ABSTRACT
Objective
We assessed the prevalence, clinical characteristics, and severity of
respiratory tract and ear symptoms among Finnish Non-steroidal
anti-inflammatory drug (NSAID) exacerbated respiratory disease (N-ERD)
patients.
Design
A retrospective cross-sectional questionnaire study.
Setting
A university tertiary care center.
Participants
A total of 232 patients with both asthmatic and polypoid ICD-10
diagnoses treated at our university tertiary care center between January
2016 and May 2017 were identified by an electronic patient record
search. The patient charts were manually reviewed and 102 patients with
specified symptoms on NSAID exposure, in addition to asthma and nasal
polyposis diagnosis, were considered potential N-ERD patients. The
patients received a questionnaire with an informed consent form, and the
66 patients who responded and confirmed diagnoses of asthma, nasal
polyposis, and acetylsalicylic acid (ASA) or NSAID intolerance were
included.
Results
The first diagnosis received was asthma, followed by NSAID intolerance
and nasal polyposis, when evaluated by mean age of contracting the
condition. When evaluating individual patients, there was considerable
variation in the order and timing of the separate conditions. The
majority of the patients received all three diagnoses within a few
years’ time. The diagnostics and treatment of N-ERD patients seemed to
only partially follow the international guidelines. The proportion of
N-ERD patients with recurrent or chronic middle ear infection was 18%.
Patient-reported disease control was good in asthma, but only mediocre
in nasal polyposis and ear symptoms. As many as 14% reported a positive
family history of N-ERD.
Conclusions
Structured cross-department diagnostics and care could benefit N-ERD
patients in Finland. Rhinological and aural symptoms seem to affect a
patient’s quality of life more than asthma. The high proportion of
familial cases warrants further studies.
Keywords: Asthma, Aspirin-Induced, Nasal Polyps, Aspirin, NSAIDs,
Heredity, Ear, Middle, Finland
KEY POINTS
- N-ERD is an eosinophilic inflammatory disease of the upper and lower
airway mucous membranes characterized by the co-existence of asthma,
nasal polyposis and hypersensitivity to NSAIDs.
- We present the clinical characteristics and patient-assessed disease
control of N-ERD in our university tertiary care center in Finland
with special emphasis on ear symptoms.
- The diagnostics and treatment of N-ERD patients in our study group
seemed to only partially follow the international guidelines.
- Ear symptoms were common and the majority of the ear-symptomatic
patients had needed an intervention to control their symptoms.
- The patient-assessed control of nasal polyposis and ear symptoms was
poorer than the control of asthma symptoms.
1. INTRODUCTION
Non-steroidal anti-inflammatory drug (NSAID) -exacerbated respiratory
disease (N-ERD) is an adult-onset inflammatory disease of the upper and
lower respiratory mucous membranes characterized by the co-existence of
asthma, nasal polyposis, and sensitivity to NSAIDs. The spectrum was
originally described by Samter and Beers in 1968.1,2It was formerly referred to as aspirin-exacerbated respiratory disease
(AERD) or Samter’s Triad. Since hypersensitivity comprises not only
aspirin but also other cyclo-oxygenase-1 (COX-1) inhibitors, the term
N-ERD is more accurate for describing the disorder 3.
The prevalence of N-ERD is suggested to be 0.3-0.9% in the general
population. The prevalence is higher among patients with asthma (7%),
chronic rhinosinusitis with nasal polyps (10%), or severe asthma (15%)4-6, and is up to 30% in asthmatics with nasal
polyposis 7. In most studies, rhinitis symptoms are
the presenting feature. Generally, in about five years’ time the
diagnosis of asthma is set, with symptoms of NSAID intolerance
subsequently leading to a diagnosis of nasal
polyposis.8 The clinical course of asthma and nasal
polyposis is often severe 3,4,9-11. However, patients’
subjective experience of disease control and quality of life is better
than expected 12,13.
