Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults

BACKGROUND Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Interventions for asthma therapies have been traditionally based on symptoms and spirometry. OBJECTIVES To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was on 31 October 2006. SELECTION CRITERIA All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS Results of searches were reviewed against pre-determined criteria for inclusion. Three sets of reviewers selected relevant studies.Two review authors independently assessed trial quality extracted data. Authors were contacted for further information but none were received. Data was analysed as "treatment received" and sensitivity analyses performed. MAIN RESULTS Three adult studies were included; these studies were clinically and methodologically heterogenous (use of medications, cut off for percentage of sputum eosinophils and definition of asthma exacerbation). There were no eligible paediatric studies. Of 246 participants randomised, 221 completed the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms; pooled odds ratio (OR) was 0.49 (95% CI 0.28 to 0.87); number needed to treat to benefit (NNTB) was 6 (95% CI 4 to 32).There were also differences between groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids but the reduction in hospitalisations was not statistically significant. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was similar in both groups and no adverse events were reported. However sputum induction was not always possible. AUTHORS' CONCLUSIONS Tailored asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. This review supports the use of sputum eosinophils to tailor asthma therapy for adults with frequent exacerbations and severe asthma. Further studies need to be undertaken to strengthen these results and no conclusion can be drawn for children with asthma.

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults

Background The measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry. Objectives To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. Search methods We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was completed in February 2009. Selection criteria All randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). Data collection and analysis Results of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one. Main results Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). Authors' conclusions Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.

Effect of acarbose on biochemical responses and clinical symptoms in dumping syndrome

A dose of 50 mg of acarbose was administered with a standard breakfast to 13 subjects with dumping syndrome. Significant attenuation of hyperglycaemia (p less than 0.01) was observed, and rises in plasma gastric inhibitory polypeptide, insulin and enteroglycagon were reduced (p less than 0.05). Plasma levels of neurotensin, vasoactive intestinal polypeptide and somatostatin were not affected. Dumping score was reduced, but this did not achieve statistical significance. In a longer-term study, 9 patients took acarbose, 50 mg t.i.d., for 1 month. No significant reduction in the number or severity of dumping attacks was observed, but a majority expressed a preference for the drug and some individuals experienced a marked improvement of symptoms.

Vaginal Flora Alterations and Clinical Symptoms in Low-Risk Pregnant Women

Background: To evaluate associations between alterations in vaginal flora and clinical symptoms in low-risk pregnant women. Methods: Vaginal specimens from 245 pregnant women were analyzed by microscopy for vaginal flora. Signs and symptoms of vaginal infection were determined by patient interviews and gynecologic examinations. Results: Abnormal vaginal flora was identified in 45.7% of the subjects. The final clinical diagnoses were bacterial vaginosis (21.6%), vaginal candidosis (10.2%), intermediate vaginal flora (5.2%), aerobic vaginitis (2.9%), mixed flora (2.9%) and other abnormal findings (2.9%). The percentage of women with or without clinical signs or symptoms was not significantly different between these categories. The presence of vaginal odor or vaginal discharge characteristics was not diagnostic of any specific flora alteration; pruritus was highly associated with candidosis (p < 0.0001). Compared to women with normal flora, pruritus was more prevalent in women with candidosis (p < 0.0001), while vaginal odor was associated with bacterial vaginosis (p = 0.0026). Conclusion: The prevalence of atypical vaginal flora is common in our low-risk pregnant population and is not always associated with pathology. The occurrence of specific signs or symptoms does not always discriminate between women with different types of atypical vaginal flora or between those with abnormal and normal vaginal flora. Copyright (C) 2010 S. Karger AG, Basel

[Which clinical symptoms suggest distinct autoantibody measurements?]

The detection of autoantibodies is an important cornerstone in the diagnosis of systemic autoimmune disorders such as autoimmune connectivitides and small vessel vasculitides. Antinuclear antibodies (ANAs ) and antineutrophil cytoplasmic antibodies (c+p-ANCAs) are appropriate diagnostic screening tools for autoimmune connectivitides and small vessel vasculitides. For economic and intellectual/didactic reasons more extensive autoantibody diagnostics should be performed only in particular situations when patients history and clinical exam lead to strong diagnostic suspicion.

The nasopalatine duct cyst: an analysis of the relation between clinical symptoms, cyst dimensions, and involvement of neighboring anatomical structures using cone beam computed tomography

This study evaluates the dimensions of nasopalatine duct cysts (NPDCs) and the involvement of neighboring anatomical structures using standardized limited cone beam computed tomography (CBCT) and a possible correlation to the patient's age, gender, preoperative symptoms, and postsurgical complications.

Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.

