The role of airborne mold in chronic rhinosinusitis.
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Air Microbiology↗
Biomedical subjects
Jens U Ponikau
Publications and source records attributed to Jens U Ponikau.
Rhinosinusitis: developing guidance for clinical trials.
The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.
Chronic Disease↗
Rhinosinusitis: Developing guidance for clinical trials.
The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication, "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.
Chronic Disease↗
Airway manifestations of pediatric eosinophilic esophagitis: a clinical and histopathologic report of an emerging association.
OBJECTIVES: Pediatric eosinophilic esophagitis (EE) typically presents with dysphagia, vomiting, dyspepsia, or food impaction. The purpose of this study was to highlight the emerging association of pediatric EE and airway disease. An additional goal of this study was to describe the unique histopathologic findings found in EE and specifically explore the potential role of the cytotoxic protein called eosinophil major basic protein (MBP) in the pathophysiology of the disease. METHODS: A retrospective review of 3 children with EE and airway symptoms included symptom presentation, aerodigestive tract endoscopic findings, ambulatory 24-hour dual pH-metry, allergy tests, treatment modalities, and treatment response. Esophageal tissue obtained from biopsies of each patient was evaluated by hematoxylin and eosin to determine the number of eosinophils per high-power field, by immunofluorescent anti-MBP staining to determine the presence of MBP, and by standard light and transmission electron microscopy to evaluate eosinophil migration patterns. RESULTS: All patients had airway inflammation that included nonspecific laryngeal edema and grade I or II subglottic stenosis. Allergy testing was positive in the 2 patients who were tested. All patients had symptoms refractory to standard reflux therapy. Ambulatory pH-metry findings were normal in 2 patients and abnormal in 1 patient despite maximum treatment. Two patients had visual abnormalities seen during esophageal examination. The number of eosinophils ranged from 20 to 45 per high-power field. Intracellular and extracellular MBP deposition was found in all esophageal biopsy specimens. All patients were treated with swallowed fluticasone, and 2 had symptom relapses that required repeat treatment. CONCLUSIONS: The spectrum of pediatric EE can include upper airway disease. Intracellular and extracellular MBP deposition is present in EE, which potentially releases cytotoxic mediators that explain the esophageal and airway clinical symptoms seen in those with the disease. Eosinophilic esophagitis should be considered in patients with a history of atopic diseases and unexplained upper airway findings refractory to reflux treatment. Treatment with swallowed fluticasone is successful; however, relapses are common and require repeat treatment and close follow-up.
Adolescent↗
The role of ubiquitous airborne fungi in chronic rhinosinusitis.
Chronic rhinosinusitis (CRS) is a confusing disease for both allergists and otorhinolaryngologists, partly because of its poorly understood pathophysiology and partly because of its limited treatment options. Several recent reports have provided evidence for a better understanding of the etiology and the relationship of CRS to airborne fungi-especially to Alternaria. First, the development of novel methods enables detection of certain fungi in mucus from the nasal and paranasal sinus cavities. Second, a non-IgE-mediated immunological mechanism for reactivity of patients with CRS to certain common fungi has been described. Third, these fungi are surrounded by eosinophils in vivo, suggesting that they are targeted by eosinophils. Finally, the preliminary results of studies using antifungal agents to treat patients with CRS are promising. Overall, these recent discoveries provide a logical mechanism for the pathophysiology of CRS, and they also suggest promising avenues for treatment of CRS with antifungal agents.
Air Microbiology↗
Nonpathogenic, environmental fungi induce activation and degranulation of human eosinophils.
