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7/28/2019 pathophysiologic mechanisms of chronic rhinosinusitis
1/11
Pathophysiologic mechanisms of
chronic rhinosinusitis
Ruby Pawankar, MD, PhD*, Manabu Nonaka, MD, PhD,Shigeo Yamagishi, MD, PhD, Toshiaki Yagi, MD, PhD
Department of Otolaryngology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-Ku, Tokyo,
113-8603, Japan
Rhinosinusitis is one of the most common disorders and is a major health
problem worldwide [1]. This multifactorial disease has a complex nature, and the
limited understanding of its relationship with associated factors makes it difficult
to precisely define and classify. Broadly speaking, rhinosinusitis may be defined
clinically as a condition manifested by an inflammatory response involving the
mucous membranes of the nasal cavity and paranasal sinuses.
Although conventionally called sinusitis, it often is preceded by rhinitis andrarely occurs without concurrent rhinitis. The term rhinosinusitis now is used
more widely. Histologically, the nasal passages and sinus cavities have many
similarities: The mucous blanket of the sinuses is in continuity with that of the nasal
cavity, and a CT scanning study has shown that the mucosal linings of the nose and
sinuses are involved simultaneously in the common cold [2]. Symptoms associated
with rhinosinusitis include nasal obstruction, nasal congestion, nasal discharge,
nasal purulence, postnasal drip, facial pressure and pain, alteration in the sense of
smell, cough not caused by asthma, fever, halitosis, fatigue, dental pain, pharyn-
gitis, otologic symptoms (eg, ear fullness and clicking), and headache.
Cause, pathophysiology, and histopathology
The development of rhinosinusitis depends on a variety of environmental and
host factors, including, but not limited to, host factors, such as cystic fibrosis or
immotile cilia syndrome, allergic or immune conditions, anatomic abnormalities,
systemic disease, endocrine and metabolic, neuromechanisms, or tumors; and en-
vironmental factors, such as infectious and viral agents, trauma, noxious chemi-cals, iatrogenic, medications, and surgery.
0889-8561/04/$ see front matterD 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S0889-8561(03)00109-7
* Corresponding author.
E-mail address: [email protected] (R. Pawankar).
Immunol Allergy Clin N Am
24 (2004) 7585
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It is common for rhinosinusitis to coexist with other conditions, such as allergic
rhinitis, cystic fibrosis, or asthma. Like acute otitis media, rhinosinusitis often is
preceded by an acute viral illness. Subsequently, acute rhinosinusitis has fourbasic clinical courses: resolution, development of adverse sequelae, or develop-
ment of symptomatic or silent chronic rhinosinusitis (CRS). CRS also can have
four basic clinical courses: resolution, persistence, or development of adverse
sequelae with or without possible progression to generalized airway reactivity.
Histopathologically, acute rhinosinusitis is viewed predominantly as an
exudative process that is associated with necrosis, hemorrhage, or ulceration,
in which neutrophils predominate. CRS is predominantly a proliferative process
that is associated with fibrosis of the lamina propria, in which lymphocytes,
plasma cells, and eosinophils predominate and changes in bone may occur. Avariety of findings, including varying degrees of eosinophils in tissues and se-
cretions, polyp formation, and the presence of granulomas, bacteria, or fungi, has
been reported. The causal relationship of allergic rhinitis to rhinosinusitis and
fungal rhinosinusitis is discussed elsewhere in this issue.
Chronic rhinosinusitis
CRS basically is defined by the duration of time over which the symptomspersist [1]. CRS in adults has been defined [3] as a disease of 8 weeks or more
with persistent symptoms and signs, or four episodes per year of recurrent acute
sinusitis, each lasting for at least 10 days in association with persistent changes in
CT scanning. CT scanning of the sinuses should be done 4 weeks after medical
therapy without intervening acute infection. In children, the respective figures are
12 weeks of symptoms or more than six episodes of sinusitis per year. Although
the precise cause of the inflammation associated with CRS is unclear, the pres-
ence of bacteria within the nose and paranasal sinuses in this population often
is well documented [4,5]. CRS can be classified broadly as CRS without na-sal polyps (NPs) and CRS with NPs, the latter of which usually is not related
to infection.
