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1.  Spontaneous Eosinophilic Nasal Inflammation in a Genetically-Mutant Mouse: Comparative Study with an Allergic Inflammation Model 
PLoS ONE  2012;7(4):e35114.
Eosinophilic inflammation is a hallmark of chronic rhinosinusitis with nasal polyps. To model this disease process experimentally, nasal sensitization of mice with ovalbumin or aspergillus has been described. Here, we describe a genetically mutant mouse that develops robust spontaneous nasal eosinophilic inflammation. These mice lack the enzyme SHP-1 that down-regulates the IL-4Rα/stat6 signaling pathway. We compared nasal inflammation and inflammatory mediators in SHP-1 deficient mice (mev) and an ovalbumin-induced nasal allergy model.
A novel technique of trans-pharyngeal nasal lavage was developed to obtain samples of inflammatory cells from the nasal passages of allergic and mev mice. Total and differential cell counts were performed on cytospin preparations. Expression of tissue mRNA for IL-4, IL-13, and mouse beta-defensin-1 (MBD-1) was determined by quantitative PCR. Eotaxin in the lavage fluid was assessed by ELISA.
Allergic and mev mice had increased total cells and eosinophils compared with controls. Expression of IL-4 was similarly increased in both allergic and mev mice, but expression of IL-13 and eotaxin was significantly greater in the allergic mice than mev mice. Eotaxin was significantly up-regulated in both allergic rhinitis and mev mice. In both models of eosinophilic inflammation, down-regulation of the innate immune marker MBD-1 was observed.
The mev mice display spontaneous chronic nasal eosinophilic inflammation with potential utility for chronic rhinosinusitis with nasal polyps research. The eosinophilic infiltrate is more robust in the mev mice than allergic mice, but Th2 cytokine expression is not as pronounced. Decreased MBD-1 expression in both models supports the concept that Th2-cytokines down-regulate sinonasal innate immunity in humans, and suggests a role for mouse models in investigating the interaction between adaptive and innate immunity in the sinonasal mucosa.
PMCID: PMC3324406  PMID: 22509389
2.  Patient-Centered Research 
1). To be able to recognize allergic fungal sinusitis (AFS), a common and underdiagnosed condition.
A 28 years old man presented with yet another flare up of chronic sinusitis (he also had a history of allergic rhinitis), complaining of impaired taste and smell, itching in ears, and minimal epistaxis—mainly on the right side—after blowing his nose. The physical exam revealed a hyperemic nasal mucosa smeared with bright red blood and covered with yellowish crusts. The right inferior turbinate was pink and swollen. Investigations: skin prick test for Curvularia lunata was positive, white blood cell count was 7.700, with 9% eosinophils (with an absolute eosinophil count of 704), radio-allergo-sorbent test for Curvularia lunata was positive, total serum immunoglobulin E was 1926 IU/ml, serum eosinophilic cationic protein was 80 micrograms/l. A CT scan of the sinuses revealed pansinusitis and a soft tissue process (with multiple areas of calcification) in the right maxillary sinus eroding through the supero-medial wall into the right orbit. The patient was treated surgically. Analysis of debrided tissue revealed on histology large amounts of eosinophil-rich mucoid material, necrosis and bone remodeling. The bacterial smears and tissue cultures were negative. The silver impregnation stain revealed fungal short hyphal elements. Tissue fungal cultures grew Curvularia lunata.
Although responsible for many cases of chronic rhino-sinusitis, AFS is heavily underdiagnosed. We present a case with some unusual features. Our patient had AFS, which tends to affect patients with significant immune deficiencies (our patient was immunocompetent).
The invasion into orbit (usually a disastrous complication) was discovered only as accidental finding on a CT scan.
Positive radioallergosorbent test (RAST) results, skin test results, or presence of serum precipitins for fungal allergens, in combination with fungal culture results that match that particular fungal species, are crucial in making a diagnosis of allergic fungal sinusitis.
Some believe that allergic fungal sinusitis may be a trigger of chronic rhinosinusitis in up to 93% of cases. Taking into consideration the lack of specificity of nasal eosinophilia, and the ubiquicity of fungal colonization of the nose, it has been proposed to apply the term AFS only to those patients with chronic rhinosinusitis that fulfill the above criteria. Therapy is surgical.
PMCID: PMC1495752
3.  241 Nasal Cytology is Important in the Classification of Patients with Allergic and Non-Allergic Rhinitis 
The purpose of the study is the classification and clinical characterization of patients with allergic rhinitis and non-allergic and differentiate the presence of eosinophils and neutrophils in nasal cytology.
Prospective study of 405 patients with chronic symptoms of sneezes, pruritus, nasal congestion and rhinorrhea were evaluated by clinical examination, skin prick test and nasal cytology. Patients with diseases and/or treatments that could alter the outcome of these tests were excluded.
405 patients from 3 to 80 years were evaluated; 248 female patients (61%) and 157 males (39%). The sample was divided into 2 groups according to skin prick tests: allergic 270 (67%), 135 non-allergic (33%). The mean age of onset of symptoms was 14.27 and 23.47 years in allergic and nonallergic respectively. Nasal symptoms (nasal congestion, sneezes/pruritus, rhinorrhea, postnasal secretion) and signs (turbinates color and edema, secretion and oropharynx redness) were accessed using scores from 0 to 3, ranging from 0 to 24. In the allergic group the mean total nasal symptoms and signs scores were 6.64 and 4.66, while in non-allergic were 5.67 and 3.52. Allergic patients had an average 27.82% of eosinophils and 64.09% of neutrophils in nasal smears, whereas non-allergic patients 8.38% and 85.30%. Using skin prick test and nasal cytology we were able to diagnose allergic rhinitis in 69.6% (208) of the patients. 20.7% (62) had neutrophilic non-allergic rhinitis (NARNA) and 9.7% (29) non-allergic rhinitis with eosinophilia syndrome (NARES). No idiopathic rhinitis patients were found.
