bene˚ts and˜harm of˜systemic steroids for˜short- and˜long ......for˜short- and˜long-term use...
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Hox et al. Clin Transl Allergy (2020) 10:1 https://doi.org/10.1186/s13601-019-0303-6
REVIEW
Benefits and harm of systemic steroids for short- and long-term use in rhinitis and rhinosinusitis: an EAACI position paperValerie Hox1* , Evelijn Lourijsen2, Arnout Jordens3, Kristian Aasbjerg4, Ioana Agache5, Isam Alobid6,7, Claus Bachert3,8, Koen Boussery9, Paloma Campo10, Wytske Fokkens2, Peter Hellings11, Claire Hopkins12, Ludger Klimek13, Mika Mäkelä14, Ralph Mösges15, Joaquim Mullol6, Laura Pujols6, Carmen Rondon10, Michael Rudenko16, Sanna Toppila‑Salmi14, Glenis Scadding17, Sophie Scheire9, Peter‑Valentin Tomazic18, Thibaut Van Zele3, Martin Wagenmann19, Job F. M. van Boven20 and Philippe Gevaert3
Abstract Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosi‑nusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that—potentially severe—side‑effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease.
Keywords: Glucocorticosteroids, Rhinitis, Rhinosinusitis
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IntroductionChronic upper airway inflammation is one of the most prevalent chronic disease entities in the world with rhi-nitis being the most common presentation form affecting 30% of the Western population [1].
Rhinitis is defined as an inflammation of the lining of the nose and is characterized by nasal symptoms includ-ing rhinorrhoea, sneezing, nasal blockage and/or itch-ing of the nose. Allergic rhinitis (AR) is the best-known form of non-infectious rhinitis and is associated with an IgE-mediated immune response against allergens [1]. However, a substantial group of rhinitis patients has no known allergy and they form a very heterogeneous non-allergic rhinitis (NAR) patient population suffering from
drug-induced rhinitis, occupational rhinitis, irritant-induced rhinitis, hormonally linked rhinitis and idiopathic rhinitis [2, 3]. When inflammation of the nasal mucosa extends to the mucosa of the paranasal sinuses, the con-sensus term of rhinosinusitis is used. Rhinosinusitis has been shown to affect about 10% of the Western popula-tion [4]. In addition to rhinitis symptoms, rhinosinusitis is characterized by postnasal drip, facial pressure and reduction or loss of smell [5]. Acute rhinosinusitis (ARS) is a very common condition and mostly of viral origin [5]. About 0.5–2% of the viral ARS are complicated by a bac-terial infection [5].
Chronic rhinosinusitis (CRS) is defined as the pres-ence of two or more nasal symptoms, one of which should be either nasal blockage or nasal discharge, and/or smell problems, and/or facial pain for more than 12 weeks, in combination with inflammatory signs con-firmed by nasal endoscopy and/or CT scan. CRS can
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*Correspondence: [email protected] Cliniques Universitaires Saint‑Luc Brussels, Av. Hippocrate 10, 1200 Brussels, BelgiumFull list of author information is available at the end of the article
Clinical andTranslational Allergy
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Page 2 of 27Hox et al. Clin Transl Allergy (2020) 10:1
either present with nasal polyps (CRSwNP) or without (CRSsNP). Additionally, chronic upper airway disease often coexists with lower airway problems, most fre-quently asthma, but also a link with chronic obstruc-tive pulmonary disease (COPD) and bronchiectasis has been reported [6].
Glucocorticosteroids (GCS) are the oldest and most widely used anti-inflammatory therapy. Since their introduction in the 1950s, GCS have played a key role in the treatment of various inflammatory, allergic, and immunologic disorders. Consequently, they are known as a very effective drug for treating chronic airway inflammatory diseases involving both lower as well as upper airways [1, 4, 7]. GCS can be administered topi-cal or systemically. If possible topical GCS are preferred over systemic GCS treatment as it is well known that this systemic GCS treatment is linked to an extensive range of potential adverse effects (AE’s) that have been well-described in the literature and vary from uncom-fortable to life-threatening [8]. Notably, reports on AE and/or toxicity of systemic GCS cover a heterogeneous group of GCS-treated diseases, which complicates the interpretation of the actual risk for the rhinitis/rhinosi-nusitis patients.
Therefore, the risk–benefit ratio of treating non-life-threatening upper airway diseases with systemic GCS remains debatable and needs clarification.
This document summarizes the current evidence for beneficial as well as harmful effects of administration of systemic GCS in the different types of upper airway disease and aims at providing recommendations about its use in rhinitis and rhinosinusitis based on the cur-rent evidence. For each topic 2 experts in the field were appointed to review the literature and topics that were appropriate for clinical recommendations were consid-ered as evidence-based reviews with recommendations. The experts then provided a recommendation based upon the guidelines of the American Academy of Pedi-atrics (following the recommendation strategy used by the International Consensus on Allergy and Rhinology [9]). Table 1 summarizes the recommendation devel-opment based on the combination between levels of
evidence and the benefit/harm balance. Generally, the search was focused on adults. Two experts reviewed the literature specifically for the pediatric population.
The search was performed in the MEDLINE (Ovid 1946—current; and PubMed 1966—current) and Cochrane databases. The search strategy was based on a combination of MeSH-terms and free text words. Search terms are listed in Additional file 1.
Mechanisms and actions of GCSCorticosteroids, which are produced by the adrenal glands, can be classified as glucocorticoids and mineralo-corticoids. Cortisol is the endogenous glucocorticoid in humans, naturally derived from cholesterol metabolism upon stimulation by the hypothalamic–pituitary–adrenal axis (Fig. 1), which is regulated initially by the circadian rhythm, but also by negative feedback by glucocorticoids and glucocorticoid increment induced by stressors such as pain, inflammation or infections [10].
GCS are involved in several physiologic functions. They control the metabolism of carbohydrates, proteins and lipids, as well as the balance of calcium [11, 12]. However, the most explored effects of GCS are the anti-inflamma-tory and immune-suppressive functions. GCS inhibit the activation and survival of inflammatory cells and modu-late the activity of structural cells [13, 14]. The main anti-inflammatory effects of GCS are based on their ability to reduce the synthesis of several cytokines (IL-1, -2, -3, -4, -5, -6, -8, TNF-α, IFN-γ, GM-CSF) from many cells (macrophages, monocytes, lymphocytes, fibroblasts, and epithelial and endothelial cells). This affects recruitment, localization, protein synthesis, and survival of inflam-matory cells such as eosinophils [15]. The recruitment of inflammatory cells is also diminished by an inhibited expression of adhesion molecules such as ICAM-1 and VCAM-1 [16], which affects the influx of basophils and mast cells in the epithelial layers of nasal mucosa. Finally, GCS are involved in the pathological wound repair mechanism called remodelling. Remodelled tissue such as the stroma of nasal polyps contains abundant infiltra-tion of inflammatory cells, increased fibroblasts numbers and increased extra-cellular matrix deposition. However,
Table 1 American Academy of Pediatrics defined strategy for recommendation development [9]
RCT randomized controlled trial
Evidence quality Preponderance of benefit over harm
Balance of benefit and harm
Preponderance of harm over benefit
A. Well‑designed RCTs Strong recommendation Option Strong recommendation againstB. RCT’s with minor limitations; overwhelming consistent evi‑
dence from observational studiesRecommendation
C. Observational studies (case–control and cohort design) Recommendation against
D. Expert opinion; case reports; reasoning from first principles Option No recommendation
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Page 3 of 27Hox et al. Clin Transl Allergy (2020) 10:1
GCS appear to be minimally effective in reversing the structural changes resulting from remodelling [17].
All these effects are exerted by intracellular activa-tion of the glucocorticoid receptor (GR) [18]. The GR belongs to the superfamily of ligand regulated nuclear receptors [19] and alternative splicing of the GR primary transcript generates two receptor isoforms, named GRα and GRβ. GRα has a widespread distribution in cells and
tissues [20], including healthy and diseased upper airway mucosa. Inactive GRα is found primarily in the cytoplasm of cells as part of a large multi-protein complex [21]. Glu-cocorticoids diffuse across the cell membrane and bind to GRα resulting in a nuclear entry (Fig. 2) [22] where GRβ modulates either positively or negatively the expression of target genes. GRβ has a very low level of expression
Fig. 1 The hypothalamic–pituitary–adrenal axis. Stress stimuli induce the production of CRH by the hypothalamus. CRH induces the production of ACTH by the pituitary gland which stimulates the production of glucocorticoids (cortisol) in the adrenal gland cortex. Cortisol acts on many cells, tissues, and organs including the immune system. The excessive release of cortisol as well as proinflammatory cytokines have a negative feedback on the central nervous system by inhibiting this circadian cycle. CRH corticotrophin releasing hormone, ACTH adrenocorticotrophin hormone
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Page 4 of 27Hox et al. Clin Transl Allergy (2020) 10:1
compared to GRα [20] and acts mainly as a negative inhibitor of GRα-mediated gene modulation [23].
