The follow-up lasted 76 weeks. One patient in each group was considered a non-responder. Spirometry did not worsen in either group. There was a significant intragroup reduction in annual exacerbation rate and MP consumption but no differences were detected in the intergroup comparison. Omalizumab offered the same clinical benefits in the two cohorts regardless of whether the asthma was caused by a seasonal or a perennial allergen. These results strongly suggest that allergens are the trigger in chronic asthma but that it is the persistent exposure to IgE that causes the chronicity.Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Our purpose was to investigate whether omalizumab is also effective in persistent severe asthma due to seasonal allergens. Thirty patients with oral corticosteroid-dependent asthma were treated with Omalizumab according to the dosing table. For each patient with asthma due to seasonal allergens, we recruited the next two consecutive patients with asthma due to perennial allergens. The dose of oral methyl prednisolone (MP) was tapered at a rate of 2 mg every two weeks after the start of treatment with omalizumab depending on tolerance. At each monthly visit, a forced spirometry and fractional exhaled nitric oxide (FeNO) measurement were performed and the accumulated monthly MP dose was calculated. At entry, there were no differences between groups in terms of gender, body mass index or obesity, year exacerbation rate, monthly dose of MP, FeNO and blood immunoglobuline E (IgE) values, or spirometry (perennial: FVC: 76%; FEV Omalizumab has been the only monoclonal antibody marketed for treatment of severe allergic asthma for more than 10 years. It was first included in Global Initiative for asthma (GINA) guidelines in November 2006 . Since tAn issue that has never been discussed in the literature is whether omalizumab is equally effective in patients with severe chronic asthma caused by seasonal allergens as in patients with asthma caused by perennial allergens. We designed a pilot study to evaluate whether the effectiveness of omalizumab treatment in chronic severe asthma depends on the perennial or seasonal nature of the allergen. Parietaria), and so the comparison was made between 9 patients from the seasonal group and 19 from the perennial group. There were no differences in year exacerbation rate, age  body mass index (BMI), eosinophils, or fractional exhaled nitric oxide (FeNO) (p = 0.698) or obesity . IgE concentrations were slightly higher in seasonal allergen patients, although the difference was not statistically significant. Pulmonary function tests (PFTs) were slightly better in the seasonal group (with FEV1 around 200 mL higher), although the difference was not statistically significant. The omalizumab dose and methyl-prednisolone (MP) intake were the same in the two groups. The follow-up lasted 76 weeks. The allergen sensitization is described in The demographic data at entry are shown in e (FeNO) . Applyinp = 0.678).Although we compared the number of exacerbations during the 76 weeks previous to omalizumab treatment with the 76-week follow-up, data are given as annual exacerbation rates. Both groups showed a statistically significant decrease A–C and np < 0.001), but no inter-group differences were found (p = 0.856), (p < 0.001); again, no differences were observed between groups (p = 0.851). At week 76, mean monthly MP intake was 32.5 ± 66.8 mg in the perennial group and 23.1 ± 46.0 mg in the seasonal group. MP was withdrawn in 73.9% of patients in the perennial group and in 77.8% in the seasonal group.During this period, MP consumption progressively decreased in both groups ( 0.856), A. Figurep = 0.086) but not in percentage (p = 0.251) (p = 0.194), and in seasonal patients from 55.6% at entry to 22.2% at 24 weeks, remaining at 22.2% at 76 weeks (p = 0.134) (Eosinophils showed a trend towards a decrease in the absolute number of cells (= 0.251) A,B. The = 0.134) . FENO median values at entry were within normal limits . Figure p = 0.001) with a βweek = 0.030. Although the trend was similar in the two groups, the values were consistently higher in the seasonal group  (IgE concentration increased significantly (= 0.026) D.1/FVC values were 60.7% ± 13.1% and 69.1% ± 12.8% for perennial and seasonal patients respectively at entry and 61.3% ± 12.2% and 73.4% ± 11.6% at the end of follow-up.Despite oral MP decrease, PFTs did not deteriorate  in eitheThe treatment was well-tolerated and no relevant side effects were detected.In November 2006, the GINA  later foOmalizumab has been tested in cases of rhinitis caused by seasonal allergens causing symptoms during the season of pollination, with great success  as well We were careful to identify seasonal allergic patients as reliably as possible in order to distinguish them from perennial allergen patients. We recruited two patients allergic to perennial allergens for every patient with seasonal allergy. This procedure was chosen to allow a better comparison of the behavior of the perennial group with that of our previously published cohort , which iIn the past few years, several attempts have been made to categorize severe asthma into phenotypes by the application of unsupervised cluster analyses. Apart from allergic asthma, the most prominent phenotype to emerge is characterized by eosinophilic airway inflammation in spite of using high-intensity anti-inflammatory treatment ,16. AbouFeNO values were mainly normal or quite low, in any case lower than the values found in the DREAM  and MENS1 value in the seasonal group that, though not statistically significant, was clinically relevant (200 mL at entry and maintained during the follow-up). This suggests that permanent exposure to allergens may be more harmful than episodic exposure. The side-effect profile was highly favorable in both groups.The behavior of the two groups was quite similar and no statistically significant intergroup differences were found. The decrease in the year exacerbation rate in both groups despite the decrease in the oral corticosteroid (OC) consumption endorses the clinical effect of omalizumab toward a better disease stabilization and control. The only sustained difference was the permanently higher FEVThe study has several limitations, the most important being the reduced number of patients and the lack of a placebo randomized control group. Rather than comparing two different treatments, we assessed the clinical response to the same treatment in two different populations: patients allergic to perennial allergens and patients allergic to seasonal allergens. The only way to perform a randomized study would be to have had a treated and a placebo arm in each group. Considering the impossibility of preparing a reliable placebo, and the fact that omalizumab is indicated only for patients allergic to at least one perennial allergen, a study of this kind would have to be done by the pharmaceutical company. Thus, we believe that our study represents the only way to make this information available in the literature. Finally, distinguishing between perennial and seasonal patients is extremely complex although we are confident that we were able to do so. Our discussion, based on our results helps to make understandable why chronic severe allergic asthma patients sensitized to seasonal allergens can also benefit from anti-IgE treatment. Since it has been shown in previous studies that sensitization to different allergens is not associated with significant differences in severity and control of asthma  one coulThe results of several large randomized trials have shown that omalizumab is effective and well-tolerated as an add-on therapy in patients with severe persistent allergic asthma due to perennial allergen exposure. Omalizumab treatment significantly improves symptoms and disease control, reduces asthma exacerbations, and increases patients’ quality of life . Our stuIn this prospective interventional study performed at the Corporació Sanitària Parc Taulí, a 750-bed university hospital with a reference area of 450,000 inhabitants, two groups of patients with uncontrolled severe oral corticosteroid dependent allergic asthma were treated with the same drug, omalizumab. The study was approved by the hospital’s ethics committee (CEIC/CEIm Institut d'Investigació i Innovació Parc Taulí-2017/527). Since the treatment for asthma attributed to a seasonal allergen was an off-label indication, its use was considered as compassionate; in accordance with the Spanish legislation, written informed consent was obtained in these patients.Eligible patients met the ERS/ATS criteria for a diagnosis of severe asthma; all had stable treatment requirements of at least 1000 µg fluticasone propionate with 100 µg of salmeterol or equivalent. Patients were considered to be corticosteroid-dependent when they required a minimum of 4 mg of methyl-prednisolone (MP) per day ≥1 year or boosters of MP equivalent to a mean daily dose of 4 mg of MP. Participants had to maintain their treatment (standard of care) throughout the study. Exclusion criteria included past or present smoking, substantial uncontrolled comorbidity, possibility of pregnancy, and history of poor treatment adherence. 1 < 80% predicted (in the presence of reduced FEV1/FVC defined as less than the lower limit) following a withhold of both short-and long-acting bronchodilators.Uncontrolled asthma was defined according to the ERS/ATS criteria . PatientWe classified patients into two groups: (a) those with asthma due to seasonal allergens, and (b) those with asthma due to perennial allergens. In both situations, a cause-effect relationship had to be clinically established. For each patient with asthma due to seasonal allergens, we recruited the next two consecutive patients with asthma due to perennial allergens. The criteria used to discern the type of allergen causing the asthma were the following: (a) when a single perennial allergen was involved (dust mites or moulds), the asthma was considered to be caused by a perennial allergen; (b) When the single allergen was a pollen, and the hospital patient’s folder revision revealed that the asthma showed seasonal symptoms at the beginning, the asthma was considered seasonal; (c) in cases in which both seasonal and perennial allergen sensitization was detected, in patients sensitized to epithelia at the time of the first skin prick tests, we made all possible efforts to ensure that exposure was stopped. In addition to the clinical information at the hospital we reviewed the electronic medical records of patients in which the primary care physician had documented the absence of animal exposure. In case of doubt, we personally contacted the patient's primary care physician. Thus, although persisting, this sensitization was considered irrelevant to disease’s evolution. All patients with pollen seasonal allergy had perennial symptoms before the appearance of house dust mite sensitization. Non-responders were those patients in which omalizumab did not allow a decrease in the number of exacerbations and/or oral corticosteroid consumption.The primary outcomes were the oral corticosteroid-sparing effect of omalizumab and the rate of exacerbations. The secondary variables were changes in pulmonary function tests (PFTs) and the exhaled fraction of nitric oxide (FeNO). The safety outcome was the reporting of side effects. We planned to recruit a minimum of ten patients in the seasonal group. For each patient with asthma due to a seasonal allergen, we recruited the next two consecutive patients with asthma due to a perennial allergen that fulfilled the criteria. We assumed a loss of 10% in each group.® testing allergens); (b) The test was considered positive when the reaction was ≥ to histamine and ≥3 mm; (c) Omalizumab dose was calculated according to the Novartis® dosing table based on IgE concentration and patient's weight. Depending on the total dose, the drug was administered subcutaneously, either bi-weekly or monthly; (d) Patients were considered responders or non-responders after 24 weeks of omalizumab treatment; (e) The dose of oral MP was tapered at a rate of 2 mg every two weeks depending on tolerance, as in previous studies [(a) A skin prick test was performed in every patient  At t-test, Wilcoxon rank-sum, or Fisher’s exact test was used to analyze the homogeneity between groups. Linear mixed-models with two levels (subject and visit) were fitted to analyze the evolution of the different parameters of interest over time. Because the distributions of residuals of corticoids, FeNO and IgE were skewed, data were log-transformed for analysis. In all cases, a p score less than 0.05 was considered statistically significant. Software STATA version 11.2  was used.Descriptive analysis was performed using central tendency and dispersion measures for continuous variables and the distribution of frequencies for categorical variables. Depending on the variable distribution, These findings have two direct implications, one pathophysiological and one clinical. From the pathophysiological point of view, we can now confirm that it is the presence of the IgE that causes the persistence of the allergic cascade, and that allergens are merely a trigger factor. This would at least be proven in case of asthma due to seasonal allergens. In case of perennial allergens, the continuous exposure to the allergen precludes us extending this conclusion to this group. The clinical implication is that omalizumab prescription should be extended to severe asthma patients allergic to seasonal allergens.