Pathogens associated with chronic rhinosinusitis in children and adults
Although several studies have shown the presence of bacterial pathogens in
CRS, there is much diversity in the type of pathogens identified. Such differences
also exist in reports about the normal flora. Gordts et al studied the microbiology
of the middle meatus in normal adults and children and reported that 75% ofsubjects had bacterial organisms with coagulase-negative staphylococci (35%).
The presence ofCorynebacterium species (23%) and Staphylococcus aureus (8%)
was more common in adults, and infection with Haemophilus influenzae (40%),
Moraxella catarrhalis (34%), and Streptococcus pneumoniae (50%) was more
common in children [6]. In CRS, however, a mixed flora of anaerobes and aer-
obes, including gram-positive and gram-negative organisms, has been reported.
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In children, samples from the ethmoid sinus contained S aureus (19%) and
hemolytic streptococci (23%) or staphylococcus epidermidis, and viridans group
streptococci [7,8]. In adults, Doyle and Woodham found high rates of anaerobesand streptococcal variants (coagulase negative staphylococci [70%] and viridans
group streptococci [33%]) in the maxillary sinus, but no anaerobes were isolated
[9]. Klossek et al evaluated the ostiomeatal flora in patients with CRS and
controls and found Corynebacterium species, coagulase-negative staphylococci,
Peptostreptococcus species, and Propionibacterium species in the control popu-
lation, and H influenzae, staphylococci, S pneumoniae, and Prevotella species in
patients with CRS [10]. Finegold et al reported that the recurrence of signs and
symptoms was twice as frequent in patients whose cultures showed anaerobic
bacterial counts greater than or equal to 103
CFU/mL [11]. Nadel et al [12]compared host factors, such as a history of asthma, allergic rhinitis, previous sinus
surgery, and concurrent use of antibiotics, steroids, and irrigations. Gram-negative
bacteria were present in 27% of cultures and were more common in patients who
had previous sinus surgery or were using irrigations. Propionibacterium aerugi-
nosa was more common in patients taking systemic steroids.
Talbot et al demonstrated a strong correlation between middle meatal cultures
and maxillary sinus cultures [13]. Kremer et al evaluated the bacteriology of mu-
cosal biopsies in patients with CRS and controls [14] and identified coagulase-
negative staphylococci in almost all samples in both groups. Hwang et alevaluated the bacteriology of bone in CRS in a limited number of patients with
in situ hybridization [15] but could not identify bacterial RNA within the bone
using this technique, although in situ hybridization did show the presence of
microorganisms in some of the samples. Keech et al used polymerase chain
reaction to analyze aerobic bacterial strains in CRS, as compared with standard
culture data [16], and identified bacteria in 62% of mucosal specimens, versus
50% using routine cultures.
Bacterial colonization of paranasal sinuses
In patients with CRS without any underlying infection, the possibility of
bacterial colonization needs to be considered. In patients with chronic obstructive
pulmonary disease, Fornier showed that the prevalence of bacterial coloniza-
tion ranges from 30% to 50% and that mucosal polynuclear cell amplification
is associated with colonization [17]. Similarly, Monso reported that bacterial
colonization negatively impacted the quality of life in patients with chronic bron-
chitis [18]. Bacterial colonization might exacerbate a noninfectious inflammatory
process in CRS through bacterial allergic mechanisms. Calenoff comparedbacteria-specific IgE levels in patients with CRS with levels in patients with
allergic rhinitis. Bacteria-specific IgE was identified in 57% of patients with CRS,
as compared with only 10% of patients with allergic rhinitis [19]. Other published
reports have suggested that bacterial allergy might have a role in a number of
chronic inflammatory diseases involving the respiratory or gastrointestinal tracts,
including asthma, nasal polyposis, and chronic gastritis [20,21]. The quantifica-
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tion of bacterial specific IgE must be done carefully to avoid interference by the
potential presence of much greater amounts of bacterial-specific IgG.
