Availability of a range of techniques and devices allow measurement of many variables related to the stiffness of large or medium sized arteries. There is good evidence that, pulse wave velocity is a relatively simple measurement and is a good indicator of changes in arterial properties. The pulse wave velocity calculated from pulse wave recording by other methods like doppler or tonometry is tedious, time-consuming and above all their reproducibility depends on the operator skills. It requires intensive resource involvement. For epidemiological studies these methods are not suitable. The aim of our study was to clinically evaluate the validity and reproducibility of a new automatic device for measurement of pulse wave velocity that can be used in such studies.In 44 subjects including normal healthy control and patients with coronary artery disease, heart brachial, heart ankle, brachial ankle and carotid femoral pulse wave velocities were recorded by using a new oscillometric device. Lead I and II electrocardiogram and pressure curves were simultaneously recorded. Two observers recorded the pulse wave velocity for validation and one observer recorded the velocity on two occasions for reproducibility.Pulse wave velocity and arterial stiffness index were recorded in 24 control and 20 coronary artery disease patients. All the velocities were significantly high in coronary artery disease patients. There was highly significant correlation between the values noted by the two observers with low standard deviation. The Pearson's correlation coefficient for various velocities ranged from (r = 0.88–0.90) with (p < 0.0001). The reproducibility was also very good as shown by Bland-Altman plot; most of the values were lying within 2 SD. The interperiod measurements of pulse wave velocity were also significantly correlated (r = 0.71 – 0.98) (P < 0.0001). Carotid-femoral pulse wave velocity was found to correlate significantly with heart brachial, heart ankle, brachial ankle pulse wave velocity and arterial stiffness index values. Reproducibility of our method was good with very low variability in both interobserver and interperiod analysis.The new device "PeriScope" based on oscillometric technique has been found to be a simple, non-invasive and reproducible device for the assessment of pulse wave velocity and can be used to determine arterial stiffness in large population based studies. Interest in, and measurement of the velocity of arterial wave propagation as an index of vascular stiffness and vascular health dates back to the early part of the last century. Many methodologies; both invasive and non-invasive have been applied to the assessment of arterial elasticity in vivo. The assessment of cardiovascular risk is one of the most important tasks. The predictive value of pulse wave velocity (PWV) is becoming increasingly recognized and it is one of the classical indices of arterial stiffness (AS). Several arterial assessments improve risk stratification. Three of the most cost-effective assessment parameters are pulse pressure, arterial stiffness and ankle brachial index. Arterial stiffness can be directly measured by non-invasive techniques like computerized oscillometry, tonometry and ultrasonography .In one study  of 30 paA recent important observation, that AS is an independent predictor of cardiovascular mortality -4, has gRecently non-invasive methods to measure AS have become available and are relatively easy to perform -12. A siTotal twenty-four male healthy subjects with mean age 24.7 ± 5.5 years, mean height 168.3 ± 5 cm and mean weight 52.6 ± 6.4 kgs were recruited for interperiod and interobserver reproducibility study. All the subjects gave their consent for the study, approved by the Institutional Ethics Committee, Nizam's Institute of Medical Sciences, Hyderabad. Before the inclusion in the study, subjects were thoroughly examined clinically to confirm the inclusion criteria. No subject was on any medication and had normal blood pressure, CVS, renal, hepatic functions, blood sugar, serum cholesterol and uric acid levels.All subjects refrained from smoking and caffeine containing beverages at least 24 hours before the measurements. The entire test was performed in the morning, after 10 hours over night fasting condition in a quite room with controlled temperature. In each subject two sequences of measurements were performed, and their mean was considered for analysis. All procedures were repeated by two observers (observer 1 and observer 2) for analysis of the inter-observer reproducibility, between the two sequences of measurements of PWV, the BP cuffs were rewrapped at each measurement. For inter period reproducibility assessment, PWV was measured twice by the same observer with an interval of at least one day between the two measurements.Additionally 20 patients  with CAD having mean age 50 ± 13 years, mean height 157.9 ± 10 cm, mean weight 67 ± 16 kgs were also included in interobserver study from the OPD. History of diabetes mellitus, hypertension, smoking, and drug use were recorded. All patients had coronary angiographically confirmed CAD. Patients were allowed to take their prescribed medication during the study period. All patients gave their consent for study participation. Every time the PWV recording was carried out at least 10 minutes after resting.The subjects were examined in supine position. Electrodes of electrocardiogram were placed on ventral surface of both wrists and medial side of ankles and BP cuffs were wrapped on both upper arm brachial artery and above tibial artery of ankles. The cuffs were connected to a plethysmographic sensor that determines volume pulse form and an oscillometric pressure sensor that measures blood pressure volume waveforms from the brachial and tibial arteries. All the pressure recordings were done for about 10 seconds and data was stored in the computer for analysis.New device  is an 8-channel real-time PC based simultaneous acquisition and analysis system. The acquisition rate is 200 samples/second, which is sufficient because the significant frequency content of the pressure as well as ECG waveform is not more than 40 Hz. According to Nyquist's criteria the minimum sampling rate should be 80 samples/second. Hence a sampling rate of 200 Hz per second is optimum. It supports a sophisticated digital signal-processing algorithm to calculate all the results. System has dedicated hardware module connected to 4 ECG electrodes and 4 Blood pressure measuring cuffs. It is very user friendly and fully automatic. Once started, the test recording completes itself by displaying results directly. The report contains 8-second traces of Lead I and II ECG, all Pressure Pulse Waveforms and all calculated results. Device has a built-in database that can be used to store patient folders for further referrals at any point of time. PeriScope is a PC based low cost instrument. When used with a laptop, it can be carried to remote locations. It uses of ECG as marker. It does not use phonocardiogram. PeriScope thus facilitates use in epidemiological studies.This method measures the blood pressure by detecting the pulsation of the artery, which is caused by the heart, as the pressure oscillation in the cuff. When the cuff around< the upper arm is fully inflated, blood flow stops but pulsation of the artery continues and causes oscillation of the pressure in the cuff. As the pressure in the cuff is decreased slowly, the amplitude of the pressure oscillation in the cuff gradually increases and eventually reaches to a peak. Further decrease of the cuff pressure causes the oscillation amplitude to decrease. Cuff pressure when the oscillation reaches a peak, is taken as the mean arterial pressure (MAP).Figure Pulse wave velocity is the speed at which the blood pressure pulse travels from the heart to the peripheral artery after blood rushes out during contraction. It is mainly used to evaluate stiffness of the artery wall. Pulse wave velocity increases with stiffness of the arteries.With new device, the PTT (Pulse Transit Time) of each segment is calculated from the waveform taken from each sensor.It calculates heart-brachial PWV of both upper limbs, heart-ankle PWV of both lower limbs, brachial-ankle PWV of both right and left limb pairs and effective estimated carotid-femoral PWV is calculated.Where Lha = Distance between heart and respective ankle.Lhb = Distance between heart and respective brachium.Lba = Distance between respective brachium and ankle.Distances were measured by direct superficial measurement with a measuring tape of 1 mm resolution as follows:Heart to brachial distance = Heart to shoulder + shoulder to midpoint of brachial cuff.Heart to ankle distance = Heart to midpoint of ankle cuff.Brachial ankle distance = Heart to brachial distance + Heart to ankle distancePulse Transit Time (PTT) between heart and extremity (i.e. PTT hb and PTT ha) is calculated using R wave as pulse start maker and maximum pressure gradient as pressure wave arrival marker. This is due to the fact that the QRS complex designates highest-pressure deviation in the left ventricle where as maximum pressure gradient marks the highest-pressure deviation in the artery of the extremity Fig. . A proprPulse Transit Time (PTT) between brachium and respective ankle is calculated as the time difference between the feet of respective pulse wave originated by the same QRS complex. The carotid femoral PWV (C-F PWV) is estimated from the composite brachial ankle pulse wave velocity (ba PWV) found out by averaging left and right ba PWV. The regression analysis between ba PWV and C-F PWV yields the following equation:Estimated carotid femoral PWV = 0.8333 * (Avg. ba PWV) - 233.33.This equation is arrived at by internal data collection and confirmed by studies conducted elsewhere .Oscillometric envelope is a graphical depiction of compressibility of the artery. It is derived from the oscillations in the artery when the BP cuffs are deflating while taking the BP reading. It is the graph of amplitude of oscillations verses the instantaneous pressure in the blood pressure cuff. In a normal arterial condition, the shape of the oscillometric envelope is like a bell, when arteries are stiffened or atherosclerosed the oscillometric envelope flattens out.Arterial stiffness index is another measure of arterial stiffness. It quantifies the shape of the oscillometric envelope. As the arterial stiffness increases, it becomes harder to collapse the arteries by applying external pressure; hence the oscillometric envelope becomes flatter as the stiffness increases. The ASI value gives a clear indication of this flattening process Fig. . The higASI =  - .The device acquires and computes the following parameters simultaneously: 2 channels of ECG, brachial BP of both limbs, ankle BP of both limbs, 4 channels of pulse pressure waveforms, mean arterial pressure (MAP), % MAP, ABI, pulse wave velocities, UT (Upstroke Time), arterial stiffness index.Data are expressed as mean ± SD. Pearson's correlation analysis, determination of coefficient of variation and Bland-Altman plotting were performed for the assessment of validity and reproducibility . When twTotal 44 subjects (24) healthy controls and (20) CAD patients participated in the present study. The demographic characteristic of all subjects is shown in the table-The mean PWV obtained in two groups is shown in table The mean velocities obtained by the two separate observers in control and CAD group are shown in tables In the control group, the Pearson's