The anti-inflammatory effects of GCS are explained by three broad molecular mechanisms: the decreased expression of pro-inflammatory genes (trans-repression), the increased expression of anti-inflammatory genes (trans-activation), and non-genomic mechanisms. Trans-repression is thought to be mainly due to direct interac-tions between GRα and pro-inflammatory transcription factors such as the activator protein-1 (AP-1) and NF-κB [24]. Trans-activation is explained by the interaction of GRα to specific target DNA sequences, named gluco-corticoid-responsive elements (GRE). Among the genes activated by GRα through GRE with anti-inflammatory functions, there are the mitogen activated protein kinase phosphatase-1, the glucocorticoid inducible leucine zip-per and tristetraprolin. In addition, the activated GRα can also reduce inflammation at the post-transcriptional (altering mRNA stability), translational (affecting protein synthesis) and post-translational levels (altering protein processing, modification or degradation) (Fig. 2). For example, the expression of cyclooxygenase-2, TNF-α
and GM-CSF are regulated by one or more of these post-genomic mechanisms [25].
Increased expression of GRβ has been reported in dif-ferent inflammatory diseases, including asthma, and nasal polyposis and has been proposed as one of the potential mechanisms explaining GC resistance [26]. The expression of GRβ is higher in nasal polyps than in nasal mucosa epithelial cells and correlates with increased infiltration of inflammatory cells [27]. Although down-regulation of GRα after treatment with glucocorticoids has been reported [28] and could account for secondary steroid resistance, a recent study in patients in patients with nasal polyps has shown that this effect does not occur in vivo [29].
Evidence for efficacy of systemic GCS in different inflammatory upper airway diseases1. Allergic rhinitisAR is the most prevalent presentation form of all allergic diseases and the most com-mon chronic disorder in chil-dren. It is considered a risk factor for the development of asthma and a major public health problem, due to its
Fig. 2 Molecular mechanisms of glucocorticoid action. After crossing the cell membrane by passive diffusion, glucocorticoids bind to GRα, associated heat‑shock proteins (HSP) are released, and the ligand bound receptor translocates into the nucleus. Through the activation of MAP kinase (MAPKs) intracellular cascade, inflammatory stimuli induce the production of transcription factors. A GRα dimer can bind glucocorticoid responsive elements (GRE) on the promoter region of target genes and activate anti‑inflammatory gene (MKP‑1, GILZ, TTP, lipocortin‑1) transcription. B Binding of GRα to a negative GRE (nGRE) leads to gene (POMC, osteocalcin) repression. C Protein–protein interactions between GRα and transcription factors (AP‑1, NF‑κB) repress the transcription of pro‑inflammatory genes (COX‑2, TNF‑α, VEGF, IL‑8). D GRα can alter mRNA or protein stability of inflammatory mediators
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Page 5 of 27Hox et al. Clin Transl Allergy (2020) 10:1
prevalence and impact on patients’ quality of life, work/school performance, and economic burden [30].
Intranasal GCS and oral/topical antihistamines are the most effective symptomatic treatment for AR and should be the first-line therapy for mild to moderate disease [30, 31]. Moderate to severe disease not responsive to intra-nasal GCS, should be treated with additional pharmaco-logical therapies (including cromolyns and leukotriene receptor antagonists), allergen immunotherapy (AIT) and non-pharmacologic therapies (such as nasal irriga-tion) [30, 31]. Usually a combination of intranasal GCS and a topical or oral antihistamine is used for moderate to severe AR.
Regarding the use of systemic GCS in AR, the current evidence is scarce. Three studies compared the effect of systemic GCS in adult patients (> 15 year old) with AR (Table 2).
The first randomized controlled trial (RCT) from 1987 showed a beneficial effect of a depot injection of 80 mg methylprednisolone (MP) vs. placebo on nasal obstruc-tion and eye symptoms in 48 AR patients, which lasted for 4 weeks [32]. The second study by Brooks et al. [33] investigated the efficacy of different doses of oral MP and placebo in patients not treated with other medica-tions. Thirty-one patients were randomized to receive 0, 6, 12, or 24 mg MP. Oral GCS produced dose-related reduction in all symptoms. The difference between pla-cebo and 24 mg MP was significant for all the symptoms monitored, except itching, which benefited marginally. With 6 mg MP, congestion, drainage, and eye symptoms showed significant drug-placebo differences, but itching, running/blowing, and sneezing did not. The third study by Laursen et al. [34] compared prednisone 7.5 mg for 3 weeks with a single intramuscular injection of beta-methasone dipropionate also in patients not treated with other medications. This study showed a therapeutic index in favour of the depot injection versus oral treatment in AR [33].
Despite the therapeutic benefits of systemic GCS in the treatment of AR that were shown in these studies, their use is strongly recommended against in view of the AE’s GCS that are discussed below, and a short course of systemic GCS is only indicated in rare cases. These cases include patients with severe symptoms who do not respond to other drugs, or those who are intolerant to intranasal drugs [1, 35]. Systemic GCS should never be considered as a first-line of treatment for AR [1]. Con-sequently, oral GCS can be used for a few days as in carefully selected cases when other medical treatment options have failed.
• Evidence level: B.
• Benefits–harm assessment: AE’s of systemic GCS outweigh advantages of therapeutic value, except for patients suffering from very severe and therapy-resistant symptoms.
• Recommendation: Strong recommendation against. Option in patients suffering from very severe and therapy-resistant symptoms.
2. Non‑allergic rhinitisAlthough, the prevalence of NAR among the chronic rhinitis patients ranges from 20 to 50% [36], their dis-ease mechanisms and treatment options are much less studied than their allergic peers. NAR comprises a het-erogeneous group of chronic rhinitis subtypes, such as drug-induced rhinitis, hormonal-induced rhinitis, some forms of occupational rhinitis and rhinitis linked to sys-temic diseases [37]. However, in about 50% of the NAR patients, no specific causal factor can be found and this is addressed as idiopathic rhinitis (IR) [37]. Up till now, no studies are available that investigate the effectiveness of systemic steroids in NAR or IR patients. However, since it is believed that in IR neurogenic pathways are involved, rather than classical inflammatory pathways [38], sys-temic GCS are not the therapy of choice. Of note, all IR patients included in a recent study investigating the effect of capsaicin in IR, reported lack of clinical response to intranasal GCS [38]. By extrapolation, there is a low like-lihood of oral GCS being effective in this patient popu-lation, unless more than one etiologic or inflammatory mechanism underlies the development of rhinitis.
Only in selected cases of other subtypes of NAR, such as rhinitis linked to vasculitic or systemic diseases, oral GCS might play a role in the treatment strategy (see below) [39]. Although oral GCS are often prescribed in patients suffering from rhinitis medicamentosa to over-come the withdrawal period of topical decongestants, there are no valuable studies supporting this clinical practice.
• Evidence level: D.• Benefits–harm assessment: AE’s of systemic GCS
outweigh advantages of therapeutic value.• Recommendation: Recommendation against.
3. Acute rhinosinusitisCompared to the literature on effectiveness of systemic GCS in CRS, data on acute rhinosinusitis (ARS) are scarce. In 2014 an update of a Cochrane review was pub-lished [40] concluding that systemic GCS as a monother-apy are ineffective compared to placebo in ARS patients,
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Page 6 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 2
Sum
mar
y of
the
evid
ence
for ‘
effica
cy o
f sys
tem
ic s
tero
ids
in A
R in
adu
lts’
RCT
rand
omiz
ed c
ontr
olle
d tr
ial,
MP
met
hylp
redn
isol
one,
AR
alle
rgic
rhin
itis,
IM in
tram
uscu
lar
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
‑poi
nt e
ffica
cyCo
nclu
sion
Boru
m e
t al.
1987
1bRC
T 1.
80
mg
MP
(n =
12
adul
ts w
ith A
R) v
s. pl
aceb
o ea
rly in
the
seas
on (n
= 1
2 ad
ults
w
ith A
R)2.
80
mg
MP
(n =
12)
vs.
plac
ebo
late
in th
e se
ason
(n =
12)
1. N
asal
and
ocu
lar s
ympt
oms
2. N
umbe
r of s
neez
ings
and
nos
e bl
owin
g/da
yTh
e eff
ect o
f MP
on n
asal
blo
ckag
e is
mar
ked
and
last
for 4
wee
ksM
P ad
min
istr
atio
n be
fore
the
polle
n se
ason
is
effec
tive
but n
ot re
com
men
ded
in c
linic
al
prac
tice
to a
void
too
wid
espr
ead
use
Laur
sen
et a
l.19
871b
RCT
1. 1
0 m
g be
tam
etha
sone
dip
ropi
onat
e IM
si
ngle
dos
e an
d or
al p
lace
bo (n
= 1
7 ad
ults
w
ith A
R) ×
3 w
eeks
2. 7
.5 m
g or
al p
redn
isol
one ×
3 w
eeks
and
IM
plac
ebo
(n =
19
adul
ts w
ith A
R)
1. N
asal
and
ocu
lar s
ympt
oms
2. B
lood
eos
inop
hils
Both
trea
tmen
ts e
qual
ly c
ontr
olle
d ha
y fe
ver
sym
ptom
sRe
duct
ion
of b
lood
eos
inop
hils
with
bot
h dr
ugs
Broo
ks e
t al.
1993
1bRC
T 1.
Pla
cebo
(n =
7 a
dults
with
AR)
2. 6
mg
MP
(n =
8 a
dults
with
AR)
3. 1
2 m
g M
P (n
= 8
adu
lts w
ith A
R)4.
24
mg
MP
(n =
8 a
dults
with
AR)
1. N
asal
and
ocu
lar s
ympt
oms
2. D
ose–
resp
onse
effe
ct3.
Min
imal
effe
ctiv
e do
se4.
Rel
ativ
e eff
ectiv
enes
s ag
ains
t var
ious
sy
mpt
oms
MP
prod
uced
dos
e‑re
late
d re
duct
ion
in a
ll sy
mpt
oms
24 m
g M
P re
duce
d si
gnifi
cant
ly a
ll sy
mpt
oms
exce
pt n
asal
itch
ing
6 m
g M
P re
duce
d si
gnifi
cant
ly n
asal
con
gest
ion,
dr
aina
ge, a
nd e
ye s
ympt
oms
Not
all
rhin
itis
sym
ptom
s re
spon
ded
equa
lly to
co
rtic
oid
trea
tmen
t. Th
ose
that
resp
onde
d le
ast c
ould
refle
ct h
ista
min
e eff
ect,
whi
ch w
as
not e
ffect
ivel
y su
ppre
ssed
by
low
‑dos
e, s
hort
‑te
rm c
ortic
oid
trea
tmen
t
-
Page 7 of 27Hox et al. Clin Transl Allergy (2020) 10:1
but might have a beneficial effect on short-term symptom relief when used as an adjunctive therapy to antibiotics.
Up to date, five randomized, placebo-controlled trials investigating the effect of oral GCS in adults with ARS are available and included in the Cochrane meta-analysis (Table 3). From those, only one focused on systemic GCS as a monotherapy [41]. In this high-quality second-line clinical trial, patients with clinically diagnosed ARS were randomized to receive either prednisolone 30 mg/day or placebo for 7 days. In the 174 patients who completed the trial, no clinically relevant benefit of prednisolone over placebo was found regarding facial pain or pressure, other nasal symptoms or quality of life.
Four other RCTs investigated the adjunctive effect of systemic GCS to oral antibiotics in ARS. Gehanno et al. [42] reported the adjuvant effect of 5 days of 3 × 8 mg MP/day to amoxicillin–clavulanate in 417 patients. On day four, patients showed significantly less pain in the steroid group whereas nasal discharge did not signifi-cantly improve. The use of additional medication was not reported.
In 2004, two similar studies were published; a French study [43] showed a beneficial effect on pain with oral prednisone as an add-on therapy to cefpodoxime in 291 ARS patients. Also Ratau et al. [44] reported a significant benefit of 1 mg of oral betamethasone per day as adjunct to amoxicillin–clavulanate in 42 patients.
In 1990 Cannoni already published similar findings showing a better symptom resolution in ARS patients treated with 40 mg prednisolone/day in combination with antibiotics, compared to patients receiving a non-steroidal anti-inflammatory drug (NSAID) with antibiot-ics [45].
Altogether, these limited data suggest that systemic GCS as a monotherapy appear to be ineffective in ARS patients. However, oral GCS in combination with antibi-otics may be modestly beneficial for short-time symptom relief in adults suffering from ARS, compared to antibiot-ics alone, with a number needed to treat of seven [40]. Due to the small number of included studies (n = 5) and their methodological bias, a definite conclusion would only be justified if large controlled trials would be avail-able. Given the self-limiting nature of ARS, the rela-tively small additional clinical benefit of adding GCS to antibiotics, and the potential AE’s, GCS should not be used routinely, but may be considered an option after informed discussion and shared decision making with the patient in the setting of severe pain.
• Evidence level: B.• Benefits–harm assessment: AE’s of systemic GCS
outweigh advantages of therapeutic value in mild and moderate disease.
• Recommendation: Strong recommendation against when only mild to moderate symptoms. Option in patients suffering from severe headaches/symp-toms when combined with antibiotics.
4. Chronic rhinosinusitis without nasal polypsFor clinical purposes, the definition of CRS includes nasal polyposis (NP) and currently it is still unclear why some CRS patients develop NP and others do not. CRSsNP is characterized by basement membrane thickening, goblet cell hyperplasia, fibrosis, subepithe-lial oedema and influx of inflammatory cells that are mainly of the neutrophilic subtype with a cytokine pat-tern deviated towards the Th1 subtype [5].
Based on available data, medical therapy for CRS should begin with daily application of intranasal ster-oids in conjunction with saline irrigation and subse-quent therapies are based on the patient’s severity of symptoms and/or quality of life impairment [4].
There is limited data showing efficacy of oral GCS in CRSsNP and a systematic review analysed the available literature in 2011 [46].
No RCT investigated the effects of oral GCS in CRSsNP and only two retrospective case series in adults are available [47, 48] that both considered CRSwNP and CRSsNP patients, but sub-group analy-sis allowed an evaluation specific to CRSsNP (Table 4). Both retrospective studies investigated the effects of oral prednisone in conjunction with 1 month of oral antibiotics added to intranasal steroids and irrigations. Improved subjective and objective outcomes were seen after multimodality treatment schemes in both stud-ies for CRSsNP. The study of Subramamian et al. [48] pooled both CRSwNP and CRSsNP patients and found that the CRSsNP patients had better outcomes than CRSwNP patients. Lal et al. [47] demonstrated that the CRSsNP patients showed total symptom resolution 2 months after treatment of 54.9% compared to 51% for the total CRS group. There are no studies available that investigated the benefits of systemic GCS in monother-apy in treating CRSsNP.
Because of a lack of RCTs or even prospective stud-ies, evidence for clinical efficacy of oral GCS therapy in CRSsNP is Level 4 or 5 and in view of the AE discussed later on, not recommended for the management of CRSsNP.
• Evidence level: C.• Benefits–harm assessment: AE’s of systemic GCS
outweigh advantages of therapeutic value.• Recommendation: Recommendation against.
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Page 8 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 3
Sum
mar
y of
the
evid
ence
for ‘
effica
cy o
f sys
tem
ic s
tero
ids
in a
cute
rhin
osin
usit
is in
adu
lts’
RCT
rand
omiz
ed c
ontr
olle
d tr
ial,
MP
met
hylp
redn
isol
one,
NSA
ID n
on-s
tero
idal
ant
i-infl
amm
ator
y dr
ug
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
‑poi
nt e
ffica
cyCo
nclu
sion
Cann
oni e
t al.
1990
1bRC
T 1.
Adu
lts w
ith (s
ub)a
cute
, non
‑alle
rgic
si
nusi
tis w
ith a
ntib
iotic
s an
d pr
edni
solo
ne
40–6
0 m
g/da
y fo
r 7 d
ays
2. A
dults
with
(sub
)acu
te, n
on‑a
llerg
ic s
inus
itis
with
ant
ibio
tics
and
NSA
ID fo
r 7 d
ays
1. T
hera
peut
ic s
ucce
ss d
efine
d as
com
bina
‑tio
n of
reso
lutio
n of
pai
n an
d ab
senc
e of
na
sal d
isch
arge
clin
ical
ly a
nd e
ndos
copi
‑ca
lly a
t day
7
Bene
ficia
l effe
ct o
f pre
dnis
olon
e in
com
bina
‑tio
n w
ith a
ntib
iotic
s
Geh
anno
et a
l.20
001b
RCT
1. A
dults
with
acu
te s
inus
itis
trea
ted
with
an
tibio
tics
and
met
hylp
redn
isol
one
8 m
g;
3×/d
ay fo
r 5 d
ay2.
Adu
lts w
ith a
cute
sin
usiti
s tr
eate
d w
ith a
nti‑
biot
ics
and
plac
ebo
for 5
day
s
1. C
linic
al re
cove
ry o
n d
142.
Cou
rse
of s
ympt
oms
on d
ay 4
3. S
ympt
oms
and
radi
olog
ical
sig
ns o
n da
y 30
Sign
ifica
nt p
ain
relie
f in
com
bina
tion
with
ant
i‑bi
otic
s co
mpa
red
to a
ntib
iotic
s in
mon
othe
r‑ap
y, n
o ad
ditio
nal e
ffect
on
nasa
l dis
char
ge
Klos
sek
et a
l.20
041b
RCT
1. A
dults
with
acu
te m
axill
ary
sinu
sitis
tr
eate
d w
ith a
ntib
iotic
s an
d pr
edni
sone
0.
8–1.
2 m
g/kg
/day
for 3
day
s2.
Adu
lts w
ith a
cute
max
illar
y si
nusi
tis tr
eate
d w
ith a
ntib
iotic
s an
d pl
aceb
o fo
r 3 d
ays
1. D
iffer
ence
in V
AS
for p
ain
at b
asel
ine
and
day
32.
Diff
eren
ces
in V
AS
for n
asal
obs
truc
tion
3. T
ime
to p
ain
relie
f4.
Adm
inis
trat
ion
of p
arac
etam
ol5.
Glo
bal s
ubje
ctiv
e eff
ect o
f tre
atm
ent o
n da
y 3
6. G
loba
l sub
ject
ive
effec
t of t
reat
men
t on
days
10–
12
Bene
fit o
f sho
rt c
ours
e tr
eatm
ent o
f pre
dnis
one
in c
ombi
natio
n w
ith a
ntib
iotic
s vs
. ant
ibio
tics
with
pla
cebo
Rata
u et
al.
2004
1bRC
T 1.
Adu
lts w
ith a
cute
sin
usiti
s tr
eate
d w
ith
antib
iotic
s an
d be
tam
etha
sone
1 m
g/da
y fo
r 5 d
ays
2. A
dults
with
acu
te s
inus
itis
trea
ted
with
ant
i‑bi
otic
s an
d pl
aceb
o fo
r 5 d
ays
1. Im
prov
emen
t of s
ympt
oms
betw
een
day
0 an
d da
y 6
2. P
erce
ntag
e of
par
ticip
ants
with
phy
sica
l si
gns
pres
ent o
r abs
ent o
n da
y 0
and
day
63.
Num
ber o
f par
acet
amol
tabl
ets
take
n
Bene
fit o
f ste
roid
s tr
eatm
ent i
n co
mbi
natio
n w
ith a
ntib
iotic
s vs
. ant
ibio
tics
with
pla
cebo
Vene
kam
p et
al.
2012
1bRC
T 1.
Adu
lts w
ith a
cute
sin
usiti
s tr
eate
d w
ith
pred
niso
lone
30
mg/
day
for 7
day
s2.
Adu
lts w
ith a
cute
sin
usiti
s tr
eate
d w
ith
plac
ebo
for 7
day
s
1. R
esol
utio
n of
faci
al p
ain/
pres
sure
at d
ay 7
2. R
esol
utio
n of
oth
er c
linic
ally
rele
vant
sym
p‑to
ms
on d
ay 7
3. T
ime
to re
solu
tion
of to
tal s
ympt
oms
4. M
edia
n du
ratio
n of
sym
ptom
s5.
Qua
lity
of li
fe6.
Res
umpt
ion
of d
aily
act
iviti
es
No
clin
ical
ly b
enefi
cial
effe
cts
of s
yste
mic
co
rtic
oste
roid
mon
othe
rapy
-
Page 9 of 27Hox et al. Clin Transl Allergy (2020) 10:1
5. Chronic rhinosinusitis with nasal polypsCRSwNP is different from CRSsNP by the presence of nasal polyps consisting of a large quantity of extracellular oedema with the presence of a dense inflammatory cell infiltrate [49, 50], which is characterized in about 80% of the Caucasian CRSwNP patients, by activated eosino-phils [51, 52] and is associated with a predominant Th2 cytokine profile (IL-4, IL-5, IL-10, eotaxin) [53, 54].
A recent suite of Cochrane Reviews has considered the efficacy of interventions for CRSwNP. Two reviews were performed with respect to short-term oral GCS; one comparing oral GCS alone versus placebo or other treat-ment [55], and a second comparing oral GCS used as an adjunct to other treatments, versus control [56].
For oral GCS alone, 8 trials with a total of 474 partici-pants, all of whom were adult patients CRSwNP, were identified [57–64]. All studies followed up patients to the end of the treatment course, and 3 followed patients for 3 to 6 months after completion. Patients receiving oral GCS achieved better quality of life (standardized mean difference (SMD) of − 1.24 95% CI − 1.92 to − 0.56, measured with RSOM-31), lower nasal symptom scores (SMD − 2.84, 95% CI − 4.09 to − 1.59) and greater polyp reduction (SMD − 1.21) than control groups at the end of the course of treatment. However, there was no differ-ence between groups at 3 to 6 months after the course of treatment.
Treatment doses utilized in included studies included prednisone at 30 mg and reduced over 14 days, pred-nisolone at 60 mg reducing over 17 days, or at con-stant dosage of 50 mg or 25 mg for 14 days, or reducing dosages of MP over 20 days. Of the three studies that
followed patients beyond the course of treatment, 2 prescribed ongoing intranasal GCS after completion of the systemic dose to both groups while one did not [58, 62, 63].
Included trials were considered to be at low risk of bias, but overall the quality of evidence was rated as low due to the small numbers of participants, heteroge-neity of outcome measures and limited follow-up time in most studies.
Another trial considered oral GCS versus placebo as an adjunct to treatment with intranasal GCS in CRSwNP patients [65]. This study recruited 30 participants and was considered at high risk of bias because of lack of blinding and lack of information on randomization. It reported greater reduction in polyp size in the active treatment arm (MD − 0.46, 95% CI − 0.87 to − 0.05).
One trial included in the Cochrane review of oral GCS as an adjunctive treatment recruited children [66] and is therefore considered later in this document.
Table 5 summarizes the evidence of these stud-ies and provides a recommendation for the treatment of CRSwNP by systemic GCS. There is good evidence that systemic GCS are effective in the management of CRSwNP, at least in the short-term. However, consid-ering the evolving understanding of CRSwNP and the chronicity of this condition, the short-lived benefits of systemic GCS therapy need to be balanced with the long-term potential AE’s which are discussed below. Therefore, systemic GCS should not be considered as a first line of treatment for CRSwNP. They can be used in a short course during 2–3 weeks as a last resort of treatment when combinations of other medications are ineffective.
Table 4 Summary of the evidence for ‘efficacy of systemic steroids in CRSsNP in adults’
CRS chronic rhinosinusitis, CRSsNP chronic rhinosinusitis without nasal polyps, CRSwNP chronic rhinosinusitis with nasal polyps
Study Year LOE (1a to 5) Study design Study groups Clinical end‑point efficacy Conclusion
Subramanian et al. 2002 4 Retrospective CRS patients (23 CRSsNP and 17 CRSwNP) treated with 1 month antibiot‑ics + intranasal ster‑oids + prednisone tapered over 10 days (20 mg 2×/day for 5 days, 20 mg 1×/day for 5 days). Mostly adult patients (2 patients under 18)
Change in CT scores, symp‑tom scores post‑treatment. Time to relapse
Beneficial effect of multimodal therapy on scoring of CT, symptoms or both in 90% of all CRS patients, no specific subanalysis for CRSsNP. Beneficial effect continued beyond 8 weeks in 60% of patients. No subanalysis made for CRSsNP
Lal et al. 2009 4 Retrospective Adult CRS patients (23 CRSsNP and 17 CRSwNP) treated with antibiot‑ics + intranasal ster‑oids + intranasal decon‑gestants + prednisone tapered over 12 days (60, 40, 20, 10 mg for 3 days each)
Complete endoscopic and symptomatic resolution of symptoms 2 months after start of treatment
Beneficial effect of treatment in 54.9% of CRSsNP
-
Page 10 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 5
Sum
mar
y of
the
evid
ence
for ‘
effica
cy o
f sys
tem
ic s
tero
ids
in c
hron
ic rh
inos
inus
itis
wit
h na
sal p
olyp
s’
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
‑poi
nt e
ffica
cyCo
nclu
sion
Alo
bid
et a
l.20
141b
Pros
pect
ive
non‑
blin
ded
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
in
tran
asal
bud
eson
ide
800
μg d
aily
fo
r 2 w
eeks
in c
ombi
natio
n w
ith o
ral
pred
niso
ne (3
0 m
g da
ily fo
r 4 d
ays
follo
wed
by
a 2‑
day
redu
ctio
n of
5
mg)
(n =
67)
or n
othi
ng (n
= 2
2)
1. P
olyp
gra
de m
easu
red
by C
T2.
Nas
al c
onge
stio
n3.
Los
s of
sen
se o
f sm
ell
3. P
olyp
tiss
ue e
osin
ophi
ls4.
Nas
al n
itric
oxi
de
Com
bine
d or
al a
nd in
tran
asal
cor
ticos
‑te
roid
s im
prov
e sm
ell a
nd n
asal
con
‑ge
stio
n, d
ecre
ase
tissu
e eo
sino
phili
a an
d in
crea
sed
dete
ctio
n of
nN
O
Beni
tez
et a
l.20
061b
Pros
pect
ive
non‑
blin
ded
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
or
al p
redn
ison
e, 3
0 m
g fo
r 4 d
ays
and
a 2‑
day
redu
ctio
n of
5 m
g fo
r a to
tal
dura
tion
14 d
ays
follo
wed
by
intr
ana‑
sal b
udes
onid
e fo
r 12
wee
ks (n
= 6
3)
or n
o tr
eatm
ent (
n =
21)
1. D
isea
se in
divi
dual
sym
ptom
sco
ring
of n
asal
obs
truc
tion,
loss
of s
ense
of
smel
l, rh
inor
rhoe
a an
d sn
eezi
ng2.
Pol
yp s
ize
mea
sure
d by
end
osco
py3.
Nas
al fl
ow m
easu
rem
ents
14 d
ays
of o
ral s
tero
ids
impr
oved
all
nasa
l sym
ptom
s, po
lyp
size
, and
nas
al
flow
, whi
ch is
mai
ntai
ned
by in
tran
asal
st
eroi
d
Ecev
it et
al.
2015
1bPr
ospe
ctiv
e do
uble
‑blin
d RC
T A
dult
CRS
wN
P pa
tient
s tr
eate
d w
ith
oral
pre
dnis
olon
e, 6
0 m
g/da
y (6
tab‑
lets
per
day
) for
7 d
ays,
then
redu
ced
to 1
0 m
g (1
tabl
et) t
aken
eve
ry o
ther
da
y, s
topp
ing
on d
ay 1
7 (n
= 1
1) o
r pl
aceb
o (n
= 1
0)
1. V
isua
l ana
logu
e sc
ale
for s
ense
of
smel
l, na
sal d
isch
arge
, nas
al o
bstr
uc‑
tion
and
pres
sure
ove
r the
sin
uses
2. S
mel
l tes
ting
3. P
eak
nasa
l ins
pira
tory
pea
k flo
w
The
impr
ovem
ent i
n th
e co
rtic
oste
roid
gr
oup
in th
e VA
S sc
ores
, sm
ell t
ests
an
d PN
IF v
alue
s sh
owed
sta
tistic
ally
si
gnifi
cant
diff
eren
ces
com
pare
d to
the
plac
ebo
grou
p
His
saria
et a
l.20
061b
Pros
pect
ive
doub
le‑b
lind
RCT
Adu
lt C
RSw
NP
patie
ts tr
eate
d w
ith
pred
niso
lone
, 50
mg/
day
for 1
4 da
ys
(n =
20)
or p
lace
bo (n
= 2
1)
1. H
ealth
‑rel
ated
qua
lity
of li
fe (R
SOM
‑31
)2.
Phy
sici
an a
sses
smen
t of n
asal
sy
mpt
oms
(con
gest
ion,
hyp
osm
ia,
rhin
orrh
oea,
sne
ezin
g, p
ostn
asal
drip
an
d itc
h)3.
Pol
yps
size
mea
sure
d by
end
osco
py4.
MRI
of t
he p
aran
asal
sin
uses
The
pred
niso
lone
‑tre
ated
gro
up s
how
ed
sign
ifica
nt im
prov
emen
t in
nasa
l sy
mpt
oms.
The
RSO
M‑3
1 im
prov
ed in
bo
th g
roup
s, bu
t the
pre
dnis
olon
e‑tr
eate
d gr
oup
had
sign
ifica
ntly
gre
ater
im
prov
emen
t tha
n th
e pl
aceb
o gr
oup.
Th
ere
was
sig
nific
ant r
educ
tion
in
poly
p si
ze, a
s no
ted
with
nas
endo
s‑co
py (P
< 0
.001
) and
MRI
(P <
0.0
01),
only
in th
e pr
edni
solo
ne‑t
reat
ed g
roup
Kapu
cu e
t al.
2012
2bPr
ospe
ctiv
e un
blin
ded
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
or
al m
ethy
lpre
dnis
olon
e 1
mg/
kg/
day.
The
dos
e w
as a
pplie
d fo
r 3 d
ays
and
tape
red
grad
ually
, with
a re
duc‑
tion
rate
of 8
mg/
3 da
ys (n
= 1
2) o
r no
med
icat
ion
(n =
12)
Apo
ptot
ic in
dex
Stat
istic
ally
sig
nific
ant d
iffer
ence
s in
ap
opto
tic in
dex
wer
e fo
und
betw
een
each
ste
roid
‑med
icat
ed g
roup
and
the
cont
rol g
roup
Kirt
sree
saku
l et a
l.20
121b
Pros
pect
ive
doub
le‑b
lind
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
or
al p
redn
isol
one
50 m
g da
ily fo
r 14
day
s (n
= 6
7) o
r pla
cebo
(n =
47)
1. S
ympt
om s
corin
g fo
r blo
cked
nos
e,
runn
y no
se, s
neez
ing,
nas
al it
chin
g,
hypo
smia
, pos
tnas
al d
rip, c
ough
and
si
nona
sal p
ain
2. N
asal
pol
yp s
ize
mea
sure
d by
en
dosc
opy
The
pred
niso
lone
‑tre
ated
gro
up s
how
ed
sign
ifica
ntly
gre
ater
impr
ovem
ents
in
all
nasa
l sym
ptom
s, na
sal fl
ow a
nd
poly
p si
ze th
an th
e pl
aceb
o‑tr
eate
d gr
oup
-
Page 11 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 5
(con
tinu
ed)
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
‑poi
nt e
ffica
cyCo
nclu
sion
Vaid
yana
than
et a
l.20
111b
Pros
pect
ive
doub
le‑b
lind
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
pr
edni
solo
ne ta
blet
s, 25
mg/
day,
2
wee
ks (n
= 3
0) o
r pla
cebo
(n =
30)
in
pat
ient
s on
intr
anas
al s
tero
ids
1. Ju
nipe
r min
i rhi
noco
njun
ctiv
itis
Qua
lity
of L
ife Q
uest
ionn
aire
2. T
otal
nas
al s
ympt
oms
scor
e3.
Sen
se o
f sm
ell
4. N
asal
pol
yp s
core
by
endo
scop
y5.
Pea
k na
sal i
nspi
rato
ry fl
ow ra
te6.
Ser
um e
osin
ophi
l‑der
ived
neu
roto
xin
7. H
igh‑
sens
itivi
ty C
‑rea
ctiv
e pr
otei
n le
vels
Shor
t ora
l ste
roid
ther
apy
follo
wed
by
topi
cal s
tero
id th
erap
y is
sig
nifi‑
cant
ly m
ore
effec
tive
over
6 m
onth
s th
an to
pica
l ste
roid
ther
apy
alon
e in
de
crea
sing
pol
yp s
ize
and
impr
ovin
g ol
fact
ion
in C
RSw
NP
patie
nts
with
at
leas
t mod
erat
e na
sal p
olyp
s
Van
Zele
et a
l.20
101b
Pros
pect
ive
doub
le‑b
lind
RCT
Adu
lt C
RSw
NP
patie
nts
trea
ted
with
or
al m
ethy
lpre
dnis
olon
e (3
2 m
g/da
y on
day
s 1
to 5
; 16
mg/
day
on d
ays
6 to
10;
8 m
g/da
y on
day
s 11
to 2
0)
(n =
14)
or p
lace
bo (n
= 1
9)
1. P
olyp
s si
ze m
easu
red
by e
ndos
copy
2. N
asal
pea
k in
spira
tory
flow
3. B
lood
ana
lysi
s fo
r eos
inop
hils
, eo
sino
phili
c ca
tioni
c pr
otei
n an
d so
lubl
e IL
‑5 re
cept
or4.
Nas
al s
ecre
tion
anal
ysis
for e
osin
o‑ph
ilic
catio
nic
prot
ein,
IL‑5
, IgE
, mat
rix
met
allo
prot
eina
se‑9
, mye
lope
roxi
‑da
se5.
Nee
d fo
r res
cue
surg
ery
and
need
for
resc
ue n
asal
ste
roid
s
Met
hylp
redn
isol
one
sign
ifica
ntly
de
crea
sed
nasa
l pol
yp s
ize
com
pare
d w
ith p
lace
bo. T
he e
ffect
was
max
imal
at
wee
k 3
and
last
ed u
ntil
wee
k 8.
M
ethy
lpre
dnis
olon
e si
gnifi
cant
ly
redu
ced
leve
ls o
f EC
P, IL
‑5, a
nd Ig
E in
na
sal s
ecre
tions
RCT
rand
omiz
ed c
ontr
olle
d tr
ial,
CRS
chro
nic
rhin
osin
usiti
s, CR
SwN
P ch
roni
c rh
inos
inus
itis
with
nas
al p
olyp
s
-
Page 12 of 27Hox et al. Clin Transl Allergy (2020) 10:1
• Evidence level: A.• Benefits–harm assessment: AE’s of systemic GCS
outweigh advantages of therapeutic value in the long-term, except in patients with severe symptomatology.
• Recommendation: Strong recommendation against. Option for a short-term course in patients with severe symptoms and therapy-resistance.
A separate indication, for which oral GCS have been prescribed in CRSwNP patients, is the preoperative setting, in order to reduce perioperative bleeding and improve surgical conditions for the surgeon during endo-scopic sinus surgery (ESS). Of the five studies that have been performed studying this topic in adults (Table 6), four are RCTs, however, their outcomes are not con-clusive The study from Ecevit demonstrated a signifi-cant improvement on all perioperative variables studied (perioperative bleeding, visibility of the operative field, operative time, hospital stay) after a preoperative course of GCS in CRSwNP patients [59]. However, while some other studies confirm a significant improvement of intra-operative bleeding time [67] or quality of the operating field [68] and surgical time [69], these differences were not found to be significant by their colleagues [67–70]. A recent meta-analysis reported on a significant reduction in operating time, perioperative blood loss and improved surgical field quality when patients were given preopera-tive steroid treatment, however, the result was mainly based on a large RCT reporting on intranasal GCS [71]. Therefore, the use of oral GCS is currently not recom-mended in the preoperative setting of CRSwNP patients.
• Evidence level: B.• Benefits–harm assessment: AE’s of systemic GCS
outweigh advantages of therapeutic value.• Recommendation: Strong recommendation against.
6. Allergic fungal rhinosinusitisAllergic fungal rhinosinusitis (AFRS) is a form of a non-invasive fungal rhinosinusitis and although it is not characterized by a specific phenotype, it seems to be an immunologically distinct subtype of CRS [72]. The diag-nosis is based on the criteria proposed by Bent and Kuhn: (1) production of eosinophilic mucin without fungal invasion into sinonasal tissue; (2) positive fungal stain of sinus contents; (3) nasal polyposis; (4) characteristic radi-ographic findings; and (5) allergy to fungi [73]. In view of the locally aggressive character of the disease, the corner-stone of AFRS treatment is surgery [74]. However, a lot of uncertainty remains concerning the medical options and postoperative therapy. Although no RCTs are avail-able, we found four smaller studies that investigated
the role of GCS in the management of AFRS mostly in adults (Table 7). Two prospective non-controlled studies examined the effects of GCS in a small number of AFRS patients without surgery [75, 76]. Woodworth showed a significant reduction in nasal endoscopy scores and inflammatory markers in the AFRS group after 18 days of prednisone [76]. Landsberg [75] showed a more sig-nificant reduction in radiologic and mucosal scoring in AFRS patients compared to CRSwNP patients after 10 days of prednisolone. An older retrospective study from Kupferberg [77] in 26 AFRS patients, found that patients who received postoperative GCS showed more symptom improvement and less endoscopic disease com-pared to treatment with oral antifungals or no treatment. However, disease recurrence was noted after cessation of GCS. Similar findings were seen in a non-controlled ret-rospective study from Kuhn and Javer [78] who showed a maintenance of low endoscopic scores in AFRS patients, only after long-term GCS use. No AE’s were reported in any of the four studies. It has to be noted that all of these studies have a high risk of bias and the level of evidence for the use of oral GCS in AFRS patients remains at level C.
• Evidence level: C.• Benefits–harm assessment: Balance of harm and
benefit in patients with severe disease.• Recommendation: Option in patients with severe
AFRS (severe symptoms and/or locally invasive dis-ease) in conjunction with ESS.
7. Nasal manifestations of auto‑immune diseaseMany auto-immune disorders can involve the nose: thyroid auto-immunity, various vasculitis, Sjogren’s syndrome and sarcoidosis are the most frequently encountered, but other connective tissue diseases, such as systemic lupus erythematosus, polyarteritis nodosa, scleroderma and relapsing polychondritis can also have nasal symptoms [39].
GCS have been the major therapeutic option for some of these diseases as an immune suppressant for the past decades, probably being most effective where eosino-phils, which are exquisitely steroid-sensitive, are involved [79]. However, the quality of the evidence for their effi-cacy is poor, with studies mostly being reviews or open pilots, even in seminal trials such as those of Fauci for Wegener’s granulomatosis [80–82]. The reasons for this include not only time-hallowed use, but also difficulty in undertaking placebo-controlled trials in severe dis-eases, differences in the manifestations and their inten-sity between individual patients, disease complexity and plasticity and probably lack of interest in funding. This
-
Page 13 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 6
Sum
mar
y of
the
evid
ence
for ‘
effica
cy o
f sys
tem
ic s
tero
ids
befo
re e
ndos
copi
c si
nus
surg
ery
in C
RSw
NP’
RCT
rand
omiz
ed c
ontr
olle
d tr
ial,
CRS
chro
nic
rhin
osin
usiti
s, CR
SwN
P ch
roni
c rh
inos
inus
itis
with
nas
al p
olyp
s
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
poin
ts e
ffica
cyCo
nclu
sion
Ecev
it et
al.
2015
1bPr
ospe
ctiv
e do
uble
‑blin
d RC
T A
dults
with
CRS
wN
P w
ith s
urgi
cal i
ndic
atio
n re
ceiv
ing
eith
er o
ral p
redn
isol
one,
60
mg/
day
for 7
day
, the
n re
duce
d to
10
mg
(1
tabl
et) t
aken
eve
ry o
ther
day
, sto
ppin
g on
d
17 (n
= 1
1) o
r pla
cebo
(n =
10)
1. P
erio
pera
tive
blee
ding
2. V
isib
ility
of t
he o
pera
tive
field
3. O
pera
tive
time
4. H
ospi
tal s
tay
Perio
pera
tive
blee
ding
, ope
rativ
e tim
e an
d ho
spita
l sta
y w
ere
sign
ifica
ntly
redu
ced
in
patie
nts
who
rece
ived
ora
l ste
roid
s. Vi
sibi
lity
of th
e op
erat
ive
field
was
sig
nific
antly
bet
ter
afte
r rec
eivi
ng s
tero
ids
Wrig
ht e
t al.
2007
1bPr
ospe
ctiv
e do
uble
‑blin
d RC
T 26
adu
lt C
RSw
NP
patie
nts
with
sur
gica
l ind
i‑ca
tion
rece
ivin
g ei
ther
30
mg
of p
redn
ison
e fo
r 5 d
ays
preo
pera
tivel
y or
pla
cebo
1. D
ifficu
lty o
f sur
gery
2. O
pera
tive
time
3. P
erop
erat
ive
bloo
d lo
ss
Surg
eons
rate
d th
e su
rger
y in
the
plac
ebo‑
trea
ted
grou
p as
mor
e di
fficu
lt th
an th
e st
eroi
d‑tr
eate
d gr
oup
No
diffe
renc
es w
ere
note
d in
ope
rativ
e du
ra‑
tion
and
bloo
d lo
ss
Gün
el e
t al.
2015
1bPr
ospe
ctiv
e do
uble
‑blin
d RC
T 65
adu
lt C
RSw
NP
patie
nts
with
sur
gica
l in
dica
tion
rece
ivin
g ei
ther
ora
l pre
dnis
o‑lo
ne (1
mg/
kg fo
r 2 d
ays
and
then
tape
red
dow
n, w
ith tr
eatm
ent c
ompl
eted
on
the
day
10) o
r pla
cebo
1. In
trao
pera
tive
bloo
d lo
ss2.
Qua
lity
of s
urgi
cal fi
eld
No
diffe
renc
e in
intr
aope
rativ
e bl
ood
loos
w
hen
patie
nts
rece
ived
ora
l ste
roid
s pr
eop‑
erat
ivel
yN
on‑s
igni
fican
t im
prov
emen
t of q
ualit
y of
su
rgic
al fi
eld
afte
r ora
l ste
roid
s
Frai
re e
t al.
