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33.5.11 Allergic Fungal Sinusitis (AFS)
Sometimes, mold living commensally in the
sinuses can cause activation of innate immune
pathways and synergistically evoke robust TH2
lymphocyte and eosinophilic inammatory
responses. Initially, AFS was only attributed to
Aspergillus species, but it is now known that
many fungi species can be associated with AFS,
including Cladosporium, Alternaria, Penicillium,
Curvularia, and Bipolaris [84]. The key feature of
AFS is specic IgE sensitization, which is demonstrated by skin prick tests or serum immunoassays and measurement of increased total serum
IgE concentrations. AFS generally develops in
young, immunocompetent, and atopic subjects
[54]. AFS has some features that distinguish it
from other forms of eosinophilic sinusitis, such as
its often being unilateral and limited to one or a
few sinuses. Dense material lls and expands the
sinuses and can typically be detected with CT
scan [85]. The mucous and inammatory
responses frequently occupy a space in the nasal
cavity and lead to expansion into proximate tissue. This blocks the sinus ostia and subsequently
causes bone absorption with resultant expansion
into the orbits and cranium [86].
33.5.12 Genetics ofAFS
There is only one study that shows a genetic linkage with AFS.In a study of 74 subjects including
44 enrolled with AFS, a weakly signicant association of disease was determined with the MHC
class II allele HLA-DQB1*03 [87], however,
many subjects from the control group had at least
one fungal species in the skin prick test.
Caucasians. There are approximately 80,000
children and young adults with CF in the world.
Genetic and nongenetic factors contributing to
the disease and its variants have been widely
investigated. Though the major gene responsible
for the pathophysiology of CF is the cystic brosis transmembrane conductance regulator
(CFTR) gene, recent research suggests that variations in other so-called modier genes have an
important inuence on phenotypic differences in
this disease. In recent years, multiple candidate
modier genes have been investigated, in particular, genes that are involved in the control of infection, immunity, and inammation [88].
33.6.2 Rationale forCystic Fibrosis
Subjects with CF typically present with the disease in the lungs, sweat gland, pancreas, intestine
(which is especially important during the newborn period), liver, and male reproductive tract
[89]. CFTR controls chloride across the apical
membranes of polarized epithelia [90]. Disruption
in CFTR function inhibits the transport of
sodium, chloride and water across epithelial tissues and so it causes insufcient hydration of
mucous secretions in CF patients. Certain organs
are eventually damaged from/by a blockage in
the luminal space and follow recurrent cycles of
inammation and brosis [89, 91]. Many CF
patients suffer from intestinal malabsorption and
an abnormal nutritional status due to obstruction
of the exocrine pancreas. The major cause of
death in CF patients is complications arising
from obstructive lung disease, a condition that
occurs in approximately 90% of patients [92].
33.6 Genetics ofCystic Fibrosis
andPathophysiology inAirways
33.6.1 Introduction
Cystic brosis (CF) is the most common lethal
autosomal recessive genetic disorder, with a rate
of approximately 1 in 2500 live births among
33.6.3 Genetics andCF
Lung function measurements are notably different among CF patients with identical CFTR genotypes (e.g., F508del homozygotes) [93]. In fact,
an analysis of almost 88,000 patients in the
CFTR2 database showed a low correlation
between CFTR mutations and FEV1. There are
only a few mutations that cause a milder pancre-
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atic phenotype (e.g., p. Arg455Glu) [94, 95]. In
aggregate, these studies show that factors other
than the CFTR genotype affect the progression of
airway obstruction in CF.
Recurrence of complications in affected siblings at rates higher than in unrelated patients
indicates a genetic effect, but care must be taken
to account for the effect of a similar environment
for siblings. A more powerful approach is to
compare monozygous (MZ) and dizygous (DZ)
twin pairs for concordance for qualitative traits
and correlation for quantitative traits. When MZ
pairs show a stronger correlation than DZ pairs
for a clinical feature, it shows that genetic factors
may be responsible [96].
A higher correlation between composite measures of lung function and body mass index (BMI)
was observed in 29 MZ versus 12 DZ twin pairs.
This was the rst twin-based assessment of the
contribution of gene modiers to CF disease severity and suggested genetic control of this trait [97].
Analysis of lung function and weight for height as
independent measures did not show signicant differences between the MZ and DZ twin pairs.