correlation coefficient was 0.88, 0.91, 0.89 and 0.90 (p < 0.0001) for hb, ha, ba and C-F PWV respectively. The coefficient was 0.85 for ankle ASI with p < 0.0001. Similarly in CAD group, and in data from all subjects combined also the correlation was highly significant, suggesting high reproducibility of our method for PWV determination.The relationship and Bland-Altman plot for hb, ha, ba and C-F PWV obtained by two observers is shown in figures The mean of hb, ha, ba, C-F PWV and ASI recorded during two-separate occasions in same subject was shown in the table Our present study was not aimed to detect differences in the measured parameters between control group and CAD group; therefore no sub group analysis was performed. The CAD group was included to provide a wide range of PWV values, thus strengthening the reproducibility of method.In recent years with the development of readily available noninvasive assessment techniques investigation of arterial stiffness, especially of the large arteries has gathered pace. These include the measurement of PWV, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure and analysis of arterial wave forms obtained by applanation tonometry. For the measurement of AS, several new techniques have been developed, but their association with aortic PWV, an established measure of central arterial stiffness has not been validated. Because of its size and elasticity, the aorta is the main determinant of systemic arterial compliance  and thusPerhaps the best and most widely used technique to estimate the distensibility and stiffness of the aorta and proximal vessels is PWV. Although the properties of large arteries have been studied for several decades, the field of clinical arterial biomechanics remains in its infancy. The clinical value of any of the available techniques is yet to be proved convincingly and no single parameter of compliance or stiffness can ever be expected to describe all clinically relevant arterial wall properties. Measurement error can be substantial, including problems related to the measurement of both transit time and distance traveled by the pulse wave. There is a need for a simple, reliable, noninvasive method of detecting early disturbances at the time when therapeutic intervention can be most beneficial. Currently, none of the methodologies available are yet suitable for use in wide spread clinical practice. The results of our study indicate that a new device provides a simple non-invasive method for the assessment of arterial stiffness and PWV in clinical settings and operator does not require prolong period of training to achieve measurements.We have determined the C-F PWV along with determination of other velocities like hb, ha, ba PWV. The present experiment included both healthy control and patients with CAD to provide a wide range of values. The correlation with C-F PWV was very high with other PWV estimated. Analysis of data was done by using Bland-Altman Plots and reproducibility was reported as the SD of the differences between the paired measurements. This method was used rather than only reporting coefficient of variance, as the latter is a less satisfactory method of assessing reproducibility and can some time misleading .Arterial stiffness index (ASI) also well correlated with C-F PWV . Similar correlation between ASI and C-F PWV has been documented earlier in elderly hypertensive patients . Our resThere are a number of different ways to measure PWV, and these are generally simple to perform.The results of this study indicate that, the measurement of arterial PWV by oscillometric technique using PeriScope is reproducible and simple. The validity and reproducibility of the measurement of PWV in interobserver and interperiod evaluation was high with a low SD for measurement difference. Derived carotid femoral velocity correlated well with hb, ha and ba PWV and arterial stiffness index. Simultaneous measurement of all velocities and stiffness index provide better over all assessment of arterial functions. New device may be useful in studying arterial stiffness in large population.ABI – Ankle Brachial IndexAS – Arterial StiffnessASI – Arterial Stiffness Indexba – Brachial ankleBP – Blood PressureCAD – Coronary Artery DiseaseC-F – Carotid FemoralCV – Coefficient of variationCVD – Cardiovascular DiseaseDBP – Diastolic blood pressureDSP – Digital signal processingECG – Electrocardiogramha – Heart anklehb – Heart brachialHR – Heart rateMAP – Mean Arterial PressureOPD – Out Patient DepartmentPP – Pulse pressurePTT – Pulse Transit TimePWV – Pulse Wave VelocitySBP – Systolic blood pressureSD – Standard DeviationSE – Standard ErrorUT – Upstroke TimeMURN conceived and designed the study and drafted the manuscript. BMR and YS performed the study as two separate observers under the supervision of MURN. YS compiled and analyzed the data statistically. ANP performed and evaluated the angiogram of cardiac patients. PUR participated in the design and coordination of the study. All authors read and approved the final manuscript.


Cardiac asthma is common, but has been poorly investigated. The objective was to compare the characteristics and outcome of cardiac asthma with that of classical congestive heart failure (CHF) in elderly patients.Prospective study in an 1,800-bed teaching hospital.2  at admission. In the cardiac asthma group, patients had greater distal airway obstruction: forced expiratory volume in 1 second of 1.09 vs. 1.33 Liter (p < 0.05), and a forced expiratory flow at 25% to 75% of vital capacity of 0.76 vs. 0.99 Liter (p < 0.05). The in-hospital (23% vs. 19%) and one year mortality (48% vs. 43%) rates were similar.Two hundred and twelve consecutive patients aged ≥ 65 years presenting with dyspnea due to CHF (mean age of 82 ± 8 years) were included. Findings of cardiac echocardiography and natriuretic peptides levels were used to confirm CHF. Cardiac asthma patients were defined as a patient with CHF and wheezing reported by attending physician upon admission to the emergency department. The CHF group (n = 137) and the cardiac asthma group (n = 75), differed for tobacco use , history of chronic obstructive pulmonary disease , peripheral arterial disease . Patients with cardiac asthma had a significantly lower pH , and a higher PaCOPatients with cardiac asthma represented one third of CHF in elderly patients. They were more hypercapnic and experienced more distal airway obstruction. However, outcomes were similar. In Western countries, the population is getting older, and it is projected that there will be a doubling of individuals over the age of 65 and 80 years by 2030 . It is eTherefore, the objectives of this study were to 1) determine the incidence of wheezing, though to reflect the occurrence of bronco-obstruction ("cardiac asthma"), during CHF, and 2) compare the characteristics , and prognosis of patients with cardiac asthma to that of classical CPE (non wheezing CPE) in patients aged 65 years and over.A single-center prospective study was conducted between February 2001 and September 2002, in an emergency department (ED) of a 1,800 bed teaching urban hospital. This work was an ancillary analysis of an epidemiological study of acute respiratory failure in elderly patients (EPIDASA study) which has been previously described in detail elsewhere . In the 2 ≤ 70 mmHg; 3) PaCO2 ≥ 45 mmHg with pH ≤ 7.35; 4) peripheral oxygen saturation (SpO2) ≤ 92 %. To be included in the present study, patient should have CHF as defined by experts (see below). There was no exclusion criteria in the EPIDASA study; we excluded only patients with obvious acute bronchial asthma, as defined by experts.The criteria for inclusion in the EPIDASA study were: age ≥ 65 years and acute dyspnea. In addition, one of the following criteria had to be fulfilled: 1) respiratory rate ≥ 25/min; 2) PaO1) (L), FEV1 (percentage of predicted), FEV1/FVC ratio (%), and forced midexpiratory flow rate (FEF25–75%) (percentage of predicted). Since measurement of lung volumes by pletysmography was rarely ordered by physicians in charge and subsequently performed, we did not report the results.For every patient, medical care instituted by physicians in charge included: medical history especially cardiac risk factors, previous cardiac and respiratory diseases, physical examination, arterial blood gas analysis , 12 lead electrocardiogram, and chest X-ray. Emergency treatments and admission were decided by the emergency physician according to normal practices and recommendations ,15. CreaThe complete medical chart was reviewed, especially noting medications including loop diuretics, nitrate, bronchodilatators and other treatments. Response to diuretic or vasodilator, results of echocardiography-Doppler, or BNP and NT-proBNP levels ,18 when The diagnosis of COPD was made by experts according to reports from a general practioner, respirologist or medical chart from previous admission; patients' current symptoms (chronic cough and sputum production), clinical findings ; and radiographic findings (Chest X-ray or CT scan) of thoracic distension ,22. On tTo determine the rate of readmission and long term survival, all patients were followed-up by a phone call three months and one year after discharge.Data are expressed as mean ± standard deviation (SD) or median (and interquartile 25–75%) for non-Gaussian variables. Comparison of two means was performed using the Student's t test, comparison of two medians using the Mann and Whitney test, and comparison of two proportions using the Fisher's exact method. A multivariable analysis was performed in order to assess predictors of cardiac asthma. We used a conservative approach and included in this test only variables with a p value <0.10 in the univariate analysis. All statistical comparisons were two-tailed and a p value of less than 0.05 was required to reject the null hypothesis. Statistical analysis was performed using computer NCSS 6.0 software .Five hundred and fourteen patients were included, of which 212 patients had a final diagnosis of CHF . From thThe triggers of acute CHF were similar in the classical CPE group as compared to the cardiac asthma group: systolic arterial hypertension , myocardial ischemia , acute pneumonia , tachyarrhythmia , anemia .Doppler-echocardiography was performed in 152 (72%) patients during the hospitalization. The rate of non systolic heart failure was similar in both groups . The median (interquartile 25–75%) BNP (n = 130) and NT-proBNP (n = 106) levels were similar in the cardiac asthma group as compared to that of classical CPE, 576 pg/mL  versus 615 pg/mL  and 4747  versus 3921 pg/mL  respectively.All patients were hospitalized. The in-hospital mortality was 22 %, and the rate of re-admission at three months was 42%. The one year mortality was 54 %. The prognosis of the two groups was similar Fig. . The med1/FVC ratio). Cardiac asthma patients experienced obstructive airflow disorders in smaller distal airways  confirmed similar severity of CHF in both groups.The population in our study of acute heart failure in elderly patients seems similar to previous studies in term of past medial history and prognosis. The in-hospital mortality was 22 %, compared to a mortality ranging from 13% to 29 % in other studies . The ratThe method used in our study to diagnose CHF and COPD requires further comment. For the diagnosis of CHF there is no ideal standard. Thus, as in several previous studies, we used consensus diagnosis by experts to assess the final diagnosis of CHF supported with