The frequencies of the types of rhinitis were: allergic rhinitis 69.6%, RENA 9.7%, NARNA 20.7% and idiopathic rhinitis 0%. Despite the fact that each sub group of nonallergic rhinitis has particularities, in allergic rhinitis we found early onset of complaints, signs and symptoms more intense and a greater number of eosinophils, compared with the nonallergic patients.
PMCID: PMC3512858
4.  Elevation of soluble interleukin-2 receptor levels in nasal allergy 
Mediators of Inflammation  1995;4(1):39-42.
To investigate soluble IL-2 receptor (sIL-2R) levels in nasal allergy, the sera and nasal secretions from patients with nasal allergy and from healthy subjects were subjected to a double-epitope enzyme-linked immunosorbent assay. Significant elevation of sIL-2R concentrations in the sera and nasal secretions was observed in the allergy patients (n = 26) compared with those of healthy subjects (n = 9). IL-2R-positive (CD25+) cells were observed in the crust formed in an allergic nasal mucosa. The concentration of sIL-2R in the sera correlated neither with the eosinophil count of the peripheral blood count nor with clinical severity. The concentration of sIL-2R in the nasal secretions was significantly higher compared with that in the sera from allergic patients (p < 0.01), whereas no significant difference was observed between sIL-2R levels in the sera and nasal sections from normal subjects. These findings indicate that sIL-2R plays an essential role in allergic processes by regulating IL-2R-positive cells recruited into the nasal mucosa.
PMCID: PMC2365605  PMID: 18475614
5.  The role of High Mobility Group Box 1 chromosomal protein in the pathogenesis of chronic sinusitis and nasal polyposis 
Chronic rhinosinusitis with nasal polyposis is considered to be a multifactorial disease where different stimuli (mechanical, viral, bacterial, fungal infection, immunological disorders or dysreactivity, environmental pollution), acting on the mucosa of nasal cavities and paranasal sinuses, lead to epithelial damage and mucosal inflammation. Inflammatory cell infiltration (predominantly eosinophils, but also neutrophils, mast cells, macrophages and lymphocytes), cytokine release and sub-epithelial oedema are the histological pictures that are associated, from the clinical point of view, with nasal congestion, secretion and/or post-nasal drip and facial pain/headache. Recently, the importance of the HMG B-1 protein in the pathogenesis of several inflammatory diseases has been demonstrated. This protein is released from necrotic/damaged cells or immune-activated cells, and by acting on specific membrane receptors causes the release of pro-inflammatory mediators, endothelial activation and the survival of inflammatory cells. The objective of the present study was: i) to determine whether HMG B1 is augmented in chronic rhinosinusitis with nasal polyps; ii) if its expression is associated with eosinophils, TNF-α, IL 5 and IL 8 cytokines typically present in chronic inflammation of the nose and paranasal sinuses; iii) to investigate a hypothetical role of this protein in the pathogenesis of nasal polyposis. Nasal polyps tissue from 21 patients affected by CRSwNP and nasal mucosa from 8 controls was collected at the ENT Department of the Chinese PLA General Hospital and underwent immunohistological staining for detection of HMG B1 protein and IL -5, IL -8 and TNF-α inflammatory cytokines. The degree of HMG B1 protein expression was evaluated by dividing the stained sections in 4 portions: 1) nucleus of epithelial cells, 2) cytoplasm of epithelial cells, 3) focal extracellular infiltration, 4) inflammatory cells. HMG B1 was more expressed in the nucleus of epithelial cells of patients compared with controls. In contrast, epithelial cytoplasm HMG B1 staining was significant lower in patients. Sub-epithelial focal infiltration of HMG B1 protein expression was lower in controls, whereas the expression of HMG B1 in the inflammatory cells in patients was significantly increased in comparison with controls. These data, together with the correlation we found between HMG B1 protein expression in different portions and the number of eosinophils infiltrating cells, or IL -5, IL -8 and TNF-α positive cells in patients, suggest that HMG B1 may play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps.
PMCID: PMC3552540  PMID: 23349558
HMGB1 chromosomal protein; Chronic rhinosinusitis; Nasal polyposis
6.  Nasal inflammation induced by a common cold: comparison between controls and patients with nasal polyposis under topical steroid therapy 
The evolution of nasal inflammation during a common cold in patients with nasal polyposis under topical steroid treatment is not clearly defined in the literature. Objective of this study was to analyse nasal inflammation during a common cold in patients with nasal polyposis under topical steroid treatment in comparison with control subjects. Two groups of subjects (35 consecutive patients with nasal polyposis receiving medical treatment, and 17 control subjects without any symptoms of chronic rhino-sinusitis) were studied: 10 patients with nasal polyposis and 11 controls had a common cold during a one-year follow-up period. Nasal lavage was performed at baseline and during the common cold. Soluble inflammatory mediators and permeability markers were determined in the nasal lavage fluid, as well as total and differential counts of the cells present. At baseline, no significant difference between controls and patients was observed, except for eosinophils. Paired comparisons between baseline and cold in controls revealed that all measured parameters, except for eosinophils, increased in the second nasal lavage. In nasal polyposis patients, the total cell neutrophil counts tended to increase. However, most of the concentrations of soluble parameters did not vary significantly in the second lavage, except for interleukin-6. In conclusion nasal inflammation markers appear to be similar in patients with and without nasal polyposis during a common cold when nasal polyposis patients are under topical steroid treatment.
PMCID: PMC2640005  PMID: 17608135
Nose; Common cold; Nasal polyposis; Therapy
7.  Increased Expression and Role of Thymic Stromal Lymphopoietin in Nasal Polyposis 
Nasal polyposis is a chronic inflammatory disease of the upper airways often associated with asthma and characterized by markedly increased numbers of eosinophils, Th2 type lymphocytes, fibroblasts, goblet cells and mast cells. Previous studies have shown elevated levels of thymic stromal lymphopoietin (TSLP) in atopic diseases like asthma, atopic dermatitis and mainly in animal models of allergic rhinitis (AR). Here, we investigated the expression of TSLP in nasal polyps from atopics and non-atopics in comparison with the nasal mucosa and its potential role in nasal polyposis.