N-ERD has been proposed to be acquired with unknown epigenetic triggers
combined with underlying genetic predisposition. The clinical
presentation in adulthood and lack of replication in genetic studies
together with the continuing upper and lower respiratory mucosal
inflammation independent of aspirin exposure indicate that epigenetic
mechanisms may contribute more to the pathogenesis than genetic
variations 14. The chronic eosinophilic inflammation
of the upper and lower airway mucous membranes is known to be related to
disturbances in arachidonic acid metabolism. Arachidonic acid is the
precursor of the inflammation mediators leukotrienes and prostaglandins3,15,16.
International recommendations for diagnostics and treatment options for
N-ERD include multimodal disease-specific treatment3,17. Inhaled corticosteroids with long-acting beta-2
agonists and leukotriene-modifying drugs (LTMD) are the treatment of
preference for N-ERD-related asthma. Biologic anti-IgE therapy with
omalizumab and regular peroral corticosteroids are reserved for severe
cases. Daily saline irrigation and topical corticosteroid drops are
basic treatments for nasal polyposis accompanied by short courses of
peroral corticosteroids. Sinonasal polypectomy and functional endoscopic
sinus surgery are warranted in cases with uncontrolled symptoms despite
adequate medication 17. LTMD also relieves nasal
symptoms. Omalizumab and the biologics targeting eosinophilic
inflammation (mepolizumab, reslizumab, dupilumab) are effective options
for recurrent operations and corticosteroid courses. Aspirin
desensitization is an effective option for both nasal polyposis and
asthma. The disease control is often challenging, and multimodal
treatment with recurrent surgical procedures is frequently needed4,18,19.
One-quarter (26%) of N-ERD patients exhibit ear symptoms such as aural
fullness, otorrhea, and conductive hearing loss 20.
There are a few case reports of binaural middle ear polyposis among
female N-ERD patients 21. Interestingly, the histology
of middle ear polypoid mass biopsies is similar to the nasal polyps seen
in N-ERD 22. If present, symptoms of otitis media with
effusion usually develop subsequent to other manifestations of N-ERD23.
The aim of this study was to assess the clinical characteristics and
patient-reported severity of symptoms of N-ERD in the Finnish
population. In addition, we wanted to evaluate the presence and severity
of coexisting chronic or recurrent middle ear infections.
1.1 ETHICAL CONSIDERATIONS
The study protocol was approved by the [removed for blind peer
review]1 Ethics Committee ([removed for blind peer
review]2/3078/2017). The authors of this article
declare no conflict of interest.
2. MATERIALS AND METHODS
[removed for blind peer review]3 is a tertiary
referral center providing healthcare services for [removed for blind
peer review]4 inhabitants. The [removed for blind
peer review]5 electronic patient records cover all
medical specialties, excluding primary healthcare.
We conducted a retrospective database search for patients with ICD-10
diagnoses of asthma (J45.0, J45.1, J45.8, J45.9) and nasal polyposis
(J33.0, J33.1, J33.8, J33.9) between January 2016 and May 2017. Patient
charts were manually reviewed to identify patients with clinical history
and symptoms of NSAID intolerance. Aspirin challenge was not required. A
questionnaire with informed consent was sent to patients with suspected
N-ERD. The non-respondents were sent a new questionnaire and informed
consent once. Patients returning the questionnaires between April 2018
and May 2019 and all returned questionnaires were analyzed.
In the questionnaire, patients were first asked to confirm having
diagnoses of asthma, nasal polyposis, and NSAID intolerance. Only
patients confirming these conditions were included. In addition, we
asked about current medication for asthma and nasal polyposis, number of
recent oral corticosteroid courses, surgical history for nasal
polyposis, and family history of asthma, nasal polyposis, NSAID
intolerance, or N-ERD. We also asked patients to assess the current
control of their symptoms, their NSAID exposure-related symptoms, and
the presence and control of ear symptoms. We focused on a subgroup of
patients confirming adult-onset recurrent or chronic middle ear
infection and analyzed them separately.
Associations between patient characteristics and clinical variables were
calculated using Fisher exact tests. A P-value < 0.05 was
considered statistically significant. Descriptive statistics were used
for means, medians, and ranges. In this study we followed the STROBE
reporting guideline for observational studies.