results of Doppler-echocardiography when available during hospitalization , and BNP1/FVC<70% [Usually, COPD is usually defined by spirometry: i.e. presence of a FEV/FVC<70% ,22. In o/FVC<70% . The FEVThe only criteria listed for "cardiac asthma" was wheezing reported by the physician's exam in the ED. There was no objective criteria given to differentiate this from co-existing lung disease and could lead to misclassification of CHF as being the primary event. However, the inclusion of the NT-proBNP and BNP data soundly confirms that this was a comparison of two cohorts with CHF (i.e. the wheezing group indeed did have CHF as reflected by the similar levels of BNP and NT-prBNP). At the time of the study, we were aware that patients with CHF were undertreated  because only two thirds of patients in both groups received either diuretics or nitrates .Since the method used to evaluate expiratory flow limitation in our study is questionable, we suggest that obstructive pattern has been underestimated ,33. ThisMeasurement of lung volumes by pletysmography was rarely performed, therefore we did not report the results of lung volumes measurement . Thus, we can only suggest, and not strongly confirm that a restrictive defect was present in patients with CHF.In our study, PFTs were performed according to physicians' orders, because the routine care of the patient was not modified. The percentages of patients who had PFT were quite similar in those with (35%) and without (30%) wheezing at the admission, thus we do not think that it could have biased the results. However, we agree that some hypothesis or conclusions are based upon a small number of patients who had PFTs (only one third). Due to the methodology of this observational study, we did not demonstrate that cardiac asthma was formally associated with distal airway obstruction. The limited sample size of our population precluded us to perform a case control study to confirm this hypothesis.There was a low prevalence of bronchodilators given to the wheezing patients. This is attributed to the fact that the medical care was decided by the physicians in charge, and that bronchodilators have not been demonstrated to to be surely effective in cardiac asthma ,26-29. ACardiac asthma defined as CHF associated with wheezing represents one third of CHF in elderly patients. Cardiac asthma patients were more hypercapnic and had greater peripheral airway obstruction. However, in these patients short and long term outcomes were not dissimilar from those of patients with classical CPE.The author(s) declare that they have no competing interests.PR conceived of and designed the study, performed analysis and interpretation of data, edited the manuscript, and gave final approval of the manuscript. SJ performed interpretation of data, drafted the manuscript, and gave final approval of the manuscript. SD, MHB performed analysis and interpretation of data and gave final approval of the manuscript. RA, BR, RI and MB revised the manuscript critically for important intellectual content, and gave final approval of the manuscript.The pre-publication history for this paper can be accessed here:


Allergic rhinitis (AR) and asthma are inflammatory conditions of the airways that often occur concomitantly. This global survey was undertaken to understand patient perspectives regarding symptoms, treatments, and the impact on their well-being of comorbid AR and asthma.n = 813) and parents of children with asthma (n = 806) from four countries each in the Asia-Pacific region and Europe. Patients included in the survey also had self-reported, concomitant AR symptoms. Patients and parents were recruited by telephone interview or by direct interview.Survey participants were adults with asthma (Most patients (73%) had pre-existing symptoms of AR when their asthma was first diagnosed. Shortness of breath (21%) was the most troublesome symptom for adults, and wheezing (17%) and coughing (17%) the most troublesome for children. Patients used different medications for treating asthma  and for treating AR . The concomitant presence of AR and asthma disrupted the ability to get a good night's sleep (79%), to participate in leisure and sports activities (75%), to concentrate at work or school , and to enjoy social activities . Most patients (79%) reported worsening asthma symptoms when AR symptoms flared up. Many (56%) avoided the outdoors during the allergy season because of worsening asthma symptoms. Many (60%) indicated difficulty in effectively treating both conditions, and 72% were concerned about using excessive medication. In general, respondents from the Asia-Pacific region reported more disruption of activities caused by symptoms and more concerns and difficulties with medications than did those from Europe. Differences between the two regions in medication use included more common use of inhaled corticosteroids in Europe and more common use of Chinese herbal remedies in the Asia-Pacific region.Results of this survey suggest that comorbid asthma and AR substantially impact patient well-being and that the worsening of AR symptoms in patients with asthma can be associated with worsening asthma symptoms. These findings underscore the need for physicians who treat patients with asthma to evaluate treatment options for improving symptoms of both AR and asthma when present concomitantly. Asthma and allergic rhinitis (AR) are chronic inflammatory conditions of the airways that affect a large proportion of the general population ,2. TheseIn addition to the symptomatic burden of AR in patients with asthma, comorbid AR may be associated with more asthma-related healthcare resource use, including emergency room visits and hospitalizations, and greater treatment costs than for patients with asthma alone ,8-10. ThWhile there are several surveys assessing patient perspectives on asthma and on AR ,15, relaAdult patients 18–64 years of age and parents of patients 6–18 years of age were recruited for the study from four countries in the Asia-Pacific region  and from four countries in Europe . Households were randomly called, and potential respondents were screened to ensure recruitment of an equal number of adult patients and parents of pediatric patients with concomitant asthma and symptoms suggestive of AR. Potential respondents in the Asia-Pacific countries were also referred by other patients or intercepted at clinics, hospitals, and pharmacies and were interviewed face to face. A prior diagnosis of asthma and the presence of AR were self-reported by patients. AR was defined as congestion, sneezing, runny or itchy nose, and red, watery, itchy eyes.The survey was conducted by an international research firm, which coordinated the translation of questions into the language of each country and collected and summarized the survey results. Telephone interviews lasted up to 15 minutes. Survey questions were not validated. The survey comprised 21 questions, some with multiple parts, investigating the onset and nature of allergic and asthmatic symptoms, the extent to which daily activities and sleep were affected by these symptoms, the types of allergy and asthma therapies, and the attitudes about these therapies.Survey participants included 809 patients from four countries in Europe and 810 patients from four countries in the Asia-Pacific region  had experienced ≥5 symptoms identified in the survey. When the diagnosis of asthma was made at an earlier age (mean age 12.1 years), patients reported ≥9 symptoms of asthma and AR. By contrast, when the diagnosis was made later (age 15.6 years), patients reported fewer symptoms (≤5).Overall, 73% of adults and 76% of children experienced cough at one time or another; 77% of adults and 81% of children experienced wheeze; 80% of adults and 79% of children experienced sneeze; 75% of adults and 79% of children experienced stuffy or blocked nose or nasal congestion; 77% of adults and 76% of children experienced a runny nose; 70% of adults and 72% of children experienced an itchy nose; and 61% of adults and 62% of children experienced red, watery, itchy, or puffy eyes.The most frequently experienced symptoms and the most troublesome symptoms are presented by region and by age group in Table P ≤ 0.05).Almost two-thirds of patients (64%) believed that people with AR were, in general, also likely to have asthma. This was supported by the fact that a majority (69% of adults and 76% of children) had pre-existing symptoms of AR when asthma was first diagnosed. In this subgroup of patients with AR, however, only 43% had concerns (versus 51% with no concerns) about developing asthma before the diagnosis, although more parents were concerned about their children than adults were about themselves  between the European and Asia-Pacific regions for each category of asthma medication except leukotriene receptor antagonists, which were used by 3% of patients in each region . A majority of patients on asthma medications (84% of adults and 85% of children) reported that they were very or fairly satisfied with their asthma treatment. Fewer parents of children than adults  were very satisfied or fairly satisfied with inhaled corticosteroids or long-acting β-agonists.The proportions of patients using asthma medications were significantly different  between the European and Asia-Pacific regions; antihistamines and nasal corticosteroids were used by more (P ≤ 0.05) patients in Europe than in the Asia-Pacific region  than children to use medications for their AR (77% versus 85%). Among those who used corticosteroids for their AR, 73% of adults and 80% of children were satisfied (very satisfied or fairly satisfied) with the treatment. Among antihistamine users, 77% of adults and 84% of children were satisfied.The percentages of patients using most categories of allergy medications were significantly different  were very interested or fairly interested in a single medication for treating both asthma and AR. The major reasons described by patients for this interest were as follows : 'easier to use' (36%), 'convenient' (26%), 'one tablet covers everything' (25%), 'less medication' (24%), and 'fewer side effects' (5%).Attitudes about medications for asthma and AR are summarized in Table Overall, most patients (75%) agreed that asthma and AR bothered them in their day-to-day life. Moreover, most patients (60%) agreed that it was difficult to effectively treat both asthma and allergy at the same time and were concerned about using too much medication for both asthma and allergies  than those in the European region  as a result of asthma and AR Figure . Patientn Figure .Among the overall survey population, comorbid asthma and AR disrupted the ability to get a good night's sleep (79%), to concentrate at work and school (71%), to participate in leisure and sports (75%), and to enjoy social activities (54%). Even among those reporting satisfaction  with their treatment for asthma, 52–78% reported an impairment in their well-being, with most (78%) reporting disruption in their ability to get a good night's sleep. Similarly, among those expressing satisfaction with their treatment for AR, 54–80% reported impairments, with most (80%) reporting disruption in their ability to get a good night's sleep. Among adults, 25–34% in each country believed that asthma and AR were equally disruptive to their well-being; parents of 30–35% of children believed the same. By country within region, 28–29% of patients in the European countries and 27–39% of patients in the Asia-Pacific region believed that