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The level of diagnostic assessment in severe asthma: A nationwide real-life study

Respiratory Medicine, March 2017, Pages 21 - 29

Abstract

Introduction

Systematic assessment of patients with severe asthma is pivotal to decide which patients are eligible to new biological therapies. However, the level of diagnostic work-up in patients with severe asthma is only poorly investigated.

Aims & objectives

To describe the diagnostic work-up in a complete population of patients with severe asthma including: objective confirmation of the asthma diagnosis, and identification of potential treatment barriers, such as poor adherence and poor inhaler technique.

Methods

A retrospective cross-sectional multicenter study was performed in 2013. We evaluated patient record forms of all patients (aged 18–65 years) consecutively referred with asthma to one of five respiratory outpatient clinics over two years. Patients were included in the study, if they fulfilled ERS/ATS guidelines for having severe asthma.

Results

Among 1563 patients with asthma, 98 (6.3%) patients fulfilled the criteria for having severe asthma. The diagnosis of asthma was confirmed objectively in 53/98 patients (54.1%). In total, 83.7% underwent at least one diagnostic test for asthma: reversibility test: 63.3%, PEF: 52% and bronchial challenge test: 21.4%. Among patients eligible for a bronchial challenge test (FEV1 ≥ 70%; negative PEF measurement/reversibility test), only 23.1% had such a test performed. Inhalation technique and adherence were assessed in 19.4 and 30.6% of patients, respectively.

Conclusion

Among patients managed for severe asthma in a specialist setting, only half had the asthma diagnosis confirmed objectively, and adherence and inhaler technique were infrequently assessed.

Highlights

  • Systematic assessment of patients with severe asthma is pivotal to decide which patients are eligible to new biological therapies.
  • Only half of patients with severe asthma in specialist care had the diagnosis of asthma objectively confirmed.
  • Adherence, inhaler technique and most comorbidities were infrequently assessed in patients with severe asthma.

Keywords: Asthma, Asthma diagnosis, Asthma assessment, Severe asthma, Asthma management, Difficult to treat asthma.

Abbreviations

ENT

Ear, nose and throat specialist

FeNO

Fractional exhaled nitric oxide.

HRCT

High resolution computer tomography

ICD-10

International Classification of Diseases –Tenth revision

PEF

Peak expiratory flow

PRF

Patient record form

ICS

Inhaled corticosteroids

SABA

short-acting beta-2-agonist

1. Introduction

With the emergence of novel, but expensive biological treatments for severe asthma, a systematic evaluation of patients with severe asthma becomes decisive to identify the eligible patients to these new therapies [1] and [2].

The prevalence of severe asthma is estimated to 4–8% [3] and [4]. Despite being a minority, patients with severe asthma possess the largest burden of morbidity with frequent asthma exacerbations, low quality of life and higher risk of experiencing adverse effects from treatment [5] and [6]. Severe asthma is defined as asthma that requires intensive asthma therapy, and either remains uncontrolled, or becomes uncontrolled if treatment is down-titrated [1].

However, there are many potential competing causes of poor asthma control in patients with severe asthma [7]. Hence, patients receiving high-dose asthma treatment are recommended to undergo a proper systematic assessment in a specialist setting to confirm the diagnosis of asthma and identify and address potential aggravating comorbidities, poor adherence and environmental triggers before as being classified as having severe asthma [1], [2], [8], and [9].

A clinical diagnosis of asthma may be based solely on the presence of typical asthma symptoms, such as episodic breathlessness, chest tightness, wheezing or cough. However, a symptom-based diagnosis is associated with a significant risk of over-diagnosis of asthma [10], [11], and [12] leading to potential over-treatment. Consequently, international guidelines recommend that the diagnosis of asthma should be confirmed in all patients with asthma by demonstrating variable airflow obstruction [9]. Nevertheless, demonstration of variable airflow obstruction may be difficult [9] and time-consuming in patients receiving high doses of ICS [13]. In addition, no validated protocol exits to confirm the diagnosis in patients with severe asthma [1] and [2]. Nonetheless, repeated failure of demonstrating variable airflow obstruction with reversibility test and bronchial challenge test should call into question whether the asthma diagnosis is correct [2].