Bacterial superantigen
It is well recognized that bacteria (eg, S aureus) possess the ability to elicit
exotoxins, which can be pathogenic in humans (eg, toxic shock syndrome
toxin 1]) [22]. The term superantigen is used to describe these bacterially
produced particles because of their ability to activate larger subpopulations of the
T lymphocytes (5%30%) in contrast to typical antigens (
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seen in osteomyelitis. A subsequent rabbit-model study demonstrated that a
combination of a surgical procedure with experimentally induced maxillary si-
nusitis caused by P aeruginosa consistently allowed the inflammation to spreadthrough the Haversian canals of the bone, even across the midline to the bone of
the contralateral sinuses [30]. It seems that this inflammation within the bone may
induce inflammatory changes in the overlying mucosa at a significant distance
from the site of infection.
Cells, cytokines, chemokines, and mechanisms
Chronic sinusitis is associated with significant morbidity and a lower quality of
life. The response to medical or surgical treatment often provides only temporaryrelief, suggesting that an understanding of the role of inflammatory mediators
such as cytokines and chemokines in the pathogenesis of chronic sinusitis is
crucial. The presence of bacteria within the nose or paranasal sinuses can give rise
to a chronic infectious inflammatory process, cause persistence of disease, or
might exacerbate a noninfectious inflammatory process through bacterial coloni-
zation. The model of infectious mucosal disease is that of acute bacterial
rhinosinusitis, and no model of chronic disease is available. In a mouse model
of acute bacterial rhinosinusitis (ABRS), the luminal exudate was composed pri-
marily of neutrophils and eosinophils, microabscess formation, epithelial degen-eration, and mucosal infiltration with lymphocytes, neutrophils, and plasma cells
[31]. Studies of human ABRS are limited primarily to examination of inflam-
matory cells and cytokines in sinus exudate. These studies are in agreement with
the animal studies and have found a neutrophilic inflammatory process and the
presence of interleukin 1 (IL-1), IL-6, and IL-8 in the exudates [32,33].
In humans, the histologic appearance of inflamed mucosa and the inflammatory
cells in sinus exudate depend somewhat on the allergic status of the patient. In the
sinus fluid of patients with CRS, the main inflammatory cells are neutrophils, as
normally observed in acute sinusitis, but a low percentage of eosinophils, mastcells, and basophils also may be observed [34,35]. High concentrations of his-
tamine; leukotrienes C4, D4, and E4; and prostaglandin D2 were found, suggesting
mast-cell and basophil activation in chronically inflamed sinuses.
In a study of tissues from patients with chronic sinusitis, a small proportion
showed the presence of IL-1b, intercellular adhesion molecule 1 (ICAM-1), and
E-selectin by immunohistochemistry, but the cytokine and adhesion receptors
were found to be expressed regularly in the mucosa of frontoethmoidal muco-
celes [36]. The levels of IL-8 in nasal discharge of patients with chronic sinusitis
were significantly higher than those in patients with allergic rhinitis [37]. IL-8 wasdetected in polymorphonuclear cells, epithelial cells, and gland duct cells of
patients with chronic sinusitis, but considerably lower levels were detected in
patients with allergic rhinitis. Once these polymorphonuclear cells are chemo-
attracted into the inflamed mucosa, they further can amplify the inflammation by
inducing the recruitment of neutrophils into the sinus by synthesizing IL-8. Viral
infections could pave the way for subsequent chronic sinusitis, as IL-8 has been
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shown to be released in the course of the common cold [14]. This finding is
supported by clinical observations. Apart from IL-8, neutrophils produce IL-1,
IL-6, interferon g (IFN-g) and tumor necrosis factora (TNF-a) in vitro [3840],further contributing to the chemotaxis and activation of other inflammatory cells.
