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M. J. Aw and S. J. Kilty
10.1 Pathophysiology
Classically, CRS is dichotomized by the following clinical phenotypes: chronic rhinosinusitis
with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) [10].
Specically, CRSwNP represents 25–30% of
CRS cases and is associated with substantial
morbidity and disease outcomes [2]. Evidence
now suggests this represents an oversimplied
understanding of disease and greater emphasis
should be placed on CRS endotypes [10, 11].
While the aetiology of CRS remains poorly
understood, multiple factors including fungal
colonization, bacterial superantigens and host
barrier deciencies have been implicated in the
loss of regulation over the normal inammatory
responses, toxic mucosal inammation and the
development and persistence of CRS [12]. More
importantly, CRS pathophysiology appears to
follow one of the three types of immunological
responses, either in isolation or in parallel [13].
Notably, type 2 inammation, which represents
an eosinophilic inammation, is the most prevalent, strongly associated with CRSwNP [13].
Both fungal and bacterial colonization,
namely Alternaria and Staphylococcus aureus,
have been implicated in CRS disease severity.
Fungal organisms have been found to inhabit
nearly 100% of persons with CRS and these individuals demonstrate exaggerated peripheral
blood mononuclear cell responses following
Alternaria exposure compared to healthy controls [14, 15]. Alternaria antigen can elicit eosinophil degranulation and fungal wall components,
chiey chitin, can promote type 2 inammatory
responses [16, 17]. However, antifungal therapies
have been largely unsuccessful in treating CRS,
which may indicate that fungal infection only
represents a major disease modifying factor for a
subset of patients [12, 18, 19]. Additionally, the
intranasal bacterial microbiome of patients with
CRS differs from healthy controls [20].
Specically, Staphylococcus aureus is found in
greater abundance. While traditionally associated
with eliciting Th17 responses, it is hypothesized
that S. Aureus enhances type 2 inammation
through superantigenic effects [12]. These supe-
rantigenic exotoxins can increase eosinophilic
degranulation and bypass traditional antigenpresenting mechanisms to incite massive T cell
activation [21, 22]. Furthermore, a signicant
portion of nasal polyps from CRSwNP patients
are colonized with S. Aureus [23]. Albeit it
remains unclear whether bacterial infection precedes CRS development or merely exacerbates
the established inammation. Currently, it is
believed that these microorganisms play an role
in disease presentation, but are not directly implicated in CRS development [12].
The prevailing theory for CRS pathophysiology is that deciencies in host barrier defences
permit infectious invasion and the resultant skewing of inammatory responses [12]. This theory
is substantiated by the fact that patients with cystic brosis and carriers of the CFTR gene mutation, who have impaired mucociliary function,
have high CRSwNP and CRSsNP prevalence
[24, 25]. Dysfunction of sinonasal epithelial cells
is associated with an impairment of the barrier
function, mucociliary clearance, the regulation of
eosinophils, dendritic cells, T cells and complement synthesis as well as taste receptor function
[26]. Interesting, bitter taste receptors are
impaired in a subset of patients with CRS and
these receptors have been implicated in responding to bacterial presence [27]. Furthermore, the
sinonasal epithelium in CRSwNP is more porous
than healthy tissue, which increases its susceptibility to exogenous antigen stimulation [28].
Moreover, the expression of innate antimicrobial
proteins such as lactoferrin and S100 are
decreased in CRSwNP and CRSsNP and PLUNC
are decreased in CRSwNP [29–31]. Ultimately, it
is possible that host barrier defects facilitate
exogenous antigen exposure, which perpetuates
inappropriate inammatory responses. Notably,
the release of epithelium-derived alarmins, IL-33
and thymic stromal lymphopoietin (TSLP) promotes type 2 inammatory responses [32].
