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M. Al‐Ahmad, E. Jusufovic, N. Arifhodzic, J. Nurkić

BACKGROUND AND AIM   Skin prick test (SPT) with a wheal diameter of >3 mm, generally accepted as a positive, is most commonly use diagnostic tool for Allergic rhinitis. Aim was to validate wheal size of Skin Prick Test for the Bermuda grass, in desert environment, with positive Bermuda grass Nasal challenge in same environment. METHODS In 53 adults, mean age 33.43 ± 9.36 years, both gender (females: 33.96%), SPT positive on Bermuda grass with cut off wheal longest diameter of 3 mm, Bermuda grass nasal challenge test (bgNCT) was carried out. Response was assessed subjectively (scored) and objectively (PNIF). Safety profile was assessed by PEF measurement. RESULTS Mean weal size of SPT (mm) was bigger in bgNCT positive patients (n=47; 88.68%) 8 [4, 15] vs 5 [3, 6] (p<0.0001). ROC analysis showed Bermuda Grass SPT at the threshold of >6.5mm enabled identification of Bermuda challenge with sensitivity of 82.98% and specificity of 100.0% (area under the curve 0.9326, standard error 0.03528; 95% confidence interval (CI): 0.8635 to 1.002; p=0.0006203). CONCLUSIONS A SPT wheal size ≥6.5mm  might be considered as an appropriate wheal size for confirming Bermuda grass allergy in adults with SAR, avoiding the demanding, time consuming and often unavailable bgNCT, especially in patients eligible for allergen immunotherapy. In these patients, bgNCT is recommended if SPT wheal size is <6.5 mm.

M. Al‐Ahmad, J. Nurkić, Yasmine Othman, E. Jusufovic, A. Maher

M. Al‐Ahmad, J. Nurkić, C. Bachert, O. Pfaar, H. Schunemann, W. Czarlewski, A. Bedbrook, J. Bosquet

A worldwide increase in prevalence of allergic diseases has led to adaptations in national and international health care systems. ARIA (Allergic Rhinitis and Its Impact on Asthma) initiative develops internationally applicable guidelines for allergic respiratory diseases. In collaboration with international initiatives, ARIA offers updates of real-life integrated care pathways (ICPs) for digitally assisted, integrated, and individualized treatment of allergic rhinitis (AR). This article presents certain aspects of the health care system in Kuwait with reference to the management of AR and the objective of introducing ICPs and adopting the latest ARIA recommendations. Guidelines for ICPs include aspects of patients and health care providers and cover key areas of management of AR. This model of guidelines supports real-life health care better than traditional models. ARIA recommendations will be locally integrated in the health care system with the aim of improving both pharmacotherapy and allergy immunotherapy.

E. Jusufovic, V. Žugić, M. Košnik, M. Drvenica, S. Hromis, J. Nurkić, M. Al‐Ahmad, L. B. Kardum et al.

E. Jusufovic, M. Košnik, J. Nurkić, N. Arifhodzic, M. Al‐Ahmad, L. Bulat-Kardum, M. Bećarević, M. Osmić et al.

Despite multistep efforts many asthma patients remain symptomatic. Anti-inflammatory activities of curcumin were shown. Aim was to analyse the add-on therapy with curcumin on inflammatory parameters, lung function, disease control and quality of life in asthma patients. 150 non-smokers with moderate partially controlled asthma were treated during 3 months with stable moderate dose of inhaled glucocorticoids and divided into three groups (n=50): curcumin group (receiving curcumin 500 mg per os twice daily), placebo and control group. Before study, sputum eosinophils (sEo), blood eosinophils (bEo), high sensitive C-reactive protein (hsCRP), predicted forced expiratory volume in first second (FEV1%), Asthma Control Test (ACT) and Asthma Quality of Life Questionnaire (AQLQ) were similar between groups. After study, FEV1%, ACT and AQLQ were improved in all groups, but these improvements were more prominent in curcumin group than in placebo and control. Additionally curcumin group only showed improvement in sEo, bEo and hsCRP. Furthermore, curcumin group showed also more frequent clinically significant improvement in ACT score (change>3) and in AQLQ score (change≥0.5) when compared to placebo and control. However, placebo and control showed similar distribution in FEV1%, ACT, AQLQ, hsCRP, sEo and bEo after study. This is the first placebo controlled and single-blind study to suggest that add-on therapy with curcumin could improve lung function, disease control and quality of life in moderate partially controlled asthma. Future studies may benefit from a larger sample size, longer study duration, double blind design, different dose of curcumin and/or improvements in oral bioavailability.

