Journal of Asthma

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An update on asthma diagnosis

Charis Armeftis, Christina Gratziou, Nikolaos Siafakas, Paraskevi

Katsaounou, Zoi Dorothea Pana & Petros Bakakos

To cite this article: Charis Armeftis, Christina Gratziou, Nikolaos Siafakas, Paraskevi
Katsaounou, Zoi Dorothea Pana & Petros Bakakos (2023) An update on asthma diagnosis,
Journal of Asthma, 60:12, 2104-2110, DOI: 10.1080/02770903.2023.2228911

To link to this article: https://doi.org/10.1080/02770903.2023.2228911

© 2023 Taylor & Francis Group, LLC

Published online: 02 Jul 2023.

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Journal of Asthma
2023, VOL. 60, NO. 12, 2104–2110
https://doi.org/10.1080/02770903.2023.2228911

An update on asthma diagnosis

Charis Armeftis, MDa, Christina Gratziou, MD, PhDb, Nikolaos Siafakas, MD, PhDc, Paraskevi Katsaounou, MD, PhDb,
Zoi Dorothea Pana, MD, MSc, PhDd and Petros Bakakos, MD, PhDb
Pulmonology Unit, Ygeia Hospital, Limassol, Cyprus; bPulmonology, National and Kapodistrian University of Athens, Athens, Greece;
a

Thoracic Medicine, University of Crete, Heraklion, Greece; dPediatrics, European University of Cyprus, Nicosia, Cyprus
c

ABSTRACT ARTICLE HISTORY

Objective: Asthma imposes a significant health and socioeconomic burden with an average Received 21 May 2023
prevalence impacting 5-10% of the global population. The aim of this narrative review is to Revised 15 June 2023
Accepted 20 June 2023
update the current literature on topics related to asthma diagnosis.
Data Sources: Original research articles were identified from PubMed using the search terms KEYWORDS
"asthma diagnosis" and “asthma misdiagnosis”. Misdiagnosis; phenotype;
Study Selections: Recently published articles (n = 51) detailing the diagnosis, misdiagnosis of endotype; treatable trait;
asthma, and the updated recommendations of the European and international asthma guidelines; Lancet Commission;
guidelines. overdiagnosis; underdiagnosis
Results: Emerging evidence revealed that asthma might represent a rather heterogenous
clinical entity with varying underlying molecular mechanisms. Attempts have been made to
unravel these traits to better provide accurate diagnosis and a more efficient patient-based
management approach. The lack of a gold standard test for asthma diagnosis has contributed
to its over- and underdiagnosis. This is problematic, given that overdiagnosis might lead to
delay of both diagnosis and prompt treatment of other diseases, while underdiagnosis might
substantially impact quality of life due to progression of asthma by increased rate of
exacerbations and airway remodeling. In addition to poor asthma control and potential
patient harm, asthma misdiagnosis is also associated with excessive costs. As a result, current
international guidelines emphasize the need for a standardized approach to diagnosis,
including objective measurements prior to treatment.
Conclusion: Future research is warranted to define the optimal diagnostic and treatable traits
approach especially for patients with severe asthma, as they may benefit from the advent of
newly targeted asthma management.

Introduction approach (8,9). Although lung function with dynamic

Asthma is the most common chronic respiratory dis-
ease affecting millions of people of all ages across the
globe (1–6). The average global prevalence ranges
between 5–10% (2). Traditionally, asthma diagnosis
was based on the history and the response to a trial
of various treatments, but emerging evidence shows
that under the umbrella of asthma, several subtypes
exist with multiple underlying pathophysiological and
molecular mechanisms, known as endotypes. This
partially explains the phenotypic (interindividual)
asthma patient variability (7,8). Moreover, the transi-
tion from the “symptom-based” to the more refined
“omics-based” asthma approach could contribute to
an eventual new era of applying precision medicine
to asthma classification, diagnosis, and treatment
tests remains fundamental for asthma diagnosis, evi-
dence reveals that asthma is inadequately diagnosed
across the world, triggering an ongoing debate on the
optimization of the latest asthma diagnostic guidelines
based on objective testing that can improve diagnostic
accuracy (2). Both over- and underdiagnosis could
lead to additional costs, inappropriate treatment, and
potential patient harm.
The aim of the present mini-review is to update
the current international literature on topics related
to asthma diagnosis with a focus on: 1) the
epidemiology-burden of disease, 2) the transition of
the traditional asthma diagnosis to a more “refined”
asthma classification, 3) the published literature on
asthma misdiagnosis, and 4) a comparison of the
current recommendations for asthma diagnosis from

CONTACT Charis Armeftis charmeftis@gmail.com Pulmonology, Ygeia Hospital, Limassol, Cyprus.

