A real – life observational pilot study to evaluate the effects of two-week treatment with montelukast in patients with chronic cough

BACKGROUND: Different conditions make the proximal airways susceptible to tussigenic stimuli in the chronic cough (CC) syndrome. Leukotrienes can be implicated in the inflammatory mechanism at play in it. Montelukast is a selective cysteinyl-leukotriene receptor antagonist with proven effectiveness in patients with asthma. The aim of our real-life pilot study was to use montelukast to relieve cough symptoms in patients with CC allegedly due to the two frequent causes other than asthma – upper airway cough syndrome and gastroesophageal reflux (GER). METHODS: 14 consecutive patients with CC were evaluated before and after 2 weeks of treatment with montelukast 10 mg daily. Cough was assessed by validated cough questionnaire. Questionnaires regarding the presence of gastroesophageal reflux were also completed. Cough reflex sensitivity to incremental doubling concentrations of citric acid and capsaicin was measured. Lung function, airway hyperresponsiveness and exhaled breath temperature (EBT), a non-invasive marker of lower airway inflammation, were evaluated to exclude asthma as an underlying cause. Thorough upper-airway examination was also conducted. Cell counts, eosinophil cationic protein (ECP), lactoferrin, myeloperoxidase (MPO) were determined in blood to assess systemic inflammation. RESULTS: Discomfort due to cough was significantly reduced after treatment (P < 0.001). Cough threshold for capsaicin increased significantly (P = 0.001) but not for citric acid. The values of lactoferrin and ECP were significantly reduced, but those of MPO rose. EBT and pulmonary function were not significantly affected by the treatment. CONCLUSION: Patients with CC due to upper airway cough syndrome or gastroesophageal reflux (GER) but not asthma reported significant relief of their symptoms after two weeks of treatment with montelukast. ECP, lactoferrin, MPO altered significantly, highlighting their role in the pathological mechanisms in CC. Clinical trial ID at Clinicaltrials.gov is NCT01754220

A novel deep intronic "SERPING1" variant as a cause of hereditary angioedema due to C1-inhibitor deficiency

Background In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration

Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene = Wybrane aspekty genotypowania wrodzonego obrzȩku naczynioruchowego w erze NGS: Gen F12

Objective. To screen a cohort of patients diagnosed with non-FXII angioedema for carriage of variants of F12 gene. Material and methods. DNA samples from 191 patients suffering from primary angioedema with normal C1-INH, 54 samples from non- -affected family members, and 161 samples from C1-INH-HAE (154 type I, 7 type II) patients were included in the study. The F12 gene was genotyped by targeted NGS (100% coverage of translated regions). Sanger sequencing was performed for the verification of all identified variants and family segregation studies. Results. The pathogenic F12 variant c.983C&gt;A was detected in three patients from two unrelated families initially diagnosed as U-HAE. Six additional mutations were identified, four of which were characterized as benign (c.41T&gt;C, c.418C&gt;G, c.1025C&gt;T, c.530C&gt;T) and two of uncertain significance (c.1530G&gt;C, c.1768T&gt;G). Two synonymous variants (c.756C&gt;T and c.711C&gt;T), the common polymorphism c.619G&gt;C, and the functional polymorphism c.-4T&gt;C were detected in allele frequencies similar to those presented in the ExAC database for the European population. One more not yet reported synonymous variant (c. 1599A&gt;G) was also found. Conclusion. Analyzing the entire translated region of F12 gene is important in order to identify new variants that possibly affect HAE expressivity. Interestingly, genetic analysis of F12 supports not only the diagnosis of FXII-HAE but also the correct exclusion diagnosis of U-HAE

Management of chronic urticaria in Asia: 2010 AADV consensus guidelines

This guideline is a result of a consensus reached during the 19th Asian-Australasian Regional Conference of Dermatology by the Asian Academy of Dermatology and Venereology Study Group in collaboration with the League of Asian Dermatological Societies in 2010. Urticaria has a profound impact on the quality of life in Asia and the need for effective treatment is required. In line with the EAACI/GA2LEN/EDF/WAO guideline for the management of urticaria the recommended first-line treatment is new generation, non-sedating H1-antihistamines. If standard dosing is ineffective, increasing the dosage up to four-fold is recommended. For patients who do not respond to a four-fold increase in dosage of non-sedating H1-antihistamines, it is recommended that therapies such as H2-antihistamine, leukotriene antagonist, and cyclosporine A should be added to the antihistamine treatment. In the choice of second-line treatment, both their costs and risk/benefit profiles are the most important considerations

recombinant human c1 esterase inhibitor as short term prophylaxis in patients with hereditary angioedema

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H1-antihistamines for chronic spontaneous urticaria: An abridged Cochrane Systematic Review

Background Chronic spontaneous urticaria is characterized by recurrent itchy wheals. First-line management is with H1-antihistamines. Objective We sought to conduct a Cochrane Review of H1-antihistamines in the treatment of chronic spontaneous urticaria. Methods A systematic search of major databases for randomized controlled trials was conducted. Results We included 73 studies with 9759 participants; 34 studies provided outcome data for 23 comparisons. Compared with placebo, cetirizine 10 mg daily in the short and intermediate term (RR 2.72; 95% confidence interval [CI] 1.51-4.91) led to complete suppression of urticaria. Levocetirizine 20 mg daily was effective for short-term use (RR 20.87; 95% CI 1.37-317.60) as was 5 mg for intermediate-term use (RR 52.88; 95% CI 3.31-843.81). Desloratadine 20 mg was effective for the short term (RR 15.97; 95% CI 1.04-245.04) as was 5 mg in the intermediate term (RR 37.00; 95% CI 2.31-593.70). There was no evidence to suggest difference in adverse event rates between treatments. Limitations Some methodological limitations were observed. Few studies for each comparison reported outcome data that could be incorporated in meta-analyses. Conclusions At standard doses, several antihistamines are effective and safe in complete suppression of chronic spontaneous urticaria. Research on long-term treatment using standardized outcome measures and quality of life scores is needed

Rhinorrhea, cough and fatigue in patients taking sitagliptin

Sitagliptin is a dipeptidyl peptidase-4 (DPP IV, CD26) inhibitor indicated for treatment of Type II diabetes as a second line therapy after metformin. We report fifteen sitagliptin intolerant patients who developed anterior and posterior rhinorrhea, cough, dyspnea, and fatigue. Symptoms typically developed within 1 to 8 weeks of starting, and resolved within 1 week of stopping the drug. Peak expiratory flow rates increased 34% in 8 patients who stopped sitagliptin. Similar changes were found in 4 out of 5 persons who had confirmatory readministration. Chart review identified 17 patients who tolerated sitagliptin and had no symptomatic changes. The sitagliptin intolerant group had higher rates of clinically diagnosed allergic rhinitis (15/15 vs. 6/18; p = 0.00005), Fisher's Exact test) and angiotensin converting enzyme inhibitor - induced cough (6/13 vs. 1/18; p = 0.012). Nasal and inhaled glucocorticoids may control the underlying allergic inflammation and abrogate this new sitagliptin - induced pharmacological syndrome. Potential mucosal and central nervous system mechanisms include disruption of neuropeptides and/or cytokines that rely on DPP IV for activation or inactivation, and T cell dysfunction