3. RESULTS
The patient retrieval process is summarized in Figure 1. A total of 232
patients had ICD-10 diagnoses for both asthma and nasal polyposis. After
manual review of patient charts, we identified 102 patients (102/232,
44%) with a clinical history of NSAID intolerance. These patients were
considered possible N-ERD patients, and they received the questionnaire
and informed consent form. Seventy patients (70/102, 69%) responded and
the inclusion criteria (confirmed asthma, nasal polyposis, and NSAID
intolerance) were met by 66 respondents (66/70, 94%). Their demographic
characteristics are shown in detail in Table 1. Of the 66 patients, 12
(18%) reported recurrent or chronic middle ear infection.
Based on the inquiry, the diagnoses of asthma, NSAID intolerance, and
nasal polyposis were set in a close time frame. The median time span was
four years and the average six years. When taking into account only the
mean contraction ages, the first diagnosed condition was asthma,
followed by NSAID intolerance and nasal polyposis. However, considerable
variation existed in the order and timing of the separate conditions for
individual patients. Six patients (9%) received all three diagnoses in
the same year. The disease-specific contraction time of individual
patients is shown in Figure 2.
3.1 ASTHMA
The median age of onset for asthma was 33 years. The majority (94%) of
the patients used inhaled corticosteroids. Less than half (38%) took
leukotriene modifiers regularly, and only two (3%) had biological
medical therapy. Two-thirds (64%) had needed peroral corticosteroid
treatment either continuously or as a course in the past five years. The
number of corticosteroid courses required varied from 1 to 20. The
majority (83%) reported the experienced disease control of asthma to be
good or very good. Only 12% reported poor or very poor asthma control.
Twelve patients (18%) had had asthma for over 30 years, and four of
these (33%) reported poor disease control. Detailed asthma
characteristics are presented in Table 1.
3.2 NASAL POLYPOSIS
The median age of onset of nasal polyposis was 34 years. The majority
(88%) used topical nasal steroids regularly. Of these, 23 (35%) used
corticosteroid drops and the remainder nasal sprays. Nearly all (95%)
had undergone surgical removal of nasal polyps, and the number of
reported operations varied from 1 to 70. More than half (59%) had
needed a course of oral corticosteroids in the past five years. The
number of courses varied from 1 to 30. The proportion of patients
regarding polyp control to be good or very good was 58%; the
corresponding figure for poor or very poor polyp control was 38%. The
condition diagnosed first did not affect the reported severity of nasal
symptoms. Detailed nasal polyposis characteristics are presented in
Table 1.
3.3 ASPIRIN OR NSAID INTOLERANCE
The median age of onset of NSAID intolerance was 35 years. Reported
aspirin or NSAID-related symptoms included worsening of asthma (38%),
breathing difficulties (86%), swelling, itching, or irritation of oral
or pharyngeal mucous membranes (42%), skin symptoms (21%), and other
symptoms (32%), including nasal congestion and discharge, sneezing,
worsening of polyps, eye irritation, nausea, abdominal pain, and
swelling of the face. Anaphylaxis was reported by three patients (5%).
None reported exclusively skin symptoms caused by NSAID, which makes
NSAID-related urticaria unlikely. Thirty patients (45%) had undergone
an aspirin challenge. Twenty-three patients (35%) were further treated
with aspirin desensitization between the years 1999 and 2018. Twelve of
the desensitized patients (52%) reported relief of symptoms, including
decreased growth of nasal polyps, less nasal congestion and discharge,
and less shortness of breath and asthma-related symptoms. Two of the
challenged but not desensitized patients reported anaphylaxis on NSAID
exposure. Aspirin treatment (250 mg) was used by five patients (8%) at
the time of inquiry, which is less than half of those who had undergone
successful desensitization with relief of their symptoms. Detailed NSAID
intolerance characteristics are presented in Table 1.
