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PubMed2006

Surfactant therapy for bronchiolitis in critically ill infants.

BACKGROUND: Viral bronchiolitis is a common cause of respiratory failure in infants and children, and accounts for a significant portion of intensive care unit (ICU) admissions during seasonal epidemics. Currently there is no evidence to support the use of anything but supportive care for this disease. Surfactant is a potentially promising therapy; alterations in its composition have been described in bronchiolitis, and it may play a role in the host immunity for this disease. OBJECTIVES: The objective of this review was to assess the efficacy of exogenous surfactant for the treatment of bronchiolitis in mechanically ventilated infants and children. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006); MEDLINE (1966 to Week 1, February 2006); and EMBASE (1990 to September 2005). We reviewed reference lists of relevant articles and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing surfactant with placebo or surfactant with no surfactant in mechanically ventilated infants and children with viral bronchiolitis. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Unpublished data were requested from trial authors when necessary. MAIN RESULTS: Three trials containing a total of 79 patients met the inclusion criteria. No mortality or adverse effects associated with surfactant administration were reported in any of these trials. In the three trials, use of surfactant was associated with a decrease in duration of mechanical ventilation by 2.6 days (95% confidence interval (CI) -5.34 to 0.18 days; P value 0.07) and a decrease in ICU length of stay by 3.3 days (95% CI -6.38 to -0.23 days; P value 0.04). In two studies with 59 patients, in which duration of mechanical ventilation in the control groups was more comparable, surfactant was associated with a decrease in ventilator days by 1.21 days (95% CI 0.75 to 1.67 days) and a decrease in ICU stay by 1.81 days (95% CI 1.19 days to 2.42 days). Individually the studies reported some short term benefit of surfactant on pulmonary mechanics and gas exchange. AUTHORS' CONCLUSIONS: Available data on surfactant were not sufficient to provide reliable estimates of its effects in mechanically ventilated infants and children with bronchiolitis. Future studies should be adequately powered and will need to address unresolved questions regarding which surfactant preparation may be best suited for the treatment of bronchiolitis, the appropriate dose and administration interval, and how the choice of ventilator strategy may modify its effects.

Bronchiolitis, Viral↗

PubMed2005

A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus.

We studied epidemiologic and immunologic factors in infants with bronchiolitis caused by influenza virus. The proportion of these infants who were male and who had an immediate family member with a history of asthma was similar to that of a control group of infants with respiratory syncytial virus (RSV) bronchiolitis. In subjects with influenza virus infection, concentrations of the beta chemokine macrophage inflammatory protein-1alpha (MIP-1alpha), but not other beta chemokines, in nasopharyngeal secretions (NPS) were greater among infants with more severe, hypoxic bronchiolitis than in subjects with mild, nonhypoxic bronchiolitis, or upper respiratory tract infection alone. Quantities of MIP-1alpha were also correlated with lower values of oxygen saturation. These findings point out epidemiologic and immunologic similarities between bronchiolitis caused by influenza and RSV, and suggest that host factors are more important than the nature of the infecting virus in the development of severe forms of bronchiolitis caused by influenza and RSV.

Bronchiolitis, Viral↗

PubMed2001

Eosinophil cationic protein in infants with respiratory syncytial virus bronchiolitis: predictive value for subsequent development of persistent wheezing.

Infants with acute bronchiolitis during the first months of life are at increased risk of developing persistent wheezing and bronchial asthma later in life. The study of eosinophil cationic protein (ECP) suggests that eosinophil-related inflammatory mechanisms may play a role in respiratory syncytial virus (RSV) bronchiolitis. The aim of our study was to verify whether serum ECP (s-ECP) measurements are useful in predicting the development of persistent wheezing in children affected by RSV bronchiolitis during a 5 years follow-up period. Forty-eight infants were enrolled prospectively (mean age: 153.5 days). All had a clinical and radiological diagnosis of acute bronchiolitis and confirmed RSV infection. Peripheral eosinophil counts, levels of s-ECP, and serum IgE concentrations were measured during bronchiolitis. Five years later the children were re-evaluated in regard to their respiratory symptoms (standardized questionnaires) and atopic status (specific IgE levels). We observed significantly higher s-ECP levels (P < 0.001) at enrollment in subjects who developed persistent wheezing compared to subjects who did not show late wheezing. Initial s-ECP values allowed significant and correct prediction of persistent wheezing (P < 0.001). The risk to develop respiratory symptoms was 9.73 higher for infants with s-ECP levels > or = 8 microg/L than for those with s-ECP levels <8 microg/L (P < 0.0001). In conclusion, our study suggests that s-ECP levels in infants with bronchiolitis are useful in predicting the risk to develop wheezing in the subsequent 5 years.

