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PubMed2006

Cough sensitivity in pure cough variant asthma elicited using continuous capsaicin inhalation.

BACKGROUND: Cough variant asthma has recently been described, mainly as airway inflammation in relation to bronchial asthma, but the relationship between the two types of asthma remains unclear. Further studies of cough receptor sensitivity are necessary to fully characterize cough variant asthma. METHODS: We assessed the relevance of testing cough sensitivity using an Astograph with continuous capsaicin inhalation, and compared the results with those obtained using intermittent inhalation. We showed the clinical applicability of testing cough sensitivity (0.156-80 microM capsaicin; five or more coughs, 1 minute of continuous inhalation at each concentration) using this method. We compared cough sensitivity among patients with pure cough variant asthma who did not develop bronchial asthma after an observation period of at least 1 year, patients with bronchial asthma and healthy individuals. RESULTS: The continuous cough sensitivity test using the Astograph was reproducible and reliable. Cough sensitivity in patients with pure cough variant asthma was significantly higher than that in healthy individuals. CONCLUSIONS: The cough sensitivity of patients with cough variant asthma is not necessarily identical to that of healthy individuals.

Administration, Inhalation↗
PubMed1997

Cough frequency and cough-receptor sensitivity are increased in man at altitude.

1. Travellers to high altitude often complain of paroxysmal cough, which has not been previously investigated. We recorded overnight cough frequency and cough-receptor sensitivity to inhaled citric acid in a group of climbers travelling to 5300 m or higher. 2. Cough frequency, monitored in ten subjects, increased from a median of 0 coughs at sea level (range 0-1) to 5 coughs at 5000 m (range 0-13) and to over 60 coughs in subjects ascending to 7000 m. Citric acid cough threshold, measured in 42 subjects, was unchanged on arrival at 5300 m compared with sea level (geometric mean difference 1.26, 95% confidence intervals 0.84-1.89, P = 0.25), but was significantly reduced after 6 days, or more, at altitude compared with sea level (geometric mean difference 2.2, 95% confidence intervals 1.54-3.15, P = 0.0002). Cough threshold was not related to symptoms of acute mountain sickness, oxygen saturation, carbon dioxide tension or lung function. 3. These results indicate an increase in cough and cough-receptor sensitivity after some days at altitude. This may be due to respiratory tract damage from breathing cold dry air at increased ventilatory rates. Other explanations, such as sub-clinical pulmonary oedema or an effect on the cough centre of acclimatization to altitude, cannot be excluded.

Altitude↗
PubMed2003

Cough reflex testing with inhaled capsaicin in the study of chronic cough.

OBJECTIVES: To assess the utility of capsaicin test in the differential diagnosis of non-productive causes of chronic cough and to examine the effects of treatment on this reflex. PARTICIPANTS: 86 healthy volunteers and 101 patients with chronic cough: asthma (n: 54) gastroesophageal reflux (n: 35) and post-nasal drip syndrome (n: 12). DESIGN: Prospective intervention trial. Spirometry, bronchoprovocation test with histamine (PC20), and cough challenge with ascending concentrations of capsaicin (0.49-500 microM) were initially performed in all subjects. Patients were treated for 3 months according to the origin of the cough. Concentrations that elicited two (C2) and five or more coughs (C5) were determined before and after treatment. RESULTS: In healthy subjects, cough sensitivity to capsaicin was not influenced by gender or smoking status; however, women with chronic cough were more sensitive to cough challenge than men. C2 and C5 were significantly lower in patients with asthma or gastroesophageal reflux than in post-nasal drip syndrome. No significant correlation was observed between the capsaicin cough threshold and PC20. Cough sensitivity did not improve significantly in most patients with asthma or gastroesophageal reflux despite adequate medical treatment during 3 months. Discriminative value of capsaicin test to differentiate healthy subjects from patients with asthma or reflux was poor. CONCLUSIONS: Cough sensitivity to inhaled capsaicin is a safe and reproducible tool in the study of chronic cough. However, its usefulness for the management and differential diagnosis is limited.

