Download Allergic Rhinitis

Special Issue on
Allergic Rhinitis
Volume V, Issue III
July-August 2015
Chest Research Foundation Bulletin, Pune - India
Allergic Rhinitis: Diagnostic and Therapeutic Implications
A
llergic rhinitis (AR) is a potentially
debilitating condition that globally
affects individuals from all age
groups. As recently reported by the World
Allergy Organization, AR prevalence rates are
increasing worldwide, and this condition affects
an estimated 10-30% of the global population.
Recent data published by Kubavat and also by
the International Study of Asthma and Allergies
in Childhood (ISAAC) suggest that AR has an
estimated prevalence between 10-13% in India.
Since AR is an independent risk factor for
developing asthma, it is extremely important
to raise physician awareness regarding AR,
especially the need to promptly diagnose and
effectively manage this condition.
In order to recognize and effectively manage
the heterogeneous clinical manifestations of
AR, we must first understand the complex
pathophysiology underlying this condition.
AR pathophysiologic mechanisms revolve
around allergen-induced sensitization and
the associated pro-inflammatory responses
mediated by Th2 cytokines as well as key
effectors cells (e.g. mast cells, basophils, T
cells, eosinophils). Allergens are taken up and
processed by antigen presenting cells (APCs),
which are found on the nasal mucosal surface.
Peptides from the allergens are presented by
the APCs through major histocompatibility
complex (MHC) class II molecules. MHC class
II molecules, in combination with the antigen
complex, serve as a ligand for T-cell receptors
on CD4+ T cells. Once stimulated, CD4+ T
cells differentiate into allergen-specific Th2
cells, which may produce pro-allergic (IL-4, IL5, IL-13) cytokines. These cytokines collectively
enhance IgE production by B cells as well
as eosinophil activation and recruitment.
Antigen-specific IgE binds to high-affinity
FcεR1 receptors on mast cells and/or basophils.
Antigen cross-linking of bound IgE results in
mast cell and/or basophil degranulation and
the release of inflammatory mediators (e.g.
histamine), thereby contributing to the clinical
symptoms associated with AR.
The clinical evaluation of AR is primarily
based on detailed history taking, physical
examination, and allergy testing. A thorough
medical history can help to identify symptoms
that are likely due to AR and to ascertain
potential triggers. In considering a diagnosis
of AR, clinicians should consider the
development/onset/temporality of symptoms
Sunit P. Jariwala
Director of Allergy/Immunology Research,
Albert Einstein College of Medicine and
Montefiore Medical Center, Bronx, NY, USA
(especially seasonal versus perennial),
precipitating and/or aggravating factors,
medication history, family history, social and
occupational history, and the impact of AR
on the patient’s quality of life. AR commonly
presents with nonspecific symptoms including
sneezing, nasal congestion, nasal pruritus,
anosmia, and/or rhinorrhea. A history of
seasonal (i.e. during specific seasons) or
perennial (i.e. year round) symptoms may
help elucidate potential environmental
triggers. For example, common seasonal
allergens may include mold spores as well as
pollens from weeds, grass, and trees. Perennial
allergens include cockroaches, dust mites, pet
dander, and mold spores (can persist year
round in unusually warm climates). Physical
examination may identify “allergic shiners”,
the “nasal crease”, pale and swollen blue-gray
nasal mucosa, and/or Dennie-Morgan lines.
Clinicians must also note findings that reflect
systemic diseases associated with rhinitis and/
or conditions that may mimic AR.
In evaluating patients with suspected
AR, clinicians must consider other possible
diagnoses that may have similar clinical
findings. For example, one must consider
anatomic abnormalities, ciliary dysfunction,
nasal polyps (commonly co-exist in the setting
of AR), nasal septal deviation, tumors, nasal
turbinate or adenoidal hypertrophy, systemic
conditions (e.g. vasculitis, sarcoidosis),
and cerebrospinal fluid (CSF) rhinorrhea.
Clinicians must also consider nonallergic (i.e.
not IgE-mediated) rhinitis, which may present
similarly to AR. Examples of nonallergic
rhinitis include vasomotor rhinitis, gustatory
rhinitis, infectious rhinitis, nonallergic
rhinitis with eosinophilia syndrome (NARES),
occupational rhinitis, hormonal rhinitis (e.g.
hypothyroidism-induced),
drug-induced
rhinitis (including rhinitis medicamentosa),
and atrophic rhinitis.