E. Jusufovic, M. Košnik, J. Nurkić, N. Arifhodzic, M. Al‐Ahmad, L. B. Kardum, M. Bećarević, M. Osmić et al.

Sputum eosinophils might predict response to inhaled corticosteroids (ICS) in patients with advanced chronic obstructive pulmonary disease (COPD). Induction of sputum requires expertise and may not always be successful. Aim was to investigate correlation and predictive relationship between peripheral blood eosinophils (bEo) and sputum eosinophils (sEo), and impact of peripheral blood eosinophilia on outcome of COPD exacerbation. 120 current smokers with COPD (GOLD group C) (57.4 ± 0.92 years, M/F ratio 1.4), with no blood (≥7% or >0.43x109/L) nor sputum (≥3%) eosinophilia, were treated with moderate dose of ICS and long-acting bronchodilatator during stable disease, but systemic corticosteroids and antibiotics during exacerbation. According to sputum eosinophilia (≥4%) during exacerbation, patients were divided into eosinophilic (n=45) and non-eosinophilic group (n=75). In stable disease, bEo and sEo were similar in both groups (p>0.05). During exacerbation, bEo and sEo were significantly higher in eosinophilic group (eosinophilic vs. non-eosinophilic: blood: 1.42 ± 0.39 x109/l vs. 0.23 ± 0.02 x109/l, p<0.001; sputum: 8% (4, 19) vs. 1% (0, 3), p<0.0001), but bEo correlated with sEo in both groups (eosinophilic: r=0.52, p<0.001; non-eosinophilic: r=0.25, p<0.05). Relative bEo predicted sputum eosinophilia (area under the curve=0.71, standard error=0.05; 95% confidence interval [CI] =0.61-0.81; p<0.001) and enabled identification of the presence or absence of sputum eosinophilia in 82% of the cases at a threshold of ≥4% (specificity=83.56%, sensitivity=93.83%, positive likelihood ratio=3.67). Eosinophilic group during exacerbation showed less frequent hospitalisations and shorter exacerbation (eosinophilic vs. non-eosinophilic: hospitalisations: 26.7% vs. 60.0%, p<0.001; duration of exacerbation (days): 8.1±0.35 vs. 10.13±0.31, p<0.0001). In COPD exacerbation, relative peripheral blood eosinophils ≥4% might identify sputum eosinophilia. Blood eosinophilia indicate better outcome of COPD exacerbation. Further investigations are needed to predict eosinophilic exacerbation in COPD patients, with prior absence of sputum or blood eosinophilia.

