two types of coating techniques were compared, i.e. manual and automated coating. A standardized bioassay setup was designed for testing coated spores against malaria mosquitoes. Results K-bar coating provided consistent applications of spore layers onto paper substrates. Viscous Ondina oil formulations were not suitable and significantly reduced spore infectivity. Evaporative Shellsol T solvent dried quickly and resulted in high spore infectivity to mosquitoes. Smooth proofing papers were the most effective substrate and showed higher infectivity than cardboard substrates. Manually and mechanically applied spore coatings showed similar and reproducible effects on mosquito survival. The standardized mosquito exposure bioassay was effective and consistent in measuring effects of fungal dose and exposure time. Conclusions K-bar coating is a simple and consistent method for applying fungal spore suspensions onto paper substrates and can produce coating layers with accurate effective spore concentrations. The mosquito bioassay was suitable for evaluating fungal infectivity and virulence, allowing optimizations of spore dose and exposure time. Use of this standardized application method will help achieve reliable results that are exchangeable between different laboratories.

  • Avian Aspergillus fumigatus strains resistant to both itraconazole and voriconazole. by Beernaert LA, Pasmans F, Van Waeyenberghe L, Dorrestein GM, Verstappen F, Vercammen F, Haesebrouck F, Martel A. (2009) Abstract

    The in vitro susceptibilities of 59 avian Aspergillus fumigatus strains to amphotericin B, itraconazole, and voriconazole were determined using the standard microdilution broth method (CLSI M38-A2). Four isolates showed acquired resistance to itraconazole and voriconazole, harboring implications for the treatment of aspergillosis in both birds and humans.

  • Characterization of the oral fungal microbiome (mycobiome) in healthy individuals by Ghannoum MA, Jurevic RJ, Mukherjee PK, Cui F, Sikaroodi M, Naqvi A, Gillevet PM (2010) Abstract

    The oral microbiome-organisms residing in the oral cavity and their collective genome-are critical components of health and disease. The fungal component of the oral microbiota has not been characterized. In this study, we used a novel multitag pyrosequencing approach to characterize fungi present in the oral cavity of 20 healthy individuals, using the pan-fungal internal transcribed spacer (ITS) primers. Our results revealed the "basal" oral mycobiome profile of the enrolled individuals, and showed that across all the samples studied, the oral cavity contained 74 culturable and 11 non-culturable fungal genera. Among these genera, 39 were present in only one person, 16 genera were present in two participants, and 5 genera were present in three people, while 15 genera (including non-culturable organisms) were present in >/=4 (20%) participants. Candida species were the most frequent (isolated from 75% of participants), followed by Cladosporium (65%), Aureobasidium, Saccharomycetales (50% for both), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%). Four of these predominant genera are known to be pathogenic in humans. The low-abundance genera may represent environmental fungi present in the oral cavity and could simply be spores inhaled from the air or material ingested with food. Among the culturable genera, 61 were represented by one species each, while 13 genera comprised between 2 and 6 different species; the total number of species identified were 101. The number of species in the oral cavity of each individual ranged between 9 and 23. Principal component (PCO) analysis of the obtained data set followed by sample clustering and UniFrac analysis revealed that White males and Asian males clustered differently from each other, whereas both Asian and White females clustered together. This is the first study that identified the "basal mycobiome" of healthy individuals, and provides the basis for a detailed characterization of the oral mycobiome in health and disease.

  • Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity by Chai LY, van de Veerdonk F, Marijnissen RJ, Cheng SC, Khoo AL, Hectors M, Lagrou K, Vonk AG, Maertens J, Joosten LA, Kullberg BJ, Netea MG (2009) Abstract

    Summary Both interferon-gamma-producing type 1 T helper (Th1)- and interleukin-17 (IL-17)-producing Th17 cells have been proposed to be involved in anti-fungal host defence. Although invasive aspergillosis is one of the most severe human fungal infections, little is known regarding the relative importance of the Th1 versus Th17 cellular immune pathways for the human anti-Aspergillus host defence. Using human peripheral blood mononuclear cells and a system consisting of monocyte-derived macrophages with lymphocytes, we found that Aspergillus fumigatus is a weak inducer of human IL-17 but induces a strong Th1 response. These data were validated by the very low IL-17 levels in bronchoalveolar lavage fluid and serum of patients with invasive aspergillosis. Surprisingly, live A. fumigatus reduced IL-17 production induced by mitogenic stimuli. This effect was mediated through the propensity of A. fumigatus to metabolize tryptophan and release kynurenine, which modulates the inflammatory response through inhibition of IL-17 production. In conclusion, A. fumigatus does not stimulate production of IL-17 and human host defence against aspergillosis may not rely on potent Th17 responses.