Although the aetiology of chronic cough in guidelines is clearly stated as asthma and related syndromes, gastro-oesophageal reflux disease (GORD), and upper airways disease, the inflammatory mechanisms underlying these conditions differ. Recent studies on asthma have increasingly focused on its molecular phenotypes instead of clinical characteristics. Here, we proposed the hypothesis that divides cough into two groups; the eosinophilic and neutrophilic. This division will enhance our ability to recognise the type of airway inflammation which, as a consequence will lead us to more targeted and personalized treatment approaches. Cough is one of the most common symptoms in respiratory disease which forces patients to seek medical attention. The etiological mechanisms of cough is poorly understood causing a challenge to the management . Even afFor the majority of patients who suffer from acute cough the cause is usually a viral respiratory tract infection. This is initially disruptive but is generally self-limiting . ConversChronic cough is a common but poorly diagnosed condition. It has been typically defined as a cough that persists for more than eight weeks . EpidemiChronic cough has a significant impact on physical and psychological morbidity. Patients suffer from various physical symptoms including chest pain, headaches, sore throat, voice changes, vomiting, incontinence, sleep deprivation and syncope , 8, 9. CIn the literature it has been reported that there are three common aetiologies of chronic cough: 1)asthma and related syndromes, 2) gastro-oesophageal reflux disease (GORD), and 3) upper airways cough syndrome characterised by postnasal drip, rhinitis, and sinonasal disease. However, despite following diagnostic algorithms in cough guidelines, in many patients the cause of cough remains obscure leading to term “idiopathic” chronic cough , 12, 13.1Chronic cough is one of the predominant asthma symptoms. However, what defines the diagnosis of “asthma” is unclear . It has Patients with cough variant asthma characteristically suffer from non-productive cough in the absence of other asthma symptoms such as wheezing and dyspnea . This coAtopic cough is characterised by cough hypersensitivity and sputum eosinophilia in the absence of bronchial hyper responsiveness and airway obstruction . A histoEosinophilic bronchitis is a condition in which chronic cough is present with sputum eosinophilia without variable airflow obstruction (bronchoconstriction) and bronchial hyperresponsiveness . Eosinop2Classic gastro-oesophageal reflux disease (GORD) has been identified in 2 - 40% of cases in prospective studies of chronic cough. However, diagnosis of the more important extra-oesophageal reflux is problematic as there are no clear diagnostic criteria .Classically, the retrograde movement of acid and other gastric contents of the stomach into the oesophagus and beyond is termed gastro-oesophageal reflux. In the majority of patients, this is due to impaired function or brief relaxation of the lower oesophageal sphincter (LOS). GORD causes symptoms such as acid regurgitation, and heart burn which improve by anti-acid therapy such as the proton pump inhibitors (PPIs) , 13. How3Postnasal drip (PND) is defined as a sense of nasal secretions or dripping into the back of the throat from the nose or sinuses. PND is said to lead to symptoms such as cough, frequently clearing the throat (throat-clearing) and nasal discharge or nasal stuffiness. Belief in the syndrome arose from the observation of first generation of antihistamines causing an improvement in cough in significant number of patients . HoweverRecently, molecular phenotypes of asthma (eosinophilic asthma and neutrophilic asthma) based on inflammatory biomarkers have been developed to understand the mechanistic insights and pathology of asthma . SimilarEosinophilic airway inflammation characterised in sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies. Classically, it is believed T helper 2 cells (Th2) by releasing interleukin 4 (IL-4), IL-5, and IL-13 play a vital role to induce eosinophilic allergic asthma. Therefore, new treatment of asthma has been developed which blocks these cytokines . RecentlThe adaptive immune system has long been recognised as the major factor in allergic asthma through epithelial cell-derived cytokines TSLP, IL-25 and IL-33 secreted during allergen exposure. As a result, Th2 cells release large amounts of inflammatory cytokines  , 44.IL-4 stimulates B cells class switching to IgE, which can bind to high-affinity IgE receptors (FcεR1) on basophils and mast cells. Activated basophils and mast cells release inflammatory mediators such as cytokines, chemokines, histamine, heparin, serotonin and proteases. These mediators cause constriction in smooth muscles, increase vascular permeability and mucus hypersecretion , 45, 46.Recently, the involvement of the innate immune system in airway eosinophilic inflammation has been clarified through a series of studies on humans and mice. Anti-IL-4 and anti-IL5 therapies in humans led to a favourable result in asthmatic patients with a high level of eosinophils. Surprisingly, these patients responded to the therapies regardless of being atopic or not . Non atoILCs are activated by IL-33 or a combination of IL-2 and IL-25, and they express Sca-1, c-Kit, IL-33R, and IL-7R. However, they do not express antigen-specific receptors or lineage markers  thus, they cause nonspecific immune responses. Innate lymphoid cells are classified into three groups based on their ability to secrete Th cell-associated cytokines. ILC1 secrete interferon-γ (IFN-γ), ILC2 produce IL-5 and IL13 and finally ILC3 produce IL-17 and IL-22 , 48, 49.1).There is thus a clear molecular mechanism for the production of non-atopic EB in patients with chronic cough. Epithelial damage induces the innate immune system to release TH2 cytokines without the need for an adaptive response.ILC2 are activated in the presence of IL-25, IL-33 or thymic stromal lymphopoietin (TSLP). They are dependent on the TH2-defining transcription factor GATA-binding protein 3 (GATA-3) and the transcription factor retinoic acid receptor-related orphan receptor (RORa) for their development. GATA-3 is required to produce ILC lineages in bone marrow for ILC2 differentiation and maintenance  Fig. (1)In eosinophilic inflammation, the numbers of eosinophil cells in peripheral blood and in airways secretions are increased. Several studies showed that the number of eosinophil cells have a correlation with the severity of asthma. For example, Bousquet and colleagues  have repBronchoalveolar lavage and endobronchial biopsies are the gold standard methods to detect eosinophilic inflammation. However, these methods are invasive and costly and also have many other disadvantages. Therefore, a number of non-invasive sampling methods have been developed which are reliable and complementary to the reference standards. In this section we will discuss sputum induction, blood eosinophilic biomarkers and measurement of fractional exhaled nitric oxide (FeNO) methods as diagnostic approaches to the assessment of eosinophilic inflammation , 53.1According to the European Respiratory Society (ERS) guidelines sputum induction is a validated tool to diagnose respiratory inflammation and monitor anti-inflammatory drug outcomes . Sputum Sputum induction in comparison with bronchial biopsy or BAL biopsy is safer, cheaper and easier to administer. However, there are some limitations that reduce success rate of this technic. Inhalation of hypertonic saline is an unpleasant experience for subjects which may cause bronchoconstriction. Not all patients are able to produce sputum, even if they produce a sample not all the samples are suitable for analysis. Analysing the sputum sample is a time-consuming and difficult procedure which requires adequate equipment and a highly trained technician .2Measurement of blood eosinophil count is another valuable, easy and non-invasive method to identify patients with EB. Blood eosinophil count measures systemic eosinophilic inflammation that is an indirect but useful tool to assess airways inflammation severity, and consequently predict and direct treatment in respiratory patients , 57.Several studies show that there is a positive relationship between sputum eosinophils and blood eosinophils. However, there is only a moderate correlation between these two components -58. It i3The measurement of exhaled nitric oxide is widely accepted as a non-invasive marker of airway Inflammation and, amongst other uses, has been proposed to monitor the response to anti-inflammatory medications. In 2005 clinical guidelines for the measurements of nitric oxide (NO) from the upper and lower respiratory tract has been published by the American Thoracic Society (ATS) .Previous studies have shown that a rise in FeNO value can be detected in patients with asthma and a further increase has been seen during exacerbations . BiologiIn a recent study it has been found that the prevalence of current asthma and wheeze increased 3 times more among patients with high FeNO values than patients with normal FeNO . MoreoveIt has been reported that the level of FeNO in patients using corticosteroids decreases quickly while airway inflammation and hyperresponsiveness can still be detected by other markers of airway inflammation . TherefoFeNO and blood eosinophilia have been considered as replacement markers for sputum eosinophilia as each of them is able to distinguish eosinophilic inflammation phenotype from neutrophilic. However there is only a modest correlation between FeNO and sputum eosinophilia , and a moderate to good correlation between blood and sputum eosinophilia  in asthmatic patients . A systeConsequently, based on the above evidence, it is believed that these biomarkers cannot individually diagnose eosinophilic inflammation accurately. Particularly, it is evident that FeNO and blood eosinophilia are triggered by two different cytokine mechanisms and there is a weak correlation between these two elements , 58. As Despite substantial clinical investigation on anti-cytokines therapy, treating airway inflammation has, as yet, seen partial success . CorticoMontelukast is another treatment preference that is generally considered as an add-on therapy in patients with poorly controlled asthma. However, recently it has been suggested that montelukast might have wider range of anti-inflammatory properties than originally thought .Corticosteroids have been supported as an anti - inflammatory therapy in airway diseases for five decades. Systemic corticosteroids (SCS) and inhaled corticosteroids (ICS) are two forms of steroid therapy which have been used in airway inflammation.ICSs are widely used in chronic cough . ICSs arWhilst oral prednisolone is a SCS which is the most commonly used steroid in the treatment of patients with chronic asthma  in chronIn addition to the lack of literature and large randomised control trials in this area, there is no consistent guidelines on dose or duration of corticosteroids therapy for treatment of cough syndromes .By considering all the present evidence of prednisolone efficacy on airway inflammation and its many unwanted effects, particularly in the chronic therapy, we believed that it is necessary to fully evaluate the relative efficacy of prednisolone and montelukast in chronic cough. Brightling (2006) believed that “The role of other potential therapeutic agents such as antihistamines and antileukotrienes needs to be fully explored” .Montelukast is a pharmacological antagonist of type 1 cysteinyl leukotriene receptors (CysLT1Rs). Cysteinyl leukotriene (cysLTs) are the most potent bronchoconstrictors known that have a crucial role in both immediate and late asthmatic responses. Montelukast effectively inhibited the activities