asthma and AR were equally disruptive to their well-being.Most patients reported that the symptoms of AR affected their asthma and their well-being during the allergy season all of the time, much of the time, or some of the time Figure . Fifty-sThe results of this survey highlight the limitations imposed on daily life by the presence of comorbid asthma and AR. Approximately 70% or more of all patients reported a disruption in daily activities, including the ability to get a good night's sleep, to participate in leisure and sports activities, and to concentrate at work or school. More than one-half of patients reported that their symptoms had a negative affect on their ability to enjoy social activities.More than two-thirds of the patients included in this survey were already experiencing AR symptoms when the diagnosis of asthma was made; this result reflects the comorbid nature of these disorders. For three-quarters of adult and pediatric patients, asthma symptoms increased some to all of the time when symptoms of AR flared up; similar numbers reported developing nasal and chest symptoms when coming into contact with allergy triggers. Interestingly, a recent small, prospective cohort study found that patients with concomitant asthma and AR experienced significantly worse physical functioning at pollen peak than those with only AR . In the Some differences were seen between the two geographic regions in the frequency of asthma and AR symptoms, the bothersome nature of these symptoms, and the extent and duration of symptoms. In particular, the disruption of activities caused by symptoms was reported more commonly by respondents in the Asia-Pacific region than in Europe. Seventy-one percent of Asian respondents reported avoiding the outdoors during the allergy season because of fears that their asthma symptoms might worsen, while over 80% reported disruption of sleep, of concentration at work or school, and of participation in leisure or sports activities. Moreover, higher percentages of respondents from the Asia-Pacific region than from Europe reported concerns and difficulties with medications, including concerns about potential side effects of corticosteroids and about using too much medication for their asthma and allergies. Possible reasons for these differences between the two geographic groups of respondents could be cultural differences or differences between the two regions in the environment, allergic triggers, or treatments used.2-agonists and inhaled corticosteroids for their asthma and received oral antihistamines for AR. By contrast, patients in the Asia-Pacific region used these treatments, particularly inhaled corticosteroids, less frequently and instead relied more on Chinese herbal remedies for both their asthma and their AR symptoms. It has been recently reported that such nonconventional treatments may have some benefit [Differences between the two regions were seen also in medication use by patients. In Europe, most patients received short-acting β benefit . The met benefit .It would have been interesting to know to what degree AR in and of itself contributed to decreased well-being. Among patients consulting with general practitioners for their AR in one study, 40% of those with mild rhinitis and >80% of those with moderate/severe rhinitis reported impaired activities, including impaired quality of life, sleep, daily activities, and work performance . DistingAn inability to treat both asthma and AR together was a concern of respondents to the survey: approximately 60% of patients in each age group found it difficult to treat both conditions effectively at the same time. Moreover, two-thirds of adult patients and three-quarters of parents of pediatric patients were concerned about using too much medication to treat the two conditions.The route of administration was an important consideration among survey respondents. Nearly 60% of all patients reported that they found nasal sprays uncomfortable or unpleasant for treating AR; and over one-half of all patients reported that they preferred using an oral medication to nasal sprays for treating these symptoms.Patients' negative perceptions about side effects were also highlighted in the survey. Most respondents were concerned about the potential side effects of using corticosteroids for treating asthma or AR, and a majority of adult patients and parents were concerned that the allergy medicine might make them or their children drowsy.A limitation of this survey is that participants were identified according to self-reports of asthma and symptoms of AR. Moreover, the survey questionnaire was not a validated instrument. In addition, patients' and parents' answers to questions about the impact of asthma and AR on well-being could be subject to recall bias.A strength of this study is the large sample size (800 patients in Europe and 800 in the Asia-Pacific region). The representativeness and comparability of the two groups of participants is not certain, however, because survey participation in Europe was limited to individuals with a telephone in the household, whereas in Asia-Pacific countries some patients were recruited by other patients or at clinics. A combination of telephone and door-to-door surveys has been used by other surveys to evaluate asthma, including the Asthma Insights and Reality study .As highlighted by the Allergic Rhinitis and its Impact on Asthma guidelines , asthma AR and asthma are most commonly managed in the primary care setting. Physicians treating patients with asthma or AR must remain vigilant to the possible presence of the other condition, be aware of the risks posed by one condition to the development of the other, and evaluate treatment options for improving symptoms of both conditions when present concomitantly. In addition, physicians must be aware of possible patient concerns about medications, particularly patient concerns about potential side effects of corticosteroids and about using too much medication for their asthma and allergies. More generally, there is a need to promote the use of combined therapies that are safe and effective for treating symptoms of both asthma and AR, and that address the inflammatory nature of these two conditions affecting the 'one airway.'AR = allergic rhinitis.EV has received speaker's honoraria from Merck & Co. RP declares that she has no competing interests.


Neutrophils are increased in the airways and in induced sputum of severe asthma patients. We determined the expression of activation markers from circulating neutrophils in severe asthma, and their supressibility by corticosteroids.We compared blood neutrophils from mild, moderate-to-severe and severe steroid-dependent asthma, and non-asthmatics (n = 10 each). We examined the effect of adding or increasing oral prednisolone .Flow cytometric expression of CD35 and CD11b, but not of CD62L or CD18, was increased in severe asthma. F-met-leu-phe increased CD11b, CD35 and CD18 and decreased CD62L expression in all groups, with a greater CD35 increase in severe asthma. In severe steroid-dependent asthma, an increase in prednisolone dose had no effect on neutrophil markers particularly CD62L, but reduced CD11b and CD62L on eosinophils. Phorbol myristate acetate-stimulated oxidative burst and IL-8 release by IL-1β, lipopolysaccharide and GM-CSF in whole blood from mild but not severe asthmatics were inhibited after prednisolone. There were no differences in myeloperoxidase or neutrophil elastase release from purified neutrophils.Because blood neutrophils in severe asthma are activated and are not inhibited by oral corticosteroids, they may be important in the pathogenesis of severe asthma. Inhaled corticosteroids, particularly in combination with long-acting β-agonists, are efficient in reducing symptoms and exacerbations. However, a proportion of patients with asthma are not controlled and have persistent symptoms, recurrent exacerbations and/or persistent airflow obstruction despite using high doses of inhaled corticosteroids, and often oral corticosteroids, and long-acting βdilators . This grdilators . There mdilators . The neudilators -7 Increadilators ,9. In addilators .Neutrophils may therefore be involved in the pathogenesis of asthma through their activation -13. NeutGlucocorticoids, an important treatment for asthma, exert inhibitory effects on neutrophil activation and functions such as chemotaxis, free radical generation, and adhesion -24. They20 < 4 mg/ml when baseline FEV1 was > 70%, or by demonstrating > 15% improvement in baseline FEV1 following inhalation of salbutamol (400 μg) when the FEV1 was < 70%. Normal subjects had no chest symptoms, with FEV1 > 90% predicted. All subjects were non-smokers and have never smoked previously, and asthmatics were stable with no changes in asthma symptoms and medication for at least one month, except for the use of short-acting inhaled β2 agonists. No subject had a history of an upper respiratory tract infection within the previous 6 weeks.We studied 10 patients with mild asthma, 10 with moderate-to-severe asthma, 10 severe steroid-dependent asthmatics, and 10 healthy non-asthmatic volunteers  via a metered-dose inhaler, but not requiring chronic oral prednisolone therapy. Severe steroid-dependent asthmatics were defined as having persistent symptoms with frequent exacerbations, limited physical activity and frequent night-time symptoms requiring high dose inhaled corticosteroids , and with maintenance oral prednisolone (> 5 mg per day for at least one year). The mean maintenance dose of oral prednisolone was 14 mg/day (range 10–20 mg/day).Mild asthmatics had symptoms less than once a week, requiring only a short-acting inhaled βDermatophagoides pteronyssinus, mixed grass pollen, and cat hair. FEV1 was measured with a calibrated, dry-wedge spirometer . All patients gave informed consent, and the study was approved by the Royal Brompton Hospital Ethics Committee.Atopic status was evaluated by skin prick tests to The effect of prednisolone on neutrophil function in peripheral blood was determined by treating mild asthma patients with prednisolone 30 mg/day for 1 week, and steroid-dependent patients with a dose of 30 mg/day added to their usual maintenance dose for one week. Blood samples were obtained before and on the day after the seventh dose of prednisolone had been taken. The study was not blinded or placebo-controlled, but the person analysing the cells ex-vivo was blinded to the treatment received by the asthmatics.Fluorescein isothiocyanate (FITC)-conjugated monoclonal antibodies directed against CD11b, CD62L (L-selectin), CD35 and CD18, along with the appropriate isotype controls  and phycoerythrin (PE)-conjugated CD16 monoclonal antibody  were added to heparinised whole blood (100 μl) at 4°C for 30 min in the dark. Cells were washed with phosphate-buffered saline  containing 0.5% bovine serum albumin  and 0.5% sodium azide . After centrifugation  the supernatant was discarded and 2 ml of freshly-prepared Erythrolyse  were added . Cells were then washed with 2 ml PBS-BA and centrifuged as above and resuspended in 0.5 ml of 0.5% paraformaldehyde .