Another comparison of 38 MZ pairs with six
same-sex DZ pairs and 61 same-sex sibling pairs
under 3years of age demonstrated the heritability
of lung function based on FEV1 measurements
ranging from 0.54 to 1.0 [98]. Variance analysis of
231 pairs of affected siblings showed an insignicantly higher estimate of heritability for the FEV1
measures (0.68–1.0) [98]. In aggregate, these studies show that genetic modiers have an essential
role in determining FEV1, a key measure of lung
function, which is correlated with survival.
Collaco etal. recruited 134 MZ twins and 272
DZ twins and siblings when living together and
after moving apart to estimate the relative effect
of genetic and environmental factors on FEV1
among CF patients. Differences in lung function
between MZ twin pairs while living together in
the same house supplied an estimate of the effect
of unique environmental and stochastic contributions. Changing the home environment to independent living was used to assess the effect of a
shared environment. The effect of genetic factors
was estimated by comparing the similarities in
lung function measures in MZ and DZ twin pairs
when living together and subsequently when living apart. These methods showed that genetic and
nongenetic factors had approximately equal
effects on lung function. Analysis of 58 MZ twins
and 568 DZ twins and siblings showed similar
estimates for the genetic and nongenetic contributions to lung function variance [99].
33.6.4 Modier Genes inCF
Two independent studies with more than 500
patients combined showed that more than nine
genes can be involved in modifying some features of the CF phenotype. Several recent studies
provide detailed lists of all the CF-related/modier genes that have been studied thus far [99,
100]. These studies demonstrated the role of vari-
ous modier genes such as MBL2, EDNRA, and
TGF-β1 in lung function; MBL2 in age at rst P.
aeruginosa infection; MSRA in meconium ileus;
TCF7L2 in CF-related diabetes; SERPINA1 in
CF-related liver disease.
Three studies in CF patients showed an earlier
age of infection with Pseudomonas aeruginosa
(Pa) to be related to mannose-binding lectin
(MBL) deciency genotypes. Lung disease severity, which is measured by FEV1 and infection status, is correlated with and two of them are changed
by the age of the patient and by CFTR genotype.
In aggregate, MBL2 genotype was found to be
related to infection status more than the other variables [101]. Hence, decits in MBL causes/can
cause a predisposition to early infection with Pa,
which leads to more severe lung disease than that
observed in patients of the same age and CFTR
genotype but who do not have MBL deciency.
The Genetic Modier Study (GMS), one of
the largest CF genetic modier studies to date,
analyzed 808 F508del homozygotes drawn from
the extremes of lung function (highest 30 percentile and lowest 30 percentile) and reported that
alleles in the promoter (−509) and rst exon
(codon 10) of TGF-b1 are correlated with worse
lung function [102]. This nding was studied in
498 patients with different CFTR genotypes and
was separately conrmed when a haplotype composed of the opposite alleles at −509 and codon
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10 was correlated with improved lung function
[103]. Six studies including over 2500 CF
patients determined a relationship between
TGFb1 and CF lung function (see Table 33.1)
while one study including 118 patients did not
[104] and another involving 171 patients [105]
found a relation between worse lung function and
the opposite alleles than those reported by
Drumm etal. and Bremer etal. [102, 103].
Three SNPs in the highest ranking gene, the
interferon-related developmental regulator 1 gene
(IFRD1), were identied in the whole GMS sample and showed a relationship using transmissionbased methods in the family-based CF Twin and
Sibling Study (TSS) [98]. IFRD1 acts via transcriptional mechanisms to alter neutrophil function in response to bacterial infection, as
demonstrated by cell- and mouse-based studies.
It was demonstrated that variants in the interleukin- 8 (IL-8) gene correlated with lung function. This result supported the idea that
modication of CF lung disease may be caused by
an altered neutrophil response to infection [106].
There are other mechanisms, which seemingly contribute to CF lung pathology as demonstrated by evidence that variants in the
endothelin receptor type A (EDNRA) gene correlate with lung disease severity. Correlation
between a variant in the 3′ untranslated region
of EDNRA was identied in 709 F508del homozygous patients in the GMS study and replicated
in three independent samples of CF patients.
Also, alleles of the EDNRA variant are associated with differences in RNA transcript level,
which indicates a possible functional role.