of CysLT1Rs which is recognised in international guidelines as a novel therapy in asthma treatment . Accordi2).The Cysteinyl leukotrienes (cysLTs) are a family of inflammatory lipid mediators including leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). Leukotrienes are produced from nuclear membrane phospholipids in multiple enzymatic cascade. They are synthesised from arachidonic acid through a number of pathways, one of which is the 5-lipoxygenase pathway . In this2).A crucial question that remains unanswered is that through which mechanism(s) cysteinyl leukotriene receptors antagonists accomplish their antitussive effect on airway inflammation. Previously, it has been shown that CysLT1R is upregulated by Th2 cytokines, including IL-4 and IL-13 on human subjects . FurtherThere are numerous studies that confirm a significant effect of montelukast on eosinophilic inflammation in asthmatic patients.Gagro and colleagues (2004) in a study in 14 children with allergic asthma reported that after 6 weeks treatment with montelukast peripheral blood eosinophil count decreased significantly . A signiThere are several clinical studies that have reported the effectiveness of montelukast on patients with cough variant asthma (CVA) as defined by cough with bronchial hyper responsiveness and eosinophilia airway inflammation, in absence of bronchoconstriction or airway obstruction. In a study on adults, patients with chronic cough received diagnosis of CVA and AC (atopic cough). Two weeks therapy with montelukast demonstrated a significant decrease in cough scores which was assessed with a subjective cough symptom scale. However, in subjects with AC compared with a placebo group, cough scores did not show a significant change, so montelukast was ineffective in these patients . In a smTwo small studies have evaluated the effects of montelukast in patients with chronic cough of diverse aetiology. In a real life observational pilot study 14 patients with chronic cough (which is not due to asthma) were assessed before and after two weeks treatment with montelukast. Cough scores were measured with a validated questionnaire (Leicester Cough Questionnaire) and demonstrated a significant reduction of cough after treatment. Cough reflex sensitivity to capsaicin decreased significantly. While there was a decrease in cough reflex sensitivity for citric acid, it was not significant. Moreover, it has been reported that the eosinophil cationic protein (ECP) value as a marker of eosinophil activation significantly decreased . In an o Children who responded to the therapy had a higher level of ECP in their pre-treatment sample compared with children who did not respond to the therapy. Absolute peripheral eosinophil blood counts and IgE levels also were significantly higher in the responders to therapy before treatment. Two of the children who did not respond to montelukast were diagnosed to have GORD. However there are no randomized controlled trials in this patient population.In conclusion the role of induced sputum, FeNO and blood eosinophilic to diagnose eosinophilic inflammation and monitor therapies in chronic cough has yet to be fully defined. Currently, all three methods are in use, with anti-inflammatory therapy directed at eosinophilic inflammation prescribed mainly on clinical judgement rather than evidence. There is an urgent need for the rational application of objective measures of eosinophilic inflammation to avoid excessive and potentially harmful anti-inflammatory treatment in patients with chronic cough.Not applicable.The author (editor) declares no conflict of interest, financial or otherwise.Declared None.


The aim of current study was to assess the effectiveness of losartan 50 mg in reducing blood pressure among post-dialysis euvolemic hypertensive patients, observing their survival trends and adverse events during the course of study. A multicentre, prospective, randomised, single-blind trial was conducted to assess the effect of losartan 50 mg every other day (EOD), once a morning (OM) among post-dialysis euvolemic hypertensive patients. Post-dialysis euvolemic assessment was done by a body composition monitor (BCM). Covariate Adaptive Randomization was used for allocation of participants to the standard or intervention arm. Of the total 229 patients, 96 (41.9%) were identified as post-dialysis euvolemic hypertensive. Final samples of 88 (40.1%) patients were randomized into standard and intervention arms. After follow-up of 12 months’ pre-dialysis systolic (p < 0.001) and diastolic (p 0.01), intradialysis diastolic (p 0.02), post-dialysis systolic (p < 0.001) and diastolic (p < 0.001) blood pressure was reduced from the baseline among intervention-arm patients Compared to only pre-dialysis systolic blood pressure (p 0.003) among standard arm patients after 12 months of follow. Total of six deaths were reported among standard-arm patients compared to 2 deaths among the intervention arm. Losartan 50 mg achieve an overall significant decline in blood pressure among post-dialysis euvolemic hypertensive patients. Every year, between 10–20% of patients on haemodialysis die, 45% of these deaths are attributed to cardiovascular events2. Net cardiovascular events in haemodialysis patients are multi-factorial, but elevated blood pressure in particular has a profound effect3. As the role of the kidney is impaired in end-stage renal disease patients, chronic volume overload of the renin-angiotensin-aldosterone system (RAAS), increased sympathetic activity and several other factors contribute to elevated blood pressure among haemodialysis patients. Despite known etiological causes, prevalence of hypertension among haemodialysis patients ranges between 60–80%4.The risk of mortality among end-stage renal disease (ESRD) patients receiving haemodialysis is 100 times greater than for the general population6. This suggests that plasma volume and plasma-renin activity are two major factors contributing to hypertension among haemodialysis patients. A study on haemodialysis patients looking into response in RAAS with change in volume reported that patients with high plasma-renin activity before saline loading had an increase in blood pressure compared to normal or low plasma-renin activity7. Other studies have reported blood pressure to be more volume-dependent among haemolysis patients8. Textor et al. took this concept further and identified two groups of hypertensive haemodialysis patients: as volume-dependent and renin-dependent9.Exchangeable sodium, plasma volume and plasma-renin activity are almost twice as high in hypertensive haemodialysis patients as normotensive patients and are directly correlated with mean blood pressure10. However, despite a reliable estimation of dry weight, and attaining post-dialysis euvolemic state, a group of patients are still hypertensive12, because of RAAS and are known as renin-dependent hypertensive patients9.Volume-dependent hypertensive haemodialysis patients can be managed by appropriate fluid removal. This is done by identifying the correct dry weight and extracting fluid accordingly. A body composition monitor (BCM) allows quantifiable analysis of excess extracellular volume through a comparison with a healthy population, thereby providing a reliable account of a patient’s dry weight and hydration statusThe current study was an attempt to analyse both concepts simultaneously, i.e accurately identifying patients’ dry weight, achieving euvolemic state post-dialysis, and treating post-dialysis euvolemic-but-hypertensive patients with an RAAS inhibitor. Thus the aim of current study was to assess the effectiveness of Losartan (ARB) in reducing blood pressure among post-dialysis euvolemic patients and assessing their survival trends.12. The study was a multicentre, prospective, randomised, parallel design, single-blind trial. The Hospital Universiti Sains Malaysia (HUSM) in Kelantan and its associated dialysis centres were the main research site. The study protocols were approved by the ethical and research committee of Universiti Sains Malaysia (USM/JEPeM/15050173), and the trial was registered under Australian New Zealand Clinical Trials Registry . The study protocols met consolidated standard of reporting trials (CONSORT) guidelines. All study procedures were in accordance with clinical practice guidelines for haemodialysis from National Kidney Foundation Kidney Disease Outcome Quality Initiative (NKF KDOQI)13. The study purpose was explained and informed consent was obtained before enrolling study participants.The study protocol with complete research design has been publishedPost-dialysis euvolemic patients with systolic blood pressure >140 mmHg post-dialysis, patients aged 30–80, patients undergoing dialysis for of at least 12 months, and patients willing to participate were included in the trial. Patients with amputations, pre-existing heart disease, neoplasm and cystic kidneys, patients treated with ARBs and patients with symptomatic, predialytic hypotension (SBP less than 110 mm Hg) or high blood pressure >200/100 mmHg were excluded from the study.14. After assessing dry weight, all efforts were made to ensure patients achieved their dry weight at the end of the dialysis sessions. Patients with systolic blood pressure >140/90 mmHg thirty minutes after the dialysis sessions underwent a volume assessment by a BCM device. The blood pressure (BP) readings were taken at sitting position by a haemodialysis staff nurse using a manually calibrated sphygmomanometer. Post-dialysis hypertensive patients (>140/90 mmHg) found euvolemic in three consecutive dialysis sessions were included in the trial. In addition, a regular BCM assessment for dry weight was done to ensure patients attained their specific dry weights and euvolemic states. Literature suggests that systolic blood pressure is constantly associated with cardiovascular adverse events15, which is why systolic blood pressure was considered as a marker for outcomes in the current trial.A body composition monitor device (BCM) made by Fresenius (BCM 4BJA3641) was used for assessing the volume status of patients at the end of a dialysis session and was also used for estimating patients’ dry weight16. On the basis of pre-existing literature, the covariates considered for the current study were age, gender, diabetes, and year of dialysis. All participants were randomized using covariate-adaptive randomization to prevent any influence of covariates on randomization17. Randomization of study participants was done by a computer program to minimize the risk of selection bias and avoid any influence of the researcher, the prescriber or the participant in the selection of group or medication18. Furthermore, all enrolled patients underwent a minimum two-week wash-out period to avoid any bias in the study.Covariate-adaptive randomization was used for assigning all pre-screened participants who agreed to participate in the study to the intervention or standard arms19. Based on cost-effectiveness and availability, and the opinion of a panel of experts, a decision was taken to use an ARB (Losartan) for the intervention group.An observational study suggests that an ARB in combination with other antihypertensive medication (but not an ACEI) may have a beneficial effect on cardiovascular mortality among ESRD patients on dialysis by reducing blood pressureThe standard-arm patients received antihypertensive therapy (except RAAS inhibitors) including calcium channel blockers, diuretics, alpha and beta blockers, whereas the intervention-arm patients were prescribed ARB (losartan) alone or in combination with standard antihypertensive pharmacotherapy. In both study arms, upon discussion with a panel of experts, patients were allowed multiple antihypertensive pharmacotherapies to control blood pressure when necessary, to avoid any