In order to determine specific allergic
triggers and to confirm the diagnosis of AR,
clinicians may perform allergy testing. The
most commonly utilized methods to evaluate
for allergies in the setting of suspected AR
include allergy skin testing (immediate
hypersensitivity testing) in vivo and specific
IgE testing in vitro. Since allergenic pollen
types vary between ecozones, physicians in a
given region must be aware of the predominant
allergy-causing pollen in that area. For each
geographic location, allergy testing panels
and immunotherapy can be tailored based
on the main pollen types. In light of the wide
geographic diversity in India, predominant
allergenic pollen types have been extensively
characterized for each region. Based on the
allergy test results, environmental control
measures can be performed and allergen
immunotherapy may be considered. Patients
with negative allergy testing and a clinical
history strongly suggestive of AR might be
evaluated for local allergic rhinitis (LAR),
which is characterized by the local production
of specific IgE and the absence of systemic
atopy. To accurately diagnose LAR, a nasal
allergen provocation test can help to identify
the allergens causing the symptoms.
In patients that are refractory to standard
medical therapy, specialized testing such as
imaging and endoscopy may be considered.
For example, radiographic studies may help
to evaluate for structural abnormalities and/or
>>Continued on page 2
|Volume V, Issue III, July-August 2015|RespiMirror 1
>>Continued from page 1 Allergic Rhinitis: Diagnostic......
comorbid conditions (e.g. adenoid hypertrophy,
sinusitis). A computed tomography (CT)
scan of the sinuses is more sensitive and
specific than conventional radiography in
the evaluation of sinusitis. Sinus CT may also
help to identify septal abnormalities and nasal
polyps. In the setting of complicated sinusitis
and/or suspected comorbid conditions,
rhinolaryngoscopy may be performed.
AR management strategies include
environmental control, pharmacotherapy,
and allergen immunotherapy. Once potential
environmental triggers are identified following
history taking and/or allergy testing, patients
may be advised to avoid allergens such
as dust mites or pet dander. For example,
recommended dust mite avoidance strategies
may include dust mite encasings for bedding,
humidity control, and high-efficiency
particulate air (HEPA) vacuuming of carpet;
multiple interventions are recommended over
isolated interventions. Possible medication
options include oral antihistamines (secondgeneration are preferred over first-generation),
oral antihistamines used in combination
with decongestants, intranasal mast cell
stabilizers (e.g. cromolyn), intranasal
antihistamines, intranasal corticosteroids,
intranasal anticholinergics (may reduce
rhinorrhea, but are usually not effective for
other nasal symptoms) intranasal antihistamine
combined with intranasal corticosteroid,
leukotriene receptor antagonists, and nasal
saline. In most cases of AR, intranasal steroids
are typically considered as first-line therapy
and are not typically associated with systemic
side effects. However, intranasal steroids must
be used with extreme caution in the setting
of epistaxis and glaucoma (in this setting,
intraocular pressure must be monitored by
an ophthalmologist).
A brief course of oral corticosteroid therapy
may be prescribed in the setting of severe
nasal symptoms and/or when nasal polyps are
present. Omalizumab has been shown to be
effective in allergic rhinitis, but in the United
States is presently only approved for allergic
asthma and chronic urticaria.
With increasing worldwide prevalence
rates, AR is often under diagnosed and
undertreated. AR and its comorbid conditions
may significantly impact an individual’s quality
of life, school/work performance, and social
interactions. In order to prevent the potentially
devastating complications of AR, effective
management strategies must include patient
education, targeted environmental control
measures, pharmacotherapy, and considering
allergen immunotherapy in the appropriate
setting. Refractory AR cases must be further
investigated for potential masquerading
conditions with prompt referrals for imaging
and/or specialized evaluations (e.g. endoscopy)
when indicated. Further AR research is
necessary in order to enhance the available
diagnostic and treatment modalities with
hopes of improving disease-related quality of
life and offering cost-effective medical care.
Red Blood Cells
RBCs are the most
abundant blood cells which
are produced in the bone marrow by
hemocytoblasts. They have a unique biconcave
shape which helps them to accommodate
more hemoglobin and therefore, transport
oxygen more efficiently. Due to absence
of nuclei(because they want to utilize that
space for packing hemoglobin)RBCs do not
replicate andtheir life span is around 120
days after which they are degraded in the
spleen. RBC’s comprise 99% of the circulating
blood cells.
