I don't know if it will let me post this whole thing, but is very improtant to read.
<div class="cit"><a title="Chest." href="http://www.ncbi.nlm.nih.gov/pubmed/20472859" rel="nofollow" target="_blank">Chest.</a>2010 Nov;138(5):1186-95. Epub 2010 May 14.
<h1>Sputum<span class="highlight">Candidaalbicans presages FEV? decline and hospital-treated exacerbations in<span class="highlight">cystic fibrosis.</h1>
<div class="auths"><a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chotirmall%20SH%22%5BAuthor%5D" rel="nofollow" target="_blank">Chotirmall SH</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22O'Donoghue%20E%22%5BAuthor%5D" rel="nofollow" target="_blank">O'Donoghue E</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bennett%20K%22%5BAuthor%5D" rel="nofollow" target="_blank">Bennett K</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Gunaratnam%20C%22%5BAuthor%5D" rel="nofollow" target="_blank">Gunaratnam C</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22O'Neill%20SJ%22%5BAuthor%5D" rel="nofollow" target="_blank">O'Neill SJ</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22McElvaney%20NG%22%5BAuthor%5D" rel="nofollow" target="_blank">McElvaney NG</a>.
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<h3 class="label">Source</h3>
Department of Respiratory Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Republic of Ireland. schotirmall@rcsi.ie
<div class="abstr">
<h3>Abstract</h3>
<h4>BACKGROUND:</h4>
The role of<span class="highlight">Candidaalbicans in the<span class="highlight">cystic fibrosis(CF) airway is underexplored. Considered a colonizer, few question its pathogenic potential despite high isolation frequencies from sputum culture. We evaluated the frequency and identified the strongest predictors of C albicans colonization in CF. Independent associations of colonization with clinical outcomes were determined, and the longitudinal effects of C albicans acquisition on BMI and FEV? were evaluated.
<h4>METHODS:</h4>
A prospective observational study of 89 patients with CF was performed (3,916 sputum samples over 11 years). Frequency of C albicans growth in sputum allowed classification of the cohort into colonizers and noncolonizers. BMI, FEV?, hospital-treated exacerbations, and other clinical parameters were followed throughout the study to determine association with colonization status. Multivariate regression determined the strongest predictors of colonization and for clinical effects after adjustment for confounders. Repeated-measures analysis of variance assessed the longitudinal effect of colonization on BMI and FEV?.
<h4>RESULTS:</h4>
Colonization with C albicans was frequent (49.4%) and best predicted by pancreatic insufficiency (P = .014), osteopenia (P = .03), and cocolonization with<span class="highlight">Pseudomonasspecies (P = .002). C albicans colonization significantly predicted hospital-treated exacerbations (P = .004) after adjustment for confounders. Exacerbation rate significantly increased in patients with chronic or intermittent colonizations following first acquisition of C albicans. Colonization accelerated rates of decline for BMI (P < .0001) and FEV? (P < .001).
<h4>CONCLUSION:</h4>
Airway colonization with C albicans presaged a greater rate of FEV? decline and hospital-treated exacerbations in CF.
also by this same group:
<div class="arttitle"><em>Candida</em>species in cystic fibrosis: A road less travelled
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November 2010, Vol. 48, No. O1 , Pages S114-S124 (doi:10.3109/13693786.2010.503320)
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<div class="artAuthors"><a class="entryAuthor" href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=%2Bauthorsfield%3A%28Chotirmall%2C+Sanjay+H.%29" rel="nofollow" target="_blank">Sanjay H. Chotirmall<span class="NLM_xref-aff">*<sup>#</sup>,</a><a class="entryAuthor" href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=%2Bauthorsfield%3A%28Greene%2C+Catherine+M.%29" rel="nofollow" target="_blank">Catherine M. Greene<span class="NLM_xref-aff">*&</a><a class="entryAuthor" href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=%2Bauthorsfield%3A%28McElvaney%2C+Noel+G.%29" rel="nofollow" target="_blank">Noel G. McElvaney</a>
<div class="fulltext">Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland
<div class="NLM_author-notes">
<div class="NLM_corresp">Correspondence: Sanjay H. Chotirmall, Respiratory Research Division, Education & Research Centre, Beaumont Hospital, Beaumont Road, Dublin 9, Republic of Ireland. Tel: +353 87 979 3833; Fax: +353 1 8093765. E-mail: schotirmall@rcsi.ie
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<tr><th align="left" valign="middle" width="95%">ABSTRACT</th>
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<p class="first last"><em>Candida</em>species are isolated with high frequency from cystic fibrosis patients, yet their definitive role in the disease remains unclear. Previously considered to have minimal inherent virulence owing to their commensal ability, the last decade has heralded an increasing recognition of<em>Candida</em>infection among patients with cystic fibrosis. What has been more recently hypothesized is that the organism possesses virulence factors that play diverse roles at different body sites during varied stages of an infection. Currently, limited data is accessible in the area of cystic fibrosis. This review aims to provide an overview of the role of<em>Candida</em>species in cystic fibrosis as it is currently understood including the common local and systemic infections observed in clinical practice. The uncertain role of airway colonization and insight into emerging fields such as<em>Candida</em>–bacterial interactions are also addressed. Finally, we outline the current understanding of the innate, cellular and humoral immune responses associated with this genus which has been the major focus of work performed to date.
