Researchers from the Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital and Trinity College Dublin have conducted a study which has found that Ireland has one of the highest incidences in the world of a genetic condition that causes severe hereditary emphysema.

The study raises the possibility that hundreds of people suffering from chronic lung disease could have this genetic condition but have yet to be diagnosed. It is hoped the findings of this study will lead to increased awareness of the disease and earlier diagnosis, which can contribute to a better quality of life for people with the condition.

The inherited condition Alpha-1 antitrypsin deficiency (Alpha-1) results in the most severe form of hereditary emphysema. The genetic disorder is caused by a deficiency in Alpha-1 antitrypsin, which protects the lungs from the harmful effects of cigarette smoke and bacterial infection. People with the condition develop chronic obstructive pulmonary disease (COPD) in their 40s and 50s and can also develop liver disease.

Thought to be a rare disease, this study has revealed that Alpha-1 is much more common than was expected in Ireland. One in 25 Irish individuals were found to be carriers for the gene responsible for the most severe form of Alpha-1, making the condition the most common fatal inherited lung condition in Ireland after cystic fibrosis. In its most severe form, Alpha-1 is estimated to affect more than 2,000 people nationally.

The study found that a further 10,000 Irish individuals are also at increased risk from a less severe form of the condition and an even larger number of 170,000 individuals are carriers of the condition and may be at risk of developing lung disease, particularly if they smoke.

Prof Gerry McElvaney, Professor of Medicine at the RCSI and senior author on the research, said: “Our study shows the prevalence of Alpha-1 in Ireland is among the highest in the world and although a simple blood test is all that is required to diagnose this condition, over 90 per cent of Alpha-1 individuals remain undiagnosed. The importance of an early diagnosis of Alpha-1 cannot be overstated as the proper medical follow-up and lifestyle changes can help prevent or at least delay the development of lung and liver disease associated with this condition and greatly increase life expectancy.”

In addition to examining the DNA of 1,100 individuals, randomly sampled from the general population, this study drew on results from the first 3,000 individuals screened as part of the ongoing Irish National Targeted Detection Programme for Alpha-1. This screening programme tested individuals suffering from lung and liver disease and identified more than 80 Alpha-1 individuals and over 400 carriers of Alpha-1. The team at Beaumont Hospital is working with some 25 hospitals around the country in an effort to identify Alpha-1 as early as possible.

Respiratory Research 2011, 12:91 doi:10.1186/1465-9921-12-91.

Smokers are twice as likely to quit their habit when receiving motivational text messages on their mobile phones through a quit-smoking programme, a report in the Lancet reveals.

Motivational texts included encouragement up to the actual quit day, advice on keeping weight off while quitting and help dealing with cravings, while non-motivational or ‘placebo’ texts simply thanked people for their participation or said a range of other things not connected to smoking itself.

The trial, the first such study to verify quit rates using biochemical testing, randomly allocated 5,800 UK smokers who were willing to quit to either the txt2stop intervention (2,915 smokers) or to a control group receiving only non-motivational texts (2,885 smokers).

Participants in the intervention group using pay-as-you-go mobile phone schemes were given a £20 top-up voucher to provide sufficient credit to participate in the intervention. At six months, the txt2stop group had a 10.7 per cent rate of biochemically confirmed abstinence, versus 4.9 per cent in controls.

“In this trial the intervention was effective on its own and when used alongside other smoking cessation interventions,” the authors said.

An accompanying comment said it was unfortunate that the continuous abstinence rate at six months in the intervention group compared with the control group was low (10.7 per cent), but that it was broadly similar to those of other behavioural interventions for smoking cessation trials.

It also noted, “the lessons learned could not only provide a new approach to smoking cessation in high- and middle-income countries, but could also be a useful starting point… in resource-poor settings”.

Lancet 2011. doi:10.1016/S0140-6736(11)60882-9

'Patients with severe persistent allergic asthma have symptoms despite optimised standard therapy'

Mary Anne Kenny reports on a new Irish study, which demonstrated how treating patients with severe persistent allergic asthma with Xolair could save hospital bed-days.

A new Irish study has shown how patients with severe persistent allergic asthma can benefit from omalizumab (Xolair) treatment and how this can also result in financial savings.

There are several different asthma classifications, one of the most troublesome of which is severe persistent allergic asthma. Patients with asthma who have persistent symptoms, despite treatment with inhaled steroids and long-acting beta agonists, are considered to have severe persistent asthma. They usually experience symptoms throughout the day, on most days, and also have frequent symptoms at night. These symptoms tend to limit a person’s physical activity. Patients may need to use a short-acting beta agonist several times daily, for symptom control.

A subset of this group is patients with severe persistent allergic asthma, in whom an allergic inflammatory cascade is triggered by allergens in the air. There are estimated to be 450 patients in Ireland with this even more severe type of asthma, whose quality of life is greatly affected by the condition.

People with severe persistent allergic asthma are generally initially treated with a combination of asthma medications, including long-term control medicines (inhaled corticosteroids) that reduce inflammation of the airways to prevent asthma symptoms and attacks; long-acting bronchodilators; and a quick-relief medicine (short-acting beta agonist or bronchodilator). This additional medication is used as needed to relieve acute symptoms by relaxing tightened muscles around the airways.