Administration, Inhalation↗
PubMed2003

Cough reflex induced by microinjection of citric acid into the larynx of guinea pigs: new coughing model.

We developed a new coughing model that evoked coughs by microinjection of citric acid into the larynx in unanesthetized unrestrained guinea pigs; additionally, we recorded synchronous sounds and waveforms of coughing utilizing built-in microphones and a whole body plethysmograph. The coughing model was able to distinguish a coughing response from other expiratory responses, such as an expiratory reflex or a sigh, by examining the waveform of the expiratory response and the existence of sound. It was not necessary to distinguish a cough from a sneeze, since the administration site was restricted to the larynx. Microinjection of 0.4 M citric acid, total of 20 microl (10 times, 2 microl at 30-s intervals), induced coughs (27.03 +/- 4.03 coughs in 10-min observation) that were stable and independent of the inhalation volume. In the inhalation studies, animals were exposed to citric acid only once, because the number of coughs remarkably decreased with repeated administration at intervals of 24 h (tachyphylaxis). However our coughing model was able to repeatedly challenge the microinjection of citric acid at an interval of 24 h. These results indicated that this coughing model was highly sensitive and correctly assessed the cough response.

Animals↗
PubMed2002

Relationship between cough, cough receptor sensitivity and asthma in children.

In childhood asthma, cough is a major symptom in some but not in others. There is only limited data on the frequency, severity and prevalence of cough in children with classical asthma. Studies have largely shown no relationship between cough frequency and cough receptor sensitivity with various asthma severity indices. However relating cough severity with asthma severity is limited by various methodological and sensitivity issues, and these are presented in this paper. Mild asthma exacerbations in a group of children with cough as a dominant symptom were characterised by an increase in cough severity (daytime cough scores) and eosinophilic inflammation but not neutrophilic inflammation. However neither cough receptor sensitivity or cough scores related to airway IL-8, eosinophil cationic protein, myeloperoxidase or serum eosinophil cationic protein, and, asthma scores consistently related to cough score only early in the asthma exacerbation phase.

Asthma↗
PubMed2000

Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough.

BACKGROUND: We have shown that some patients presenting with chronic bronchodilator-resistant non-productive cough have global atopic tendency and airway cough hypersensitivity without non-specific bronchial hyperresponsiveness, abbreviated as atopic cough. The cough is successfully treated with histamine H1-antagonists and/or glucocorticoids. OBJECTIVE: This prospective study was conducted to elucidate the histological feature of atopic cough. METHODS: Tracheal and bronchial mucosa obtained by transbronchoscopic biopsy and bronchoalveolar lavage (BAL) cell component were studied with special emphasis on eosinophils in eight non-smokers diagnosed with atopic cough, all of whom had increased sensitivity of cough response to inhaled capsaicin, normal lung function and bronchial responsiveness to methacholine and normal chest roentgenogram. Their cough completely resolved on histamine H1-antagonists and/or glucocorticoids. Transbronchoscopic tracheal and bronchial biopsy and BAL were also performed in healthy non-smokers as a control. RESULTS: A small number of eosinophils was detected in subepithelium of trachea in six of seven patients and in subepithelium of bronchi in seven of eight cough patients. The numbers of eosinophils in subepithelium of trachea and bronchi were significantly increased in the patients compared with control subjects. There was no BAL eosinophilia in any patients. CONCLUSION: It is concluded that eosinophilic tracheobronchitis and cough hypersensitivity are pathological and physiological characteristics of atopic cough.

Aged↗
PubMed2006

Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy.