Studies describing a complete clinical population of patients with potential severe asthma are lacking. Previous studies in severe asthma have shown that following a systematic assessment, more than 50% were no longer difficult-to-treat [7] and [14]. Currently, it remains unknown to which extent patients with severe asthma are systematically assessed in order to objectively confirm the asthma diagnosis and identify competing causes of poor asthma control like poor adherence, comorbidities and environmental triggers.

Despite comprehensive assessment to confirming the asthma diagnosis, the diagnosis may be based solely on symptoms in a minority of patients (e.g. due to low lung function excluding bronchial challenge testing). Consequently, it would seem appropriate that patients with non-confirmed asthma were more extensively assessed in order to investigate airway inflammation, comorbidities and rule out potential alternative diagnosis. However, it is unknown whether this is actually the case.

The aim of this study was to describe the diagnostic work-up in a complete real-life population of patients with severe asthma:

  • 1 Evaluate to which extent patients treated by respiratory specialists for severe asthma had the diagnosis of asthma objectively confirmed by demonstration of variable airflow obstruction.
  • 2. Describe the level of assessment of competing causes of poor asthma control, including adherence, inhalation technique, triggers and comorbidities.
  • 3 Investigate whether the assessment of asthma was different in patients with a non-confirmed asthma diagnosis compared to patients with confirmed variable airway obstruction.

2. Methods

2.1. Design

We performed a “real-life”, retrospective, descriptive, non-interventional cohort study. To achieve a high level of external validity, we identified the complete population of all patients consecutively referred to one of five respiratory outpatient clinics in Denmark (Bispebjerg University Hospital, Aarhus University Hospital, Aalborg University Hospital, Naestved Hospital, Roskilde Hospital) over a two years (2009–2010) with a diagnosis of asthma or suspected asthma (referral ICD-10 code: DJ45-DJ459). To allow time for assessment all patients were evaluated two years after referral. Patients were included in the study population if they fulfilled the criteria for having severe asthma according to the ERS/ATS guidelines [1] after two years of assessment (Fig. 1).

Fig. 1

Fig. 1

Consort diagram: The selection of the study population.

 

The retrospective study-design was purposefully chosen to avoid bias, as the outcome was to evaluate the diagnostic work-up of severe asthma in specialist care.

2.2. Material

Data were obtained from patient record forms (PRF): all patients had an electronical PRF in which all physicians notes were recorded. In addition, patients had a paper PRF containing test results (spirometry, skin prick test, blood samples etc.). Using the electronic PRF, the study population was identified in a stepwise manner (Fig. 1). First, we identified patients having a physician's diagnosis of asthma or suspected asthma. Patients in whom the referral code was incorrect or patients never assessed by a pulmonologist (e.g. failed to appear in the outpatient clinic) were excluded. Subsequently, asthma severity was analyzed according to the level of treatment after two years of assessment in the outpatient clinic. If patients were dismissed from the outpatient clinic before two years, we analyzed the level of asthma severity at the last visit in the outpatient clinic. At this step, patients were excluded if information regarding current asthma treatment was lacking. In addition, patients were excluded if the paper PRF was missing.

2.2.1. Definition of severe asthma

Patients were included in the study population (Fig. 1) if they had a physician's diagnosis of asthma and fulfilled the criteria of having severe asthma by receiving high dose ICS treatment with a second controller (long acting beta-2-agonist, theophylline or leukotriene-antagonist) or oral steroids at the last visit in the outpatient clinic within the two-year period of observation. Furthermore, they should have received high dose ICS (≥1600 μg budesonide or equivalent) for a minimum of twelve months or oral steroids for minimum six months [1].

2.3. Methods

Data on basic characteristics i.e. assessment of asthma symptoms, as well as assessment of smoking history, adherence to treatment, inhaler technique, lung function, diagnostic test, examination for comorbidities and asthma phenotyping was examined within the two-year period of observation (date of first physicians visit in the outpatient clinic and the subsequent two years).

