bene˚ts and˜harm of˜systemic steroids for˜short- and˜long ......for˜short- and˜long-term use...

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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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


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


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


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,


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


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.


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


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


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


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


• 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


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


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


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.


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


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

bene˚ts and˜harm of˜systemic steroids for˜short- and˜long ......for˜short- and˜long-term use...

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