Given that variation of EDNRA has been implicated in vasoconstrictive diseases as a result of
effects on smooth muscle function, it was
hypothesized that this gene may modulate CF
lung disease by changing smooth muscle tone in
the airways and vascular system [107].
appearing as recurrent sinusitis, rhinitis, and/or
nasal polyposis [108, 109]. The frontal sinuses
seldom develop in these patients, perhaps because
of the early occurring/earlier occurring disorder
of sinusitis which hinders pneumatization [110].
Sinusitis onset and nasal polyposis commonly
occur between 5 and 14years of age, with adult
onset being unusual.
Most patients with CF (over 90%) [111, 112]
develop chronic and recurring rhinosinusitis with
or without nasal polyps. Modied mucus composition and viscoelasticity cause decreased mucociliary clearance and blockage in paranasal sinus
drainage ostia, thereby promoting local inammation, hypoxia and increased carbon dioxide
partial pressure. Mucosal edema generally develops after impaired ciliary function and bacterial
colonization, usually by Staphylococcus aureus
and Pseudomonas aeruginosa [113, 114].
Franco etal. reported a relation between nasosinusal symptoms and cystic brosis. They found
(the?) most common symptoms like cough (45%),
oral breathing (44%), sleep disorders (42%), and
nasal obstruction (37%) in CF patients. Twentyeight patients (28%) had purulent nasal discharge
and 41% had medial bulging of the nasal lateral
Wall [115]. It is reported that nasosinusal involvement may worsen pulmonary disorder [116].
Hence, otorhinolaryngologists should investigate
these patients in more detail for signs of pulmonary diseases. A recent study in Brazil [117] demonstrated more attention to the nasosinusal
ndings of CF patients, because CF is genetically
very heterogeneous, with many types of mutations
and a wide diversity in clinical presentations [118].
ΔF508 homozygosity was found more frequently in the patients undergoing sinus surgery
(58%) compared with a control population (48%)
[119]. Lastly, a study reported that ΔF508 homozygosity was associated with clinical severity of
paranasal sinus diseases and with the presence of
polyps on endoscopy in 113 patients [120].
33.6.5 Cystic Fibrosis andNasal
Findings
Clinical manifestations in the upper airways
(UAW) occur in almost 100% of CF patients,
33.6.6 CF andNasal Polyposis
Nasal polyposis in CF patients was rst described
almost 50 years ago [121] but there is a little
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known about its pathophysiology [122]. The
prevalence of nasal polyposis varies by population [117]. The incidence of nasal polyps has
been observed in 6–48% of cases [123] depending on cystic brosis was diagnosed. Nearly 4%
of patients already have symptomatic nasal polyposis when their diagnosis of CF is established
and it is expected that nearly 14% of patients will
undergo surgical intervention for their nasal
polyp disease [113].
Weber et al. showed that nasal polyps were
estimated in 39.1% of CF patients and, interestingly, all of them were older than 6years of age,
presenting with recurrent pneumonia in 82.6%,
pancreatic insufciency in 87%, and malnutrition
in 74%. No correlation was seen between nasal
polyps and sweat chlorine concentration, genotype, clinical signs of severity, and nasal symptoms. Nasal polyps regressed in seven patients
treated with topical steroids, while six patients
showed complete resolution [124].
Some researchers reported that patients with
nasal polyposis had better pulmonary function,
however a higher rate of Pseudomonas aeruginosa colonization, more hospitalizations, and
more prevalence of allergy to Aspergillus fumigatus than the comparison group. They found no
statistically different genotype distribution
between the group with polyposis and the control
group. But they also emphasized that the prevalence of the compound heterozygous genotype is
higher within the nasal polyposis group than
within controls [113].
33.7 Role ofGenetics inNasal
Polyposis
33.7.1 Introduction
tides, cytokines, and growth factors. These
molecules lead to an extensive network of cellular interactions. In addition, resident structural
cells can synthesize many of these molecules.
Fibroblasts, epithelial cells, and endothelial cells
help to organize the inammatory process in
nasal polyps [126].
Recently, it has been shown that there are proinammatory cytokines such as tumor necrosis
factor-α (TNF-α) and interleukin-1b (IL-1b) in
the epithelial and endothelial cells of nasal polyps. Also, cell adhesion molecules such as very
late antigen-4 (VLA-4) have been found on the
surface of eosinophils, while integrins such as
vascular cell adhesion molecule-1 (VCAM-1)
have been shown on the surface of the small
venules of the nasal polyp. Lastly, the presence of
chemokines such as regulated upon activation of
normal T cell expressed and secreted (RANTES),
eotaxin, and IL-8in the epithelium of the nasal
polyps has been determined.