Immunoglobulin E
Severe persistent allergic asthma may additionally be treated with leukotriene modifiers. These are taken in pill form and are used in combination with the other medications. Another add-on option is omalizumab, a humanised monoclonal antibody directed against Immunoglobulin E (IgE), which is a root cause of the allergic inflammatory cascade that is triggered by allergens in patients with severe persistent allergic asthma. More than 120,000 patients worldwide have been treated with the drug, 190 of whom are Irish patients, according to the manufacturer’s data.

Omalizumab is recommended in the Global Initiative for Asthma (GINA) as an add-on treatment for patients who have moderate-to-severe persistent asthma, allergic sensitisation to an allergen and whose symptoms are inadequately controlled with inhaled corticosteroid and long-acting bronchodilator therapy. Studies have shown that treatment leads to a reduction in exacerbations and a reduction in the need for oral and inhaled corticosteroids.

In addition, immunohistochemical studies have shown that therapy with omalizumab reduces airway inflammation. Hence, omalizumab is a clinically and mechanistically effective therapy for patients who have a high morbidity from their asthma. However, as with all monoclonal antibody therapies, omalizumab is associated with a financial cost.

Cost-effectiveness
However, a recently published clinical paper on the cost-effectiveness of omalizumab shows that the treatment significantly reduced asthma exacerbations, hospitalisations and hospital bed-days for Irish patients. Published in the Irish Journal of Medical Science (entitled ‘Therapy with omalizumab for patients with severe allergic asthma improves control and reduces overall healthcare costs’), the principal investigator involved with the research was Prof Richard Costello, Consultant Respiratory Physician at Beaumont Hospital, Dublin.

“The aim of our observational retrospective cohort study was to assess the clinical benefit and healthcare utilisation of patients who responded to omalizumab therapy and to establish an overall cost implication,” he explained. “We hypothesised that despite the cost of the extra medication, there would be an overall cost-saving with the medication. To address this, we compared the number of exacerbations of asthma – including hospitalisation rates and use of oral corticosteroids – before and after six months of treatment with omalizumab in Irish patients.”

Omalizumab is recommended, within its licensed indication, as an option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy in adults and adolescents aged over 12 years.

To be included in the study, patients had to have been on omalizumab treatment for at least six months at the severe asthma clinics in respiratory centres in Ireland. Patients were identified and asked to participate by the lead consultant respiratory physician, nurse specialist or other senior members of the team.

They had received optimum standard therapy prior to starting omalizumab and had been fully compliant with other treatments, and yet their severe persistent allergic asthma had not been controlled. Optimised standard therapy was defined as a full trial of, and documented compliance with, inhaled high-dose corticosteroids and long-acting beta agonists in addition to leuko-triene receptor antagonists, theophyllines, oral corticosteroids and beta agonist tablets. On average, these patients had been hospitalised five times per year and had spent 24 days in hospital annually before treatment with omalizumab, due to their condition.

The study centres included: Beaumont Hospital; Mater Misericordiae Hospital; St Michael’s Hospital; the Adelaide and Meath Hospital, incorporating the National Children’s Hospital; the Midwestern Regional Hospital; and Merlin Park, Galway.

The study compared patient outcomes for six months pre treatment and six months post treatment. Sixty-three (32 male) patients were studied. “The primary endpoint was the number of exacerbations in the six months prior to and after omalizumab,” explained Prof Costello. “Secondary endpoints were: firstly, the number of emergency visits/hospital admissions pre- and post-treatment; secondly, lung function pre- and post-treatment; and thirdly, the use of oral corticosteroids, pre- and post-treatment.”

Audit results
In the six months prior to omalizumab, 41 patients (66 per cent) had been hospitalised and this fell to 15 (24 per cent) in the six months after treatment was started. The overall cost saving per omalizumab responder patient for six months was €834. The results of the audit showed a 67 per cent reduction in hospitalisations (p<0.0001) and a 68 per cent reduction in bed days  (p<0.0001). “This equated to a saving of 12 bed days per six months, per patient,” Prof Costello explained.

There was also a 61 per cent reduction in exacerbations. With regard to oral corticosteroid use in the six months before compared to the six months after, this was reduced from 27 (13 per cent) patients to 20 (7 per cent) patients. The median dose of corticosteroid was unchanged at 10mg. From an economic point of view, the results were impressive – the mean number of work days lost was 13.4 days in the six months before commencing omalizumab, whereas it was just 1.4 days in the six months after starting treatment.

“For the 450 severe persistent allergic asthma patients in Ireland, the benefits these patients have received from omalizumab are very impressive. They’ve significantly reduced the frequency and length of their hospitalisations and the treatment has allowed them to return to work and lead a normal life, as seen by the improvement in work days,” said Prof Costello.

Reimbursement programme
Overall, the figures for the study show that 77 per cent of patients who started omalizumab responded to treatment, with the remaining 23 per cent discontinued at the 16-week evaluation point. To ensure that the treatment is cost effective for every patient and for every hospital, Novartis Ireland is now introducing the Xolair Patient Outcomes Reimbursement Programme.

Under this scheme, Novartis will only charge hospitals for the patients who respond to treatment. For those patients who have not responded at the standard 16-week assessment and are having their omalizumab discontinued, the company will replace the stock used on the patients. The 16-week assessment should be carried out by a consultant respiratory physician and the decision to classify the patient as a non-responder and to discontinue treatment should be based on their clinical judgment. This innovative approach is designed to ensure that patients have access to treatment during this time of austerity.

So, what is the explanation for these patient improvements across so many areas with omalizumab treatment? “Omalizumab is a recombinant humanised gamma immunoglobulin 1 monoclonal antibody that binds IgE with high affinity,” the authors reported in the study paper. “It binds to a constant domain on the IgE heavy chain and causes down-regulation of IgE receptors on mast cells and basophils.