<div class="keywords"><strong>Keywords:</strong><a href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=keywordsfield%3A(%22Candida%22)" rel="nofollow" target="_blank">Candida</a>,<a href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=keywordsfield%3A(%22infection%22)" rel="nofollow" target="_blank">infection</a>,<a href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=keywordsfield%3A(%22colonization%22)" rel="nofollow" target="_blank">colonization</a>,<a href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=keywordsfield%3A(%22immune+response%22)" rel="nofollow" target="_blank">immune response</a>,<a href="http://informahealthcare.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=keywordsfield%3A(%22cystic+fibrosis%22)" rel="nofollow" target="_blank">cystic fibrosis</a>
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<p class="last">Major advances in the care of cystic fibrosis (CF) patients have positively influenced prognosis over the last decade. Significant inroads into understanding the basic defect have accelerated the development of targeted therapies. However, the disease continues to present new challenges to clinicians and researchers, for example fungal airway colonization. The consequences of bacterial infection, colonization and need for segregation in outpatient clinics have all been confronted and curbed to the point that fungal colonizers with an undetermined role on the course of disease and progression are becoming increasingly recognized. Both yeasts and filamentous fungi have been identified as microbial pathogens in CF, particularly in the context of invasive disease in the transplanted population and allergic responses, for instance allergic bronchopulmonary aspergillosis (ABPA). One particular fungal genus isolated at high frequencies from sputum cultures is<em>Candida</em>but limited literature is available addressing the issues of<em>Candida</em>colonization and infection in CF. This is possibly because its manifestations are still considered relatively minor in comparison to other infectious agents. As a consequence, the role of<em>Candida</em>has received little attention in terms of clinical and scientific research. This review aims to provide an overview of our current understanding of<em>Candida</em>species in CF, its associated local and systemic infections and an insight into emerging data on its role in airway colonization and associated immune response.
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<tr><th align="left" valign="middle" width="95%">The<em>Candida</em>genus</th>
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Oral thrush was the first infection of the<em>Candida</em>species described in humans and following identification of its reproductive potential by budding, the fungus was originally named<em>Oidium albicans</em>.<em>Candida albicans</em>became the adopted name used and since then many other species have been identified as playing roles in human infection. The most common of these are<em>C. albicans</em>,<em>Candida glabrata, Candida krusei</em>,<em>Candida parapsilosis</em>and<em>Candida tropicalis</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0001&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">1</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0002&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">2</a>].
The genus has exponentially grown with hundreds of newer species being identified and described, but unlike dimorphic fungi, the morphology of a given<em>Candida</em>species remains fundamentally comparable<em>in vitro</em>or<em>in</em><em>vivo</em>.<em>Candida</em>species are capable of causing chronic, localized or systemic infection collectively termed ‘candidiasis’ although most commonly act as commensals within the oropharynx, skin folds, gastrointestinal tract and vagina, but on occasion they can cause opportunistic infections [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0003&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">3</a>]. Once infection ensues, significant morbidity and mortality results and consequently, systemic candidiasis has high mortality rates (>75%) [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0004%20CIT0005%20CIT0006&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">4–6</a>].
Identification in the microbiology laboratory is achieved on Sabouraud dextrose media and<em>C. albicans</em>can be identified through germ tube testing or colorimetric detection of L-proline aminopeptidase and beta-galactosaminidase. Since recent isolation of<em>Candida dubliniensis</em>which produces false positive results in the above tests, a chromogenic agar culture method that allows isolation and identification of<em>C. albicans</em>,<em>C. tropicalis</em>and<em>C. krusei</em>has been widely adopted. A modified version of this media is available to more clearly distinguish<em>C. dubliniensis</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0007&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">7</a>]. Alternative older methods to distinguish between<em>C. albicans</em>and<em>C. dubliniensis</em>include assessment of their growth ability at higher temperatures (45°C for<em>C. albicans</em>) or specific DNA sequencing.
Patients with CF are at an increased risk of<em>Candida</em>acquisition and colonization due to use of inhaled steroids, diabetes mellitus and lifelong antibiotic treatment. However despite its frequent isolation from sputum, oral and vaginal swabs, it remains unclear what such positive cultures actually mean in practical terms for CF clinicians. We believe that a spectrum of ‘commensal–colonizer–pathogen’ most likely exists for the organism and where specifically the organism is on this spectrum at a particular time point may be dictated by the clinical state of the CF patient and whether bacterial co-colonizers are present in the airway.
<p class="last">Although frequently identified in CF, the clinical role of<em>Candida</em>species has yet to be definitively determined [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0010&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">8–10</a>]. Bakare<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0011&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">11</a>] identified<em>Candida</em>as the second most frequent fungus to<em>Aspergillus</em>in the CF airway and as such the growth of the yeasts has been associated with more severe CF in patients who have received prolonged treatment with antibiotics, glucocorticoids and probiotics [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0012%20CIT0013%20CIT0014&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">12–14</a>]. In terms of infection, Cimon<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0015&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">15</a>] performed a 5-year epidemiological study assessing the frequency of bronchopulmonary mycoses in a CF population and examined the aetiological role of individual fungal species in disease. The filamentous fungi<em>Aspergillus</em>and<em>Scedosporium apiospermum</em>, together with<em>Candida</em>contributed the largest burden. Despite high isolation of<em>Candida</em>from CF patients, only a single case of candidiasis was observed and this low rate was attributed to the antifungal ability of various bacterial colonizers in CF. However, while invasive airway infections are rare events, the extent of airway damage from hypersensitivity phenomena remain unknown. We will now address the localized and systemic infections associated with<em>Candida</em>species in CF and subsequently tackle the complex issues of airway colonization, cross kingdom interaction and the immune response.