2.3.1. Objective confirmation of the asthma diagnosis

A “confirmed asthma” diagnosis was defined as demonstration of variable airflow obstruction by either one of the following:

  • Day-to-day Peak expiratory flow (PEF) monitoring,
  • Reversibility test (short-acting beta-2-agonist (SABA) or oral steroids)
  • Airway hyperresponsiveness (methacholine, mannitol, exercise test, eucapnic voluntary hyperventilation test).
  • Any statement of an objectively confirmed asthma diagnose before referral in the medical record (e.g. a positive reversibility test performed at the General Practitioner).

Patients with no positive test demonstrating variable airflow obstruction were categorized having “non-confirmed asthma”.

Definitions of positive test results:

  • Reversibility testing (SABA or oral steroids): FEV1 increase of ≥200 ml and ≥12% post-SABA/oral steroids [9]. Furthermore, an asthma diagnosis based on spontaneous FEV1 variability (≥200 ml and ≥12%) over time were recorded as confirmed [9].
  • PEF: day-to-day variation≥20% [9].
  • Bronchial challenge test (airway hyperresponsiveness): at least one positive methacholine test, mannitol test, eucapnic voluntary hyperpnoea test or exercise test. Patients with a cumulative dose of inhaled methacholine ≤8 μmol and a decrease in FEV1 ≥20% were defined as having a positive methacholine test [15]. The cut-off for a positive mannitol test was a decrease in FEV1≥15% with a provocation dose of inhaled mannitol ≤635 mg [16]. Eucapnic voluntary hyperpnoea test was recorded positive, if patients had decrease in FEV1 of at least 10% on two consecutive measurements [17]. Exercise test was considered positive, if patients had a decrease in FEV1 of at least 10% [15] or if there was a PEF decrease ≥ 15% [15] and [18]. If the specific test result was not to be found in the PRF, the test was categorized positive, if the physician had recorded the test as positive in the PRF.
2.3.2. Adherence

Any written comment in the PRF regarding assessment of adherence to therapy (e.g. “the patient is taking the medication as prescribed” or “the patient has poor compliance to treatment”).

2.3.3. Inhaler technique

Any written term in the PRF regarding assessment of inhaler technique.

2.3.4. Spirometry

FEV1, FEV1% and FVC were registered at the first visit in the outpatient clinic (V1).

2.3.5. Fractional exhaled nitric oxide (FeNO)

If performed, the first FeNO value (ppb) performed was registered.

2.3.6. Blood eosinophil count

if performed, the first blood eosinophil count (x109/L) performed was registered.

2.3.7. Atopy

Evaluation of atopy was defined as performance of either a skin prick test and/or specific IgE to one or more of ten aeroallergens: pollens (Birch Betula verrucosa, grass Phleum pratense, mugwort), animal dander (horse, cat, dog), house dust mites (Dermatophagoides pterynyssinus et farinae), fungi (Alternaria tenuis, Cladosporium herbarum). Atopy was defined as sensibilization to at least one allergen (skin prick test wheal diameter ≥3 mm and/or a specific IgE >0.35 kU/L).

2.3.8. Ear-nose-throat-assessment

If the patient were referred or had been assessed by an ENT specialist according to the PRF.

2.3.9. Assessment of rhinitis, gastro esophageal reflux symptoms or psychiatric symptoms/disease

Any written comment in the PRF regarding assessment of rhinitis symptoms (sneezing, runny nose, itchy watery eyes etc.), gastro esophageal reflux symptoms (acid reflux, heartburn) or psychiatric symptoms or disease (anxiety, depression symptoms).

2.3.10. Use of rescue oral steroids

Use of oral steroids ≥25 mg for at least five days due to aggravating asthma symptoms within the two-year period of observation.

2.3.11. Data analysis and statistics

Data were presented for the entire study population, and for the two subgroups (“confirmed asthma” resp. “non-confirmed asthma” groups). Continuous variables were reported as mean (standard deviation, SD) for normally distributed data versus median (with 25% and 75% quartiles) for non-parametric data, and analysed using unpaired t-test or Mann-Whitney-U-test, respectively. Categorical data were presented as numbers and percentages and inter-group analysed by Chi2-test or Fischer's exact test (if any cell number <5).

Statistical significance was defined as a p-value <0.05. All data analyses were performed using SPSS 22.0 (SPSS, Inc, Chicago, Ill).