OBJECTIVE: The objective of this prospective, randomized, controlled study (N = 28) was to evaluate the effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. METHODS: Patients were selected based on a clinical history consistent with postviral vagal neuropathy and a history of an antecedent upper respiratory tract infection. All patients had been tried on antireflux medication (proton pump inhibitors) and had a negative chest x-ray before presentation. All were nonsmokers without a history of asthma. Patients on angiotensin-converting enzyme inhibitors were excluded from the study. All patients completed a pretreatment, validated cough-specific quality-of-life (QOL) survey. Patients were randomized by chart numbers to either 10 mg amitriptyline at bedtime or 10 to 100 mg/5 mL, 10 mL codeine/guaifenesin every 6 hours standing dose while awake. Both groups were instructed to complete 10 days of therapy and then asked to subjectively rate the reduction in the frequency and severity of their cough by 100%, 75%, 50%, 25%, or 0% as well as completing the posttreatment cough QOL questionnaire. Those patients experiencing a 75% to 100% reduction were recorded as having a complete response, 25% to 50% a partial response, and 0% as having no response. Final results and the cough QOL survey were recorded and used for statistical analysis. RESULTS: A majority of patients in the amitriptyline group achieved a complete response on the initial dose of 10 mg. None of the codeine/guaifenesin group achieved a complete response. The data were analyzed using a logistic regression model, and amitriptyline was found to be a highly significant predictor of a greater than 50% response when compared with codeine/guaifenesin (P = .0007). The same data were analyzed using a proportional odds model and similar results were noted. CONCLUSIONS: Chronic cough can have a profound impact on the psychosocial function of patients. The most common causes of a persisting cough in the absence of infection or chronic smoking are laryngopharyngeal reflux, asthma, particularly the cough variant, allergy, rhinosinusitis, bronchitis, and medications, in particular angiotensin-converting enzyme inhibitors. Currently, there are few effective treatments for cough with an acceptable therapeutic ratio and more selective drugs with a more favorable side effect profile are needed. This is this first prospective, randomized, controlled study comparing the effectiveness of amitriptyline versus codeine/guaifenesin for select cases of chronic cough resulting from suspected postviral vagal neuropathy.

Amitriptyline↗
PubMed2002

Should we advise parents to administer over the counter cough medicines for acute cough? Systematic review of randomised controlled trials.

AIMS: To determine the effectiveness of over the counter (OTC) cough medicines for acute cough in children. METHODS: Systematic review of randomised controlled trials (RCTs). An all language search of the Cochrane Acute Respiratory Infections Group specialised register, Cochrane Controlled Trials Register, Medline, Embase, and the UK Department of Health National Research Register was performed. RCTs comparing oral OTC cough preparations with placebo in children suffering from acute cough as a result of upper respiratory tract infection (URTI) in ambulatory settings, using cough symptoms as an outcome, were included. RESULTS: Six trials involving 438 children met all inclusion criteria. Antitussives, antihistamine-decongestant combinations, other fixed drug combinations, and antihistamines were no more effective than placebo in relieving symptoms of acute cough. Based on a single study, the mucolytic preparation letosteine was superior to placebo, with differences in cough scores ranging from 0.1 to 0.3 points from day 4 to day 10. Most drugs appeared to be well tolerated with a low incidence of mostly minor adverse effects. CONCLUSION: OTC cough medicines do not appear more effective than placebo in relieving symptoms of acute cough. Even if statistically significant, effect sizes were small and of doubtful clinical relevance. The number of trials in each category was small, and the results of this systematic review have to be interpreted with caution. Based on the available evidence from a small number of studies, we cannot recommend OTC cough medicines as a first line treatment for children with acute cough.

Acute Disease↗
PubMed1996

Effect of loratadine, an H1 antihistamine, on induced cough in non-asthmatic patients with chronic cough.