Eosinophils and their products are probably important in the pathophysiology of allergic diseases, such as bronchial asthma, and in host immunity to certain organisms. An association between environmental fungal exposure and asthma has been long recognized clinically. Although products of microorganisms (e.g., lipopolysaccharides) directly activate certain inflammatory cells (e.g., macrophages), the mechanism(s) that triggers eosinophil degranulation is unknown. In this study we investigated whether human eosinophils have an innate immune response to certain fungal organisms. We incubated human eosinophils with extracts from seven environmental airborne fungi (Alternaria alternata, Aspergillus versicolor, Bipolaris sorokiniana, Candida albicans, Cladosporium herbarum, Curvularia spicifera, and Penicillium notatum). Alternaria and Penicillium induced calcium-dependent exocytosis (e.g., eosinophil-derived neurotoxin release) in eosinophils from normal individuals. Alternaria also strongly induced other activation events in eosinophils, including increases in intracellular calcium concentration, cell surface expression of CD63 and CD11b, and production of IL-8. Other fungi did not induce eosinophil degranulation, and Alternaria did not induce neutrophil activation, suggesting specificity for fungal species and cell type. The Alternaria-induced eosinophil degranulation was pertussis toxin sensitive and desensitized by preincubating cells with G protein-coupled receptor agonists, platelet-activating factor, or FMLP. The eosinophil-stimulating activity in Alternaria extract was highly heat labile and had an M(r) of approximately 60 kDa. Thus, eosinophils, but not neutrophils, possess G protein-dependent cellular activation machinery that directly responds to an Alternaria protein product(s). This innate response by eosinophils to certain environmental fungi may be important in host defense and in the exacerbation of inflammation in asthma and allergic diseases.
Alternaria↗
The role of ubiquitous airborne fungi in chronic rhinosinusitis.
Chronic rhinosinusitis (CRS) is a confusing disease for both allergists and otorhinolaryngologists, partially due to its poorly understood pathophysiology and partially due to its limited treatment options. Several recent reports now provide evidence for a better understanding of the etiology and the relationship of CRS to airborne fungi, especially to Alternaria. First, the development of novel methods enables detection of certain fungi in mucus from the nasal and paranasal sinus cavities. Second, a non-immunoglobulin E-mediated immunologic mechanism for reactivity of CRS patients to certain common fungi has been described. Third, these fungi are surrounded by eosinophils in vivo, suggesting that they are targeted by eosinophils. Fourth, the preliminary results of studies using antifungal agents to treat patients with CRS are promising. Overall, these recent discoveries provide a logical mechanism for the pathophysiology of CRS, and they also suggest promising avenues for treatment of CRS with antifungal agents.
Air Microbiology↗
Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial.
BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. Its etiology is unknown, and there is a paucity of effective medical treatments. OBJECTIVE: We tested the hypothesis that intranasal antifungal treatment improves the objective computed tomography (CT) findings (inflammatory mucosal thickening), nasal endoscopy stages, and symptoms of CRS. METHODS: A randomized, placebo-controlled, double-blind, single-center trial used amphotericin B to treat 30 randomly selected patients with CRS. Patients were instructed to instill 20 mL amphotericin B (250 mug/mL) or placebo to each nostril twice daily for 6 months. The primary outcome was a quantitative reduction in inflammatory mucosal thickening on CT scans of a standardized coronal cut. Secondary outcome measures were endoscopic scores, patient symptom scores, and levels of intranasal inflammatory mediators. RESULTS: Twenty-four patients completed the 6 months of treatment. Patients receiving amphotericin B achieved a relative reduction in the percentage of mucosal thickening on CT scans (n = 10; -8.8%) compared with placebo (n = 14; +2.5%; P = .030). Likewise, the changes in the endoscopic scores improved in the amphotericin B group compared with placebo ( P = .038). Between-group comparisons of the changes in the intranasal mucus levels of eosinophil-derived neurotoxin showed a reduction in the amphotericin B group and an increase in the placebo group ( P = .046); levels of IL-5 showed similar tendencies ( P = .082). CONCLUSION: Intranasal amphotericin B reduced inflammatory mucosal thickening on both CT scan and nasal endoscopy and decreased the levels of intranasal markers for eosinophilic inflammation in patients with CRS.
Administration, Intranasal↗
Striking deposition of toxic eosinophil major basic protein in mucus: implications for chronic rhinosinusitis.
BACKGROUND: The mechanisms by which eosinophilic inflammation damages the epithelium and contributes to recurrent acute exacerbations in chronic rhinosinusitis (CRS) have not been fully elucidated. OBJECTIVE: We tested the hypotheses that eosinophils deposit toxic major basic protein (MBP) in the mucus and that MBP reaches concentrations able to damage the sinonasal epithelium. METHODS: Tissue specimens with mucus attached to the tissue were carefully collected from 22 patients with CRS and examined by using immunofluorescence staining for MBP. This immunofluorescence was digitally analyzed to determine the area covered by MBP and the intensity of the staining (estimating MBP concentration). Levels of MBP in extracts from nasal mucus were quantitated by means of RIA. RESULTS: Heterogeneous eosinophilia was evident within tissue and mucus specimens. All tissue specimens showed intact eosinophils, but diffuse extracellular MBP deposition, as a marker of eosinophil degranulation, was rare. In contrast, all mucus specimens showed diffuse MBP throughout and abundant diffuse extracellular MBP deposition within clusters of eosinophils. Digitized analyses of MBP immunofluorescence revealed increased area coverage (P < .0001) in mucus compared with that seen in tissue. Estimated concentrations of MBP within the clusters suggested toxic levels. MBP concentrations in mucus extract reached 11.7 microg/mL; MBP was not detectable in healthy control subjects. CONCLUSION: In patients with CRS, eosinophils form clusters in the mucus where they release MBP, which is diffusely deposited on the epithelium, a process not observed in the tissue. Estimated MBP levels far exceed those needed to damage epithelium from the luminal side and could predispose patients with CRS to secondary bacterial infections.
Adolescent↗
New paradigm for the roles of fungi and eosinophils in chronic rhinosinusitis.
PURPOSE OF REVIEW: Chronic rhinosinusitis represents a challenge with its poorly understood pathophysiology and limited treatment options. Potential roles of fungi and eosinophils in the etiology and pathophysiology of chronic rhinosinusitis are summarized. RECENT FINDINGS: Previously, the fungal role in chronic rhinosinusitis was limited to the rare subgroup, allergic fungal rhinosinusitis. Critical examination of earlier diagnostic criteria for allergic fungal rhinosinusitis reveals limitations. By using updated diagnostic standards and novel sensitive techniques to detect fungi, a higher number of patients can now be diagnosed with fungal rhinosinusitis. A novel non-IgE-mediated immunologic mechanism in chronic rhinosinusitis patients links the predominant eosinophilic inflammation to certain fungi. Overall, these new findings have implications for surgical and medical approaches, including anti-inflammatory and antifungal medications. SUMMARY: Several classification schemes and diagnostic criteria describe chronic rhinosinusitis and make comparisons difficult. Preselection of patient groups within the chronic rhinosinusitis population and the lack of sensitive diagnostic techniques have prevented a full understanding of the syndrome complex of chronic rhinosinusitis. New results suggest a broader role for fungi in the pathophysiology of chronic rhinosinusitis, linking the eosinophilic inflammation to the presence of certain molds in the nasal and paranasal cavities. Although fungi are commonly found in nearly everyone, only chronic rhinosinusitis patients respond to them with an eosinophilic inflammation. These findings support a shift in the etiologic understanding of chronic rhinosinusitis away from a bacteriologic infectious pathogenesis to a fungal-driven inflammatory pathophysiology. Herein, the authors review earlier studies and describe an updated view on an old paradigm.
Chronic Disease↗
Chronic rhinosinusitis: an enhanced immune response to ubiquitous airborne fungi.
BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common long-term illnesses in the United States. The etiology of CRS is unknown, and no effective treatment has been established. OBJECTIVE: We investigated the hypothesis that abnormal immunologic responses to ubiquitous airborne fungi contribute to the pathogenesis of this disease. METHODS: The proliferative and cytokine responses of PBMCs to extracts from 4 common airborne fungi-including Alternaria , Aspergillus , Cladosporium , and Penicillium -were examined by in vitro culture. Serum specimens were tested for specific IgE and IgG to these fungi. RESULTS: PBMCs from approximately 90% of the patients with CRS, but not those from normal individuals, produced both IL-5 and IL-13 when exposed to Alternaria. Furthermore, PBMCs from patients with CRS produced significantly more IFN-gamma than PBMCs from normal individuals in response to Alternaria (median, 553 pg/mL vs 98 pg/mL; P < .01). Levels of serum IgG antibodies to Alternaria and Cladosporium were clearly increased in patients with CRS compared with normal individuals ( P < .01). Less than 30% of the patients with CRS had specific IgE antibodies to Alternaria or Cladosporium. The increased humoral (serum IgG) response strongly correlated with the increased cellular (IL-5 production) response to Alternaria ( r = 0.619; P < .01). CONCLUSION: Patients with CRS show exaggerated humoral and cellular responses, both T(H)1 and T(H)2 types, to common airborne fungi, particularly Alternaria. The anomalous immune and inflammatory responses to ubiquitous fungi may explain the chronicity of airway inflammation in CRS.
Adult↗
Features of airway remodeling and eosinophilic inflammation in chronic rhinosinusitis: is the histopathology similar to asthma?
BACKGROUND: Asthma and chronic rhinosinusitis (CRS) coexist clinically in >50% of patients with CRS. Although epithelial damage and basement membrane thickening are well-known features of airway remodeling in asthma, they have not been described in CRS. OBJECTIVE: In this study, we tested the hypothesis that histopathologic features of asthma, namely, the chronic eosinophilic inflammation, epithelial damage, and basement membrane thickening of the airway mucosa, are also present in sinonasal specimens from patients with CRS. METHODS: We examined histologic specimens from 22 randomly selected patients with refractory CRS undergoing endoscopic sinus surgery and 4 healthy control subjects. The shedding of the epithelium and basement membrane thickening were evaluated by 3 independent observers' scores of hematoxylin-and-eosin staining. Eosinophilic inflammation was monitored with immunohistochemistry for eosinophil major basic protein. A novel, computerized method objectively analyzed confocal microscopic images of major basic protein immunofluorescence to determine areas with the least and most inflammation per specimen. RESULTS: Specimens from all patients with CRS (22/22) revealed epithelial damage (shedding) and basement membrane thickening. Strikingly heterogeneous eosinophilic inflammation, which did not differ between allergic and nonallergic patients, was detected in all patients with CRS and was absent in all healthy control subjects. CONCLUSION: The histopathologic findings of asthma, namely, heterogeneous eosinophilic inflammation and features of airway remodeling, are also present in CRS. These findings, coupled with the common clinical coexistence of both diseases, suggest that the same pathologic disease process is manifest as CRS in the sinonasal tissue and as asthma in the lower airway.
Adolescent↗
Eosinophilic fungal rhinosinusitis of the lacrimal sac.
OBJECTIVES/HYPOTHESIS: Chronic sinusitis is a condition affecting millions of individuals each year. Recent findings indicate that chronic rhinosinusitis is a response to fungi mediated by the eosinophil in some of these individuals. We report a case of eosinophilic fungal rhinosinusitis of the lacrimal sac, an entity not previously reported. STUDY DESIGN: Case report. METHODS: A 69-year-old man presented with a 1-cm cystic lesion in the right-side medial canthal region. This lesion was fluctuant, and mucoid material was freely expressed from the medial canthal area. Endoscopic examination revealed bilateral nasal polyps anteriorly and superiorly with mucopurulent drainage from both maxillary sinuses. He had undergone three prior sinus surgeries and two prior lacrimal cannulations elsewhere. A computed tomography scan showed opacification of both maxillary sinuses, ethmoid sinuses, and the left sphenoid sinus and moderate thickening in the frontal sinuses. There was significant soft tissue prominence in the area of both lacrimal fossae with erosion into the medial orbit. The patient underwent bilateral endoscopic revision ethmoidectomies, middle meatal antrostomies, sphenoidotomies, frontal sinusotomies, and endoscopic right-side dacryocystorhinostomy at the Department of Otorhinolaryngology, Mayo Clinic (Rochester, MN). RESULTS: At the time of surgery, massive amounts of thick mucoid material were aspirated from both lacrimal regions. The aspiration of the lacrimal duct on the left side was sufficient treatment, whereas the dacryocystorhinostomy was necessary to decompress the cyst of the face on the right side. The material aspirated was allergic mucin, and the patient met the criteria for diagnosing eosinophilic fungal rhinosinusitis. The patient was started on a regimen of antifungal nasal irrigations postoperatively and has done well in follow-up. CONCLUSIONS: Although never previously reported, eosinophilic fungal rhinosinusitis can occur in the lacrimal sac. It is important to recognize this so that the underlying disease process can be treated appropriately.
Aged↗
The chemotactic behavior of eosinophils in patients with chronic rhinosinusitis.
OBJECTIVE: To characterize peripheral eosinophil migration in patients with chronic rhinosinusitis in the presence of nasal mucin and nasal tissue extracts. STUDY DESIGN: Prospective, controlled, ex-vivo. METHODS: Peripheral blood eosinophils, nasal mucin, and nasal tissue were harvested at the time of sinus surgery in 10 patients, as well as obtained in 10 healthy control subjects. Extracts were prepared from nasal mucin and nasal tissue. A modified Boyden chamber was used to study eosinophil migration from both patients and healthy control subjects in the presence of both extracts. RESULTS: Patients with chronic rhinosinusitis and all healthy control subjects demonstrated a concentration-dependent increased migration of eosinophils in the presence of both nasal mucin and nasal tissue extracts. The percentage of migration was consistently higher for eosinophils from patients with chronic rhinosinusitis compared with control subjects. The difference attained statistical significance in the presence of 50% tissue extract (median percentage of migration, 23.3% vs. 7.8% [ P=.033]). CONCLUSIONS: Nasal mucin and nasal tissue in chronic rhinosinusitis contains chemoattractants, which can induce active eosinophil migration. The eosinophil migration from patients with chronic rhinosinusitis was consistently higher compared with eosinophils from healthy control subjects. Because the eosinophils were obtained from the peripheral blood, this finding suggests activation of eosinophils in the systemic circulation in chronic rhinosinusitis.
Chemokine CCL11↗
Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis.
BACKGROUND: Chronic rhinosinusitis (CRS) is the most common chronic disease that is frequently refractory to treatment. OBJECTIVE: We sought to establish the safety and demonstrate the clinical efficacy of intranasal antifungal drug therapy in patients with CRS in a pilot trial. METHODS: A prospective open-label trial used amphotericin B as a medical treatment in 51 randomly selected patients with CRS. The antifungal agent was applied intranasally as 20 mL of a 100 microg/mL solution twice daily. The outcome was measured by using their symptoms and by using an endoscopic scoring system in all patients. In addition, pretreatment and posttreatment coronal computed tomographic scans of the nose and sinuses were available for evaluation in 13 patients. RESULTS: By using amphotericin B, improvement of sinusitis symptoms was observed in 38 (75%) of 51 patients. Endoscopically, 18 (35%) of 51 patients became disease free, and an additional 20 (39%) of 51 had improvement of at least one stage (P <.001). No effect was seen in 13 (25%) of 51 patients. The available computed tomographic scans before and after treatment demonstrated a significant reduction in the inflammatory mucosa thickening that had occluded the paranasal sinuses (P <.0001 in maxillary sinus). CONCLUSION: This open-label pilot trial demonstrates that direct mucoadministration of an antifungal drug appears to be both safe and effective in the treatment of patients with CRS. Therefore controlled and blinded trials are indicated to clarify the novel role of intranasal antifungal drugs in the treatment of CRS.
Administration, Intranasal↗
Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein.
BACKGROUND: The ability to identify fungal hyphae in patients with chronic rhinosinusitis (CRS) has been inconsistent. A new fluorescein-labeled staining method targets chitin found in fungal cell walls. OBJECTIVE: We hypothesize that this method would be able to more consistently detect fungi within the mucin of CRS patients. METHODS: Fifty-four consecutive CRS surgical patients were evaluated. After ensuring sensitivity and specificity of this new method, all specimens were stained with either fluorescein-labeled chitinase or Grocott methanamine silver stain for comparison. RESULTS: All 54 specimens contained eosinophilic mucin on hematoxylin and eosin staining. One or more fungal hyphae could be visualized within the mucin of 54 (100%) of 54 specimens stained using the fluorescein-labeled chitinase. Only 41 (76%) of 54 of the specimens stained with the Grocott methanamine silver stain technique demonstrated fungi. CONCLUSION: The fluorescein-labeled chitinase-staining technique has greater sensitivity in detecting fungal organisms within eosinophilic mucin. Fungal organisms are present in the mucin of CRS patients.
Adolescent↗