2.3.12. Ethics

Approval was given from the Danish Health and Medicines Authority (Journal number: 3-3013-350/1/). This retrospective study was not under the jurisdiction of the Scientific Ethics Committee system.

3. Results

In total, 2023 patients were consecutively referred to one of five respiratory outpatient clinics in Denmark with a referral code of asthma (ICD-10: DJ45-DJ459) within two years. The selection of the study population is illustrated in Fig. 1: 106 patients (6.8%) fulfilled the criteria for severe asthma, among whom 98 patients had a complete dataset and were included in the study population. Within the study population, 83,7% had undergone at least one attempt of confirming the diagnosis of asthma (Fig. 2). However, only 54.1% (n = 53) had a confirmed asthma diagnosis defined as having at least one positive objective test for asthma (“confirmed asthma” group). We observed no significant differences in the proportion of confirmed asthma vs. non-confirmed asthma between the five centers (data not shown).

Fig. 2

Fig. 2

The proportion of diagnostic tests1 performed in patients with severe asthma (Fig. 2a) and according to whether the asthma-diagnosis was confirmed or not confirmed by objective demonstration of variable airflow obstruction (Fig. 2b).

1 Reversibility test (SABA/oral steroids), PEF diary, methacholine test, mannitol test, exercise test and/or eucapnic voluntary hyperpnoea test performed within the two- year period of observation. 2 One patient had no diagnostic test performed within the period of observation, but had a confirmed asthma diagnosis due to a known positive diagnostic test for asthma before referral.

 

As summarized in Table 1, patients with confirmed asthma were characterized by more severe airflow obstruction, as well as a higher level of FeNO, compared to those with non-confirmed asthma in several spirometric and inflammatory variables. This was in spite of a similar use of medications, except for LAMA (Table 2). Furthermore, patients with confirmed asthma had more frequent visits at the outpatient clinic (Median: 7 vs. 5, p = 0.006) and were less likely to have a known asthma at referral according to the referring physician compared with the group with non-confirmed asthma (75.5 vs. 93.3%, p = 0.02). In addition, patients with confirmed asthma used more rescue oral steroids (median: 1 vs. 0, p = 0.044). Conversely, no difference was seen, regarding the assessment or presence and type of asthma symptoms between patients with confirmed asthma vs. non-confirmed asthma (data not shown).

Table 1

Baseline characteristics.

 

All patients
n = 98
Confirmed asthma
n = 53
Non-confirmed asthma
n = 45
P-value e
Gender (male) n (%) 41 (41.8) 26 (49.1) 15 (33.1) 0.15
Age (years) mean (SD) 43.0 (11.8) 44.0 (12.3) 41.7 (11.1) 0.33
BMI mean (SD) 28.5 (6.5) 28.0 (6.5) 29.1 (6.3) 0.37 f
FEV1 (L) mean (SD) 2.43 (0.86) 2.33 (0.82) 2.56 (0.90) 0.18
FEV1% mean (SD) 74.0 (22.7) 69.8 (21.9) 79.0 (22.9) 0.046
FEV1/FVC mean (SD) 0.68 (0.15) 0.66 (0.16) 0.72 (0.14) 0.04
FEV1% ≥ 70% n (%) 59 (60.2) 29 (54.7) 30 (66.7) 0.23
FeNO (pbb) Median (min,max) (n/n) 16 (1.1–118.7) (66/98) 20 (1.1–118,7) (38/53) 13.5 (5.0–42.0) (28/45) 0.01 g
Blood eosinophil count (x109/L) Median (min,max) (n/n) 0.19 (0.00–1.47) (82/98) 0.20 (0.00–1.47) (46/53) 0.17 (0.00–1.26) (36/45) 0.37 g
Atopy %a(n/n) 65.4 (55/84) 65.2 (30/46) 65.8 (25/38) 0.96
Smoking-status
 Current smoker %b (n/n) 22.1 (19/86) 19.2 (10/52) 26.5 (9/34) 0.43
 Ex-smoker %b (n/n) 30.6 (26/85) 25.2 (13/51) 38.2 (13/34) 0.21
Numbers of physician's visits c Median (min,max) 6 (2,20) 7 (2,18) 5 (2,20) 0.006 g
Physician's diagnosis of asthma at referral d n (%) 82 (83.7) 40 (75.5) 42 (93.3) 0.02
Daily ICS dose (μg budesonide equivalent) mean (SD) 1967.35 (746.0) 1992.45 (677.06) 1937.78 (826.6) 0.8
Rescue oral corticosteroids Median (min,max) 0 (0–9) 1 (0–9) 0 (0–9) 0.044 g
Hospital admission Median (min,max) 0 (0–3) 0 (0–3) 0 (0–3) 0.592 g

a Atopy: Positive skin prick test and/or RAST test among patients in whom the tests were performed.

