Impact of self-reported environmental mould exposure on COPD outcomes.

BACKGROUND: Indoor and outdoor mould exposure can affect respiratory symptoms, but its contribution to COPD outcomes such as exacerbation rates or antibiotics courses is not well defined. Some patients with COPD develop chronic pulmonary aspergillosis (CPA), but the contribution of environmental exposure is not known. METHODS: We correlated activities or exposures related to mould with COPD outcomes in patients with COPD with or without CPA using a questionnaire. RESULTS: One hundred and forty patients were included and 60 had CPA in addition to COPD. Seventy-six were male and mean age was 66.9 years (range 40-87). Thirty-nine (28%) were active cigarette smokers. On multivariate analysis, occupational contact with agricultural resources (p = 0.017), vacuuming once weekly or more often (p = 0.026) and not asking visitors to remove shoes on home entry (p = 0.035) were significantly more common in participants reporting ≥ 4 office visits for COPD symptoms in the last year. Living within one mile of industrial composting sites (p = 0.013), vacuuming once weekly or more often (p = 0.016) and not asking visitors to remove shoes on home entry (p = 0.028) were significantly more common in participants reporting ≥4 antibiotics courses in the last year. Patients with CPA showed a trend for residence within one mile of farms or agricultural areas (P = 0.088, OR 2, 95% CI 0.9-4.4). CONCLUSION: Activities potentially leading to mould exposure were common in a population with COPD with or without CPA and were associated with adverse COPD outcomes. Environmental mould exposure may play a role in the development of CPA in patients with COPD.

ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi.

The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana-Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients.

Performance of two Aspergillus IgG EIA assays compared with the precipitin test in chronic and allergic aspergillosis.

Detection of Aspergillus IgG antibodies is important in the diagnosis of chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Immunoprecipitation techniques to detect these antibodies appear to lack sensitivity and accurate quantitation compared with enzyme immunoassays (EIA). This study assessed the performance of two commercial EIAs compared with counterimmunoelectrophoresis (CIE). This was a prospective cohort study of 175 adult patients with chronic or allergic pulmonary aspergillosis. Aspergillus IgG antibodies were detected using CIE, Phadia ImmunoCap Aspergillus IgG and Bio-Rad Platelia Aspergillus IgG. Inter-assay reproducibility was determined for each method and 25 patients had two serum samples analysed within a 6-month interval. When compared with CIE, both ImmunoCap and Platelia Aspergillus IgG had good sensitivity (97 and 93%, respectively) for detection of Aspergillus IgG antibodies. The level of agreement between the two EIAs for positive results was good, but the concentration of antibodies was not correlated between the tests or with CIE titre. ImmunoCap IgG inter-assay coefficient of variation was 5%, whereas Platelia IgG was 33%. Median ImmunoCap IgG values for CPA and allergic aspergillosis were 95 and 32 mg/L, respectively, whereas Platelia IgG values were >80 and 6 AU/mL. The direction of CIE titre change over 6 months was mirrored by ImmunoCap IgG levels in 92% of patients, and by Platelia IgG in 72% of patients. Both ImmunoCap and Platelia Aspergillus IgG EIAs are sensitive measures of Aspergillus IgG antibodies compared with CIE. However, ImmunoCap appears to have better reproducibility and may be more suitable for monitoring patient disease.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.

This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/- flucytosine. In ocular candidiasis, liposomal amphotericin B +/- flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT).

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

Development of a standardised multidrug-resistant/extensively drug-resistant tuberculosis assessment and monitoring tool.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) threaten global TB control. The MDR/XDR-TB Assessment and Monitoring Tool was developed to standardise evaluations of country capacity to prevent, diagnose and treat MDR/XDR-TB and identify program gaps. It provides data to guide national plans, generates baseline data to measure progress, provides information for Green Light Committee (GLC) and Global Fund to Fight AIDS, Tuberculosis and Malaria applications, guides technical assistance and informs donor investment. In field testing, the tool scoring system performed equally well in high- and low-prevalence settings. This GLC-endorsed tool supports global efforts to contain MDR/XDR-TB and is useful in developing national MDR/XDR-TB control strategies.

Fungal colonization of haematological patients receiving cytotoxic chemotherapy: emergence of azole-resistant Saccharomyces cerevisiae.