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<tr><th align="left" valign="middle" width="95%">Airway<em>Candida</em>colonization in CF</th>
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It remains controversial as to whether<em>Candida</em>species are transient or persistent colonizers of the respiratory tract in CF patients. A study by Muthig<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0031&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">31</a>] showed that the mean persistence of<em>Candida</em>species was at least 9 months and that the species identified were genetically related and transmissible but susceptible to all antifungals tested. Although concerns of transmissibility persist, it is unsure whether they conclusively contribute to chronic infection and the inflammatory milieu in CF. We have assessed colonization rates at our own centre over prolonged time periods and found persistence rates in excess of that previously described. We have established that the main factors predicting colonization by<em>C. albicans</em>in CF patients are pancreatic insufficiency, osteopenia and co-colonization with<em>Pseudomonas</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0032&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">32</a>]. At first glance, this suggests that the more advanced a patient's disease, the likelier their sputum contained<em>C. albicans</em>, a view of many clinicians and it may be that the organism acts as nothing more than a microbiological marker of disease severity in CF. To challenge this paradigm, we performed a complex multivariate regression analysis that allowed for the adjustment of confounders commonly found in CF to determine the strongest predictors of major clinical effects. The clinical outcomes we assessed included FEV1, BMI, hospitalizations for infective exacerbations and sputum colonization with<em>Pseudomonas</em>or<em>Aspergillus</em>species. Through such analyses, we found that<em>C. albicans</em>colonization significantly predicted hospital-treated exacerbations (<em>P</em>= 0.004) after adjustment for confounders. Exacerbation rate was also significantly increased following first acquisition of<em>C. albicans</em>. This latter finding is vitally important as it refutes the alternate view that frequent antibiotic treatment for large numbers of exacerbations gave rise to the<em>C. albicans</em>in sputa that we observed. We additionally detected that although<em>C. albicans</em>colonization was not a significant predictor of FEV1 or BMI, it longitudinally accelerated rates of decline for both parameters (<em>P</em>< 0.001 and <0.0001 respectively). The FEV1 dataset followed the trend suggested by a previous cross sectional analysis of a European CF registry which stated that<em>C. albicans</em>colonization was associated with 5–10% predicted decrease in pulmonary function [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0033&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">33</a>]. Our study concluded that sputum colonization with<em>C. albicans</em>presaged a greater rate of FEV1 decline and increased hospital-treated exacerbations in CF and was the first longitudinal study in this area to suggest a potential pathogenic role for the organism in the CF airway [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0032&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">32</a>]. What our data could not establish was whether the fungus itself, a virulent co-colonizer or cross-kingdom interaction, was promoting the increased hospital admissions recorded. This is an avenue for future clinical investigation.
<p class="last">Newer airway<em>Candida</em>species have also emerged over the last decade and one pertinent example is the high recovery rates (10–25%) of<em>C. dubliniensis</em>from the oral cavity of HIV patients [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0034&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">34</a>]. This new organism was subsequently described in the non-HIV population particularly in individuals receiving high antibiotic burdens [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0035&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">35</a>]. Therefore, its detection in CF came as no surprise, but did involve a complex isolation procedure involving Staib agar [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0036&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">36</a>]. What was surprising was that its prevalence rate in CF was higher than that found in HIV. However virtually nothing about its potential for virulence is known. There is no clear clinical or experimental evidence of differences in terms of pathogenic potential but cell surface hydrophobicity is known to play a role as compared to<em>C. albicans</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0037&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">37</a>].<em>Candida dubliniensis</em>is reported to exhibit cell surface hydrophobicity not observed in the adhesion of<em>C. albicans</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0038&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">38</a>] and thus can take advantage of the dehydrated respiratory secretions in CF and consequently proliferates. These observations may also explain why patients who are older (>30 years) and have more advanced disease are colonized by this yeast. Peltroch<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0036&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">36</a>] followed six CF patients with<em>C. dubliniensis</em>and while all patients remained stable with no invasive infection detected, its effect on lung function could not be conclusively established because of the small numbers. A larger epidemiological study of this<em>Candida</em>species in CF is warranted.
<p class="last">
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<tr><th align="left" valign="middle" width="95%">Localized<em>Candida</em>infection in CF</th>
<td class="sectionHeading" nowrap="nowrap" width="62" height="16"><span class="fulltext">Section:</td>
<td class="sectionHeading" align="right" valign="middle" nowrap="nowrap" width="92" height="16"><form target="_blank"><select class="fulltextdd" name="select23"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#abstract">ABSTRACT</option><option value="#h2">Introduction</option><option value="#h3">The Candida genus</option><option value="">Localized Candida infecti... <<</option><option value="#h7">Systemic Candida infectio...</option><option value="#h10">Airway Candida colonizati...</option><option value="#h11">Candida-bacterial interac...</option><option value="#h13">Interactions with Staphyl...</option><option value="#h15">Candida and the immune re...</option><option value="#h19">Conclusion and future dir...</option><option value="#h20">References</option></select></form></td>
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<div id="ss4" class="NLM_sec NLM_sec_level_2"><span id="d3154443e466" class="title2">Oral candidiasis
<p class="last"><em>Candida</em>species are isolated from the oral mucosa in up to 40% of healthy adults and therefore considered to be commensals [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0016&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">16</a>]. A cut-off point to distinguish between commensalism and colonization remains undetermined. Common risk factors associated with oral recovery include poor dentition, older age, diabetes mellitus, use of inhaled or systemic steroids, smoking, malignancy and frequent antibiotic use. Oral thrush usually presents as discomfort associated with a dry mouth and associated dysphagia. In some cases, altered taste is experienced. The diagnosis is usually straightforward and by direct observation of white membraneous plaques on the buccal mucosa or soft palate. This may be confirmed microbiologically by staining a swab or culturing a rinse from the associated area. Atypically, foci of oral erythematous inflammation or angular cheilitis may present. There are clearly significant risk factors in the CF state that predispose to oral colonization and subsequent infection including impaired salivary secretion, steroid use, CF-related diabetes and recurrent courses of antibiotics. Antibiotics alter the homeostasis of oral flora and as such have a permissive action on<em>Candida</em>growth. In a study from Manchester, patients on direct questioning of those with major symptoms of CF, 40% (<em>n</em>= 17) complained of a sore mouth, 24% (<em>n</em>= 10) of thrush five times annually and 38% (<em>n</em>= 16) of a hoarse voice every three months [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0017&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">17</a>]. In our own institution's experience, we encounter regular instances of oral candidiasis annually following courses of antibiotics, but they resolve after a short burst of antifungal treatment (Fluconazole). We recommend microbiological confirmation in all cases by scrapings unless white plaques are directly observed on oral examination. This is because some of the symptoms described are not specific to oral thrush but can be found in associated vitamin deficiencies (B<sub>6</sub>, B<sub>12</sub>) or by simple blistering. We recommend that CF patients attending routine clinic be screened for risk factors and questioned at 3-month intervals with regard to the symptoms of oral thrush including frequency of sore or dry mouth, crusting lips, dysphagia, dysphonia or hoarseness and difficulties with taste. Any relationship to antibiotic treatment should be teased out. Clearly oral candidiasis is recognized in CF but the dearth of available literature suggests it is probably misdiagnosed, ignored or missed in several cases. A simple risk factor and symptom screen would probably result in improvements in both quality of life and compliance with other CF treatments. With the advent of newer and increasingly earlier administration of antibacterial therapies, oral candidiasis is likely to become a more significant issue in the future care of CF patients.