“These effects lead to clear effects on airway inflammation and exacerbations of asthma, but not bronchial hyperreactivity. Hence, it is not too surprising that the major benefit of omalizumab is in its effect on exacerbation rates and severity.”

The results of this study are in keeping with a number of recent reports in the literature from Europe, in which similar findings in terms of effect of omalizumab on exacerbation numbers and response occurring, regardless of the severity of the level of serum IgE.

“In summary, the results of this study show that there is a clear reduction in asthma exacerbations leading to reduced hospitalisation and a reduction in corticosteroid use among patients who responded to omalizumab,” the authors concluded. “These data suggest that this medication has clear clinical and economic benefits for appropriately chosen patients with severe persistent allergic asthma.”

References on request.

New research suggests widespread use of CT pulmonary angiography (CTPA) has led to substantial over-diagnosis of pulmonary embolism.

Writing in the Archives of Internal Medicine, the study authors suggested patients diagnosed with “clinically insignificant” PE through imaging may ironically be at more risk from the treatment than the PE itself.

The study, based on US nationwide data, found the introduction of CTPA in 1998 was associated with an 80 per cent increase in PE incidence, without a corresponding change in mortality — consistent with over-diagnosis.

Despite most surgical patients now receiving prophylaxis, PE incidence had risen substantially among the surgical population, and “dramatically” among obstetric patients (nearly tripling in the eight years after CTPA), the figures showed.

Meanwhile, PE mortality decreased more in the period before CTPA introduction (1993-1998) than after it (1998-2006) — 8 per cent vs 3 per cent reduction. And while the pre-CTPA anticoagulation complication rate was stable, the post-CTPA rate had increased by 71 per cent (P<0.001).

The authors said some of the “emboli” detected on CTPA may have been false-positives, while others might have been clinically insignificant. In both cases, treatment could be harmful.

They concluded that the evidence base for over-diagnosis needed strengthening and advocated a trial randomising stable patients with small emboli to observation versus anticoagulation.

An accompanying comment echoed this conclusion but pointed out that while there was good evidence that over-diagnosis was a real phenomenon, “it is very likely that a subset of patients with ‘incidental’ PE benefits from therapy”.

Archives of Internal Medicine 2011;171:831-837

Mortality associated with severe exacerbations is reported to be 40 per cent within 12 months of hospitalisation

Dr Ross Morgan outlines the different grading systems in chronic obstructive pulmonary disease and the various treatment methods tailored for different patient types.

Chronic obstructive pulmonary disease (COPD) is a progressive condition that is almost entirely preventable. It is increasingly recognised that there are significant extra-pulmonary effects that contribute to morbidity in the COPD patient. These include heart disease, osteoporosis, lung cancer, depression and musculoskeletal disorders, which also contribute to the exercise restriction seen in this condition.

Exacerbations of respiratory symptoms are very important clinical events in COPD. Cigarette smoking is by far the most significant risk factor for developing COPD. Of the top five major causes of death in developed countries, only COPD-related mortality continues to rise. The World Health Organization now ranks COPD as the fourth-leading cause of death worldwide, trailing only cardiovascular disease, pneumonia and HIV/AIDS.

The principal characteristic of COPD is irreversible airflow obstruction, as measured by a reduced forced expiratory volume in one second (FEV1). Spirometry, which provides the FEV1, can be performed in the office with a hand-held device and it allows simple severity assessment based on the degree of impairment in lung function.

Stage I represents mild impairment, with stage IV representing the most severe obstruction when the FEV1 is less than 30 per cent of predicted values, or where the patient has associated chronic respiratory failure. Individuals with signs and symptoms (i.e. chronic cough and dyspnoea) but who have normal lung function by spirometry are considered to be at risk (Stage 0) for developing the disease (see www.goldcopd.com for further information).

While this classification based on FEV1 is reproducible and a useful tool for assessing COPD severity in epidemiological studies, FEV1 is not a very good predictor of mortality. As a target for therapy, it almost always falls short. This has led in recent years to interest in a more meaningful, outcome-based stratification that takes into account the effects of the disease on the individual patient.

One such multidimensional grading system of patients includes body-mass index (advanced COPD is associated with cachexia), airflow obstruction (the FEV1), symptoms (dyspnoea scores), as well as exercise capacity. This composite BODE score has been shown to be a better predictor of healthcare utilisation and mortality.

What is most clinically relevant for COPD patients and their care-givers are the symptoms and exacerbations of the disease that adversely affect quality of life and often result in hospitalisation.

In relation to chronic bronchitis, chronic cough and sputum production should not be considered normal and when present, should trigger a search for an underlying cause. Chronic bronchitis is defined as a cough productive of sputum for at least three consecutive months during a period of two consecutive years.

Many patients minimise this symptom, referring to it as a simple ‘smoker’s cough’. However, chronic bronchitis reflects a deeper problem that relates to ongoing airway inflammation and injury. Even in the absence of accompanying airflow obstruction, it has been found to be associated with increased vascular morbidity in smokers.

Exacerbations
The most important event for patients with COPD is an exacerbation and could be considered in the same way as a myocardial infarct in the patient with underlying ischemic heart disease. Exacerbations typically occur suddenly (within three days) but can be associated with prolonged dyspnoea and exercise limitation, as well as significant morbidity from cardiovascular disease.