Amongst North American and European populations, eosinophilic type 2 CRS represents the
prevailing disease endotype. By contrast, individuals of Asian decent and those with cystic
brosis often demonstrate dominant type 1 or
type 3 inammatory proles [10, 33, 34]. It is
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estimated that 80% of nasal polyps follow a type
2 prole from Western populations, whereas only
20–60% of nasal polyposis is attributed to type 2
inammation in Eastern Asia [35]. Consequently,
CRS endotypes are generally classied as either
type 2 or non-type 2 inammation [10]. In type 2
CRS, exogenous antigen stimulation of nasal epithelium triggers the release of the alarmins IL-25,
IL-33 and TSLP [36]. These cytokines stimulate
and activate myeloid dendritic cells [37] to
migrate to lymphoid tissue and present antigen in
the context of IL-4 to favour the differentiation of
naïve CD4 T cells into effector Th2 cells [38].
Th2 cells secrete hallmark cytokines associated
with type 2 inammation including IL-4, IL-5,
IL-13 and encourage isotype class-switching of
B cells towards immunoglobulin E (IgE).
Furthermore, IL-25, IL-33 and TSLP encourage
IL-4, IL-5 and IL-13 production in type 2 innate
lymphoid cells [39], which create a local type 2
inammatory prole in situ [39]. IgE binds to
mast cells via FcϵRI receptor, which when crosslinked with antigen, then degranulate and release
inammatory markers including histamine, cytokines, pro-angiogenic factors and proteases [40].
Additionally, IL-5 recruits and activates eosinophils which play a pivotal role in nasal tissue
remodelling [10, 41]. Tissue remodelling in CRS
consists of brosis, collagen deposition, osteitis,
angiogenesis and mucosal hypertrophy.
Clinically, type 2 CRS more frequently impacts
the ethmoid sinuses and is associated with headaches, nasal polyposis and anosmia, asthma,
allergic rhinitis and or Aspirin Exacerbated
Respiratory Disease (AERD) [10].
Non-type 2 CRS is characterized by neutrophil invasion and represents a mix of type 1 (Th1)
and type 3 (Th17) inammation [10]. Following
irritant or pathogen exposure, epithelial cells and
macrophages secrete IL-6, IL-8, tumour necrosis
factor alpha [42] and interferon gamma [13, 43].
The presence of IFN-γ in the context of dendritic
cell [37] stimulation of naïve T cells promotes
Th1 differentiation, which produces Il-2 and
IFN-γ and propagates type 1 inammation.
Alternatively, IL-6 triggers the differentiation of
Th17 cells, which produce IL-17 and promote
neutrophilic responses [44]. Moreover, IL-6 and
IL-8 recruit and activate neutrophils, which
release inammatory mediators and chronically
mediate tissue remodelling [10]. Clinically, nontype 2 CRS favours the maxillary sinus and is
attributed to pollution and bacterial exposure
with purulent nasal discharge [10]. Of note, in the
last 20years, there has been a signicant shift in
some Asian countries towards greater prevalence
of eosinophilic CRS, which further highlights the
importance of type 2 CRS endotype [35].
10.2 Current Therapies
Treatment for CRS includes medical and surgical interventions: nasal saline irrigation, corticosteroids, antibiotics and endoscopic sinus
surgery [45, 46]. While ineffective as a disease
modifying therapy in isolation, nasal saline irrigation represents a cheap and accessible adjuvant therapy for symptom management. Nasal
irrigation has been shown to facilitate debris and
irritant clearance, enhance intranasal medication
delivery and improve mucociliary clearance
[47–49]. Topical and oral corticosteroids repre-
sent hallmark rst- line therapies for CRS [50].
