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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.  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
3.  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
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.  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
6.  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
7.  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
8.  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
9.  Eosinophilic and neutrophilic leukemoid reaction in a woman with spindle cell sarcoma: a case report 
We report a case of a patient with marked eosinophilia and neutrophilia as a manifestation of a spindle cell sarcoma.
Case presentation
A 41-year-old African American woman presented with an enlarging, painful mass in her right knee area. Four years previously, she had had a mass similar to this diagnosed as an osteosarcoma, and had undergone a radical resection and hinge-knee replacement. Before the surgery, she was treated with neoadjuvant docetaxel and gemcitabine. A biopsy was taken from the recurrent mass, and histological examination revealed high-grade soft-tissue sarcoma. The patient received no further treatment. Complete blood counts revealed a white blood cell (WBC) count of 13.6 to 17.9 × 109/L, with neutrophils being 8.2 to 10.9 × 109/L and eosinophils 1.8 to 1.9 × 109/L. At readmission six months later, WBC was 126.7 × 109/L, with neutrophils being 57.02 × 109/L and eosinophils 60.82 × 109/L. The eosinophils peaked at 77.79 × 109/L two days later. Evaluations for allergies, infection, and autoimmune mechanisms were negative. Bone marrow revealed increased eosinophils without blasts. After resection, blood counts abruptly decreased to the normal range. Pathology confirmed high-grade spindle cell sarcoma. Approximately one year after resection, the patient was readmitted with metastatic disease to her lungs. During this presentation, her eosinophil and neutrophil count was again increased. WBC was 107.8 × 109/L, with eosinophil count of 47.43 × 109/L and neutrophil count of 44.10 × 109/L. Interleukin-5 was normal, and granulocyte–macrophage colony-stimulating factor (GM-CSF) was elevated at 208.8 (normal < 4.8).
In our case, the patient had eosinophilia and neutrophilia associated with a spindle cell sarcoma, possibly representing a paraneoplastic syndrome secondary to GM-CSF. There were no signs of infectious, allergic, or autoimmune causes for the eosinophilia or neutrophilia. Even though the occurrence of eosinophilia and neutrophilia with malignancy is rare, patients who have either condition without an apparent cause should be checked for malignancy.
PMCID: PMC2984466  PMID: 20964813
10.  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
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.  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
13.  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
14.  Normal values for peripheral blood white cell counts in women of four different ethnic origins. 
Journal of Clinical Pathology  1984;37(2):188-193.
Total and differential white cell counts were studied in 399 women living in the same community in Britain but drawn from four different ethnic groups. The groups were white (northern European), Indian, black (African and West Indian), and Oriental. The total white cell count and absolute neutrophil count were significantly lower in the black group than in each of the other groups. The absolute monocyte count was higher in whites than in each of the other groups. Contrary to earlier reports, the absolute eosinophil count in blacks was no higher than in whites, suggesting that the high eosinophil counts previously found had an environmental rather than a genetic cause. The eosinophil count of Indians was only marginally higher than that of whites and the difference was not significant, again suggesting that high eosinophil counts previously reported had an environmental cause. No ethnic variation was found in the absolute lymphocyte count. The lower white cell count and neutrophil count found in blacks is of considerable practical importance, and blacks should not be assessed in relation to reference ranges derived for whites. Nevertheless, the eosinophil count in healthy blacks is no higher than that of whites and counts above reference ranges for whites should be considered clinically important. The differences between white cell counts of Indians and Orientals and those of whites are minor and for practical purposes they can be assessed in relation to reference ranges derived for whites.
PMCID: PMC498676  PMID: 6693578
15.  Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice 
Sputum cell counts have identified inflammatory subtypes of bronchitis in relatively small numbers of subjects with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough in research studies. The prevalence of different subtypes of bronchitis in routine clinical practice, however, has not been reported.
To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction.
A retrospective cross-sectional survey based on a computerized database of spontaneous or induced sputum cell counts examined in a large university tertiary respiratory outpatient clinic.
The database contained 4232 consecutive sputum records from 2443 patients with chronic cough (39%), asthma (37%), asthma with COPD (9%), COPD (13%) and bronchiectasis (3%). Total and differential cell counts were obtained from 86% of successful sputum samples. Induced sputum provided more viable samples than spontaneous expectorate. Approximately one-third of patients with asthma and one-fifth of patients with COPD experience eosinophilic bronchitis. Asthmatic patients with moderate to severe airflow obstruction had a greater number of sputum eosinophils. There was a significantly higher number of total cell counts and percentage of neutrophils in the sputum of COPD patients with moderate and severe airflow obstruction than in those with mild airflow obstruction.