<div id="ss5" class="NLM_sec NLM_sec_level_2"><span id="d3154443e502" class="title2">Genital candidiasis
Genital candidiasis is a common occurrence in the general population with rates of a single occurrence of up to 75% and 50% recurrent episodes [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0002&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">2</a>]. It may be asymptomatic or present with balanitis in males and pruritis with vaginal discharge in females. Most infections are caused by<em>C. albicans</em>(95%), but<em>C. glabrata</em>(5%) infections have been described [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0002&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">2</a>]. There is limited but important literature available addressing these infections in CF patients with the majority focused on female manifestations. It has been more than a decade since Sawyer<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0018&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">18</a>] first reviewed the subject with a self-administered questionnaire in young women with CF (<em>n</em>= 55). Vulvovaginal candidiasis was more common in CF (35%) versus controls (13%) and additionally more persistent and difficult to treat. Antibiotic use was a significant association and the work concluded that ‘health professionals generally trivialize illnesses and diseases that are common, easily treated and not life-threatening’. More recent work has included male patients and addressed symptomatic partners. Lyon<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0019&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">19</a>] evaluated 40 adults with CF (19 male, 21 female) and similarly found large proportions (62.5%,<em>n</em>= 25) experiencing symptoms of infection, but few (15%,<em>n</em>= 6) of them had been directly questioned about it at CF clinics. Patients refused to discuss if their partners were symptomatic. This highlighted to CF clinicians a major deficiency of clinical practice and questions about candidiasis should be featured during annual review clinic consultations. It is also important to consider that vaginal discharge in young CF women can be caused by other pathogens such as<em>Chlamydia, Gonococcus</em>or<em>Trichomonas</em>species and that there is an observed unexplained high incidence of genital<em>Chlamydia</em>in CF.
<p class="last">A third study addressing the same subject was performed by interviews of 101 CF patients and addressed symptom frequency and medical risks associated with<em>Candida</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0020&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">20</a>]. Patients were asked to report on personal risk factors for<em>Candida</em>infection and their desire to be questioned about ‘thrush’ in CF clinic. Many had two or more risk factors (92.1%,<em>n</em>= 93), however the only significant factor associated with genital<em>Candida</em>was long-term antibiotics (87.1%,<em>n</em>= 88,<em>P</em>= 0.001). Over 70% of patients, both males and females had symptoms of either oral or genital<em>Candida</em>or both simultaneously. Forty percent (18/45) of those with oral and two-thirds (33/50) of those reporting genital candidiasis described ‘distress’, but it did not affect desire for treatment. Most cases of oral infection were diagnosed by a CF physician while genital infections were mainly self-diagnosed. It is noteworthy that general practitioners diagnosed more cases of genital infection as compared to CF physicians. This is potentially explained by differing doctor-patient relationships in different settings or alternatively, because the focus of the CF unit remains on respiratory or gastrointestinal symptoms leading patients to believe that this forum is inappropriate for discussing other complaints. Most patients in the study did, however, want to discuss such issues and were unconcerned who their discussant was although some females predictably preferred to discuss the issues with female staff. This Manchester-based study is the largest to date and detected similar patterns as found in previous work. The most concerning new discovery was the high incidence of symptoms among CF patients, but only on direct questioning which places a future onus on CF clinics. A major criticism of all these studies was that symptom recording was not supported by microbiological confirmation of infections, an important point for future work. Additionally, although several publications have assessed the benefits and efficacy of antifungal treatment in vulvovaginal candidiasis in the ‘normal’ population, none have been performed in CF [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0021&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">21</a>]. Despite this clear lack of available literature, we strongly recommend screening questions for infections at all CF clinic visits and depending on clinical findings, that antifungal treatment be prescribed either empirically or following microbiological confirmation.
<p class="last">
<div id="ss10" class="NLM_sec NLM_sec_level_1">
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<tr><th align="left" valign="middle" width="95%"><em>Candida</em>-bacterial interactions</th>
<td class="sectionHeading" nowrap="nowrap" width="62" height="16"><span class="fulltext">Section:</td>
<td class="sectionHeading" align="right" valign="middle" nowrap="nowrap" width="92" height="16"><form target="_blank"><select class="fulltextdd" name="select23"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#abstract">ABSTRACT</option><option value="#h2">Introduction</option><option value="#h3">The Candida genus</option><option value="#h4">Localized Candida infecti...</option><option value="#h7">Systemic Candida infectio...</option><option value="#h10">Airway Candida colonizati...</option><option value="">Candida-bacterial interac... <<</option><option value="#h13">Interactions with Staphyl...</option><option value="#h15">Candida and the immune re...</option><option value="#h19">Conclusion and future dir...</option><option value="#h20">References</option></select></form></td>
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According to Costerton<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0039&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">39</a>], biofilms are ‘a structured community of bacterial cells enclosed in a self- produced polymeric matrix and adherent to an inert or living surface’. Traditionally biofilms have been thought to comprise a single bacterial species, however it is now increasingly recognized that mixed biofilms exist involving interactions between both prokaryotes and eukaryotes. Bacteria and fungi are found together in a variety of environments, but particularly in biofilms, where adherent species interact through diverse signaling mechanisms. In the host,<em>C. albicans</em>can often be found growing with bacteria in polymicrobial biofilms and interspecies interactions occur that can impact on the transition of<em>C. albicans</em>between virulent and nonvirulent states [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0030&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">30</a>]. Under conditions of immune dysfunction, such as in the CF lung, colonizing<em>C. albicans</em>can become opportunistic pathogens causing mucosal and disseminated infections potentially impacting on patient mortality. In the biofilm environment, microbial species use ‘quorum-sensing’ (QS) molecules for cell-to-cell communication to promote collective behaviour within the population, enhance access to nutrients and niches, and provide a combined defense against competitor organisms [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0040&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">40</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0041&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">41</a>]. The process of QS can cross the prokaryote–eukaryote boundary [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0040%20CIT0041%20CIT0042%20CIT0043&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">40–43</a>].