They cause major changes in health-related quality of life and increase hospitalisation and mortality. Importantly, they are inflammatory events associated with raised levels of C reactive protein (CRP) and white-cell count. Fatigue, in particular, can be a lasting component, taking months to resolve and for baseline exercise levels to return. Early pulmonary rehabilitation may have potential to speed up this recovery.

In most cases, acute exacerbations result from viral and/or bacterial infections. Air pollution may also contribute. The pathogens causing infectious exacerbations change as lung function declines. In early stages, viral infection and community-acquired bacteria are the most common pathogens, whereas in late stages of COPD, gram-negative bacteria, in particular pseudomonas aeruginosa, are thought to play a more significant role.

Treatment involves antibiotics as well as systemic corticosteroids that are usually required for two weeks. Mild exacerbations may be treated on an outpatient basis; however, during severe exacerbations, patients should be hospitalised. The mortality associated with severe exacerbations is reported to be as high as 40 per cent within 12 months of the hospitalisation.

An advance in the management of acute exacerbations has been the use of non-invasive positive pressure ventilation (NIPPV). This therapy, which makes use of a face or nasal mask to deliver air or oxygen under pressure to the patient, improves gas exchange, decreases the need for invasive mechanical ventilation and reduces in-hospital mortality and length of stay among COPD patients. Importantly, exacerbations of COPD tend to cluster and 30 per cent of patients hospitalised with acute exacerbation of COPD require readmission within eight weeks. Patients should therefore be followed carefully, probably with review at two weeks to ensure progress.

‘Bloaters’ and ‘Puffers’
COPD is a heterogenous disease with a number of well-described patient phenotypes. In the past, patients with end-stage disease were divided into ‘blue bloaters’, (dominance of bronchitic symptoms, fluid retention and chronic ventilatory failure) and ‘pink puffers’ (thin, emphysema predominant). Most patients with COPD, however, do not fit either classical description, particularly in earlier disease.

There is growing interest in identifying patient groups with particular characteristics that might be targeted for more or newer therapies. One such group may be the ‘frequent exacerbator’, as suggested by a recently published longitudinal study of over 2,000 patients with COPD followed for over three years.

The investigators found that while exacerbations were more common and more sev-ere with increasing stages of COPD, the single best predictor of an exacerbation throughout all stages of COPD (as defined by worsening FEV1) was exacerbation frequency in the previous year. In addition, most patients who had frequent exacerbations (three or more/year) in the first two years of the study continued to have frequent exacerbations in the third year. The other major association demonstrated in the study was that a history of reflux doubled the risk of exacerbations.

These findings suggest that disease activity, rather than disease severity as measured by the FEV1, could be a useful guide for intervention and therapy development in COPD. These therapies could be des-igned to control the current symptoms, as well as reduce future risks, mainly through a prevention of exacerbations.

Inhaled steroids have been found to reduce exacerbations in patients with advanced COPD (FEV1 less than 50 per cent) and recently an oral phosphodiesterase 4 inhibitor has received licensing in the UK for the same indication. In addition, the yearly influenza vaccination is recommended in all patients with COPD and reduces serious exacerbations and mortality. Most importantly, smoking cessation remains the most effective intervention for prevention and management of this disease.

References on request.

• Dr Ross Morgan, Consultant in Respiratory Medicine, Beaumont and Bon Secours Hospitals, Dublin

Dr Reggie Spelman looks at the latest studies and international best-practice guidelines for prescribing combination therapies

Combination therapies comprise an inhaled corticosteroid (ICS) and a long-acting β agonist (LABA), providing a dual anti-inflammatory and bronchodilator action. According to the British Thoracic Society (BTS) asthma guidelines, LABAs are the first choice of add-on therapy to inhaled steroids in adults and children aged between five and 12 years, but they are not recommended in the youngest group – those aged five years and younger.

It is suggested in the guidelines that a maximum dose of 400mg/day of steroid (beclomethasone equivalent) is used before adding in a LABA for children aged between five and 12 years old, and 800mg/day for adults.

Before starting combination therapy, it should be confirmed that there has been adequate adherence with previously prescribed ICS, and in the case of a child, that they have an appropriate delivery device and reasonable technique.

There is, however, concern being expressed in the various medical publications that they are being used by a majority of asthma patients (particularly children) with milder asthma.

This is significantly more costly and not in keeping with best practice, as recommended in international guidelines.

The Brussels Declaration on Asthma, sponsored by the Asthma, Allergy and inflammation Research Charity, was developed in 2007. One of its aims is to call attention to the shortfalls in asthma management. Its findings were published in the European Respiratory Journal in 2008, where it reported its concern that ‘’prescribing trends among children show that a combination of ICS and β-agonist therapy has become the mainstay of treatment in children’’. In this context, the authors referred to a study undertaken by Hans Bisgaard, Professor of Paediatrics at the University of Copenhagen and Head of the Danish Pediatric Asthma Centre, which was published in 2007 in The Journal of Allergy and Clinical Immunology.

By using a nationwide database on prescriptions filled, the study found a disconnect between the guideline recommendations on the use of a combination of ICS plus LABA for treatment of asthma in schoolchildren, with an excessive use of this combination therapy – particularly its use in approximately half of all children starting first-time ICS therapy.

A study of GP data in Australia attempted to outline the proportion of children with persistent asthma who may require combination therapy. Infrequent episodic asthma was described as the most common pattern found, accounting for 70-75 per cent of children with asthma.

Persistent asthma accounted for only 5-10 per cent of childhood asthma. Despite this, the percentage of prescriptions for combined therapy for children with asthma was found to be 20.6 per cent of the total of steroid inhalers.