E. Jusufovic, M. Košnik, N. Arifhodzic, J. Nurkić, M. Al‐Ahmad, Azra Jusufovic, Dženan Halilović, R. Sejdinović

Background: Despite multistep efforts, many asthma patients remain symptomatic. Anti-inflammatory activities of curcumin are shown. Aim of the study was to analyse the impact of curcumin add-on therapy on inflammatory parameters, lung function, disease control and quality of life in asthma patients. Subjects and methods: Three-months lasting study was done on 150 non-smokers with asthma, that were treated with stable, moderate dose of inhaled glucocorticoids (IGK) and divided into three groups (n=50 each): curcumin group (receiving curcumin 500 mg per os twice daily), placebo group (receiving placebo tablets) and control (non-intervention) group. Sputum eosinophils (sEo), blood eosinophils (bEo), high sensitive C-reactive protein (hsCRP), predicted forced expiratory volume in first second (FEV1%), Asthma Control Test (ACT) and mini Asthma Quality of Life Questionnaire (mAQLQ) were compared before and after study, as well as between groups. Results: Before study, all followed parameters were similar between groups. After study, FEV1%, ACT and AQLQ were improved in all groups, but these improvements were more prominent in curcumin group than in placebo and control. Additionally curcumin group only showed improvement in sEo, bEo and hsCRP. Furthermore, curcumin group showed more frequent clinically significant improvement in ACT score (change>3) and in mAQLQ score (change≥0.5) when compared to placebo and control. On the other side, after study FEV1%, ACT, mAQLQ, hsCRP, sEo and bEo were similarly distributed among placebo and control group. Conclusion: This is the first placebo controlled and single-blind study to suggest that add-on therapy with curcumin could improve lung function, disease control and quality of life in moderate partially controlled asthma. Future studies may benefit from a larger sample size, longer study duration, double blind design, different dose of curcumin and/or improvements in oral bioavailability.

M. Al‐Ahmad, E. Jusufovic, N. Arifhodzic, J. Nurkić, A. L. Hanoun

Introduction: Although the skin prick test (SPT) is a reliable diagnostic tool in perennial allergic rhinitis (PER) for patients allergic to cats, the minimum necessary SPT wheal size required to distinguish cat sensitization from true allergy remains controversial. The cat nasal challenge test (cNCT) could be considered the gold standard for detecting true cat allergy. Aims: To assess the difference in the frequency of cNCT positivity between cat owners and non-owners and to determine an appropriate cut-off level for SPT wheal size in detecting positive cNCT in PER patients who are candidates for allergen immunotherapy (AIT) with cat allergen extracts. Subjects and Methods: cNCT in the form of a nasal spray was administered to 60 adult patients with PER, i.e., cat owners (n = 19) and cat non-owners (n = 41) with positive SPT to cat fur allergen (Diater, Spain). Subjective (total nasal symptom score [TNSS]) and objective measurements (peak nasal inspiratory flow [PNIF]) for assessment of nasal patency and nasal eosinophil count [NEo]) were used to assess the nasal response. Peak expiratory flow (PEF) was used as a safety parameter during cNCT. Results: No differences were obtained in SPT wheal size and cNCT positivity between cat owners and non-owners. Positive cNCT detecting true cat allergy could be predicted by a cat SPT wheal size > 6.5 mm with 71.11% sensitivity and 100% specificity. Conclusions: In adult patients with PER, the frequency of cat allergy was similar among cat owners and non-owners. A cat SPT wheal size ≥6.5 mm could be helpful in detecting true cat allergy by avoiding the demanding, time-consuming, and often unavailable cNCT when cat AIT is needed.

J. Nurkić, M. Al‐Ahmad, A. Maher, N. Arifhodzic, E. Jusufovic

Aim To assess efficacy of omalizumab in moderate to severe asthma and notable factors affecting it, such as treatment compliance during the period of ten years. This retrospective, observational real life study is the first of this kind in the Gulf region and one of the worldwide rare long term omalizumab treatment studies. Methods The treatment for 35 patients started in 2008. Twenty patients (ongoing group) proceeded with treatment and were assessed annually until 2017. Reasons for treatment discontinuation in 15 patients (drop-out group) were also assessed. Results Before starting omalizumab the ongoing group of patients had history of ≥2 asthma exacerbations per year, which significantly decreased during the first year of the treatment (p<0.001), and for 14 (70%) patients ≤1 exacerbation stayed during the next 10 years. Since 2014 six (30%) patients had had ≥2 annual asthma exacerbations (p<0.05 in 2013; p<0.05 in 2014; p<0.001 in 2015; p<0.01 in 2016; p<0.001 in 2017). At the same time there was a significant drop in compliance index (CI) (p<0.0001). Conclusion To our knowledge this is the first 10-year study of compliance and effectiveness, which may help finalize some practical suggestions to improve CI in clinical practice and to note acceptable variation in CI. It is important to recognize factors that can possibly affect effectiveness of the treatment and identify the patients who will have the best benefit from a long term omalizumab treatment.