Topical corticosteroid monotherapy may be sufcient for mild cases; however, it may not provide long-term symptom control in more severe
manifestations of the disease [50]. It is hypothesized that topical steroids ineffectively penetrate
the ostiomeatal complex, which is implicated in
sinus ventilation and drainage, due to the mechanism of application and inherent anatomic complexity of the area [51]. Combined topical and
oral treatment can reduce polyp size and improve
disease symptomatology, including hyposmia
and post-nasal drip [51–53]. Yet, a subset of
patients fail to meaningfully respond to corticosteroid treatment and while steroids reduce
polyp size, they do not effectively ablate nasal
polyps. Tuncer et al. treated patients with
CRSwNP with dual corticosteroid therapy and
discerned that 12% of patients were unresponsive to treatment [52]. Moreover, polyp ablation
was unachievable in 88% of patients [52]. While
emerging evidence implicating bacteria and the
microbiome as negative effectors of the mucosal
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M. J. Aw and S. J. Kilty
barrier in CRS, the use of antibiotic treatment
remains controversial [54, 55]. Soler etal. conducted a systematic review evaluating eight
classes of antimicrobial treatments for CRS
using the methodology of the Center for
Evidence-Based Medicine [54]. The investigation identied short-term use (<3 week) oral
antibiotics and long-term macrolide antibiotics
as viable options for routine CRS treatment.
Based on insufcient evidence and lack of clinically meaningful effects, topical antibiotics,
long-term (>3 weeks) oral/IV antibiotics and
antifungals were recommended against [54].
Nonetheless, further understanding of microorganism involvement in CRS is necessary to elucidate the potential role of current or emerging
antimicrobial therapies [46]. Surgery is the most
invasive approach to disease modication and
symptom treatment and is generally considered
when CRS is refractory to medical therapy [2].
ESS is generally reserved for more severe presentations since preoperative symptom scores
correspond with postoperative success and
patients with the most serious preoperative
symptom scores generally gain the most benet
from ESS [56–58]. Unfortunately, a signicant
proportion of patients have refractory polyposis
following surgery. Bassiouni and Wormald
reviewed 338 operations and found that 19.8%
and 22.7% of patients had polyp recurrence postoperatively 6 and 12months, respectively [59].
Notably, asthma and AERD comorbidity were
the most signicant risk factors for polyp recurrence. At 40 months postoperatively, nearly
60% of patients with CRSwNP and asthma had
polyp recurrence and 90% of patients with the
triad of CRSwNP, asthma and NSAID intolerance (AERD) had polyp recurrence. A recent
systematic review of 45 studies evaluating postoperative outcomes for CRS, identied asthma
(22.6%), AERD (28.7%) and allergic fungal
rhinosinusitis (28.7%) as factors associated
with polyp relapse in CRSwNP [60]. Moreover,
the literature suggests allergic rhinitis may be
as prevalent as 50–84% in patients with
CRSwNP [61]. Type 2 inammation and atopy
appear to be a common theme amongst difcult
to treat patients. Consequently, a signicant
effort has been made to explore the use of biologics originally designed to treat other inammatory diseases, particularly asthma, for CRS
management.
10.3 Biologic Therapies
10.3.1 Anti-IgE Antibodies
One of the rst biologics developed and approved
for the treatment of atopic diseases is omalizumab, an anti-IgE humanized monoclonal antibody. IgE, which is produced by IgE
class-switched B cells binds to mast cells and
basophils via FcϵRI, which when cross-linked
with antigen degranulate and release inammatory markers including histamine, cytokines, proangiogenic factors and proteases [40]. Currently,
omalizumab is indicated in patients with moderate to severe allergic asthma who are not well
controlled with inhaled corticosteroids and
inhaled long-acting β2 agonist bronchodilators
[62]. There is compelling evidence that omalizumab may represent an effective treatment for
eosinophilic CRSwNP. An early randomized
double-blinded clinical trial of 24 participants in
Belgium found that subcutaneous (SC) omalizumab (max dose 375mg) every 2weeks signicantly reduced total nasal endoscopic polyp
scores (TPS) as early as 8weeks (p=0.001); this
polyp size difference was signicantly different
than in the placebo group (p = 0.005) [63].