RBC production is regulated by the
kidneys. When the level of oxygen in the
blood is reduced, kidneys secrete the hormone
erythropoietin (EPO). EPO travels from the
kidney to the bone marrow where, it binds to
its receptors on the stem cells (hemocytoblast)
and stimulate them to produce RBC’s.
Prenatally the liver is the primary site of EPO
synthesis and the production is switched to
the kidneys around birth. People with kidney
failure become anemic because the kidneys
no longer make enough EPO to stimulate red
blood cell production.
Secondary polycythemia is mostly due to
increased erythropoietin (EPO) production
either in response to chronic hypoxia or
from an erythropoietin secreting tumor.
Polycythemia in COPD is the body’s attempt
to adjust to decreased levels of blood oxygen
by increasing the production of red blood cells.
While this may be useful in the short term,
overproduction eventually clogs small blood
vessels.
Apart from their role in transporting
oxygen, RBC’s are also a major storage site
for glucose in the body, which is circulating all
the time. It stores more glucose than the liver.
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RespiMirror|Volume V, Issue III, July-August 2015|
CAT
About 93% of the glucose
is located in plasma
and 7% of the glucose
in the red blood cells
Mr. Nitin Vanjare
DOG
About 87.5 % of the
glucose is located in
plasma and 12.5%
of the glucose in the
red blood cells
HUMAN
About 58 % of the
glucose is located in
plasma and 42 % of
the glucose in the
red blood cells
The human body produces
~2.4 million red blood cells per
second. Under stress this
number can increase by 7 times
The cumulative surface area
of all the RBC’s in the human
body is roughly around 2,000
times as that of the body’s
exterior surface.
One drop of blood consists of
around 500,000 RBC’s
RBC’s contain Hemoglobin
as the main transporter of
oxygen. The total amount of
Hb present in the RBC’s is
750 gms (3/4th of a Kg)
RBC’s travel from the heart
through the body and back
to the heart in merely
20 to 60 seconds.
Each red blood cell contains
about 280 million hemoglobin
molecules
Nose and nasal physiology & Rhino Manometry
Dr Rahul Kodgule
Chest Research Foundation, Pune
Himesh Reshamiya – “The nose does matter”
Listening to the famous hindi song “O
Bavariya” by Himesh Reshamiya makes
one realize how much a nose can affect our
lives. Nasal physiology and anatomy plays
a big role in the respiratory and olfactory
function. Nasal symptoms are highly prevalent
and by themselves can hamper our daily
activities. Knowledge of nasal physiology and
anatomy can be helpful in understanding the
contribution of nose in effective and defective
functioning of respiration.
Nasal Cycle
Eye sockets
Upper turbinate
Middle turbinate
Shaded areas
of congestion
Maxillary sinus
Lower turbinate
Nasal septum
Protection:
Performing the role of door-keeper, the
nose provides a “gate-pass” for air entry in the
lungs. In order to ensure proper functioning of
the muco-ciliary system and gas transfer in the
lower airways, the air is required to be clean,
warm and humid. Particles larger than 3µm
which largely included particulate pollutants
are trapped by nasal vibrissae. Particles between
0.5µm to 3µm usually consist of pathogens that
are dealt mainly by the muco-ciliary system.
The goblet cells in nasal mucosa secrete a
mucus blanket which is moved backwards
towards nasopharynx like a conveyer belt by
the cilia. Proteins secreted in the mucus further
ensure destruction of the pathogens. Particles
<0.5µm can travel all the way towards smaller
airways and alveoli.
Thermo-regulation:
Nose is also called as “the air-conditioner”
for the lungs. The surface area of the nasal
mucosa is large particularly in the region of
middle and inferior turbinates and the adjacent
parts of the septum and is highly vascular with
cavernous venous spaces. This creates an
effective “radiator” effect leading to warming
up of cold air. The nose has an unbelievable
Turbinates
(Shelves)
Tip
of
Nose
Adenoid
Area
Nostril
Tongue
Throat
Palate
Teeth
Decongeated
Side
Congeated
Side
capacity to warm inhaled air from subzero
temperature to near body temperature in just
0.25 seconds. Interestingly hot air is also cooled
to body temperature.
Humidification:
The typical aero-dynamics of the nose
leads to crowding of air in the narrow portion
of the upper airway ensuring close
contact between the airstream and mucosal
surfaces. Rich blood supply keeps the mucosal
surface extremely moist. Evaporation of the
mucosal moisture leads to rapid humidification
of inhaled air up to 75-80%. Adults condition
more than 14,000 litres of air every day,
using approximately 20% of our daily water
intake.
