Long-term Macrolide Research Articles

Long-term low-dose macrolides for chronic rhinosinusitis in adults - a systematic review of the literature.

Chronic rhinosinusitis is a very common inflammatory disease that impairs quality of life and is associated with high healthcare spending. Chronic rhinosinusitis treatment commonly involves the use of intranasal corticosteroids, oral antibiotics, and surgery. Macrolides have been identified as a potential treatment option for chronic rhinosinusitis due to their immunomodulatory effects; however, the evidence supporting their use is still conflicting. The purpose of this systematic review was to evaluate new evidence along with previously reported studies of the use of macrolides in the treatment of chronic rhinosinusitis. Medline, EMBASE, Cochrane CENTRAL, LILACS, clinicaltrials.gov, and the International Clinical Trials Registry Platform were all searched (until June 2015 Medline and EMBASE searches were updated January 2016). Randomised controlled trials comparing low-dose macrolide antibiotics versus placebo, as an adjunct to other therapies, or low-dose macrolide therapy alone versus other therapies were included in this review. Quality of the evidence was evaluated using the Cochrane risk of bias tool. Continuous outcomes were expressed as mean differences or standardised mean differences with 95% confidence interval. Data were pooled using fixed-effects models. Nine randomised controlled trials met the inclusion criteria. Studies were classified into three distinct comparisons: Low-dose macrolide therapy vs. placebo, low-dose macrolide +/- nasal steroids vs. nasal steroid and low-dose macrolides vs. other therapies. The overall quality of the evidence is low due to limitations in study design, imprecision, and indirectness. Positive results were seen with the use of macrolide therapy in the postoperative period in patients with nasal polyps. A firm conclusion with respect to the effectiveness of the use of macrolides for the treatment of chronic rhinosinusitis cannot be reached based on the available evidence. Further study using a placebo-controlled design evaluating the use of macrolides in clearly defined chronic rhinosinusitis populations is needed.

Macrolides for Clinically Significant Bronchiectasis in Adults: Who Should Receive This Treatment?

Long-term macrolide therapy offers an evidence-based treatment to reduce frequent exacerbations in stable adult patients with bronchiectasis. There is limited evidence that these agents also attenuate the decline in lung function and improve health-related quality of life. The benefits and risks of long-term macrolide use need to be clearly explored for individual patients. Further work is needed to understand the optimal drug, dose, and regimen, the mechanisms behind these benefits, appropriate patient selection, sustainability of efficacy, potential long-term risk for the lung microbiome; and their use with or without inhaled antibiotic treatment. We reviewed the current evidence on long-term macrolides in adults with bronchiectasis.

Bronchiectasis in yellow nail syndrome.

Yellow nail syndrome (YNS) is a rare and poorly described disease process. In this case-control study, clinical features and findings on HRCT were compared with idiopathic bronchiectasis (IBx). A review of all patients attending an adult bronchiectasis clinic between 2007 and 2013 identified 25 YNS patients. IBx patients were matched in a 2:1 ratio for age, duration of symptoms and gender. Median age of onset was 53 years. There were 12 male and 23 Caucasian YNS patients. Respiratory manifestations included chronic productive cough (100%), chronic rhinosinusitis (88%), pleural effusions (20%) and lymphoedema (12%). Chest symptoms preceded yellow nails in the majority (68%). Abnormal nails persisted at follow-up in 23 of 25 patients but improved in 14. In both disorders, there was symmetrical, predominantly lower lobe bronchiectasis on HRCT. Extent (P = 0.04), severity (P = 0.03) and bronchial wall thickness (P = 0.05) scores were lower in YNS, with less upper and middle lobe disease. Multivariate analysis showed an independent association with increased mucus plugging in YNS. There was a similar prevalence of Pseudomonas aeruginosa infection and mild lung function abnormalities. Bronchiectasis in YNS is less severe than IBx but is associated with increased mucus plugging, onset is in middle age and there is no female predominance. Treatment targeted at improved secretion clearance may improve both chest and nail symptoms, with consideration of long-term macrolide antibiotics.