UK figures
In 2007, a UK study published in Archives for Diseases in Children studied the trends in paediatric asthma drug prescribing in the UK in order to assess the potential impact of the publication of the British Thoracic Society (BTS) Asthma Guidelines.

The estimated community paediatric prescribing figures for asthma medications in the UK were studied using data from the NHS Information Centre for Health and Social Care for the years 2000-2006.

It reported that the percentage of steroid inhalers prescribed as combination inhalers of a steroid and a long-acting β agonist increased from 2.6 per cent in 2000 to 20.6 per cent in 2006.

The study concluded that the increase in the number of combination inhalers prescribed is not consistent with the guideline recommendations that combination inhalers should only be introduced in those patients with asthma not controlled on adequate doses of inhaled steroids.

Further education of health professionals is required, the authors suggested.

A UK Primary Care Trust Board Report (May 2010) rev-ealed that in the period from December 2004 to December 2009, prescribing and spending of LABA/ICS preparations had doubled to 2.4 million items, costing £125.6 million. They accounted for 54 per cent of all ICS prescribing and 80 per cent of the cost.

The increased prescribing trends and drug costs associated with combination therapy in Ireland can be seen from the annual statistical reports published by the Primary Care Reimbursement Service (PCRS). In Ireland in 2008, combination therapies accounted for 63 per cent of all ICS prescribing in the General Medical Services (GMS) scheme, and 73 per cent of the cost.

In the four-year period from 2005 to 2008, the GMS prescribing frequency for combination therapy rose from 329,556 items to 550,928, a percentage increase of 67 per cent. Prescribing costs for combination therapy increased from €22.3 million to €35.43 million – a percentage increase of 58.8 per cent. The number of patients in the GMS scheme during this period only increased by 17 per cent.

Clinical and cost benefits
Such dramatic increases in both prescribing frequency and medication costs of combined therapy would be appropriate if there was a demonstrable clinical benefit.

A recent study, however, presented at last year’s Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology found that nearly two-thirds of asthma patients were taking combination therapy – with no apparent additional clinical benefit.

The study evaluated 8,424 patients treated for mild asthma and found that 5,523 (66 per cent) were on combined ICS/LABA therapy and only 2,901 (34 per cent) were using an ICS alone. Among the two groups of patients, there was no significant difference in their use of acute asthma medications, Emergency Department visits or hospitalisations, indicating that there was no apparent additional clinical benefit gained from using the combined therapy compared to ICS monotherapy.

However, the study did find a difference in costs: the average asthma-related healthcare costs for those using the combination ICS/LABA therapy were $264 (€203) higher per patient per year than those using the ICS treatment alone. (In the GMS scheme, as illustrated in this article, the average difference in prescribing costs bet-ween these groups is €426.)

The study included all combination ICS/LABA drugs, confirming that this is a class effect rather than attributed to a single product. This study confirms that, based on pharmacy and medical claims, patients with mild asthma using only an inhaled corticosteroid seem to control their asthma just as well as those who take a combined ICS/LABA treatment.

The cost versus benefit of combination preparations was questioned by the authors, who reported on the highly-regarded Finnish 10-year asthma programme, which was published in Thorax. They observed: “The combination of inhaled steroids/β2 agonists may have improved the overall asthma control slightly, but at a high cost. They are therefore not recommended as first-line drugs. The unnecessary increase in drug costs should be halted.”

It would be expected that if asthma control had improved as a result of any intervention (i.e. increased combination therapy use), reliever medication use would reduce. During the period 2005-2008, when GMS combination therapy prescribing rose by 67 per cent, there was no reduction in the prescribing of reliever medication.

During this period, the prescribing frequency for inhaled salbutamol actually increased by 12 per cent.

The possibility that combination therapy has now become the treatment of choice by doctors for most asthmatics in Ireland is well known. The prescribing of combination therapy is seen to be in stark contrast to the prescribing of the three most commonly-used ICS over the same period.

The percentage of inhaled steroids prescribed as combination inhalers in the GMS in 2008 was 63.4 per cent (N.B. GPs are not solely responsible for GMS prescribing costs). A similar prescribing pattern for the prescribing of ICS alone and combination therapy can be seen in the Drug Payment Scheme (DPS).

The cost difference between initiating either low-dose ICS and combination therapy (step 2) is illustrated in the following charts, as is the cost difference between doubling the ICS dose or replacing it with low-dose ICS combination therapy (step 3).

Step 2
Beclomethasone 200μg daily
E38 per year
Combination Therapy
E324-E540 per year *
(In Denmark this option
has been taken in 50% of children)

Step 3
Double ICS dose
E38 per year additional cost
Combination Therapy
E324 – E504 per year
additional cost *

* Depending on product and delivery device.

A cost-benefit evaluation of ICS alone versus combination therapy can be made from a recent study published in CHEST in November last year by Postma et al. They studied 1,432 patients aged 12-75 years with mild persistent asthma in a randomised, double-blind, placebo-controlled study for 52 weeks. The authors estimate that mild, persistent asthma constitutes about 70 per cent of patients with asthma.

They compared benefits of first-line treatment with the ICS ciclesonide 160mg once daily (GMS cost €127) per year, and a combination of fluticasone 100mg and salmeterol 50mg twice daily (GMS cost €324 per year) in patients with mild asthma. Each medication was administered via a metered-dose inhaler. The primary variable was time to first severe asthma exacerbation; the co-primary variable was the percentage of poorly-controlled asthma days.

