Excerpt of

Pathophysiology of chronic rhinosinusitis, pharmaceutical therapy options,

C. Bachert, G. Holtappels

Current Topics in Otorhinolaryngology - Head and Neck Surgery 2015, Vol. 14, pp 1-40

(published: 2015-12-22)

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Abstract

... Research in immunology has brought great progress in knowledge of inflammatory processes in the last 2 decades, which also has an impact on the upper airways. Our understanding of the pathophysiology of chronic rhinosinusitis developed from a rather mechanistic point of view with a focus on narrow clefts and mucociliary clearance to the appreciation of a complex network of immunological pathways forming the basis of disease. We today differentiate various forms of inflammation, we start to understand complex immune-regulatory networks and the reasons for their failure, and have already developed innovative approaches for therapy for the most severely ill subjects. Due to this new knowledge in inflammation and remodeling processes within mucosal tissue, specifically on the key driving factors, new diagnostic tools and therapeutic approaches for chronic rhinosinusitis have developed; the differentiation of endotypes based on pathophysiological principles will be crucial for the use of innovative therapies, mostly humanized monoclonal antibodies. Several hundred of those antibodies are currently developed for various indications and will impact our specialty as well as pneumology to a great extent.

1 Introduction: From pathophysiology to endotypes of chronic rhinosinusitis and their treatment

...The differentiation of the inflammation types based on T helper cells allows a more differentiated classification according to pathomechanical principles into so-called endotypes within the clinical phenotypes which can finally be used to define innovative therapeutic objectives and to implement them in daily clinical routine.

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... epigenetic processes lead to functional modifications in the genome without change or modification of the basic DNA nucleotide sequence. ... A first investigation on methylation modifications in CRSwNP found DNA hypermethylation in 332 loci of 296 genes. The relevant gene products contributed

• to lymphocyte and cellular proliferation,
• to the activation of leukocytes,
• to the biosynthesis and secretion of cytokines,
• to immune reactions,
• to inflammatory processes, and
• to the immunoglobulin synthesis [19].

In comparison, hypomethylation was identified in 158 loci of 141 genes with involvement

• in ectodermal development,
• in hemostasis,
• in wound healing,
• in the binding of calcium ions, and
• in oxidore-ductase activity.

...

2.2.3 Receptors of congenital immune defense: Toll-like, NOD-like, and RIG-like receptors

Epithelial cells of the nose and the paranasal sinuses do not only represent a physical barrier, but have active functions in the context of innate and acquired immune defense [40]. They express membrane-bound and cytoplasmatic pattern recognition receptors (PRR) that recognize pathogen-associated molecular patterns (PAMPs) [41]. The activation of those receptors leads to the release of chemokines and cytokines and components of the innate immune system activating further immune cells (for example neutrophils). Different microbial factors or PAMPs, such as for example bacterial lipopolysaccharides (LPS), flagellin, lipoteichoic acid, peptidoglycan, double stranded RNA, and unmethylized CpG motives, can be recognized by many PRRs [42]. The activation of PRRs in the nasal epithelium may lead either to the induction of tolerance or to the expression of inflammatory mediators attracting neutrophil lymphocytes. ...

2.2.4 Indicators of cellular death: damage-associated molecular patterns (DAMPs)

Beside pathogen-associated molecular patterns (PAMPs), cells also recognize cellular damages because of their damage-associated molecular pattern (DAMPs). The combination of foreign material plus cellular damages triggers a reaction of the innate immune system and activated the adaptive immune defense or contributes substantially to its manifestation [53].

In addition to actively secreted inflammatory messengers, recently also those messengers are in the focus of scientific attention that are part of the endogenous intracellular or extracellular matrix of the host and can be released passively into the extracellular space. When released, the original functions of those components change so that they modulate inflammatory reactions under pathologic circumstances in their new environment. In analogy to the PAMPS, those molecules were named DAMPs [54], [55], [56]....