Messenger RNA expression for TSLP, thymus and activation-regulated chemokine (TARC) and macrophage derived chemokine (MDC) in nasal polyps and nasal mucosa of atopics and non-atopics was analyzed by real time PCR. Immunoreactivity for TSLP in nasal polyps and in the nasal mucosa of patients with AR and non-allergic rhinitis (NAR) was analyzed by immunohistochemistry. Eosinophil counts was analyzed by Wright-Giemsa staining and nasal polyp tissue IgE, by ELISA.
Messenger RNA expression for TSLP,TARC and MDC was markedly higher in nasal polyps as compared to the allergic nasal mucosa. Immunoreactivity for TSLP was detected in epithelial cells, endothelial cells, fibroblasts and inflammatory cells of the nasal mucosa and nasal polyps. The number of TSLP+ cells was significantly greater in the nasal mucosa of AR than NAR patients. The number of TSLP+ cells in nasal polyps from atopics was significantly greater than that of non-atopics and that in the allergic nasal mucosa. The number of TSLP+ cells correlated well with the number of eosinophils and the levels of IgE in nasal polyps.
The high expression of TSLP in nasal polyps and its strong correlation to eosinophils and IgE suggest a potential role for TSLP in the pathogenesis of nasal polyps by regulating the Th2 type and eosinophilic inflammation.
PMCID: PMC3121060  PMID: 21738884
Nasal polyps; Th2 cytokines; TSLP; eosinophils; IgE
8.  411 The Classification of Allergic Rhinitis and Its Cytological Correlate 
The ARIA document introduced a new classification of allergic rhinitis, based on its duration and severity, which is graded on the basis of the impact of AR on daily activities and quality of life. Nasal cytology is a simple and reliable diagnostic tool to identify the presence and type of inflammation in rhinitis. Thus, we assessed severity of AR by nasal cytology on the basis of the ARIA classification.
Patients suffering from AR caused by grass pollen only, and healthy subjects were studied. The severity of rhinitis was defined according to ARIA. All subjects underwent nasal cytology, using a Rhino-probe. Scrapings were air-dryied and stained by May-Grunwald-Giemsa. Differential cell count was expressed as % of the total leukocytes. Unpaired t test was used for comparisons.
Sixty-two grass-allergic patients (34 men, mean age 35.2 years) and 18 healthy subjects (10 men, mean age 32) were studied. 67.8% of patients had intermittent AR (33.9% mild and 33.9% moderate-severe) and 32.2% had persistent AR (14.5% mild and 17.7% moderate-severe). The patients with moderate-severe AR had significantly more mast cells and lymphocytes than those with mild AR, with a relatively smaller number of neutrophils and eosinophils. Mast cells and/or lymphocytes could be detected in only 3/30 patients with mild rhinitis, and in 19/32 patients with moderate/severe rhinitis. No difference in cell counts was found when comparing intermittent and persistent AR.
Moderate/severe allergic rhinitis displays a cytological inflammatory pattern different from mild rhinitis.
PMCID: PMC3512961
9.  Relationship between Clinical Measures and Histopathologic Findings in Chronic Rhinosinusitis 
Describe detailed histopathologic findings from a cohort of patients with chronic rhinosinusitis and evaluate whether histologic measures correlate with baseline clinical factors.
Study Design
Cross-sectional study with planned data collection
Tertiary medical center
Subjects and Methods
Adult patients with chronic rhinosinusitis were prospectively enrolled and demographic data and medical comorbidities recorded. Disease severity was measured by computed tomography (CT), endoscopy, Smell Identification Test (SIT), the Chronic Sinusitis Survey, Rhinosinusitis Disability Index, and SF-36 General Health Survey. Mucosal specimens were assessed for the presence of mucosal inflammation, including cellular (eosinophils, neutrophils, lymphocytes, mast cells, plasma cells, macrophages), epithelial (squamous metaplasia, basement membrane thickening, goblet cells), and stromal markers (subepithelial edema, fibrosis). Histopathologic findings were correlated to baseline clinical factors.
A total of 147 subjects were enrolled with histologic samples available for review. Presence of inflammatory markers was diverse with lymphocytes present in 100% of subjects, eosinophils in 49.7%, and neutrophils found in 0.7%. Total eosinophil counts correlated with the presence of nasal polyposis (r =-0.367;p<0.001), asthma (r=0.264;p=0.001), and aspirin intolerance (r=0.279; p=0.001). Mucosal eosinophilia correlated with worse disease severity on CT (r=0.414;p<0.001), endoscopy (r=0.376; p<0.001), and SIT (r=-0.253;p=0.002) with the highest correlations seen in subgroups without nasal polyps. Histopathologic findings did not significantly correlate with any quality-of-life measure.
Mucosal eosinophilia correlates with objective disease severity as defined by CT, endoscopy, and SIT scores. Although other histologic markers of inflammation are present, none show similar correlations. The presence of mucosal eosinophils does not correlate with quality-of-life scores.
PMCID: PMC2766519  PMID: 19786212
Chronic rhinosinusitis; sinusitis; histology; pathology; quality of life
10.  MBP-Positive and CD11c-Positive Cells Are Associated with Different Phenotypes of Korean Patients with Non-Asthmatic Chronic Rhinosinusitis 
PLoS ONE  2014;9(10):e111352.
Asthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea.
Tissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters.
In comparisons between UP from each group, CRSwNP had a higher number of MPB+, CD68+, and CD11c+ cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP+, CD163+, CD11c+, 2D7+ and HNE+ cells, whereas fewer CD68+ cells were found in NP. In addition, MBP+ and CD11c+ cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP+ and CD11c+ cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP+, tryptase+, CD11c+, 2D7+ cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE+ and 2D7+ cells.