In patients with allergy or asthma and chronic hyperplastic sinusitis, the
paranasal tissue was found to be infiltrated extensively by eosinophils, and
extracellular deposition of major basic protein (MBP) was found to be associated
with the damage to sinus respiratory epithelium [41]. In general, nonallergic
patients show some evidence for a neutrophilic inflammatory process, whereas
allergic patients tend to show fewer neutrophils and somewhat more eosinophils
in the inflammatory process [42,43]. The relative abundance of eosinophils and
fewer numbers of neutrophils in most cases of CRS has led to the speculation thatthis type of inflammatory response may be independent of infection and may
represent an allergic inflammation. There is evidence that this type of mucosal
response is more prevalent in patients with coexisting asthma [44,45]; however, it
is likely that infection impacts on this disease process. On clinical grounds, there
seems to be a continuous spectrum of illness, ranging from chronic infectious
rhinosinusitis to relatively pure noninfectious inflammation.
The cytokinechemokine profiles in acute bacterial rhinosinusitis, presumably
infectious CRS, and chronic noninfectious hyperplastic sinusitis with nasal
polyposis are different. In acute rhinosinusitis, increases in levels of proinflam-matory cytokines, like IL-1 and IL-6, and chemokines, like IL-8, were noted [46].
In presumably infectious CRS, however, increased levels of IL-8 and IFN-g have
been reported [47,48]. Up-regulation of adhesion molecules, such as ICAM-1,
and of E-selectin on endothelial cells, which can facilitate the tissue infiltration of
inflammatory cells like neutrophils and lymphocytes, has been reported [49].
Because IL-8 is a chemotactic factor for neutrophils and because the infiltrating
neutrophils are a source of proinflammatory cytokines that can up-regulate
ICAM-1 and E-selectin, the cellular infiltration and inflammatory response may
be amplified further.There are four histologic types of NPs, and the eosinophilic (mainly eosino-
phils) or chronic inflammatory type (mainly neutrophils and lymphocytes) are the
most common [46]. In chronic hyperplastic sinusitis with NPs, the presence of
T helper cell type 2 (TH2) cytokines, most importantly IL-5 and IL-13, is docu-
mented [50,51]. The coexisting presence of asthma in patients with nasal polyps
has a bearing on the intensity of eosinophils found in the tissues of these patients,
and the coexisting presence of positive allergy skin tests also was associated with
the presence of IL-4 mRNA in the mucosa [52]. In allergic patients, the increased
presence of IL-4 and IL-13 can have a role in up-regulating vascular cell adhesionmolecule 1 (VCAM-1), which can facilitate the migration of eosinophils into the
tissue, partially explaining the increased presence of eosinophils in these patients.
Activated mast cells, through the release of histamine and tryptase, can up-regu-
late the production of RANTES and granulocyte-macrophage colony-stimulating
factor (GM-CSF) from epithelial cells and amplify eosinophil infiltration and
survival, because RANTES is important for eosinophil chemotaxis, and GM-CSF
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is important for eosinophil survival [53,54]. IL-4 and IL-13 from mast cells and T
cells can up-regulate eotaxin production [51,55]. Increased levels of tryptase and
histamine (exceeding levels of 4000 ng/mL) have been found in NPs, and a goodcorrelation between the levels of eosinophil cationic protein (ECP) and histamine
and tryptase have been documented [51,56]. The authors previously have reported
increased number of mast cells in NPs [57], and Kim et al [58] reported high levels
of stem cell factor (SCF), which is an important growth and survival factor for
mast cells. In addition to increased levels of cytokines and chemokines, increased
levels of immunoglobulins, such as IgA, IgE, IgG and IgM, also have been re-
ported in polyp fluid and tissue [56].
Matrix metalloproteinases (MMPs) have an important role in tissue degrada-
tion and may be involved in the pathogenesis of NPs. A significant amount ofconstitutive MMP-1 mRNA has been reported in NP fibroblasts, and this
expression was found to be up-regulated by cytokines [59]. Cells expressing
mRNA for MMP-1 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were
detected around areas with loose stroma, suggestive of rapid extracellular matrix
degradation [59]. The authors studies also showed an increased expression of
MMP-9 in NPs, and this increase may contribute to the extracellular matrix
degradation (Pawankar et al, unpublished data, 2002).
