Kevin J. Keen

The Role of Allergy and Smoking in Chronic Rhinosinusitis and Polyposis

Objectives/Hypothesis: The article considers the interrelatedness of allergic rhinitis and chronic rhinosinusitis (CRS). The negative impact of perennial allergy and tobacco use on polyposis in sinus surgery patients is explored.

Prevalence of allergy in patients with chronic rhinosinusitis

OBJECTIVES: The purpose of this study was to provide further evidence that allergic rhinitis is an important factor in chronic and recurrent acute rhinosinusitis. Specifically, this study shows that perennial allergens play a more significant role than seasonal allergens. STUDY DESIGN AND SETTING: Census by chart review of patients with chronic and recurrent acute rhinosinusitis presenting to the Department of Otolaryngology at the MetroHealth Medical Center, Cleveland, OH. METHODS: All participants had allergy testing done either by RAST or intradermal skin endpoint titration utilizing a battery of seasonal and perennial antigens. RESULTS: Of the 48 voluntary participants analyzed in this study, 57.4% had a positive allergy test. Most patients in the study were sensitive to more than one allergen. Of the patients with a positive allergy test, 92% demonstrated sensitivity to one or more perennial allergens—most prominently, molds and dust mites. CONCLUSIONS: Perennial allergy has a statistically significant association with chronic and recurrent acute rhinosinusitis. SIGNIFICANCE: The diagnosis and management of perennial allergies may be beneficial when treating chronic sinus disease. (Otolaryngol Head Neck Surg 2004;130:545-52.)

International Classification of Functioning, Disability and Health Core Set construction in systemic sclerosis and other rheumatic diseases: a EUSTAR initiative

OBJECTIVES To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. METHODS A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. RESULTS The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. CONCLUSION This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour.

L-selectin and Skin Damage in Systemic Sclerosis

Background L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients. Methodology and Principal Findings Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R2 = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively). Conclusions and Significance No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L-selectin could serve as an outcome measure for dSSc patients in clinical trials.

Estimation of reliability in a three‐factor model

Reliability measures have been well studied over many years. Such measures have been thoroughly studied for two-factor models. Motivated by a medical research problem, point and confidence interval estimates of the intraclass correlation coefficient are extended to models containing three crossed random factors-subjects, raters, and occasions. The estimation is conducted using both analysis of variance and Monte Carlo Markov chain methods.

Impact of pulmonary disease on patient-reported outcomes and patient-performed functional testing in systemic lupus erythematosus

Objectives This study examines the effect of pulmonary disease on patient-reported outcomes (PROs) and patient-performed outcome (PPO) in systemic lupus erythematosus (SLE) patients at a single tertiary referral center. Methods Pulmonary function tests (PFTs), chest imaging, SLE-related damage, and disease activity were examined in 110 SLE patients. Presence was noted of abnormal PFTs, pleural disease, pulmonary hypertension (PH), pulmonary infarction, interstitial lung disease (ILD), and shrinking lung syndrome (SLS). PROs included the Medical Outcome Short Form-36 Health Survey, Pittsburgh Sleep Quality Index, Fatigue Severity Scale, Borg Dyspnea Scale, patient dyspnea and cough. The PPO of interest was the six-minute walk test (6MWT). Relationships amongst PROs, 6MWT, and pulmonary disease were studied. Results Pulmonary disease was present in 62 (56%) of 110 subjects: 54 (49%) abnormal PFT, 13 (12%) pleural disease, 12 (11%) ILD, 11 (10%) SLS and five (5%) PH. Dyspnea was the only PRO found to be significantly associated with pulmonary disease (P = 0.0004). Participants with pulmonary disease compared to those without had significantly reduced distance (P = 0.00015, 95% CI for mean 39–125 m) and predicted distance (P = 0.00001, 10%–26%) on 6MWT. Conclusions Pulmonary disease is common in SLE and adversely impacts 6MWT distance and dyspnea without apparent influence on other PROs. The 6MWT may be a promising tool in the assessment of pulmonary disease in SLE.