Fungal colonization during cytotoxic chemotherapy was studied in 42 patients with a recent diagnosis of a haematological malignancy. In total, 2759 surveillance cultures were taken from the nostrils, throat, urine, stool and perineal region. Seven hundred and ninety-six positive surveillance cultures (28.9%) yielded 968 fungal isolates. The rate of fungal colonization did not differ between patients with acute leukaemia, patients with other haematological malignancies and control patients in the same ward at admission (71% vs. 67% vs. 80%). Patients with acute leukaemia were colonized at a significantly lower rate in samples from the throat (32%), urine (10%), stool (45%) and perineum (29%) taken during hospitalization when compared with other haematological patients (respective values 58%, 21%, 67% and 45%; P-values 0.001). This could be attributed to differences in the use of antifungal drugs. Although 21/42 (50%) of our patients had multiple-site fungal colonization at the end of follow-up, only one systemic Candida infection was diagnosed. Extensive use of antifungal treatment may have influenced the low incidence of systemic fungal infections during the follow-up. In addition to Candida species, Malassezia furfur, Geotrichum candidum and Saccharomyces cerevisiae were frequently isolated. The rate of S. cerevisiae isolation increased significantly over time after admission (1%, vs. 18% of isolates, P<0.001), suggesting hospital-acquired transmission. These isolates were highly resistant to azole antifungals (MIC90 128 microg/mL for fluconazole and 16 microg/ml, for itraconazole), and caused persistent multiple site colonization in 12 patients. Extensive use of antifungal agents in a haematological ward may keep the incidence of invasive fungal infections low in spite of heavy fungal colonization. However, there may be a risk of emergence of resistant fungal strains.

Sampling of Aspergillus spores in air.

Nosocomially acquired aspergillosis typically occurs in the setting of treatment for leukaemia or other haematological malignancy. As Aspergillus species can be readily found in the environment, it has been widely believed that aspergillosis occurs as a consequence of exogenous acquisition of the fungus. Stringent environmental controls in transplant units have included high-efficiency air filtration, positive-pressure ventilation and frequent room air changes. Although there have been several well-documented examples of aspergillosis outbreaks as a result of hospital demolition and reconstruction, it has not always been possible to demonstrate elevated spore counts in clinical areas during building work. The sampling of air for Aspergillus is very problematic. Careful attention must be given to the design of air sampler, sampling protocols and an understanding of air sampling data. This review outlines many of the physical and environmental parameters that influence meaningful air sampling and recommends a simple procedure that has been tried and tested in many aspergillosis outbreaks.

Aspergillus flavus endocarditis in a child with neuroblastoma.

We report a case of Aspergillus flavus endocarditis in a 6-year-old boy with stage IV neuroblastoma with no pre-existing cardiac disease. The infection was successfully treated with high-dose liposomal amphotericin (AmBisome) once daily. Recurrence was prevented with itraconazole oral solution once daily as maintenance therapy. Adjunctive surgery was not required. The patient's cardiac function was uncompromised, but subsequent death from progressive neuroblastoma prevented long-term follow-up.

Ollier's disease: varus angulation at the lower femur and its management.

Attention is drawn to the high incidence of varus angulation in the lower femur in Ollier's disease; eight of a total of 14 patients with this condition have this deformity. There may be retardation or arrest of the medial portion of the lower femoral growth plate. One case demonstrates a bone bridge, a condition not previously described in Ollier's disease. The limb-length inequality and varus angulation require concurrent management by a variety of techniques, which are described. Three of the eight patients have reached skeletal maturity; the remainder provide useful information on the condition and are a stimulus for discussion of future management.

Diagnosis and prevention of fungal infection in the immunocompromized patient.

Profound and prolonged neutropenia following chemotherapy is a major risk factor for systemic fungal infections. Mortality associated with disseminated fungal infection is high and treatment with conventional amphotericin B is complicated by renal toxicity. Candida and Aspergillus are among the major pathogens in this patient population. Many patients remaining neutropenic over a prolonged period of time will receive empirical antifungal therapy. The clinical and laboratory diagnosis of these infections are neither sensitive nor specific and are generally limited in the early detection of invasive fungal infection. However, several new approaches to diagnosis are being developed which should be translated into routine practice. These include antigen detection and PCR. It is still unclear how effective the various measures that are currently being used are in preventing serious fungal infection. Refinements in the prophylactic use of fluconazole, itraconazole and aerosolized amphoteric in B, and the introduction of new formulations of existing antifungals may reduce the incidence of systemic fungal infections in some patient groups. Patients with presumed fungal infection require more intense and accurate monitoring for signs of disseminated infection. Early diagnosis may guide appropriate treatment and prevent mortality.