The infiltration of MBP+ and CD11c+ innate immune cells show a significant association with phenotype and disease extent of CRS and allergic status also may influences cellular phenotype in non-asthmatic CRSwNP in Korea.
PMCID: PMC4216068  PMID: 25361058
11.  Patients with allergic rhinitis and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen challenge 
Patients with allergic rhinitis and allergic asthma demonstrate comparable local and systemic eosinophil inflammation, and yet they present with different clinical pictures. Less is even known about the contribution of neutrophil inflammation in allergic diseases. The aim of the study was to examine the propensity and selectivity of granule release from primed systemic eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen exposure. We hypothesize that the dissimilar clinical manifestations are due to diverse eosinophil and neutrophil degranulation.
Nine birch pollen allergic patients with rhinitis, eight with asthma and four controls were studied during pollen season and after nasal and bronchial allergen challenge. Eosinophils and neutrophils were incubated in vitro with assay buffer and opsonized Sephadex particles for spontaneous and C3b-induced granule protein release. The released amount of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) was measured by specific radioimmunoassay.
C3b-induced degranulation resulted in increased release of ECP and MPO from primed blood eosinophils and neutrophils in both allergic rhinitis and allergic asthma during pollen season and after both nasal and bronchial challenge (p-values 0.008 to 0.043). After bronchial challenge, the ECP release was significantly higher in the rhinitic group compared to the asthmatic group [19.8 vs. 13.2%, (p = 0.010)]. The propensity for EPO release was weak in all challenge models but followed the same pattern in both allergic groups.
Systemically activated eosinophils and neutrophils have similar patterns of degranulation after allergen exposure in allergic rhinitis and allergic asthma. The released amount of ECP, EPO and MPO was similar in all allergen challenge models in both allergic groups. Our results indicate that other mechanisms than the magnitude of eosinophil and neutrophil inflammation or the degranulation pattern of the inflammatory cells determines whether or not an allergic patient develops asthma.
PMCID: PMC3031270  PMID: 21255397
12.  Fungal extracts detected in eosinophilic chronic rhinosinusitis induced cytokines from the nasal polyp cells 
The Laryngoscope  2014;124(9):E347-E353.
The role of fungi in chronic rhinosinusitis (CRS) is still controversial. The present study was conducted to detect and identify fungal species from the nasal polyp tissues of eosinophilic and noneosinophilic CRS, and to determine the role of fungal antigens in cytokine production.
Study Design
Prospective study.
Thirty-five specimens of nasal polyps were collected from patients with CRS and examined for fungus using culture, histology, and polymerase chain reaction analysis. The secretion of 14 cytokines stimulated by fungal extracts using dispersed nasal polyp cells (DNPCs) was determined by multiplex immunoassay.
There was no microbiological growth (including fungus) in the cultures of homogenized nasal polyps. Furthermore, Grocott methanamine silver staining for all nasal polyps showed no fungal bodies. Sixteen of 35 samples of the nasal polyps showed amplification of fungal DNA. In none of the mucosa of the sphenoid sinus was fungal DNA detected. The number of eosinophils in the nasal polyps in which fungal DNA was detected was significantly higher than in the nasal polyps in which fungal DNA was not detected (P < .01). The extract of fungus enhanced the secretion of eosinophil-associated cytokines such as interleukine (IL)-5, IL-13, IL-17A, and RANTES (regulated on activation normal T-cell expressed and secreted), and proinflammatory cytokines such as IL-6, IL-8, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor from DNPCs.
The present study offers direct evidence supporting that fungal elements modify the inflammatory response in the nasal polyps of eosinophilic CRS.
Level of Evidence: NA
PMCID: PMC4298786  PMID: 24615892
Fungus; nasal polyp; polymerase chain reaction; cytokine; eosinophil
Macacus rhesus and Macacus cynomolgus exhibit a striking sensitivity to the presence of the virus of poliomyelitis on the nasal mucous membranes. Irrespective of whether detectable symptoms of clinical poliomyelitis do or do not arise in the nasally instilled animals, the cerebrospinal fluid changes quickly in response to virus placed in the nasal passages. Two sets of changes occur in the cerebrospinal fluid: the constant and most pronounced change consists of increase in the content of white cells, chiefly of the lymphocytic type; the inconstant and less profound one consists of detectable amounts of globulin in the fluid (free from red corpuscles) withdrawn by cisterna puncture. As early as 48 hours after instillation of the virus, a marked increase in cells is already detectable in the fluid; the increase grows from day to day, reaching a maximum sometimes in another day or two, sometimes not until 4, 5, or 6 more days elapse. In many instances a rise of temperature follows or coincides with the rising tide of cells; and the onset of clinical symptoms of disease bears also a relation to the cell count. The number of cells in the cerebrospinal fluid and the temperatures tend to be higher in monkeys which develop paralytic symptoms; occasionally exceptions to this rule occur, in which instilled monkeys remaining asymptomatic exhibit high cell counts; very rarely do the latter show the higher temperatures. Monkeys once instilled which fail to become symptomatically affected again react by cerebrospinal fluid changes to later courses of instillation. A second or still later course may induce paralysis; or highly exceptional or refractory animals may go through several courses of instillation without developing clinical symptoms, although never failing to respond with changes in the cerebrospinal fluid. The virus instillations of Macacus monkeys do not lead to active immunization unless clinical symptoms of infection have resulted from the inoculations and attended the cerebrospinal fluid changes. In the complete absence of clinical symptoms the instilled animals fail to develop blood antiviral properties, and they are as susceptible to the cerebral injection of virus as are the control monkeys. On the other hand, instilled monkeys which have shown even mild and fleeting (abortive) clinical symptoms of infection, resist cerebral inoculation and exhibit blood antiviral or neutralizing properties. Monkeys which have developed clinical symptoms of disease and have recovered are, as stated, actively immunized; they remain, however, sensitive to the presence of virus on the nasal membrane, reacting with cerebrospinal fluid changes, differing only in degree from the nonimmune animals. Detectable virus does not appear in the pleocytic cerebrospinal fluid at any stage of the pathological processes. The current belief is that mass immunization is proceeding in an unperceived manner through the chance entrance of virus into the nasal passages of children. It is not known whether, apart from all symptoms of disease, cerebrospinal fluid changes occur in the course of this unexpressed, spontaneous process. A large gap seems to exist between man and the monkey in the capacity of the former to become immunized by way of the nasal membrane, and the inability of the latter to do so. It is common knowledge that monkeys do not become immune through unsuccessful cerebral inoculations of virus, and the same seems to be true of the nasal channel of virus penetration into the central nervous organs.