3.4 EAR SYMPTOMS
Recurrent (more than twice a year) or chronic (more than two months)
adult-onset middle ear infections were reported by about one-fifth
(12/66, 18%) of patients. The median age of onset was 37 years. Eleven
(11/12, 92%) of the ear-symptomatic patients were women (p = 0.0205).
The number of infections varied from two to over ten in the past five
years. Adulthood myringotomy was performed for the majority (9/12, 75%)
from one to five times. Over half (7/12, 58%) had been placed on
tympanostomy tubes from one to eight times in adulthood. Six patients
(50%) reported a history of adulthood tympanic membrane perforation and
five reported currently having a tympanic membrane perforation. Two had
hearing aids, both bilateral.
The subjective clinical control of ear symptoms was regarded as good or
very good by 73% and poor or very poor by 15% of the 66 patients. In
contrast, in the recurrent or chronic middle ear infection subgroup the
majority (7/12, 58%) regarded the control of ear symptoms as poor or
very poor and only one-third (4/12, 33%) as good or very good. Detailed
ear symptom characteristics are presented in Table 2.
3.5 FAMILY HISTORY
Positive family history was most common in asthma (56%), followed by
nasal polyposis (21%) and NSAID intolerance (9%). Notably, 14%
reported a positive family history of N-ERD. For details, see Table 1.
4. DISCUSSION
4.1 KEY RESULTS
This study is the first to describe the clinical characteristics and
patient-reported disease control of N-ERD in the Finnish population and
one of the largest to describe ear symptoms associated with N-ERD.
When mean onset ages were considered, the first reported diagnosis was
asthma, followed by NSAID intolerance and nasal polyposis. The time span
for setting all three diagnoses was relatively short, the median time
span being four years and the average six years. For 13 patients (20%),
all diagnoses had been set within two years. However, for individual
patients considerable variation existed in the timing and order of
separate diagnoses.
The diagnostics and treatment of N-ERD patients in our study group
seemed to only partially follow the international guidelines. Less than
half were diagnosed with aspirin challenge or treated with aspirin
desensitization, and only a few were on aspirin treatment after
desensitization. LTMD was reported to be used by less than half of
respondents. Only two had biological anti-IgE medical treatment for
asthma, and none had any biological treatment for nasal polyposis
despite abundant use of corticosteroid courses for both asthma and nasal
polyposis and numerous surgical procedures for nasal polyp control.
Patient-reported disease control was best in asthma, followed by nasal
polyposis and ear symptoms. More efficient follow-up and treatment for
nasal polyposis in N-ERD are required.
Ear symptoms were common, with one-fifth (18%) of patients reporting
them. The ear-symptomatic patients were mainly women (92%, p=0.0205).
The majority had needed an intervention of myringotomy or tympanostomy
tubes to control their ear symptoms. Almost half had current tympanic
membrane perforation, indicating chronic inflammation. Considering the
commonness of ear symptoms and needed interventions and the shortages in
N-ERD-associated nasal polyposis care, patients would benefit from
cross-department diagnostics and care for N-ERD. The patient’s
perspective of disease control should be taken into account when
planning the follow-up and treatment of N-ERD.
Up to 14% of patients reported a positive family history of N-ERD,
which warrants further investigations.
4.2. STRENGTHS AND LIMITATIONS OF THE STUDY
Data collection was conducted by a database search for ICD-10 diagnosis
codes for asthma and nasal polyposis. Thus, it is possible that some
patients not having a registered diagnosis in the database were missed,
and the number of patients having both diagnoses might be underestimated
in the study. This might have influenced the high proportion (44%) of
N-ERD among asthma and nasal polyposis patients. To our knowledge, this
is the largest study describing the number and nature of ear symptoms
among N-ERD patients.
The study design relies on information collected from patients, thus
carrying a risk of reporting bias. Furthermore, we did not require a
positive aspirin challenge for the diagnosis of N-ERD. Instead,
intolerance was based on registered symptoms by aspirin intake in
patient charts and the patient’s subjective confirmation of intolerance.
However, in previous studies, clinical history of NSAID intolerance
appears to be reliable 3,6,24.