Craniofacial and otic capsule abnormalities in a transgenic mouse strain with a Col2a1 mutation.

Abnormal craniofacial features of a transgenic mouse model of chondrodysplasia with a type II collagen mutation (Gly574Ser) are described in this report. In addition to a shortened mandible and cleft palate, a misshapen otic capsule was observed. Interestingly, hearing impairment is often a component of the chondrodysplasia phenotype that results from mutations in COL2A1. To identify a potential mechanism in the hearing loss associated with type II collagen mutations, we examined the development of the otic capsule in the transgenic mice. It appeared to be smaller overall, relative to the skull proportions, and rather than the normal rounded dimensions, the transgenic capsule was flattened and elongated. We speculate that the cartilage of the developing otic capsule was less able to resist the mechanical forces from the developing brain and other tissues within the cranium and thus became deformed under pressure. We further speculate that the hearing loss associated with the chondrodysplasia phenotype is at least partially due to these defects in the developing cartilage matrix of the otic capsule.

The efficacy of intra-articular morphine for postoperative knee arthroscopy analgesia.

This article describes two prospective, randomized, double-blind clinical trials designed to investigate this. Trial 1 compared a conventional local anaesthetic agent (100 mg bupivacaine) injected intra-articularly (i.a.) with a control (normal saline) and 1 mg of i.a. morphine. No significant difference was noted in the first 4 hours between the groups with respect to visual analogue pain (VAS) scores. However, at 6 and 24 hours, the group of patients who received 1 mg i.a. morphine recorded lower pain scores and required less supplementary analgesia. Trial 2 assessed the dose response relationship for i.a. morphine comparing 5 mg intravenous (i.v.) morphine (control) with 1 mg and 5 mg i.a. morphine. At early time points (1, 2, and 4 hours) similar VAS pain scores were recorded for both 5 mg i.v. morphine and 5 mg i.a. morphine, both significantly lower than the group receiving 1 mg i.a. morphine. At 6 and 24 hours, 5 mg of i.a. morphine produced significantly lower pain scores, less analgesic requirement, and less sleep disturbance on the first postoperative night than the other groups. It can be concluded from these two studies that 5 mg i.a. was the most effective analgesic following knee arthroscopy.

Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation. British Society for Medical Mycology.

Invasive fungal infections are increasing in incidence and now affect as many as 50% of neutropenic/bone marrow transplant patients and 5 to 20% of solid organ transplant recipients. Unfortunately, many of the diagnostic tests available have a low sensitivity. The guidelines presented here have been produced by a working party of the British Society for Medical Mycology in an attempt to optimise the use of these tests. The yield of fungi from blood cultures can be increased by ensuring that at least 20 ml of blood are taken for aerobic culture, by using more than one method of blood culture, and by employing terminal subculture if continuous monitoring systems are used with a five-day incubation protocol. Skin lesions in febrile neutropenic patients should be biopsied and cultured for fungi. The detection of galactomannan in blood or urine is of value in diagnosing invasive aspergillosis only if tests are performed at least twice weekly in high-risk patients. Antigen detection tests for invasive candidiasis are less valuable. Computed tomography scanning is particularly valuable in diagnosing invasive pulmonary fungal infection when the chest radiograph is negative or shows only minimal changes. Bronchoalveolar lavage is most useful in patients with diffuse changes on computed tomography scan. The major advances in the diagnosis of invasive fungal infection in patients with haematological malignancy or solid organ transplantation have been in the use of imaging techniques, rather than in the development of new mycological methods in the routine laboratory.

GM-CSF-modulated phagocytosis of Trichosporon beigelii by human neutrophils.

Trichosporon beigelii has emerged as a lethal opportunist pathogen in granulocytopenic and corticosteroid-treated patients. Little is known of the host defence mechanisms against this yeast. The interaction between human neutrophils and serum-opsonised T. beigelii and the effect of GM-CSF on binding and ingestion of the yeast by neutrophils were investigated by a microscopic analysis of neutrophil monolayers stained with FITC-Concanavalin A. Positive staining with FITC-Concanavalin A distinguished between intracellular and extracellular yeast cells. Binding of T. beigelii to neutrophils was an energy- and complement-dependent process involving movement of actin in the neutrophil cytoskeleton. The mean percentage binding of T. beigelii was 37.5% and the mean binding index (BI) was 1.30 whereas the mean percentage ingestion was 3.5% and the mean phagocytic index (PI) was 1.34. GM-CSF increased percentage ingestion of T. beigelli from 2.8% to 30.5% and the PI was increased from 1.3 to 1.86. The percentage binding was 36.8% and the mean BI was 1.3 in control experiments compared with 49.3% and 1.6, respectively, in the presence of GM-CSF. In conclusion, GM-CSF significantly increased percentage ingestion of opsonised T. beigelii by neutrophils, but its effect on percentage binding of the yeast was not statistically significant.