There is heterogeneity in the cellularity of sputum in various airway diseases. Patients with clinically stable airway diseases may have high sputum cell counts. During exacerbations, more patients may experience neutrophilic bronchitis. Severity of airflow obstruction is associated with eosinophilic bronchitis in patients with asthma, and neutrophilic bronchitis in patients with nonasthmatic COPD.
PMCID: PMC3328881  PMID: 21766077
Asthma; Bronchitis heterogeneity; Clinical practice; COPD; Sputum cell counts
16.  Beclomethasone dipropionate aerosol in allergic rhinitis. 
Treatment with beclomethasone dipropionate aerosol (BDA), 50 mug four times daily in each nostril, was compared with placebo therapy in a double-blind non-crossover trial of 30 matched patients with allergic rhinitis induced by ragweed pollen. The trial was started at the beginning of the ragweed season and continued for 42 days. Response to treatment was assessed from information on daily diary cards, weekly objective measurements of nasal patency and measurement of total eosinophil count (TEC) before treatment and at week 4. Patients in the BDA group had significantly less (P less than 0.05) sneezing, rhinorrhea and nasal stuffiness at 36 days, cough at 10 days and antihistamine consumption at 17 days. There was no significant difference between the groups in eye symptoms, nasal airway inspiratory resistance, maximum inspiratory nasal flow or TEC. Overall comparison with previous pollen seasons by the patients indicated moderate to great improvement in 86% of the BDA group and in 13% of the placebo group (P less than 0.01). Minor side effects were noted by two patients in each group.
PMCID: PMC1878740  PMID: 782679
17.  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
18.  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
19.  The sequential appearance of antibody and immunoglobins in nasal secretion after immunization of volunteers with live and inactivated influenza B virus vaccines 
The Journal of Hygiene  1973;71(3):433-445.
The sequential development of the immune response in nasal washings was studied in 54 volunteers immunized with either attenuated or inactivated influenza B/Eng/13/65 virus vaccines.
Eleven of the 15 volunteers given the inactivated vaccine by deep subcutaneous inoculation showed no rise in nasal wash protein or immunoglobins due to the immunization procedure nor was specific neutralizing antibody detected in their nasal washings after immunization. Neutralizing antibody was detected in nasal washings of three volunteers in this group who also showed a 20-fold or greater increase in serum haemagglutinin-inhibiting antibody after immunization and in one volunteer who had antibody present in pre-trial nasal washings.
Eleven of 15 volunteers who were successfully infected by the live attenuated vaccine showed a characteristic rise in protein and IgA and IgG immunoglobin concentrations in nasal washings 5-14 days after the administration of the live virus vaccine. Neutralizing antibody was detected in the nasal washings of these 11 volunteers and appeared at the same time as or 1-2 days after the initial rise of protein and immunoglobin. Neutralizing antibody was also detected in the nasal washings of one other volunteer who did not show a rise in protein or immunoglobin concentration in nasal washings after immunization.
IgA was detected (≥ 3 mg./100 ml.) in the majority (84%) of nasal wash specimens which had a protein concentration of 0·2 mg./ml. or greater while IgG was not detected (≥ 4·5 mg./100 ml.) until the protein concentration rose to 0·4 mg./ml. or greater. The geometric mean concentration for normal nasal wash protein in this study was 0·3 ± 0·1 mg./ml.
Regression analysis indicated that the concentrations of both IgA and IgG immunoglobins were directly proportional to the protein concentration in nasal washings but that this relationship varied considerably between individuals.
Absorption studies indicated that neutralizing and haemagglutinin-inhibiting antibodies in nasal secretion to influenza B/Eng/13/65 virus were predominantly associated with the IgA class of immunoglobin.
PMCID: PMC2130575  PMID: 4518342
20.  The Hematologic Profile of the Fetus with Systemic Inflammatory Response Syndrome 
Journal of Perinatal Medicine  2011;40(1):19-32.
The Fetal Inflammatory Response Syndrome (FIRS) is associated with the impending onset of preterm labor/delivery, microbial invasion of the amniotic cavity and increased perinatal morbidity. FIRS has been defined by an elevated fetal plasma interleukin-6 (IL-6), a cytokine with potent effects on the differentiation and proliferation of hematopoietic precursors. The objective of this study was to characterize the hematologic response of fetuses with FIRS.