2013
3bPr
ospe
ctiv
e no
n‑ra
ndom
ized
CT
Adu
lt C
RS p
atie
nts
with
sur
gica
l ind
icat
ion
(CRS
sNP
and
CSR
wN
P) re
ceiv
ing
eith
er
2×/d
ay 3
0 m
g m
ethy
lpre
dnis
olon
e on
5
cons
ecut
ive
days
prio
r to
surg
ery
(n =
27)
vs
. no
trea
tmen
t (n =
27)
1. In
trao
pera
tive
blee
ding
2. S
urgi
cal t
ime
3. Q
ualit
y of
sur
gica
l fiel
d
Ope
rativ
e bl
eedi
ng w
as s
igni
fican
tly re
duce
d in
CRS
wN
P pa
tient
s w
ho re
ceiv
ed o
ral s
ter‑
oids
pre
oper
ativ
ely.
No
sign
ifica
nce
obta
ined
in
qua
lity
of o
pera
ting
field
. No
diffe
renc
e in
su
rgic
al ti
me
Sies
kiew
icz
2006
1bRC
T 36
adu
lt C
RSw
NP
patie
nts
with
sur
gica
l ind
i‑ca
tion
rece
ivin
g ei
ther
pre
dnis
one
(30
mg/
day
for 5
con
secu
tive
days
dire
ctly
bef
ore
the
surg
ery)
or n
o pr
eope
rativ
e tr
eatm
ent
1. In
trao
pera
tive
blee
ding
2. S
urgi
cal t
ime
3. Q
ualit
y of
sur
gica
l fiel
d
Qua
lity
of th
e op
erat
ing
field
and
sur
gica
l tim
e w
ere
sign
ifica
ntly
impr
oved
in C
RSw
NP
patie
nts
who
rece
ived
ora
l ste
roid
s pr
eop‑
erat
ivel
y. N
o si
gnifi
canc
e ob
tain
ed in
tota
l bl
ood
loss
-
Page 14 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 7
Sum
mar
y of
the
evid
ence
for ‘
effica
cy o
f sys
tem
ic s
tero
ids
in a
llerg
ic fu
ngal
rhin
osin
usit
is’
CRS
chro
nic
rhin
osin
usiti
s, CR
SwN
P ch
roni
c rh
inos
inus
itis
with
nas
al p
olyp
s, AF
RS a
llerg
ic fu
ngal
rhin
osin
usiti
s, IL
inte
rleuk
in, M
CP m
onoc
yte
chem
otac
tic p
rote
in
Stud
yYe
arLO
E (1
a to
5)
Stud
y de
sign
Stud
y gr
oups
Clin
ical
end
‑poi
nt e
ffica
cyCo
nclu
sion
Woo
dwor
th e
t al.
2004
3bPr
ospe
ctiv
e ca
se c
ontr
ol s
tudy
Adu
lts w
ith C
RSw
NP
from
whi
ch 8
AFR
S en
6 e
osin
ophi
lic m
ucin
rhin
osin
usiti
s w
ere
trea
ted
with
ora
l pre
dnis
one
(60
mg
for 3
day
s, 40
mg
for 3
day
s, 30
mg
for 3
day
s, 20
mg
for 1
2 da
ys)
1. S
NO
T‑20
2. N
asal
end
osco
py s
core
3. M
ucos
al IL
‑5, I
L‑13
, eot
axin
, MC
P‑4
Sign
ifica
nt re
duct
ion
in n
asal
end
osco
py
scor
es a
nd in
flam
mat
ory
mar
kers
, non
‑si
gnifi
cant
redu
ctio
n in
SN
OT‑
20 s
core
s
Land
sber
g et
al.
2007
3bPr
ospe
ctiv
e ca
se c
ontr
ol s
tudy
Adu
lt A
FRS
and
CRS
wN
P pa
tient
s re
ceiv
ed 1
mg/
kg p
redn
ison
e fo
r 10
day
s
1. C
T Lu
nd M
acka
y sc
ores
2. N
asal
end
osco
py s
core
, but
no
scor
ing
syst
em u
sed
CT
scor
e ch
ange
s w
ere
sign
ifica
ntly
gr
eate
r in
AFR
S pa
tient
s co
mpa
red
to
CRS
wN
P
Kupf
erbe
rg e
t al.
1997
4Re
tros
pect
ive
case
con
trol
stu
dyA
dult
and
adol
esce
nt A
FRS
patie
nts
(13–
69 y
ears
) tha
t und
erw
ent s
urge
ry
and
rece
ivin
g: (1
) no
trea
tmen
t; (2
) ora
l st
eroi
ds (4
day
s 40
mg,
then
4 d
ays
30 m
g, th
en 2
0 m
g/da
y un
til 1
mon
th
post
op);
(3) o
ral s
tero
ids
and
oral
an
tifun
gals
; (4)
ora
l ant
ifung
als
1. N
asal
end
osco
py s
core
2. S
ympt
om s
corin
gPo
stop
erat
ive
trea
tmen
t with
ora
l ste
roid
s al
one
impr
oved
90%
of t
he p
atie
nts,
how
ever
, dis
ease
recu
rren
ce w
as s
een
afte
r ces
satio
n of
ste
roid
s
Kuhn
and
Jave
r20
004
Case
ser
ies
Post
oper
ativ
e st
eroi
ds in
adu
lt A
FRS
patie
nts
(0.4
mg/
kg/d
ay fo
r 4 d
ays,
then
0.3
mg/
kg/d
ay fo
r 4 d
ays,
then
0.
2 m
g/kg
/day
mai
nten
ance
dos
e)
Nas
al e
ndos
copy
sco
reEn
dosc
opic
sta
ge 0
mai
ntai
ned
if or
al
ster
oid
was
mai
ntai
ned
for a
n av
erag
e of
4.5
mon
ths
-
Page 15 of 27Hox et al. Clin Transl Allergy (2020) 10:1
situation is now changing with the advent of newer thera-pies, particularly monoclonal antibodies, which are being trialled against older therapies including GCS [83].
Churg–Strauss syndrome, now called eosinophilic granulomatosis with polyangiitis (EGPA), is classically considered a Th2-mediated disease and affects sino-nasal mucosa in > 80% of the patients. Treatment must be tai-lored according to prognostic factors identified by the French Vasculitis Study Group [84]. GCS alone are used for mild disease, high-dose GCS and cyclophosphamide is still the gold standard for severe cases [85], but biologi-cal agents such as rituximab or anti-IL-5 biologicals are promising, though costly, alternatives [86].
The hallmark of granulomatosis with polyangiitis (GPA; previously known as Wegener’s disease) is the coexist-ence of vasculitis and granuloma and again over 80% of patients show sino-nasal involvement [87]. GCS alone are insufficiently effective: the induction treatment for severe GPA comprises GCS combined with another immu-nosuppressant, cyclophosphamide or rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate.
GCS decrease the frequency, duration, and severity of flares in relapsing polychondritis, but do not stop disease progression in severe cases [88].
The presence of sino-nasal disease is associated with more severe sarcoidosis and the need for systemic GCS therapy [89].
Treatment for systemic lupus erythematosus (SLE) by various organ systems is not evidence-based beyond the usual first- or second-line treatment, however a recent meeting achieved consensus in several scenarios, includ-ing anti-phospholipid syndrome [90].
GCS, often combined with NSAIDs, are used in Sjogren’s syndrome to treat associated interstitial lung disease and/or sensorineural hearing loss [91].
Table 8 shows the evidence available for auto-immune disorders for which GCS are frequently used.
• Evidence level: D.• Benefits–harm assessment: Depending on other
organ involvement and severity.• Recommendation: Following the recommendation
for the management of the specific auto-immune dis-ease.
8. Sino‑nasal pathology and concomitant asthmaAsthma is a chronic inflammatory disease of the lower airways involving inflammation of the bronchial mucosa, and variable obstruction of bronchi due to
intrinsic/extrinsic stimuli, and leading to symptoms such as episodic breathlessness and wheezing with air-way hyperresponsiveness to environmental stimuli [92]. Since the introduction of the “United Airway Disease” concept [1], a large series of scientific publications from clinical epidemiology, pathophysiology, histology, and treatment outcomes has correlated asthma and upper airway disease. AR and asthma often coexist and AR is regarded as a risk factor for the development of asthma. Uncontrolled rhinitis impacts asthma control. Asthmatic patients have a higher CRS severity score than non-asthmatic patients, and more nasal polyps, indicative of a strong relationship between CRS sever-ity and asthma [93]. It has been reported that 20–60% of patients with CRSwNP have asthma [94, 95].
The first use of GCS to treat acute asthma exacerba-tion was in 1956 [96]. Development of GCS that have less mineralocorticoid activity, like prednisone, and later those that have no mineralocorticoid activity, like dexamethasone, made steroid use more attractive ther-apies to use in asthma. Prescribing a short course of oral GCS following the treatment of acute asthma exac-erbations was found to reduce the rate of relapse [97]. However, courses longer than 5 days were not found to provide any additional benefit [98].