The value of a feasibility study into long-term macrolide therapy in chronic rhinosinusitis

There is currently conflicting level 1 evidence in the use of long-term antibiotics for chronic rhinosinusitis without nasal polyps. The primary aim of this feasibility study was to optimise future randomised trial design by assessing recruitment and retention of patients alongside providing preliminary data on symptomatic control. Prospective, multicentre feasibility (cohort) study with all patients receiving macrolide therapy for 12 weeks and a further subsequent 12-week follow-up. Participants received a 12-week course of clarithromycin 250 mg alongside twice daily topical mometasone and nasal douching. Primary outcomes focused on recruitment, retention and compliance. Clinical and quality-of-life outcomes measures were also recorded. Patients were prospectively recruited from six UK outpatient clinics. Adult patients with chronic rhinosinusitis without nasal polyps and no prior endoscopic sinus surgery underwent baseline assessment and then follow-up at 3 and 6 months. Six-month recruitment and retention data. Over 13 months, 55 adults were recruited from five centres. Four patients declined participation. 75% of patients were retained within the study. Dropouts included one medication contraindication, three unable to tolerate medication and 10 not attending full follow-up. Sino Nasal Outcome Test-22 and endoscopic scores showed statistically significant improvement. No other clinical or quality-of-life assessment improvements were seen. Retention and recruitment to a trial using long-term clarithromycin to treat chronic rhinosinusitis without nasal polyps is achievable and this data will support a future randomised controlled trial. The study provides vital insight into trial design, thus informing UK research networks and rhinology researchers internationally.

Acute exacerbation of COPD.

The literature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is fast expanding. This review focuses on several aspects of acute exacerbation of COPD (AECOPD) including epidemiology, diagnosis and management. COPD poses a major health and economic burden in the Asia‐Pacific region, as it does worldwide. Triggering factors of AECOPD include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. Disruption in the dynamic balance between the ‘pathogens’ (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. The diagnostic approach to AECOPD varies based on the clinical setting and severity of the exacerbation. After history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest X‐ray and blood tests for inflammatory markers. Arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. Depending on the severity, the acute management of AECOPD involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. Hospitalization may be required, for severe exacerbations. Nonpharmacological interventions including disease‐specific self‐management, pulmonary rehabilitation, early medical follow‐up, home visits by respiratory health workers, integrated programmes and telehealth‐assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent AECOPD. Pharmacological approaches to reducing risk of future exacerbations include long‐acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long‐term macrolides. Further studies are needed to assess the cost‐effectiveness of these interventions in preventing COPD exacerbations.

Lung transplantation for diffuse panbronchiolitis: 5 cases from a single centre.

Diffuse panbronchiolitis is a rare complex genetic disease predominantly affecting East Asians, and is characterized by chronic inflammation of the respiratory bronchioles and sinobronchial infection. Although long-term macrolide therapy has been shown to significantly improve the survival in patients with diffuse panbronchiolitis, some patients continue to deteriorate, eventually requiring lung transplantation. However, lung transplantation for diffuse panbronchiolitis has rarely been reported and the outcome in these patients remains unknown. We describe our experience of lung transplantation for diffuse panbronchiolitis. A total of 5 patients received long-term macrolide therapy and had airway colonization by Pseudomonas aeruginosa preoperatively. Three patients had undergone sinus surgery for chronic rhinosinusitis before the transplantation. Bilateral cadaveric lung transplantation was performed in 4 patients, and living-donor lung transplantation in 1. After the lung transplantation, 1 patient developed an A3 acute rejection episode; however, none of the recipients developed severe pneumonia or any fatal infections. One recipient developed chronic lung allograft dysfunction 3 years after the transplantation; however, none developed recurrence of diffuse panbronchiolitis. All of the 5 patients were still surviving after a median follow-up period of 4.9 years (3.7-12.3 years). Lung transplantation is a viable option for the treatment of progressive diffuse panbronchiolitis resistant to long-term macrolide therapy.