The nasal polyp tissue and the nasal mucosa
have a sufcient collection of inammatory molecules to combat efciently against different
agents such as allergens, bacteria, fungi, chemical particles, and viruses that come into the nose
from the external environment. One of the most
signicant cells to offer an immune response may
be the lymphocyte subpopulations. The percentages of TH1 lymphocytes (which produce IL-2
and interferon-α [INF- α]) and TH2 lymphocytes
(which produce IL-4 and IL-5 cytokines) in the
nasal pharyngeal tonsillar lymphocytes and
peripheral blood lymphocytes have been determined in patients with nasal polyposis [127].
These same researchers have described the lymphocyte subpopulations and cytokines in nasal
polyps [128].
The nasal polyp is one of the nal manifestations
of chronic inammation. Nasal polyposis is a
chronic inammatory disorder of the upper
respiratory tract that 1–4% of the human population suffers from [125]. The lamina propria of
nasal polyps usually presents great numbers of
eosinophils and lymphocytes. In chronic inammation, inammatory cells produce neuropep-
33.7.2 Mucosal Irritation
andtheRole
ofStaphylococcal Exotoxin
As the nasal polyp symbolizes a nal point in
chronic inammation, it is difcult to describe
the initial events that trigger the inammatory
process in the lateral wall of the nose. Some
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substances, such as allergens, bacteria, viruses,
air pollutants, and fungal elements, enter the submucosa of the lateral wall of the nose and damage the airway epithelium. These irritants lead to
changes in some of the possible modications of
the respiratory epithelium that may take place
after the entrance of these particles. These
changes include the following: rst, the synthesis
of inammatory eicosanoids, which are potent
cell activators and chemoattractants; second, proinammatory cytokines such as TNF-α and IL-1,
which have major effects on growth, differentiation, migration, and activation of inammatory
cells; and, third, specic cell adhesion molecules,
which have an essential role in managing the
inammatory cell. Lastly, major histocompatibility class II antigens have a crucial role in antigen
presentation to T cells [129] and are also responsible for consequent activation of T cells.
Figure33.2 shows the possible changes in respiratory epithelium after the entrance of bacteria,
viruses, allergens, and fungal elements.
Various cytokine subtypes are produced by the
stimulation of epithelial cells by these elements.
Shortly after exposure, activation of specic
inammatory cells occurs. Hence, the early
growth of nasal polyposis may be the effect of
stimulation of the epithelium by allowing irritants to change or damage the surface epithelium
metabolically or physically. A cascade of inammatory alterations takes place after this surface
epithelium is damaged (Fig.33.2).
A superantigen concept for massive nasal polyposis has been postulated. S. aureus is the most
common bacterial species found in the nasal
mucus. It has been shown in different studies that
these bacteria synthesize exotoxins and that the
corresponding variable-β region of the T cell
receptor is also upregulated in polyp lymphocytes [130]. Based on these results, it is postulated that toxin-producing Staphylococci cause
preliminary damage to the lateral wall of the
nose. These exotoxins can act as superantigens,
which lead to the proliferation of lymphocytes,
which in turn synthesize cytokines that are associated with the massive proliferation of inammatory cells that are observed in massive nasal
polyposis.
Fig. 33.2 Schematic presentation of epithelial damage in nasal polyp
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33.7.3 Proinammatory Cytokines
Produced inNasal Polyps
TNF-α and IL-1β cytokines play a role in the
second process involved in the development of
nasal polyposis after the initial mucosal irritation. The basic function of these two cytokines in
the upregulation of endothelial adhesion molecules implicated in inammatory reactions.
TNF-α and IL-1β increase the production of
endothelial adhesion molecules such as intracellular cell adhesion molecule-1 (ICAM-1) and
VCAM-1. It has lately been shown by invitro
studies and animal experiments that certain
adhesion molecules are important for adherence
of eosinophils to endothelium and their subsequent extravasations.