2.2.5 Lymphoid cells of innate immune defense (ILCs, innate lymphoid cells)

Epithelial cells in the airways produce numerous inflammatory cytokines as normal reaction of the stimulation of PAMP and DAMP receptors [51], among those

• IL-1,
• tumor necrosis factor α (TNF-α),
• type 1 interferons (IFN-α/β),
• granulocyte macrophage colony stimulating factor (GM-CSF),
• eotaxins,
• RANTES (regulated upon activation normal T-cell expressed and secreted),
• IFN-γ-inducible protein 10 (IP-10),
• IL-6,
• IL-8,
• the growth-regulated oncogene α (GRO-α),
• monodansylcadaverine (MDC),
• stem cell factor (SCF),
• TARC (thymus and activation regulated chemokine),
• monocyte chemotaxis protein 4 (MCP-4),
• B cell activating factor (BAFF),
• osteopontin,
• IL-32, and
• Th2 immune reaction associated cytokines such as
• IL-25,
• IL-33, and
• TSLP (thymic stromal lymphopoietin) [26], [49].

...

2.2.6 Dendritic cells and macrophages

Dendritic cells (DCs) are the link between innate and adaptive immune defense on mucosa. In the airways, several functional subgroups of DCs have been described that differ with regard to their stage of maturity and the expressed combination of PRRs [87]. DCs recognize antigens and process and present them to antigen unversed or “naïve” T cells. Because of these functions, DCs play a key role in the fine adjustment of immune reactions and favor the production of Th1, Th2, or Th17 reactions or regulatory T cells (Tregs) [80].

...

2.3 Adaptive immune defense: T cells as central components

The adaptive immune defense consists on the one hand of T cells that are especially targeted for this challenge. They may be subdivided into several groups according to the released cytokines and their functions. On the other hand there is the B cell response that is targeted to the production of specific antibodies. The resulting T cell response should be subject to the regulation of T regulatory cells; if not, persisting inflammation occurs. Other bystander cells such as eosinophils and mast cells further modify and amplify the inflammation process, in particular in cases of Th2 reaction. Such cell components sum up the processes that finally lead to most severe diseases of the mucosa, mainly Th2 characterized.

2.3.1 T helper cell patterns [Kuby, Berki, CD-marker]

While CRSsNP appears as an only moderate, mainly neutrophil Th1 polarized inflammation, CRSwNP is characterized beside the neutrophil component by a moderate to high eosinopilic Th2 polarized inflammation, at least in Caucasians [95]. ...

• Both in the healthy and in the affected nasal mucosa, a heterogeneous population of T helper cells was present: Th1, Th17, Th22, and Tfh (follicular helper) cells were found. A certain plasticity of the T helper cells could be revealed because for example the Th17 cell population produced not only IL-17, but also IFN and IL-22. The reason for this heterogeneity among the effector T cells might be associated with their protector function, i.e. according to the type of the entering microorganisms, several optimal immune reactions should be possible.

• The results show that the T cell profile of CRSsNP [sNP = without nasal polyps, wNP = with nasal polyps] specimens only differs little from the control specimens which confirms previous findings that CRSsNP is rather a remodeling process than a specific inflammatory reaction [21].
• It was remarkable that Th2 cells could only be identified in CRSwNP specimens while asthma patients had the highest number of cells. This pattern correlates with protein data of homogenized tissue specimens after multiplex cytokine analyses [99].
• Even if IFN gamma is the most important intracytoplasmatic cytokine in T cells, as protein only low concentrations can be detected in tissue homogenates; apparently IFN is not spontaneously released under basic conditions whereas high concentrations were found after stimulation in the cell free supernatant.
• IL-5, however, is only expressed by relatively few CD4 positive T cells, but regularly released spontaneously by a CRSwNP endotype; this spontaneous release can be significantly increased by intramucosal Staph. aureus germs (see later).

Beside CD4 positive T cells, there is a larger population of T cells in the nasal mucosa that belong to the CD8 cell line and that are the main source of IFN gamma. CD8 positive cytotoxic T cells (Tc cells) express high quantities of Fas ligand that may induce apoptosis in other cells. Another important function of IFN producing CD8 positive T cells (so-called Tc1 cells) is their ability to inhibit IgE response.

The presence of Th2 cells and the expression of IL-5 is associated with eosinophilia, an increased ECP (eosinophil cationic protein) and the total amount of IgE in the mucosa, independent of the atopic status of the patients [97].