Moreover, the Lund-MacKay computed tomography score, a radiologic measure of paranasal
sinus inammation, signicantly improved in the
study group compared to placebo after 16weeks
[63]. These positive ndings have been validated
by two recent phase 3 multicentre clinical trials,
POLP1 and POLYP2 [64]. Collectively, 265
patients were randomized 1:1 to receive 600mg
SC omalizumab every 2 or 4weeks and intranasal mometasone or intranasal mometasone alone
for 24weeks. The mean TPS treatment arm differences between the omalizumab and placebo
groups were−1.14 (95% CI=−1.59 to −0.69;
p<0.0001) and −0.59 (95% CI=−1.05 to −0.12;
p = 0.0140) in POLYP1 and POLYP2 respect-
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fully [64]. Sino-Nasal Outcome Test 22 (SNOT-
22) scores improved between the two cohorts as
early as 4weeks and were clinically different in
both POLYP1 and POLYP2 trials at the 24-week
endpoint for the treatment and placebo cohorts
(−16.12 [95% CI=−21.86 to −10.38], p<0.0001
and −15.04 [95% CI = −21.26 to −8.82],
p < 0.0001 respectfully). The University of
Pennsylvania Smell Identication Test (UPSIT)
[65] scores improved from baseline to 24weeks
in the omalizumab groups and the improvement
was signicant compared to placebo. Similar
ndings were reported for loss of smell scores,
postnasal drip scores and nasal congestion scores
(NCS) [64]. Interestingly, patients with comorbid
asthma and AERD experienced comparable
improvements in TPS and TPS to those without
either comorbidity, when treated with omalizumab. Patients with comorbid asthma in the
treatment arm saw signicant improvements in
asthma quality of life questionnaire scores [66]
compared to placebo [64]. Omalizumab appears
to be well tolerated, with few adverse events
reported, the most common being headache,
nasopharyngitis and injection site reaction [63–
65]. Overall, these results demonstrate promising
support for the use of omalizumab for CRSwNP
with comorbid asthma. Currently, omalizumab
has been approved in Canada for the treatment of
severe CRSwNP refractory to inhaled nasal
corticosteroids.
10.3.2 Anti-IL-5 Antibodies
Eosinophilia is a hallmark cellular inltrate in the
majority of CRSwNP cases and is believed to
play a signicant role in disease propagation and
tissue-remodelling associated with polyp formation [10]. Specically, IL-5 is considered the
most important cytokine in the recruitment and
activation of eosinophils, which makes it an ideal
target for reducing eosinophilia [10, 41]. A number of humanized anti-IL-5 antibodies have been
developed including: Reslizumab, Mepolizumab
and Benralizumab. A randomized 2-centre study
of Reslizumab in CRSwNP determined that a
single 1mg/kg or 3mg/kg SC dose of Reslizumab
was able to signicantly reduce blood eosinophilia for up to 8weeks [67]. However, this effect
was transient and there was rebound eosinophilia
noted 24weeks post-injection. Moreover, while
there was evidence of improvement in TPS in the
treated cohort, there was unconvincing clinical
improvement with regards to other symptom
improvements [67]. More promising results have
been found with the use of mepolizumab. Gevaert
etal. demonstrated that 2 IV injections of 750mg
of mepolizumab one month apart were able to
reduce nasal burden in 20 patients with CRSwNP
refractory to corticosteroids [68]. There was a
treatment difference of −1.30 (standard deviation
(SD) +/−1.51; p=0.028) in TPS scores between
the treatment and placebo cohorts at 8 weeks.