Biological monoclonal antibody medication for severe allergic and
eosinophilic asthma and nasal polyposis is a relatively recent
therapeutic option. Thus, the timing of data collection might have
influenced the scarce usage of biological medication in our cohort.
Patients’ subjective reported disease control could likewise be better
with more efficient medication, at least for asthma and nasal polyposis.
4.3 COMPARISON WITH OTHER STUDIES
In this study, the proportion of asthmatic and nasal polyposis patients
with NSAID intolerance was relatively high (44%) compared with earlier
studies reporting prevalence rates of 30% 7. Data
were collected in a university tertiary care center, excluding primary
healthcare, which might have led to a higher prevalence of N-ERD among
our asthma and nasal polyposis patients.
In most previous studies, rhinitis symptoms are the presenting feature,
with supervening diagnoses of asthma, NSAID intolerance, and nasal
polyposis over a time span of about six years.8 In our
study, this was the sequence of the diagnoses when only the mean onset
ages were considered. However, when individual patients were viewed
separately, remarkable variation existed in the sequence of the separate
conditions. The onset age in the fourth decade of life and the female
predominance are consistent with data from previous studies8. The prevalence of 18% and the female predominance
among patients suffering from ear symptoms is similar to the proportion
(26%) and sex distribution described earlier 2023. Ear symptoms might be underrated in the care of
N-ERD patients. In our study, multiple interventions were needed for the
control of ear symptoms, and ear-symptomatic patients regarded this
condition as the worst controlled.
The number of patients reporting a positive family history of N-ERD
(14%) was unexpectedly high and warrants further studies. The number of
familial cases of N-ERD has previously been markedly lower (1-6%)8 9.
4.4 CLINICAL APPLICABILITY OF THE STUDY
N-ERD is a systemic condition and the diagnoses of upper and lower
respiratory tract disorders are often set close to each other, albeit
usually on separate occasions. Tertiary healthcare may be provided in
only the ear, nose, and throat or pulmonary department, delaying the
diagnosis of either asthma or nasal polyposis, with the overall picture
of the patient’s condition being missed. There is a clear demand for
structured diagnostics and treatment for this challenging patient group
in Finland.
When considering the multimodal diagnostics and therapy recommended for
N-ERD, it is crucial to refer all patients to tertiary healthcare for
optimal treatment and follow-up, and, even more importantly, the
collaboration between different specialties should be enhanced. In our
cohort from a university tertiary care center, the N-ERD patients did
not appear to have all the diagnostic and therapy options available from
which they could derive a benefit. This finding has also recently
emerged in a comprehensive register study 25.
The patient-assessed control of nasal polyposis and ear symptoms was
poorer than the control of asthma symptoms. Therefore, more emphasis
must be placed on controlling these symptoms. According to our findings,
nasal symptoms together with chronic ear infection seem to affect the
patient’s quality of life more than asthma. Whether this is due to
inadequate use of medication or more severe disease remains to be
evaluated. The ear symptoms, although not an official component of the
triad, deserve adequate evaluation and treatment.
4.5 CONCLUSIONS
More accurate N-ERD diagnostics and treatment are needed in Finland.
Otological symptoms are common and together with rhinological symptoms
are poorer controlled than asthma symptoms. The unexpectedly high number
of familial cases warrants further investigations.
5. REFERENCES
5.1 DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.
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6. TABLE AND FIGURE LEGENDS
6.1 The Questionnaire
6.2 Figure 1. The Patient retrieving process. NSAID non-steroidal
anti-inflammatory drug.
6.3 Table 1. Clinical characteristics of the included 66 patients. † in
five past years as a course or regularly. N number of patients. n/a Not
answered. ASA acetylsalicylic acid. NSAID non-steroidal
anti-inflammatory drug.
6.4 Figure 2. The disease-specific contraction time of the individual
patients. Each symbol represents one of the 66 included patients. NSAID
non-steroidal anti-inflammatory drug.
6.5 Table 2. Characteristics of the twelve ear-symptomatic patients. N
number of patients. n/a Not answered.