b Among patients, in whom smoking assessment were performed.

c Within the two year period of observation.

d Known asthma at the time of referral, according to the referring physician.

e Unless other indicated: Xb-test.

f Unpaired t-test.

g Mann-Whitney-U-test.

Table 2

Asthma treatment at the last visit within the observation period.

 

Study population
n = 98
Confirmed asthma
n = 53
Non-confirmed asthma
n = 45
P-valuea
ICS n (%) 98 (100) 53 (100) 45 (100) 1
LABA n (%) 94 (95.9) 52 (98.1) 42 (93.3) 0.33b
SABA n (%) 97 (99.0) 53 (100) 44 (97.8) 0.28
LTRA n (%) 42 (42.9) 20 (37.7) 22 (48.9) 0.27
Xanthines n (%) 10 (10.2) 4 (7.5) 6 (13.3) 0.51b
LAMA n (%) 14 (14.3) 13 (24.5) 1 (2.2) 0.001
Omalizumab n (%) 14 (14.3) 8 (15.1) 6 (13.3) 0.80
Oral steroids n (%) 11 (11.2) 4 (7.5) 7 (15.6) 0.34b
Oral steroids (min. six months) n (%) 11 (11.2) 4 (7.5) 7 (15.6) 0.34b
Azathioprin/methotrexat n (%) 3 (3.1) 2 (3.8) 1 (2.2) 0.56b

a Unless other indicated: Xb-test.

b Fischer's Exact test.

P < 0.05 was considered significant.

3.1. Objective confirmation of the asthma diagnosis

In total, one third of the non-confirmed asthma group (16.3% of total study population) had not had any diagnostic test performed to objectively demonstrate the presence of variable airflow obstruction (Fig. 2). Thus, patients with confirmed asthma had more diagnostic tests performed, compared with patients with non-confirmed asthma (Table 3, Fig. 2).

Table 3

Diagnostic tests for asthma performed (attempt of demonstrating variable airflow obstruction).

 

Study-population
n = 98
Confirmed asthma
n = 53
Non-confirmed asthma
n = 45
p-value h
Numbers of diagnostic testa performed mean (SD) 1.43 (0.94) 1.79 (0.79) 1 (0.93) <0.001i
Reversibility-testb performed % (n) 63.3 (62) 79.2 (42) 44.4 (20) <0.001
 Positive reversibility test % (n) 31.6 (31) 58.5 (31) 0
Reversibility-test (SABA) Yes % (n) 62.2 (61) 77.4 (41) 44.4 (20) 0.001
 Positive reversibility test (SABA) % (n) 29.6 (29) 54.7 (29) 0
Reversibility test (oral steroids) Yes % (n) 3.1 (3) 5.7 (3) 0 (0) 0.25
 Positive reversibility test (oral steroids) % (n) 3.1 (3) 5.7 (3) 0
FEV1 variability over time (Yes) % (n) 1 (1) 1.9 (1) 0 (0) 0.54
 Positive FEV1 variability over time %(n) 1 (1) 1.9 (1) 0
Peak Expiratory Flow Yes % (n) 52.0 (51) 60.4 (32) 42.2 (19) 0.07
 Positive Peak Expiratory Flow % (n) 17.3e (17) 32.1e (17) 0
Bronchial challenge testc Yes % (n) 21.4 (21) 30.2 (16) 11.1 (5) 0.02
 Positive Bronchial challenge test % (n) 12.2f (12) 22.6f (12) 0
Mannitol Yes % (n) 13.3 (13) 20.8 (11) 4.4 (2) 0.03
 Positive mannitol test % (n) 7.1 (7) 13.2 (7) 0
Methacholine Yes % (n) 8.2 (8) 11.3 (6) 4.4 (2) 0.28
 Positive Methacholine % (n) 4.1f (4) 7.5f (4) 0
Exercise test Yes % (n) 6.1 (6) 7.5 (4) 4.4 (2) 0.68
 Positive Exercise test % (n) 1 (1) 1.9 (1) 0
Eucapnic voluntary hyperpnoea test Yes % (n) 1 (1) 0 (0) 2.2 (1) 0.46
 Positive Eucapnic voluntary 0 (0) 0 (0) 0
 hyperpnoea test % (n)
Positive diagnostic test for asthma before referrald% (n) 3.1 (3) 5.7 (3) 0
 