Eotaxin and RANTES, which are cysteine/
cysteine chemokines, attract and stimulate eosinophils invitro and direct eosinophils into inammatory lesions. There is strong evidence
supporting the hypothesis that cytokines released
from activated CD4 T cells mostly account for
the restricted accumulation and activation of
eosinophils in allergy-related disorders. It has
been reported that these T cells produce some
cytokines such as IL-4 and IL-13, which are also
known as TH2 cytokines. These cytokines play a
role in favored extravasations of eosinophils
through selective stimulation of VCAM-1 and
IL-5. Also, granulocyte-macrophage colonystimulating factor (GM-CSF) and IL-3 are essential for eosinophil activation and survival [131].
However, many studies propose that TH1 cells are
the main cells in nasal polyps and their release of
INF-γ and IL-2 are highly present in nasal polyps. Thus, the recruitment of eosinophils may be
linked to both TH1 and TH2 cytokines [132].
The specic localization of the eosinophil
onto the vascular endothelial surface of the nasal
polyp occurs due to the interaction of VLA-4 on
eosinophils and VCAM-1 on venule endothelial
cells. Eosinophil migration occurs within the
nasal polyp venules after blood ow slowing
down, and the subsequent transepithelial migration of these eosinophilic cells into the lamina
propria of the nasal polyp occurs via the inu-
ence of chemokines such as RANTES and
eotaxin. One study suggests that the eosinophil is
the main cell in the nasal polyp, where eosinophils constitute up to 80% of the inammatory
cells [133].
Lymphocytes are enormously widespread
cells accompanied by eosinophils found in the
lamina propria of the nasal polyp. It is believed
that protracted survival of these cells occurs via
the autocrine upregulation of cytokines within
the lamina propria of the nasal polyp. For
instance, at least three cytokines (IL-3, GM-CSF,
IL-5) are shown to decrease the apoptosis of
eosinophils [134]. They have an impact on the
long-term survival of eosinophils and their activation. Among these, IL-5 appears to have the
most powerful effect in increasing the survival of
eosinophils in the nasal polyp. Also, it was determined that the eosinophil itself can react by producing similar cytokines in an autocrine
upregulation pattern. This vicious cycle of autocrine upregulation increases the recruitment of
more eosinophils into the nasal polyp so that the
chronic inammatory state of eosinophils is
extended.
33.7.4 Eosinophils
andElectrophysiology
ofRespiratory Surface
Epithelium
Airway mucus secretion is stimulated by eosinophilic cationic protein and inhibited by eosinophilic major basic protein (MBP) [135]. Just over
a decade ago, Jacoby and colleagues (1988)
showed that MBP increased net chloride secretion [136]. Also, MBP signicantly facilitates
sodium ux into the epithelial cell. Although
there was a large change of chloride in and out of
the cell, the net ux of chloride was not clearly
determined. Finally, the short-circuit current
seemed to be increased signicantly with MBP
compared with the control group.
One of the potential new strategies for the
management of nasal polyps is based on the
effect of amiloride and other sodium channel
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blocking agents (such as furosemide) on water
movement into and out of nasal mucosa.
Amiloride notably reduced sodium absorption
and the short-circuit current. Hence, amiloride
or furosemide may be useful as topical agents
that could reduce sodium absorption into the
cell and thereby reduce cellular and subcellular
edema. It is approved by the ndings from the
bioelectric studies suggesting that nasal polyp
epithelial cells have a normal luminal chloride
channel which was controlled by increased
chloride permeability after isoproterenol administration. Amiloride caused a larger decrement
in sodium absorption in nasal polyp cells than in
cells from the inferior turbinate mucosa.
Amiloride is a specic blocker of the apical
sodium channel and reduces the basal voltage
and basal short-circuit current. These results
show that sodium absorption may be increased
in nasal polyps.
The mediators such as MBP produced by
inammatory cells of nasal polyps may increase
sodium absorption, which could cause water
retention in the epithelium of the lamina propria
of polyps. The efcacy of corticosteroid treatment for nasal polyps depends on the inhibition
of the synthesis of multiple cytokines. Decreased
expression of the CFTR protein in remodeled
human nasal epithelium from non-CF patients
was demonstrated [137]. In normal adult pseudostratied human nasal surface epithelium, the
CFTR is localized to the apical domain of the
ciliated cells, whereas in CF, the mutated DF 508
CFTR gene causes an abnormal cytoplasmic
location of the CFTR protein. Airway epithelial
damage, in CF or non-CF patients, may induce a
remodeling of the surface epithelium characterized by a change in the morphologic structure
from normal columnar pseudostratied to basal
hyperplasia, mucus cell hyperplasia, or squamous metaplasia. These histological ndings are
found in human polyp epithelium in the non-CF
patient. Thus, abnormally low expression of the
CFTR protein not only may be caused by the
CFTR gene mutation in CF but also may be associated with airway surface epithelial differentiation and remodeling as occurring in nasal polyps
from non-CF patients.