...

Figure 3

...

2.4 Remodeling of the mucosa of the paranasal sinuses

Cellular remodeling processes are dynamic processes where the production and degradation of the extracellular matrix (ECM) are balanced and regulated by different mediators among them TGF-β.

...

2.5 Interaction between bacteria (microbiome) and immune defense

... With the advent of the field of molecular biology, culture independent methods have been developed in order to examine microorganisms based on their genetic patterns. As a consequence, a clearly more complex flora was discovered in the upper airways than it had been suspected until that time. Due to the development of culture independent means it is meanwhile possible to identify species of microorganisms that could not be detected with previous growth methods. Today it is known that the human body is the home of 10–100 billions of microorganisms, an amount that is far higher than the number of body cells. The bacterial flora that has been known only for a short time is called human microbiome.

Different regions of the body such as the nasal mucosa, skin, urogenital tract etc. have their own microbiomes encompassing ideally many microorganisms in relatively similar low frequencies (“richness, evenness”). If single germs disturb this balance by proliferation and by suppression of others, a pathologic situation occurs.

... Additionally, the relationship between microbiome and immune defense in the mucosa could be bidirectional, i.e. the bacteria exercise a certain pressure while on the side of the host an insufficient defense is present, for example because of alternatively activated macrophages, that show a reduced phagocytosis and an insufficient killing of intracellular germs [93]. Scientific examinations on how certain germs influence the immune reaction of the mucosa of the nose and paranasal sinuses, could shed new light on the pathophysiology of CRS and lead to new treatment approaches. The manipulation of the flora or the introduction of specific healthy germs (e.g. lactic acid bacteria) might turn out to be helpful for the treatment of inflammatory diseases and break the dominance of certain germs such as for example Staph. aureus or Pseudomonas aeruginosa.

2.5.1 Interaction between viruses and bacteria

2.5.2 The role of Staphylococcus aureus as amplificator of the inflammation

2.7 Biomechanisms of recurrences after surgery

In the same way as concomitant asthma, also the probability of recurrences after total surgical removal might be calculated from biopsies of CRSwNP patients. The claim of completeness is based on the fact that in every polyp an immunological memory is saved in the form of so-called memory cells that maintain the existing immune reaction unless they are surgically removed during an intervention.

• Surgeries of recurrences in CRSwNP are frequently performed.
• A follow-up examination over 12 years performed in Ghent, Belgium, revealed recurrences in nearly 80% of the patients requiring at least intensive drug therapy (Gevaert, in press).
• A total of 36% of the patients underwent at least one revision surgery while the 2nd interventions were performed over all 12 years.
• Corticosteroid resistant recurrences may even develop 10 years after the first surgical intervention.

In a study performed over a shorter interval of 7 years, we examined the immune profiles that were associated with recurrences [9]. Biopsies of CRSwNP patients who had developed a recurrence within this time were compared to biopsies of patients who had not recurrence within this same period of time. In all specimens the following parameters were measures:

• Th1, Th2, and Th17 cytokines,
• IgE,
• pro-inflammatory cytokines and mediators of eosinophilic (ECP) and neutrophil inflammation (MPO).

Patients with recurrences had significantly higher concentrations of total IgE, SE-IgE, ECP, and IL-5 (OR 6.4) at first surgery, whereas IFN-γ was significantly reduced (OR 0.047). The concentrations of IL-17, IL-6, TGF-β1, and IL-1β did not differ between the groups. Asthma and NERD, both Th2 weighted, as clinical parameters were also more frequent in the group of recurrences.

• The conclusion can be drawn that the polypous tissue of patients with high risk of recurrences is different from tissue with low risk for recurrence.
• The immune profile that has to be antagonized can be deducted, and the prognosis of the individual patient can be estimated.
• Those findings show as well as observations of comorbid asthma how heterogeneous chronic rhinosinusitis is and which great influence is exercised by T helper cells on the disease, their therapy, and prognosis.
• So we have to move away from the idea that a simple classification into CRSsNP and CRSwNP meets the differentiation of CRS.
• Beside endoscope and computed tomography we will have to introduce biomarkers into the diagnostic concepts in order to meet the individual requirements in the sense of personalized medicine. ...