Negative reversibility testb and negative peak flow measurements and FEV1≥70%g
% (n/n)
33.8 (26/77) 12.5 (6/48) 69.0 (20/29) <0.001
Performance of bronchial challenge test, if negative reversibility test and neg peak flow measurements and FEV1≥70% g
% (n/n)
23.1 (6/26) 66.7 (4/6) 10.0 (2/20) <0.003

a Reversibility test (SABA), Reversibility test (oral steroids), PEF diary, methacholine test, mannitol test, exercise test and/or eucapnic voluntary hyperpnoea test performed within the period of observation.

b Reversibility test for SABA and/or oral steroids performed.

c Methacholine, mannitol, exercise test and/or eucapnic voluntary hyperpnoea test performed.

d Statement of an objectively confirmed asthma diagnose before referral in the PRF.

e Missing: Four patients had no peak flow diary in the medical or indication of the test-result in the PRF.

f Missing: In one subject, the result of a bronchial challenge test (methacholine) was not to be found in the PRF.

g Among those having PEF measurements or Reversibility test (SABA/oral steroids) performed.

h Unless other indicated xb-test. If < 5 patients: Fischer's exact test.

i Independent t-test.

Patients with confirmed asthma were more likely to have had a reversibility test for SABA (77.4 vs. 44.4%, p = 0.001) and bronchial challenge test to mannitol (20.8 vs. 4.4%, p = 0.03). However, no differences between the two groups were seen in the proportion having PEF measurements performed. In general, in both groups, airway hyperresponsiveness to methacholine, exercise test or EVH test was rarely performed (Table 3).

Among those in the study population, in whom a bronchial challenge was indicated, i.e. patients with a normal PEF variability and/or a negative reversibility test, and who had a lung function that allowed for a bronchial challenge test (FEV1≥70%), only 23.1% had such a test performed. Overall, a bronchial challenge test was significantly more frequently performed among the confirmed asthma group compared with the non-confirmed group (66.7 vs. 10.0%, p < 0.003) (Table 3).

3.2. Assessment of treatment barriers, triggers and comorbidities

In general, the assessment of inhaler technique and adherence to treatment was low in the study population (19.4% and 30.6%, respectively) (Fig. 3). However, patients with confirmed asthma were more likely to have adherence (45.3% vs. 13.3%, p = 0.001) and inhaler technique evaluated (30.2% vs. 6.7%, p = 0.004) (Fig. 5). Smoking status was evaluated in the majority of patients (87.8%) and a confirmed asthma diagnosis increased the likelihood of having smoking status evaluated (98.1% vs. 75.6%, p = 0.001) (Fig. 5).

Fig. 3

Fig. 3

Proportion of patients with severe asthma who had inhaler technique and adherence evaluated.

 

Apart from atopy and rhinitis, examination of other potential comorbidities/alternative diagnosis was relatively rare (Fig. 4). Confirmation of the diagnosis of asthma did not influence the proportion of patients who had atopy, plethysmography or HRCT assessed (Fig. 5).

Fig. 4

Fig. 4

Proportion of patients with severe asthma, who were evaluated diagnostic for potential comorbidities based on either symptom history or additional diagnostic test.

1 Defined if either skin prick test or specific IgE was performed. 2 Evaluation of symptoms of rhinitis, psychiatric symptoms and gastro esophageal reflux symptoms in the PRF.

