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Contributors
xiii
AminR.Javer, M.D. Department of Otolaryngology—Head and Neck Surgery,
University of British Columbia, Vancouver, BC, Canada
AshutoshKacker,M.D. Department of Otolaryngology– Head & Neck Surgery,
NewYork-Presbyterian/Weill Cornell Medicine, New York, NY, USA
Keonho Albert Kong, M.D. Department of Otolaryngology-Head and Neck
Surgery, University of Mississippi Medical Center, Jackson, MS, USA
Anthony F. LaCava, M.D. Section of Allergy & Immunology, Division of
Pulmonary, Allergy, & Critical Care Medicine, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA
Devyani Lal, M.D. Department of Otolaryngology-Head & Neck Surgery,
Mayo Clinic Arizona, Phoenix, AZ, USA
DanielP.Lander,M.D. Department of Otolaryngology-Head & Neck Surgery,
Washington University School of Medicine, St. Louis, MO, USA
JivianneT.Lee,M.D., F.A.C.S., F.A.R.S. Divsion of Rhinology & Endoscopic
Sinus and Skull Base Surgery, Department of Head and Neck Surgery, David Geffen
School of Medicine at UCLA, Los Angeles, CA, USA
WilliamDerekLeight,M.D. Ear, Nose and Throat Institute, Boys Town National
Research Hospital, Boys Town, NE, USA
Stephen Leong, M.D. Vagelos College of Physicians & Surgeons, Columbia
University Irving Medical Center, New York, NY, USA
Donald Arthur Leopold, M.D. Ear, Nose and Throat Institute, Boys Town
National Research Hospital, Boys Town, NE, USA
TranB.Locke,M.D. Department of Otolaryngology—Head and Neck Surgery,
Baylor College of Medicine, Houston, TX, USA
Patricia A. Loftus, M.D. Department of Otolaryngology—Head and Neck
Surgery, University of California San Francisco, San Francisco, CA, USA
Justin P. McCormick, M.D. Department of Head and Neck Surgery and
Communication Sciences, Rutgers Robert Wood Johnson Medical School,
New Brunswick, NJ, USA
Amar Miglani, M.D. Department of Otolaryngology-Head & Neck Surgery,
Mayo Clinic Arizona, Phoenix, AZ, USA
DafnaGershnabel Milk,M.D. Department of Otolaryngology Head and Neck
Surgery, Eastern Virginia Medical School, Norfolk, VA, USA
Department of Otolaryngology Head and Neck Surgery, Meir Medical Center,
Kfar Saba, Israel
Craig Miller, M.D. Otolaryngology, Virginia Mason Franciscan Health,
Seattle, WA, USA
xiv
Contributors
Zhang Nan, M.D., Ph.D. First Afliated Hospital, Sun Yat-sen University,
International Airway Research Center, Guangzhou, China
Upper Airways Research Laboratory, Department of Oto-Rhino-Laryngology,
Head and Skin, Ghent University, Ghent, Belgium
KazuhiroOmura,M.D. Department of Otorhinolaryngology, The Jikei University
School of Medicine, Tokyo, Japan
Nobuyoshi Otori, M.D., Ph.D. Department of Otorhinolaryngology, The Jikei
University School of Medicine, Tokyo, Japan
Neil N.Patel, M.D. Department of Otolaryngology—Head and Neck Surgery,
University of California San Francisco, San Francisco, CA, USA
PrayagS. Patel, M.D. Department of Otolaryngology—Head & Neck Surgery,
Maimonides Medical Center, Brooklyn, NY, USA
NoraW.Perkins, M.D., M.B.A. Albany ENT & Allergy Services, Albany, NY, USA
Shilpa M. Rao,M.D. Department of Otolaryngology-Head and Neck Surgery,
University of Alabama in Birmingham, Birmingham, AL, USA
DanielR.Romano,M.D. Department of Otolaryngology-Head & Neck Surgery,
Washington University School of Medicine, St. Louis, MO, USA
Peta-Lee Sacks, M.D., Ph.D. Department of Otolaryngology, Macquarie
University Hospital, Sydney, NSW, Australia
Firas Sbeih, MD Department of Otolaryngology, University of Florida,
Jacksonville, FL, USA
JohnS.Schneider,M.D. Department of Otolaryngology-Head & Neck Surgery,
Washington University School of Medicine, St. Louis, MO, USA
Kachorn Seresirikachorn, M.D. Department of Otolaryngology, Faculty of
Medicine, Chulalongkorn University, Bangkok, Thailand
Daniel B. Spielman, M.D. Department of Otolaryngology, Emory University,
Atlanta, GA, USA
ScottP.Stringer,M.D. Department of Otolaryngology-Head and Neck Surgery,
Virginia Commonwealth University School of Medicine, Richmond, VA, USA
Jonathan Tyes, M.D. School of Medicine, University of Louisville,
Louisville, KY, USA
Thibautvan Zele,M.D., Ph.D. Department of Oto-Rhino-Laryngology, Münster
University, Münster, Germany
Upper Airways Research Laboratory, Department of Oto-Rhino-Laryngology,
Head and Skin, Ghent University, Ghent, Belgium
Contributors
xv
VivianWang,M.D. Department of Allergy and Immunology, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Troy Woodard, M.D. Head and Neck Institute, Cleveland Clinic Foundation,
Cleveland, OH, USA
BradfordA. Woodworth,M.D. Department of Otolaryngology-Head and Neck
Surgery, University of Alabama in Birmingham, Birmingham, AL, USA
Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, AL, USA
Michelle Yu, M.D. Department of Otolaryngology—Head & Neck Surgery,
NewYork-Presbyterian/Weill Cornell Medicine/Columbia University Irving
Medical Center, New York, NY, USA
Joseph Yusin, M.D. Department of Allergy and Immunology, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Part I
Introduction
Introduction toRecalcitrant Chronic
Rhinosinusitis
1
AlexanderM.Choi andTranB.Locke
Key Points
• Chronic rhinosinusitis (CRS) is a multifactorial disease resulting from a complex
interplay between extrinsic environmental exposures and intrinsic system factors
resulting in chronic sinonasal inammation.