BACKGROUND: H1 antihistamines have been shown to have an antitussive effect in patients with asthma, postnasal drip, and allergic rhinitis. No study has been performed to determine whether orally administered H1 antihistamines can reduce the number of coughs induced by stimulation of cough receptors in non-asthmatic patients with chronic dry cough. METHODS: The effect of loratadine (10 mg) on the number of coughs induced by ultrasonically nebulised distilled water (UNDW) was examined in 10 patients with nasal disease and in seven patients with unexplained chronic cough using a randomised, double blind crossover method. Eleven normal volunteers were also studied. Each subject inhaled UNDW for one minute, and the numbers of coughs during the one minute inhalation and the 30 seconds following it were counted. RESULTS: There was no difference in the results of pulmonary function tests performed before and one minute after UNDW inhalation for either patients or normal subjects. There was also no significant difference between the results of pulmonary function tests before or after oral administration of loratadine. Loratadine significantly reduced the number of coughs in patients with nasal disease and in those with unexplained chronic cough, but not in normal subjects. CONCLUSIONS: The H1 antihistamine loratadine reduces cough induced by UNDW. The release of histamine may contribute to the chronic cough in patients with unexplained chronic cough or nasal disease.

Adult↗
PubMed1994

Cough receptor sensitivity and bronchial responsiveness in patients with only chronic nonproductive cough: in view of effect of bronchodilator therapy.

Twenty-two patients with only chronic nonproductive cough lasting for more than 2 months were prospectively examined to determine whether airway cough receptor sensitivity and bronchial responsiveness relate to the efficacy of bronchodilator therapy on the cough. Clenbuterol (10 micrograms, 4 times a day for 1 week) was effective on the cough in 10 patients (group 2) but not in the other 12 patients (group 1). Cough threshold to inhaled capsaicin was significantly less in group 1 than in group 2 at the first visit but not after the therapy when the cough stopped. Bronchial responsiveness to methacholine (PC20-FEV1) was not heightened in group 1, while that in group 2 was hyperreactive. These findings suggest that nonproductive cough is elicited based on two different mechanisms: (1) heightened airway cough receptor sensitivity in bronchodilator-resistant cough and (2) bronchoconstriction in bronchodilator-responsive cough such as cough-variant asthma.

Adult↗
PubMed2003

[Effects of Bakumondo-to (Mai-Men-Dong-Tang) on cough sensitivity to capsaicin in asthmatic patients with cough hypersensitivity].

UNLABELLED: Some patients with bronchial asthma have increased cough sensitivity. In such patients coughing may be an inducer of wheeze. The aim of the present study was to investigate the effect of Bakumondo-to on the cough sensitivity and respiratory tract inflammation in asthmatic patients with increased cough sensitivity. In addition influences of intensity of respiratory tract inflammation, gender, type of asthma, and disease period on the effect of Bakumondo-to on the cough sensitivity were examined. Twenty-one bronchial asthmatics whose cough thresholds to capsaicin were less than 3.9 microM were examined. METHODS: Cough thresholds to capsaicin (concentration of inhaled capsaicin solution causing 5 or more coughs) was measured before and after 2 months or more treatment with Bakumondo-to (9 g/day, TJ-29). Number of eosinophils in peripheral blood, sputum eosinophil ratio, and ECP level in the serum were also measured before and after treatment. RESULTS: Bakumondo-to significantly increased the cough threshold. Although respiratory tract inflammation was not significantly improved, number of eosinophils in peripheral blood, sputum eosinophil ratio and ECP level in the serum were remarkably decreased more than the half. And Bakumondo-to was more effective in asthmatic subjects with severe airway inflammation. Furthermore, a greater effect of it was observed in women. A greater effect was also observed in patients having a disease duration of less than 1 year. CONCLUSION: Our results suggest that Bakumondo-to may be an effective therapeutic preparation for coughing in asthmatic patients with cough hypersensitivity.

Adolescent↗
PubMed2006

Whooping cough in school age children with persistent cough: prospective cohort study in primary care.