-7M, Sigma Aldridge, Poole, UK) for 10 min at 37°C. The reaction was stopped by adding cold PBS solution. The tubes were then centrifuged for 5 min at 1800 rpm and the supernatant discarded. Blood was then incubated with conjugated monoclonal antibodies.Blood was incubated with N-formyl-methionyl-leucine-phenylalanine (FMLP 10+) or eosinophil (CD16-) populations and reflected into a histogram so that cells can be labelled with a further fluorochrome (eg. CD11b or CD18). Results were recorded as mean fluorescence intensity (MFI) which represents the cell surface receptor density.Flow cytometry was performed using a FACScan analyser  with Argon-ion laser. Fluorescence gain was adjusted using a gate drawn around the granulocyte population on an unstained lysed whole blood sample, and then placing this population in the first log decade. Compensation was set by using blood incubated with either FITC- or PE-labelled monoclonal antibodies in order to correct for spectral overlap. As an instrumental control measure, CaliBRITE beads (Becton Dickinson) were used to ensure the correct alignment and calibration of the flow cytometer. Ten thousand events were collected from each sample. We used the method described by Gopinath et al for identification of neutrophils and eosinophils in lysed whole blood using side scatter and CD16 negativity . Granulo-3M, Molecular Probes, Upssala, Sweden), and the cells were incubated for 5 min at 37°C. Phorbol myristate acetate  was added for 20 min at 37°C. Reagent blank tubes were prepared by adding only PBS to the cell suspension, while resting cells were initially incubated with PBS, followed by the addition of dihydrorhodamine.Respiratory burst was measured according to the method of Rothe and Valet . BrieflyAfter the final incubation, samples (250 μl) were analysed immediately on the FACS scanner. The FACS machine was set up so that unstimulated cells were placed in the first log decade. DHR 123 reacts with hydrogen peroxide as a result of the respiratory burst to give rhodamine which emits a green fluorescence which was measured on the FL1 channel at a wavelength of 530 nm.2-rhodamine 110 . The samples were analysed on the flow cytometer after 20 min.Elastase was also measured according to the method described by Rothe and Valet . HBSS suVenous blood was collected in heparinized tubes and diluted 1:10 with RPMI 1640  containing 10% fetal calf serum (FCS), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM L-glutamine. The blood was distributed in 1 ml wells and the plates were incubated at 37°C with 5% CO2 for 24 hours. In addition, in duplicate wells, diluted blood was stimulated with IL-1β , lipopolysaccharide (LPS 10 ng/ml), and GM-CSF (1 ng/ml) prior to incubation. The plates were then centrifuged at 1800 rpm for 5 minutes, following which the supernatants were removed and frozen at -70°C until analysed.++- and Mg++-free). Granulocytes (1 × 106/ml) were then added to 1 ml wells of a 48-well plate and incubated with IL-β (10 ng/ml) or PBS for 30 min, and incubated at 37°C under 5% CO2. After each time-point, the plates were centrifuged  following which the supernatant was withdrawn and stored at -70°C until analysed for MPO levels.Granulocytes were isolated by Ficoll-Hypaque gradient centrifugation of heparinised whole blood (20 ml). After centrifugation , all the layers above the red cells were removed and 10 ml PBS and 3 ml 3% Dextran T-500  were added. The supernatant was centrifuged and red cells were lysed by adding 2 ml 10% HBSS in distilled water for 20 seconds, following which excess HBSS (minimum 12 ml) was added and the contents of the tube mixed and centrifuged at 1800 rpm for 5 minutes. The cells were washed twice in HBSS  and neutrophil myeloperoxidase  concentrations were measured in the culture supernatants with specific immunoassay kits according to the manufacturer's instructions. The detection limit was 31.2 pg/ml for IL-8 and 1.6 ng/ml for MPO.in vitro were analysed by the Wilcoxon signed-rank test. A p value of 0.05 or less was considered to be statistically significant.Unless otherwise stated, data are expressed as mean ± standard error of the mean (SEM). Differences in surface marker expression between groups were evaluated using Kruskall Wallis test. Differences between each of the groups and controls were evaluated using the Mann-Whitney U-test, with application of Bonferroni correction. The effects of prednisolone therapy or of the stimulation with various stimulants In unstimulated blood, there was an increased expression of CD35 and CD11b on neutrophils in patients with severe steroid-dependent asthma compared to mild and moderate-to-severe asthmatics, and non-asthmatic volunteers (p < 0.05). There were no significant differences in the expression of CD62L or CD18 between the groups . The oxidative burst in mild asthmatics was greater than that in normal subjects (p = 0.02), while similar levels of oxidative burst were seen between normal subjects and severe asthma patients Fig . After pIn unstimulated blood, IL-8 was not detectable in serum in patients with mild or severe asthma but after 24 hours, IL-8 was detectable. IL-8 levels from mild asthmatics were not significantly elevated after stimulation with IL-1β, LPS, and GM-CSF compared to severe asthmatics. In the mild group, however, there was a significant decrease in IL-8 production induced by IL-1β, LPS and GM-CSF following prednisolone therapy; this effect of prednisolone was not seen in the severe group Fig . There wFlow cytometric analysis of whole blood showed no difference in the baseline level of neutrophil elastase between mild or severe asthmatics, and there was no significant effect of prednisolone on these levels. No significant difference was seen in the baseline or IL-β-stimulated MPO levels in purified blood neutrophils between the mild and severe asthmatics. There was no significant effect of prednisolone on the MPO levels in either group.We determined whether circulating neutrophils in patients with severe asthma exhibited evidence of activation in terms of expression of surface markers or mediator release. CD35 and CD11b expression was higher on resting peripheral blood neutrophils in severe steroid-dependent asthmatics compared to normal and mild asthmatics, suggesting that neutrophils are in a more activated state in the circulation of severe asthmatics. In addition, CD35 expression on neutrophils from severe asthmatics was increased further above that seen in normal patients following stimulation of whole blood with fMLP. No difference in the expression of these surface molecules was seen on eosinophils in any of the groups.In previous studies of neutrophil surface marker expression in asthma, no differences in expression of CD11b and CD62L had been observed compared to non-asthmatic controls , althougThe cause of the increase in CD35 and CD11b expression on neutrophils from patients with severe asthma is unclear. One confounding factor is that the patients with severe asthma were on chronic oral prednisolone therapy which can induce blood neutrophilia attributable to bone marrow release of neutrophils, and also to mobilisation of a marginating blood pool ,34. PredOne of the problems of doing comparative studies of these groups of asthmatic patients separated according to disease severity is that the severe group is usually on chronic prednisolone therapy and it is difficult to exclude the effects of such therapy on neutrophil function in the severe asthma group as accounting for any observed differences. For this reason, we have studied the effect of a course of high dose prednisolone on blood neutrophil function, albeit for only one week.We found no effect of prednisolone on the expression of CD11b, CD62L, CD35 or CD18 in severe asthma, while, in mild asthma, prednisolone caused a significant decrease in CD62L expression without affecting the expression of CD35, CD11b and CD18. Thus, while the expression of CD62L by prednisolone was suppressed in mild asthma, this was not the case in severe asthma. Our observation in mild asthma patients is consistent with two reports of reduction in CD62L expression following intravenous dexamethasone in normal individuals ,37; simiIn addition to the loss of the effect of prednisolone on neutrophil surface markers in severe asthma, there was also lack of inhibition on the stimulated release of IL-8, and oxidative burst. Levels of IL-8 after whole blood culture were not significantly different between mild and severe steroid-dependent asthmatics, but IL-8 levels from severe patients were less readily suppressed after a course of prednisolone compared to mild asthmatics. It must be noted that although neutrophils stimulated with IL-1β, LPS and GM-CSF may be an important source of IL-8, other cells such as monocytes may also be contributory. We conclude that either of these cells were likely to represent the site of reduced corticosteroid responsiveness seen in the blood samples of patients with severe asthma.The oxidative burst activity of neutrophils was greater in mild asthmatics compared to normal patients and severe asthma patients. Furthermore, prednisolone decreased oxidative burst activity in neutrophils from mild asthmatics, as reported previously in isolated bovine neutrophils , but thein vitro, no difference was seen in the basal or IL-1β stimulated myeloperoxidase release from purified granulocytes between normal, mild, or severe asthmatics. The isolation procedure itself may alter the neutrophil to such an extent as to abolish any differences in activation. Monocytes are a source of myeloperoxidase but we have not studied monocytes in this study. No difference was seen in peripheral blood neutrophil elastase levels between mild and severe asthmatics using a flow cytometric method of analysis. Increased levels of neutrophil elastase have been reported in sputum from asthmatics with an exacerbation due to a respiratory tract infection [In comparison to whole blood release, when neutrophils were purified and studied nfection , and in nfection ,9.What is the relevance of our findings on circulating blood neutrophils and on the pathophysiology of the airways of severe asthma? The lack of inhibition of CD62L expression and of the release of reactive oxygen species and IL-8 by prednisolone may explain why there may be ongoing inflammation and asthma in patients with severe asthma. Heightened expression of CD62L may increase the ability of the neutrophil to transmigrate from the circulation into the airway submucosa. Interestingly, the ability of prednisolone to suppress the eosinophil expression of CD11b and CD62L in severe asthma would indicate that eosinophils may be less likely to contribute to the pathophysiological changes in the airways. The lack of inhibition of IL-8 release would also lead to increased neutrophilic inflammation since IL-8 is considered to be an important molecule for the development of neutrophuilic inflammation in asthma. Concentrations of IL-8 are correlated with neutrophil accumulation in asthmatic airways , and IL-Why is the blood neutrophil less responsive to corticosteroids? Previous studies on circulating blood cells have focused on the peripheral blood mononuclear cell as being the site of corticosteroid resistance ,46. DecrThe circulating neutrophil in severe asthma shows evidence of activation, as measured by the increased expression of the adhesion molecules, CD11b and CD35, and of resistance to the effects of prednisolone. The neutrophil may be an important contributor to the inflammatory process in severe asthma, and further studies are needed on lung neutrophils to support this notion. The mechanism of loss of corticosteroid inhibition of neutrophils in severe asthma is not known and deserves further study.The author(s) declare that they have no competing interests.KFC designed the project, BSM carried out all the studies and both wrote up the manuscript.