The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.

Cognitive emotion regulation as a mediator between posttraumatic stress symptoms and hypomanic personality within a non-clinical population

Background: There is a high prevalence of traumatic life events within individuals diagnosed with bipolar disorder. However, currently there is limited theoretical understanding of this relationship. Aims: To explore whether non-clinical symptoms of posttraumatic stress have a direct effect on the non-clinical symptoms of bipolar disorder, or whether this relationship is mediated by cognitive emotion regulation strategies. Method: A cross-sectional design within non-clinical participants completing an online survey including the Impact of Events Scale, Cognitive Emotion Regulation Questionnaire and the Hypomanic Personality Scale. Results: Posttraumatic stress symptoms were associated with hypomanic personality. Intrusive memories contributed a small but significant proportion of the variance between these two measures. Rumination of negative emotions mediated the relationship between posttraumatic stress and hypomanic personality. Conclusions: The relationship between traumatic events and an increased prevalence of bipolar disorder remains poorly understood. Further research should explore rumination as a potential target for treatment within those suffering from both posttraumatic stress and bipolar disorder.

Clinical Signs and Symptoms and Laboratory Findings of Methadone Poisoning in Children

Background: Poisoning accounts for about 7% of all accidents in children under 5 years and is implicated in over 5% of all childhood deaths in developing countries. Objectives: Due to the potential risks of methadone poisoning in children and increased cases of methadone poisoning among Iranian children, this study was conducted to investigate the clinical signs and symptoms and laboratory findings of methadone toxicity in children. Patients and Methods: The present retrospective, descriptive, cross-sectional study describes the clinical symptoms and signs and laboratory findings of methadone poisoning in children under 12 years old in Shahid Beheshti Hospital, Kashan, during the years 2009 to 2013. Results: Of 58 patients, 33 (56.9%) were male and 25 (43.1%) female (P = 0.294). The mean age of patients was 5.2 ± 1.0 years. All the cases of poisoning happened with methadone syrup, due to unsafe keeping of methadone in mineral water bottles and containers of other drugs. Signs and symptoms included drowsiness (91.4 %), miosis (75.9%), vomiting (69.0%), ineffective breathing (any kind of breathing problem except apnea) (62.1%), apnea (53.4%), cyanosis (43.1%), seizure (8.6%), ataxia (6.9%) and delirium (3.4%). Conclusions: Keeping methadone in appropriate containers and warning methadone consumers about the dangerous side effects of its consumption and the symptoms of methadone poisoning in children may minimize the occurrence of this form of poisoning and its complications in children.

Reproducibility and clinical utility of tendon palpation to detect patellar tendinopathy in young basketball players

Background—Palpation is an important clinical test for jumper's knee. Objectives—To (a) test the reproducibility of palpation tenderness, (b) evaluate the sensitivity and specificity of palpation in subjects with clinical symptoms of jumper's knee, and (c) determine whether tenderness to palpation may serve as a useful screening test for patellar tendinopathy. The yardstick for diagnosis of patellar tendinopathy was ultrasonographic abnormality. Methods—In 326 junior symptomatic and asymptomatic athletes' tendons, palpation was performed by a single examiner before ultrasonographic examination by a certified ultrasound radiologist. In 58 tendons, palpation was performed twice to test reliability. Tenderness to palpation was scored on a scale from 0 to 3 where 0 represented no pain, and 1, 2, and 3 represented mild, moderate, and severe tenderness respectively. Results—Patellar tendon palpation was a reliable examination for a single examiner (Pearson r = 0.82). In symptomatic tendons, the positive predictive value of palpation was 68%. As a screening examination in asymptomatic subjects, the positive predictive value of tendon palpation was 36–38%. Moderate and severe palpation tenderness were better predictors of ultrasonographic tendon pathology than absent or mild tenderness (p<0.001). Tender and symptomatic tendons were more likely to have ultrasound abnormality than tenderness alone (p<0.01). Conclusions—In this age group, palpation is a reliable test but it is not cost effective in detecting patellar tendinopathy in a preparticipation examination. In symptomatic tendons, palpation is a moderately sensitive but not specific test. Mild tenderness in the patellar tendons in asymptomatic jumping athletes should be considered normal.