OBJECTIVE: To estimate the proportion of school age children with a persistent cough who have evidence of a recent Bordetella pertussis infection. DESIGN: Prospective cohort study (October 2001 to March 2005). SETTING: General practices in Oxfordshire, England. PARTICIPANTS: 172 children aged 5-16 years who presented to their general practitioner with a cough lasting 14 days or more who consented to have a blood test. MAIN OUTCOME MEASURES: Serological evidence of a recent Bordetella pertussis infection; symptoms at presentation; duration and severity of cough; sleep disturbance (parents and child). RESULTS: 64 (37.2%, 95% confidence interval 30.0% to 44.4%) children had serological evidence of a recent Bordetella pertussis infection; 55 (85.9%) of these children had been fully immunised. At presentation, children with whooping cough were more likely than others to have whooping (odds ratio 2.85, 95% confidence interval 1.39 to 5.82), vomiting (4.35, 2.04 to 9.25), and sputum production (2.39, 1.14 to 5.02). Children with whooping cough were also more likely to still be coughing two months after the start of their illness (85% v 48%; P = 0.001), continue to have more than five coughing episodes a day (P = 0.049), and cause sleep disturbance for their parents (P = 0.003). CONCLUSIONS: For school age children presenting to primary care with a cough lasting two weeks or more, a diagnosis of whooping cough should be considered even if the child has been immunised. Making a secure diagnosis of whooping cough may prevent inappropriate investigations and treatment.

Adolescent↗
PubMed2002

Sex-related differences in cough reflex sensitivity in patients with chronic cough.

Among patients attending specialist cough clinics there is an excess of females, but the reason for this sex difference is unknown. We tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. Inhalation cough challenges with capsaicin and citric acid were performed in a large group of patients with chronic cough. The concentrations of tussive agent causing two (C2) and five (C5) coughs were calculated. Measurements of capsaicin cough reflex sensitivity (median [interquartile range]) were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] micro M, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to > 100] micro M, p = 0.0007). Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to > 1,000] versus 830.4 [300.0 to > 1,000] mM, p = 0.032). There were significant correlations between capsaicin and citric acid C2 values (r(s) = 0.54, p < 0.0001) and C5 values (r(s) = 0.57, p < 0.0001). These findings indicate a sex difference in cough sensitivity in patients with chronic cough, as previously reported in healthy volunteers. This may explain the female preponderance in cough clinics.

Adult↗
PubMed2006

Cellular composition of bronchial brushings obtained from healthy dogs and dogs with chronic cough and cytologic composition of bronchoalveolar lavage fluid obtained from dogs with chronic cough.

OBJECTIVE: To determine whether bronchial brushings from dogs with chronic cough have increased numbers of goblet cells and WBCs, compared with numbers for healthy dogs, or have differing WBC populations, compared with populations in bronchoalveolar lavage (BAL) fluid obtained from dogs with chronic cough. ANIMALS: 9 healthy dogs and 10 dogs with chronic cough. PROCEDURE: Specimens were collected by use of bronchoscopy. Cellular composition was determined for brushings, and results from dogs with chronic cough were compared with those from healthy dogs. Cellular composition of brushings was compared with composition of BAL obtained from dogs with chronic cough. RESULTS: Brushings from healthy dogs contained a median of 2.9 x 10(6) epithelial cells, comprising 100% epithelial cells (96% ciliated, 3% goblet, and 1% other) and no WBCs. Brushings from dogs with chronic cough had 4.5 x 10(6) epithelial cells, comprising 93% epithelial cells (86% ciliated, 2% goblet, and 12% other). Dogs with chronic cough had significantly greater percentages of WBCs (7%) and neutrophils (6%), compared with values for healthy dogs. Five dogs with chronic cough had no neutrophilic inflammation evident in BAL, but 4 of these had evidence of neutrophilic inflammation in brushings. CONCLUSIONS AND CLINICAL RELEVANCE: Neutrophils, but not goblet cells, were increased in brushings from dogs with chronic cough. Analysis of bronchial brushings provides information about airway inflammation that differs from that found by examination of BAL in some dogs with chronic cough and is a more sensitive indicator of airway inflammation than cytologic examination of BAL in these dogs.