• Multiple theories have been proposed to explain the pathogenesis of CRS, such
as phenotypic descriptions based on presence of nasal polyposis and underlying
inammatory prole, but these inadequately describe the disease process.
• Current literature has moved towards classifying CRS based on endotype, the
specic underlying cytokines, effectors, and biomarkers that may better explain
the underlying pathogenesis of CRS and allow for personalized treatment regi-
mens for impacted patients.
Introduction toRecalcitrant Chronic Rhinosinusitis
Chronic rhinosinusitis (CRS) is a disease process dened by at least 12weeks of
symptoms, consisting of at least two of the following: facial pain or pressure, anosmia, anterior/posterior rhinorrhea, and nasal congestion. In addition, patients must
show objective evidence of mucosal inammation on either nasal endoscopy or
computed tomography (CT). CRS is classically divided into two clinical phenotypes, CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP).
The prevalence of CRS varies throughout the world. In Asian countries, prevalence
from 2.6% to greater than 11% has been reported [1, 2]. European and U.S.
A. M. Choi · T. B. Locke (*)
Department of Otolaryngology—Head and Neck Surgery, Baylor College of Medicine,
Houston, TX, USA
e-mail: Alexander.Choi@bcm.edu; Tran.Locke@bcm.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
J. T. Lee etal. (eds.), Advances in Surgical and Medical Interventions for
Recalcitrant Chronic Rhinosinusitis,
https://doi.org/10.1007/978-3-031-89191-5_1
3
4
A. M. Choi and T. B. Locke
prevalence studies report a 6.9–27.1% prevalence in Europe and 4.8–12% prevalence in the U.S.A [3–5]. In addition, based on a large Korean database study, there
is an overall higher prevalence of patients with CRSsNP (5.8%) compared to
CRSwNP (2.6%) [6].
The incidence of CRS remains poorly dened. Two epidemiologic studies conducted in the U.S.A. and Canada used database evaluation to generate an estimated
incidence of 1048 cases per 100,000 person-years, and 2.5 cases per 1000 individuals, both with variation based on geography and CRS phenotype [7, 8].
CRS is often treated in a multi-faceted approach, combining various medical
therapies and surgical interventions. The reported outcomes of these therapies result
in short- and long-term symptom reduction and improvement in quality of life in
85% of patients [9]. However, the remaining 15% of patients, who suffer from recalcitrant CRS, are plagued with chronic symptoms that require other medical regimens and revision surgeries.
CRS results in a signicant economic healthcare burden. Based on cost analysis
reports, the overall annual cost of CRS is $22billion USD with $14billion associated with direct costs. These direct costs include annual medication costs of $1547–
$2700 per patient and $8200–$10,500 per endoscopic sinus surgery [10]. For those
with recalcitrant CRS, it can be presumed that their costs would be greater as the
pathogenesis of the disease is more complicated and less understood.
CRS is a multifactorial condition involving a complex interplay between extrinsic environmental exposures and intrinsic immune system factors, resulting in
chronic inammation in the sinonasal mucosa. This has fostered development of
multiple theories to explain the pathogenesis of the disease process and why recalcitrant disease is difcult to treat.
The environmental exposures that are often a component to CRS include fungal
infections, bacterial superantigen infections, biolm formation, and microbiome
changes. Host immune factors that are involved in the pathogenesis of CRS include
defects in the epithelial barrier and dysregulation of the immune response [11].