Previous studies have linked smaller kidney dimensions to increased blood pressure. However, patients with Balkan Endemic Nephropathy (BEN), whose kidneys shrink during the course of the disease, do not manifest increased blood pressure. The authors evaluated the relationship between kidney cortex width, kidney length, and blood pressure in the offspring of BEN patients and controls.102 offspring of BEN patients and 99 control offspring of non-BEN hospital patients in the Vratza District, Bulgaria, were enrolled in a prospective study and examined twice (2003/04 and 2004/05). Kidney dimensions were determined using ultrasound, blood pressure was measured, and medical information was collected. The parental disease of BEN was categorized into three groups: mother, father, or both parents. Repeated measurements were analyzed with mixed regression models.In all participants, a decrease in minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg (p = 0.005). There was no association between kidney length and blood pressure. A maternal history of BEN was associated with an increase in systolic blood pressure of 6.7 mm Hg (p = 0.03); paternal BEN, +3.2 mm Hg (p = 0.35); or both parents affected, +9.9 mm Hg (p = 0.002). There was a similar relation of kidney cortex width and parental history of BEN with pulse pressure; however, no association with diastolic blood pressure was found.In BEN and control offspring, a smaller kidney cortex width predisposed to higher blood pressure. Unexpectedly, a maternal history of BEN was associated with average increased systolic blood pressure in offspring. There is a large body of evidence that patients with Balkan Endemic Nephropathy (BEN), in contrast to other chronic kidney diseases ,2, do noWe conducted a prospective study in the Vratza District of Bulgaria, a rural area, and measured the kidney cortex width, kidney length, and blood pressure of the offspring of BEN patients and control offspring at two time points, one year apart. We hypothesize the following:- A smaller kidney cortex width is related to a higher average systolic blood pressure and a higher pulse pressure.- An offspring with parental history of BEN has a higher average systolic blood pressure and a higher pulse pressure.In the period of October, 2003, to April, 2004, we recruited adult offspring (102 study subjects) whose father and/or mother were included in the Vratza Hospital registry of BEN patients in 2001 and who resided in one of three communities . The diagnosis of BEN in the parent generation is based on three groups of criteria: epidemiological, clinical/laboratory, and pathological/anatomical /3600)To test the hypothesis that offspring of BEN parents have increased blood pressure, we grouped parental disease status into three groups: mother, father, or both parents affected. None of the comparison offspring fell into any of these groups (reference). The effect of cortex width and parental BEN status was tested in the same model.In order to estimate the association of minimal kidney width and parental history of BEN with blood pressure based on repeated measurements, we applied linear mixed models. Measurements of the two investigations are not independent and mixed models allow adjusting for within-participant effects . The mixTo compare the agreement between measurements of continuous variables in 2003/04 and 2004/05 we used the intra-class correlation coefficient (ICC). This is the between-subject minus the within-subject variance divided by the sum of the two variances. The ICC quantifies the proportion of total outcome variance that is due to inter-individual variation.Of the 201 participants in the first investigations (2003/04), 189 participated in the follow-up . Two were deceased, one moved out of the area, two could not be contacted, and 7 decided not to participate further. Of the 12 lost, 9 were offspring of BEN patients. Potential risk factors show similar distributions in each of the two investigations . When analyzing blood pressure differences while controlling for confounders, cortex width and parental BEN status had significant effects on systolic and pulse pressure, but not on diastolic blood pressure. A decrease in the minimal kidney cortex of 1 mm was linearly related to an increase in systolic blood pressure of 1.4 mm Hg (p = 0.005) and an increase of pulse pressure of 1.1 mm Hg (p = 0.002).Figure A maternal history of BEN was associated with an increased systolic blood pressure in offspring of 6.7 mm Hg (p = 0.03), and when both parents had BEN, an increased systolic blood pressure of 9.9 mm Hg (p = 0.002). There was no statistically significant effect of a paternal history of BEN.To investigate whether the use of antihypertensive medication had distorted our findings, we repeated the model excluding those observations with antihypertensive drug use. This reduced the number of repeated observation from 388 to 322 (176 subjects), but did not change our findings.Our findings show that a decrease of the minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg. There was no association between kidney length and blood pressure. A maternal history of BEN was associated with a significant increase in systolic blood pressure of 6.7 mm Hg, paternal BEN with a non-significant increase of 3.2 mm Hg, and both parents affected, a significant increase of 9.9 mm Hg. The lack of association of either kidney cortex width or a parental history of BEN with diastolic blood pressure may either stem from the larger individual variance of this parameter or may indicate that there is no such link.In a study with healthy volunteers in England, Raman et al. did not identify a clear pattern between measurements of the right and left kidneys and blood pressure . In anotFor adult Aboriginals in Australia, Singh et al. found that a 10 mL decrease in kidney volume was associated with a 0.5 mm Hg increase in systolic blood pressure . The stuMackenzie et al. posited the hypothesis that the total nephron supply at birth is a factor in determining a susceptibility to increased blood pressure . Given tHence, a maternal history of BEN may have both a direct and an indirect effect on blood pressure in offspring. Indirectly, maternal BEN seems to decrease kidney cortex width, which in turn increases blood pressure in adult offspring. Directly, maternal BEN seems to initiate regulations likely to raise the average blood pressure in affected offspring. However, hypertension is not a predominant feature in BEN offspring. Thus, it is unlikely that the reduction in kidney cortex width in BEN offspring results from hypertension.Renal mass is considered to contribute directly to the development and maintenance of hypertension ,19,28. AHowever, in BEN patients, whose kidneys shrink, the lack of increased blood pressure has been considered to be a typical characteristic before the disease reaches its final stage -9. The rSince our data is based on adult offspring, we are uncertain about the future development of blood pressure in this group. There are three possibilities: (I) Offspring of BEN patients will not develop BEN but maternal BEN may lead to subclinical changes such as an increase in average blood pressure. An argument against this option is that we have found reduced kidney sizes and increased protein excretion in the BEN offspring, which may be considered as early signs of BEN . (II) BEWe found that adult offspring of BEN patients have an average increased blood systolic pressure and pulse pressure, determined in two repeated measurement one year apart. This is contrary to reports in BEN patients, who do not have this characteristic. Surprisingly, the increase was related to a maternal history of BEN, or a history of BEN in both parents, but not to a paternal history alone. Increased blood pressure was also associated with a reduction of the minimal width of the kidney cortex, but not with a reduction in kidney length. In our understanding, these findings emphasize the role of maternal priming in determining susceptibility for increased blood pressure. Balkan endemic nephropathy may serve as a model to better understand the development of both kidney disorders and their related blood pressures.The author(s) declare that they have no competing interests.PSD developed and designed the study and helped write the report. SDT assisted in analyzing the data, literature review, and writing the discussion. RBG conducted the analyses of lead in blood, and assisted in writing the discussion. VAS conducted the clinical examinations of the study subjects and contributed to the interpretation. AGB conducted the ultrasound examinations of the study subjects and contributed to the interpretation. WJK helped design the study and conducted the statistical analysis and worked on the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The risk factors for progression of chronic kidney disease (CKD) in type 2 diabetes mellitus (DM) have not been fully elucidated. Although uncontrolled blood pressure (BP) is known to be deleterious, other factors may become more important once BP is treated.All patients seen in the outpatient clinics of our hospital between January 1993 and September 2002 with type 2 DM and clinical evidence of CKD were evaluated. Progression of kidney disease was evaluated by rate of decline of glomerular filtration rate (GFR) as estimated from the simplified MDRD formula. Variables associated with progression in univariate analyses were examined by multivariate analysis to determine the factors independently associated with kidney disease progression.2-1 yr-1 (range -14 to +32). Low initial serum albumin (p < 0.001), black race (p < 0.001), and degree of proteinuria (p = 0.002), but not blood pressure, glycated hemoglobin, or serum cholesterol, were independently associated with progression.343 patients  were studied. Mean BP, glycated hemoglobin, and serum cholesterol during the study period were 138/72 mmHg, 8.1%, and 4.8 mmol/L, respectively. Mean decline of GFR was 4.5 ml min-1 1.73 mIn a cohort of diabetic patients with CKD in whom mean BP was < 140/80 mmHg, the potentially remediable factors hypoalbuminemia and proteinuria but not blood pressure were independently associated with progression of kidney disease. Further understanding of the relationship between these factors and kidney disease progression may lead to beneficial therapies in such patients. Diabetic nephropathy is the most common cause of end-stage kidney disease (ESKD) in the United States and worldwide. Most diabetic patients with ESKD have type 2 diabetes. Since only a minority of type 2 diabetic patients develop kidney disease, predisposing factors for development of the disease are operative. In addition, once clinical kidney disease is evident, the rate of decline of glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20 ml min-1 yr-1 . Blood pThe purpose of the present study was to determine the factors independently associated with chronic kidney disease (CKD) progression assessed by rate of decline of GFR in a cohort of male predominantly elderly veteran patients with type 2 diabetes. In this population, in whom BP was generally well controlled, hypoalbuminemia, black race, and degree of proteinuria, but not blood pressure, were associated with disease progression.2-1) = 186 × (SCr)-1.154 × (age)-0.203 ×  × (1.210 if black)]; b) chronic kidney insufficiency, defined by a persistent elevation of serum creatinine (SCr) level; at least 3 serum creatinine values of > 124 μmol/L with at least a six-month interval between the first and last serum creatinine value were required for inclusion; c) proteinuria [positive urine dipstick or urine protein > 0.15 g/d or urine albumin/creatinine ratio ≥ 30 mg/g]. GFR was calculated using the simplified MDRD formula [GFR (ml min-1 1.73 m2) was then calculated using the weight and height values. Race was self-reported. Blood pressure was measured at each clinic visit by a medical technician or a nurse  in the seated position using a mercury sphygmomanometer. Glycated hemoglobin was measured by high performance liquid chromatography. Hemoglobin values were measured by Coulter counter. Serum values of creatinine, cholesterol, and albumin were measured by automated analyzer. Urinary protein was measured by the pyrogallol red-molybdate method and urinary albumin by immunoturbidemetry. The degree of proteinuria was classified as mild, moderate, or heavy. Mild proteinuria was defined as dipstick trace-0.3 g/L and/or protein 0.15–0.5 g/d and/or spot urine albumin/creatinine ratio of 30–300 mg/g; moderate proteinuria was defined as dipstick 1.0 g/L and/or protein 0.5–3.0 g/d and/or spot urine albumin/creatinine ratio of 300–2000 mg/g; and heavy proteinuria was defined as dipstick 3.0 g/L and/or protein > 3.0 g/d and/or spot urine albumin/creatinine ratio of > 2000 mg/g.Information on age, race, weight, height, use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), blood pressure, glycated hemoglobin, serum cholesterol, hemoglobin, serum albumin, and urine protein excretion was obtained from the computerized patient record system. Age, weight (kg) and height (m) were defined as the recorded values at the time of the first laboratory creatinine measurement > 124 μmol/L. Body mass index (BMI) , initial hemoglobin and serum albumin values  were used. Univariate analyses were performed using t-test for continuous variables and Chi-square analysis for categorical variables. Multivariate linear regression analyses using rate of decline (slope) of GFR as the dependent variable were then performed in both age-adjusted and non-age-adjusted fashion using an automated backwards elimination procedure to delete factors with a P-value > 0.15 from the model one at a time. Multivariate analyses were performed using all variables as well as using only those variables found to be significantly associated with progression on univariate analysis.Data are expressed as mean ± SD. All P values were two sided and a P value of <0.05 was used to indicate statistical significance. Statistical analyses were performed using Systat software .This study complied with the recommendations of the Declaration of Helsinki and was approved by the local Institutional Review Board.Demographic and clinical variables in the 343 patients who met study criteria are given in Table 2-1 yr-1 (range -14 to +32). The variables most highly associated with progression on univariate analysis were lower initial serum albumin and greater degree of proteinuria (p < 0.001), followed by younger age and black race (p = 0.002), higher glycated hemoglobin (p = 0.007), higher mean diastolic blood pressure (p = 0.012), lower initial hemoglobin (p = 0.014), and higher systolic blood pressure (p = 0.048) 2 were entered into the regression equation, neither was significantly associated with BP decline (p = 0.943 for diastolic BP and p = 0.935 for (diastolic BP)2). In addition, systolic blood pressure and glycated hemoglobin were not independently associated with progression in this analysis. Lower initial serum albumin, black