Animals↗
PubMed1990

[Whooping cough epidemiology in Denmark prior to and after the introduction of whooping cough vaccination. Protective effect of the vaccine and herd immunity].

The epidemiology of whooping cough in Denmark is described on the basis of the notified cases of the disease. The frequency of whooping cough has decreased to approximately one sixteenth of the previous level in children following the introduction of vaccination for whooping cough in 1961. Following change to a programme with only three vaccinations with a weaker, non-aluminium-adsorbed pure whooping cough vaccine in 1970, whooping cough became again slightly more frequent in the nineteen seventies and eighties. No definite reduction in the proportion of cases of whooping cough among infants could be detected although this was what the 1970 programme was particularly aimed at. Isolated deaths from whooping cough still occurred in the eighties, all of these among unvaccinated infants. The risk of whooping cough in an unvaccinated child is approximately one sixth of the risk prior to introduction of vaccination. In a vaccinated child, the risk, as judged from the notified cases, is one twentieth of the risk during the time prior to introduction of vaccination. In all age groups "herd immunity" is considered to have contributed considerably to the reduced incidence. The incidence in Denmark is, however, high compared with the incidence in some other industrialized countries. A vaccination programme with more numerous whooping cough vaccinations and possibly with a more immunogenic vaccine may be recommended on the basis of the strategy aimed at keeping the incidence of whooping cough, and thus the risk of exposure, as low as possible.

Cross-Sectional Studies↗
PubMed1994

Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study Group.

OBJECTIVE: To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). DESIGN: An international, multicentre, randomized double-blind, parallel-group controlled trial. SETTING: Outpatient clinics at 20 tertiary care medical centres in 11 countries. PATIENTS: One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study. INTERVENTION: After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks. MAIN OUTCOME MEASURES: Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale. RESULTS: The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide. CONCLUSION: The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

Adult↗
PubMed1995

ACE inhibitors, angiotensin II antagonists and cough. The Losartan Cough Study Group.

One hundred and thirty five non-smoking hypertensive patients with ACE inhibitor cough confirmed by lisinopril rechallenge and placebo dechallenge were recruited into a double-blind random parallel-group comparison of losartan 50 mg, lisinopril 20 mg and hydrochlorothiazide 25 mg each given once daily for a maximum of 8 weeks. The aim of the study was to compare the incidence of cough with the angiotensin II antagonist losartan, the ACE inhibitor lisinopril and the hydrochlorothiazide in hypertensive patients with previous ACE inhibitor cough. Cough detected by self-administered questionnaire was the primary end-point, and cough frequency by visual analogue scale a secondary end-point. The incidence of cough with losartan (29%) was lower than that for lisinopril (72%, P < 0.01) and similar to that for hydrochlorothiazide (34%). Cough frequency by visual analogue scale was lower for losartan than lisinopril (P < 0.01) and similar to that for hydrochlorothiazide. The specific selective AT1 angiotensin II receptor antagonist losartan is significantly less likely than lisinopril to cause cough in patients who previously have had ACE inhibitor cough. ACE inhibitor cough is likely to be related to non-specific kininase II inhibition.

Adult↗
PubMed1996

Cough threshold for capsaicin increases by azelastine in patients with cough-variant asthma.

To assess the effects of azelastine in patients with cough-variant asthma, we measured the cough threshold for capsaicin (the concentration required to elicit more than five coughs) in 16 patients with cough-variant asthma before and after 4 weeks of treatment with azelastine (2 mg; b.i.d.) or placebo. After treatment, coughing decreased in all patients and the cough threshold for capsaicin increased significantly, from 0.67 +/- 0.30 microM to 4.76 +/- 1.55 microM (P < 0.01) in the azelastine group. However, the cough threshold for capsaicin did not increase significantly, from 0.86 +/- 0.33 microM to 1.11 +/- 0.35 microM (P > 0.10) in the placebo group. These results suggest that azelastine inhibits coughing in patients with cough-variant asthma.

Adult↗