Asthma↗

PubMed1989

Wheezing at 8 and 13 years: changing importance of bronchiolitis and passive smoking.

A group of 153 children (51 with a history of bronchiolitis and 102 matched controls) were evaluated in a historical cohort study at a mean age of 8 years and again at 13 years to test the primary hypothesis that mild bronchiolitis, far more common than severe (hospitalized) bronchiolitis, predicts wheezing. A secondary hypothesis was that passive smoking also predicts wheezing. Many potentially confounding variables such as family history of asthma were controlled in analyses. Analysis at 13 years produced results that were not anticipated from previous analysis of interviews at age 8. Although mild bronchiolitis was a powerful predictor of wheezing at age 8 years, it was no longer a strong predictor of wheezing at age 13 in either bivariate or multivariate analysis. Although epidemiologic studies, by their nature, cannot prove causality, findings are consistent with the hypothesis that sequelae often follow mild bronchiolitis but diminish during childhood. Maternal smoking was a powerful predictor of wheezing at age 13 in bivariate analysis (Kendall's Tau B = 0.19, P less than 0.01) and in multivariate analysis (odds ratio = 2.67, P less than 0.01). In children at highest risk for wheezing, males with a family history of asthma, multivariate analysis suggested that maternal smoking is associated with an increase in wheezing from 36% to 60%. We conclude that passive smoking, previously identified as a risk factor in this population for both bronchiolitis in infancy and wheezing at age 8, is a risk factor for wheezing-associated morbidity throughout the childhood years.

Adolescent↗

PubMed1990

Acute viral bronchiolitis in infancy: epidemiology and management.

Acute bronchiolitis due to viral agents (RSV, parainfluenza, influenza, adenovirus) is a relatively frequent disease of infancy. Seasonal epidemic pattern have been recognized, and nosocomial infections in pediatric wards occur. Until age 2 years most children have experienced some form of airway disease attributable to RSV. Some patients require hospital treatment; about 15% of our patients had to be transferred to the intensive care unit. Bronchiolitis seems to be frequently the first manifestation of asthma and we found higher IgG antibody titers to viruses causing bronchiolitis in children with asthma than in controls. Retrospective analysis of the charts of 147 cases of bronchiolitis revealed considerable uncertainty regarding therapeutic concepts. Mainstays of conservative therapy include oxygen, adequate hydration (often IV), and sometimes bronchodilators (based on the clinical impression of effectiveness in the individual patient). Mist therapy and secretolytic agents remain popular, although no clinical effect has been demonstrated. Attention should be directed toward the relief of upper airway obstruction caused by swelling, secretions, and nasogastric tubes. Oxygen administration in infants with coexisting chronic airway disease (e.g., BPD) and bronchiolitis may cause CO2 retention. Bronchodilators can cause hypoxia and increase bronchial compressibility by reducing smooth muscle tone. However, in severe cases a trial under pulse oximetry control seems worthwhile. Steroids seem to bring no clinical improvement, except in infants with protracted wheezing after bronchiolitis and patients with preexisting BPD.