Remission of ALK-negative primary pulmonary inflammatory myofibroblastic tumor on treatment with clarithromycin: A case report and review of the literature.

Inflammatory myofibroblastic tumors (IMTs) belong to an intermediate group of soft-tissue tumors, they are relatively rare but exhibit a wide range of pathologies, from benign to malignant. At present, no standard treatment has been established, however, it is known to be important to determine the grade of malignancy of the tumor, prior to treatment. The present study reports a 73-year-old female patient with no clinical manifestations, who, when examined radiographically at a health check exhibited bilateral thoracic infiltrative shadows and nodular shadows by chest CT. A metastatic tumor or an organizing pneumonia were suspected. Blood examination showed no abnormal findings, and a pathological diagnosis of IMT was given from the histological findings of the tissue extracted by video-assisted thoracic surgery. Histological analysis established the lack of expression of anaplastic lymphoma kinase (ALK1) and immunoglobulin subtype G4 (IgG4). Alteration of the radiological shadows was observed over several weeks, and after concluding that chronic inflammation was worsening the patient's condition, clarithromycin was administered as a long-term macrolide therapy. The IMT decreased in size, and eight months later it had almost resolved. The patient was last reported to be maintaining a stable condition with no relapse. Some IMT cases have malignant pathology, and should be carefully followed-up. However, in the present case, where the IMT is both ALK1-negative and IgG4-negative, its biological immune responsiveness appears to differ from positive cases, and an inflammatory response was predominant. Clarithromycin, has immunomodulatory and anti-inflammatory effects and appeared to be effective in treating the IMT of the patient in the present study.

Long-term postoperative azithromycin in patients with chronic rhinosinusitis: A randomized clinical trial.

Chronic rhinosinusitis (CRS) is recognized as a common disease that imposes a big burden on the health system worldwide. There is ongoing evidence of the anti-inflammatory effect of long-term macrolide in the management of patients with CRS. The aim of this randomized clinical trial was to evaluate the efficacy of long-term consumption of low-dose azithromycin after functional endoscopic sinus surgery. Sixty-six patients who fulfilled the inclusion criteria were randomly divided into intervention and control groups. The subjects received the standard conventional treatment (fluticasone nasal spray plus normal saline solution irrigation) or the conventional treatment plus 250 mg of azithromycin on a daily basis for 3 months. Evaluation was made based on the 22-item Sino-Nasal Outcome Test (SNOT-22) immediately before surgery and 3 months after surgery. The intervention group showed a statistically significant improvement in SNOT-22 scores after the treatment and a higher percentage change after 3 months of therapy compared with the control group. A significant correlation was found between the percentage change of SNOT-22 scores and smoking in the placebo group. Lund-Mackay scores, patient age, and the duration of symptoms had no significant correlation with the percentage change. Treatment with long-term low-dose azithromycin in combination with the conventional therapy could statistically reduce the recurrence rate of CRS symptoms after functional endoscopic sinus surgery, but there was not sufficient evidence to support clinical significance of azithromycin at the investigated dose. Further larger scale trials, along with a longer follow-up period, is needed to evaluate the effectiveness of the therapy.

Pharmacological management of chronic obstructive pulmonary disease.

There have been significant changes in the approach to the management of chronic obstructive pulmonary disease (COPD) over the pastdecade. The World Health Organization suggests four componentsto a COPD management plan: (i) assess and monitor disease; (ii) reducerisk factors; (iii) manage stable COPD; and (iv) manage exacerbations. Encouraging patients to limit their risk exposure is essential, whetherit be smoking cessation or removing exposure to biomass.The main objective of treatment is to relieve daily symptoms, improve quality of life and importantly decrease the risk of futureexacerbations. Current guidelines are based on grade A and B evidence. Pneumococcal and annual influenza vaccinations are encouraged.A holistic approach that augments pharmacological treatment includes good nutrition and pulmonary rehabilitation.Bronchodilators are the cornerstone of management. Depending on the patient’s placement in the GOLD ABCD classification, treatmentis individualised. Short-acting bronchodilators are used as rescue medication, while long-acting bronchodilators or/and long-actingmuscarinic agents are the treatment of choice for patients in groups B, C and D. Inhaled corticosteroids are only recommended for groups Cand D. Most patients respond well to combinations of the abovementioned medications. For patients who still have frequent exacerbations,alternative choices include long-term macrolides and phosphodiesterase 4 inhibitors.