Aspergillosis in immunocompromised paediatric patients: associations with building hygiene, design, and indoor air.

BACKGROUND: Nosocomial aspergillosis is a well known complication of immunosuppression in cancer patients and those undergoing transplantation and has usually been associated with major building construction or demolition. An observational study is reported of the hospital environment associated with an outbreak of aspergillosis in a paediatric oncology ward. METHODS: All cases of aspergillosis were identified from the hospital records and categorised as definite or probable according to the extent of supportive clinical and laboratory findings. All relevant aspects of building ventilation, air filtration, and aerosol generation considered relevant were examined and air samples for fungi were taken in triplicate at 25 sites using a slit sampler with appropriate culture media. RESULTS: Six cases of aspergillosis were identified over one year out of the 148 patients who attended the unit - the only part of the hospital where cases were found. Examination of the building services and function suggested that the cause or source was isolated to this paediatric oncology/haematology ward and may have been attributed to a defective disposal conduit door as well as the dispersal of a contaminated aerosol from the ward vacuum cleaner which had the highest measured concentrations of Aspergillus fumigatus in or around the building (65 colony forming units (cfu)/m3 compared with 0-6 cfu/m3 elsewhere). No further cases were identified in the two years after these hygiene arrangements were changed. CONCLUSIONS: The investigation of this outbreak of nosocomial aspergillosis identified several possible sources of fungally contaminated aerosol which could have been implicated as the cause. Their modification was followed by a reduction in the incidence of further cases. Each should be incorporated as an issue of importance in hospital building design and hygiene.

A comparative study of the efficacy of fluconazole and amphotericin B in the treatment of oropharyngeal candidosis in patients undergoing radiotherapy for head and neck tumours.

Radiotherapy given during treatment of oral and pharyngeal malignancy is frequently associated with colonization of the oral mucosa by Candida species. Treatment of these infections has included topical and systemic agents. In the present study 73 patients with oropharyngeal candidosis were treated with either amphotericin B (10 mg lozenges, four times daily for 14 days, 36 patients) or fluconazole (50 mg daily for 7 days, 37 patients). The yeasts most frequently isolated were C albicans and C glabrata. Clinical signs and symptoms showed improvement at end of treatment in 72% of patients who received amphotericin B compared with 92% of patients who received fluconazole. Mycological cure at end of treatment was achieved in 31% of the amphotericin B group and 46% of patients who received fluconazole. For both treatments the cure rate was less in denture wearers than in non denture wearers.

Matrix deposition by a calcifying human osteogenic sarcoma cell line (SAOS-2).

Procollagen and proteoglycan biosynthesis was defined in long-term culture of a human osteogenic sarcoma cell line, SAOS-2. An osteoblast phenotype was maintained by these cells up to 40 days post-confluent in the presence of ascorbic acid. Under these conditions, cells deposited around them an extensive collagenous matrix that was able to mineralize in the presence of an exogenous phosphate donor (beta-glycerophosphate). The collagenous matrix was comprised predominantly of collagen type I with significant amounts of collagen type V, and greater than 80% of the collagen in the matrix was involved in covalent crosslinkages. With increasing time in culture there was a decrease in the collagen synthetic rate, although the collagenous matrix was maintained. The proteoglycans synthesized by nonmineralizing and mineralizing cultures were purified after biosynthetic labeling with [35S]sulfate and [3H]glucosamine. Two major species were apparent: a large chondroitin sulfate proteoglycan (CSPG), and a small chondroitin sulfate proteoglycan, decorin. In nonmineralizing cultures, decorin partitioned equally between the cell layer and culture medium, whereas the large CSPG species partitioned exclusively into the cell layer-associated matrix. In the presence of extensive mineral deposition, greater than 90% of the newly synthesized proteoglycans were secreted into the medium. Northern blot hybridization indicated that SAOS-2 cells express mRNA encoding a range of bone proteins, including decorin, osteonectin, and bone sialoprotein.