Limited Cutaneous and Diffuse Cutaneous Scleroderma: Circulating Biomarkers Differentiate Lung Involvement

Study background: Insufficient or absent angiogenesis are hallmarks of scleroderma (SSc). Microvascular change is an early manifestation of SSc followed by intimal proliferation and fibrosis of arterioles resulting in reduced blood flow and tissue ischemia. This ongoing vasculopathy in the lungs presents clinically as pulmonary hypertension and characteristically precedes lung fibrosis in patients. The purpose of this preliminary study is to elucidate possible interrelationships amongst circulating microparticles, angiogenic and angiostatic factors in SSc patients that are predictive of interstitial lung disease and high values of right ventricular systolic pressure (RVSP) by trans-thoracic Doppler-echocardiography (TTE). Methods: Nineteen cases with limited cutaneous SSc (lcSSc) and 11 cases with diffuse cutaneous SSc (dcSSc) were compared to 30 age- and sex-matched healthy controls. High resolution computed tomography was used to establish the diagnosis of interstitial lung disease and TTE was used to estimate RVSP and to diagnose putative pulmonary arterial hypertension (PAH). Plasma concentrations of circulating factors were assessed in patients and controls. Results: Angiopoetin-2, endostatin, E-selectin and platelet microparticles were higher in lcSSc cases compared to healthy controls (p<0.0001, p=0.0008, p=0.0003, p=0.0020, respectively). Only endostatin was higher in dcSSc cases (p=0.0020). In a classification tree analysis, concentrations of soluble E-selectin of at least 44.7 ng/ml and 37.2 ng/ml were predictive of ILD and PAH, respectively, in lcSSc cases, whereas, endothelial microparticle levels higher than 96 per μl were predictive of ILD in dcSSc cases. Conclusion: Scleroderma cases can be differentiated from healthy controls based on higher concentrations of the angiostatic factor endostatin. E-selectin was associated with lung involvement in lcSSc, whereas, high levels of endothelial microparticles were associated with ILD in dcSSc.

Systematic Review of the Role of Microparticles in Systemic Sclerosis.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science(®), PubMed(®) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science(®) or PubMed(®) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

In response to The role of allergy and smoking in chronic rhinosinusitis and polyposis (Laryngoscope, 118: 1521-1527, 2008).

We thank Dr. Pa-Chun Wang for his interest in our recent article. Dr. Wang is concerned that there are errors in our statistical calculations and suspects errors specifically in Table II and Figures 3 and 4. After thorough review, we find no errors in the table, the figures, or the accompanying discussion in the text of the article. We suspect that the source of Dr. Wang’s concern is his misunderstanding regarding the distinction between ever smoked and current smoking. These are two different events of concern to epidemiologists. These distinct events have separate estimates of prevalence in the national surveillance of smoking trends. Hence, we report a prevalence of 21.6% for current smoking status among the 365 endoscopic sinus surgery (ESS) patients with a complete smoking history and a prevalence of 34.0% estimate of ever having smoked for this group of patients (as noted in Fig. 3). This is not a case of two different prevalence estimates for smoking status as concluded by Dr. Wang. Likewise, there are not two different estimates of the prevalence of smoking among the 225 ESS patients with chronic rhinosinusitis (CRS), a complete smoking history, and adequate allergy testing, but rather an estimate of 20.9% for the prevalence of current smoking status and 32.9% (as also noted in Fig. 4) for the prevalence of ever having smoked. The number of never smokers among the 225 ESSCRS patients is reported as 151 in Figure 4 and is also found by summing the numbers 65 and 86 in the first column of Table II. This table is a multiway table with the third dimension reporting the count of patients with nasal polyps in a two-way contingency involving perennial allergy status and tobacco exposure among those who ever smoked. The third dimension is reported as a percentage and equivalently as a ratio of the number of cases with nasal polyps over the number of total cases for a row and column combination of characteristics, as indicated in the footnote in Table II. We suspect Dr. Wang’s unfamiliarity with this layout led to his incorrect conclusion that the total of patients reported in Table II is 215 rather than the 225 actually there. Our assertion of the association between smoking exposure and the risk of nasal polyps is based in part on the 95% confidence interval for the adjusted odds ratio of ever having smoked tobacco of (2.342, 1000.000) reported in Table I from a multiple linear logistic regression model involving four smoking exposure variables and counts of seasonal and perennial allergens. This led to the production of Table II to understand what we reported as a ‘‘counterintuitive result that more packs per day is protective against polyps with a point estimate of the adjusted odds ratio of 0.007 (P 1⁄4 .00644).’’ We do not make the claim that heavy smoking is to be recommended as protective against nasals polyps. The adjusted odds ratio for tobacco exposure measured by the product of packs per day multiplied by years of smoking is 1.204 (95% confidence interval: 1.030, 1.407) and is on a par with that for the count of perennial allergens, which is 1.160 (95% confidence interval: 1.041, 1.292), as reported in Table I. Our opinion is that our finding regarding the tobacco packs per day could be the result of heavy tobacco use blocking immune response to allergens. However, we do consider in our article other causes for this curious result, including this result being an artifact of small sample sizes. We concluded this discussion in our article, as in this response, with a call for prospective study with a detailed registry.