Asthma↗

PubMed2004

Bronchoalveolar lavage cytokine profile in a cohort of lung transplant recipients: a predictive role of interleukin-12 with respect to onset of bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome is the main long-term complication of lung transplantation that limits survival of lung transplant patients. Its pathophysiologic mechanisms are still poorly understood but it seems to result from a chronic immunologic/inflammatory insult leading to excessive fibroproliferation. The aim of this longitudinal study of 44 lung recipients was to determine whether a number of bronchoalveolar lavage and clinical variables are associated with a higher risk of developing bronchiolitis obliterans syndrome. METHODS: Bronchoalveolar lavage studies involved assessment of several cytokines including: interleukin-8, monocyte chemoattractant protein-1, regulated-upon-activation normal T cell expressed and secreted (RANTES), gamma-interferon, interleukin-12, interleukin-10 and transforming growth factor-beta. RESULTS: The predictivity of bronchoalveolar lavage (BAL) features with respect to onset of bronchiolitis obliterans syndrome was assessed by the Cox regression model. Among clinical variables, bacterial and viral infections were found to significantly predict occurrence of bronchiolitis obliterans syndrome (hazard ratio [HR] for bacterial infection: 13.044, 95% confidence interval [CI] 1.34 to 126.69, p = 0.027; HR for viral infections: 4.88, 95% CI 1.004 to 22.87, p = 0.05). Among BAL variables, only IL-12 was significantly predictive of bronchiolitis obliterans syndrome (HR 0.956, 95% CI 0.901 to 1.01, p = 0.03). In addition, in a sub-group cross-sectional analysis, bronchiolitis obliterans syndrome patients were compared with clinically stable patients, and significant increases in median levels of interleukin-8 and monocyte chemoattractant protein-1 BAL fluid were detected. CONCLUSIONS: These findings support the contention that interleukin-12 plays a role in the modulation of the local pro-/anti-fibrotic balance of allograft airways.

Adult↗

PubMed2005

The link between bronchiolitis and asthma.

Bronchiolitis and asthma are common wheezing illnesses of childhood. Respiratory syncytial virus is the main causative agent of Bronchiolitis. Rhinovirus is the most common trigger of exacerbations of asthma, but also has been detected increasingly in doing children with Bronchiolitis. Reportedly, childhood asthma develops in 40% of children with a history of Bronchiolitis. No convincing link has been reported between Bronchiolitis and development of atopy, although atopy generally is regarded as the main risk factor for chronic asthma. This article focuses on the association between bronchiolitis and the development of asthma. The authors address the question how respiratory syncytial virus and rhinovirus infections in young children, together with genetics and immunologic immaturity, may contribute to the development of asthma.

Adolescent↗

PubMed1997

Cellular immunity is activated and a TH-2 response is associated with early wheezing in infants after bronchiolitis.

OBJECTIVE: To determine whether abnormalities of cellular immunity are present and linked to early wheezing after bronchiolitis. METHODS: We prospectively studied 26 infants hospitalized for a first episode of bronchiolitis and without any prior immune, cardiac, or respiratory disease. Blood was obtained at the time of enrollment and 5 months later for the assessment of the total cellular and differential counts, CD4+ (helper) and CD8+ (suppressor/cytotoxic) lymphocytes, and the activation markers CD23 (low-affinity immunoglobulin E receptor) and CD25 (interleukin-2 (IL-2) receptor). The cytokines interferon gamma (T-helper (TH) type-1 cytokine) and IL-4 (TH-2) were measured in plasma and in vitro after stimulation with IL-2 or with the house-dust mite (Dermatophagoides farinae) antigen. A daily log of episodes of wheezing was kept by parents after discharge. RESULTS: We found an increase in blood eosinophils, an increased percentage of CD4+, CD25+, and CD23+ lymphocytes in subjects at 5 months compared with the time of bronchiolitis and with healthy subjects of the same age (p < 0.05). Plasma IL-4 levels, although not different from those of healthy subjects, also increased significantly. Peripheral blood lymphocytes from infants who wheezed produced more IL-4 in vitro, 5 months after bronchiolitis, in response to D. farinae antigen. In babies who wheezed, a positive correlation was found between the total number of days that wheezing occurred and the blood eosinophil count. Babies who wheezed more often (> 20 days) had more peripheral blood basophils and eosinophils, and peripheral blood lymphocytes obtained from these subjects at the time of bronchiolitis produced less interferon gamma on stimulation with IL-2. CONCLUSIONS: Bronchiolitis is followed by activation of cellular immunity, and early wheezing in infants is associated with a TH-2 response.