M. Al‐Ahmad, J. Nurkić, A. Maher, N. Arifhodzic, E. Jusufovic

BACKGROUND: There is a lack of data related to real life, long-term safety, tolerability and compliance of omalizumab treatment in asthma patients beyond 6 years. AIM: Study aimed to assess safety, tolerability, compliance and all reasons for treatment discontinuation during 10 years on omalizumab. SUBJECT AND METHODS: This is a retrospective, observational study of uncontrolled asthma patients receiving omalizumab for the last 10 years. All data were collected from patients’ files (demographics, adverse events, comorbidities, compliance index, reasons for discontinuation of omalizumab). Reactions to omalizumab were classified as local and systemic, and their severity as mild, moderate or severe. Reactions were either immediate (minutes to hours after drug administration) or delayed (after days). Compliance to omalizumab, defined as Compliance index (CI), was calculated by comparing milligrams of given to milligrams of prescribed dose/ per year. RESULTS: Out of 35 patients receiving omalizumab, 15 drop out at different time points mostly due to treatment efficacy or appearance of new comorbidities. Patients who continue for the next ten years had mild to moderate adverse events related to omalizumab. There was no increased risk of severe adverse events during 10 years on omalizumab. Patient’s treatment tolerability, despite mild to moderate adverse events, is in favour of compliance. CONCLUSION: Compliance with omalizumab mildly decreased over 10 years but was not affected by severe adverse events of treatment or new comorbidities. Although, omalizumab is safe medicine appearance of new comorbidities has to be closely followed up.

M. Al‐Ahmad, N. Arifhodzic, J. Nurkić, A. Maher, T. Rodriguez-Bouza, Nasser Al-Ahmed, A. Sadek, E. Jusufovic

Objective: To evaluate the long-term efficacy and safety of omalizumab in asthma in a real-life setting. Subjects and Methods: This 4-year observational study included 65 patients treated with omalizumab during clinic visits; treatment response was rated as excellent, good, and partial based on a modified physician’s Global Evaluation of Treatment Effectiveness (mGETE) scale of emergency room visits (ERV), hospitalization, use of oral corticosteroids, inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) dose, and short-acting β-agonist rescue. The following tests were done: forced expiratory volume in 1 s (FEV1) and the asthma control test (ACT). Measurements were performed 1 month before therapy and at 16 weeks, 1 year, and 4 years of treatment. Statistical analyses were done using the Wilcoxon signed-rank test, Spearman rank correlation, and McNemar χ2 test. Results: The dropout rate was 15 (18.5%): 8 nonresponders (10.0%); 2 patients died (2.5%), and 5 were lost to follow-up (6.25%). Treatment response was excellent in 35 (53.8%); good in 23 (35.4%), and partial in 7 patients (10.8%). The number of excellent responders increased from 35 (53.8%) at 16 weeks to 48 (73.8%) at the 4-year follow-up. The number of patients who did not require ERV improved from 0 to 59 (90.8%), and the lowest rate of hospitalization was 1 in year 4 (p < 0.001); patients who did not require courses of oral corticosteroids improved from 0 to 54 (83%). ICS/LABA dose significantly reduced from 65 (100%) to 25 (38.5%) after 4 years of treatment (p < 0.001); ACT scores significantly increased from 15 ± 3 at baseline to 23 ± 3 (p < 0.001) and FEV1 level from 55.6 ± 10.6 to 76.63 ± 10.34 at year 4. Conclusion: In this study, omalizumab therapy resulted in better asthma control, and was effective and well tolerated as an add-on therapy for patients with moderate-to-severe asthma.