Extrinsic Factors
Previously, it was thought that fungi played a central role in CRS.Studies evaluating fungal organisms in patients with CRS noted a 100% identication of fungi in
the sinonasal cavities, specically Alternaria species. However, further studies and
randomized clinical trials evaluating antifungal therapy demonstrated minimal efcacy in treating CRS, disproving this hypothesis [12, 13]. Currently, fungal elements are considered a component of the CRS pathogenesis for select individuals as
fungi contain proteases that can elicit cytokine activation and subsequent T helper
(Th) type 2 response, remaining an essential component in allergic fungal sinusitis
[14, 15].
Bacterial colonization of the sinonasal tract remains an understudied area.
Historical data suggest that superantigen exotoxins produced by Staphylococcus
aureus (S. aureus) elicit an inammatory cascade conducive to nasal polyp
1 Introduction toRecalcitrant Chronic Rhinosinusitis
5
formation and signicant eosinophilic and type 2 immune response [16]. In addition, studies have isolated S. aureus in a large portion of nasal polyposis patients
[17]. The superantigen exotoxin activates an immense immunologic response compared to the normal immune response prompting T lymphocyte proliferation and
cytokine release. However, when evaluating control, CRSsNP, and cystic brosis
(CF) patients, the effects of the superantigen were non-specic and did not elicit a
Th2 response. Therefore, it is now hypothesized that the superantigen exotoxin
amplies the inammatory changes already present in the nasal mucosa. This results
in worse clinical symptoms and could serve as an indicator of recalcitrant CRS [11].
Biolm formation is a microbial property that aids in the development of antibiotic resistance. Biolms are organized structures comprised of bacteria within a
protective external matrix, preventing the bacteria from being exposed to host
defenses and antibiotics. Bacterial species capable of forming biolms include
S. aureus, P. aeruginosa, S. pneumoniae, H. inuenzae, and M. catarrhalis. S. aureus
is the most common offending agent in the sinonasal tract. Of the CRS patients
undergoing sinus surgery, 42–75% had biolm formation [18, 19]. The data supporting this hypothesis is scant but has not been identied without the presence of
S. aureus superantigen exotoxin. Ultimately, this hypothesis highlights the phenotypic representation of CRS in the setting of superantigenic S. aureus infections [11].
Lastly, given the contributions of both fungal and bacterial infections, the sinonasal tract microbiome is ever changing. There remains a paucity of data regarding
the microorganisms that normally inhabit the sinonasal cavity, but some studies
have suggested differences in quantity and diversity in patients with CRS [20]. The
literature regarding restoration of the natural symbiosis of the microbiome stems
from the gastrointestinal literature and probiotic therapy. The International Sinonasal
Microbiome Study (ISMS) 16S gene sequencing evaluation of the sinonasal microbiome identied three microbiotypes: Corynebacterium-dominant microbiotype,
Staphylococcus-dominant microbiotype, and a mixed microbiotype. [21] While
results remain untested, negative correlation between Corynebacterium and
Staphylococcus suggest that Corynebacterium may have probiotic properties to
bring about balance in dysbiosis [21–24]. Microbiotypes did not, however, correspond to a particular disease state or clinical traits, precluding its ability to serve as
a biomarker. To complicate the pathogenesis of CRS further, there are geographic
variations in microbiotype distributions. Asia and Australia were noted to have
more Corynebacterium representation whereas Europe had more Staphylococcus
representation. Currently, the reasons behind this variation remain too numerous
and broad to classify and require further large-scale evaluation [21, 25].
Intrinsic Factors
The immune hypothesis theory proposes that defects in the physical barrier and
innate immune response predispose individuals to CRS.This theory shifted the
paradigm of CRS pathogenesis to genetic and epigenetic variations and abnormalities. This hypothesis was readily applicable to CF patients due to their
6
A. M. Choi and T. B. Locke
impaired mucociliary clearance. However, studies have advocated that CRS
patients also have increased transit time and increased risk for protease degradation and, thus, a weakened mechanical barrier [26, 27]. Additional studies have
identied variations in host defense molecules which permit increased pathogen
access and chronic inammatory changes [28–31]. For instance, defects in the
eicosanoid pathway are hypothesized as a cause of chronic inammation due to
the strong relationship between CRS and aspirin sensitivity. Although there is
some evidence supporting symptomatic improvement with the use of leukotriene
antagonists in CRSwNP, the evidence remains scarce and would require further
assessment [32].