As described above, systemic GCS should not be con-sidered as a treatment for AR. We could not identify any systematic review, randomized trial, or controlled study that evaluated the use of systemic GCS in patients with AR with concomitant asthma not responding to other therapy.
When analysing the evidence of oral GCS for patients with CRS and coexisting asthma there are a few rand-omized controlled trials and uncontrolled prospective interventional studies that evaluated the efficacy of dif-ferent treatments (Table 9) of which only one looked at systemic GCS use. This study was carried out in adults by Ikeda et al. [99] and included 21 CRS patients with concomitant asthma. Fifteen patients underwent ESS, and 6 other patients remained on medical therapy. Seven patients of the ESS group showed a reduction in the need for GCS during the 6 months following sur-gery, whereas two patients were unchanged and two patients required larger dosages.
Generally, due to a lack of studies investigating the efficacy of GCS in asthmatics with CRS, the same rules apply as for non-asthmatic CRS patients. With regards to the morbidity and potential mortality that is asso-ciated with asthma, the use of GCS in asthmatic CRS patients should be directed in the first place by the severity of the lower airway symptoms.
-
Page 16 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 8
sum
mar
y of
the
evid
ence
for e
ffica
cy o
f sys
tem
ic s
tero
ids
in th
e tr
eatm
ent o
f aut
o-im
mun
e di
seas
e
Aut
o‑im
mun
e di
seas
e +
stud
yYe
arLO
ESt
udy
desi
gnSt
udy
grou
psCo
nclu
sion
EGPA
Moo
sig
et a
l.20
133
A re
tros
pect
ive
coho
rt s
tudy
at a
vas
culit
is re
fer‑
ral c
entr
e15
0 fu
lfille
d th
e in
clus
ion
crite
ria. O
f tho
se, 1
04
had
mor
e th
an o
ne fo
llow
‑up
visi
t sev
ere
orga
n m
anife
stat
ions
: hea
rt (4
6%),
kidn
ey
(18%
) and
lung
s (1
0%).
Cycl
opho
spha
mid
e w
as u
sed
in 1
07 p
atie
nts
(71%
). Th
e pr
edni
‑so
lone
‑dos
es o
f all
patie
nts
wer
e w
ithin
the
targ
eted
rang
e (i.
e. ≤
7.5
mg)
in 6
9% o
f the
to
tal f
ollo
w‑u
p tim
e; th
e m
edia
n do
se a
t end
of
follo
w‑u
p w
as 5
mg/
day
10‑y
ear s
urvi
val r
ate
was
89%
, mor
talit
y co
m‑
para
ble
to th
e ge
nera
l pop
ulat
ion
(SM
R 1.
29).
Patie
nts
with
car
diac
failu
re h
ad in
crea
sed
mor
talit
y (S
MR
3.06
)
GPA
WG
ET R
esea
rch
Gro
up20
051b
180‑
patie
nt m
ultic
entr
e, p
lace
bo‑c
ontr
olle
d RC
T ex
amin
ing
the
effica
cy o
f eta
nerc
ept i
n W
GC
T Se
vere
dis
ease
rece
ived
cyc
loph
osph
amid
e an
d co
rtic
oste
roid
s; lim
ited
dise
ase
rece
ived
m
etho
trex
ate
and
cort
icos
tero
ids
etan
erce
pt
(25
mg
twic
e w
eekl
y) o
r pla
cebo
was
add
ed to
co
nven
tiona
l the
rapy
Add
ition
of e
tane
rcep
t did
not
lead
to m
ore
sust
aine
d re
mis
sion
s; lo
wer
leve
ls o
f dis
ease
ac
tivity
; red
uctio
n in
tim
e to
rem
issi
on n
or th
e nu
mbe
r or r
elat
ive
risk
of fl
ares
; nor
few
er s
ever
e or
life
‑thr
eate
ning
adv
erse
eve
nts
or d
eath
s
Rela
psin
g po
lych
ondr
itis
McA
dam
et a
l.19
763
Revi
ew15
9 re
port
ed c
ases
, 23
thos
e of
the
auth
ors
Thre
e‑fo
urth
s of
our
pat
ient
s re
quire
d ch
roni
c co
rtic
oste
roid
ther
apy
with
an
aver
age
dose
of
25 m
g pe
r day
of p
redn
ison
e. C
ortic
oste
roid
s de
crea
se th
e fre
quen
cy, d
urat
ion,
and
sev
erity
of
flar
es, b
ut d
o no
t sto
p di
seas
e pr
ogre
ssio
n in
sev
ere
case
s. M
orta
lity
rate
30
perc
ent i
n ou
r se
ries
and
22 p
erce
nt in
the
othe
r 136
repo
rted
ca
ses
EGPA
Ribi
et a
l.20
082
RCT
72 p
atie
nts
with
new
ly d
iagn
osed
EG
PA (F
FS o
f 0)
trea
ted
with
CS
alon
e. A
t tre
atm
ent f
ailu
re o
r re
laps
e, p
atie
nts
wer
e ra
ndom
ized
to re
ceiv
e 6
mon
ths
of o
ral A
ZA o
r 6 p
ulse
s of
CYC
93%
ach
ieve
d re
mis
sion
with
CS
alon
e, 3
5%
rela
psed
, mai
nly
durin
g th
e fir
st y
ear o
f tre
at‑
men
t. A
mon
g th
e 19
pat
ient
s ra
ndom
ized
to
addi
tiona
l im
mun
osup
pres
sion
, 5 o
f 10
rece
iv‑
ing
AZA
and
7 o
f 9 re
ceiv
ing
puls
e C
YC a
chie
ved
rem
issi
on, P
= N
SSu
rviv
al ra
tes
in a
ll pa
tient
s at
1 a
nd 5
yea
rs w
ere
100%
and
97%
, res
pect
ivel
y. A
t the
end
of
follo
wup
, 79%
of t
he p
atie
nts
who
se d
isea
se
was
in re
mis
sion
requ
ired
low
‑dos
e C
S th
erap
y,
mai
nly
to c
ontr
ol re
spira
tory
dis
ease
. CS‑
rela
ted
adve
rse
even
ts w
ere
obse
rved
in 3
1% o
f the
72
patie
nts
-
Page 17 of 27Hox et al. Clin Transl Allergy (2020) 10:1
Tabl
e 8
(con
tinu
ed)
Aut
o‑im
mun
e di
seas
e +
stud
yYe
arLO
ESt
udy
desi
gnSt
udy
grou
psCo
nclu
sion
GPA
Hoff
man
et a
l.19
923
An
open
‑labe
l pilo
t stu
dy o
f wee
kly
low
‑dos
e m
etho
trex
ate
(MTX
) plu
s gl
ucoc
ortic
oids
(GC
) fo
r tre
atm
ent o
f pat
ient
s w
ith W
G
Wee
kly
adm
inis
trat
ion
of M
TX (a
t a m
ean
stab
le
dosa
ge o
f 20
mg)
and
GC
in 2
9 W
G p
atie
nts
Mar
ked
impr
ovem
ent i
n 76
%. R
emis
sion
ach
ieve
d in
69%
. 7%
impr
oved
but
had
inte
rmitt
ent
smol
derin
g di
seas
e th
at p
recl
uded
tota
l with
‑dr
awal
of G
C, a
nd 1
7% h
ad p
rogr
essi
ve d
isea
se
with
in 2
–6 m
onth
s of
sta
rtin
g th
e st
udy
trea
t‑m
ent.
Two
patie
nts
who
initi
ally
ach
ieve
d re
mis
‑si
on la
ter r
elap
sed
afte
r GC
dis
cont
inue
d. O
f th
ose
who
rem
ain
in re
mis
sion
(mea
n fo
llow
up
time
14.5
mon
ths)
, 72%
hav
e no
t req
uire
d G
C
for a
mea
n pe
riod
of 1
0 m
onth
s
Sarc
oido
sis
Aub
art e
t al.
2006
3Re
tros
pect
ive
sing
le‑c
ente
r stu
dyTw
enty
pat
ient
s w
ith h
isto
logi
cally
pro
ven
SNS
(men
/wom
en, 7
/13;
mea
n ag
e, 3
2 ±
9 y
ear)
wer
e co
mpa
red
with
con
trol
pat
ient
s w
ith s
ar‑
coid
but
with
out s
inon
asal
(SN
) inv
olve
men
t. Ea
ch p
atie
nt w
as m
atch
ed w
ith 2
con
trol
s fo
r th
e da
te o
f adm
ittan
ce in
our
inst
itutio
n
SNS
had
sign
ifica
ntly
mor
e fre
quen
t and
sev
ere
invo
lvem
ent o
f vita
l org
ans
than
con
trol
s, ha
d a
long
er h
isto
ry o
f sar
c