Moreover, Mepolizumab use was associated with
a signicant reduction in blood eosinophils
(p < 0.01), serum eosinophil cation protein
(p=0.022) and serum IL-5Rα (p<0.001) compared to placebo [68]. While there were changes
favouring treatment-related improvements in
postnasal drip, loss of smell and nasal congestion
in the treated group compared to placebo these
ndings were neither clinically nor statistically
signicant [68]. A subsequent randomized controlled study of 105 patients with bilateral recurrent CRSwNP requiring surgery found that
750 mg Mepolizumab every 4 weeks (6 doses
total) signicantly reduced the need for ESS and
reduced nasal polyposis severity visual analogue
scores (VAS) (treatment difference at week 25
favouring mepolizumab −1.8, 95%CI −2.9 to
−0.8; p=0.001) [69]. While the SNOT-22 scores
improved over the study period for both the intervention and control groups, there was a signicant difference from baseline in the SNOT-22
scores between the cohorts at 25weeks favouring
the mepolizumab group (−13.2, 95%CI −22.2 to
−4.2, p=0.005). Additionally, at the study end-
point of 25weeks, the mepolizumab group demonstrated signicant improvements in loss of
smell VAS (p < 0.001), peak nasal inspiratory
ow (p=0.027) and rhinorrhea (p<0.001) compared to placebo [69]. Overall, anti-IL-5 biologics appear well tolerated with no serious adverse
events reported from the aforementioned studies.
The most common adverse events include upper
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M. J. Aw and S. J. Kilty
respiratory tract infections, pyrexia oropharyngeal pain and injection site reactions [67–69].
More recently, Benralizumab has been developed, which may have greater anti-eosinophilic
effects by directing targeting IL-5Rα expressing
cells independent of ligand as a humanized
anti- IL- 5Rα monoclonal antibody [70]. Further,
the antibody is afucosylated, which enables it to
induce cell-mediated cytotoxicity of eosinophils.
Benralizumab has demonstrated therapeutic benets for severe asthmatics; however, no direct
CRS clinical trials have been conducted [71].
There is evidence to suggest that patients with
comorbid asthma and CRSwNP are more likely
to respond to Benralizumab after Mepolizumab
treatment compared to those with asthma alone
[72]. A small study of 10 patients with eosinophilic CRSwNP and severe asthma received
30 mg SC Benralizumab every 4 weeks. After
24weeks, all clinical parameters improved compared to baseline [73]. Specically, the following
markers of disease severity decreased including
SNOT-22 scores (p < 0.001), TPS (p<0.001),
Lund-Mackay CT scores (p<0.001) and blood
eosinophilia (807.3±271.1 cells/μL to 0 cells/
μL, p < 0.0001) [73]. Likewise, Matsuno and
Minamoto report that Benralizumab treatment
exerted more rapid therapeutic action in patients
with eosinophilic asthma and comorbid CRSwNP
compared to those with asthma alone [66].
Rigorous clinical trials evaluating Benralizumab
in CRSwNP are warranted to elucidate whether
this biologic is benecial for CRS alone.
10.3.3 Anti-IL-4/Il-13 Antibodies
Type 2 inammation in CRS is mediated by
effector ILC2 and Th2 cells, with the latter promoting B cell class switching and eosinophil
recruitment. Specically, IL-4 signalling encourages differentiation of naïve T cells to Th2 cells
and is necessary for IgE B-cell class switching.