© 2023 Taylor & Francis Group, LLC

the most recently published European and interna-
tional asthma guidelines.
Methods
Data sources: PubMed. Methodology and search strat-
egy: An initial search was performed in November
2022, with a final update in January 2023, with the
following search string: ((("asthma diagnosis"[Title/
Abstract]) OR "asthma overdiagnosis"[Title/Abstract])
OR "asthma underdiagnosis"[Title/Abstract]) OR
"asthma epidemiology"[Title/Abstract]) AND ("asthma
guidelines"[All Fields])). From 51 articles, only orig-
inal studies, reviews, and guidelines were selected.
Only articles in English were included. The Quality
assessment was performed by the authors, and dis-
agreements were resolved through consensus focusing
on adult populations and on recently published arti-
cles with a time frame from 2010 to date.
Results
The epidemiology and the socioeconomic burden
of asthma
Asthma is reported to be the most common chronic
respiratory disease and a non-communicable disease
with major public health consequences at a global
level (1). The 2022 Global Asthma Report ranked
asthma as 24th in the leading causes of years lived
with disability, and 34th among the leading causes of
burden of disease, as measured by disability adjusted
life years index (DALYs) (1). A systematic analysis
for the global burden of disease study stated that in
2019, asthma affected approximately 262 million peo-
ple (age-standardized rate of 3416 cases per 100 000
population) with an attributed mortality reaching 455
000 deaths (2,3). Future prediction models suggest
the likelihood that by 2025, an additional 100 million
people may be affected worldwide (1).
According to the recently published Organization
for Economic Co-operation and Development OECD
report entitled, Health at a Glance, Europe 2022, the
average prevalence of asthma accounts for 6% of the
EU population, ranging from approximately 2% in
Romania and Bulgaria to approximately 8% or more
in Finland, Germany, and France (4). In most
European countries, the prevalence of asthma has
remained stable during the last 10 years, yet it is
higher among less-educated people as compared to a
more educated population (4). Further research is
warranted to estimate the actual epidemiological
asthma prevalence over time and among different
Journal of Asthma 2105
populations focusing on data accuracy. The direct
costs of asthma care in the European region have
reached 17.7 billion EUR per year (4). Similarly, as
described in the 2018 report from the Centers for
Disease Control and Prevention (CDC), the economic
burden of asthma in the United States for the period
2008 to 2013 was $3 billion in losses from missed
work and school days, $29 billion from asthma-related
mortality, and $50.3 billion in medical costs (total
cost $81.9 billion) (5). Based on a computer model
projection specifically for uncontrolled asthma, the
estimated financial, humanistic and health burden will
be $300 billion in direct and $963 billion in direct
and indirect medical costs by 2040 (6).
Asthma pathophysiology and classification: the
role of “phenotypes” and “endotypes”
Asthma pathophysiology is characterized by the pres-
ence of airway obstruction, hyperresponsiveness, and
inflammation. Cell hyperplasia, subepithelial fibrosis,
collagen deposition, mucosal gland hyperplasia,
smooth muscle hypertrophy, changes in the extracel-
lular matrix and airway remodeling are the main fac-
tors resulting in asthma airway obstruction. These
phenomena are more evident in severe asthma which
is characterized by a greater degree of incompletely
reversible airflow limitation and a more severe airway
remodeling. Among asthmatic patients a heterogeneity
of the airway inflammation was also observed. Type
2 high (T2) inflammation involves mainly the release
of interleukin (IL)-4, IL-5, IL-13 and the production
of immunoglobulin E (IgE), while T2 Low inflamma-
tion involving mainly neutrophilic inflammation
driven by CD4+ T cells, T-helper type 1 and type 17
cells, respectively (7,8).
The “traditional” asthma classification was based
on allergic (extrinsic) factors with triggers like pollen,
dust, food, air pollution and non-allergic (intrinsic)
factors with respective triggers like stress, exercise and
infections (7). Over time, the asthma definition
evolved to include the combination of characteristic
clinical factors features, such as persistent airflow lim-
itation or exacerbation-prone asthma, together with
pathophysiological factors focusing mainly on airway
inflammation (7–9). This definition enabled the clus-
ter stratification into different asthma phenotypes
according to demographic, clinical, and pathophysio-
logical factors. A recently published systematic review
by Cunha et al. revealed significant variability of
asthma phenotypes derived from data-driven methods,
with the most frequently reported phenotypes to be
atopy, gender, and severe disease (9,10). Currently,
2106 C. ARMEFTIS ET AL.
four phenotypic clusters were proposed based on large
multi-center studies: early-onset allergic asthma,
early-onset allergic moderate-severe asthma, late-onset
non-allergic eosinophilic asthma and late-onset
non-allergic non-eosinophilic asthma (11). Moreover,
based on the Severe Asthma Research Program
(SARP) multiple asthma phenotypes focusing on the
spectrum of asthma severity have been proposed
(early-onset allergic asthma, late-onset severe asthma,
and severe asthma with chronic obstructive pulmonary
disease characteristics) (12,13).
The characteristic clinical symptomatology of
asthma is accompanied by objective tests, such as
pulmonary function tests and biomarkers, which are
characterized as observable traits (10,14). The clinical
significance of the use of valid biomarkers is that
they will be able to predict asthma outcomes and a
therapeutic response to targeted therapies. However,
currently, their clinical utility in diagnosis, prognosis
and therapy is still debatable. Studies are still needed
to identify the populations most likely to benefit
from biomarker-guided treatment adjustments
(15–17).
Emerging evidence shows that this traditional defi-
nition of asthma might be little more than a descrip-
tive label for a collection of symptoms that
oversimplifies and overgeneralizes a rather heteroge-
neous clinical entity (11,18). Asthma encompasses
several types with varying underlying molecular mech-
anisms, known currently as asthma endotypes (7,12).
Eventually, these endotypes could explain the pheno-
typic and interindividual-patient variability, and to
some extent, the differential response to treatment
(14,19). Given this possibility, the Lancet Commission
has recommended the use of endotypes of treatable
traits as offering a new opportunity for optimal
patient-centered asthma care (15,20). The transition
from the “symptom based” to the “omics-based”
asthma definition and management could unleash a
new era of applying a precision medicine approach
to this field.
The Lancet Commission was a lengthy manuscript
published in 2018 as a self-proclaimed opinion article
meant to identify where progress in understanding
asthma has stalled, challenge dogma, and issue a call
to action. The manuscript proposed a more revolu-
tionary approach with focus beyond the optimal dis-
ease control-based principles into prevention- and
cure-based principles (15,20). The main perspective
was to shift the research and medical community
from the management of a heterogenic chronic respi-
ratory disease into the development of personalized
treatment approaches that focus on prevention and
optimal care and/or cure based on the genetic and
pathophysiological endotypes-treatable treats (15,20).
Among other priorities named in the Lancet
Commission agenda were the need to deconstruct the
airway disease into component parts before planning
treatment, with a focus on two dominant identifiable
and treatable traits: risk of attacks associated with
eosinophilic airway inflammation; and symptoms as
a result of airflow limitation. Going forward, the
vision is to apply these principles to the non-specialist
care framework (15,20).
These recommendations may revolutionize the defi-
nition of asthma in the near future, and subsequently,
the diagnosis and treatment algorithms pathways.
Additional research is warranted to define and validate
the optimal treatable traits, especially for patients with
severe asthma, as they may benefit from the advent
of newly targeted asthma management. In the future,
the definition of a phenotype will require consistent
clinical and physiological characteristics, an underlying
pathobiology with identifiable biomarkers and a pre-
dictable response to general and specific biological
therapies, especially for moderate and severe asthma
(Figure 1).
Asthma misdiagnosis: the magnitude and
implications
There are several reasons indicating that asthma mis-
diagnosis is still an existing global problem with sub-
stantial impact on the patient’s health, as well as the
healthcare system (2,13,16,17,22). Asthma remains a
clinical diagnosis based primarily on the history, phys-
iological tests, and trials of treatment (13,17). Although
it is difficult to assess the magnitude of asthma mis-
diagnosis worldwide, mainly because of variability in
asthma definitions, methodology and patient subsets,
it is evident that both under- and overdiagnosis are
directly associated with inappropriate treatment and
patient harm. Overdiagnosis might contribute to delay
of diagnosis and prompt treatment of other diseases,
while underdiagnosis might substantially impact the
quality of life, with progression of asthma resulting
from increased rate of exacerbations and airway
remodeling (16,22).
Major obstacles toward a more straight forward
diagnostic accuracy of this clinical entity include: the
lack of gold standard tests for the diagnosis of asthma;
current conflicts among the guidelines for the stan-
dardized cutoffs of these tests, the issue of false neg-
ative results in patients who started treatment before
testing, limited test access in primary care settings,
and the suboptimal compliance by physicians to the

Figure 1. Overview of asthma diagnosis, phenotypes (12) and treatment (21) with focus on severe asthma.
existing guidelines (2,16,18,22,23). Moreover, challenge
tests can be positive in patients outside the spectrum
of asthma, and negative in patients with asthma
already receiving corticosteroid treatment (2,18,23).
Finally, fractional exhaled nitric oxide (FeNO) test-
ing—an important type of airway inflammation
marker without consensus on cutoffs—and acknowl-
edging that risk can be influenced by several factors,
such as diet and smoking, are not suggested for diag-
nostic purposes (7,24). The European Respiratory
Society (ERS) 2022 guidelines (2) acknowledge the
considerable variation between the tests, the lack of
test consensus, and test sequence. Furthermore, the
guidelines emphasize the need to better diagnose
asthma, plus the need to determine which of the com-
monly used tests are most helpful.
The issue of overdiagnosis was assessed in a
Canadian cohort study conducted by Aaron et al.
(19,25), which focused on reexamining 613 Canadian
adults with a primary diagnosis of asthma with con-
secutive bronchial provocation tests. The participants
performed a pre- and post-bronchodilator spirometry,
and had subsequent bronchial challenge tests for a
follow-up of one year. Study results showed that after
one year of follow-up, there were false positive diag-
noses in one-third (33%) of the patients. Similar
Journal of Asthma 2107
methodology and results were reported in a recently
published study by Armeftis et al., by reexamining a
randomly selected cohort of adult patients in Cyprus
with the primary diagnosis of asthma with a bronchial
challenge test (BCT) using methacholine (20,26). In
accordance with those results, a previously published
study in the UK by Shaw et al. (22,27) revealed that
30% of patients with asthma diagnosis had normal
spirometry and provocation tests.
Asthma underdiagnosis is a major issue in several
countries (13,17,28). This was evident in an Italian
study carried out by De Marco et al. (23,29), in which
32% of study participants were diagnosed with asthma
for the first time by reporting symptoms on question-
naires, and by subsequent performance of a clinical
and test set (methacholine challenge testing, skin prick
and serum IgE measurement). Similar results were
presented in a study conducted in Denmark, whereby
the group of participants, after completing a ques-
tionnaire for symptoms suggestive of asthma, were
clinically assessed and received tests for reversible
airflow obstruction (24,30). According to their results,
493/10 000 participants aged 14-44 years were diag-
nosed with asthma according to the Global Initiative
for Asthma (GINA) guidelines, yet 50% did not have
a prior diagnosis and were untreated (24,30).
2108 C. ARMEFTIS ET AL.

Discussion Τhe GINA guidelines include international recom-

mendations for the pragmatic diagnostic and thera-
Historically, the first widely disseminated asthma
peutic approaches in low- and middle- income
guidelines were released by the Thoracic Society of
countries and healthcare settings. The 2019 GINA
Australia and New Zealand back in 1989, followed
strategy focused on the prevention of deaths and
by the British Thoracic Society (BTS) and the national
severe exacerbations, and on symptom control by
Canadian report in 1990. In the United States, the
enhancing a more personalized management based on
first guidelines were released by the National Heart,
asthma severity (21,32). The fundamental change was
Lung, and Blood Institute Expert Panel Report in
the discontinuation of recommending the treatment
1992 (8,25–27,31–33). The first global asthma guide-
of adults/adolescents with asthma with short-acting
lines developed by GINA, in conjunction with the
bronchodilators alone. Instead, it was recommended
NHLBI, were published in 1995 (27,33). Since then,
they receive a symptom-driven or a daily
the BTS together with the Scottish Intercollegiate
corticosteroid-containing inhaler to reduce risk of
Guideline Network (SIGN) developed a united guide-
severe exacerbations (21,32). In the asthma diagnosis
line report, with the latest update in 2016 (28,34).
section, and aligning with the NICE guidelines, the
Finally, NICE, BTS and SIGN reported that they are
2019 and the 2021 GINA recommendations include
on progress toward producing the Joint Guideline
both the clinical assessment and the use of objective
for the Diagnosis, Monitoring and Management of
testing (spirometry, bronchodilator reversibility, peak
Chronic Asthma, which is expected to be completed
flow variability and bronchial challenge testing), with-
by 2024 (29,35).
out specifying the most efficient testing sequence
In the UK, a significant contribution toward a more
(21,32,33,38). Moreover, in urgent cases, GINA guide-
cost-effective approach to asthma was initially made
lines encourage the trial of treatment. Finally, both
in 2013 by the National Institute for Health and
the 2019 guidelines and the 2021 update acknowledge
Clinical Excellence (NICE), introducing for the first
the presence of different endotypes or subgroups of
time, the issue of misdiagnosis and health economics.
asthma with the possibility of different therapeutic
Since then, NICE published a comprehensive report
inventions, but without embedding them into different
in November 2017 entitled Asthma: diagnosis, moni-
diagnostic and/or therapeutic algorithms (21,32,33,38).
toring and chronic asthma management, which was
The ERS regularly updates the asthma recommen-
updated on March 2021 (30,31,36,37). The NICE
dations, with the most recent one published in 2022
guidelines supported for the first time the use of com-
(2). From a methodological point of view, the ERS
pulsory objective direct and indirect testing for asthma
task force (TF) tried to systematically review the lit-
diagnosis (with an algorithm for sequential tests)
erature on the diagnostic accuracy of testing using
(30,36). This algorithm is based on tests related to
the Population, Index, Comparator, and Outcome
airflow obstruction (i.e. spirometry), bronchodilator
(PICO) and Grading of Recommendations, Assessment,
reversibility (BDR), airway inflammation, i.e. FeNO,
Development and Evaluation (GRADE) systems. The
and airflow variability, plus bronchial challenge tests
aim was to foster real-life experiences in the diagnosis,
if results are inconclusive (30,31,36,37). As such, the
including the patient’s perspective, and to enhance
current NICE guidelines strongly endorse the utility
the development of an evidence-based pragmatic clin-
of FeNO testing for increasing the accuracy of asthma
ical guideline to determine which tests to use in the
diagnosis. In addition, the use of histamine and
primary and the specialist settings, respectively (2).
methacholine described in recommendations 1.3.11
Specifically, ERS TF recommends in patients suspected
and 1.3.12 of the 2017 NICE guidelines was deemed
of asthma, in whom the diagnosis is not established
off label (30,36).
based on the initial spirometry combined with bron-
The main criticisms of these guidelines are that
chodilator reversibility testing, to perform the FeNO
they are primarily focused on the issue of applicability,
and bronchial challenge test to confirm the diag-
and there is a lack of a single standardized test
nosis (2).
sequence to diagnose asthma with both high sensi-
tivity and specificity. The latest NICE update includes
advice on the personalized action plan of minimizing
Conclusions
indoor air pollution, and reducing exposure to out-
door air pollution, as well as promoting It is evident that over the last two decades, there has
self-management monitoring both for children and been substantial progress in asthma classification and
adults (31,37). diagnosis moving toward a more refined patient-based

approach. However, current literature still reveals that
asthma over- and underdiagnosis remains an existing
global problem. There is an unmet need to establish
a more straightforward diagnostic accuracy of this
clinical entity unifying best practice diagnostic algo-
rithms by including objective diagnostic tests and
other asthma specific biomarkers for the future opti-
mization of asthma diagnosis and treatment approach.
There is an array of main obstacles, namely the lack
of gold standard objective tests for the diagnosis of
asthma, the current conflicts among the guidelines
for the standardized cut offs of these tests, the issue
of false negative results in patients who started treat-
ment before testing, the limited test access in the
primary care setting, and the suboptimal compliance
by physicians to the existing guidelines. The updated
recommendations state that there is currently no gold
standard diagnostic test for the accurate diagnosis of
asthma, and there are still conflicts regarding the
sequence, type and threshold of the various tests pro-
posed, especially in spirometry, peak expiratory flow
variability (PEFv) and exercise challenge testing.
Despite these contradictions amongst asthma diag-
nostic guidelines, it is evident that future recommen-
dations are trending toward diagnosing asthma using
objective tests. Future research is warranted to define
the optimal diagnostic and treatable traits approach,
especially for patients with severe asthma, as they
may benefit from the advent of newly targeted asthma
management.
Declaration of interest
No financial or non-financial interests that are directly or
indirectly related to the work submitted for publication.
There are no conflicts of interest.
Funding
The author(s) reported there is no funding associated with
the work featured in this article.
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