race, and degree of proteinuria were the only variables independently associated with progression at the p < 0.05 level As regression diagnostics for data from two of the patients indicated high leverage and one was an outlier  in the linear regression model, further analyses were performed excluding these cases. The results were not changed after exclusion of these cases, with initial serum albumin (p = 0.001), proteinuria (p = 0.002) and black race (p = 0.003) the only significant variables independently associated with GFR decline.2 were examined in the multivariate regression analyses. In these analyses, there was no independent association between systolic BP or either diastolic BP or (diastolic BP)2 and rate of GFR decline in this population.The most important finding of this study is that the potentially modifiable factors hypoalbuminemia and proteinuria were strongly and independently associated with kidney disease progression in a mostly elderly male type 2 diabetic population with generally well-controlled blood pressure. As shown in Figure Blood pressure control is known to be important in preventing adverse cardiovascular and renal outcomes in diabetic patients . HoweverA recent observational study from Japan investigated factors affecting progression of kidney failure in type 2 diabetic patients . In thisThe results of our study indicate that hypoalbuminemia independently predicted GFR decline. In a study investigating the relationship between blood pressure and diabetic kidney disease progression, Dillon  found thWhy would hypoalbuminemia be predictive of kidney disease progression? One possibility is that the serum albumin level reflects the degree of proteinuria, a known risk factor for progression in most kidney diseases, including diabetes ,21-27. HAs has been done by other investigators ,16,18, wWe included patients who had the diagnosis of diabetes mellitus and/or mean glycated hemoglobin values > 6.5% in our analysis. We did not utilize blood glucose values for study inclusion or for analysis since it was not always possible to determine if a sample was a fasting or random sample. We did not find an association between blood glucose control (as reflected by glycated hemoglobin) and progression in our study. The role of hyperglycemia in progression of nephropathy in type 2 diabetes is not clear, in large part because many studies have lacked statistical power. However, in post-hoc analyses of two large clinical trials, RENAAL  and IDNT2-1 and/or if the serum creatinine concentration is not calibrated to MDRD laboratory creatinine values [2-1. Moreover, the National Kidney Foundation currently recommends using this prediction equation to calculate GFR and monitor progression of kidney disease [The observational nature of our study does have limitations. For instance, there was no control over the type of medication used for hypertension, nor any control over diabetes management or dietary intake. We utilized a formula to estimate rate of GFR decline instead of performing direct clearance measurements. The formula utilized, namely the four-variable MDRD estimate, was developed from a largely non-diabetic patient population. Moreover, this formula loses accuracy when the GFR is > 60 ml min-1 1.73 me values . However disease . Indeed,The results of our study may have important clinical implications. Although blood pressure control is undeniably important in delaying progression of kidney disease in hypertensive diabetic patients, attention to other potentially remediable factors may be more important in delaying progression once BP is effectively treated. Antiproteinuric agents (such as ACE inhibitors and ARBs) may exert beneficial actions beyond those due to BP control. In addition, the finding that hypoalbuminemia is independently associated with progression of CKD due to type 2 diabetes after adjustment for the effects of proteinuria suggests the possibility that inflammation  may be a progression promoter. In particular, further understanding of the role of inflammation in CKD may lead to therapies which favorably affect kidney disease progression in type 2 diabetic patients.The author(s) declare that they have no competing interests.DJL conceived and designed the study, supervised data collection, carried out the statistical analyses, and prepared the manuscript. HJK assisted in statistical analyses and manuscript preparation. TMD, MPC, and MAI collected data and prepared the spreadsheet for data analysis.The pre-publication history for this paper can be accessed here:


Blood pressure measurements frequently guide management in critical care. Direct readings, commonly from a major artery, are considered to be the gold standard. Because arterial cannulation is associated with risks, alternative noninvasive blood pressure (NIBP) measurements are routinely used. However, the accuracy of NIBP determinations in overweight patients in the outpatient setting is variable, and little is known about critically ill patients. This prospective, observational study was performed to compare direct intra-arterial blood pressure (IABP) with NIBP measurements obtained using auscultatory and oscillometric methods in overweight patients admitted to our medical intensive care unit.2 or greater and a functional arterial line (assessed using the rapid flush test) were enrolled in the study. IABP measurements were compared with those obtained noninvasively. A calibrated aneroid manometer (auscultatory technique) with arm cuffs compatible with arm sizes and a NIBP monitor (oscillometric technique) were used for NIBP measurements. Agreement between methods was assessed using Bland-Altman analysis.Adult critically ill patients with a body mass index (BMI) of 25 kg/m2. Mean arm circumference was 32 ± 0.6 cm. IABP readings were obtained from the radial artery in all patients. Only eight patients were receiving vasoactive medications. Mean overall biases for the auscultatory and oscillometric techniques were 4.1 ± 1.9 and -8.0 ± 1.7 mmHg, respectively (P < 0.0001), with wide limits of agreement. The overestimation of blood pressure using the auscultatory technique was more important in patients with a BMI of 30 kg/m2 or greater. In hypertensive patients both NIBP methods underestimated blood pressure as determined using direct IABP measurement.Fifty-four patients  with a mean (± standard error) age of 57 ± 3 years were studied. The mean BMI was 34.0 ± 1.4 kg/mOscillometric blood pressure measurements underestimated IABP readings regardless of patient BMI. Auscultatory measurements were also inaccurate, tending to underestimate systolic blood pressure and overestimate mean arterial and diastolic blood pressure. NIBP can be inaccurate among overweight critically ill patients and lead to erroneous interpretations of blood pressure. Although the prevalence of critically ill, morbidly obese patients in the USA is not known, it has been estimated that the incidence of morbidly obese patients requiring intensive care treatment approaches 14 cases per 1,000 intensive care unit (ICU) admissions each year. This is probably a conservative estimate, considering that the database was restricted to nonsurgical patients and the growing number of bariatric surgeries performed in the USA . DiscrepBecause of the frequent need for prolonged monitoring of blood pressure among critically ill patients, automated oscillometric NIBP measurements are commonly used in the ICU ,4. SourcThe present observational clinical study was conducted to test the hypothesis that IABP measurements are not accurately reflected by NIBP measurements in a population of overweight critically ill patients. We also assessed the effects of different body mass index (BMI) and blood pressure levels on the accuracy of the NIBP measurements when compared with direct IABP readings.2 or greater who required continuous blood pressure monitoring because of their underlying clinical condition and who agreed to participate in the study were included. None of the patients received an intra-arterial catheter purely for the purposes of the present study. Patients with any of the following criteria/conditions were excluded: BMI below 25 kg/m2; unwillingness to participate in the study; unstable IABP readings (more than 5 mmHg variation in mean blood pressure during the period of data collection); presence of edema, wounds, or arm skin or subcutaneous tissue infection; presence of a peripherally inserted central catheter in one arm; and nonfunctional arterial catheter (defined as presence of overshooting or undershooting phenomenon following rapid flush test) [The study protocol was approved by the Wayne State University investigational review board. All patients admitted to the medical ICU with a BMI of 25 kg/msh test) .Each patient's height, weight, and arm circumferences at the mid-arm level were recorded. After being in a steady, supine position, auscultatory and oscillometric blood pressure measurements were obtained from the arm into which the arterial catheter was inserted . The corArterial catheterization was performed by the primary team according to their determination of the clinical indication. A 20-gauge radial artery set  was used for continuous IABP monitoring. The sets were connected to a disposable pressure transducer  using rigid pressure tubing of identical length. The transducer set system was set up by the critical care nurse and checked by the investigators in all cases. Air bubbles were flushed carefully from the system before data collection. To test the adequacy of the pressure monitoring system, a rapid flush test was performed and recorded for each patient . The zerOscillometric measurements were obtained using a Hewlett-Packard monitor (model 66) and nondisposable blood pressure cuffs  models M4554A, M1575A, and M1576A to match arm circumferences ranging from 20.5 to 28.5 cm, from 34 to 43 cm, and from 42 to 54 cm, respectively. Auscultatory measurements were obtained using an aneroid manometer  with reusable blood pressure cuffs  matching the patients' arm circumferences. Standard recommendations for cuff bladder length-to-width ratio and technical details and cautions before and during measurements were strictly followed ,12. All 2, ≤30 kg/m2, and >30 kg/m2; and systolic blood pressure below or above 140 mmHg for each NIBP method. A two tailed P value of less than 0.05 was considered statistically significant.Unless stated otherwise, summary values are expressed as mean ± standard error. Different methods of blood pressure measurement were compared by Bland-Altman analysis . Unpaire2 (range 25–87.2 kg/m2) and mean arm circumference was 32.4 ± 0.6 cm (right and left arms were similar). An adult size cuff (suitable for arm circumferences <42 cm) was used in all but seven patients, in whom a large cuff was used based on their arm circumferences (41.6 ± 1.5 cm). All direct IABP measurements were obtained from radial lines, and only eight patients were receiving vasoactive medications during data collection.Fifty-four patients  with mean age 57 ± 3 years who were admitted to the medical ICU requiring invasive blood pressure monitoring were included in the study. Mean BMI was 34.0 ± 1.4 kg/mP < 0.0001), with limits of agreement ranging from +53.0 to -44.6 mmHg and from +33.6 to -49.5 mmHg for auscultatory and oscillometric methods, respectively. Most of the points below the lower limit of agreement seen in both plots represent patients who were receiving vasopressor infusions. Discrepancies according to arterial blood pressure levels are shown in Table Plots of agreement between the auscultatory and oscillometric methods and IABP measurements  are shown in Figure 2 and >30 kg/m2, respectively (P < 0.05), whereas measurements were similar for the oscillatory method regardless of BMI. Table Figure P < 0.001). On the other hand, mean bias was positive for both NIBP methods in patients with normal blood pressure.The effects of blood pressure levels on accuracy of NIBP measurements are shown in Figure Accurate measurement of arterial blood pressure is essential for rational hemodynamic management of critically ill patients. Morbidly obese patients requiring intensive care treatment are becoming increasingly common and, because of their body size and habitus, it is unclear whether invasive and noninvasive blood pressure measurements could be used interchangeably. Our data suggest that a wide discrepancy exists between blood pressure monitoring methods, supporting the use of direct intra-arterial methods in monitoring and to guide treatment decisions because of their accuracy.Oscillometric measurements underestimated direct intra-arterial readings, and although this was observed for all levels of blood pressure the negative bias was larger for systolic blood pressure measurements. Although our study focused on overweight critically ill patients, these findings are in agreement with those of previously reported trials conducted in different patient populations ,14,15. BThe mean bias for the auscultatory technique was 4.2 mmHg, but when broken down for each level of pressure our data are consistent with previous observations, namely that auscultatory measurements underestimate systolic and overestimated diastolic blood pressure readings ,7,8. The2 had little impact on the overall findings. Oscillometric measurements consistently underestimated direct blood pressure measurements. On the other hand, our findings are in agreement with those of previous investigations demonstrating that auscultatory readings overestimated diastolic blood pressure [2. Although hypothetical, an inability to properly position the blood pressure cuff in these large patients might have resulted in a bad signal/noise ratio, which could account for these findings [BMI above 30 kg/mpressure ,8. Mean findings .Arterial hypertension increased the negative bias for systolic blood pressure measurements for both noninvasive monitoring methods. This observation has been reported for the auscultatory technique ,8 and apAlthough widely used, automated oscillometric measurements of blood pressure were inaccurate in this subset of critically ill patients, and the parameters obtained should be used cautiously. When critical therapeutic decisions are required, IABP monitoring may be the preferred monitoring method.• NIBP measurements are inaccurate among overweight critically ill patients.• Oscillometric NIBP measures underestimates blood pressure as determined using the direct IABP technique.• When critical therapeutic decisions are required, IABP monitoring is the preferred monitoring method.BMI = body mass index; IABP = intra-arterial blood pressure; ICU = intensive care unit; NIBP = noninvasive blood pressure.The authors declare that they have no competing interests.AA was involved in design, data collection, and manuscript preparation. JB was involved in manuscript drafting and critical revisions. JG was involved in data analysis and interpretation, manuscript drafting, and critical manuscript revisions. All authors read and approved the final manuscript.