deterioration in a patient’s health. Study intervention (losartan) and antihypertensive medication was given to the patients on a weekly basis by the principle investigator. Only the study participants were blinded during the course of study.20. The primary end point was achieving a post-dialysis blood pressure of <140/90 mmHg and maintaining this for four weeks, whereas the secondary end point was all causes of mortality. Figure A medication dose of losartan 50 mg/day was initiated for three weeks as a test dose to note any incidence of hypotension. Upon satisfaction, patients were continued with 50 mg/day every day apart from dialysis days. A persistent > 180 mmHg post-dialysis blood pressure despite adding three hypertensive agents resulted in dose titration. The dose titration was initiated with losartan 50 mg to 100 mg followed by non-RAAS antihypertensive agents for the intervention group. For the standard group, the choice of dose titration was left to expert opinion21.The sample size for the current study was based on a statistical superiority trial (continuous data) design of a randomized control trial2 = Polled standard deviation of both comparison groups The sample size calculated from statistical superiority for randomized control trials is 35 for each arm, so altogether 70 euvolemic hypertensive patients. Moreover a 25% dropout was also included, making total of 88 patients (44 in each arm).Calculating the sample size using the equation above:P less than 0.05.Results were expressed as mean or percentage. Comparisons between treatment groups were made by using Wilcoxon tests after adjustment for the dynamic stratification variables . Cohen’s d test was applied to note the effect size. In addition, linear regression was applied to note any influence of patient characteristics on treatment outcome. This data is presented as hazard ratios and 95% confidence intervals. Statistical significance was set at At the end of patient follow-up, both arms underwent survival analysis. Note that the patients that were dropouts/withdrew or transferred from the study could not be followed up. However, their final status at the end of patient follow-up was tracked. At the end of the trial, all transferred and withdrawn cases were alive and hence were categorised as living. Kaplan-Meier analyses were used for survival analysis after 12 months of patient follow-up. For this purpose, patient demographics and characteristics were analysed against patient status at the end of the trial through Kaplan-Meier analysis. All statistical calculations were performed using SPSS version 20.A total of 229 haemodialysis patients underwent post-dialysis BCM analysis: 130 (56.8%) male and 99 (43.2%) female patients. The mean age of haemodialysis patients was 55.98 (SD ± 12) years. Since the study was carried out in the Malaysian state of Kelantan, the overwhelming majority of patients were of Malay ethnicity . Of the total 229 patients, 113 (49.3%) had completed primary education and 117 (51.1%) were urban residents. 98 patients (42.8%) were categorised as normal weight, and 86 as overweight (37.6%), according to BMI classification. Thirty six (15.7%) patients were smokers and 2 (0.9%) patients were alcoholic. The largest number of patients  were on dialysis for 2–3 years, followed by 1–2 years , 3–4 years , >5 years  and 4–5 years on dialysis . Hypertension , anaemia  and diabetes  were the most common comorbidities among haemodialysis patients. A calcium channel blocker was the most prescribed antihypertensive among patients  followed by a diuretic   were classified as post-dialysis hypervolemic, 37 (16.2%) were post-dialysis hypervolemic and 144 (62.9%) were post-dialysis euvolemic, according to post-dialysis BCM analysis. Furthermore, post-dialysis euvolemic patients  were further classified with respect to their post-dialysis blood pressure. A total of 43 (18.8%) patients were euvolemic normotensive, 5 (2.2%) patients were euvolemic hypotensive whereas 96 (41.6) patients were classified as euvolemic hypertensive  patients experienced blood pressure variations and were thus dropped from the study. Altogether, final samples of 88 post-dialysis euvolemic patients were equally randomized into the standard and intervention arms. Twenty one (47.7%) male patients were randomized to the standard arm whereas 24 (54.5%) male patients were randomized to the intervention arm. Similarly, 23 (52.3%) female patients were randomized to the standard arm compared to 20 (45.4%) females in the intervention arm. The mean age of study participants was also comparable in the standard (54 ± 10.2 years) and intervention arms (53.7 ± 10.8 years). Thirty one (70.5%) diabetic patients were randomized to the standard arm, compared to 28 (63.6%) diabetic patients in the intervention arm. A calcium channel blocker was the most prescribed antihypertensive drug in both the study arms  , which at the end of the 12-month follow-up was reduced to 162.4 mmHg (SD ± 10.2), giving a difference of 5.1 mmHg. This drop in pre-dialysis systolic blood pressure was statistically significant . Whereas baseline pre-dialysis systolic blood pressure in the intervention arm was 168.65 mmHg (SD ± 16.33), at the end of the 12-month follow-up it was reported as 158.45(SD ± 10.65), giving a difference of −10.23 mmHg. Statistical analysis suggests a significant decline in pre-dialysis systolic blood pressure (p < 0.001) with a large effect size (Cohen’s d 0.94).Post-dialysis systolic blood pressure among standard-arm patients was 157.5 ±14.3) mmHg, which at the end of the 12-month follow-up was reduced to 156.8 (±11.3) mmHg, giving a difference of 0.7 mmHg. This reduction is post-dialysis blood pressure was statistically non-significant  compared to baseline post-dialysis blood pressure that was 156.34 (SD ± 13.40) and at the end of the 12-month follow-up was 149.73 (SD ± 10.21), so a difference of 6.6 mmHg. This decline in post-dialysis systolic blood pressure was statistically significant (p < 0.001) with a large effect size (Cohen’s d 1.19) among intervention-arm patients  was related to post-dialysis systolic blood pressure among both study arm patients. Diabetes and ex-smokers p 0.04) were statistically associated with post-dialysis blood pressure among standard arm patients. Similarly, male gender (p 0.02), patients that never smoked (0.04) and patients that were on diuretics (p 0.03) were statistically associated with post-dialysis blood pressure among intervention-arm patients  deaths were reported among patients in the standard arm compared to 2 4.5%) deaths in the intervention arm. The probability of survival of standard-arm patients after 12 months of follow-up was 84% compared to 95% for intervention-arm patients  from baseline and as compared to standard-arm patients that were treated with non-RAAS therapy .The analysis of the current study suggests that blood volume and RAAS are two of the main factors contributing to hypertension among haemodialysis patients. Identifying, attaining ideal dry weight, and treating patients with RAAS inhibitors helps in reducing blood pressure significantly compared to non-RAAS antihypertensive therapy. The study findings are in line with preliminary findings that suggest that after 8 weeks of patient follow-up, intervention-arm patients were able to achieve a drop of 2.4 mmHg in post-dialysis systolic blood pressure compared to those in the standard arm 23.Not only was losartan 50 mg (OD) able to achieve a significant decline in post-dialysis blood pressure as compared to standard-arm patients, but patients in the intervention arm also observed a significant decline in pre-dialysis systolic blood pressure , pre-dialysis diastolic blood pressure , and intradialysis diastolic blood pressure . Perhaps the most vivid explanation in support of our findings with respect to the importance of volume control and RAAS was noticed among anephric patients, where both of the kidneys have been removed. These patients have no functioning RAAS and consequently have very low levels of aldosterone in their blood. Blood pressure in these patients is entirely dependent upon volume changes and is sensitive to changes in extra-cellular volume, with no response to changes in plasma-renin activity or hypotensive response to saralasin24. Moreover, the findings of the HELD trial also reported diabetes as a common predictor (both study arms) associated with post-dialysis high blood pressure. Possible explanation for diabetes as a factor for uncontrolled blood pressure among haemodialysis patients may include: diabetic patients have more comorbidities than non-diabetics; diabetic patients may not tolerate changes in systolic blood pressure as well as patients without diabetes; diabetes is associated with the aging process and patients with diabetes of a given age may experience higher mortality rates associated with changes in systolic blood pressure compared to older patients without diabetes24. Other factors that contributed towards post-dialysis systolic blood pressure were male gender and diuretics, among intervention-arm patients, compared to ex-smokers among standard-arm patients.Predictors for blood-pressure control among haemodialysis patients are multi-factorial. However, our analysis suggests that diabetes was the only patient factor that affected post-dialysis systolic blood pressure among both study arms. This finding was in agreement with previous literature that reported that higher mortality rates and uncontrolled blood pressure were common in diabetic patients on haemodialysis25, thereby suggesting their role in managing blood pressure among haemodialysis patients. Bilateral nephrectomy was performed in patients with high levels of renin. However, with greater understanding of the blood-pressure mechanism in these renin-dependent individuals, bilateral nephrectomy was abandoned, as drugs that block RAAS activity were effective in controlling it, including ARBs, thereby suggesting they should be used. The results of the current study are an extension of these findings26.RAAS inhibitors are effective in lowering blood pressure and reducing cardiac events in non-haemodialysis patients27. Davenport et al. reported a higher incidence of intradialytic hypotension in patients achieving post-dialysis BP targets28. In turn, intradialytic hypotension is associated with mortality30, thereby raising questions regarding the recommended post-dialysis blood-pressure target range. Similarly, studies indicate a U-shaped or reverse J-shaped relationship between systolic blood pressure and mortality among ESRD patients32. Hence, a targeted post-dialysis of <140 mmHg systolic blood pressure was adopted for the current study.Another important aspect often neglected is defining an optimal blood-pressure range among haemodialysis patients. National 4 kidney foundation guidelines recommend a pre-dialysis blood pressure of <140/90 mmHg and a post-dialysis blood pressure of <130/80 mmHg as targeted BPs for haemodialysis patients. However, there are some concerns regarding the targeted blood pressures, since most of the data is largely manipulated from observational studies from non-ESRD patients. Hence, targeted blood pressures among haemodialysis patients remain unclearA total of 88 post-dialysis euvolemic hypertensive patients were randomized into standard and intervention arms (44 each). 