PMCID: PMC2133307  PMID: 19870448
14.  Reliability of fetal nasal bone length measurement at 11–14 weeks of gestation 
Nasal bone assessment has been incorporated into Down syndrome screening in first trimester. Several studies have established the normal reference values for fetal nasal bone length in the first trimester, which were found to be varied by population. However, the study on reliability of nasal bone length measurement was limited with contradictory results. This study aimed to investigate the reliability of fetal nasal bone length measurement at 11–14 weeks of gestation in the Thai population.
A total of 111 pregnant women at 11–14 weeks of gestation attending for the routine first-trimester ultrasound examination were recruited. Each case was measured separately by two examiners. Examiner 1 performed the first measurement in all cases; any of the other 5 examiners consecutively performed the second measurement. Three independent measurements were performed by each examiner and they were blinded to the results of the others. Intraobserver and interobserver variabilities were evaluated with the intraclass correlation coefficient (ICC).
Nasal bone measurement was successfully performed in 106/111 cases (95.5%) by at least one examiner; 89 cases were performed by two examiners. The intraobserver variability was excellent for all examiners (ICC, 0.840-0.939). The interobserver variability between different pairs of examiners varied from moderate to excellent (ICC, 0.467-0.962). The interobserver variability between examiner 1 and any other examiner was good (ICC, 0.749). The Bland-Altman plot of the interobserver differences of nasal bone length measurements between examiner 1 and any other examiner showed good agreement.
The reliability of the fetal nasal bone length measurement at 11–14 weeks of gestation was good. The nasal bone length measurement was reproducible. Ethnicity has an effect on fetal nasal bone length, but reliability of nasal bone length measurement is critical to accuracy of screening and should be audited on an ongoing basis.
PMCID: PMC3565861  PMID: 23324624
Ultrasound; Fetal nasal bone; First trimester; Reliability; Reproducibility
15.  A two-year course of specific immunotherapy or of continuous antihistamine treatment reverse eosinophilic inflammation in severe persistent allergic rhinitis 
Aim of the study was to evaluate the effect of a 2-year course of subcutaneous specific immunotherapy or continuous oral antihistamine treatment on the eosinophilic inflammation in nasal secretions of patients with severe persistent allergic rhinitis caused by house dust-mites. After informed consent, 31 rhinitis patients, sensitive to dust-mite antigens, were enrolled: 12 were randomly assigned to specific immunotherapy (group A), 11 to continuous oral antihistamine (cetirizine) treatment (group B), and 8 to an oral antihistamine (cetirizine) on demand (group C). Nasal scrapings were performed with a cotton-tipped swab and cells counted before and after 24 months of therapy. Intercellular adhesion molecule-1 and eosinophil cationic protein expression in cytological smears were assessed by immunohistochemistry. All patients completed the study. The percentage of inflammatory cell types was comparable in the 3 groups at the beginning of the study. Eosinophils, identified as cells expressing eosinophil cationic protein, significantly decreased dropping to zero after 2 years of treatment in groups A and B, while no change was observed in group C. Expression of intercellular adhesion molecule-1 also decreased significantly in groups A and B, but not in group C. This decrease was associated with a significant reduction in epithelial shedding. In the 2-year period studied, specific subcutaneous immunotherapy and continuous oral antihistamine treatment were found to be effective in reducing eosinophilic infiltration and adhesion molecule expression in the nasal mucosa of patients with persistent allergic rhinitis. Furthermore, immunotherapy was more effective in controlling epithelial disruption while antihistamines appeared to be more active in controlling nasal inflammation. Both treatments induced a significant decrease in intercellular adhesion molecule-1 expression in epithelial cells and also a dramatic reduction of eosinophil cationic protein positive staining. These parameters can be considered useful means for controlling the state of persistent inflammation which is typical of persistent respiratory allergy. Nasal scraping was demonstrated to be a simple and safe procedure for monitoring some nasal inflammation parameters.
PMCID: PMC2639903  PMID: 16602327
Allergic rhinitis; Medical treatment; Immunotherapy; Eosinophilic infiltration
16.  Oral Delivery of a Probiotic Induced Changes at the Nasal Mucosa of Seasonal Allergic Rhinitis Subjects after Local Allergen Challenge: A Randomised Clinical Trial 
PLoS ONE  2013;8(11):e78650.
To determine effects of probiotic consumption on clinical and immunological parameters of seasonal allergic rhinitis (SAR) in an out-of-season single nasal allergen challenge.
In a study registered at ClinicalTrials.Gov (NCT01123252), a 16-week dietary intervention was undertaken in 60 patients with allergic rhinitis (>16 years old). Using a double-blinded, placebo-controlled anonymised design, the patients were divided equally into two groups. One group was given a dairy drink containing Lactobacillus casei Shirota to ingest daily while the other consumed a similar drink without bacteria. Participants attended the clinic on two consecutive days before the intervention and then again at the end of the study period. On the first day of each 2-day visit, following clinical examination, assessments were made of total nasal symptoms scores and peak nasal inspiratory flow. Nasal scrapings, nasal lavage and blood were collected for laboratory analyses of cellular phenotypes, soluble mediator release and in vitro responses to pollen allergen. These procedures were repeated 24 hours following nasal allergen challenge.