Acute Disease↗

PubMed1995

Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management.

With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation. Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence. We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present. Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis. Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p < 0.05). These results indicate that acute rejection is the most significant risk factor for development of obliterative bronchiolitis and that obliterative bronchiolitis responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.

Adolescent↗

PubMed2004

Respiratory repercussions in adults with a history of infantile bronchiolitis.

BACKGROUND: Viral bronchiolitis in infancy has been identified in previous studies as a potential precursor to the development of lower respiratory tract illness in later childhood and beyond. OBJECTIVE: To evaluate the long-term respiratory repercussions of acute infantile viral bronchiolitis. METHODS: We studied 71 individuals aged 19 to 24 years with a history of a viral bronchiolitis in infancy and 32 controls. All participants underwent the following evaluation: medical history, forced spirometry, methacholine challenge, and skin prick testing. RESULTS: The bronchiolitis group had a higher prevalence of respiratory symptoms (P = .03) and bronchial hyperresponsiveness (P = .003) than controls. The bronchiolitis group also had a lower peak expiratory flow rate (P = .02). Skin prick test responses were similar in both groups. CONCLUSIONS: The findings from this study support and extend those from previous studies by suggesting that viral bronchiolitis may be a predisposing factor for lower respiratorytract problems in young adulthood.

Acute Disease↗

PubMed2003

[Potential impact and cost-efficacy of bronchiolitis prophylaxis with palivizumab in preterm infants with a gestational age of less than 33 weeks].

INTRODUCTION: Respiratory syncytial virus (RSV) is the main cause of bronchiolitis in children aged less than 2 years. The effectiveness of palivizumab has recently been reported in several clinical trials. OBJECTIVE: The aim of this study was to evaluate the hypothetical impact of a treatment strategy using palivizumab for the prevention of bronchiolitis in premature infants. METHODS: Neonates born in our hospital between January 1995 and December 1998 who were admitted for bronchiolitis were included. Using information from the Impact-RSV study, the effects and impact of different cut-off points in the gestational age of the study group were measured. Cost-effectiveness analysis included the cost of hospitalization as well as the direct cost of palivizumab prescriptions. RESULTS: Of 7,766 newborn infants, 56 had a gestational age of < or =32 weeks. Of these, bronchiolitis was diagnosed in eight infants (14.28%), and RSV was isolated in seven (14.28%). After hypothetical prophylaxis in premature infants the best results were obtained in the group with a gestational age of 30 weeks. In this group the relative risk of admission for bronchiolitis was 12.1 (95% CI: 4.8-30.5) and treatment would be required in nine infants to avoid one admission (cost Euros 12,915), with a cost 3.8 times greater than the current cost, without prophylaxis. CONCLUSIONS: Measurement of the impact and cost-effectiveness analysis of palivizumab prophylaxis provides a useful method for determining recommendations for the prevention of bronchiolitis in premature infants.

Acute Disease↗

PubMed2000

Bronchoalveolar lavage cellular composition in acute asthma and acute bronchiolitis.

OBJECTIVE: To compare cellular inflammation in the airways between acute bronchiolitis and asthma. STUDY DESIGN: Using a bronchoalveolar lavage with flexible bronchoscopy procedure, we investigated the cellular constituents of BAL fluid in children with acute exacerbation of asthma (n = 18) and infants with acute bronchiolitis caused by respiratory syncytial virus (n = 20). These results were compared with those of healthy control subjects (n = 14). RESULTS: Total lavage fluid recovered was similar in all groups. The total cell numbers were highest in the bronchiolitis group. The BAL cellular profile in the asthma group was characterized by a higher median (interquartile range) ratio of eosinophils (2.4% [1.6%-9.5%]; P <.01) than in the bronchiolitis group (0% [0%-0%]) or the control group (0% [0%-0%]). Neutrophil ratio was higher in the bronchiolitis group (40.0% [26.5%-50.0%]; P <.01), with no difference found between the asthma group (3.3% [2.0%-7.9%]) and the control group (2.0% [0.8%-5.5%]). CONCLUSIONS: Asthma and acute bronchiolitis are characterized by an elevated cellular percentage of eosinophils and neutrophils, respectively, in bronchoalveolar lavage fluid.