36 patients in each arm completed one year of follow-up. A total of 6 deaths and 2 transfer cases were reported among standard-arm patients, compared to 2 deaths, 2 drop-outs and 4 patients reaching end points among intervention-arm patients. None of the patients in the standard arm were able to achieve the study’s primary end point . The 2 drop-outs reported in the intervention arm were due to hyperkalemia (>5.5 mEq/L).24. In our study, the majority of mortalities were reported with patients >50 years old. This may be due to the presence of accelerated arthrosclerosis, which is common among haemodialysis patients. Previous studies have demonstrated that hypertension in haemodialysis patients is associated with increased mortality among patients that survive the first three years of dialysis33.Survival analysis among standard and intervention arms suggest higher mortality rates among standard-arm patients compared to intervention-arm patients, though the results are not statistically significant. Similarly, 75% of total deaths were reported in male patients whereas 62.5% of deaths were reported in patients aged >50 years, but neither of these variables were found to be statistically significantly associated with mortality rates after 1 year of follow-up. The literature suggests that the relationship between systolic blood pressure and mortality is not uniform across all age groups among the haemodialysis population, thereby suggesting optimal BP targets with different age groups22. Four cases of coughing, three cases of dizziness and one case of dyspepsia were recorded during the course of the study. However, they were treated and none of participants concerned dropped out.ARBs are usually well-tolerated; however hyperkalemia is frequently encountered among haemodialysis patients on RAAS inhibitors. Hence potassium levels and other blood parameters were closely tracked, to avoid any unwanted events. Two cases of hyperkalemia were reported in the current study, which resulted in study drop-outs. On the contrary, none of the study participants in the HELD trials reported any incidence of hyperkalemia34. A further difference in measuring BP also exists, namely whether to take the BP reading in either the supine or sitting position, though the literature reported no difference between the two. In any case, there is no consensus on the optimal method of BP measurement among haemodialysis patients35.A small sample size is one of the main limitations of this study. In addition, there could be some concerns about generalizing the results of this study, as the majority of participants were Malays, so the results cannot be generalized for the whole population of Malaysia. Keeping in mind the principle of genetic influence, it might be possible that other ethnic groups, i.e. Chinese or Indians, might have different outcomes to Malays. There is no consensus on an optimal blood-pressure goal among end-stage renal disease patients. Moreover, while an accurate BP measurement is fundamental to clinical practice and research, there is no consensus on which BP method is the best representation of actual blood pressure among haemodialysis patients, as studies indicate that routine pre-dialysis or post-dialysis BP readings may overestimate BPThe current study indicates the importance of accurate assessment of clinical dry weight and treating post-dialysis euvolemic hypertensive patients with losartan, as this resulted in a significant decline in blood pressure. Inhibition of RAAS among post-dialysis euvolemic patients not only resulted in a significant decline in overall blood pressure but also reduced mortality compared to non-RAAS antihypertensive therapy. Reduction in overall blood pressure would not only lead to an increase in overall survival rates but may also improve the quality of life among ESRD patients.The study protocols are approved from the Ethical and Research Committee of the Universiti Sains Malaysia (USM/JEPeM/15050173). The trial is registered under the Australia New Zealand Clinical Trial Registry (ACTRN12615001322527). The trial was registered on 2/12/2015 and the first patient was enrolled on 10/12/2015. The trial was formally initiated on 16/02/2016 and patients were followed up for 12 months.Consort 2010 checklist


Off-line, we derived indexes of SVR, cardiac output (CO) and baroreflex sensitivity from the continuous BP recordings (Modelflow). During oxygen supplementation, systolic, and diastolic BP both increased dose-dependently from 128 ± 24 and 72 ± 19 mmHg respectively at baseline to 141 ± 23 (p < 0.001) and 80 ± 21 mmHg (p < 0.001) at 1.0 ATA oxygen. Comparing baseline and 1.0 ATA oxygen, SVR increased from 1440 ± 546 to 1745 ± 710 dyn·s/cm5 (p = 0.009), heart rate decreased from 60 ± 8 to 58 ± 6 bpm (p < 0.001) and CO from 5.0 ± 1.3 to 4.6 ± 1.1 L/min (p = 0.02). Baroreflex sensitivity remained unchanged (13 ± 13 to 15 ± 12 ms/mmHg). These blood pressure effects were absent in a negative control group of eight young healthy subjects. We conclude that oxygen supplementation in CKD patients causes a non-baroreflex mediated increased in SVR and blood pressure.Renal hypoxia is thought to be an important pathophysiological factor in the progression of chronic kidney disease (CKD) and the associated hypertension. In a previous study among CKD patients, supplementation with 100% oxygen reduced sympathetic nerve activity (SNA) and lowered blood pressure (BP). We aimed to assess the underlying haemodynamic modulation and hypothesized a decreased systemic vascular resistance (SVR). To that end, 19 CKD patients were studied during 15-min intervals of increasing partial oxygen pressure (ppO Hypertension is a hallmark of chronic kidney disease (CKD). There is substantial evidence that this can be attributed to increased sympathetic nerve activity (SNA) . Of all patients, values of hemoglobin and proteinuria were available from clinical routine testing within 3 months before the study. Baseline characteristics, including medication use and disease background are given in Table 2). The study was carried out in accordance with the Declaration of Helsinki of the World Medical Association (2013). The Medical Ethics Review Committee of the Academic Medical Center  approved the study protocol. Before inclusion all participants provided written informed consent.We studied 19 CKD patients  0.21 ATA, was provided over the mask at 15 L/min for another 15 min. Thereafter the ppO2 in the breathing gas was increased to 50% O2 (ppO2 0.5 ATA) and 100% O2 (ppO2 1.0 ATA) respectively again for 15 min at each dose , a non-rebreathing mask was positioned over nose and mouth. Blood pressure measurement (see below) was continued while room air, partial pressure of oxygen (ppO2 0.21 ATA), under hyperbaric conditions at 2.4 ATA (ppO2 0.5 ATA) and at 2.4 ATA during 100% oxygen supplementation  at atmospheric pressure ppO 0.21 ATADuring all sessions, continuous blood pressure was measured using finger arterial photo-plethysmography . The device has been validated for use in CKD patients  was systolic BP (SBP) minus diastolic BP (DBP). All hemodynamic parameters were derived from the last minute of the measurements at baseline and at each oxygen dose. Time domain cross-correlation baroreflex sensitivity (xBRS) was calculated from the same intervals as the other parameters, using dedicated software . This algorithm provides a validated beat-to-beat estimate of left ventricular stroke volume (SV), based on a nonlinear 3-element model of the input impedance of the aorta  = 12.6, p < 0.001 for SBP and F = 8.8, p < 0.001 for DBP  = 5.8, p = 0.002, Figure 2, F = 25.1, p < 0.001] and CO  decreased during oxygen supplementation  = 4.3, p = 0.009, Figure 2 , DBP , MAP  and PP , did not change  = 13.0; p < 0.001] and CO  decreased with oxygen supplementation  = 0.884; p = 0.47, Figure During the normobaric oxygen challenge in the control group, SVR increased significantly from 903 at baseline to 985 dyn·s/cm1 Figure . SBP [F Oxygen supplementation causes a dose-dependent blood pressure increase among CKD patients. (2) This blood pressure increase is caused by an SVR increase. (3) The simultaneous HR decrease with unchanged baroreflex sensitivity indicates that the SVR increase is caused by a direct vascular effect of the increased plasma ppOOur results seem to contradict previous findings in CKD patients  its ability to simultaneously hinder vasodilatation by reducing nitric oxide (NO) bioavailability  do not support nor exclude the existence of a CKD-kidney specific hypoxic triggering of  chemo receptors. The overwhelming effects of oxygen on systemic vasoconstriction render the experimental set-up unsuitable to detect any possible subtle effects of kidney specific oxygenation on sympathetic outflow.A possible clinical implication of these results is that oxygen supplementation might act as a cardiovascular stressor in CKD patients. Interestingly, this is in line with observations that oxygen supplementation in selected clinical patients is associated with worse outcome Kones, . Additio2 partial pressure during oxygen supplementation. However, this has previously been shown not to be influenced by oxygen supplementation  pronounced effect on RAAS activity or intrarenal oxygen delivery. However, this may only have blunted the hemodynamic effects and thereby would not have affected our eventual conclusions, especially since patients acted as their own control. The same holds for the heterogeneous distributed baseline parameters  in our relatively small patient group. Secondly, we did not assess changes in COWe have shown that oxygen supplementation in CKD patients increases blood pressure in a dose dependent fashion. This response is mediated by an increase in SVR, likely as the result of hyperoxic vasoconstriction independent of baroreflex function.Study conception and design by RB, RH, ES, CK; Data acquisition, analysis and/or interpretation by RB, MÇ, RH, JL, CK; Drafting of the manuscript by RB, CK; Revising by MÇ, RH, JL, ES, CK; Final approval of manuscript provided by RB, MÇ, RH, JL, ES, CK.This project was funded by the Dutch Kidney Foundation (Project KJPB 12.029 to CP). CP is supported by the Netherlands Organization for Health Research and Development .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Supplemental Digital Content is available in the text Essential hypertension is one of the most common chronic diseases, as well as one of the leading risk factors for cardio-cerebrovascular diseases. Tianma Gouteng decoction has been commonly used in clinical practice for patients with essential hypertension. It is important to update the search and evaluation to provide the best available evidence for essential hypertension. Here, we provide a protocol to evaluate the efficacy and safety of Tianma Gouteng decoction (TGD) for essential hypertension.Retrieve literature on the TGD treatment for essential hypertension in the databases including PubMed, Cochrane Library, EMBASE, Chinese Biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chinese Science and Technology Periodical database (VIP) on computer. The literature to be collected will be those published from the time when the respective databases were established to January 2018. The therapeutic effects according to the blood pressure (BP) will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed.This study will provide a high-quality synthesis of current evidence of TGD for essential hypertension from several aspects including BP, life quality, heart rate, and adverse events.The conclusion of our systematic review will provide evidence to judge whether TGD is an effective intervention for patient with essential hypertension.PROSPERO CRD 42018082319. Their major complications include stroke, myocardial infarction, heart failure, and chronic kidney disease, which not only result in high disability and fatality rate but need great healthcare and social resources input, a heavy burden for both the families and national healthcare system.,4 It is estimated that 1 billion people have high blood pressure worldwide, and about 7.1 million deaths are linked to the disease every year. High blood pressure is becoming increasingly common due to prolonged life expectancy, widespread obesity, reduced physical activity, and unhealthy diets.Essential hypertension is defined as high blood pressure that no secondary cause has been found and the patients diagnosed with the disease have systolic pressure >140 mmHg, or diastolic pressure >90 mmHg. They may lack a medical explanation and support, however, part of CAM therapies  are widely accepted. Today, more patients with cardiovascular disease adopt CAM treatment. TCM is one of the most important parts of CAM, and many studies have shown that Chinese herbal medicine or acupuncture may help control blood pressure.