33.7.5 Medical Treatment
ofChronic Rhinosinusitis
withMassive Nasal Polyposis
Based ontheMolecular
Biology ofInammation
Patients with CRS and massive nasal polyposis
typically have eosinophilic and lymphocytic
inltration in the lateral wall of the nose. In the
phases of inammation, there is a complex interaction between cytokine molecules. It gives rise
to increased numbers and survival of eosinophils
and lymphocytes in the nose. Hence, a rational
approach to the medical treatment of this chronic
inammatory disorder can be properly achieved
only after a complete understanding of the cytokine network (Table33.3).
The major pathologic aspect of CRS with and
without nasal polyposis is chronic inammation.
Hence, the application of specic antiinammatory drugs such as corticosteroids,
which are the most commonly utilized drugs in
the treatment of CRS, particularly with nasal polyposis, is useful. Antileukotriene therapy has also
been found useful in the management of nasal
polyposis. This drug may be especially effective
in the aspirin-sensitive patient who has CRS with
nasal polyposis.
Erythromycin and clarithromycin have prominent effects against neutrophils and some inammatory cytokines, and interest in the potential
anti-inammatory effects of macrolide antibiotics has increased in the last 50years. However,
there are many reports of increasing bacterial
resistance to macrolides for many signicant species that specically cause upper respiratory tract
infection.
Microorganisms can stick on various surfaces
and shape a three-dimensional constitution
known as biolm. After a biolm has been
formed on the mucosal surface, the bacteria har-
Table 33.3 Inammation changes in different CRS
subtype
CRS with NP CRS without NP
TGF-β1 ↑
T
↑
reg
Edema
TH2 +
TH2 −
TGF-β1↑↑↑↑
T
↑↑↑↑
reg
Fibrosis
TH1
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bored in the biolm are less exposed to the
immune response and less vulnerable to antibiotics. One study mentions that the use of furosemide and amiloride was found to be valuable in
the postoperative treatment of CRS with nasal
polyposis [138].
Anti-IgE therapy is a compelling new therapeutic molecule for the neutralization of IgE and
the inhibition of IgE synthesis [139]. Monoclonal
anti-IgE therapy may be a logical approach in the
treatment of chronic hyperplastic sinusitis when
allergy is a major factor in a patient with IgEmediated hypersensitivity.
33.8 Vasomotor Rhinitis andIts
Genetic Background
M. Gunduz et al.
Fig. 33.3 Possible mechanism of VMR
33.8.1 Introduction
Rhinitis is an inammation of the nasal area and
generally characterized by rhinorrhea, nasal congestion, sneezing, and/or nasal itching [140]. It is
classied into subtypes of allergic, nonallergic,
occupational, hormonal (pregnancy and hypothyroidism), drug induced, and food ingestion
induced [141]. Vasomotor rhinitis (VMR) is the
most common type of chronic nonallergic rhinitis
(NAR). Millions of people suffer from vasomotor
rhinitis and it causes uncomfortable symptomatology. VMR is an idiopathic condition diagnosed after exclusion of infection, allergy,
eosinophilia, hormonal changes (such as pregnancy), and exposure to drugs. Hence, sometimes
scientists have described it as a “wastebasket
diagnosis” [142, 143].
Certain odors, alcohol, spicy foods, emotions,
and environmental factors such as temperature,
barometric pressure changes, and bright lights
exacerbate these symptoms [144] (Fig. 33.3).
Allergic and nonallergic rhinitis have notably
overlapping symptoms, but the causes appear to
be entirely different [144].
Skin testing or invitro tests for allergen- specic
IgE are usually used for allergic rhinitis (AR) or
VMR diagnosis. Also, a patient may have both
allergic and nonallergic components and this is
named “mixed rhinitis.” These patients must be
recognized properly because positive testing for a
specic allergen may cause the clinician to ignore
the role and management of non- allergic factors.