M. Al Ahmad, N. Arifhodzic, J. Nurkić, E. Jusufovic, A. L. Hanoun, T. Rodriguez

Summary Introduction. Sensitization to cat allergens is common worldwide. Currently, there is a trend towards costly and often unavailable diagnostic analysis. Objectives. The aim is to assess the reliability of skin prick test (SPT) and serum specific IgE (ssIgE) to cat sensitization, by performing nasal challenge test (NCT) in a community with low cat ownership but common presence of stray cats. Patients and methods. Forty-one pa-tients with perennial allergic rhinitis (AR) who were mono or polysensitized (including cat) were included. We had 31 cat non-owners and 10 present cat owners. SPT (> 5 mm / diameter), ssIgE (≥ 0.70 IU/ml), nasal smear for eosinophil (Eo) and NCT were compared between groups. Outcomes included nasal challenge score, nasal Eo positivity, peak inspiratory and expiratory flow (PIF and PEF) 2 and 8 hours after the NCT, and were compared to baseline. Results. Baseline SPT wheal size and ssIgE level were similar in both groups. NCT positivity was more frequent in cat owners. The strongest nasal reaction was on the top concentration in both groups. Nasal Eo positivity in cat owners was higher before and 2 hours after NCT, but similar to non-owners at last measurement. NCT positive cat non-owners had bigger SPT wheal size than NCT negative non-owners, but smaller than NCT positive cat owners. In contrast to PEF, a significant fall in PIF was noticed in both groups. Mono and polysensitised patients showed similar NCT positivity. Conclusion. Stray cats may pose a relevant risk of developing perennial AR. Regardless of cat ownership status, SPT and ssIgE should be the first diagnostic tool. Nasal Eo and NCT seem to be good diagnostic tools in cat non-owners if diagnosis is elusive.

E. Jusufovic, M. Košnik, M. Bećarević, M. Osmić, Azra Jusufovic, M. Al‐Ahmad, J. Nurkić, Alma Nadarević et al.

E. Jusufovic, M. Košnik, Azra Jusufovic, M. Bećarević, M. Al‐Ahmad, J. Nurkić, M. Osmić, Alma Nadarević et al.

Despite intensive treatment, considerable proportion of patients with asthma remains symptomatic. Anti-inflammatory activity of curcumin has been shown. Aim: analyse the impact of add-on therapy with curcumin in asthma patients on inflammatory parameters, lung function and asthma control. During 2 months, 100 non-smokers (46.8±12.4 years, F/M ratio 1.04) with moderate, partially controlled asthma were treated with moderate dose of inhaled glucocorticoids (IGK) with no changes in dose. Patients were divided into two groups (n=50): curcumin group receiving curcumin 500 mg per os twice daily and control group. Before study, sputum and blood eosinophils (Eo), blood neutrophils, high sensitive C-reactive protein (hsCRP), predicted forced expiratory volume in first second (FEV1%), Asthma Control Test (ACT) and Asthma Quality of Life Questionnaire (AQLQ) were similar between groups. After study, in curcumin group blood Eo count and hsCRP decreased, and FEV1, ACT and AQLQ increased significantly (before vs. after study: Eo: 5.9±0.6 vs. 4.1±0.4; hsCRP: 4.2±0.3 vs. 3.4±0.2; FEV1%: 77.7±0.8 vs. 83.9±0.5; ACT: 14.5 (6,19) vs. 18 (14,21); AQLQ: 3.4±0.2 vs. 4.1±0.2). There was no change in the control group. Compared to control curcumin group showed significantly lower blood Eo and hsCRP and higher FEV1% (curcumin vs. control: Eo: 4.1±0.4 vs. 5.4±0.5; hsCRP: 3.4±0.2 vs. 4.0±0.3; FEV1%: 83.9±0.5 vs. 78.3± 0.8), and improved ACT and AQLQ (ACT change>3: 72% vs. 28%; AQLQ change>0.5: 54% vs. 32%) after study. Add-on therapy with curcumin in patients with moderate partially controlled asthma seems to improve response to IGK regarding lung function, asthma control and quality of life. Further placebo controlled trials are needed.

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