<div id="ss11" class="NLM_sec NLM_sec_level_2"><span id="d3154443e860" class="title2">Interactions with<em>Pseudomonas aeruginosa</em>
<em>Pseudomonas aeruginosa</em>is the most prevalent opportunistic pathogen in individuals with CF and is the principal organism associated with biofilm formation in the CF lung, but<em>Staphylococcus aureus</em>and<em>Burkholderia</em>spp. are also considered important pulmonary pathogens in CF. The dimorphic yeast<em>C. albicans</em>is the most common eukaryotic microbe isolated from CF patient sputum [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0011&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">11</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0012&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">12</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0044&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">44</a>].<em>Candida albicans</em>can exist in a mixed biofilm where the prokaryotic and eukaryotic communities exhibit either synergistic or antagonistic interactions. Several studies suggest that<em>P. aeruginosa</em>and<em>C. albicans</em>interact with each other<em>in vivo,</em>and they are commonly found together in mixed infections [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0045&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">45</a>]. In their seminal paper, Hogan and Kolter [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0042&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">42</a>] first reported a pathogenic relationship between<em>P. aeruginosa</em>and<em>C. albicans</em>. They demonstrated how<em>P. aeruginosa</em>can form a dense biofilm on<em>C. albicans</em>filaments and kill the fungus. Interestingly this only occurred when<em>C. albicans</em>was growing in its filamentous (or hyphal) form – an essential feature associated with its virulence [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0046&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">46</a>].<em>Pseudomonas aeruginosa</em>neither bound to nor killed the yeast form of<em>C. albicans</em>and the ability of<em>P. aeruginosa</em>to kill filamentous<em>C. albicans</em>was dependent on a number of physiological factors including growth phase, nutrient availability, surface structures including flagellae and type IV pili, secreted QS factors and regulatory molecules such as<em>rpoN</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0047&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">47</a>]. By forming a biofilm on fungal filaments,<em>P. aeruginosa</em>may be able to obtain nutrients from<em>C. albicans</em>in a nutritionally scarce environment.
<p class="last">Prior to the killing of<em>C. albicans</em>by<em>P. aeruginosa,</em>signaling can occur between both organisms. The QS molecules of both species are responsible for this communication. For example the bacterial molecule 3-oxo-C12 homoserine lactone can affect<em>Candida</em>morphology, whilst the fungal 12-carbon sesquiterpene metabolite, farnesol, can interfere with<em>Pseudomonas</em>quinolone and pyocyanin production and swarming motility [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0041&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">41</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0043&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">43</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0045&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">45</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0048%20CIT0049%20CIT0050%20CIT0051%20CIT0052%20CIT0053&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">48–53</a>]. Thus eukaryotes and prokaryotes possess diverse signaling mechanisms to detect and respond to each other through QS signal molecules.
<div id="ss12" class="NLM_sec NLM_sec_level_1"><a name="h13" rel="nofollow"></a><br clear="right" />
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<tr><th align="left" valign="middle" width="95%">Interactions with<em>Staphylococcus aureus</em></th>
<td class="sectionHeading" nowrap="nowrap" width="62" height="16"><span class="fulltext">Section:</td>
<td class="sectionHeading" align="right" valign="middle" nowrap="nowrap" width="92" height="16"><form target="_blank"><select class="fulltextdd" name="select23"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#abstract">ABSTRACT</option><option value="#h2">Introduction</option><option value="#h3">The Candida genus</option><option value="#h4">Localized Candida infecti...</option><option value="#h7">Systemic Candida infectio...</option><option value="#h10">Airway Candida colonizati...</option><option value="#h11">Candida-bacterial interac...</option><option value="">Interactions with Staphyl... <<</option><option value="#h15">Candida and the immune re...</option><option value="#h19">Conclusion and future dir...</option><option value="#h20">References</option></select></form></td>
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In oral biofilms a mutually beneficial interaction called coaggregation can occur where the adhesion of<em>C. albicans</em>to oral bacteria facilitates its colonization of the oral cavity [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0054%20CIT0055%20CIT0056&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">54–56</a>]. In contrast, the interaction between<em>C. albicans</em>and<em>P. aeruginosa</em>as described above is competitive and antagonistic in nature. A third mechanism of interaction that can occur is that evident between staphylococci and<em>C. albicans</em>, which appears to be initially synergistic [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0057%20CIT0058%20CIT0059&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">57–59</a>]. Carlson<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0060&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">60</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0061&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">61</a>] described a synergistic effect between<em>C. albicans</em>and<em>S. aureus</em>in a mouse infection model leading to enhanced animal mortality following dual infection suggesting that<em>C. albicans</em>can either enhance the virulence of<em>S. aureus</em>or impair the host's immune defences. Extensive physical interactions are known to occur between<em>S. aureus</em>and both the yeast and hyphal forms of<em>C. albicans</em>in a mixed biofilm [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0062&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">62</a>] and it has been suggested that farnesol has a role in orchestrating these interactions. After the initial synergy during<em>C. albicans</em>–<em>S. aureus</em>biofilm formation, farnesol then negatively affects staphylococcal biofilm formation, compromises cell membrane integrity, viability and susceptibility of<em>S. aureus</em>to a variety of clinically important antibiotics [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0062&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">62</a>]. Thus farnesol may represent a therapeutic target for inhibiting the development of a mixed biofilm in the CF lung. However once the biofilm has been established, farnesol may actually behave as an antibacterial factor. It remains to be seen which has the more detrimental effect in the CF lung,<em>C. albicans</em>growing alone or in combination with<em>S. aureus</em>in a mixed biofilm.
