More Steroids Please


John came in to see me last week. He is 68 years old now and retired, and I’ve not seen him for around 8 years – since the diagnosis was made – he usually sees our practice nurse with a COPD interest or presents as an emergency. He came in to ask for just another week of steroids and antibiotics as his symptoms aren’t quite settled. He tells me he sees his specialist team at the local hospital, and at the annual review at the practice; he is always encouraged to treat his exacerbations early, as his two admissions a few years ago were to be avoided if possible. I scan his medical records and note that he is still smoking, is on “triple therapy” – has had 10 courses of prednisolone 30mg for 7 days and 12 courses of antibiotics over the last year. I ask him when he commences treatment for an exacerbation and he informs me he can usually tell when he wakes up if an exacerbation is on the way and initiates his self-treatment at that point with his steroids and antibiotics. He stops the course if he feels better by lunch time – but if not he will finish the course. He tells me he often has to come in like today to get further antibiotics or steroids if his symptoms haven’t settled….. 

So (I’m not going to tell you what I did … but I would like you to think about how you would manage this)…. I went off to look at the literature and guidelines. 
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It is always worth remembering that in the major worldwide respiratory trials the average exacerbation rate (for those being monitored in specialist care) is 0.79 – 0.85.1,2 So my first thought would be why is John having so many exacerbations (or are these not exacerbations)? In much of the literature exacerbations of COPD have been defined by the treatment required: 

Mild - being an increase in use of their short acting beta agonist. 
Moderate - requiring steroids or antibiotics or both. 
Severe - requiring steroids, antibiotics or both and hospital admission. 

We do however know from clinical experience that many patients can be over-treated for psycho-social reasons. We also know that those who are admitted to hospital have a considerable mortality (around 11% in a large European study died within 90 days of admission – 46% of these whilst an inpatient)3 -  hence we do need to manage exacerbations carefully. The COPD audit in England and Wales in 2014 found the inpatient mortality was 4.3% and of those discharged a further 8% died within 90 days.4


Is John right to start his treatment so early after he wakes up with symptoms?  

The literature appears to tell us that the majority of increased symptoms do not result in exacerbations. Indeed, within the first 24 hours of symptoms 55% settled spontaneously without the need for further treatment. Of those that do progress, 56% were considered acute (worsening over 1-2 days) and 44% gradual onset (worsening over 4 days) before symptoms reached the accepted severity for treatment.5

What I didn’t find in the literature was the diagnosed causes of breathlessness or cough in those with COPD either making decisions for self-treatment or seeing a clinician – the assumption being that in general if the problem is atrial fibrillation, cardiac failure, pneumonia, pneumothorax or other cause that this is different to an exacerbation. There has been research in specialist care for those seen in hospital implicating pulmonary embolus (3.3%) as an important differential even when treated as an exacerbation.6 At a practicing clinical level – it would certainly be sensible to consider face to face review if there is any doubt about symptomatology and the cause rather than try to manage over the phone. Certainly people with recurrent exacerbations with COPD should be considered for medication optimisation, exclusion of bronchiectasis or other conditions.  

And do we let our patients know after successful treatment how long an exacerbation of COPD will take to resolve? Well a follow up of more 10 patients (managed a hospital outpatient environment) for nearly 3 years suggests that symptoms will settle with a median recovery time of 7 days (interquartile range  4-14 days). Overall, at 35 days 86% of patients had recovered symptomatically – so it would not be unexpected for quite a few of our patient to still have symptoms.7

The causes of an exacerbation have been estimated – suggesting that exacerbations are due to infection (bacterial, atypical organisms, or viruses) in 50-70% and around 10% due to environmental pollution, whilst up to 30% are of unknown aetiology. The majority hence will be triggered by infection – with studies suggesting 30%-50% of these are bacterial.8 This perhaps challenges the current belief that people with an exacerbation should automatically have an antibiotic for a flare up. Indeed, with this data, less than half of exacerbations have a bacterial component.

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Now we come to the treatments.

Over recent years GOLD9 and NICE10 have been suggesting shorter courses of oral steroids – GOLD recommending a 5 day course based primarily on a trial involving 40mg for 5 days11 and NICE recommending 30mg for 5 days. These guidelines are supported by the Cochrane review12 which suggested that there was no difference in relapse rate, adverse events, length of hospital stay, lung function on shorter treatment – and a more recent Danish study of 67.000 found that longer courses of oral steroids resulted in an increased risk of pneumonia hospitalisation and all cause mortality when compared to shorter courses13 – though this study was observational and clinicians may well have been considering that longer courses were required with those with more severe exacerbations. 

The benefits of steroids in COPD when looking at the Cochrane review14 might be interesting to many. The review of all randomised trials (16 trials) suggests (with the vast majority of the trials being undertaken in specialist care – usually in hospital) that a course of steroid compared to placebo:

  • 4 studies showed no difference in treatment failure, relapse or mortality, but one of them showed a higher rate of hyperglycaemia for parenteral.
  • No difference between oral and parental corticosteroids (3 studies).
  • Treatment failure reduced by over half (odds ratio (OR) of 0.48 (95% confidence interval (CI) 0.35 to 0.67)
  • Lower rate of relapse at one month (2 studies) (hazard ratio (HR) 0.78; 95% CI 0.63 to 0.97).
  • Mortality up to 30 days not reduced with treatment
  • Adverse events increased with corticosteroids (OR 2.33; 95% CI 1.59 to 3.43) – this equated to one in every six people treated. 
  • Duration of hospitalisation was significantly shorter with corticosteroids (MD ‐1.22 days; 95% CI ‐2.26 to ‐0.18)
  • Corticosteroids made no difference to length of stay in intensive care. 
So – we should still be considering steroids for exacerbations – but their impact might not be quite as dramatic in the trials as many of us imagined.

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And what about antibiotics… 

GOLD9 suggests a 5-7 day course and NICE15 have recently produced specific guidelines regarding antibiotics and exacerbation in COPD. They suggest considering: 

  • Severity of symptoms (especially sputum colour changes and increases in volume or thickness of sputum)
  • The need for hospitalisation
  • Previous exacerbations and hospital admission history (as well as risk of developing complications)
  • Previous sputum culture and sensitivity results
  • Risk of antimicrobial resistance with repeated courses

NICE also suggest that some people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan. Again NICE suggest a five day course (first line being amoxicillin, doxycycline or clarithromycin).

A recent Cochrane review16 included 19 trials with 2663 participants (11 with outpatients, seven with inpatients, and one with ICU patients) and suggested that in those managed outside hospital

  • Reduced the risk of treatment failure (between 7 days and 1 month (212 per 1000 treated as compared to 295 per 1000 without treatment)
  • One trial in outpatients suggested no effects of antibiotics on mortality – and only one trial looked at health-related quality of life which did not show a significant difference between treatment and control
Of people who were inpatients
Antibiotics statistically significantly reduced risk of treatment failure 
Two trials showed no beneficial impact on mortality
Length of hospital stay was similar in antibiotic and placebo groups

The only trial of 93 patients admitted to intensive care showed 
Reduction in treatment failures from 565 to 107 per 1000 treated participants
Significant impact on mortality and on length of stay

So what have I learnt….

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I need to have a discussion with John – and share some of my learnings with him (and potentially others involved in his care). 

  • Not all early symptoms similar to an exacerbation proceed to become an exacerbation
  • Not every exacerbation will be the same
  • They are not all caused by a bacteria
  • The duration of an exacerbation is often longer, quite commonly 2 weeks and not uncommonly up to 5 weeks
However a person admitted to hospital has a significant mortality as does the next three months. Assuming a patient is improving – there does not appear to be evidence for a second or third course of steroids or antibiotics – and if the patient is not improving I would want to review face to face. The average patient in specialist care entered into large trials exacerbates on average less than once a year – hence more than two should alert us to other reasons for this – and an exploration of risk factors – potentially specialist review for consideration of longer term antibiotics. Similar with this frequency – I would hope that we review the patient face to face after every exacerbation.

The duration of a course of antibiotics and steroids is now from all guideline sources recommended to be 5 days – and no benefit from longer courses. Though some of the Cochrane review perhaps raises some surprises – Cochrane, GOLD and the recent NICE guidelines all continue to suggest the benefits of steroids and antibiotics for exacerbations.

References

  1. Tashkin D, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543 - 54.
  2. Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C, Jones P, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775 - 89.
  3. Hartl S, Lopez-Campos JL, Pozo-Rodriguez F, Castro-Acosta A, Studnicka M, Kaiser B, et al. Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit. European Respiratory Journal. 2016;47(1):113-21.
  4. Royal College of Physicians. COPD: Who cares? National Chronic Obstructive Pulmonary Disease (COPD) Audit Programme: Resources and organisation of care in acute NHS units in England and Wales 2014. London; 2014.
  5. Aaron SD, Donaldson GC, Whitmore GA, Hurst JR, Ramsay T, Wedzicha JA. Time course and pattern of COPD exacerbation onset. Thorax. 2012;67(3):238-43.
  6. Rutschmann OT, Cornuz J, Poletti P-A, Bridevaux P-O, Hugli OW, Qanadli SD, et al. Should pulmonary embolism be suspected in exacerbation of chronic obstructive pulmonary disease? Thorax. 2007;62(2):121-5.
  7. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-13.
  8. Sapey E, Stockley RA. COPD exacerbations · 2: Aetiology. Thorax. 2006;61(3):250-8.
  9. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD (2019). 2018.
  10. National Institute for Clinical Excellence. NG 115 Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NICE; 2019.
  11. Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309(21):2223-31.
  12. Walters, Julia A, Tan, Daniel J, White, Clinton J, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews [Internet]. 2018; (3). Available from: http://dx.doi.org/10.1002/14651858.CD006897.pub4.
  13. Sivapalan P, Ingebrigtsen TS, Rasmussen DB, Sørensen R, Rasmussen CM, Jensen CB, et al. COPD exacerbations: the impact of long versus short courses of oral corticosteroids on mortality and pneumonia: nationwide data on 67 000 patients with COPD followed for 12 months. BMJ Open Respiratory Research. 2019;6(1):e000407.
  14. Walters JAE, Tan DJ, White CJ, Gibson PG, Wood-Baker R, Walters EH. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2014(9).
  15. National Institute for Clinical Excellence. Chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing. London NICE; 2018 Dec 2018.
  16. Vollenweider DJ, Frei A, Steurer‐Stey CA, Garcia‐Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2018(10).

Dr Steve Holmes has received an honorarium from GSK for developing this article/content.

PM-GB-CPU-OGM-190002 October 2019

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PM-GB-CAU-WCNT-190006
March 2019