3 Cluster analysis of CRS: definition for CRS endotypes

Nowadays, statistical methods allow examining similar disease patterns by analyzing certain clinical or biomedical characteristics. This approach is called cluster ana-lysis ...

Table 4: Endotypes of CRS with clinical findings

[notes:

page 16/40

CRS = Chronic Rhinosinusitis,

ECP = eosinophil-cationic protein,

SE = enterotoxin, also called superantigen

Staph. aureus synthesizes and secretes numerous immune proteins and enterotoxins, among those the classical enterotoxins (SEs) SEA, SEB, SEC, SED, SEE, and toxic shock syndrome toxin-1 (TSST-1) [141]. SEs, also known as superantigens, are able to activate T cells via an antigen-unspecific binding to the variable β chain of the T cell receptor which again allows a polyclonal activation of a high number of T cells with different character-ization; up to 20% of the local T cells can be activated at the same time instead of the usual rate of less than 0.1% which may cause a “cytokine storm” [142]. This cytokine storm can lead to the sudden death of the patient, and in cases of chronic triggering it maintains a severe persisting inflammatory reaction within the tissue. Furthermore, SEs can activate B cells, eosinophils, epithelial cells and other cell populations which enhances the immune globulin synthesis including IgE and the migration of eosinophilic granulocytes in the tissue. The result is a further Th2 polarization; SE-IgE positive nasal polyps have a manifold increased IgE, ECP, and IL-5 compared to SE-IgE negative polyps. Recently, we were able to provide the proof of the local release of SEs and other immune proteins from Staph. aureus in the tissue of nasal polyps by means of proteomics (unpublished data). The changes of the innate and adaptive immune response induced by SEs [143] promote the survival of Staph. aureus. In an animal model, SEs cannot only enhance Th2 mediated inflammations of the airways but also induce them [144], [145]. The intranasal application of allergens in mice normally leads to development of tolerance; the addition of SEB, however, leads to sensitization and formation of an eosinophilic inflammation reaction of the upper and lower airways [146].

...

4 Pharmaco-therapy of chronic rhinosinusitis

The options that are currently recommended for therapy of chronic rhinosinusitis (CRS) are summarized in international and national guidelines. Most wide-spread are the EPOS [European Position Paper on Rhinosinusitis and Nasal Polyps] guidelines that have been established by an international team of experts (including myself) according to criteria of evidence-based medicine [1]. Among those treatment recommendations, topical and systemic glukocorticosteroids, antibiotics as long-term therapy or in cases of exacerbations as well as irrigations with saline solution are found. If those options do not lead to successful treatment or control of the symptoms, generally surgery is discussed. Postoperatively the same pharmacotherapeutics are continued or applied. The recommendations of the EPOS guidelines are summarized in Table 5 and Table 6 for CRS without nasal polyposis (CRSsNP) and CRS with nasal polyposis (CRSwNP)[, respectively]. They can be completely downloaded via internet (http://www.rhinologyjournal.com/Documents/Supplements/supplement_23.pdf).

Table 6: Evidence and recommendations of therapy in CRSwNP for adults (modified according to [1])

Notes:

Ib(-) = no difference compared to placebo

A(-) = degree of recommendation: not to apply [to] this therapy

Wytske J. Fokkens, Valerie J. Lund, Joachim Mullol, Claus Bachert, et al.

European Position Paper on Rhinosinusitis and Nasal Polyps 2012 (EPOS 2012)

Table 1.1. Category of evidence (10).

Ia Evidence from meta-analysis of randomised controlled trials

Ib Evidence from at least one randomised controlled trial

IIa Evidence from at least one controlled study without randomisation

IIb Evidence from at least one other type of quasi-experimental study

III Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies

IV Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both

Table 1.2. Strength of recommendation.

A Directly based on category I evidence

B Directly based on category II evidence or extrapolated recommendation from category I evidence

C Directly based on category III evidence or extrapolated recommendation from category I or II evidence

D Directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence

Version: 14 January 2018
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