Acute Disease↗

PubMed1999

Abnormal surfactant composition and activity in severe bronchiolitis.

A prospective study of infants under 1 y of age, ventilated for severe viral bronchiolitis, was carried out in four paediatric intensive care units in order to study surfactant activity and composition in this condition. Lung lavage fluid from 24 infants with bronchiolitis, 19 with bronchiolitis and sepsis or cardiac failure and 12 controls were analysed by the "click test" for surfactant activity and for phospholipids. Surfactant activity was present in all controls, but in only 2 of the 24 infants with bronchiolitis alone. The presence of phosphatidylglycerol correlated perfectly with the click test, suggesting that reduced activity is due to changes in surfactant lipid composition. In those with bronchiolitis plus coexisting disease, surfactant activity and phosphatidylglycerol were absent in only half. Surfactant activity and phosphatidylglycerol re-appeared by extubation. Severe viral bronchiolitis is associated with an absence of surfactant activity and PG, which resolves by clinical recovery. Infants with coexisting conditions are not always surfactant deficient. Surfactant administration is likely to be beneficial, but requires a selective approach.

Bronchiolitis↗

PubMed1998

High prevalence of "Simkania Z," a novel Chlamydia-like bacterium, in infants with acute bronchiolitis.

The newly described microorganism "Simkania Z" ("Z"), an obligate intracellular, penicillin-resistant microorganism most closely related to the chlamydiae, has been associated with adult community-acquired pneumonia. The possible involvement of "Z" in bronchiolitis in infants was examined in a prospective study of 239 infants with bronchiolitis and 78 controls. Other potential etiologic agents sought were respiratory syncytial virus (RSV), adenovirus, and cytomegalovirus. Evidence for the presence of "Z" in nasopharyngeal wash specimens (polymerase chain reaction and/or culture) was found in 25% of infants with bronchiolitis, while controls were all negative (P < .001). A serum IgA response to "Z" infection was detected by immunoperoxidase assay in 15% of infants with bronchiolitis versus 1.3% of controls (P < .001). Clinical findings were not different for infants with bronchiolitis associated with RSV alone, "Z" alone, or RSV and "Z" together. The high prevalence of "Z" in infants with bronchiolitis, often accompanied by an immune response, suggests a possible etiologic role of this agent in the disease.

Adenoviruses, Human↗

PubMed1993

Hospitalization of Jewish and Bedouin infants in southern Israel for bronchiolitis caused by respiratory syncytial virus.

We conducted a prospective study to determine the clinical picture and impact of respiratory syncytial virus (RSV) on hospitalization for acute bronchiolitis of pediatric patients less than 2 years of age belonging to two different ethnic groups in Southern Israel: Jews and Bedouins. All patients younger than 2 years of age hospitalized for bronchiolitis during a typical RSV season were enrolled. During the study period 120 patients with bronchiolitis were hospitalized, and 83 (69%) were RSV-positive. Their age ranged from 20 days to 9 months. Fifty-five percent of all patients with RSV bronchiolitis were < or = 3 months old and 92% were < or = 6 months old. Patients with RSV bronchiolitis represented 18% of all hospitalized infants < or = 9 months old and 35% of all hospitalizations for respiratory problems of infants < or = 9 months old. The yearly incidence of hospitalization for RSV bronchiolitis was 5.4/1000 live births for Jews and 18/1000 live births for Bedouins. The total number of hospitalization days calculated for 1000 births was 32.1 for the Jews and 86.7 for the Bedouins. RSV has a serious impact on infant morbidity in Southern Israel.