Fetal blood sampling was performed in patients with preterm prelabor rupture of membranes and preterm labor with intact membranes (n=152). A fetal plasma IL-6 concentration >=11 pg/ml was used to define FIRS. Hemoglobin concentration, platelet count, total white blood cell (WBC) count, differential count and nucleated red blood cell (NRBC) count were obtained. Since blood cell count varies with gestational age, the observed values were corrected for fetal age by calculating a ratio between the observed and expected mean value for gestational age.
1) The prevalence of FIRS was 28.9% (44/152); 2) fetuses with FIRS had a higher median corrected WBC and corrected neutrophil count than those without FIRS (WBC median 1.4; range 0.3–5.6 vs. median 1.1; range 0.4–2.9 p=0.001; neutrophils median 3.6; range 0.1–57.5 vs. median 1.8; range 0.2–13.9 p<0.001); 3) neutrophilia (defined as a neutrophil count >95th centile of gestational age) was significantly more common in fetuses with FIRS than in those without FIRS [71% (30/42) vs. 35% (37/105); p<0 001]; 4) more than two thirds of fetuses with FIRS had neutrophilia, while neutropenia was present in only 4.8% (2/42); 5) FIRS was not associated with detectable changes in hemoglobin concentration, platelet, lymphocyte, monocyte, basophil or eosinophil counts and; 6) fetuses with FIRS had a median corrected NRBC count higher than those without FIRS. However, the difference did not reach statistical significance (NRBC median 0.07; range 0–1.3 vs. median 0.04; range 0–2.3 p=0.06);
The hematological response of the human fetus with FIRS is characterized by significant changes in the total white blood cell and neutrophil counts. The NRBC count in fetuses with FIRS tends to be higher than fetuses without FIRS.
PMCID: PMC3380620  PMID: 21957997
FIRS; preterm labor; preterm PROM; cordocentesis; neutrophil; nucleated red blood cells; infection; hypoxia; neutrophilia; neutropenia; white blood cell count
21.  Eosinophil adhesion to nasal polyp endothelium is P-selectin-dependent 
Tissue eosinophilia is a characteristic feature of a number of inflammatory diseases including asthma and nasal polyposis. Eosinophil migration into tissues is controlled in part by interactions between eosinophil adhesion receptors and counter-structures on the vascular endothelium. To determine the receptors used by eosinophils to adhere to vascular endothelium in allergic inflammation we have adapted the Stamper-Woodruff frozen section assay (FSA) to study eosinophil adhesion to nasal polyp endothelium. Immunohistology indicated that intercellular adhesion molecule 1 (ICAM-1), E-selectin and P-selectin were well expressed by nasal polyp endothelium, whereas expression of vascular cell adhesion molecule 1 (VCAM-1) was weak or absent. Unstimulated human peripheral blood eosinophils adhered specifically to nasal polyp endothelium. Adherence was temperature and divalent cation- dependent and saturable at cell densities > 5 x 10(6) cells/ml. Eosinophil adhesion was almost completely inhibited by a monoclonal antibody (mAb) against P-selectin and by a chimeric molecule consisting of the Fc portion of human IgG and the lectin binding domain of P- selectin, which binds to the P-selectin ligand on leucocytes. Anti-Mac- 1 mAb partially inhibited eosinophil adhesion whereas mAb against E- selectin, L-selectin, ICAM-1, VCAM-1, very late activation antigen 4, and lymphocyte function-associated antigen 1 had no effect. P-selectin is stored in intracellular granules within the endothelial cell and in vitro is only transiently expressed. To determine if P-selectin was expressed on the membrane of the nasal polyp endothelium we compared P- selectin expression in normal skin and nasal polyps after acetone fixation, which permeabilizes cells, and paraformaldehyde, which only allows staining of membrane expressed receptors. In the skin, good expression was seen with acetone fixation but no expression was seen after paraformaldehyde treatment, whereas in nasal polyps, similar expression was observed with both fixatives. In addition immunofluorescence with confocal microscopy demonstrated lumenal staining of nasal polyp endothelium indicating that P-selectin was located on the surface of endothelial cells while in skin only an intracellular granular distribution was apparent. Lastly, whereas eosinophils bound consistently to nasal polyp endothelium, no binding was observed to blood vessels in normal skin further supporting the idea that eosinophils were binding to membrane expressed and not intracellular P-selectin. The importance of P-selectin in eosinophil adhesion to nasal polyp endothelium suggests that P-selectin antagonists may be effective at inhibiting eosinophil accumulation at sites of allergic inflammation.