The study reported that while only the combination therapy increased time to the first exacerbation, the ICS achieved similar levels of daily asthma control as the combination, when compared with placebo in patients with mild, persistent asthma.

Quality of life
Similar improvements were seen in poorly-controlled asthma days; percentage of asthma symptom- and rescue-medication-free days; percentage of days with asthma control; salbutamol use; asthma symptoms; and quality of life scores with the two active treatments.

In addition, the combination improved forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) compared with placebo, which is to be expected given the bronchodilation provided by the LABA and findings in earlier studies, but this may be less important than the improvements in asthma symptoms, rescue medication need and asthma control.

The difference between the two active treatments in time to first asthma exacerbation was at variance with findings in the optimal treatment for mild asthma (OPTIMA) trial, which compared the effects of adding a LABA (formoterol; 4.5μg twice daily) to budesonide (100μg twice daily) for one year in mild asthma patients.

In OPTIMA, the addition of formoterol improved lung function, but not the occurrence of exacerbations. The authors state that this study indicates that the majority of patients with mild asthma can achieve satisfactory asthma control with ICS monotherapy without the need to administer multiple medications.

This is in line with current asthma guidelines, which recommend ICS monotherapy as the preferred first-line treatment and to add a LABA only if patients fail to achieve control with ICS monotherapy.

Combination therapy may be required in some patients to attain full benefits for reducing exacerbations.

COPD
A major limiting factor in the interpretation of prescribing data for combination therapy is that it is also prescribed for patients with COPD. Just as the addition of a LABA to an ICS is only appropriate in asthma for those with moderate-to-severe disease who remain symptomatic on ICS therapy, in COPD it is the addition of an ICS to a bronchodilator (LABA or anti-cholinergic or both) that is only appropriate for those with severe COPD who also have frequent exacerbations (three or more a year).

Severe COPD is diagnosed in those with FEV1 <50 per cent predicted or FEV1/ forced vital capacity (FVC) <0.70. The combination therapies most likely to be used for severe COPD are the high-dose ICS combinations, i.e. Seretide 500 Diskus and Symbicort 400/12.

The GMS prescribing frequency for both products are readily obtainable from the HSE Primary Care Reimbursement Service.

In 2008, the ratio of low- to high-dose combination therapy prescriptions in the GMS was 65:35. In the UK, the asthma-to-COPD prescribing ratio has been reported as 79:21.

General practice study
A study conducted in nine UK general practices reported that of 434 patients who fulfilled six criteria specifically chosen to identify patients who probably had COPD rather than asthma, it was found that 72 per cent of patients diagnosed COPD were prescribed ICS.

Assuming that the BTS guidelines had been adhered to, only 10-15 per cent of these patients should have received this medication. While acknowledging therefore that 35 per cent of combination therapy prescribing and associated costs in the GMS may be for COPD, it is possible, based on UK data, that 85-90 per cent of this might be inappropriate.

In summary, ICS-alone inhalers should be the mainstay for the vast majority of patients with asthma who require controller medications.

Combination inhalers should only be introduced in those patients with asthma not controlled on adequate doses of inhaled steroids.

A significant additional benefit of the LABA/ICS combination has not been proven for milder disease and so should not be introduced earlier than guidelines recommend. The increase in the number of combination inhalers prescribed is not consistent with current guideline recommendations.

Fixed-dose combinations of an ICS and a long-acting β2 agonist (LABA) should not be used for initial therapy for patients with COPD. They are appropriate only for patients with sev-ere COPD (FEV1 <50 per cent predicted) who also have frequent exacerbations (three or more a year).

Initiating therapy
Before initiating combination therapy for a patient with asthma, it should be confirmed that:

• Control has not yet been achieved at maximum dose of 400mg/day of ICS alone (beclomethasone equivalent) for children aged five-to-12 years old, and 800mg/day for adults;

• If control has not been achieved at these doses, confirm that there has been adequate adherence with the previously prescribed ICS, and reasonable technique also that a child has an appropriate delivery device.

Before repeating a prescription for combination therapy for a patient with asthma, it should be confirmed that the initial prescription was appropriate as per the points above.

In addition:

• They should be stopped if regular use has failed to attain asthma control;
• Back-titrate when asthma symptoms have been stable for three months. Consider stepping down medication by reducing the inhaled corticosteroid dose by 25 per cent to 50 per cent or, if the combination therapy is already with the lowest inhaled corticosteroid dose, stop the LABA.

Trials have found that people with stable asthma can step down high-dose inhaled corticosteroid (alone or in combination with a LABA) without worsening symptoms, including exacerbations (over one year of follow-up).

Before initiating combination therapy for a patient with COPD, it should be confirmed that the patient has severe COPD (FEV1 <50 per cent predicted) and also has had frequent exacerbations (three or more a year).

• Dr Reggie Spelman is a general practitioner at the Health Centre, Bridgetown, Co Wexford.

Children who attend large crèches before the age of two-and-a-half years appear to develop more respiratory and ear infections at that age, but fewer such illnesses during primary-school years, according to a new report from Canada.

The report followed a study of 1,238 families with newborns in 1998. Mothers reported whether their children went to a large crèche (with more than eight children), a small crèche with three to eight children) or were cared for at home.

For eight years, the researchers regularly obtained information about how often the children had respiratory-tract infections, ear infections or gastrointestinal infections during early pre-school (before age 2.5 years), late pre-school (ages 3.5 to 4.5) and early primary school (ages 5 to 8).