 

Fig. 5

Fig. 5

Proportion of patients with severe asthma, who had treatment barriers, airway inflammation and comorbidities assessed, according to whether the asthma diagnosis was confirmed or not.

1 Defined if either skin prick test or specific IgE was performed. 2 Evaluation of symptoms of rhinitis in the PRF.

 

3.3. Evaluation of asthma phenotypes and inflammation

Within the study population, 67.3% had FeNO measured. Blood eosinophil count and total IgE were assessed in 83.7 and 70.4%, respectively.

4. Discussion

In this real-life asthma study, almost half of patients treated for severe asthma, did not have a confirmed asthma diagnosis, despite having been evaluated and managed by respiratory specialists for two years. In addition, 16% did not perform any diagnostic tests at all. Furthermore, patients in whom the diagnosis was not confirmed were less likely to have been assessed for treatment barriers and triggers of asthma, such as poor adherence, poor inhalation technique or smoking.

Patients with severe asthma are recommended to be evaluated in specialist care for at least three to six months [1] and [8]. In addition, due to receiving high doses of ICS or oral steroids it may be difficult to demonstrate variable airflow obstruction within this group of patients [9]. Consequently, an observation period of two years was found appropriate to investigate asthma severity and diagnostic assessment in patients with severe asthma. Despite two years of assessment, the asthma diagnosis was not confirmed objectively in nearly half of the patients. However, among those who performed a reversibility test, half had a positive test, which corresponds to other studies investigating severe asthma [19] and [20]. Furthermore, except for LAMA, the treatment did not differ between patients with confirmed and non-confirmed asthma. In fact, it is remarkable that 85% of those having confirmed asthma had objectively demonstrated variable airflow obstruction when assessed with only two different diagnostic asthma tests. In contrast, the majority of patients with non-confirmed asthma only performed one diagnostic test or none at all. Two previous observational studies demonstrated that only sixty percent of patients with severe asthma had significant signs of variable airflow obstruction, when assessed with a reversibility test or peak flow monitoring [19] and [20], indicating that bronchial challenge testing is an important diagnostic tool within these patients. Despite this, we demonstrated that bronchial challenge testing was only performed in a minority of patients with non-confirmed asthma, negative reversibility test and normal lung function.

These findings suggest that having non-confirmed asthma was most likely caused by inadequate assessment rather than being unable to demonstrate variable airflow obstruction. This corresponds with previous studies showing significant signs of unawareness of asthma severity and poor assessment in patients with severe asthma [4], [21], and [22]. Additionally, patients with non-confirmed asthma had fewer physician's visits in the outpatient clinic, and were less likely to have smoking habits, adherence to therapy and inhaler technique assessed compared to the group with confirmed asthma. Which suggests inadequate assessment of whether the patients with non-confirmed asthma truly had severe asthma, difficult-to treat asthma or even asthma at all [1], [2], and [3]. On the other hand, evaluation of comorbidities and airway inflammation were not predicted by whether the asthma diagnosis was confirmed or not, indicating an equal level of assessment of these parameters in both groups.

Patients with non-confirmed asthma had higher lung function, were less obstructive and had lower FeNO and less use of rescue oral steroids, compared to the group with confirmed asthma. This could suggest that the group of non-confirmed asthma patients had milder asthma with less airway inflammation and a better response to their anti-inflammatory treatment, making it more difficult to demonstrate variable airflow obstruction, when still treated with ICS. This is consistent with other studies demonstrating lower airway hyperresponsiveness in patients with higher FEV1[11] and [23], and lower levels of airway inflammation in patients with low FeNO [24]. However, no differences were seen regarding presence of typical asthma symptoms within the two groups.