Patellar tendinopathy in junior basketball players : a controlled clinical and ultrasonographic study of 268 patellar tendons in players aged 14-18 years

Anterior knee pain is a common presenting complaint amongst adolescent athletes. We hypothesised that patellar tendinopathy may occur at a younger age than is generally recognised. Thus, we studied the patellar tendons in 134 elite 14- to 18-year-old female (n=64) and male (n=70) basketball players and 29 control swimmers (17 female, 12 male) clinically and with ultrasonography. We found that of 268 tendons, 19 (7%) had current patellar tendinopathy on clinical grounds (11% in males, 2% in females). Twenty-six percent of the basketball players' patellar tendons contained an ultrasonographic hypoechoic region. Ultrasonographic abnormality was more prevalent in the oldest tertile of players (17-18 years) than the youngest tertile (14-15.9 years). Of tendons categorised clinically as 'Never patellar tendinopathy', 22% had an ultrasonographic hypoechoic region nevertheless. This study indicates that patellar tendinopathy can occur in 14- to 18-year-old basketball players. Ultrasonographic tendon abnormality is 3 times as common as clinical symptoms

Clinical utility of exhaled nitric oxide

Lower airway inflammation is generally classified as eosinophilic or neutrophilic. In conditions where eosinophilic inflammation predominates such as asthma in children, corticosteroids are usually beneficial. Traditionally, lower airway eosinophilia is measured using cellular count (through bronchoalveolar lavage or induced sputum). Both methods have limited applicability in children. When instruments to measure fractional exhaled nitric oxide (FeNO) became available, it presented an attractive option as it provided a non-invasive method of measuring eosinophilic inflammation suitable for children and adult. Not surprisingly, proposals have been made that FeNO measurement can be clinically used in many scenarios including monitoring the response to anti-inflammatory medications, to verify the adherence to treatment, and to predict upcoming asthma exacerbations. This thesis addresses the utility of FeNO levels in various scenarios, specifically in relation to asthma control and cough, a contentious aspect of the diagnosis of asthma. The thesis consists of a series of systematic reviews (related to the main question) and original studies in children. The over-arching aim of the thesis is to determine if FeNO is a clinically useful tool in the management of asthma and common asthma symptoms. The specific aims of the thesis were, to: 1. Determine if children with asthma have more severe acute respiratory symptoms at presentation with an asthma exacerbation and at days 7, 10 and 14 using validated scales. We also examined if children with asthma were more likely to have a persistent cough on day 14 than children with protracted bronchitis and/or controls. 2. Evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. 3. Evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. 4. Determine if adjustment of asthma medications based on FeNO levels (compared to management based on clinical symptoms) reduces severe exacerbations in children with asthma. 5. Examine the relationship between FeNO and exercise induced broncho-constriction and cough in children The aims above are addressed in respective chapters and all but one has been published/submitted. A synopsis of the findings are: In study-1 (Aim 1), we found that children with protracted bronchitis had the most severe acute respiratory infection symptoms and higher percentage of respiratory morbidity at day 14 in comparison to children with asthma and healthy controls. The systematic review of study-2 (Aim 2) included 246 randomised adult participants (no children) with 221 completing the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms. In the systematic review of study-3 (Aim 3), we found no significant difference between the intervention group (treatment adjusted based on FeNO) and control group (treatment adjusted based on clinical symptoms) for the primary outcome of asthma exacerbations or for the other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose ICS per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms. In contrast, in the paediatric studies, there was a significant increase in ICS dose in the FeNO strategy arm. Thus, controversy remains of the benefit or otherwise of utilising exhaled nitric oxide (FeNO) in routine clinical practice. FeNO levels are dependent on atopy and none of the 7 published trials have considered atopic status in FeNO levels when medications were adjusted. In study-4 (Aim 4), 64 children with asthma were recruited. Their asthma medications were adjusted according to either FeNO levels or usual clinical care utilising a management hierarchy taking into account atopy. It was concluded that tailoring of asthma medications in accordance to FeNO levels (compared to usual management), taking into account atopy status, reduced the number of children with severe exacerbations. However, a FeNO-based strategy resulted in higher daily ICS doses and had no benefit on asthma control. In study-5 (Aim 5), 33 children with cough and 17 controls were recruited. They were randomised to undertake an exercise challenge on day 1, or dry powder mannitol challenge on day 1 (with alternative challenge being done on day 2). In addition, a 24 hour cough meter, skin prick test, capsaicin cough sensitivity test and cough diary were undertaken. The change in cough frequency post exercise was significantly increased in the children with cough. FeNO decreases post exercise regardless of whether EIB is present or not. Limitations in the studies were addressed in the respective chapters. In summary, the studies from this thesis have provided new information on: • The severity of respiratory symptoms was increased in the early phase of the asthma exacerbation but not in the later recovery phase when compared with controls. • The utility of FeNO in the management of children with asthma. • The relationship of FeNO, cough and EIB in children. • Systematic reviews on the efficacy of tailoring asthma interventions based on eosinophilic inflammatory markers (sputum analysis and FeNO) in comparison to clinical symptoms.