Prior to and following intervention there were no detectable differences between study groups in measured clinical outcome. After intervention, there were differences between groups in their percentages of CD86+ epithelial cells (p = 0.0148), CD86+CD252+ non-epithelial cells (p = 0.0347), sIL-1RII release (p = 0.0289) and IL-1β (p = 0.0224) levels at the nasal mucosa. Delivery of probiotic also suppressed production of sCD23 (p = 0.0081), TGF-β (p = 0.0283) and induced increased production of IFN-γ (p = 0.0351) in supernatants of cultured peripheral blood.
Conclusions & Clinical Relevance
This study did not show significant probiotic-associated changes with respect to the primary clinical endpoint. An absence of overt clinical benefit may be due to an inability of single nasal challenges to accurately represent natural allergen exposure. Nevertheless, oral delivery of probiotics produced changes of the immunological microenvironment at the nasal mucosa in individuals affected by SAR.
Trial Registration
ClinicalTrials.Gov NCT01123252
PMCID: PMC3829814  PMID: 24260122
17.  The efficiency of sputum cell counts in cystic fibrosis 
Technical factors relating to processing viscid sputum in cystic fibrosis (CF) and their influence on the reproducibility and validity of cell counts need to be evaluated. In addition, the methods need to be standardized so that they can be applied clinically and in research.
To examine the efficiency, reliability and validity of processing small volumes of spontaneously expectorated sputum from subjects with CF.
Sputum was collected from adults with CF (n=35) and compared with sputum from adults with infective bronchitis or bronchiectasis (IB/B) (n=16), or with asthma or chronic obstructive pulmonary disease (AS/COPD) (n=25). Selected sputum (100 mg to 200 mg) was processed with dithiothreitol (0.1%) and filtered. Total cell count (TCC) and viability were obtained in a counting chamber and cytospins were prepared and stained with Wright’s for a differential cell count. Sputum and filter remnant were processed for TCC, viability and differential cell count, and the efficiency was determined by comparing the mean loss in cell yield to the filter. Two different portions from the same sputum sample were processed for cell counts to determine reproducibility. Results were compared with those from IB/B and AS/COPD groups.
Efficiency of cell dispersal was excellent and similar to that in AS/COPD and IB/B groups. Reproducibility of cell counts from two portions of a sputum sample was high (R≥0.80). CF sputum demonstrated a raised TCC and neutrophilia similar to IB/B but significantly higher than AS/COPD.
The selection method of evaluating cell counts in viscid CF sputum is efficient, reproducible and valid.
PMCID: PMC2676380  PMID: 17372637
Airway inflammation; Cystic fibrosis; Sputum cell counts
18.  228 PCR Analysis of Microorganisms in Chronic Rhinosinusitis with Nasal Polyps 
Chronic rhinosinusitis (CRS) with nasal polyps is characterized by tissue eosinophilia, which is speculated to be related to Staphylococcus superantigen and fungus, in European and U.S patients. However, Japanese patients with CRS with nasal polyps showed 2 distinct phenotypes of eosinophilic and neutrophilic inflammation (Hirotsu et al 2011). We attempted to analyze the microorganisms from nasal polyps of Japanese patients by PCR method.
Eleven specimens of nasal polyps with CRS were collected for examination by endoscopic sinus surgery. All specimens were treated with 70% ethanol and physiologic saline to eliminate microorganisms outside of the nasal polyps. Bacterial and fungal culture was performed for 2 weeks using 5 different culture media. We detected 16S rRNA bacteria and 18S rDNA-ITS-26S rDNA fungus, and then identified species of microorganisms by direct-sequence. In addition, the number of eosinophils in the nasal polyps was counted.
No bacteria or fungus were recovered from any of the nasal polyps by culture medium. By the PCR analysis, DNA for bacteria could not be detected, whereas 7 samples of the nasal polyps showed amplification of fungal DNA such as Candida parapsilosis, Candida glabrata, and Rhodotorula etc. Grocott dyeing for the nasal polyps, however, showed no intracellular presence of fungus. The number of the eosinophils in the nasal poly with the patients with the presence of fungal DNA (240 ± 191) was significantly (P < 0.05) higher than that in the absence (56 ± 40).
The present study suggests the participation of fungus in eosinophilic CRS with nasal polyps.
PMCID: PMC3512889
19.  130 Mutiplex Analyses of Cytokine and Chemokine Release From the Cultured Fibroblast of Nasal Polyp: the Effect of IL-17A 
Nasal polyps of chronic rhinosinusitis (CRS) are characterized by epithelial damage, basement membrane thickness and subepithelial fibrosis. The fibroblast, one of the main cell types making up nasal polyps, is thought to be a target cell of various cytokines. The role of IL-17A in immunoresponse in the nasal poly fibroblast has not yet elucidated.
Subcultured fibroblasts were established from human polyp biopsy tissues in addition to normal mucosal membranes of sphenoid sinuses (controls).
The IL-17A receptor was expressed at similar levels in all 3 groups. Simultaneous quantification of 27 kinds of cytokines and chemokines in culture supernatants was performed with a human multiplex cytokine assay system. In the eosinophilic group, basal secretion levels of IL-6 were significantly higher than those in the control and non-Eo groups. Basal secretion of MCP-1 in both the non-eosinophilic and eosinophilic groups was also higher than that of the control group. Both IL-9 and G-CSF secretion were remarkably enhanced by IL-17A stimulation in all 3 groups. The receptor-mediated response by IL-17A significantly upregulated IL-6 release alone in the non-eosinophilic and eosinophilic groups as compared with the control group. Only the basic FGF secretion was decreased by stimulation of IL-17A in all groups.