Dupilumab is a humanized monoclonal antibody
that binds to the alpha subunit of the IL-4 receptor alpha (IL-4Rα). It has been shown to be effective in the treatment of eosinophilic asthma and
atopic dermatitis [74, 75]. Targeting IL-4Rα rep-
resents a promising target for the treatment of
CRSwNP [76]. Moreover, the blockade of
IL-4Rα targets two critical type 2 inammatory
cytokines as IL-4 and IL-13 both use this receptor to elicit their effects [74]. IL-13 is implicated
in further modulating type 2 inammation and
both cytokines are directly involved in the tissue
remodelling seen in CRSwNP [76]. Currently,
dupilumab has been studied in CRSwNP in a
single Phase 2a study and two phase 3 clinical
trials [77, 78]. Two pivotal multicentre, international phase 3 trials, SINUS24 and SINUS52
have elucidated the therapeutic benet of dupilumab for CRSwNP [78]. In SINUS24, 276 participants were randomized 1:1 to receive 300mg
SC dupilumab every 2weeks plus nasal steroids
or steroids alone for 24weeks. In SINUS52, 448
participants were randomized 1:1:1 to receive
300mg SC dupilumab every 2weeks plus nasal
steroids or 300mg SC dupilumab every 2weeks
for 24weeks followed by 28weeks of 300mg SC
dupilumab every 4weeks or placebo. Both studies demonstrated strong NPS improvement compared to placebo at 24weeks (the least squares
mean change (LMSD) −2·06 [95%CI, −2·43 to
−1·69], P<0·0001) and (LSMD −1·80 [95%CI
−2·10 to −1·51], P<0·0001) for SINUS24 and
SINUS52 respectfully. At 52 weeks, the collective dupilumab groups continued to demonstrate
improved NPS compared to placebo (LSMD
−2·40 [95%CI, −2·77 to −2·02], P < 0·0001)
[78]. Similarly, SNOT-22 scores were signicantly improved compared to placebo at both
24weeks for SINUS24 (LSMD −21·12 [95%CI
−25·17 to −17·06] p< 0·0001) and SINUS52
(−17·36 [95%CI −20·87 to −13·85], p<0·0001)
respectfully. Moreover, both studies demonstrated that at 24 weeks and 52 weeks UPSIT
scores, Lund-MacKay CT scores and total symptom scores were signicantly improved in the
dupilumab cohorts compared to placebo [78].
Interestingly, biomarkers of inammation including total serum IgE, eotaxin-3, eosinophil cationic protein and nasal IL-5 levels decreased at
week 24in SINUS24 and SINUS52in the dupilumab groups. However, the improvements in
eosinophilia appeared transient as discontinuation of dupilumab were associated with the return
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of baseline blood eosinophils. Subgroup analyses
of persons with comorbid CRSwNP and asthma
found that dupilumab treatment improved asthma
symptoms and lung function. Moreover, improvements in lung function and asthma control were
independent of whether participants had high or
low blood eosinophils. Additionally, the data
showcased that the effects of dupilumab of CRS
symptom control were comparable for those with
comorbid AERD and or asthma [78]. With
regards to adverse events, dupilumab appears to
be well tolerated with the most frequent issues
including nasopharyngitis, epistaxis, headache
and injection-site reactions being more common
in the placebo arms; however, vigilance with new
medications is always warranted [77, 78]. Given
the high level of evidence, dupilumab represents
a viable option for steroid-resistant CRSwNP and
has been recently approved for CRSwNP care in
Canada.
10.3.4 Future Therapeutic Targets
Relatively recent developments in atopic research
have implicated the alarmins, IL-25, IL-33 and
TSLP as key regulators of type 2 inammation.
These mediators are expressed by epithelial and
innate lymphoid cells and favour activation and
recruitment of ILC2s, eosinophils and Th2 cells
[79]. Specically, animal studies have demonstrated that anti-Il-33 treatment reduces mucus
thickness, subepithelial collagen deposition and
neutrophil inltration within the nares [42].
Currently, the ECLIPSE phase 2 clinical trial of
subcutaneous Etokimab (anti-IL-33 mAb) is
being conducted with 106 patients with CRSwNP
[80]. Unfortunately, a press report by AnaptysBio,
Inc. revealed that Etokimab treatment every 4 or
8weeks failed to achieve statistically signicant
improvements in NPS or SNOT-22 scores at the
8-week midpoint [81]. They plan on reassessing
their ndings at the 16-week study endpoint.