Alterations in the host immune response were previously implicated in the
pathogenesis of CRS. As mentioned previously, CRS was classied into two
clinical phenotypes, CRSwNP and CRSsNP, which was further broken down
based on immune cell prole, namely eosinophilic prole for CRSwNP and neutrophilic for CRSsNP. Eosinophilic and non-eosinophilic proles of those with
CRSwNP remain nebulous. Studies conducted at various regions of Europe,
Asia, and Australia have elucidated a predominantly eosinophilic inammatory
pattern of those in Europe and Australia with CRSwNP whereas, Asian populations with CRSwNP tend to have a neutrophilic prole. This bolsters the pattern
of eosinophilic CRSwNP in Caucasians and neutrophilic CRSwNP in Asians,
suggesting inherent genetic immunologic differences between diverse ethnicities
[33–35]. To support this, Mahdavinia etal. evaluated a small cohort of 11 sec-
ond-generation Asian patients with CRSwNP from Illinois and noted similar
inammatory backgrounds to native- born Asians with CRSwNP. [36] In contrast,
histopathologic studies evaluating CRSwNP patients in Thailand and Korea in
the 1990s and in the 2010s, who required sinus surgery, demonstrated an eosinophilic shift of nasal polyposis [37, 38]. This suggests that environmental factors
play a substantial role in CRSwNP and that observing changes in immune patterns over time will emerge as an imperative part of understanding CRSwNP. Lastly,
it reveals that a simple classication of eosinophilic vs. non-eosinophilic inammation may not be adequate in CRS.
As a consequence of the uncertainty regarding inammatory cell predominance,
it is difcult to determine an overarching treatment algorithm that is applicable to
the CRS population. Instead, the transition to individualized treatment regimens has
been proposed based on a novel classication of endotypes [39]. The use of endotypes has become a stepping stone towards developing personalized treatment for
those who suffer from CRS.Use of endotype classication has both prognostic and
treatment implications allowing for prediction of success. This categorization has
also driven the development and testing of biologic therapies that target specic
cytokines to treat CRS.
The endotype classication is based on balance of the T-helper cell patterns of
inammation, namely, Th2 (type 2) vs. non-Th2. [Table 1.1] T-helper cells can
determine the character of an immune response through the cytokines produced and
the subsequent downstream differentiation or recruitment of other inammatory
1 Introduction toRecalcitrant Chronic Rhinosinusitis
7
Table 1.1
Endotype classication
Endotype Th2 (Type 2) inammation Non-Th2 inammation
Primary cytokine IL-4
Cellular predominance Eosinophils Neutrophils
IL interleukin, IFN interferon, Th T-helper
Endotype classication of CRS
IL-5
IL-13
Type 1: IL-12, IFNType 3: IL-17, IL-22
γ
cells. Type 1 endotype patients exhibit elevated interferon-gamma (IFN-γ). IFN-γ is
a cytokine with pleiotropic immunologic modulation that is secreted by activated T
cells and natural killer (NK) cells. It plays an essential component in neutrophil and
macrophage activation for clearance of intracellular pathogens, including bacteria,
viruses, and protozoa [40]. Type 3 endotypes have elevated IL-17 and IL-22, which
are cytokines that support the innate barrier defenses on mucosal surfaces by promoting recruitment of neutrophils to clear extracellular infections and induce regeneration of epithelial surfaces after inammation [41]. These two endotypes are
generally neutrophilic dominant and are associated with CRSsNP. Conversely, type
2 endotypes are characterized by elevation of cytokines IL-4, IL-5, and IL-13, are
eosinophilic dominant, and promote IgE differentiation. Type 2 endotype is associated with allergic disease, parasitic infections, and CRSwNP. [39, 42–44]
Understanding the underlying inammatory pattern of a patient’s CRS can assist
in guiding both medical and surgical therapy. Biologic therapies specically target
IL-4, IL-5, IL-13, or IgE and have proven to be efcacious as an adjunct measure to
standard medical therapy alongside surgical interventions [45–47].
While this is a simplistic summation of a complex disease, this serves as the
foundation for endotype discussion. Further research has elucidated mixed endotype representations and elevation in cytokines and biomarkers. This suggests that
rather than distinct categories of endotypes, CRS endotypes should be classied on
a continuous spectrum [48, 49].
Due to its heterogeneity, recalcitrant CRS is a difcult disease process to treat.
Despite appropriate medical therapy, alternative medical therapies, and multiple
surgical interventions, CRS continues to greatly impair the quality of life of those
affected. As more research is conducted, the complexity of CRS becomes more
apparent. The previously listed hypotheses serve as disease modiers that can
accentuate the clinical presentation of the disease but do not explain the pathogenesis of CRS as a whole. The wide gamut of CRS presentation illuminates the incomplete understanding of the associated molecular pathways that dene CRS and the
need for more evaluation. The transition to endotype classication has paved the
way for better characterization of the disease process and personalized treatment.
The following chapters serve to highlight evidence based medical and surgical treatment options available for recalcitrant CRS.
8
A. M. Choi and T. B. Locke
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