PMCID: PMC2191567  PMID: 7516413
22.  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
23.  Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis 
Respiratory Research  2010;11(1):54.
It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue.
To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation.
Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period.
Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment.
Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.
PMCID: PMC2873933  PMID: 20459697
24.  Local expression of interleukin-17a is correlated with nasal eosinophilia and clinical severity in allergic rhinitis 
Allergy & Rhinology  2014;5(1):e22-e27.
Interleukin (IL)-17A is a major cytokine produced by Th17 cells, which are associated with chronic inflammations. The local expression of IL-17A in allergic rhinitis (AR) remains to be characterized. We sought to determine the role of IL-17A expression in human inferior turbinate mucosa in the pathophysiology of AR. Inferior turbinate mucosa was sampled from medical treatment–resistant, surgery-required patients with perennial AR (PAR, n = 21), nonallergic rhinitis with eosinophilia syndrome (NARES, n = 7), and nonallergic hypertrophic rhinitis (HR, n = 13). IL-17A expression was determined with immunohistochemical staining. The mean number of IL-17A+ cells and eosinophils per field were counted. Total serum immunoglobulin E (IgE) levels, blood eosinophil count, and forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio were also examined in each patient. IL-17A was primarily expressed in infiltrating inflammatory cells. The number of IL-17A+ cells in nasal mucosa was significantly higher in the PAR group compared with HR (p = 0.002) and NARES (p = 0.021) groups. There was a significant and positive correlation between the number of IL-17A+ cells and total nasal symptom score (rho = 0.403; p = 0.011), especially sneezing score (rho = 0.471; p = 0.003). The number of IL-17A+ cells was significantly and positively correlated with the degree of eosinophil infiltration (rho = 0.623; p < 0.001), but not with total serum IgE levels (rho = 0.284; p = 0.098), blood eosinophil counts (rho = 0.302; p = 0.056), or FEV1/FVC ratio (rho = 0.092; p = 0.569). The present study provides evidence that IL-17A expression in the nasal mucosa is associated with the pathophysiology of AR, including disease severity and nasal eosinophilia.
PMCID: PMC4019741  PMID: 24758732
Allergic rhinitis; eosinophil; IL-17A; nasal mucosa; total nasal symptom score
25.  Evaluation of cytokines in nasal secretions after nasal antigen challenge: lack of influence of antihistamines 
Previous studies of inflammation in allergic rhinitis using nasal irrigation have been unsatisfactory because of 1) poor reproducibility; 2) the tendency of irrigation to overdilute mediators; and 3) the failure of this technique to evaluate interstitial concentrations of relevant mediators. For this study we used filter paper as a matrix to collect nasal secretions in patients undergoing nasal antigen challenge.
To evaluate inflammatory mediators of allergen-induced rhinitis during a clinical trial of fexofenadine.
Subjects evaluated at a referral medical center were placed on traditional dosing of fexofenadine at 60 mg, twice daily, or placebo in a double-blind, crossover fashion for 1 week before the nasal challenge. Nasal challenge was performed with nasal insufflation of either 1,000 AU timothy or 0.1 mL ragweed (1:100 wt/vol) extract outside the pollen season. Nasal secretions were collected at baseline and then at 2, 4, and 6 hours after nasal challenge. Secretions were evaluated for expression of the cellular adhesion molecule-1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, macrophage inflammatory protein (MIP)-1α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using commercially available enzyme-linked immunoadsorbent assay kits. Patients’ symptom scores were evaluated during the nasal challenge.
Significantly (P < 0.05) increased peak levels of TNF-α, IL-4, IL-10, and MIP-1α were detected after antigen challenge as compared with baseline levels. There was a nonsignificant trend toward an increase in GM-CSF after antigen challenge (P = 0.07). There was no difference in the peak levels of TNF-α, IL-4, IL-10, MIP-1α, or GM-CSF measured when patients were on fexofenadine versus placebo. Finally, there were no significant differences in patients’ symptom scores during antigen challenge when subjects were on fexofenadine versus placebo.
Collection of nasal secretions using a filter paper matrix provides a reproducible model for accurately detecting and evaluating changes in cytokine levels after nasal challenge. Cytokine levels tend to peak 3 to 4 hours after antigen challenge. Standard doses of fexofenadine do not seem to have a mitigating effect on the production of these cytokines. Symptoms of allergic rhinitis using this type of antigen challenge did not differ from treatment with fexofenadine versus placebo.
PMCID: PMC1283081  PMID: 12027065

Results 1-25 (1531764)