–11Complementary and alternative medicine (CAM) is the term for health therapies and medical products that have typically not been part of conventional medicine and treatments.Gastrodia elata, Scutellaria baicalensis Georgi, Eucommia ulmoides Oliv, achyranthes root, Loranthus parasiticus, abalone shell, Gardenia, Leonurus japonicus, caulis polygoni multiflori, and Poria cocos), all of which are standardly recorded in Chinese Pharmacopoeia 2015 edition. It has been used widely in recent decades in China to clinically treat symptoms caused by high blood pressure, such as dizziness and headache, etc. A new animal study shows that TGD could alleviate cognitive dysfunction in rats with hypertension, which was possibly by inducing alteration of glucose metabolism in different brain regions with corresponding functions.Tianma Gouteng decoction (TGD), a TCM compound, is composed of 11 commonly used herbs  in both Chinese and English will be included in the research, regardless of whether blinding or allocation concealment was adopted.2.1.2The objects of the study will be patients clinically diagnosed with essential hypertension, who have systolic pressure >140 mmHg and/or diastolic pressure >90 mmHg or take antihypertensive drugs.2.1.3The experimental group used TGD or combined with other conventional antihypertensive drugs, the control group of drugs for conventional antihypertensive drugs or placebo.2.1.42.1.4.1The primary outcome measure was blood pressure.2.1.4.2Life qualityHeart rateAdverse events2.22.2.1Retrieve literature on the TGD treatment for essential hypertension in the databases including PubMed, Cochrane Library, EMBASE, Chinese Biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chinese Science and Technology Periodical database (VIP) on computer. The literature to be collected will be those published from the time when the respective databases were established to January 2018. All references that can meet the inclusion requirements of the study will be reviewed one by one to avoid omission. TGD and essential hypertension will be the search terms. The search strategy of PubMed will be shown in Appendix A as an example, and similar strategies will be applied to other databases.2.2.2In the meantime, the relevant studies published on journals, along with their references, will be manually reviewed and retrieved as the supplementary literature.2.32.3.1Two researchers will independently conduct and cross-check the literature screening. In case of disagreement, they shall discuss with each other to come up with a solution or consult another research member. As for the information unavailable, the reviewers shall contact the author of the original paper. They will read the titles of the references first to exclude the literature that are obviously irrelevant, and then read the abstract and full text to determine whether the studies would be finally included. The process of studies selection is presented in a Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow diagram Fig. .2.3.2Two researchers will retrieve the following data independently according to the data collection table designed beforehand: information about the included trials, such as research topic, first author, which journal and when it was published etc., research design and key elements of quality evaluation, information about the patients in the treatment and control group, including how many cases are included and the ages of patients, etc., outcome indicators, relevant indicators of bias risk assessment.2.3.3Two evaluators will assess the risks of the included literature using the tool provided by Cochrane Handbook for Systematic Reviews of Interventions V.5.1.0. The tool includes 7 parts, that is, random sequence generation, allocation concealment, blinding method for patients, researchers and outcomes assessors, incomplete result data, and selective reports. The evaluation results will be divided into 3 levels, namely, low-risk, unclear, and high-risk. They will cross-check the evaluation and data retrieval. Where there are inconsistencies, the problem will be resolved through group discussion, or decided by another researcher.2.3.4The study will employ RevMan 5.3  to conduct meta-analysis. The rate ratio will be used to indicate the enumeration data while the mean difference (MD) the measurement data. A 95% confidence interval (CI) will be adopted to present the effect sizes.2.3.5If the required data are not clear or not reported in clinical papers, the reviewers will collect the missing data with the data collection table by contacting the first or corresponding author of the studies via phone, e-mail, or mail.2.3.6α = 0.1), with its value determined by I2. The heterogeneity among the trials will be considered significant if I2 is >50%, and further subgroup analysis will be carried out to investigate the potential causes.The heterogeneity of the results of the included studies will be analyzed through chi-squared test , and angiotensin II receptor blockers (ARBs).Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) checklist of this protocol is presented in online supplementary.


We propose the visualization of venous compliance (VC) using a digital red-green-blue (RGB) camera. The new imaging method, which transforms RGB values into VC, combines VC evaluation with blood concentration estimation from the RGB values of each pixel. We evaluate a non-contact plethysmography (NCPG) system for VC based on comparisons with conventional strain gauge plethysmography (SPG). We conduct in vivo measurements using both systems and investigate their differences by evaluating the VC. The results show that the two methods measure different blood vessels and that errors caused by interstitial fluid accumulation are negligible for the NCPG system, whereas SPG is influenced by such errors. Additionally, we investigate the relationship between VC and physical activity using NCPG. The daily monitoring of vital signs, such as blood pressure and heart rate, is important for the maintenance of our health. Recently, some studies have proposed new techniques that use sensors or cameras to measure or quantitatively evaluate vital signs ,4,5,6,7 Venous compliance (VC) has attracted attention because it provides important vascular function information. VC—i.e., the ability of a blood vessel to stretch—relates to various factors, such as blood vessel disease. Generally, decreased VC is associated with venous thromboembolism and studies show that VC is correlated with physical activity ,9,10,11.The conventional method for measuring VC utilizes strain gauge plethysmography (SPG) ,16, in wTo address these problems, we propose a non-contact plethysmography (NCPG) system that uses a red-green-blue (RGB) camera to measure VC . We consEarlier studies ,9,10,11 Step 1:1N that can transform RGB values into Commission Internationale de l’Éclairage XYZ (CIEXYZ) tristimulus values. The matrix N1 was determined in advance using a standard color chart. We measured the RGB values of a standard color chart  consisting of 24 color chips. The diffuse reflectance spectra O(λ) for each chip were supplied with the chart. The CIEXYZ values for the specific illuminant E(λ) were calculated as follows:iX, iY, and iZ are the CIEXYZ values; N is the total number of diffuse reflectance spectra; k is a constant whose value results in Y = 100 for a perfect diffuser. In this step, the XYZ value was calculated from each reflectance spectrum for 24 color chips (N = 24). Next, the transformation matrix N1 was determined using multiple regression analysis (MRA), in which the calculated XYZ values were the response variables and the measured RGB values were the predictor variables. The resulting regression coefficients were the elements of N1. If the RGB values of the color chips change by replacing the camera or the light source in the imaging system, the matrix N1 must be recalculated:We calculated the color transformation matrix Step 2:N2, which was used to transform the XYZ values into blood concentration values, was determined next. The skin chromophore concentrations—i.e., the melanin concentration Cm, the oxygenated blood concentration Cob, and the deoxygenated blood concentration Cdb—represent the light absorption coefficients of the skin tissue. Using various combinations of these three concentrations, we employed a Monte Carlo simulation (MCS) model of the transit of light in human skin to calculate the diffuse reflectance spectra of the skin surface O(λ). The parameters of the MCS used in this study—such as the absorption coefficient, the scattering coefficient, the refractive index, and the layer thickness of skin tissue—were those employed in an earlier study [N2, we used the simulation to calculate 300 diffuse reflectance spectra in the wavelength range 400–700 nm at intervals of 10 nm [N2 was determined using MRA:The second transformation matrix er study . Moreoveof 10 nm . After tStep 3:N1, were transformed into the skin chromophore concentrations Cm, Cob, and Cdb using matrix N2. Thus, the total blood concentration was calculated as Ctb = Cob + Cdb. The absorption coefficients of blood for the case of Ctb = 100% were set to those of blood with a 44% hematocrit and 150 g/L of hemoglobin.The XYZ values, which were transformed from the measured RGB values using the first matrix, Any CBV in the skin tissue was estimated from the RGB images of human skin acquired using NCPG, whereas the blood volume was estimated from the volumetric change in a limb or digit using SPG. The method for estimating blood concentration from RGB values was proposed by Nishidate et al. ,19,20; tVC, shown in VC obtained by the differentiation of the regression equation. The method proposed by Halliwill et al.  for evalCBV obtained using SPG is ΔBV/BVc (ΔBV = BV − BVc) and that using NCPG is ΔCtb/Ctb,c, ; BVc represents the blood volume and Ctb,c the blood concentration at the baseline (time = 0) and BV and Ctb denote these quantities at each measurement time; β0, β1, and β2 are constants; P is the cuff pressure. The VC (mL/100 mL/mmHg) at a particular cuff pressure is obtained from the differential of the regression equation:CBV is the difference in the CBV and ΔP is the difference in the cuff pressure.From the data obtained during the cuff deflation, the relationship between the CBV (mL/100 mL) and the cuff pressure (mmHg), which approximates the intravenous pressure, is obtained using the following quadratic regression equation:VC imaging process [VC could not be observed because no visualization of VC was presented. Thus, we present a new VC imaging method that combines the evaluation of VC with an estimation of the blood concentration from the RGB values of each pixel. The new imaging method can easily obtain VC images from digital RGB images and provide VC measurements using a camera-equipped device, such as a smartphone. These images will help us understand VC intuitively. The new imaging process is as follows. First, during the 1-min period in which the pressure cuff is deflated from 60 mmHg to 0 mmHg, 60 RGB images of the skin are acquired. Secondly, as discussed in Cm, Cob, and Cdb—are estimated from the RGB value of each pixel. From this estimation, we can obtain the change of each pixel in terms of blood concentration. Thirdly, the