<div id="ss13" class="NLM_sec NLM_sec_level_2"><span id="d3154443e1063" class="title2">Interactions with other microbes
Notwithstanding the ability of<em>C. albicans</em>to modulate bacterial growth, reciprocal evidence indicates that other bacteria may also play an important role in the pathogenesis of<em>C. albicans</em>infections. For example in the urinary tract,<em>Escherichia coli</em>can enhance adhesion of<em>C. albicans</em>to bladder mucosa [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0063&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">63</a>], whereas in the gut indigenous microbes can inhibit mucosal adhesion of<em>C. albicans</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0064&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">64</a>]. Consequently alterations in the normal bacterial flora following treatment with broad-spectrum antibiotics may allow<em>C. albicans</em>to proliferate and invade tissues, greatly affecting its pathogenicity [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0064&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">64</a>]. This is an important consideration for individuals with CF who are frequently prescribed antibiotics.
<p class="last">This may be most clearly studied in the oral cavity where adhesion of<em>C. albicans</em>to saliva-coated surfaces and proline-rich proteins is an important early step in colonization [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0054&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">54</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0065%20CIT0066%20CIT0067&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">65–67</a>]. Many species of oral bacteria may compete with<em>C. albicans</em>for primary adhesion receptor sites [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0054&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">54</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0065&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">65</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0068&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">68</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0069&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">69</a>], however once resident in the mouth,<em>C. albicans</em>can adhere to the major microbial constituents of early dental plaque.
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<tr><th align="left" valign="middle" width="95%"><em>Candida</em>and the immune response</th>
<td class="sectionHeading" nowrap="nowrap" width="62" height="16"><span class="fulltext">Section:</td>
<td class="sectionHeading" align="right" valign="middle" nowrap="nowrap" width="92" height="16"><form target="_blank"><select class="fulltextdd" name="select23"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#abstract">ABSTRACT</option><option value="#h2">Introduction</option><option value="#h3">The Candida genus</option><option value="#h4">Localized Candida infecti...</option><option value="#h7">Systemic Candida infectio...</option><option value="#h10">Airway Candida colonizati...</option><option value="#h11">Candida-bacterial interac...</option><option value="#h13">Interactions with Staphyl...</option><option value="">Candida and the immune re... <<</option><option value="#h19">Conclusion and future dir...</option><option value="#h20">References</option></select></form></td>
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The outer strata of<em>Candida</em>species contain elements with antigenic potential, which include mannans and mannoproteins which upon human exposure induce an immunogenic response [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0070%20CIT0071%20CIT0072%20CIT0073&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">70–73</a>]. Where mannan-deficient,<em>Candida</em>strains are clinically less virulent and during the course of a<em>Candida</em>infection, cellular, humoral and innate immune responses all play a role [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0071&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">71</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0072&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">72</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0074%20CIT0075%20CIT0076&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">74–76</a>].
<div id="ss15" class="NLM_sec NLM_sec_level_2"><span id="d3154443e1164" class="title2">Innate immunity
Recognition of microbes by the innate immune system depends on activation of specific pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). For fungi the first PAMPs encountered by the immune system are those present in the fungal cell wall. The cell wall of<em>C. albicans</em>is composed of a core structure of β-(1,3)-glucan polysaccharide fibrils covalently linked to chitin (a β-(1,4)-linked polymer of<em>N</em>-acetyl glucosamine) and β-(1,6)-glucan. The outer layer consists of<em>N</em>-linked [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0077&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">77</a>] or<em>O</em>-linked mannosylated proteins called mannans [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0078&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">78</a>]. Two classes of PRRs in particular play an important role in antifungal immunity – the C-type lectin receptors (CLRs) and Toll-like receptors (TLRs). Neutrophils, monocytes, macrophages and airway epithelial cells are all involved in defense against fungal pathogens. Dendritic cells (DCs) also respond to fungal PAMPs leading to activation of T-cell-mediated specific immunity. These various cell populations differ in their expression of CLRs and TLRs on the cell membrane, and are therefore capable of initiating different responses. CLRs and TLRs recognize the major polysaccharide cell wall components,<em>N</em>- and<em>O</em>-linked mannans, β-mannosides, β-(1,6)-glucan and phospholipomannan. CLRs comprise a large family of receptors, including the mannose receptor (MR), the dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), dectin-2, galectin-3 that share at least one carbohydrate recognition domain originally identified in mannose binding lectin (MBL) and recognize the mannan structures like TLR4. In contrast, complement receptor 3 (CR3) and dectin-1, two other CLRs, as well as TLR2 detect the β-glucans.
Much is known regarding the expression and function of TLRs in the CF lung [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0079&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">79</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0080&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">80</a>]. The most important TLRs involved in recognition of<em>Candida</em>species in the lung are TLRs 1, 2, 4, 6, while TLR9 has a more minor role. In macrophages and dendritic cells TLR9 resides in the endoplasmic reticulum (ER) and redistributes to uCpG-containing lysosomal compartments for ligand binding and signal transduction [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0081&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">81</a>]. Cell surface expression of TLR9 has been detected by fluorescence microscopy on a CF tracheal epithelial cell line and by flow cytometry on both immortalized and differentiated primary airway epithelial cells [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0082&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">82</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0083&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">83</a>].
