Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: An analysis of the FDA AERS database

Abstract

The possible role of leukotriene receptor antagonist (LTRA) therapy in the pathogenesis of Churg-Strauss syndrome (CSS) is uncertain. The aim was to examine the association between LTRA therapy and CSS in cases registered in the FDA Adverse Event Reporting System (AERS) database.
All cases of suspected drug-induced CSS reported to the AERS database between November 1997 and April 2003 were reviewed. Subjects in whom LTRAs were the suspected medication and sufficient documentation existed to confirm the diagnosis of CSS were sequentially categorised into one of the following groups: (A) CSS before treatment initiation; (B) oral or inhaled corticosteroids reduced or stopped within 6 months of CSS onset; (C) possible prodromal phase of CSS at treatment initiation; (D) unstable asthma at treatment initiation; (E) stable asthma at treatment initiation.
There were 181 case reports of suspected drug-induced CSS with sufficient documentation to confirm a diagnosis of CSS; in 163 (90%) an LTRA was a suspect medication. In 140 of these 163 cases there was sufficient documentation to sequentially categorize the case into groups, with 13 (9%) in A, 27 (19%) in B, 11 (8%) in C, 28 (20%) in D and 61 (44%) in E.
LTRA therapy was a suspect medication in most confirmed cases of CSS reported in the AERS database. In the majority of cases treated with an LTRA, CSS could not be explained by either corticosteroid withdrawal or pre-existing CSS. These findings are informative in considering the potential associations between LTRA therapy and CSS.

Full text

doi: 10.1136/thx.2009.120972
2010 65: 132-138Thorax
S Bibby, B Healy, R Steele, et al.
database
syndrome: an analysis of the FDA AERS
antagonist therapy and Churg-Strauss
Association between leukotriene receptor
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Association between leukotriene receptor antagonist
therapy and Churg-Strauss syndrome: an analysis of
the FDA AERS database
S Bibby,
1
B Healy,
1
R Steele,
1,2
K Kumareswaran,
1
H Nelson,
3
R Beasley
1,2
ABSTRACT
Background The possible role of leukotriene receptor
antagonist (LTRA) therapy in the pathogenesis of Churg-
Strauss syndrome (CSS) is uncertain. The aim was to
examine the association between LTRA therapy and CSS
in cases registered in the FDA Adverse Event Reporting
System (AERS) database.
Methods All cases of suspected drug-induced CSS
reported to the AERS database between November 1997
and April 2003 were reviewed. Subjects in whom LTRAs
were the suspected medication and sufficient
documentation existed to confirm the diagnosis of CSS
were sequentially categorised into one of the following
groups: (A) CSS before treatment initiation; (B) oral or
inhaled corticosteroids reduced or stopped within
6 months of CSS onset; (C) possible prodromal phase of
CSS at treatment initiation; (D) unstable asthma at
treatment initiation; (E) stable asthma at treatment
initiation.
Results There were 181 case reports of suspected drug-
induced CSS with sufficient documentation to confirm
a diagnosis of CSS; in 163 (90%) an LTRA was a suspect
medication. In 140 of these 163 cases there was
sufficient documentation to sequentially categorise the
case into groups, with 13 (9%) in A, 27 (19%) in B, 11
(8%) in C, 28 (20%) in D and 61 (44%) in E.
Conclusion LTRA therapy was a suspect medication in
most confirmed cases of CSS reported in the AERS
database. In the majority of cases treated with an LTRA,
CSS could not be explained by either corticosteroid
withdrawal or pre-existing CSS. These findings are
informative in considering the potential associations
between LTRA therapy and CSS.
INTRODUCTION
The possible role of leukotriene receptor antagonist
(LTRA) therapy in the pathogenesis of Churg-Strauss
syndrome (CSS) is uncertain, with conflicting views on
whether the association may be causal or due to
confounding by indication.
1e4
Anumberofhypoth-
eses have been proposed, including a causal relation-
ship suggested by the temporal relationship between
the introduction of LTRA therapy and development of
CSS, and the reporting patterns to adverse drug reac-
tions databases. Cases of CSS reported to the
Committee on Safety of Medicines in the UK since
the beginning of 1998 have mostly been associated
with LTRAs.
5
Likewise, a strong association between
CSS and LTRAs has been noted in the US Food and
Drug Administration (FDA) Adverse Event Reporting
System (AERS) database.
6
Another possibility is that
LTRA therapy may allow a reduction in corticosteroid
therapy leading to an unmasking of underlying CSS
which had been suppressed by the corticosteroid
therapy.
7e11
A related hypothesis is that LTRA
therapy may have been prescribed in response to
severe asthma which represented an early prodromal
phase of CSS, which then progressed to full expression
of the disease.
912
Previously it has been difficult to
assess these hypotheses owing to the paucity of data,
being limited primarily to either case reports or case
series in which the method of case selection was not
specified.
The clinical trial programme showing LTRAs to
be effective in the treatment of asthma
13
was not
designed to detect the occurrence of rare serious
adverse events such as CSS, which has a background
incidence of approximately three per million in the
general population.
14
For any drug therapy, only
once it is registered and widely used in clinical
practice will rare adverse events or events in popu-
lations not examined in clinical trials become
apparent and be reported by clinicians to adverse
drug reactions databases. We have analysed cases of
CSS reported to the FDA AERS database, focusing
on an investigation of (1) the percentage of cases
associated with the use of LTRA therapy; (2)
patterns of disease and their relation to treatment,
in particular corticosteroid withdrawal and possible
pre-existing disease; and (3) characteristics of the
disease present in this population.
METHODS
All cases in the FDA AERS database from
November 1997 (when the term allergic granulo-
matous angiitis was introduced) to April 2003 of
suspected drug-induced CSS were provided by the
FDA under the provisions of the Freedom of
Information Act (see online supplement). In some
of the case reports provided, key dates relating to
disease therapy and CSS onset had been variably
blacked out by the FDA; for this reason, we also
accessed cases previously provided by the FDA for
a related research project
6
in which no details were
blacked out.
Information from the MedWatch report form
was entered onto a questionnaire in Microsoft
Access. Objective data were entered by one inves-
tigator (SB or BH), while subjective data were
entered independently by both these investigators,
with any differences adjudicated by discussion with
a third investigator (RS or RB).
Exclusion criteria for case reports
Cases were excluded sequentially by the first
applicable category as outlined in box 1. Sequential
application of the exclusion criteria resulted in the
<Supplementary data are
published online only at http://
thx.bmj.com/content/vol65/
issue2
1
Medical Research Institute of
New Zealand, Wellington, New
Zealand
2
Capital and Coast
District Health Board,
Wellington, New Zealand
3
National Jewish Health,
Denver, Colorado, USA
Correspondence to
Professor R Beasley, Medical
Research Institute of New
Zealand, P O Box 10055,
Wellington 6143, New Zealand;
richard.beasley@mrinz.ac.nz
Received 10 June 2009
Accepted 1 November 2009
132 Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972
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inclusion of cases with a confirmed diagnosis of CSS in which an
LTRA agent was reported as the suspect medication and which
had been prescribed within 6 months of CSS onset. These cases
were included in further analyses.
Analysis of LTRA cases with confirmed diagnosis of CSS
The demographic characteristics and clinical features of the cases
were recorded, including organ involvement, presence of anti-
neutrophil cytoplasmic antibodies (ANCA) and histological
results from biopsy or post-mortem examination. The number
of American College of Rheumatology (ACR) criteria reached
before beginning LTRA and during the illness were also recorded.
Where documented, we calculated the time period from initia-
tion of LTRA therapy to onset of CSS, defined as the date when
the case was first documented to have met one of the three
diagnostic criteria to confirm the diagnosis of CSS, as stated in
box 1. In cases where the onset of CSS preceded LTRA
commencement, the time to onset was not calculated.
Patterns of LTRA use, disease presentation and
corticosteroid use
Criteria were used to stratify cases according to patterns of
LTRA use in relation to disease presentation and corticoste-
roid use, in line with current hypotheses proposed to explain
the association between LTRA therapy and CSS, as shown in
table 1.
RESULTS
There were 1274 case reports of suspected drug-induced CSS in
the AERS database. The date of CSS onset ranged from 18
December 1996 to 5 April 2003. The sequential application of
the exclusion criteria is shown in figure 1. There were 181 cases
of suspected drug-induced CSS reported by a health professional
in which there was sufficient documentation to confirm the
diagnosis of CSS.
Among these 181 cases there were 12 in whom an asthma
medication(s) other than an LTRA was reported as the suspect
medication (fluticasone propionate, n¼6; fluticasone propio-
nate and salmeterol, n¼4; budesonide, n¼1; zileuton, n¼1),
a further 5 in whom a non-asthma medication(s) was reported
as the suspect medication and in 1 case the LTRA agent was
stopped >6 months before the onset of CSS. There were 163/
181 (90%) cases of confirmed CSS in which an LTRA was
reported as at least one of the suspect medications, four of
which listed a non-LTRA medication as another suspect medi-
cation.
Analysis of LTRA cases with a confirmed diagnosis of CSS
Among the 163 cases, a confirmed diagnosis of CSS was made by
the documentation of $4 ACR criteria in 145 (89%), by docu-
mentation of a history of asthma, eosinophilia and histology
consistent with CSS in a further 17 (10.4%) and by post-mortem
findings of CSS in 1 additional case. There were six reported
deaths among the 163 cases. The age range was 7e80 years
(median 51 years; in two cases age not specified), with a female:
male ratio of 1.1:1. The time from starting LTRA therapy to
disease onset ranged from 3 to 1340 days (figure 2). The LTRA
medications reported included montelukast (n¼114), zafirlukast
(n¼43), montelukast and zafirlukast (n¼5), montelukast and
pranlukast (n¼1).
Figure 3 shows the percentage of patients with documentation
of the clinical features associated with CSS. A biopsy was taken
in 128 of the 163 cases (79%), with characteristic histological
features of CSS reported in 112 (88%). ANCA were measured in
89 patients, 37 of whom were positive (42%). Five patients were
both pANCA and cANCA positive, while 28 were pANCA and/or
myeloperoxidase (MPO) positive only, 3 were cANCA positive
only and 1 was not specified.
For the cases in whom an LTRA was reported as a suspect
medication and in whom the date of onset of CSS was available,
there were 19, 22, 26, 21, 14 and 6 cases reported yearly from
1997 to 2002, respectively.
Patterns of LTRA use, disease presentation and
corticosteroid use
In 140 of the 163 cases there was sufficient documentation to
sequentially categorise the patterns of disease presentation and
corticosteroid use (table 2, figure 4).
Group A included 13/140 (9.3%) patients, of whom 5 had
a previous diagnosis of CSS and 8 reached $4/6 ACR criteria
before initiation of LTRA therapy. Four would otherwise have
met the criteria for Group B but are not included in Group B
owing to sequential allocation of cases.
Group B included 27/140 (19.3%) patients, of whom there
were 21 with withdrawal or reduction in dose of OCS, 5 of ICS
and 1 in whom the route of corticosteroid therapy was not
specified.
Box 1 Exclusion criteria sequentially applied to the case
reports
1. Duplicate reports for the same case: as identified by unique
registration numbers, age, sex, date of onset of Churg-Strauss
syndrome (CSS), treatment start dates and any other unique
identifying feature. Such reports were combined and recorded
as a single case.
2. Report from a non-health professional: those not reported by
a health professional (such as a physician, pharmacist, or
nurse) were excluded (ie, reports from the patient, family
member or lawyer only).
3. Diagnosis not CSS: where the recorded diagnosis was not CSS
(ie, wrongly filed), or if at the conclusion of the report the
reporting physician considered an alternative diagnosis more
likely.
4. Other reason for exclusion: including conference proceedings,
case series (not providing data on individual patients), illegible
reports and those which were later withdrawn by the reporter.
5. Insufficient documentation to confirm the diagnosis of CSS:
where cases did not meet one of the following three criteria
(see online supplement):
– At least four of the six American College of Rheumatology
(ACR) classification criteria for CSS.
15
– History of asthma AND eosinophilia AND histology
consistent with CSS on biopsy.
– Post-mortem findings confirming the diagnosis of CSS.
6. Suspect therapy(ies) asthma medication(s) other than a leuko-
triene receptor antagonist (LTRA): where the suspect
medication(s) listed included an asthma treatment other than
an LTRA agent (regardless of concurrent LTRA use if not
reported as a suspect medication).
7. Suspect therapy(ies) not asthma medication(s): where the
suspect medication(s) was/were not used in the treatment of
asthma (regardless of concurrent LTRA use if not reported as
a suspect medication).
8. LTRA therapy ceased >6 months before onset of CSS.
Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972 133
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Group C included 11/140 (7.9%) patients.
Group D included 28/140 (20%) patients. When these cases
were sequentially allocated to the subgroups, 18 had OCS started
in the month before initiation of LTRAtherapy (17 a short course
and 1 continuous); 9 were on continuous OCS for at least
a month before starting LTRA; and 1 had no OCS but a hospital
admission for asthma in the month before starting LTRA
therapy.
Group E included 61/140 (43.6%) patients, of whom 52 were
on regular ICS (with no continuous OCS in the 6 months before
starting LTRA, and no short courses of OCS in the 1month
before starting LTRA); 9 did not take regular OCS or ICS, 5 of
whom were documented to have never received OCS or ICS
therapy.
DISCUSSION
To our knowledge, this review of the FDA AERS database
represents the largest case series of CSS. It identified that, in 90%
of the cases of confirmed CSS, an LTRA agent was a suspect
medication. Of the cases of CSS in which an LTRAwas a suspect
medication and there was adequate documentation to classify
the case, 36% had pre-existing CSS, had reduced or stopped oral
or inhaled corticosteroid therapy, or had possible prodromal CSS
at the time of initiation of LTRA therapy.
Before discussing these findings we will consider the meth-
odological issues potentially limiting this analysis. First, some
reports had inadequate details documented, others had
conflicting information from different sources and, in others, key
dates were blacked out by the FDA. As a result, less than half of
the case reports had adequate documentation to enable confir-
mation of the diagnosis of CSS. Furthermore, among the cases of
CSS associated with LTRA use, categorisation according to
clinical presentation including corticosteroid use was difficult,
with adjudication by a third investigator required in 20% of the
163 cases. Thus, one of our recommendations is that a more
comprehensive and effective method of data documentation and
investigation is required in patients who are reported to have
suffered a serious adverse event in association with a suspected
drug.
The next issue is whether there may have been preferential
reporting of LTRAtherapy because it was a novel treatment in
asthma. In 90% of confirmed cases of CSS an LTRA was
a suspect medication, compared with long-acting
b
-agonist
(LABA) drugs which were reported in <3% despite being
introduced during a similar period and recommended for use in
moderate to severe asthma. This contrasts with a recent
European case-control study in which 19% of patients with
CSS were receiving treatment with an LTRA compared with
63% on LABAs in the 3 months before the CSS diagnosis.
16
Similarly, a US-based case-control study reported that 13% of
patients with CSS were prescribed LTRA therapy in the
2e6 months before the CSS diagnosis.
17
Based on these data, it
is likely that the high percentage of cases of CSS in which
LTRAs were reported as the suspect medication in the FDA
database is due in part to reporting bias, and that many cases
of CSS occur without a medication being suspected and
therefore are not reported. In our analysis there was no trend
of an increased number of CSS events associated with LTRA
therapy throughout the initial 6-year period of the database,
despite LTRA therapy becoming a widely prescribed medica-
tion and the association with CSS being reported in the
medical literature. This suggests that increasing awareness of
the potential association between CSS and LTRA therapy did
Table 1 Criteria used to classify cases of CSS according to clinical presentation including corticosteroid use
Group A: CSS before initiation
of LTRA
Group B: Potential unmasking of CSS
by reduction in or stopping of
continuous corticosteroidsywithin
6 months of development of CSS
Group C: Possible prodromal phase
of CSS before initiation of LTRA
Group D: Unstable asthma at
time of initiation of LTRAy
Group E: Stable asthma
at initiation of LTRA
A1: Physician diagnosis of CSS before
starting LTRA therapy
B1: Reduction in dose or stopping, of
continuous OCS regardless of ICS dose
C: Documentation of ACR criteria of 3
before starting LTRA therapy
D1: Required a short course of OCS within
1 month before starting LTRA
E1: Taking continuous ICS within the
6 months before starting LTRA and no
continuous OCS
A2: ACR criteria of $4 before starting
LTRA therapy
B2: Reduction in dose or stopping
continuous ICS and not on continuous
OCS
D2: Started continuous OCS or was
required to increase the dose of
continuous OCS within 1 month before
starting LTRA
E2: Not on any continuous ICS or OCS
within 6 months of starting LTRA
A3: Presence of a characteristic biopsy* in
the presence of asthma and eosinophilia
before LTRA therapy
B3: Reduction in dose or stopping of
continuous corticosteroids (unspecified if
oral or inhaled)
D3: Taking continuous OCS at stable dose
in the 6 months before starting LTRA
Subset: E2-1: Corticosteroid-naı
¨
ve,
specifically documented never to have
taken OCS or ICS
D4: Hospital admission for asthma within
1 month of starting LTRA
Cases were sequentially designated in categories from Groups A to E in descending order for each group.
*A positive biopsy refers to the presence of extravascular eosinophils and/or granulomas and/or vasculitis and/or a pathologist’s report that the histology is consistent with CSS. This excludes extravascular eosinophils on nasal polyp, sinus or bone marrow biopsy.
y“Continuous” corticosteroid use is defined as corticosteroid use for >1 month for at least 1 month before starting LTRA. It does not include continuous corticosteroid use if commenced within 1 month before, on the same day orafter LTRA started. Short course OCS
use is defined as a course of oral corticosteroids of <1 month duration. Initiation of corticosteroids or hospital admission within 1 month includes the day that LTRA was commenced.
CSS, Churg-Strauss syndrome; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid.
134 Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972
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Figure 1 Allocation of cases with
sequential application of the exclusion
criteria as documented in the text. CSS,
Churg-Strauss syndrome; LTRA,
leukotriene receptor antagonist.
All cases of suspected drug-induced Churg
Strauss Syndrome reported to the FDA
n=1,274
Duplicate case reports
n=642
Report submitted from non health professional
n=24
Diagnosis of a condition other than CSS:
n=214
- Report wrongly filed and provided in error (n=179)
- CSS suspected but superseded by an alternative
diagnosis (n=35)
Other exclusion (includes illegible reports, case
series, reports later withdrawn)
n=7
Insufficient document to confirm diagnosis of CSS
n=206
All cases of suspected drug induced CSS with
sufficient documentation to confirm the diagnosis
of CSS by meeting one of the three criteria:
- ACR Criteria of 4 or more
- Asthma, eosinophilia and a
biopsy consistent with CSS
- CSS confirmed at post mortem
n=181
Suspect medication/s include an asthma
medication, but not an LTRA
n=12
Suspect medication/s do not include a medication
used in the treatment of asthma
n=5
LTRA stopped >6 months prior to CSS onset
n=1
Cases with an LTRA was reported as suspect
medication and sufficient documentation exists
to confirm definite diagnosis of CSS
n=163
Figure 2 Time to onset of Churg-Strauss Syndrome
(CSS) from start date of leukotriene receptor antagonist
(LTRA) therapy in 108 of 163 cases of confirmed CSS in
which an LTRA drug was reported as a suspect
medication and in which there was sufficient
documentation to determine this variable. In 13 cases the
onset of CSS preceded the initiation of LTRA therapy (not
shown).
0
5
10
15
20
25
30
1 - 60 days
61 - 120
121 - 180
181 - 240
241 - 300
301 - 360
361 - 420
421 - 480
481 - 540
541 - 600
601 - 660
661 - 720
721 - 780
781 - 840
841 - 900
901 - 960
961 - 1040
> 1040
Time to onset
(
da
y
s
)
Number of case reports
Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972 135
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not lead to a greater propensity to report cases to the FDA
database.
Despite these limitations, our study found that clinical
manifestations of CSS were similar to those reported previously,
with asthma, eosinophilia and multisystem involvement
including sinusitis, mononeuritis multiplex and polyneuropathy,
vascular skin lesions, pulmonary, musculoskeletal, gastrointes-
tinal and cardiac disease. About 40% of cases in whom ANCA
was measured were positive. As a result, it appears that the
spectrum of multisystem involvement and ANCA status was
similar to that observed in other case series of CSS.
18e20
Based on the clinical situations hypothesised to account for
the observed association between LTRA therapy and CSS, we
subsequently categorised cases from the least to the greatest
probability that the association was causal. The first situation,
where patients developed CSS before initiation of LTRA therapy,
was evident in 9% of cases.
The next situation, that LTRA therapy leads to an improve-
ment in asthma controldallowing tapering or stopping of
corticosteroids and thereby expression of CSS which was
previously partially suppressed by corticosteroid ther-
apy
7e10
dwas observed in 19% of cases. While it is debatable
whether a decrease in inhaled corticosteroid dose would be
sufficient to precipitate systemic vasculitis, it was included
within this category as previously proposed.
12 21
In contrast to
our results, Nathani et al reported that 37% of cases of CSS
associated with LTRA therapy published in the medical litera-
ture occurred in relation to corticosteroid withdrawal.
2
This
may indicate preferential reporting of corticosteroid tapering
in the medical literature or under-reporting of such cases to
the FDA.
The third situation proposes that LTRA therapy is prescribed
in response to the initial manifestations of a prodromal phase of
CSS and that subsequent progression to eosinophilic tissue
infiltration and systemic vasculitis occurred as a result of natural
disease progression.
9 12
In 8% of cases an LTRAwas prescribed in
the setting of three ACR criteria of CSS, with the subsequent
development of confirmed CSS. In these cases it was not possible
to determine whether the association was causal or simply
coincidental.
Thus, there was in total 36% of cases in whom the previ-
ously proposed hypothesis of pre-existing CSS, a reduction or
stopping of oral or inhaled corticosteroid therapy or a possible
prodromal phase of CSS were present. Conversely, in 64% of
patients, CSS could not be attributed to these hypotheses.
Among these remaining cases, approximately one-third had
poorly controlled asthma when LTRA therapy was started
Figure 3 Clinical manifestations reported in the 163
cases of confirmed Churg-Strauss syndrome in which
a leukotriene receptor antagonist drug was reported as
a suspect medication.
Table 2 Number (and percentage) of cases designated sequentially in
each category
Group Number Percentage
Group A: CSS before treatment initiation 13 9.3
Group B: Oral or inhaled corticosteroids
reduced or stop ped within 6 months
of CSS onset
27 [B1¼21, B2¼5,
B3¼1]
19.3
Group C: Possible prodromal early phase
of CSS at treatment initiation
11 7.9
Group D: Unstable asthma at treatment
initiation
28 [D1¼17, D2¼1,
D3¼9, D4¼1]
20.0
Group E: Stable asthma at treatment
initiation
61 [E1¼52, E2¼9,
E2-1¼5]
43.6
B1: Reduction in dose or stopping of continuous OCS, regardless of ICS dose.
B2: Reduction in dose or stopping of continuous ICS, and not on continuous OCS.
B3: Reduction in dose or stopping of continuous corticosteroid (unspecified if oral or inhaled).
D1: Required a short course of OCS within 1 month before starting LTRA.
D2: Started continuous OCS or was required to increase the dose of continuous OCS within
1 month before starting LTRA.
D3: Taking continuous OCS at a stable dose in the 6 months before starting LTRA.
D4: Hospital admission for asthma within 1 month of starting LTRA.
E1: Taking continuous ICS within the 6 months before starting LTRA and no continuous OCS.
E2: Not on any continuous ICS or OCS within 6 months of starting LTRA.
E2-1: Corticosteroid-naı
¨
ve, specifically documented never to have taken OCS or ICS.
CSS, Churg-Strauss syndrome; ICS, inhaled corticosteroid; LTRA, leukotriene receptor
antagonist; OCS, oral corticosteroid.
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while two-thirds had stable asthma. It could be proposed that
unstable asthma represents the earliest clinical manifestation
of CSS, but this has not been done as oral corticosteroid use for
exacerbationsofasthmaiscommonandthelikelihoodthatit
represents early CSS is extremely low. In those with stable
asthma, causation was more likely as no other cause was
identified as a precipitant of CSS. This group included five
cases who had never received oral or inhaled corticosteroid
therapy.
These findings are complemented by case-control studies of
CSS and medication use. In the European study
16
there was
a significant risk of developing CSS with montelukast (OR 6.7,
95% CI 1.3 to 34.1) but not LABA (OR 2.9, 95% CI 0.6 to 13.3) or
inhaled corticosteroids (OR 1.0, 95% CI 0.2 to 4.8), although the
wide confidence intervals led to some uncertainty in the inter-
pretation of these findings. In the US study,
17
a strong associa-
tion between LTRA use and CSS was reported (OR 4.0, 95% CI
1.49 to 10.6), but in the multivariate analysis controlling for
other asthma drug use, no significant association was observed
(OR 1.32, 95% CI 0.44 to 3.96).
The pathophysiological mechanisms by which CSS may
develop as a result of LTRA therapy are not clear. Indeed, the
mechanisms underlying all cases of CSS are not well under-
stood.
22
It has been postulated that the use of LTRAs may lead to
imbalances between blockade of the actions of cysteinyl-leuko-
triene (cysLT) (LTC4, LTD4, and LTE4) on the cysteinyl-leuko-
triene receptor 1 (cysLT1) and the actions of other mediators
such as leukotriene B4 (LTB4) and 5-oxo-6,8,11,14-eicosate-
traenoic acid.
423e26
LTB4 has been shown to have biological
effects on proinflammatory cells including neutrophils, eosino-
phils, macrophages, basophils, mast cell precursors and
lymphocytes.
27e31
The unopposed actions of cysLT through the
cysteinyl-leukotriene receptor 2 (cysLT2) or through other
uncharacterised receptors cannot be discounted.
32
More infor-
mation is required to support any postulated pathophysiological
mechanisms underlying the association of LTRAs and CSS.
In conclusion, LTRA therapy was a suspect medication in 90%
of confirmed cases of CSS in the FDA AERS database. Among
the cases of CSS associated with LTRA use in which there was
adequate documentation, about two-thirds were not related to
a reduction in oral or inhaled corticosteroid therapy, pre-existing
or possible prodromal CSS. We recognise that it is not possible to
determine in individual cases whether the association between
CSS and LTRA therapy is causal, coincidental or directly related
to other patterns of disease presentation or medication use.
However, we cautiously suggest that, in a majority of cases,
LTRA therapy may have a role in the pathogenesis of this
disorder. We consider that these findings justify more intensive
epidemiological study of the role of LTRA therapy in the path-
ogenesis of CSS.
Funding Asthma and Respiratory Foundation of NZ, P O Box 1459, Wellington, New
Zealand; Bowen Trust Board, P O Box 22117, Khandallah, Wellington, New Zealand.
Competing interests RB has received research grants and fees for consulting and/or
speaking from AstraZeneca, GlaxoSmithKline and Novartis. HN has received research
grants from Schering-Plough, Novartis, Genentech, Ception and AstraZeneca, fees for
consulting from Genentech/Novartis, Abbot Laboratories, MediciNova, AstraZeneca,
Amgen, GlaxoSmithKline, Schering-Plough, Dyson and Sepracor and is a member of the
GlaxoSmithKline Speakers’ Bureau. RB and HN were co-authors in the previous
publication of the association of asthma medication with CSS based on the FDA AERS
database
6
which was supported by GlaxoSmithKline. No pharmaceutical company had
any involvement in the planning, design, analysis or interpretation of the current study.
All other authors declare that they have no conflict of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1. Beasley R, Bibby S, Weatherall M. Leukotriene receptor antagonist therapy
and Churg-Strauss syndrome: culprit or innocent bystander? Thorax 2008;63:847e9.
2. Nathani N, Little MA, Kunst H, et al. Churg-Strauss syndrome and leukotriene
antagonist use: a respiratory perspective. Thorax 2008;63:883e8.
3. Stoloff S, Stempel D, Wechsler M, et al. Churg-Strauss syndrome: is there an
association with leukotriene modifiers? Chest 2000;118:1515e6.
4. McDanel D, Muller BA. The linkage between Churg-Strauss syndrome and
leukotriene receptor antagonists: fact or fiction? Ther Clin Risk Manag
2005;1:125e40.
5. Committee on Safety of Medicines/Medicines Control Agency. Leukotriene
receptor antagonists update on adverse reaction profiles. Curr Probl
Pharmacovigilance 1999;25:14.
6. DuMouchel W, Smith ET, Beasley R, et al. Association of asthma therapy and Churg-
Strauss syndrome: an analysis of post-marketing surveillance data. Clin Ther
2004;26:1092e104.
7. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and
cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving
zafirlukast. JAMA 1998;279:455e7.
8. Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg-Strauss
syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf
1999;21:241e51.
9. Lilly CM, Churg A, Lazarovich M, et al. Asthma therapies and Churg-Strauss
syndrome. J Allergy Clin Immunol 2002;109:S1e20.
10. Mukhopadhyay A, Stanley NN. Churg-Strauss syndrome associated with
montelukast. Postgrad Med J 2001;77:390e1.
11. Churg A, Brallas M, Cronin SR, et al. Formes frustes of Churg-Strauss syndrome.
Chest 1995;108:320e3.
12. Weller P, Plaut M, Taggart V, et al. The relationship of asthma therapy and Churg-
Strauss syndrome: NIH workshop and summary report. J Allergy Clin Immunol
2001;108:175e83.
13. O’Byrne PM, Gauvreau GM, Murphy DM. Efficacy of leukotriene receptor
antagonists and synthesis inhibitors in asthma. J Allergy Clin Immunol
2009;124:397e403.
14. Noth I, Strek M, Leff A. Churg-Strauss syndrome. Lancet 2003;361:587e94.
15. Masi A, Hunder G, Lie J, et al. The American College of Rheumatology 1990 criteria
for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).
Arthritis Rheum 1990;33:1094e100.
16. Hauser T, Mahr A, Metzler C, et al. The leucotriene receptor antagonist montelukast
and the risk of Churg-Strauss syndrome: a case-crossover study. Thorax
2008;63:677e82.
17. Harrold L, Patterson M, Andrade S, et al. Asthma drug use and the development of
Churg-Strauss syndrome (CSS). Pharmacoepidemiol Drug Saf 2007;16:620e6.
18. Keogh K, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil
cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med
2003;115:284e90.
19. Sable-Fourtassou R, Cohen P, Mahr A, et al and the French Vasculitis Study Group.
Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern
Med 2005;143:632e8.
20. Solans R, Bosch J, Perez-Bocanegra C, et al. Churg-Strauss syndrome: outcome and
long-term follow-up of 32 patients. Rheumatology 2001;40:763e71.
21. Hashimoto M, Fujishima T, Tanaka H, et al. Churg-Strauss syndrome after reduction
of inhaled corticosteroid in a patient treated with pranlukast for asthma. Intern Med
2001;40:432e4.
Figure 4 Percentage of cases designated sequentially in each category
defined by patterns of disease and their relation to treatment. The figure
includes the 140 cases in whom a leukotriene receptor antagonist was
reported as a suspect medication and where sufficient documentation
existed to both confirm a diagnosis of Churg-Strauss syndrome and
sequentially to categorise into groups A, B, C, D or E.
Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972 137
Asthma
group.bmj.com on February 16, 2010 - Published by thorax.bmj.comDownloaded from

22. Tsurikisawa N, Saito H, Tsuburai T, et al. Differences in regulatory T cells between
Churg-Strauss syndrome and chronic eosinophilic pneumonia with asthma. J Allergy
Clin Immunol 2008;122:610e6.
23. Conen D, Leuppi J, Bubendorf L, et al. Montelukast and Churg-Strauss syndrome.
Swiss Med Wkly 2004;134:377e80.
24. Guilpain P, Viallard JF, Lagarde P, et al. Churg-Strauss syndrome in two patients
receiving montelukast. Rheumatology (Oxford) 2002;41:535e9.
25. Solans R, Bosch JA, Selva A, et al. Montelukast and Churg-Strauss syndrome. Thorax
2002;57:183e5.
26. Stirling RG, Chung KF. Leukotriene antagonists and Churg-Strauss syndrome: the
smoking gun. Thorax 1999;54:865e6.
27. Dahlen SE. Treatment of asthma with antileukotrienes: first line or last resort
therapy? Eur J Pharmacol 2006;533:40e56.
28. Iikura M, Suzukawa M, Yamaguchi M, et al. 5-Lipoxygenase products regulate
basophil functions: 5-oxo-ETE elicits migration, and leukotriene B4 induces
degranulation. J Allergy Clin Immunol 2005;116:578e85.
29. Rubin P, Mollison KW. Pharmacotherapy of diseases mediated by
5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat
2007;83:188e97.
30. Evans JF, Ferguson AD, Mosley RT, et al. What’s all the FLAP about?:
5-lipoxygenase-activating protein inhibitors for inflammatory diseases. Trends
Pharmacol Sci 2008;29:72e8.
31. Harizi H, Corcuff JB, Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology
and immunopathology. Trends Mol Med 2008;14:461e9.
32. Lee TH, Woszczek G, Farooque SP. Leukotriene E4: perspective on the forgotten
mediator. J Allergy Clin Immunol 2009;124:417e21.
Pulmonary puzzle
A 69-year-old smoker with
mediastinal and hilar
lymphadenopathy
CLINICAL PRESENTATION
A 69-year-old male heavy smoker was referred to our service
with 6 months minimal productive cough and 2 weeks pleuritic
central chest pain, with no weight loss or constitutional symp-
toms. There was no relevant previous medical history. Clinical
examination demonstrated no abnormalities. CT chest revealed
extensive mediastinal and right hilar lymphadenopathy with
a conglomerate subcarinal lymph node of 733.9 cm, with no
parenchymal lung abnormalities identified.
Whole-body
18
fluorodeoxyglucose (FDG) positron emission
tomography revealed increased nodal uptake throughout the
mediastinum (figure 1) as well as in the right supraclavicular
fossa, and right hilum. Bronchoscopy demonstrated no focal
endobronchial lesions, and cytology, Gram staining and culture
of bronchoalveolar lavage fluid were non-diagnostic. Endobron-
chial ultrasound-guided transbronchial needle aspiration of the
paratracheal and subcarinal lymph nodes using a 22-gauge
transbronchial needle aspiration needle (NA-201SX-4022,
Olympus, Tokyo, Japan) with five passes was performed. Path-
ological examination revealed fibrous tissue with abundant
plasma cells. Immunohistochemical staining for immunoglob-
ulin light chains was equivocal.
QUESTION
What is the likely diagnosis and how should this be confirmed?
See page 187 for answer.
Y H Khor,
1
D P Steinfort,
1
M R Buchanan,
2
D Gunawardana,
3
P Antippa,
4
L B Irving,
1
1
Department of Respiratory Medicine, Royal Melbourne Hospital, Victoria, Australia;
2
Department of Pathology, Royal Melbourne Hospital, Victoria, Australia;
3
Department
of Nuclear Medicine, Royal Melbourne Hospital, Victoria, Australia;
4
Department of
Cardiothoracic Surgery, Royal Melbourne Hospital, Victoria, Australia
Correspondence to Dr Yet Hong Khor, Department of Respiratory Medicine,
Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia;
YetHong.Khor@mh.org.au
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Thorax 2010;65:138. doi:10.1136/thx.2009.123828
Figure 1 Positron emission tomography image demonstrating large
intensely fluorodeoxyglucose (FDG)-avid masses in (a) pretracheal and
(b) subcarinal and right hilar regions.
138 Thorax 2010;65:132e138. doi:10.1136/thx.2009.120972
Asthma
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