VC of each pixel is determined by the change in the estimated blood concentration according to Equations (4) and (5). The VC images are obtained by calculating the VC of all pixels. This imaging process was programed using MATLAB R2015a . process . The spaIn cP) is the pressure in the blood vessel and is responsible for the fluid exiting the blood vessel. The interstitial fluid colloid osmotic pressure (Πi) also enables the flow of the fluid outside the blood vessel. On the other hand, the interstitial pressure (iP) and plasma colloid osmotic pressure (Πp) enable the flow of the fluid inside the blood vessel. Thus, assuming that inward pressure is positive and outward pressure is negative, the total pressure (tP) can be expressed as follows:cP is higher than iP and Πp, the total pressure is positive (tP > 0) and the fluid flows outside the blood vessel. On the other hand, if cP is lower than iP and Πp, the total pressure is negative (tP < 0) and the fluid flows inside the blood vessel. The fluid flows inside the venous vessel because cP is lower and tP is negative. However, if the vein is occluded from the cuff pressure, the venous pressure becomes higher than usual. Thus, the fluid flows and accumulates outside the blood vessel. Since SPG measures the volumetric change in limbs, SPG measurements are affected by the fluid accumulation in the form of errors that have no relation to vasodilatation. To test these hypotheses, we conducted in vivo experiments using the two systems and compared the results.Our second hypothesis is that the NCPG method is not affected by errors in interstitial fluid accumulation, whereas SPG is influenced by such errors. The walls of capillary vessels have small holes  that supply nutrients to the cells. Moreover, fluid components exist inside and outside the blood vessels, namely, the blood plasma and interstitial fluid. Fluids can pass through the holes whereas proteins—such as hemoglobin—cannot. Four pressures, called Starling forces, determine the flow of the fluid . CapillaVC images calculated using the method shown in VC of superficial veins is spatially averaged. During the experiment, 660 frames of skin images were acquired at one frame per second (fps) by an RGB CCD camera, while 3300 measuring data were measured at five data points per second with the SPG method. Our region of interest (ROI) was 100 × 100 pixels and was placed on an area of the RGB skin image in which the vein could be observed.The experimental conditions of the NCPG measurements were as follows: As shown in The in vivo experiment was conducted on 11 male subjects  with no history or evidence of vascular diseases. VC of the ROI and evaluated it using NCPG. For their categorization, we distributed a questionnaire to all subjects regarding their physical activity. The questionnaire only consisted of two questions (Q1 and Q2) as follows:Q1 (Past habits): Did you perform any physical activity on a daily basis within the past year?Q2 (Current habits): Do you perform any physical activity more than two hours per week?In this study, we categorized the subjects into two groups—an active group and a sedentary group—according to their differences in physical activity. For each group, we compared the mean measured If the subject answered yes to either question, he was categorized into the active group, whereas if he answered no to both questions, he was classified as sedentary. All experimental procedures were approved by Nippon Sport Science University Ethics Committee.VC images constructed using the method shown in VC with respect to the venous pressure, which corresponds to the change in cuff pressure during deflation. These images demonstrate that the area of greatest VC corresponds to the vein shown in the RGB image. Moreover, VC decreases with increasing venous pressure. This can be explained by the fact that the change in vein vasodilation decreases with increasing venous pressure. y-axis represents the CBV. CBV that was calculated from the volumetric change in the strain gauge using SPG. CBV that was calculated with the NCPG method from the color change of skin images—specifically, from the mean values of the ROI shown in CBV increases rapidly after cuff inflation. However, after a 1-min increase, the CBV measured with NCPG shows only a slight increase, whereas that obtained with SPG continues to increase until cuff deflation. To analyze the difference between the two methods, the slopes of the temporal change of the CBV were compared. For this analysis, the measurement time shown in CBV/ΔTime) of each segment were calculated from the regression lines of the temporal change of the CBV shown in t-test and the results are shown in CBV measured with SPG and NCPG for each segment. As the results of the Shapiro–Wilk test show, all slopes had normality except for the slopes of NCPG at segment 2, which had no normality. As shown in CBVs of both systems increased significantly in segment 1. Then, all of the CBVs of SPG continue to gently increase in segments 2 and 3. On the other hand, as shown in CBVs of NCPG increased significantly until 5 min in segment 2. Then, as shown in CBV increase of NCPG was less than that of SPG in segment 3. Moreover, CBV9 min − CBV3 min)/CBV3 min) for each subject, and t-test comparing the percentage changes obtained with SPG and NCPG. As the table shows, a significant difference of the percentage change was observed between the two systems.As shown in This discrepancy can be explained in terms of interstitial fluid accumulation. The rapid increase of venous blood pressure that results from cuff inflation leads to the fluid exiting the venous vessel. This flow leads to a volumetric change in the strain gauge that is not associated with vasodilatation, which leads to measurement errors. However, the NCPG method is not affected by such errors because it estimates the concentration of hemoglobin (which cannot exit the venous vessel) from the RGB values of the skin images. Therefore, these results provide strong evidence for the hypothesis presented in CBV with respect to the cuff pressure during the deflation period and the quadratic regression curve. From the results, highly accurate regression equations were obtained. VC evaluated using SPG and the NCPG. These figures were obtained by the primary differentiation of the regression equations with respect to the cuff pressure P. VC obtained with SPG, whereas VC evaluated within the ROI using the NCPG. To compare the VC values of the two graphs of VC value (mL/100 mL/mmHg) at 20 mmHg as the baseline and investigated the correlation between the VC values obtained using the two measurement systems, which is shown in VC values of the subjects measured with SPG (VCPSG) and the y-axis those obtained with NCPG (VCNCPG). Pearson’s product-moment correlation coefficient between the two measurement systems is R = 0.797 (p < 0.005). Although differences exist between the two measurement systems, it can be concluded that there is positive correlation between the VCs evaluated using the two systems. VCs (VCSPG and VCNCPG) measured using the two systems. The x-axis denotes the mean of the two VCs and the y-axis their difference. This result exhibits a difference between the two VCs. As mentioned previously, the difference indicates the difference in the vein types that were measured with the two systems ). This also suggests a difference between the errors caused by interstitial fluid accumulation in the two systems.VC images of all subjects at 0 mmHg. In this study, all subjects were categorized into two groups—active and sedentary group—according to their differences in physical activity and the VC of each group was examined. By comparing the images of the two groups, we can observe that the VC values of the active group were relatively higher than those of the sedentary group. Thus, to statistically compare the VC values of the two groups, we defined the ROI and calculated the mean VC value over the ROI. Moreover, after the normality of the mean values for each group was tested according to the Shapiro-Wilk test, they were tested with the Student’s t-test. t-test. These results show that the mean VC in the active group was significantly higher than that in the sedentary group (p = 2.5 × 10−2). Similarly to the findings of earlier studies that used SPG [VC evaluated with NCPG is associated with physical activity.used SPG ,9,10,11,VC with a method that estimates the blood concentration from the RGB values of each pixel. Moreover, we simultaneously measured the VC of subjects using SPG and the proposed NCPG method and investigated the differences between these two systems. From the result shown in VC values evaluated using the two systems. The results indicated a positive correlation  between VCSPG and VCNCPG and, thus, demonstrated that, in addition to SPG , NCPG could be used for the evaluation of VC. Finally, we categorized subjects into two groups according to their differences in physical activity and compared the mean VC of each group using the non-contact system. The results showed that there was a significant difference between the mean VC of the two groups. Therefore, NCPG could investigate the relationship between VC and physical activity. We achieved non-contact imaging by combining the evaluation of VC and various conditions, such as anemia, septic shock, hypovolemia, hypothermia, and obesity, among others.In future studies, we will investigate the effectiveness of NCPG across a wider range of skin tones. Moreover, we will investigate the relationship between


This study aimed to determine the clinical profiles and prevalence trends during 1994 to 2014 among patients with allergic asthma (AA), which is a clinical phenotype of asthma.We retrospectively analyzed the characteristics of 319 patients who were diagnosed with AA between March 1, 1994 and February 28, 2014 at 3 Beijing centers.The patients included 155 males and 164 females, and the mean age was 50.86 ± 15.27 years (range 13–86 years). The proportions of asthma attacks in summer and autumn were 60.7% (1994–1999), 61.8% (1999–2004), 56.4% (2004–2009), and 33.1% (2009–2014). The most frequently used medication at home was theophylline (27.9%), which was followed by inhaled corticosteroids (20.38%), inhaled corticosteroids/long-acting beta-2-agonists (10.66%), and leukotriene receptor antagonists (9.4%). The elderly group had the highest rates of summer and autumn attacks, multiple hospitalizations, reduced pulmonary function, smoking history, and positive allergen tests. The middle-aged group had the lowest rates of summer and autumn attacks, and multiple hospitalizations. The youngest group had the lowest rates of reduced pulmonary function, smoking history, and positive allergen tests. The top 5 allergens were dust (9.1%), mites (8.8%), seafood (8.2%), pollen (6.3%), and animal fur (6%). Women were significantly more likely to have a positive allergen test (93 women vs 68 men).The present study revealed the characteristics of Chinese patients with AA, and allergen-specific differences in sex and age during 1994 to 2014. The use of therapeutic drugs at home remains insufficient. AA is the most common phenotype of asthma, and is associated with allergic disease or a family history of allergies.Asthma is characterized by chronic airway inflammation and diagnosed based on various respiratory symptoms, such as wheezing, shortness of breath, chest tightness, cough, and expiratory airflow limitation. and from 1.54% to 2.32% during 2000 to 2010 in China.,4 Furthermore, acute asthma exacerbation is associated with a substantial health burden, with approximately 2 million emergency visits and 373,000 hospitalizations in 2012. These conditions create significant public health concerns and a heavy economic burden. Thus, a better understanding of the features