Groups Issue Guideline on COPD Exacerbations

Groups Issue Guideline on COPD Exacerbations

Management of bronchiectasis in adults.

Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials.

COPD Treatment Improves Quality of Life

COPD Treatment Improves Quality of Life

The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial

Long-term macrolide treatment has proven benefit in inflammatory airways diseases, but whether it leads to changes in the composition of respiratory microbiota is unknown. We aimed to assess whether long-term, low-dose erythromycin treatment changes the composition of respiratory microbiota in people with non-cystic fibrosis bronchiectasis. Microbiota composition was determined by 16S rRNA gene sequencing of sputum samples from participants in the BLESS trial, a 12-month, double-blind, placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg) in adult patients with non-cystic fibrosis bronchiectasis and at least two infective exacerbations in the preceding year. The primary outcome was within-patient change in respiratory microbiota composition (assessed by Bray-Curtis index) between baseline and week 48, comparing erythromycin with placebo. The BLESS trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000460303. The BLESS trial took place between Oct 15, 2008, and Dec 14, 2011. Paired sputum samples were available from 86 randomly assigned patients, 42 in the placebo group and 44 in the erythromycin group. The change in microbiota composition between baseline and week 48 was significantly greater with erythromycin than with placebo (median Bray-Curtis score 0·52 [IQR 0·14-0·78] vs 0·68 [0·46-0·93]; median difference 0·16, 95% CI 0·01-0·33; p=0·03). In patients with baseline airway infection dominated by Pseudomonas aeruginosa, erythromycin did not change microbiota composition significantly. In those with infection dominated by organisms other than P. aeruginosa, erythromycin caused a significant change in microbiota composition (p=0·03 [by analysis of similarity]), representing a reduced relative abundance of Haemophilus influenzae (35·3% [5·5-91·6] vs 6·7% [0·8-74·8]; median difference 12·6%, 95% CI 0·4-28·3; p=0·04; interaction p=0·02) and an increased relative abundance of P aeruginosa (0·02% [0·00-0·33] vs 0·13% [0·01-39·58]; median difference 6·6%, 95% CI 0·1-37·1; p=0·002; interaction p=0·45). Compared with placebo, erythromycin reduced the rate of pulmonary exacerbations over the 48 weeks of the study in patients with P. aeruginosa-dominated infection (median 1 [IQR 0-3] vs 3 [2-5]; median difference -2, 95% CI -4 to -1; p=0·01), but not in those without P. aeruginosa-dominated infection (1 [0-2] vs 1 [0-3]; median difference 0, -1 to 0; p=0·41; interaction p=0·04). Long-term erythromycin treatment changes the composition of respiratory microbiota in patients with bronchiectasis. In patients without P. aeruginosa airway infection, erythromycin did not significantly reduce exacerbations and promoted displacement of H. influenzae by more macrolide-tolerant pathogens including P. aeruginosa. These findings argue for a cautious approach to chronic macrolide use in patients without P. aeruginosa airway infection. Mater Adult Respiratory Research Trust Fund.