Our results demonstrate for the first time a potentially enhanced secretion of IL-6 and MCP-1 from nasal polyp fibroblasts, and a remarkable upregulation of IL-9 and G-CSF from nasal fibroblasts by IL-17A stimulation, which might contribute to nasal polyp formation and airway remodeling.
PMCID: PMC3512987
20.  CD25+ T-lymphocytes induce CD11b on eosinophils in allergic nasal mucosa 
Mediators of Inflammation  1995;4(2):144-148.
In the allergic mucosa, there is a significant increase in numbers of CD25+ cells and activated eosinophils. To determine whether a link exists between the activated T-lymphocytes and tissue eosinophils in nasal allergy, we studied CD25+ cells in the nasal mucosa and compared the levels of soluble IL-2 receptor (sIL-2R) both in the serum and the nasal secretions, and further investigated expression of CD11b on eosinophils in the nasal lavage fluids and peripheral blood of patients with nasal allergy. We also examined the effects of the culture supernatant of Con A- and IL-2-activated T-lymphocytes on CD11b expression on eosinophils in the present study. The concentration of sIL-2R in the nasal secretions from patients with Japanese cedar pollinosis (JCP) was significantly higher than that from normal subjects (p < 0.01). The sIL-2R level was significantly higher in the nasal secretions than in the sera in patients (p < 0.01), and CD11b expression on eosinophils from nasal hvage fluid was significandy higher than that of eosinophils from peripheral blood of the same individuals (p < 0.01). The activated T-lymphocytes promoted eosinophil activation with upregulation of CD11b in vitro, and eosinophils in the nasal secretions from patients significantly expressed more CD11b in vivo. These results indicate that activation of T-lymphocytes is linked to eosinophil activation in nasal allergy.
PMCID: PMC2365614  PMID: 18475632
21.  Activity of hypertonic solution with Silver and Potassium Sucrose Octasulfate on nasal symptoms in obstructive rhinopathy with and without rhinosinusitis 
SpringerPlus  2013;2:668.
Nasal obstruction is a primary symptom of common upper respiratory tract disorders. In clinical practice nasal saline solutions are recommended for the cleansing of nasal cavities and relieving nasal symptoms.
55 patients (aged 25–70 years) suffering from obstructive rhinopathy, with nasal obstruction/congestion of moderate severity persistent since at least 10 days in advance of recruitment with/without rhinosinusitis was randomly treated with an hypertonic solution composed by Silver Sucrose Octasulfate and Potassium Sucrose Octasulfate (SILSOS) or isotonic solution for 20 days.
At baseline (T0), ten days (T10) and twenty days (T20) after SILSOS treatment, study participants were evaluated subjectively with VAS and SNOT-22, objectively by Active Anterior Rhinomanometry (AAR) and MCC/MCTt determination. Forty-four patients were followed-up 30 days after the end of treatment by a phone interview.
The AAR analysis showed in SILSOS group a significantly (p < 0.05) ameliorated in expiratory flow, at T0-T10 and T0-T20. No improvement in MCTt was observed over the 20 days study period. The mean values MCC of significantly improved at T20 (p < 0.05). VAS total score showed improvement along all time-intervals. Nasal obstruction was back 30 days after the end of treatment with SILSOS in only 3 patients and reported to be in a mild form.
The obtained results show that SILSOS hyper has added to the mechanical action of removal of secretions a specific decongestant and antiseptic effect lasting longer after the end of treatment. Could help to fluidize thick mucus, improve respiration and promote resolution of symptoms, preventing pathogens adhesion to nasal mucosa.
PMCID: PMC3967734  PMID: 24683527
Nasal obstruction; VAS; SNOT-22; Rhinopathy; Silver sucrose octasulfate; Potassium sucrose octasulfate
22.  Clinical and biochemical effects of a combination botanical product (ClearGuard™) for allergy: a pilot randomized double-blind placebo-controlled trial 
Nutrition Journal  2008;7:20.
Botanical products are frequently used for treatment of nasal allergy. Three of these substances, Cinnamomum zeylanicum, Malpighia glabra, and Bidens pilosa, have been shown to have a number of anti-allergic properties in-vitro. The current study was conducted to determine the effects of these combined ingredients upon the nasal response to allergen challenge in patients with seasonal allergic rhinitis.
Twenty subjects were randomized to receive the combination botanical product, (CBP) 2 tablets three times a day, loratadine, 10 mg once a day in the morning, or placebo, using a randomized, double-blinded crossover design. Following 2 days of each treatment and during the third day of treatment, subjects underwent a nasal allergen challenge (NAC), in which nasal symptoms were assessed after each challenge dose and every 2 hours for 8 hours. Nasal lavage fluid was assessed for tryptase, prostaglandin D2, and leukotriene E4 concentrations and inflammatory cells.
Loratadine significantly reduced the total nasal symptom score during the NAC compared with placebo (P = 0.04) while the CBP did not. During the 8 hour period following NAC, loratadine and the CBP both reduced NSS compared with placebo (P = 0.034 and P = 0.029, respectively). Analysis of nasal lavage fluid demonstrated that the CBP prevented the increase in prostaglandin D2 release following NAC, while neither loratadine nor placebo had this effect. None of the treatments significantly affected tryptase or leukotriene E4 release or inflammatory cell infiltration.
The CBP significantly reduced NSS during the 8 hours following NAC and marginally inhibited the release of prostaglandin D2 into nasal lavage fluid, suggesting potential clinical utility in patients with allergic rhinitis.
PMCID: PMC2491648  PMID: 18625073
23.  The role of surgical audit in improving patient management; nasal haemorrhage: an audit study 
BMC Surgery  2007;7:19.
Nasal bleeding remains one of the most common Head & Neck Surgical (Ear Nose and Throat [ENT]/Oral & Maxillofacial Surgery [OMFS]) emergencies resulting in hospital admission. In the majority of cases, no other intervention is required other than nasal packing, and it was felt many cases could ideally be managed at home, without further medical interference. A limited but national telephone survey of accident and emergency departments revealed that early discharge practice was identified in some rural areas and urban departments (where adverse socio-demographic factors resulted in poor patient compliance to admission or follow up), with little adverse patient sequelae. A simple nasal packing protocol was also identified.