of AA could help clinicians provide more effective care and reduce the socioeconomic burden.China is the world's largest developing country and has recently undergone many obvious changes. In addition, the prevalence of AA has been affected by these changes, which involve the traditional lifestyle and living environment. The prevalence of AA increased from 7.3% to 8.4% during 2001 to 2010 in the United States,1.2To the best of our knowledge, few studies have focused on the characteristics of patients with AA. Therefore, the present study aimed to evaluate the clinical profiles, allergens, and sex and age-specific differences in the characteristics of 319 patients who were diagnosed with AA at 3 Beijing centers between 1994 and 2014.22.1This multicenter retrospective study evaluated patients from 3 tertiary hospitals in Beijing who were hospitalized between March 1, 1994 and February 28, 2014. The hospitals were the Peking Union Medical College Hospital, the Peking University Third Hospital, and the Chinese PLA General Hospital. We collected data regarding the patients’ general characteristics , clinical features, allergens, hospitalization history, and medications used at home. One doctor performed the data collection at each hospital. This study's retrospective design was approved by the Ethics Committee of Chinese PLA General Hospital.2.2 Airflow variability was defined as having a >12% and 200-mL increase in forced expiratory volume during 1 second (FEV1) after the inhalation of salbutamol (400 μg) or a 20% reduction in FEV1 (<16 mg/mL) after the inhalation of methacholine. Patients were diagnosed with AA based on fulfilling at least 1 of the following conditions: a personal and/or family history of allergic disease , at least 1 positive result from allergen testing, increased serum levels of immunoglobulin E (IgE), and pretreatment-induced sputum that revealed eosinophilic airway inflammation. Cases with incomplete data were excluded from the study.All patients fulfilled the following criteria: age of ≥14 years; a history of at least 1 hospitalization at a participating center during the study period; and had a definitive diagnosis of asthma (history of variable respiratory symptoms and airflow variability), based on the official global guidelines.2.3P value <.05. Statistical analyses were performed by using IBM SPSS software .Continuous variables were reported as mean ± standard deviation, and categorical/binary variables were reported as number and percentage, frequency distribution, or constituent ratio. Differences between the groups were assessed using 1-way analysis of variance (ANOVA) or chi-square tests, as appropriate. Differences were considered statistically significant at a 33.1The 319 eligible patients included 22 cases from the Peking Union Medical College Hospital, 164 cases from the Peking University Third Hospital, and 133 cases from the Chinese PLA General Hospital. The patients had a mean age of 50.86 ± 15.27 years (range 13–86 years) and included 155 males.3.2The patients were divided according to their hospitalization period: group A (1994.3.1–1999.2.28), group B (1999.3.1–2004.2.29), group C (2004.3.1–2009.2.28), and group D (2009.3.1–2014.2.28). All 4 groups had similar basic characteristics , and no significant differences were observed (Table P = .02) and multiple hospitalizations  , positive allergen tests (P = .01), and positive IgE tests (P = .01) , ICS/long-acting beta-2-agonist (LABA) (P = .01), and leukotriene receptor antagonists (LTRAs) (P = .01). A decreasing trend was observed for theophylline (P = .01)  P = .0, and leu3.4Abnormal lung function was defined as <80% for the percentage of the predicted FEV1 value (FEV1%PRED) or a peak expiratory flow (PEF) value of <80%. Patients with AA and with or without allergic rhinitis did not exhibit any significant differences in FEV1%PRED or PEF Table .3.5P = .01) and cockroach (P = .03) allergens. No other significant differences were observed , which was followed by mites (8.8%), seafood (8.2%), pollen 6.3%), and animal fur (6%) . However, the sex-specific proportions of the 14 most common allergens were not significantly different.Women had significantly more positive allergen tests, compared with men , a middle-aged group (45–60 years old), and an elderly group (>60 years old). The elderly group had the highest proportions for meats and cereals, and the lowest proportions for dust, animal fur, trees, milk, egg, and seafood. The middle-aged group had the highest proportions for weeds and nuts, and the lowest proportions for mold, mites, cockroach, and pollen. The young group had the highest proportions for dust, animal fur, trees, milk, egg, seafood, mold, mites, cockroach, and pollen, but the lowest proportions for nuts and meats Table .3.8P = .02), multiple hospitalizations , reduced pulmonary function , smoking history , and positive allergen tests . The middle-aged group had the lowest proportions of summer and autumn attacks (39.3%) and multiple hospitalizations (17.1%). The young group had the lowest proportions of reduced pulmonary function , smoking history (18.5%), and positive allergen tests (46.3%) , compared with the previous 10 years (1994–2004). and air pollutants have become new AA allergens, which has induced changes in the clinical features of AA. For example, seasonal differences in pollen production are linked to seasonal trends in asthma attacks, and all 4 study groups had significantly positive allergen tests. However, the present study also revealed a gradual decrease in the proportion of seasonal asthma attacks, which may be related to the increased suspension of airborne particles containing allergens, a prolonged pollen season as a consequence of global warming, and modification of the allergen by air pollutants. Moreover, we observed an increasing prevalence of allergic rhinitis, which agrees with the increasing prevalence of AA in a previous report. Previous epidemiological studies of allergic rhinitis have confirmed that approximately 80% of asthma cases involve allergic rhinitis, and 10% to 40% of allergic rhinitis cases also involve asthma.–13 These studies concluded that allergic rhinitis may be a risk factor for the development of asthma, and that uncontrolled allergic rhinitis may worsen asthma symptoms, increase bronchial hyperactivity, and reduce lung function. Inverse relationships have also been observed for asthma affecting allergic rhinitis. However, the present study did not detect a clear relationship between uncontrolled allergic rhinitis and reduced lung function, and we hope to perform further studies to examine this issue.Allergic asthma is usually induced by specific environmental factors or foods during summer or autumn. With the rapid urbanization and industrialization of China, many serious air pollution problems have emerged,Alternaria, Aspergillus, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cat dander. Among men in the present study, the 5 most common allergens were mites, dust, pollen, seafood, and animal fur, whereas the most common allergens among women were seafood, dust, mites, animal fur, and weeds. These differences suggest that patients with AA exhibit differences according to their race, sex, and age. Thus, Chinese AA allergen data should likely be used to develop local interventions to prevent asthma exacerbation.Specific allergens are vital triggers for AA exacerbation, and the most common positive allergens in the present study were dust, mites, seafood, pollen, and animal fur. However, in the United States, the 5 most common allergens are –18 In the present study, we found that elderly patients had the highest proportion of smoking history  and the poorest lung function . In this context, impaired lung function may be related to smoking interfering with airway cleaning functions, increasing airway epithelial cell damage, accelerating airway inflammation, increasing the risk of asthma attacks, and reducing sensitivity to glucocorticoid therapy.–23 Thus, patients with asthma should stop smoking to improve their quality of life.In addition to climate change, smoking is also a critical risk factor for the exacerbation and poor control of asthma, and also an impaired corticosteroid response. In addition, women are more likely to be hospitalized, compared with men.–27 Previous studies have revealed a decreasing trend when middle-aged patients were compared with young patients, although a subsequent increase was observed among elderly patients. In the present study, the elderly group had the highest proportions of multiple hospitalizations and summer and autumn attacks, but the poorest pulmonary function. However, we also observed a gradually increasing trend among middle-aged patients, which indicates that this condition should be monitored in middle-aged patients to reduce any later increase in severity among elderly patients. Furthermore, the sex and age-specific differences that we observed may be useful for developing both preventative and therapeutic interventions, which could be adjusted for the patient's age and sex.Interestingly, we observed that female patients were more likely to have positive allergen test results, compared with male patients. Thus, it appears that women may be more vulnerable to allergens and more susceptible to allergic diseases. Asthma-related morbidities also exhibit age and sex-specific differences. For example, a higher prevalence of AA is observed among boys before puberty (vs girls), although women exhibit a higher prevalence, compared with men. ICS reduces asthma symptoms, increases lung function, improves quality of life, and reduces the risks of exacerbation, asthma-related hospitalizations, and death.–33 The present study revealed gradually increasing rates of using medications at home , as recommended by the Global Initiative for Asthma guidelines and other relevant bronchial asthma guidelines. However, these increases remain insufficient , and the usage rates are much lower than those in developed countries. These changes are likely influenced by improved treatment adherence among patients with asthma, which is related to reformed education approaches, good doctor/patient partnerships, and an increased level of medical service in the Chinese population.,36 However, the medical insurance system may not evenly cover all patients, and socioeconomic status varies greatly between different Chinese cities. Moreover, many patients express worry regarding adverse drug reactions, and ineffective treatment remains a vital cause of asthma exacerbation. Thus, the prevention of asthma attacks may be improved through more appropriate asthma therapy, further improving patient compliance, and providing more culturally and linguistically appropriate asthma education.Appropriate medication and education are 2 important factors that influence the successful prevention of asthma exacerbation.4.1The present study has several limitations that warrant consideration. First, we only evaluated records from inpatients, as the records for outpatients are often simpler and briefer. Second, we could not analyze the effects of lifestyle and diet on the patients’ changing features, as these details are not included in their inpatient clinical records. Third, the limited sample size and retrospective design are associated with known risks of bias. Thus, large high-quality prospective studies with long follow-ups are needed to confirm and explain the relationship between air pollution and the prevalence of AA.5In conclusion, the present study revealed several changes in the characteristics of patients with AA during 1994 to 2014. We observed age and sex-specific differences, and also differences between smokers and nonsmokers in the different age groups. Furthermore, the use of therapeutic drugs at home remains insufficient.