Compared with children cared for at home until elementary school, those who began attending large-group childcare before the age of 2.5 years had higher rates of respiratory infections and ear infections during early pre-school, the same risk of infection during the late pre-school period, but lower risks of contracting respiratory tract or ear infections during early elementary school.

However, those who started in small-group childcare in early pre-school and never went into large-care settings did not have any differences in infection risk. Moreover, those who were first cared for at home but then started at any size of childcare facility during late pre-school had a higher risk of ear infections at that time, but no other differences in infection risk.

Group childcare was not associated with gastrointestinal infections at any period in the children’s development.

The findings suggest that developmental processes may underlie the association between early exposure to large groups of children and reduced infection risk, the study’s authors noted.

“One possible mechanism that has received empirical support in the context of long-term protection against asthma involves an increased, repeated stimulation of the immature immune system by early and mild infections,” the researchers wrote.

“Future studies are necessary to investigate this and other mechanisms that may account for the results.”

Archives of Pediatrics and Adolescent Medicine 2010;164:1132-1137

Dr Tim McDonnell, HSE's COPD Clinical Lead

The HSE’s Clinical Lead for COPD, Dr Tim McDonnell, tells Gary Culliton about the COPD programme’s aim to cut hospital admissions and make spirometry more widely available to GPs throughout the country

Chronic obstructive pulmonary disease (COPD) is an increasing problem that has not been managed well, according to the HSE’s COPD Clinical Lead, Dr Tim McDonnell.

The condition accounts for 12,000 hospital admissions yearly and the Executive’s new COPD programme aims to cut this total by 1,500. The “over arching aim” of the programme, he said, was to save 50 deaths a year from COPD (which covers chronic bronchitis and emphysema).

UK figures show that a person who goes into hospital with a COPD exacerbation has a 15 per cent chance of dying within three months and a 25 per cent likelihood of dying within a year.

There are 100,000 people in Ireland who have been diagnosed with the disease, it is estimated. But for every patient who is diagnosed, there are probably two undiagnosed individuals.

The new programme’s objectives also include decreasing morbidity and mortality, through early diagnosis and correct treatment.

Shortness of breath interferes with quality of life for COPD patients. Exacerbations lead to chest infections during the winter months and, in serious circumstances, to hospital admissions. COPD accounts for 120,000 hospital bed-days per year: the average length of stay in hospital is 10 days. Most admissions are through the ED.

This is not the full picture, however, Dr McDonnell told IMT. “Many people who are classified as having pneumonia have underlying COPD as a cause. Many people with COPD have complications after surgery and have a prolonged time in hospital,” the Clinical Lead said.

A Working Group on COPD has been deliberating since before the summer. “We have to develop a model of care that we can all buy into,” explained Dr McDonnell. The initial aim is to get the problem recognised early, with the objective of getting better and faster diagnoses for COPD patients. “The solution is not high tech: it involves getting spirometry tests available to people working in primary care.

“Strategies will involve getting people to access smoking-cessation services and quit smoking. Medication can make a difference if there is early intervention,” he said.

Imparting information

Information for patients is vital, he stressed. A patient website will be available soon, which will contain the same information GPs are seeing. “The key is getting patients to be partners in the management of their care,” said Dr McDonnell.

Practice-guideline protocols and modes of care in emergency departments are also being defined. Self-management can often enable patients to avoid the worst effects of exacerbations through early administration of steroids. Management plans for patients are also to be outlined.

A Regional COPD Lead has been appointed in each of the HSE regions. “There is no magic about this. A lot of good things are happening around the country. The task is to take best practice from that and to get it implemented nationwide,” Dr McDonnell said. “That much can be done within existing resources.”

COPD patients fear exacerbations most of all: these are miserable events. More is now known about what causes exacerbations and what can prevent them. “We need now to look at the process of how we deliver care to these patients,” said Dr McDonnell.

Guidelines will cover professional responsibilities. These indicate what should be done in a given circumstance (they set out certain treatments that a GOLD Stage II COPD patient should get, for example). Standards outline what is compulsory in terms of delivery of service. This includes what can be delivered locally — how quickly a patient with COPD will be seen in outpatients or the work that should be done there. Protocols will describe “the way things are done in institutions”, said Dr McDonnell.

Clinical programmes

The HSE’s clinical programmes are a joint initiative with the Royal College of Physicians of Ireland and the paramedical bodies. Consultants are involved in developing processes to manage sets of illnesses in a better fashion. They set out how services should ideally be delivered.

“We need to get COPD outreach programmes functioning better,” said Dr McDonnell. “The aim is to deliver the best care to patients, at the appropriate time, in the appropriate place. Overall the aim is to avoid patients having to go through the hospitalisation process. Hospital is miserable. If you can manage people in their own environment, that’s much better.”

Primary-care involvement

Not all COPD patients need to be in hospital – but equally, some COPD patients in the community do, in fact, need to be in hospital. “You need co-operation from family doctors, to integrate the system of care. Primary-care involvement has taken some time to get going,” Dr McDonnell admitted. The Irish College of General Practitioners has drawn up guidelines, but if GPs do not have the backup to make a diagnosis, that is a problem.

Primary care needs a lot more support and this is a priority, in Dr McDonnell’s view. Family doctors currently find it difficult to get good access to spirometry in an outpatient setting. However, some hospitals are now able to provide outreach spirometry to GPs.