Asthma is one of the most common chronic diseases and a major economical burden to families and health systems. Whereas efficacy of current therapeutical options has been clearly established, cost-effectiveness analysis of public health interventions for asthma control are scarce.81 patients with severe asthma (12–75 years) joining a programme in a reference clinic providing free asthma medication were asked retrospectively about costs and events in the previous 12 months. During 12 months after joining the programme, information on direct and indirect costs, asthma control by lung function, symptoms and quality of life were collected. The information obtained was used to estimate cost-effectiveness of the intervention as compared to usual public health asthma management. Sensitivity analysis was conducted.64 patients concluded the study. During the 12-months follow-up within the programme, patients had 5 fewer days of hospitalization and 68 fewer visits to emergency/non scheduled medical visits per year, on average. Asthma control scores improved by 50% and quality of life by 74%. The annual saving in public resources was US$387 per patient. Family annual income increased US$512, and family costs were reduced by US$733.A programme for control of severe asthma in a developing country can reduce morbidity, improve quality of life and save resources from the health system and patients families. The prevalence of asthma is increasing in many countries ,2. This The primary aim of persistent asthma management is to gain symptom control, by monitoring clinical manifestations of airway inflammation and regular use of inhaled corticosteroids ,4. But tBrazil has a high prevalence of asthma, with estimated 10 million people suffering from the disease . In SalvResources for public health actions are always limited, and therefore it is crucial for policy makers , to haveThis programme was organized by Federal University of Bahia Medical School and obtained operational support from the Unified Health Service . ProAR Eighty-one patients with severe asthma, from 12 to 75 years old, living in Salvador and its metropolitan area, were consecutively selected from those attending regularly the referral clinic for ProAR. To be included in the study, patients were required to have more than one year of severe asthma according to the classification by the Global Initiative for Asthma [This is a "before and after study" (pre-post study) of 81 patients with severe asthma, managed in ProAR. The objective was to compare the cost-effectiveness, for families and the public health system, of two strategies for severe asthma management of the same patients: the regular asthma care available in the Salvador public health system they used before joining ProAR and that offered by ProAR. The analysis considered the management of asthma one year before and one year after admission to ProAR.Figure In order to compare the cost-effectiveness of treatment of severe asthma for the two strategies , the costs for the public health system, for ProAR and for the families were estimated using accounting procedures. All these costs have been brought up to values at the time of the main analysis (February 2006) and the necessary depreciation estimated.Costs were estimated for the public health system and for ProAR: health related direct costs for each patient, before and after their inclusion on the programme. The costs of outpatient care within the year before intervention, comprising doctor's visits, medications and diagnostic tests were calculated based on patient' retrospective information and using government official reimbursement values and pharmaceutical retail price. The costs of hospitalization, emergency room visits, and intensive care unit admissions, both after and before joining ProAR, were estimated based in Health Department of State of Bahia databases and public and charity hospitals' financial department surveys. To estimate the average cost of a day of hospitalization for a case of asthma we took into account the average total direct costs with hostelry , the number of total patients and the proportion of patients with asthma hospitalized per year, and the costs of specific asthma medication. The costs of ambulatory health care in ProAR were estimated as follows: the total annual stable costs with current regular expenses , office and medical supplies, communications and staff, divided by the total number of patients admitted, to obtain the cost per patient/year. The variable costs were estimated by analyzing individual expenses with diagnosis and treatment.- family's direct and indirect costs were estimated by using the Asthma Family's Costs Questionnaire (AFCQ), which collects information on the costs incurred by the families due to asthma treatment of a family member. This was adapted from a questionnaire previously created to estimate family costs of tuberculosis in Brazil [Family costsn Brazil . The AFCn Brazil  and deta- the analysis was conducted to compare two treatment strategies for severe asthma. The first one is the regular treatment offered by the public health system in Salvador, in which patients received treatment only to control exacerbations with no regular inhaled or oral preventive medications or regular follow up. The second approach, in the same patients, after admission to ProAR and being followed prospectively for one year receiving multiprofessional regular care, free inhaled preventive medication and educational sessions. The effectiveness of the intervention was measured as "hospitalizations avoided" by the programme. Cost-effectiveness incremental analysis was performed by comparing the costs and health results, dividing the difference in costs per the difference of health results obtained on each strategy [Cost-effectiveness analysis strategy .Sensitivity analysis – this was carried out to ascertain the reliability of the cost-effectiveness analysis under varied assumptions regarding costs of health care. We challenged our main findings by repeating the cost-effectiveness analysis while changing the estimated hospitalization cost from our real life calculus to what was reimbursed to the State or City Departments from the Ministry of Health, which was 76% less .The sample size was calculated by Stats Direct 7.0 software considering the estimated ProAR intervention effect of reducing hospitalizations during one year, as compared to the year before. Hospitalizations are an important parameter to assess asthma control, morbidity and costs . The min® and SPSS 11.5 spreadsheet for statistical analysis. Two tailed tests were carried out and p values lower than 0.05 considered statistically significant. The categorical variables were reported as proportions and compared with Chi-square Tests. All continuous variables were compared by using Wilcoxon Signed Rank Test [Data were entered onto a Microsoft Excelank Test .Most patients came from a poor socio economic stratum, having a median family income of US$ 2,768 per year. Many worked in the informal labor market and 14 (17%) were unemployed. They had low educational level: 68% had less than 5 years of schooling. The majority of patients were of mixed ethnicity, predominantly African origin and 68 (83%) were female. This is consistent with the literature . They haOf the 81 patients included, 64 (79%) concluded the study. In spite of the regular treatment offered, 3 (4%) patients died during the one year follow up. A total of fourteen (17%) patients did not complete the study. These patients had different characteristics from the compliers: they were younger, of a better socioeconomic status, had less comorbidity, and better access to private health care. Some noncompliers reported having left the programme because of the time spent in the regular visits answering our questionnaires.1. ACQ scores improved 29% and quality of life, as measured by mean overall AQLQ, improved 29% , the AQLQ and ACQ scores remained the same. After 3 months of medication, the scores reached significant improvement, and that was maintained until the end of the one-year follow up period.When comparing reported data for the year before registration in ProAR to the year after joining for the 64 patients that concluded the follow up, we found an increase in the use of inhaled corticosteroids, in scheduled specialist visits and spirometries performed and a substantial reduction in hospitalizations, in intensive care unit admissions and in emergency room visits/unscheduled consultations. Lung function improved 47% in PEF and 10% in FEVThe average duration of interviews was 30 minutes for AFCQ, 20 minutes for AQLQ and 10 minutes for ACQ. Nine percent of patients did not perform spirometries because of functional limitations and 5% did not answer the AQLQ because of insufficient intellectual ability.Table The evaluation of the burden of asthma in this sample of patients shows that when patients were treated in the usual public health system low socioeconomic strata families paid for 52% of the costs of severe asthma while the government paid 48%. This contrasts with patients registered in ProAR, with the poor families paid for only 17% of the costs of the management of severe asthma  were less responsive to changes in asthma control than ACQ scores, in this study, which is in agreement with previous reports.The success of asthma treatment in preventing exacerbations seems to be associated with regular adequate measures. Patients with scores of ACQ under 1.5 are considered under control  , and patient's education, is a more cost-effective alternative to manage severe asthma than the previous regular public health approach of treating exacerbations only. The reduction in government and family direct and indirect costs is so remarkable that it compensates all the costs involved in running the programme and supplying effective medicines, with incremental economy to the government and to families' budgets. And above that it has improved asthma control and asthma related quality of life. A well-structured programme for asthma control, focused in severe cases, can reduce morbidity, improve quality of life, and decrease health related costs in middle income countries.The author(s) declare that they have no competing interests.RF, AAC, MLB, and LCR designed the study, supervised field work, analyzed data, interpreted results, and wrote the paper; ACS designed the study and contributed to the analysis; HFN, CSM, EP and ASM did field work, interpreted results, and edited the paper; SL interpreted results and edited the paper.The pre-publication history for this paper can be accessed here: