Factors associated with relapse in adult patients discharged from the emergency department following acute asthma: a systematic review

Introduction

Asthma affects over 17.5 million adults in North America and its prevalence continues to rise, as evidenced by the 12.3% relative increase from 2001 (7.3%) to 2009 (8.2%).1 Worldwide, asthma prevalence ranges from low (underdeveloped countries) to high (developed countries).2 Asthma is predominantly a chronic disease that can be controlled with appropriate pharmacological and non-pharmacological interventions;3 however, exacerbations do not always respond to standard or additional treatment options, leading to urgent visits to health providers, admissions to hospital and, in severe and rare cases, death.4 In the USA, patients with exacerbations had significantly higher asthma-related healthcare costs: $1740 over 1 year compared with $847 for asthmatics without exacerbations.5 While patients with acute asthma often seek care in the emergency department (ED),6–8 most are successfully treated and subsequently discharged;7 ,8 only 6–12% of adult patients presenting to the ED with an exacerbation of asthma will be admitted.8 ,9

The understanding and management of acute asthma have advanced considerably in recent years. Current evidence-based guidelines (National Asthma Education and Prevention Plan (NAEPP),10 Global Initiative for Asthma (GINA),11 and Canadian Thoracic Society (CTS)12) suggest that early treatment with short-acting β₂-agonists, inhaled short-acting anticholinergic agents and systemic corticosteroids (SCS) will reduce hospitalisations. On ED discharge, SCS are recommended,13 ,14 and further studies suggest that prescribing inhaled corticosteroids (ICS) at discharge can reduce relapse following discharge at least in adult patients.15–17 ICS in combination with long-acting β-agonists (ICS/LABA) are more effective than ICS monotherapy in patients with persistent asthma, with the number needed to treat of 19 to prevent one exacerbation.18 On the other hand, the impact of non-pharmacological interventions (ie, ED-based educational strategies) on relapses remains unclear.19 ,20

While considerable improvement in the management of acute asthma should lead to better outcomes over time, practice variation does exist and many patients presenting to EDs do not always receive evidence-based treatment.13 Moreover, what works in certain settings may not be applicable to others. Despite the dissemination of effective interventions for the prevention of relapses after asthma exacerbations, these outcomes still occur, affect the quality of life21 of patients with asthma and represent significant costs to the healthcare system.5

A number of studies have examined factors associated with relapse outcomes in adults after ED discharge.22–26 Notwithstanding this research, there remains a relative paucity of literature attempting to compile the existing information to influence management. The objective of this study was to summarise the evidence regarding relapses and factors associated with increased relapse in patients discharged from EDs after being treated for asthma exacerbations.

Methods

Results

Search results

After combining the results of the electronic search strategy with the grey literature, removing duplicates, screening for titles and abstracts, and reviewing full-text articles, 10 studies were included in the review (figure 1). The most common reason for exclusion was a lack of multivariate analysis (n=55; including 19 randomised controlled trials (RCTs)), followed by studies that were not primary research (n=48). Studies which did not examine relapse (n=22) and those which had a partially or wholly inpatient population (n=20) were also excluded. A minority of studies (n=23) were excluded for various other reasons, such as the involvement of paediatric populations, or patient presentation to the ED was not due to acute asthma. A full list of excluded studies is available on request.

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Figure 1

PRISMA flow diagram illustrating the overview of the systematic literature search.

Primary outcomes

Relapse proportions

One RCT33 and seven observational studies22–24 ,26 ,28 ,30 ,32 ,33 reported the proportion of patients experiencing relapse after management and discharge for acute asthma. The authors of the two29 ,31 studies that failed to report their relapse proportions were contacted; however, in both cases, additional information was not obtained. Relapse proportions were recorded at 1 week,22–,24 ,26 ,32 ,33 2 weeks22–24 ,26 ,28 ,32 ,33 and 4 weeks.23 ,24 ,30 The relapse proportion at 2 weeks ranged from 4%31 to 17%.26 When 2-week and 4-week relapse proportions were examined based on the studies' last year of data collection, there were slightly lower relapse rates in recent years (figure 2). Six studies tracked relapse proportions at multiple postdischarge durations.22–,24 ,26 ,32 ,33 All six studies had the greatest proportion of relapses occurring within the first week, with a median of 61% (IQR: 50–68) of all relapses occurring during week one. After this early peak, relapse proportions appear to increase at a relatively linear rate between weeks 1 and 4 (figure 3). Median relapses were 8% at 1 week, 14% at 2 weeks, and 17% at 4 weeks (figure 3).

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Figure 2

Proportion of patients experiencing relapse relative to the year when the data were collected.

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Figure 3

Reported relapse rates at varying time periods after discharge from ED. Medians displayed with lines. Distinct studies represented by different colours. ED, emergency department.

Factors significantly associated with relapse

Although 19 RCT studies underwent a full-text review, only one paper was included.33 There were two studies which reported performing multivariate analyses, but the results were not presented.34 ,35 In the included RCT, there were three factors identified as significant on multivariate analysis: ICS use prior to ED presentation, prior intubation and female sex. The strongest association identified in the RCT was female sex (HR=7.2; 95% CI 2.3 to 23.1).

Factors commonly and significantly associated with relapse occurrence within 4 weeks of ED discharge in observational studies included: patient sex, previous healthcare usage, symptom duration and ICS usage at ED presentation (table 3). The most commonly investigated variable was female sex; from models reported in six studies,22 ,23 ,28 ,31–33 five reported a significant finding with aOR ranging from 1.17 (95% CI 1.03 to 1.34) to 7.2 (95% CI 2.3 to 23.1) (figure 4).

Table 3

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Factors significantly (p<0.05) associated, on multivariate analysis, with asthma relapse within 4 weeks of ED treatment (✓), factors studied but not found to be significant (ø) and factors not assessed (NA)

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Figure 4

Adjusted ORs for female sex acting as a predictor for acute asthma relapse after ED treatment and discharge. ED, emergency department.

Healthcare usage included subcategories (table 3) for ED asthma visits such as: visits that occurred in the past 6 months,24 1 year,26 and 2 years,22 past urgent clinic visits for asthma26 and prior hospitalisations for asthma.22 Severity at ED presentation was assessed using the Canadian Triage and Acuity Scale (CTAS) score of one.30 Symptom duration was assessed either directly by asking patients to report the length of their symptoms,23 ,26 or indirectly by asking how long they had been experiencing difficulty with activities or work.24 Symptoms present for over 24 hours had a relatively strong association with relapse, and had an aOR consistently above 1.5 (range: aOR: 1.7 (95% CI: 1.3 to 2.3) to aOR: 2.5 (95% CI: 1.2 to 5.2)). ICS usage (including ICS/LABA combination) at presentation had consistently positive associations with relapse (range: aOR: 1.39 (95% CI: 1.07 to 1.78) to aOR: 3.1 (95% CI: 1.0 to 9.8)).22 ,23 Increasing age, either by unit increase (aOR=0.98; 95% CI 0.97 to 1.0) or by age categories (eg, ages 46–55; aOR=0.81; 95% CI 0.69 to 0.94), was the only factor associated with a lower likelihood of relapse in more than one study.30 ,31

Discussion

This comprehensive systematic review identified 10 studies involving 32 923 patients that performed multivariate analysis to investigate factors associated with relapse after treatment for adult patients seen with acute asthma in the ED setting. Quality assessment showed that all included studies were of high methodological quality, which strengthens the validity of these results. Given the variations in models used to generate aORs and in the factors reported, results were not pooled in a traditional meta-analysis. Overall, there is strong evidence that women and patients on pre-existing ICS therapy are more likely to relapse, and perhaps should be managed more aggressively.

Relapse proportions were notably high within the first week in most of the studies which reinforces the need for primary care providers to see patients early after discharge to reassess response to therapy, adjust management and provide additional recommendations.11 Apart from two studies, relapses were relatively consistent across the included studies: one that reported relapse proportions of 4% at 2 weeks32 and another that reported 7.4% at 4 weeks.30 These two studies restricted their outcomes to patients relapsing to EDs and that may have influenced the estimates; all other studies provided patient-reported relapse outcomes involving multiple potential treatment location. In both studies,30 ,32 a large number (44.8% and 46.0%, respectively) of patients had outpatient follow-up arranged prior to discharge to address asthma symptoms, and this is a possible contributor to the significantly reduced proportion of patients relapsing. The author of the second study30 (based in Singapore and the only study included in this review that originated outside North America) acknowledged that the reported relapse proportions were lower than expected potentially due to differences in healthcare delivery relative to North America. One such difference is a higher availability of after-hours, or 24-hour, primary care.36 Given the relative recency of these two studies, they are potentially overstating the recent relapse reduction shown in figure 2; despite this, there is some evidence that the number of patients receiving guideline-recommended care in EDs has been increasing over recent years, leading to improved outcomes.13

It is important to highlight the large number of relapses occurring within the first few days after ED discharge. Nearly two-thirds of patients experiencing relapse do so within the first week and this appears to be an area where improved ED management, and perhaps strategies to prompt primary care follow-up, could improve outcomes.35

Many of the factors significantly associated with relapse risk on multivariate analysis make intuitive sense. Female sex is a predisposing factor for severe asthma37 and women have been shown to perceive symptoms differently, so it is perhaps not surprising that this review finds that female sex was also associated with more frequent relapses following ED visits for acute asthma. Logic predicts that patients with past tendencies to use the ED will not hesitate to return; likewise, patients who are experiencing unrelenting symptoms over a longer duration may be struggling with self-management of their asthma, or have more severe baseline disease, and may need urgent care. Indeed, lack of symptom improvement has been identified as a common cause for patients with asthma to seek urgent care.7 Although infrequently examined by these studies, medication cost and patient insurance certainly impact treatment efficacy, especially when we consider that up to 37% of patients will not fill their prescriptions after an asthma exacerbation.38 It was encouraging that results were directionally concurrent; in other words, there were no factors associated with relapse that were found to reduce relapse among the included studies.

Studies discussing asthma relapse are common in the medical literature; however, no similar systematic reviews were identified in our searches. In addition, while most guidelines do make mention of factors associated with relapse, the vast majority are not evidence-based and nor do they provide recommendations on how to use these factors in practice. For example, the most recent guideline from the GINA11 focused on medical management to prevent asthma relapse, provided no summary of factors associated with relapse, and failed to guide clinicians regarding which high-risk patients to target. In a similar vein, the National Review on Asthma Deaths (NRAD) in 2015 identified that 10% of asthma deaths in the UK occur within 28 days of discharge from the ED.39 The authors state that there is a need for health professionals to ‘be aware of the factors that increase the risk of asthma attacks’, without explicitly stating what those factors are.

Factors which could practically be screened to provide the most benefit would include female sex, previous ICS usage and healthcare resource usage. Identifying patients with these traits and targeting them for more explicit discharge planning and rigorous outpatient follow-up might mitigate the severity and frequency of relapses. Options might include the identification of care gaps that may be influencing their asthma attacks (ie, improper inhaler techniques, non-adherence to medication, lack of education), stepping up their preventer medication (ie, adding ICS to those ICS naïve at presentation15 or switching from ICS to ICS/LABA33), providing the medications in the ED rather than the prescriptions or directing strategies from the ED to ensure that patients have close follow-up with a primary care provider for monitoring of symptoms, adjustment on medication and consideration of referrals.

Strengths and limitations

There are several potential limitations to this review that require discussion. First, high-quality evidence in this field is limited and this review included a variety of prospective designs (eg, RCTs and cohorts), which was an important a priori decision. To be reported in the factors associated with relapses, all prospective studies needed to report an adjusted analysis. Second, data collected from patient interviews may be subject to recall bias. With a few exceptions,22 ,23 data were collected using slightly different interview questions, necessitating some grouping based on author discretion. In addition, differential loss to follow-up or incomplete outcome data in the included studies may have introduced attrition bias. Third, owing to the relatively small number of included studies and overall small sample size, we were unable to formally assess the potential for publication bias; however, comprehensive searches of grey and published literature were performed without restrictions on language, dates or publication status, so it is unlikely that many studies were missed. Fourth, the ORs of non-significant factors from multivariable analyses were not reported in most papers, which may over-represent the influence of some factors. Finally, selection bias is always a concern in systematic reviews; however, two independent reviewers with a separate third-party adjudicator were used throughout all stages of the review in order to minimise selection bias and ensure consistency.

Conclusion

Reducing relapses after treatment for acute asthma represents a potential improvement in the quality of life for patients with asthma and a reducible strain on crowded EDs. Moreover, they present an opportunity to improve outcomes for patients while reducing direct healthcare costs. Practical factors associated with relapse occurrence within 4 weeks of ED discharge have been identified, which may help to stratify patients based on their risks and potentially influence disposition decisions. Further research should focus on strategies to decrease relapses using validated clinical decision rules in order to identify patients at high risk for relapse after discharge, optimise their management and improve outcomes.