“GPs need to be made aware of what’s there and we can do that without any money at all,” Dr McDonnell said. The programme is to run a trial in one area, with the aim of getting spirometry to primary care teams. This has been done very successfully in Glasgow.

If a patient deteriorates, hospital is often the only option a GP has. If there were COPD outreach care available for exacerbations, GPs might be able to manage the patients in the community, Dr McDonnell said. Good outreach programmes are running at Beaumont, St James’s and Mullingar hospitals. “It’s a matter of taking those templates and making them more widely available,” said the Clinical Lead. Many of these services are best delivered by nurses and physiotherapists.

Many of the new medications help in preventing exacerbations and patients who receive pulmonary rehabilitation are less likely to have exacerbations. The Working Group has also been examining the issue of pulmonary rehabilitation programmes, a number of which exist around the country. A number of studies indicate that if one has an exacerbation, one is then more likely to have another. This identifies a subgroup of patients that might benefit from more intensive intervention.

Improve quality of life

Dr McDonnell has been involved in pulmonary rehabilitation for many years. “I know it works and is effective for patients,” he said. Such programmes aim to improve exercise tolerance and quality of life, as well as reducing breathlessness in patients. If GPs had access to such services, that would clearly be of benefit, in Dr McDonnell’s view.

Chronic obstructive pulmonary disease (COPD)

This year’s World COPD Day focuses on increasing awareness of spirometry as a simple and painless way to determine lung health

World COPD Day is a global effort to boost people’s understanding of COPD and advocate for better care for patients. The aim of the awareness day this year, which falls on November 17, is to get patients to ask their doctors about the simple breathing test, spirometry. This year’s theme is: ‘2010: The Year of the Lung – Measure Your Lung Health’.

This message aims to raise awareness of spirometry as the gold standard for diagnosis of COPD, and emphasises the actions a person can take to safeguard his or her lung health.

World COPD Day is an annual event organised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). GOLD works with healthcare professionals and public-health officials to raise awareness of COPD and to improve prevention and treatment of this lung disease for patients around the world.

The first World COPD Day was held in 2002. It is now marked in over 50 countries, making the day one of the world’s most important COPD awareness and education events.

Reduce the burden

Each year, GOLD chooses a theme and co-ordinates preparation and distribution of World COPD Day materials and resources. Activities are organised in each country by healthcare professionals, educators, and members of the public who want to help reduce the burden of COPD.

Some of the events taking place in Ireland this year include a COPD Information Day for patients and the public, organised by Benbulben COPD Support Group and the respiratory staff of Sligo General Hospital.

Also in the West, Mayo General Hospital and Mayo COPD Support Group will be offering spirometry testing on November 17 and giving advice on COPD. Members of the support group will be present to speak with those tested and will encourage people with COPD to join the group and live life to the fullest.

COPD information posters and leaflets are also being distributed to GP surgeries and hospitals throughout Ireland to mark the day, and an awareness advertising campaign is running in the national media.

Last December, in Cancún, Mexico, the Forum of International Respiratory Societies declared 2010 to be the ‘Year of the Lung’. Its declaration stated: “We recognise that hundreds of millions of people around the world suffer each year from treatable and preventable chronic respiratory disease; acknowledge that lung health has long been neglected in public discourse; understand the need to unify different health advocates behind one purpose; express the urgency for increased awareness and action on lung health…and therefore declare 2010: The Year of the Lung.”

210 million people

According to the latest World Health Organization (WHO) estimates (from 2007), currently 210 million people have COPD and three million people died of COPD in 2005. The WHO predicts that COPD will become the third leading cause of death worldwide by 2030. With a prevalence of 7.3 per cent, it is estimated that about 325,000 people have COPD in Ireland, according to the Irish Thoracic Society (INHALE Report, 2008).

However, the exact figure is unknown as COPD continues to be under diagnosed, it says. Lack of awareness of the condition in Ireland is high, with 2008 research (‘Awareness of and Attitudes to COPD’) revealing that over three quarters (76 per cent) of the Irish population do not know what COPD is.

Preventable

The disease mainly affects those over 40 years of age and although it is a major cause of death and disability throughout the world, it is preventable. Early diagnosis and treatment can greatly reduce the rate of deterioration. One simple and painless test to assist in the diagnosis is a spirometry test, which can identify COPD in its early stages.

Early intervention can slow down or prevent further deterioration of lung function.

Among patients hospitalised for acute exacerbations of chronic obstructive pulmonary disease (COPD), those who received antibiotics in the first two hospital days had improved outcomes, according to a new American study.
In the study, doctors examined the association between the use of antibiotics and outcomes among patients hospitalised for acute exacerbations of COPD at 413 acute care facilities throughout the United States, between January 2006 and December 2007.

The primary outcomes analysed included a composite measure of treatment failure, defined as the initiation of mechanical ventilation after the second hospital day, inpatient mortality, or readmission for acute exacerbations of COPD within 30 days of discharge; length of stay, and hospital costs.
Of 84,621 patients, 79 per cent received at least two consecutive days of antibiotic treatment.
The researchers found that compared with patients not receiving antibiotics in the first two days, antibiotic-treated patients were less likely to receive mechanical ventilation after the second hospital day, had lower inpatient mortality, a lower incidence of treatment failure, and lower rates of readmission for acute exacerbations of COPD. Patients treated with and without antibiotics had similar lengths of stay, but patients treated with antibiotics had lower costs.
Patients treated with antibiotic agents had a higher rate of readmissions for the bacterial infection Clostridium difficile than those who were not treated.
JAMA 2010;303:2035-2042