In this study, the majority had a physician's diagnosis of asthma at the time of referral according to the referring physician. This was especially true among those with non-confirmed asthma, which could call into question whether it is necessary to confirm the diagnosis within these patients. However, over-diagnosis of asthma has been reported as a significant problem [10], [11], and [12]. Previous studies demonstrates that 30% of adults with a physicians diagnosis of asthma did not have asthma when objectively systematically assessed with reversibility test and bronchial challenge test [10] and [11]. Severe asthma patients receive treatment with potential side effects such as high dose ICS and oral steroids, and are potential candidates for expensive biological treatments [9] and [25]. Accordingly, a higher level of diagnostic awareness is warranted in these patients. Discrepancy between the level of symptoms and airway inflammation is described in some asthma patients. Furthermore, some patients have many symptoms but only little evidence of objective airway inflammation [24] and [26]. Hence, in patients with known asthma and lack of response to high dose treatment, obtaining objective disease evidence may be important to differentiate asthma symptoms from non-specific respiratory symptoms that may relate to other factors than asthma, such as dysfunctional breathing or obesity [2] and [19]. In this study, any statement of an objectively confirmed asthma diagnosis in the PRF before referral was also recorded as confirmed astma. However, this was only the case in three patients.

Patients with severe asthma report low quality of life, on going asthma symptoms and extensive healthcare use despite receiving high dose treatment [4], [5], and [27]. Despite no specific validated and standardized evaluation protocol exist, systematic evaluation of severe asthma has been recommended for years [1], [2], [19], and [28]. Implementation of multidisciplinary assessment protocols for severe asthma have demonstrated significant improvement in several important health care outcomes, particularly better quality of life and reductions in asthma symptoms, rescue oral steroids and hospital admissions [6], [29], and [30]. Our results suggest a significant lack in the diagnostic work-up in patients with severe asthma. Increasing access to promising but expensive biological treatments for severe asthma emphasizes the need for a systematic evaluation to select which patients are most likely to respond to different biological therapies. Hence, a validated protocol exploring how to confirm the diagnosis of asthma and assess patients with severe asthma in the most efficient way is clearly a necessity.

We acknowledge there are several limitations in our study. Firstly, being a retrospective study, we can only report the data recorded in the PRF. Not all clinical information obtained during a consultation is necessarily recorded in the PRF, and this could be particularly true for information typically gathered by a nurse, such as the patient's inhalation technique. This could lead to an underestimation of the level of assessment [31]. However conversely, if not recorded in the PRF, this information would not have been available at subsequent consultations in the clinical setting either, and would thus in fact have been lacking.

A further limitation is that since not all patients had all types of diagnostic tests performed, we cannot conclude on the true proportion of patients in whom it would be possible to confirm the diagnosis of asthma objectively. Clearly, in patients on high dose asthma treatment, a proportion of patients would be expected to have negative diagnostic tests. We recently described that in an unselected population of asthma patients newly referred to a specialist setting, a positive diagnostic test for asthma was observed in 81% of patients when a complete test panel was applied [13] In the present population on high dose therapy, a smaller proportion would be expected to have objective signs of variable airflow obstruction. However, in order to describe the true proportion of severe asthma patients in whom the diagnosis can be verified, a prospective study assessing all patients with a complete test panel would be required. Finally, we included five respiratory clinics with a broad national distribution in attempt to minimize selection bias. Nevertheless, our results may be less generalizable, since obtained from one single national healthcare system.

In conclusion, among patients managed for severe asthma in five specialist hospital clinics in Denmark, only half had the asthma diagnosis confirmed objectively and treatment barriers and comorbidities were infrequently assessed. This indicates a substantial room for improvement in order to ensure that patients receiving high dose asthma therapy truly have severe asthma. Together with an increasing accessibility of new biological treatments for severe asthma, it emphasizes the need for a validated protocol exploring: how to assess patients with severe asthma in the most efficient way.

Acknowledgements

This study was supported by an unrestricted grant from Novartis, Denmark paid to the Respiratory Research Unit, Department of Respiratory Medicine L, Bispebjerg Hospital.

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Footnotes

a Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital, Bispebjerg Bakke 66, 2400 Copenhagen NV, Denmark

b Department of Respiratory and Internal Medicine, Naestved Hospital, Denmark

c Institute for Regional Health Research, University of Southern Denmark, Denmark

d Department of Respiratory and Internal Medicine, Roskilde Hospital, Denmark

e Department of Respiratory Medicine, Aalborg University Hospital, Denmark

f Department of Respiratory Medicine, Aarhus University Hospital, Denmark

Corresponding author. Respiratory Research Unit, Department of Respiratory Medicine L, Bispebjerg Hospital, Bispebjerg Bakke 66, 2400 Copenhagen NV, Denmark.