Claeys<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0084&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">84</a>] found higher mRNA expression of TLR2, but not TLR4, in nasal polyps in patients with cystic fibrosis versus healthy controls and it appears that this distribution of TLRs also extends to the lower respiratory tract. Two groups independently examined the distribution and function of TLRs in cystic fibrosis airway epithelial cells. Greene<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0082&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">82</a>] showed that CF tracheal epithelial cell lines express functional TLRs1-6 and 9, whilst Muir<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0085&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">85</a>] reported that TLRs 1–10 were expressed in CF cells. Interestingly TLR2 transcription was modestly increased in CF compared with normal epithelial cells following bacterial stimulation but not all investigators have confirmed this observation [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0086&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">86</a>]. TLR4 was present in a more basolateral distribution and appeared to have a limited role in epithelial responses. John<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0087&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">87</a>] found a similar distribution of TLR4 in the CF bronchial epithelial cell line CFBE41o- and in histologic lung sections of patients with CF. Overall it appears that TLR2 is the predominant TLR expressed on the surface of airway epithelial cells<em>in vivo</em>with TLR4 residing mainly intracellularly or displaying only low level surface expression. It can however be mobilized to the membrane following stimulation with microbial factors, e.g., RSV infection [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0088&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">88</a>].
The airway epithelium provides a vast surface area and contributes significantly to pulmonary innate immunity [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0079&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">79</a>]. However as CF is a neutrophil-dominated disease the expression of TLRs by neutrophils is also likely to be important in the host's immune response to infection with<em>Candida</em>. Hauber<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0086&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">86</a>] reported that the number of TLR4-positive neutrophils in the submucosa of patients with CF was higher than in control subjects. From other reports it appears that expression of TLR2, TLR4, and TLR9 are all increased on airway neutrophils compared with circulating neutrophils in CF patients [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0089&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">89</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0090&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">90</a>].
<p class="last">Little is known regarding the differential expression of TLRs by monocytes from CF versus healthy controls. However, accurate TLR2 and TLR4 responses in these cells are believed to depend on TLRs localizing to lipid rafts [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0091&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">91</a>]. Although it has been suggested that CF monocytes are locked in an LPS-tolerant state, the mechanism responsible does not involve altered regulation of TLR expression but rather is due to down-regulation of TREM-1 [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0092&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">92</a>]. Nonetheless there may be altered regulation of TLR4 in monocytes from CF patients [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0093&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">93</a>]. It will be interesting to determine the effect of<em>Candida</em>infection on TLR expression in various cell types in the CF lung.
<div id="ss16" class="NLM_sec NLM_sec_level_2"><span id="d3154443e1295" class="title2">Cell-mediated immunity
<p class="last">Individuals whose cell-mediated immunity is compromised are at an increased susceptibility to infection with<em>Candida</em>species illustrating the important role that this arm of the immune system plays in the host defense against the organism. The reasons underlying this observation remain ambiguous and little work has been performed in CF to examine this potential link. In non-CF animal models, interleukin (IL)-12 promotes a Th1 response to<em>Candida</em>exposure and IL-10 mediated systemic infection [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0094&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">94</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0095&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">95</a>]. In contrast interferon (IFN)-gamma appears to be protective [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0096&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">96</a>]. Allard<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0097&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">97</a>] have shown that CF oropharyngeal exposure to<em>Candida</em>lysates evoked a Th2 type immune response similar to that observed in non-CF models. However when exposed to both<em>Pseudomonas</em>and<em>Candida</em>lysates together, a deviation in the adaptive immune response from a Th2 to Th1 type associated with neutrophilia was noted. Neutrophils also damage pseudohyphae in association with IFN-gamma to provide another host resistance strategy against<em>Candida</em>species. This is mediated through granulocyte-colony stimulating factor (G-CSF) [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0098&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">98</a>,<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0099&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">99</a>]. Additionally, dectin-1 by distinguishing cell wall β-glucan can trigger cell-mediated defenses [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0100&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">100</a>]. While the cytokine milieu and neutrophil response in CF continue to be an area of intense investigation among researchers, minimal data to date remains accessible with regard solely to<em>Candida</em>species.
<div id="ss17" class="NLM_sec NLM_sec_level_2"><span id="d3154443e1351" class="title2">Humoral immunity
<p class="last">The role of the humoral immune response during<em>Candida</em>exposure and infection remains controversial. Despite this, the majority of literature with regards to<em>Candida</em>in CF exists in this area. In the late 1980s, Przyklenk<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0101&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">101</a>] first assessed serum IgG antibodies to both<em>Aspergillus fumigatus</em>and<em>C. albicans</em>in CF versus control patients and found that antibody levels were higher in CF patients irrespective of sputum isolation. In contrast to<em>A. fumigatus</em>, antibodies to<em>C. albicans</em>were observed to increase significantly with its increased isolation from sputum culture. Minimal work followed until Maiz<em>et al.</em>[<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0102&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">102</a>] assessed the prevalence of<em>Aspergillus</em>and<em>Candida</em>species in CF sputa and the serologic IgE responses to these fungi. For the first time, they additionally investigated whether the immune response had direct effects on clinical status in CF.<em>Candida</em>species were isolated in nearly half of all sputum samples analyzed (47.5%), but 87.9% of patients had at least one growth of<em>C. albicans</em>during the study course. One-quarter (26.7%) were sensitized to<em>C. albicans</em>and only patients who grew<em>C. albicans</em>at least once during the study developed an IgE response to the fungi. The clinical parameters assessed (FEV1 and CT scores) were not worse in those sensitized versus the non-sensitized. Interestingly, half of the sensitized group had confirmed ABPA whilst the remaining patients had some immunologic characteristics of ABPA. In conclusion, the group found a high prevalence of both colonization and sensitization to<em>C. albicans</em>in CF, but could not relate this to disease severity or clinical status. Although serum IgE to<em>C. albicans</em>appeared to represent an immunological marker of ABPA in CF, it is important to note that the studied group was small (<em>n</em>= 20) and only FEV1 and CT scores assessed as clinical measures. The same group extended this work recently to assess serum IgG, IgA and IgM against<em>A. fumigatus</em>and<em>C. albicans</em>and found that although no correlation was detected between the presence of<em>A. fumigatus</em>in sputum and an immune response, the converse was true of<em>C. albicans</em>. Increasing sputum isolation heralded an elevated serum response however again this could not be related to respiratory impairment [<a class="ref NLM_xref-bibr" href="http://informahealthcare.com/action/showPopup?citid=citart1&id=CIT0103&doi=10.3109/13693786.2010.503320" rel="nofollow" target="_blank">103</a>].