33.8.2 Epidemiology
Approximately 19 million people suffer from
NAR in the United States and a further 26 million
experience mixed rhinitis.
33.8.3 Pathophysiology ofVMR
Several hypotheses have been suggested for the
pathophysiology of VMR.
33.8.3.1 Trauma
Surgical and nonsurgical trauma has been
accounted to cause VMR as a long-term
complication.
33.8.3.2 Autonomic Dysfunction
Patients with vasomotor rhinitis are clinically separated into two subgroups: “runners,” who present
“wet” rhinorrhea, and “dry” patients, who show
nasal obstruction and airow resistance with minimal rhinorrhea. Many researchers have endeavored to explain the pathogenic mechanisms for
these subgroups. An imbalance in the autonomic
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input to the nasal mucosa has been held responsible for VMR since the 1950s. Recent theories postulate that increased cholinergic glandular
secretory activity is responsible for runners, while
nociceptive neurons with increased sensitivity to
generally innocent stimuli are responsible for dry
patients. Recent studies have suggested that VMR
is due to a hypoactive sympathetic nervous system
rather than a hyperactive parasympathetic system
[145]. There are some factors that trigger symptoms of VMR such as changes in temperature or
humidity, smoke, alcohol, odors, perfumes, sexual
arousal, and emotional factors [143]. A study
determined nasal hyperreactivity to cold air using
anterior rhinomanometry [146]. Numata et al.
determined nasal hyperreactivity to histamine
using acoustic rhinometry [147].
33.8.3.3 Cytokines andVMR
Chen etal. showed that there were no signicant
differences in levels of IL-10, IL-13, or IL-16
between vasomotor rhinitis and normal controls.
But the level of IL-12in vasomotor rhinitis was
lower than that of normal controls. Further
research is needed on the role of IL-12in vasomotor rhinitis [148].
33.8.3.4 Light andElectron
Microscopic Findings
Giannessi etal. recently studied microscopic and
ultrastructural alterations in the nasal mucosa of
VMR patients [149]. VMR patients who underwent inferior turbinate reduction showed abnormal epithelium in 80–90% of the nasal surface
with light microscopy. They observed decreases
in epithelial thickness and loss of ciliated and
goblet cells on the nasal surface. Also, ultrastructural studies supported light microscopic ndings. They detected ciliary loss, lack of tight
junctions, loss of vibratile cilia, loss of goblet
cells and ciliated cells, and a marked expansion
of the intercellular spaces.
VMR.Stimulation of nasal sensory nerves caused
sensations of pain and stufness. Type C nociceptive nerves synthesize some neuropeptides such
as substance P (SP) and calcitonin gene- related
peptides, and it increased plasma extravasation
and glandular secretion. Groneberg et al. [151]
studied the neuropeptide content of mucosal parasympathetic, sympathetic, and sensory nerves of
patients with toxic rhinitis caused by chronic cigarette smoke exposure. They measured concentrations of calcitonin gene-related peptides, SP,
vasoactive intestinal peptide, and neuropeptide
tyrosine (NPY) and determined signicantly
increased concentrations of vasoactive intestinal
peptide and NPY in the nasal mucosa of toxic
rhinitis compared with normal subjects. Also, the
level of SP expression was increased. SP is generally distributed in nerve bers near submucosal
glands and blood vessels, whereas NPY is found
near submucosal blood vessels. SP has many
functions in the body such as increasing plasma
extravasation, glandular secretion vasodilatation,
and mucociliary clearance. Vasoactive intestinal
peptide (VIP) is a neurotransmitter that has a role
in the inhibitory noncholinergic airway nervous
system and it always dilates bronchus and vasculature. Increased levels of VIP may lead to hypersecretion. Groneberg etal. (2003) postulated that
a separate subclass of nerves might be responsible
for the pathophysiology of toxic rhinitis and that
major changes in the content of mucosal nerves
occur in toxic rhinitis [151].
Schierhorn et al. (2002) investigated ozoneinduced releases of SP and neurokinin A, and
ozone stimulation was found to increase SP and
neurokinin A levels [152]. Also, it was reported
that the ozone-induced increase in neuropeptides
in allergic patients was higher as compared with
nonallergic patients. Ozone might increase sensory nerve activity in the upper airways and as a
result increase neuropeptide release in the upper
airways.