The aim of this audit was to determine if routine nasal haemorrhage (epistaxis) can be managed at home with simple nasal packing; a retrospective and prospective audit.
Ethical committee approval was obtained. Similar practice was identified in other UK accident and emergency centres. Literature was reviewed and best practice identified. Regional consultation and feedback with regard to prospective changes and local applicability of areas of improved practice mutually agreed upon with involved providers of care.
Retrospective: The Epistaxis admissions for the previous four years during the same seven months (September to March).
Prospective: 60consecutive patients referred with a diagnosis of Nasal bleeding over a seven month time course (September to March). All patients were over 16, not pregnant and gave fully informed counselled consent.
New Guidelines for the management of nosebleeds, nasal packing protocols (with Netcel®) and discharge policy were developed at the Hospital. Training of accident and emergency and emergency ENT staff was provided together with access to adequate examination and treatment resources. Detailed patient information leaflets were piloted and developed for use.
Previously all patients requiring nasal packing were admitted. The type of nasal packing included Gauge impregnated Bismuth Iodoform Paraffin Paste, Nasal Tampon, and Vaseline gauge. Over the previous four year period (September to March) a mean of 28 patients were admitted per month, with a mean duration of in patient stay of 2.67 days.
In the prospective audit the total number of admissions was significantly reduced, by over 70%, (χ2 = 25.05, df = 6, P < 0.0001), despite no significant change in the number of monthly epistaxis referrals (χ2 = 4.99, df = 6, P < 0.0001). There was also a significant increase in the mean age of admitted patients with epistaxis (χ2 = 22.71, df = 5, P < 0.0001), the admitted patients had a mean length of stay of 2.53 days. This policy results is an estimated saved 201.39 bed days per annum resulting in an estimated annual speciality saving of over £50,000, allowing resource re-allocation to other areas of need. Furthermore, bed usage could be optimised for other emergency or elective work.
Exclusion criteria have now been expanded to exclude traumatic nasal haemorrhage. New adjunctive therapies now include direct endoscopic bipolar diathermy of bleeding points, and the judicious use of topical pro-coagulant agents applied via the nasal tampon. Expansion of the audit protocols for use in general practice.
This original audit informed clinical practice and had potential benefits for patients, clinicians, and provision of service. Systematic replication of this project, possibly on a regional and general practice basis, could result in further financial savings, which would allow development of improved patient services and delivery of care.
PMCID: PMC2034528  PMID: 17854499
24.  147 3-D Visualization of the Anti-Obstructive Effect of Levocetirizine 
The World Allergy Organization Journal  2012;5(Suppl 2):S65-S66.
Our investigation aimed to visualize the 3-D spatial distribution of nasal cavity mucosal swelling under levocetirizine prophylactic treatment on exposure to allergens. This study made use of standard rhinologic diagnostics such as rhinomanometry and acoustic rhinometry, as well as 24 hours rhinometry and magnetic resonance imaging (MRI).
A suitable test subject with a history of allergic rhinitis was identified during the symptom-free interval after the pollen season when she showed signs of “minimal persistent inflammation,” consisting of pronounced reaction to nasal challenge with allergens. Provocation with birch pollen caused moderate symptoms of allergic rhinitis. Nasal provocation tests were performed before and after 2 and 5 weeks of treatment with levocetirizine 5 mg OD. Long-term rhinometry was carried out to detect the progress of the nasal cycle and relative flow variances over 24 hours. Flexible air tubes required for this new procedure made it possible to quantify relative pressure changes. High resolution MRI was also used to capture, visualize, and process the geometrical data of the nasal cavity immediately before and after the challenge tests. Based upon the MRI data, we computed the nasal airflow using a computational fluid dynamics (CFD) nasal model to visualize intranasal pressure and flow. Rhinomanometry and acoustic rhinometry were performed to validate the results.
After 36 days of treatment with levocetirizine, a 16% improvement in the nasal flow relative to baseline and an increase by 3.4 cm3 of the total nasal baseline volume were documented as compared to the allergen challenge of the untreated case. 3-D images illustrated that treatment inhibited the allergen provocation effects on nasal airflow and normalised nasal flow velocity and pressure, including in the olfactory region.
Besides improving the nasal airflow to an almost normal pattern, levocetirizine also helps prevents the patient from having an allergic response, even 24 hours after last drug intake. Furthermore, it can improve olfaction by restoring airflow to the olfactory region.
PMCID: PMC3512940
25.  Seasonal changes in nasal cytology in mite-allergic patients 
House dust mites (HDMs) are a major cause of allergic rhinitis (AR) and asthma worldwide. Recent studies suggested that the allergen load presents seasonal modifications, giving rise to seasonal variation in nasal inflammation and symptoms. The aim of this study was to evaluate by nasal cytology whether nasal inflammation in mite-allergic patients changes with the seasons of the year.
The study included 16 patients (seven males and nine females, mean age 38.1 years) with persistent AR caused by monosensitization to HDMs. Nasal cytology was performed in all patients once monthly for 1 year.
Nasal cytology showed that the cells most commonly detected in the nasal mucosa were neutrophils. During the period from October to April, a peak in the number of neutrophils and also the presence of significant numbers of eosinophils, mast cells, and lymphocytes/plasma cells were found, which shows the occurrence of more intense inflammation during these months.
Nasal cytology provides useful data in detecting nasal inflammation and its association with the clinical stage of AR. The seasonal variations in nasal cytology are likely to be induced by the fluctuations in the HDM allergen that have been uncovered in recent investigations.
PMCID: PMC3977553  PMID: 24715761
allergens; allergic rhinitis; house dust mite; nasal inflammation

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