There are also increases in glandular proliferation, vascularization, a-smooth
muscle actin (SMA)+
myofibroblasts and deposition of collagen types I, III, and V[60,61]. Levels of several profibrotic cytokines have been found to be increased in
NPs, including: GM-CSF, transforming growth factor (TGF)-b, platelet-derived
growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial
growth factor (VEGF), epidermal growth factor (EGF), and insulin-like growth
factor (IGF) [62]. These factors may contribute to NP growth and the remodeling
process, and the remodeling may be a sequela of chronic inflammation.
TGF-b is another cytokine that is important for inducing fibroblast prolifera-
tion, and the increased stromal fibrosis seen in NPs may be caused by the
increased expression of TGF-b [63]. Studies have shown that TGF-b can up-regulate the function of fibroblasts by enhancing the IL-4 and lipopolysaccharide
(LPS) (bacterial product)-induced production of eotaxin from these cells [64].
Because eosinophils are an important source of TGF-b, it can be hypothesized
that eosinophils can enhance their own migration into the polyp tissue by
regulating the function of fibroblasts. Levels of VEGF, which is important for
inducing angiogenesis and edema, also are increased in NPs, and VEGF
expression is up-regulated further by TGF-b.
A variety of cells in NPs, including epithelial cells, fibroblasts, T cells, and mast
cells, are potent sources of these various cytokines and chemokines, including IL-1,TNF-a, IL-8, GM-CSF, IL-5, RANTES, eotaxin, and thymus and activation-
regulated chemokine (TARC). Each of these cell types may contribute to inflam-
matory cell recruitment and TH2 cell migration into the polyp tissue. Cell-to-cell
interaction may up-regulate further the production of these cytokines and chemo-
kines. Histamine and tryptase from mast cells can up-regulate RANTES production
in epithelial cells. IL-4 and IL-13 from mast cells and T cells act in synergy with
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TNF-a to up-regulate TARC production in epithelial cells and fibroblasts and to
up-regulate VCAM-1 expression in endothelial cells. Eosinophils are an important
source of a variety of these cytokines and chemokines (IL-5, GM-CSF, TNF-a,TGF-b) and are capable of increasing their own survival, activation, and migration
in an autocrine manner. A variety of toxic proteins, like MBP and ECP, that are
released from eosinophils can induce epithelial damage.
Although the presence of atopy does not determine the type of cellular
infiltrate, in atopic individuals with NP, there is an increased expression of the
Fce receptor one (FceRI) in NP mast cells, and this finding is associated with an
increased mediator release, probably contributing to the chronicity and in part to
the tendency for recurrence as reported in allergic rhinitis [65]. In atopic
individuals, the levels of specific IgE were found to be higher in NP tissue ascompared with the levels in serum, which indicates local IgE synthesis (Pawankar
et al, unpublished data, 2002).
Summary
In acute sinusitis, which usually is preceded by viral rhinitis, the key mediators
are proinflammatory cytokines that orchestrate mucosal defense and limit the
infection without major complications. In chronic sinusitis, in addition toproinflammatory cytokines, IL-8 and IL-3 are key cytokines and chemokines
that are up-regulated. IL-8 is a neutrophil chemoattractant, and IL-3, with its
versatile role as a multiple colony-stimulating factor, can contribute to the
obstruction of the sinuses by fibrosis and thickening of the mucosa in the
ostiomeatal complex. Activated mast cells also may have a role as a source of
IL-8 and through the expression of Toll-like receptors (Pawankar et al, unpub-
lished data, 2002). In chronic hyperplastic sinusitis with NPs, tissue eosinophilia
is a prominent feature, and the ongoing inflammation may be explained by an
increased migration of eosinophils or prolonged survival of these cells. Theauthors previously have reported increased mast cells. Their data show that mast
cells can maintain this eosinophilic inflammation as a source of IL-5 and by up-
regulating the production of eotaxin, RANTES, and GM-CSF from epithelial
cells. Eosinophils are potential sources of GM-CSF [66], and mast cells and
migrated eosinophils are potential sources of profibrotic cytokines, which induce
fibrosis and probably contribute to remodeling. The locally produced IgE can
contribute to amplifying mast cell activation by way of the mast-cellIgEIgE-
receptor cascade. Because of the heterogeneous nature of CRS, further studies are
essential to a good understanding of its pathomechanisms.
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