33.8.3.5 Neuropeptides
Some scientists have investigated the neurogenic
and molecular mechanisms of VMR. Tai and
Baraniuk [150] suggest that sensory nerve endings and autonomic dysfunction have a role in
33.8.3.6 Nitric Oxide
The function of nitric oxide (NO) in the pathogenesis of VMR was studied by Giannessi etal.
(2003) and by Ruffoli etal. (2000) [149, 153].
Three isoforms of NOS have been shown in the
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human nasal mucosa. Nicotinamide adenine
dinucleotide phosphate (NADPH) is used by all
isoforms of NOS as a cofactor. Hence, NADPHdiaphorase histochemistry is used to investigate
NOS in tissues. The damaged epithelium containing cells with marked reactivity to NADPHdiaphorase was found in the nasal respiratory
epithelium in VMR by Giannessi et al. [149].
Basal cells in VMR presented strong NADPHdiaphorase activity, while NOS activity was negative in basal cells of normal subjects.
NO is known to have cytostatic and cytotoxic
effects against microbes and cancer cells.
Inducible NOS stimulation could synthesize a
high degree of NO, and it could cause decreased
viability of normal tissue and necrosis. Highlevel NOS expression in the nasal epithelium
could lead to a constant high level of NO and
result in constant epithelial damage. This has
been postulated as one of the possible pathogeneses of VMR.Repression of mucociliary clearance decreased the number of tight junctions, and
disruption in the basement membrane continuities might permit environmental agents to interact directly with the subepithelial structures.
Consequently, symptomatic VMR is caused by
increased responsiveness to the afferent trigeminal bers, and recruitment of secretory and vascular reexes could occur in the nasal respiratory
mucosa.
Cervin et al. (1999) studied the functional
effects of NPY receptors on blood ow and NO
concentrations in the human nose by using dosedependent effects of the intranasal application of
NPY [154]. They showed that application of
NPY leads to vasoconstriction and a decrease in
NO levels. Braat etal. (2002) showed that pollution and meteorologic factors are linked with the
severity of symptoms in VMR patients [155].
They determined that minimum daily temperature and the levels of ozone and NO had the highest association with the severity of symptoms.
33.8.3.7 Nasal Secretory Proteins
The protein analysis of nasal washes to differentiate VMR from other forms of rhinitis was studied
by Iguchi et al. (2002) and Tosun et al. (2002)
[156, 157]. Iguchi etal. (2002) investigated con-
trol, VMR, and perennial AR subjects [156]. The
total protein and albumin level in AR was higher
than the total protein and albumin level in NAR
(P<0.01 for both). It is shown that the difference
in total protein and albumin concentration between
normal control subjects and NAR was also statistically signicant (P<0.05 for both). The control
subjects had the lowest total protein and albumin
levels in their nasal lavage. They also found a protein with a molecular weight of 26kDa. The identity of this protein has not been determined yet, but
it is believed to derive from the nasal glands since
its secretion can be provoked in normal volunteers
with pilocarpine nasal spray. The average level of
this protein was signicantly higher in AR subjects
compared with control subjects (P < 0.01) and
NAR subjects (P<0.05). The level of the 26-kDa
protein in NAR was higher than in control subjects
but it was not statistically signicant. It is suggested that increased vascular permeability led to
increased albumin concentration in nasal discharge. The level of the 26-kDa protein is therefore enhanced due to increased gland secretion. In
the NAR group, vascular permeability may have
been increased over control subjects, but gland
secretion was minimal, and the 26-kDa protein
level remained low. Hence, the presence of the
26-kDa protein can be used to distinguish AR
from NAR.
The gel electrophoretic assessments of proteins in nasal washings of patients with AR and
VMR were studied [157]. The average total level
of proteins, 66-kDa proteins, and 26-kDa proteins was determined to be higher in AR compared with those from VMR.The lowest rate of
these proteins was seen in the control group. The
differences in the mean concentration of proteins
in AR, VMR, and control groups were statistically signicant (P<0.05).
Aust etal. (1997) studied the gene expression
of eight types of mucin in control and vasomotor
inferior turbinates, and the only difference
observed between normal and VMR turbinates
was a minor decrease in mucin 1, transmembrane
(MUC 1) gene expression in the vasomotor group
[158]. They suggested whether this decrease
could begin abnormal neurogenic signals that
lead to an increase in nasal secretions in VMR.
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