While implicated in type 2 inammation, a
murine study reported that anti-IL-33 treatment
reduced neutrophilic inltration but failed to
reduce eosinophilic inltration [42]. As the
majority of CRSwNP presentations are eosino-
philic, this may explain the failed treatment effect
observed with Etokimab. This biologic may have
a niche role in the treatment of neutrophilic
CRS. TLSP levels are greater in the nares of
patients with CRSwNP and have been shown to
promote macrophage IL-5 production [37]. A
phase 2b clinical trial investigating Tezepelumab
(anti-TLSP mAb) in patients with severe asthma
with or without nasal polyps found the treatment
to be well tolerated. Five hundred and fty
patients were randomized 1:1:1:1 to receive SC
Tezepelumab 70mg every 4weeks, 210mg every
4weeks, 280mg every 2weeks or placebo. At
the 52-week endpoint, the Tezepelumab-treated
cohorts had signicant reductions in annualized
asthma exacerbation rates, reductions in blood
eosinophils, FeNO, IL-5 and IL-13 levels irrespective of nasal polyp status compared to controls [82]. Currently, a multicentred phase 3 trial
evaluating the efcacy of Tezepelumab for
CRSwNP is underway [83]. As a relatively novel
therapeutic avenue, it is important to assess the
relative effectiveness of the varying biologics.
While many biologics are currently available, no
study to date has systematically compared the
relative effectiveness of one biologic against
another. For example, a case report found that
dupilumab clinically improved CRSwNP symptoms in a patient with severe asthma, AERD and
CRSwNP, despite Benralizumab treatment failing to provide clinical improvements even though
it reduced blood eosinophil levels [84].
Unfortunately, this represents low-level evidence
and cannot be generalized to other patients.
10.3.5 Biologic Therapy Guidelines
The cost-effectiveness of biologics dictates the
use of guidelines for their use in CRSwNP [85].
In 2014, the estimated annual cost of endoscopic
sinus surgery is 3510.31CAD, in contrast, with
current annual costs for CRS biologics varying
from $31,000 to $40,000 [86, 87]. Scangas etal.
(year) used a Markov decision-tree economic
model to estimate the long-term cost of endoscopic sinus surgery versus dupilumab as a function of quality-adjusted life years [88]. They
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M. J. Aw and S. J. Kilty
estimate dupilumab to be less effective and more
costly than surgery even when considering revision surgeries [88]. It is likely that biologic costs
will have to reduce signicantly before they can
be more broadly integrated into a publicly funded
CRS treatment model [89]. While the short-term
cost of biologic therapy is substantially greater
than that of alternative treatments, it is difcult to
truly estimate the long-term value of biologic
use. Further studies are required to appreciate the
long-term implications and impact of biologic
management. At this time, biologics should only
be considered for patients with CRSwNP with
moderate to severe disease who have failed maximal medical and surgical therapy, with sufcient
surgery having been previously undertaken.
Comorbid type 2 diseases are not required to consider biologic therapy in the setting of
CRSwNP. Physicians should evaluate patient
responses regularly and annually with a determination made at 16weeks after treatment onset to
determine treatment continuation, using both
objective and subjective measures of disease
improvement [85].
10.4 Conclusion
CRS represents a prevalent chronic disease negatively impacting a notable proportion of adults
and it represents a signicant burden from both
quality of life and nancial perspectives. Despite
conventional therapy, difcult-to-treat patients
with recurrent CRSwNP represents a population
requiring further therapeutic intervention.
Biologic therapies, which largely target the signalling mechanisms of type 2 inammation,
represent novel disease modulators which have
been shown to be effective at improving objective and subjective disease clinical signs and
symptoms and reduce inammatory markers.
There is evidence to suggest that targeting
alarmins represents another avenue to regulate
CRSwNP. However, current evidence suggests
that biologic therapy treatment effects are largely
transient, and relapse occurs following termination of biologic treatment. Further evidence is
needed to evaluate the long-term effects of bio-
logic therapy and the impact of various combined
therapies. Specic endotyping of patients may
prove to be benecial to maximize the benet
seen from biologic therapies.
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