  • Prophylaxis of invasive aspergillosis with voriconazole or caspofungin in patients with acute leukemia during building works by Chabrol A, Cuzin L, Huguet F, Alvarez M, Verdeil X, Linas MD, Cassaing S, Giron J, Tetu L, Attal M, Récher C (2009) Abstract

    Background Invasive aspergillosis is a common life-threatening infection in acute leukemia patients. The presence of building work near to hospital wards housing such patients is an important risk factor for the development of invasive aspergillosis. This study assessed the impact of voriconazole or caspofungin prophylaxis in patients undergoing induction chemotherapy for acute leukemia in a hematology unit exposed to building works. DESIGN AND METHODS: This retrospective cohort study was carried out between June 2003 and January 2006 during which building works leading to a persistent increasing risk for IA took place. This study compared the cumulative incidence of invasive aspergillosis in patients receiving or not primary antifungal prophylaxis. Diagnosis of invasive aspergillosis was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. RESULTS: Two-hundred and fifty-seven patients (213 acute myeloid leukemia; 44 acute lymphocytic leukemia) were included (mean age 54 years, mean duration of neutropenia 21 days); 88 received antifungal prophylaxis, mainly with voriconazole (n=74). The characteristics of the two groups were similar except that pulmonary antecedents were more frequent in the prophylaxis group. Invasive aspergillosis was diagnosed in 21 patients (12%) in the non-prophylaxis group and four (4.5%) in the prophylaxis group (P=0.04). Pulmonary antecedents, neutropenia at diagnosis and high-risk cytogenetics acute myeloid leukemia were positively correlated with invasive aspergillosis, whereas primary prophylaxis was negatively correlated. Survival was similar in both groups. No case of zygomycosis was observed. Three-month mortality was 28% in patients with invasive aspergillosis. Conclusions This study suggests that antifungal prophylaxis voriconazole could be useful in acute leukemia patients undergoing first remission-induction chemotherapy where there is a high-risk of invasive aspergillosis.

  • Antifungal prophylaxis in liver transplant recipients by Eschenauer GA, Lam SW, Carver PL (2009) Abstract

    Although the overall incidence of fungal infections in liver transplant recipients has declined, these infections still contribute significantly to the morbidity and mortality of patients with risk factors for infection. Although antifungal prophylaxis has been widely studied and practiced, no consensus exists on which patients should receive prophylaxis, with which agent, and for what duration. Numerous studies have attempted to ascertain independent risk factors for invasive fungal infections in liver transplant patients, and these data, in addition to clinical trials, identify several patient groups at exceedingly high risk of fungal infection. These include retransplant patients, patients with renal failure requiring hemodialysis or renal replacement therapy, and those requiring reoperations after transplant. Because the majority of infections occur in the first month after transplantation, prophylaxis should be continued for 4-6 weeks. However, local epidemiology and research should guide decisions regarding choice of agent as well as overall development of interinstitutional guidelines, because the incidence and spectrum of infection may differ dramatically among institutions.

  • Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness by Cadena J, Levine DJ, Angel LF, Maxwell PR, Brady R, Sanchez JF, Michalek JE, Levine SM, Restrepo MI (2009) Abstract

    Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients. This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality. Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.

  • Caspofungin Etest Endpoint for Aspergillus Shows Poor Agreement with the Reference Minimum Effective Concentration (MEC) by Fuller J, Schofield A, Jiwa S, Sand C, Jansen B, Rennie R (2009) Abstract