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<tr><th align="left" valign="middle" width="95%">Conclusion and future directions</th>
<td class="sectionHeading" nowrap="nowrap" width="62" height="16"><span class="fulltext">Section:</td>
<td class="sectionHeading" align="right" valign="middle" nowrap="nowrap" width="92" height="16"><form target="_blank"><select class="fulltextdd" name="select23"><option selected="selected">Choose</option><option value="#">Top of page</option><option value="#abstract">ABSTRACT</option><option value="#h2">Introduction</option><option value="#h3">The Candida genus</option><option value="#h4">Localized Candida infecti...</option><option value="#h7">Systemic Candida infectio...</option><option value="#h10">Airway Candida colonizati...</option><option value="#h11">Candida-bacterial interac...</option><option value="#h13">Interactions with Staphyl...</option><option value="#h15">Candida and the immune re...</option><option value="">Conclusion and future dir... <<</option><option value="#h20">References</option></select></form></td>
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<p class="last">In this review, we have highlighted the current knowledge base and infections caused by the<em>Candida</em>species in CF. The dearth of CF-specific literature available illustrates that it evidently is a ‘road less travelled’. Despite this lack of literature and audit, what remains clear is that the species is isolated frequently and has importance in contributing to morbidity and in some cases mortality in CF. There is a high rate of undetected symptomatic oral and genital infections in the adult CF population and the problem should not be ignored with newer antibacterial agents on the horizon that will likely select out these fungal pathogens. Long-term use of antibiotics has recurrently emerged as a contributing factor to<em>Candida</em>infection and an alteration of flora post therapy lends survival advantages to the pathogenicity of this species. In doing so,<em>Candida</em>probably contributes to the inflammatory milieu observed in CF. Although post-transplant candidiasis is a rare occurrence, port infections do occur frequently. When a port is infected, it should be removed promptly and combined with antifungal therapy results in excellent clinical outcomes. The<em>Candida</em>species interestingly elicits innate, cellular and humoral immune responses that we have yet to fully understand in the context of CF. Clearly an increasing amount of work remains left to be done to address the many unanswered questions. Future avenues for focus in this field lie within clinical care, isolation techniques and biomedical research. Healthcare professionals should maintain a positive approach in looking for manifestations of<em>Candida</em>infection during annual reviews at CF clinics and subsequently pursue microbiology in symptomatic cases. In terms of isolation techniques, selective media needs to be developed to suppress the growth of gram negative pathogens such as<em>Pseudomonas</em>and<em>Burkholderia</em>species and enhance fungal identification and isolation. Standardization of detection protocols needs to be pursued for fungi in CF as currently lab and international variation persists. Finally, basic science and clinical research avenues with regard to<em>Candida</em>species in CF need to be actively pursued so as to enable an improved understanding of its role in the CF airway,<em>Candida</em>-bacterial interaction and its potential use as a microbiological marker of CF disease severity and progression.
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<p class="first last"><strong><em>Declaration of interest:</em></strong>The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.
<a name="h20" rel="nofollow"></a><span><span>
<div class="abstr">
<div class="cit"><a title="Annales de biologie clinique." href="http://www.ncbi.nlm.nih.gov/pubmed/20348048" rel="nofollow" target="_blank">Ann Biol Clin (Paris).</a>2010 Mar-Apr;68(2):157-62.
<h1>[The fungal risk in<span class="highlight">cystic fibrosis: a pilot study].</h1>
<div class="lang">[Article in French]
<div class="auths"><a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Van%20Grunderbeeck%20N%22%5BAuthor%5D" rel="nofollow" target="_blank">Van Grunderbeeck N</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Conseil%20V%22%5BAuthor%5D" rel="nofollow" target="_blank">Conseil V</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Leroy%20S%22%5BAuthor%5D" rel="nofollow" target="_blank">Leroy S</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wallaert%20B%22%5BAuthor%5D" rel="nofollow" target="_blank">Wallaert B</a>,<a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Delhaes%20L%22%5BAuthor%5D" rel="nofollow" target="_blank">Delhaes L</a>.
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<h3 class="label">Source</h3>
Service de pneumologie-immuno-allergologie, Hôpital Calmette, CHRU de Lille, Laboratoire environnement et santé, Université Catholique de Lille, Service de mycologie parasitologie (EA3609), Faculté de médecine, Univiversité Nord de France (UDSL), CHRU de Lille.
<div class="abstr">
<h3>Abstract</h3>
Prevalence of Aspergillus fumigatus, as well as other species, and factors associated with risk induced by fungal colonization are poorly defined in<span class="highlight">cystic fibrosis(CF). We set up a national prospective study to document this risk. As a pilot study, the fungal risk was determined for 21 CF adult patients in a multidisciplinary way: using clinical parameters, notifying treatment, determining fungal presence in sputum and documenting ABPA status. 16 (76%) patients presented with fungal presence in sputum. Aspergillus fumigatus and<span class="highlight">Candidaalbicans were the predominant species, but less common mould species such as Scedosporium apiospermum, or Exophiala dermatitidis were also recovered. Factors significantly associated with fungal presence were pancreatic insufficiency, malnutrition, bacterial colonization, and corticosteroids.<span class="highlight">Candidaalbicans was correlated with more severe Shwachman Score,<span class="highlight">Pseudomonasaeruginosa colonization, and intravenous antibiotics use. Moulds species were significantly associated with inhaled corticosteroids. In conclusion, fungal presence in CF appears frequent and various, significantly associated with clinical data, such as inhaled corticosteroids and A. fumigatus. These results confirm the interest of the national prospective French study focused on 300 CF patients, in order to establish if patients could benefit from antifungal treatments or preventive measures.