Acute Disease↗

PubMed2000

Bronchiolitis-associated hospitalizations among American Indian and Alaska Native children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness among infants and young children. Respiratory system diseases account for a large proportion of hospitalizations in American Indian and Alaska Native (AI/AN) children; however, aggregate estimates of RSV-associated hospitalizations among AI/AN children have not been made. METHODS: We used Indian Health Service hospitalization data from 1990 through 1995 to describe hospitalizations associated with bronchiolitis, the most characteristic clinical manifestation of RSV infection, among AI/AN children <5 years old. RESULTS: The overall bronchiolitis-associated hospitalization rate among AI/AN infants < 1 year old was considerably higher (61.8 per 1,000) than the 1995 estimated bronchiolitis hospitalization rate among all US infants (34.2 per 1,000). Hospitalization rates were higher among male infants (72.2 per 1,000) than among females infants (51.1 per 1,000). The highest infant hospitalization rate was noted in the Navajo Area (96.3 per 1,000). Hospitalizations peaked annually in January or February, consistent with national peaks for RSV detection. Bronchiolitis hospitalizations accounted for an increasing proportion of hospitalizations for lower respiratory tract illnesses. CONCLUSIONS: Bronchiolitis-associated hospitalization rates are substantially greater for AI/AN infants than those for all US infants. This difference may reflect an increased likelihood of severe RSV-associated disease or a decreased threshold for hospitalization among AI/AN infants with bronchiolitis compared with all US infants. AI/AN children would receive considerable benefit from lower respiratory tract illness prevention programs, including an RSV vaccine, if and when one becomes available.

Age Distribution↗

PubMed2002

Malaria infection does not appear to modify the risk of bronchiolitis early in life.

BACKGROUND: The observation of an increased prevalence of allergic disorders coinciding with a decreasing frequency of infectious diseases in early childhood has led to the speculation that infections may prevent allergic sensitization. Information on the role of parasites in this context is limited. Bronchiolitis in infancy has been linked with asthmatic symptoms later in childhood, although the underlying cause of this association is unknown. METHODS: To test the hypothesis that early parasitic infections in infancy might prevent the development of allergic manifestations later in life, the effect of malaria infections during the first year of life on the risk of bronchiolitis was studied in 675 Tanzanian children at 18 months of age. The study was conducted as part of an intervention trial of malaria chemoprophylaxis and/or iron supplementation for the prevention of malaria and anemia in infants. RESULTS: The incidence of bronchiolitis up to 18 months of age in the 675 children was 0.58 episode per child per year. The risk factors analysis was based on 470 children with complete data. There was no difference in the incidence of bronchiolitis between those who had received malaria chemoprophylaxis during the first year of life and those who had not. However, the proportion of children who had bronchiolitis was lower among those who had had malaria episodes than among those who had not (48% vs. 55%, P = 0.05). CONCLUSIONS: This study does not support the hypothesis that reduced exposure to parasites may modulate the development of bronchiolitis early in life.

Age of Onset↗

PubMed2001

Bronchiolitis in infants.

Bronchiolitis is a common cause of wheezing among infants. Respiratory syncytial virus (RSV) is the most common infectious agent to cause bronchiolitis, and RSV infection accounts for more than 125,000 hospitalizations per year in the United States. Beyond supportive measures, the care of infants with bronchiolitis remains controversial. Practitioners continue to treat infants with a variety of pharmacologic agents, despite limited evidence of their efficacy. Investigators continue to search for the safest and most cost-effective methods to treat infants with bronchiolitis, not only to overcome obstructive symptoms during the acute illness, but also to prevent recurrent symptoms of airway obstruction that occur in some children for years after their initial episode of bronchiolitis. Improved understanding of the pathogenesis of RSV infection and of virus-host interactions may one day lead to the development of agents that alter the initial inflammatory response and strategies that help prevent recurrent episodes of wheezing and the development of asthma after acute bronchiolitis.

Anti-Inflammatory Agents↗