    The Clinical and Laboratory Standards Institute (CLSI) M38-A2 reference broth microdilution (BMD) method for antifungal susceptibility testing of filamentous fungi now includes guidelines for testing echinocandin activity using the minimum effective concentration (MEC) as the endpoint measurement. In this study we compared the caspofungin Etest MIC on RPMI agar and Mueller-Hinton agar (supplemented with glucose and methylene blue [MGM]) with the BMD MEC in 345 clinical Aspergillus isolates, including A. flavus, A. fumigatus, A. nidulans, A. niger, and A. terreus. The essential agreement (+/- 1 log2 dilution) of the Etest on MGM and RPMI with the reference BMD MEC was 18% and 26%, respectively. The geometric mean values for BMD MEC vs MGM Etest were 0.137 mug/ml and 0.024 mug/ml, respectively, and the geometric mean values for BMD vs RPMI were 0.128 mug/ml and 0.031 mug/ml, respectively. Comparatively, 91% of paired MGM and RPMI Etest results were within 2 log2 dilutions of each other and consistently produced clearly defined endpoints. In conclusion, the caspofungin Etest MIC, like the BMD MEC, is a reproducible endpoint but is markedly lower than the reference BMD. In anticipation of susceptibility breakpoint assignment, optimization studies will be required to improve the concordance of these two assays so that the potential for underreporting echinocandin resistance in Aspergillus is mitigated.

  • Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal beta-glucan by Kumar H, Kumagai Y, Tsuchida T, Koenig PA, Satoh T, Guo Z, Jang MH, Saitoh T, Akira S, Kawai T (2009) Abstract

    Fungal beta-glucan, such as curdlan, triggers antifungal innate immune responses as well as shaping adaptive immune responses. In this study, we identified a key pathway that couples curdlan to immune responses. Curdlan promoted the production of the proinflammatory cytokine IL-1beta by dendritic cells and macrophages through the NLRP3 inflammasome. Stimulation with Candida albicans and Saccharomyces cerevisiae also triggered the NLRP3 inflammasome-mediated IL-1beta production. In vivo, NLRP3 was required for efficient Ag-specific Ab production when curdlan was used as an adjuvant, whereas it was dispensable for the induction of Th1 and Th17 cell differentiation. Furthermore, stimulation of purified B cells with curdlan-induced CD69 up-regulation and IgM production while stimulation with other NLRP3 inflammasome activators, such as silica and aluminum salt, did not. Notably, this induction required NLRP3 but was independent of Toll-like receptor and IL-1 receptor family signaling, suggesting the presence of NLRP3-dependent and IL-1 receptor family independent mechanisms in B cells responsible for Ab responses. Collectively, these findings reveal a critical role for the NLRP3 inflammasome in the regulation of antifungal innate immune responses as well as B cell activation.

  • Activation of platelets by Aspergillus fumigatus Potential role in the immunopathogenesis of aspergillosis by Rødland EK, Ueland T, Pedersen TM, Halvorsen B, Muller F, Aukrust P, Frøland SS (2009) Abstract

    Aspergillus fumigatus is the most frequent cause of invasive mould infections worldwide. Platelets contribute to inflammation and promote thrombosis, characteristically seen in aspergillosis, and might be involved in both antifungal defense and histopathological process. In the following experiments in vitro activation of platelets by conidia, swollen conidia and hyphae from A. fumigatus was assessed by flow cytometry and enzyme immunoassays. THP-1 monocytes and human monocytes with and without platelets were cultured with hyphae from A. fumigatus, and the release of interleukin (IL)-8 was measured by enzyme immunoassay. A. fumigatus potently induced the expression of CD62p and CD63 and the release of CD40 ligand, RANTES and Dickkopf homolog-1 in platelets, with particularly enhancing effects of hyphae as compared with conidia. The hyphae-mediated activation of platelets further enhanced the release of IL-8 in both THP-1 monocytes and in human adherent monocytes. In conclusion we have found that A. fumigatus is a potent inducer of platelet-mediated inflammation, potentially promoting protective as well as harmful responses during aspergillosis.

  • Activity of aminocandin (IP960; HMR3270) compared with amphotericin B, itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus by Warn PA, Sharp A, Morrissey G, Denning DW (2010) Abstract

    Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5mg/kg/dose), oral (p.o.) ITC (25mg/kg/dose), intravenous (i.v.) aminocandin (0.25-10mg/kg/dose), i.p. aminocandin (1mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5mg/kg i.v. yielded 100% survival. Aminocandin 1mg/kg i.v., AmB 5mg/kg i.p. or ITC 25mg/kg p.o. were equivalent (P>0.05). Aminocandin 5mg/kg was superior to aminocandin 0.25mg/kg (P<0.0001) as well as all controls (P<0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5mg/kg and 1mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25mg/kg and controls (all P<0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2-10mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4mg/kg). The only fungicidal regimen was aminocandin 5mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of >/=1mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus.

 
   
 

(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.)

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