Macrolide antibiotics for treatment of asthma in adults: A meta-analysis of 18 randomized controlled clinical studies

Mounting studies have been showed that long-term macrolides used in patients with asthma could improve the lung function and symptoms. However, a large number of studies have reported inconclusive results. The aim of this meta-analysis was to investigate the effect of macrolide antibiotics in patients with asthma. We have performed a search in PubMed, Embase, China National Knowledge Internet (CNKI), and Wanfang databases. The weighed mean difference (WMD) or standardized mean difference (SMD) was used to evaluate the pooled effect. Statistical analysis was performed by STATA 11.0 software. Totally 1306 patients were included in the meta-analysis. The overall results indicated that statistically significance of long-term macrolides therapy in patients with asthma on forced expiratory volume in 1 s (FEV1) (WMD: 0.11, P < 0.01), peak expiratory flow (PEF) (SMD: 0.25, P = 0.001), airway hyper-responsiveness (AHR) (SMD: 0.90, P = 0.04), forced vital capacity (FVC) (WMD: 0.18, P = 0.05) and FEV1/FVC (WMD: 1.93, P < 0.001), but no statistically significance on FEV1/predict, FVC/predict, symptom scores, quality of life scores (QOL), reliever inhaler puffs per 24 h, and cell counts in sputum and blood. The subgroup analysis indicated macrolides could increase FEV1 and PEF in Caucasian and Asian, decrease AHR in Caucasian, while cells counts of sputum improvement among Asian. Therefore, the study suggested that long-term marolides therapy in asthma may improved the FEV1, PEF, AHR, FVC, FEV1/FVC and cells counts in sputum, but it can't improve other lung function (FEV1/predict and FVC/predict) and clinical outcomes (such as symptom, quality of life etc.).

Preliminary Findings: The Feasibility Study for a Randomized Controlled Trial of Clarithromycin in Chronic Rhinosinusitis

Objectives: There is currently conflicting level 1 evidence in the use of long-term antibiotics for chronic rhinosinusitis. The primary aim of this study was to look at recruitment and retention of patients in preparation for a formal trial. The aim of this paper is to describe the preliminary outcomes in terms of symptomatic relief in patients with CRSsNP. Methods: Adult patients fulfilling the EPOS criteria for CRSsNPs with no prior surgery were recruited in 6 UK centers during 2013. Participants received a 12-week course of clarithromycin 250 mg alongside topical mometasone and nasal douching, all twice daily. Follow-up was at 3 months and 6 months. For the purpose of this analysis, the Sinonasal Outcome Test (SNOT-22) score was recorded at baseline and both follow-up assessments. Results: Preliminary data from 29 patients at 3 months and 24 patients at 6 months showed significant symptomatic improvement in mean SNOT-22 scores on paired t tests at 3 months (40.4 to 33.7, P = .026), which was sustained at 6 months (30, P = .02). The number of subjects showing ≥9 point reduction in SNOT-22 scores was 45% (n = 13), increasing to 58% at 6 months (n = 14). Nine patients have been listed for surgery to date. Conclusions: While the results here do not have the power of the full randomized controlled trial, the findings suggest that long-term macrolides have the potential to achieve significant symptomatic reduction in approximately 50% of patients with CRSsNPs.

Long-term macrolide therapy in chronic obstructive pulmonary disease.

See also commentary on page [1127][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.140572][2] Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by worsening respiratory symptoms, which are almost always accompanied by an increase in airway inflammation.[1][3]–[3][4]

Advantages and drawbacks of long-term macrolide use in the treatment of non-cystic fibrosis bronchiectasis.

Non-cystic fibrosis (non-CF) bronchiectasis is a respiratory disease characterized by persistent airway inflammation and dilation of bronchial wall driven by various causes. Patients with bronchiectasis suffer from excessive sputum production, recurrent exacerbations, and progressive airway destruction. Major therapy for bronchiectasis is focused on breaking the "vicious cycle" of mucus stasis, infection, inflammation, and airway destruction. Growing evidences have been shown that macrolides possess immunoregulatory and anti-inflammatory functions beyond their antimicrobial effects. Macrolide antibiotics have been effectively used in the treatment of diffuse panbronchiolitis, CF and bronchiolitis obliterans syndrome. Currently a number of clinical trials were performed to assess macrolide treatment in the management of non-CF bronchiectasis. The purpose of this paper is to review the efficacy and potential risks of these recent studies on the use of macrolides in non-CF bronchiectasis.

Macrolides for bronchiectasis and chronic obstructive pulmonary disease: should we worry about antimicrobial resistance?

The past 18 months have seen a relative explosion of high-quality publications in non-cystic fibrosis (CF) bronchiectasis (hereafter just termed bronchiectasis), with important data emerging in relation to both airway microbiology [1] and inflammation [2], and their relationships to key clinical markers [1–3]. Randomized controlled trials (RCTs) have proven the efficacy of oral macrolide antibiotics [4] and evidence is emerging of novel inhaled antibiotic formulations with potential efficacy [5]. The benefits of long-term macrolide therapy in this condition have been demonstrated in four high-quality RCTs, using either erythromycin or azithromycin [6]. Macrolide antibiotics have also demonstrated benefits in CF, diffuse panbronchiolitis and chronic obstructive pulmonary disease (COPD) [7] and there are ongoing studies in asthma, creating the impression of macrolides as a panacea for inflammatory airways diseases, with few attendant serious side effects. However, the primary risk related to these agents, the development of population anti microbial resistance, is largely covert and therefore difficult to appreciate. The majority of clinicians caring for subjects with bronchiectasis or COPD would cite potential macrolide side effects as nausea and gastrointestinal complaints, risk of sudden cardiac death associated with QTc prolongation and possibly ototoxicity and drug interactions. However, I suspect few would genuinely consider antimicrobial resistance a serious potential ‘side effect’. The widespread uptake of maintenance azithromycin for common inflammatory airway diseases (e.g., COPD) poses substantial risks of induction of macrolide resistance in bacterial pathogens in the community [7]. Clinicians recognize the esoteric concept that ‘antibiotic use increases resistance’, but may have difficulty grasping how that relates to their individual prescribing practices, or do not feel it is of sufficient concern to restrict their own prescription of azithromycin to patients. In the remainder of this paper, I will use a series of statements and questions, with responses, to address issues around maintenance azithromycin prescription and induction of population-level macrolide resistance.

148 Use of whole-genome sequencing to identify transmission of Pseudomonas aeruginosa between cystic fibrosis patients

Background Increasing numbers of individuals with cystic fibrosis are becoming infected with the multidrug-resistant non-tuberculous mycobacterium (NTM) Mycobacterium abscessus, which causes progressive lung damage and is extremely challenging to treat. How this organism is acquired is not currently known, but there is growing concern that person-to-person transmission could occur. We aimed to define the mechanisms of acquisition of M abscessus in individuals with cystic fibrosis. Method Whole genome sequencing and antimicrobial susceptibility testing were done on 168 consecutive isolates of M abscessus from 31 patients attending an adult cystic fibrosis centre in the UK between 2007 and 2011. In parallel, we undertook detailed environmental testing for NTM and defined potential opportunities for transmission between patients both in and out of hospital using epidemiological data and social network analysis. Findings Phylogenetic analysis revealed two clustered outbreaks of near-identical isolates of the M abscessus subspecies massiliense (from 11 patients), differing by less than ten base pairs. This variation represents less diversity than that seen within isolates from a single individual, strongly indicating between-patient transmission. All patients within these clusters had numerous opportunities for within-hospital transmission from other individuals, while comprehensive environmental sampling, initiated during the outbreak, failed to detect any potential point source of NTM infection. The clusters of M abscessus subspecies massiliense showed evidence of transmission of mutations acquired during infection of an individual to other patients. Thus, isolates with constitutive resistance to amikacin and clarithromycin were isolated from several individuals never previously exposed to long-term macrolides or aminoglycosides, further indicating cross-infection. Interpretation Whole genome sequencing has revealed frequent transmission of multidrug resistant NTM between patients with cystic fibrosis despite conventional cross-infection measures. Although the exact transmission route is yet to be established, our epidemiological analysis suggests that it could be indirect.

The evidence base for non‐CF bronchiectasis is finally evolving

See article, page 321