Nasal cycle, why do we have two nostrils?:
Like the shifts of factory workers, each side
of the nose shifts functioning with the other.
The autonomic nerve supply creates cyclical
congestion and decongestion of each nasal side
leading to periodic turbinate hypertrophy and
unilateral nasal obstruction. This obstruction
lasts for about 2-4 hours.
Nasal resistance:
50% of the total airway resistance is
contributed by nasal resistance. Nasal resistance
plays an important role in maintaining the
elasticity of the lungs. Prolonged mouth
breathing may lead to areas of atelectasis and
poor ventilation. Increased nasal resistance
can also be conducive to emphysema. Common
factors that can reduce nasal resistance are
exercise, sympathomimetics, rebreathing,
atrophic rhinitis and erect posture. On the
other hand, nasal resistance can be increased
by causes like infective/allergic rhinitis,
vasomotor rhinitis, hyperventilation, supine
posture, alcohol, aspirin and cold air.
Measuring nasal obstruction:
Nasal obstruction can be measured and
monitored using several methods. Nasal
inspiratory peak flow measurements are
quite useful for home monitoring of nasal
obstruction. The inspiratory peak flow
meter is relatively inexpensive, portable
and easy to use. The most sensitive method
is rhinomanometry and is specific for nasal
measurements. However, rhinomanometer
is relatively expensive, requires technician
training and patient co-operation and
hence, can be conducted only in the clinics.
Acoustic rhinomanometry is relatively easier
for the patients to perform and is quite
repeatable.
Rhinomanometry:
Rhinomanometry measures the pressure
and flow of inspired or expired air through
the nose and estimates nasal resistance. The
measurements can be made for one nostril
(anterior rhinomanometry) or both the
nostrils (posterior rhinomanometry). Anterior
rhinomanometry is relatively easy to perform
and is hence most widely used. The pressure
sensing tube is placed in one nostril and the
other one is left open. The subject then blows
through the nose in the rhinomanometer
and nasal resistance is measured. It can be
repeated after a decongestant spray. If the
spray significantly reduces the resistance,
that suggests nasal congestion as cause of
symptoms. However, if the decongestant
does not reduce the resistance, anatomical
abnormality like nasal deformity or bone or
cartilage within nasal cavity is suspected.
|Volume V, Issue III, July-August 2015|RespiMirror 3
Management of Allergic Rhinitis –
Does surgery have a role?
Prof. Mohan Kameswaran
Senior Consultant ENT Surgeon, Madras ENT Research Foundation, Chennai
Allergic rhinitis (AR) results from an IgE
mediated hypersensitivity reaction of the nasal
mucosa to inhaled allergens and represents a
global health issue affecting between 10% to
25% of the world population. Allergic rhinitis is
characterized by nasal obstruction, watery nasal
discharge, itching and sneezing. Additional
associated symptoms include headache,
impairment of smell and eye irritation. The
prevalence of AR is increasing, resulting in
multiple co-morbidities, causing a significant
impact on quality of life.
Management guidelines include avoidance
of relevant allergens and triggers (house dust,
dust mites, cigarette smoke, air pollution and
seasonal pollens), pharmacotherapy such as
topical nasal steroids, systemic antihistamines,
topical
antihistamines,
decongestants,
leukotriene receptor antagonists and nasal
saline formulations. However, in some patients,
these medications are not effective or may result
in significant side effects. Immunotherapy can
be recommended in recalcitrant cases.
Pharmacotherapy still remains the mainstay
of treatment of AR. Not all patients with
moderate/severe allergic rhinitis are controlled
despite optimal pharmacotherapy. Many
surgical options exist for the treatment of allergic
rhinitis, directed primarily at the underlying
nasal obstructive component. Surgery does not
cure Allergic Rhinitis. Surgical intervention is
indicated for complicating conditions such as
rhinosinusitis, severe septal deviation, nasal
polyps or other anatomical abnormalities. The
indication for nasal and sinus surgery should
always be based on a lack of effect of adequate
drug treatment and the functional and clinical
relevance of the anatomical variation or disease.
Indications for surgery for allergic rhinitis
include pharmacotherapy resistant turbinate
hypertrophy, cartilaginous or bony obstruction
of the nasal airways (septum, bony pyramid)
which can make AR harder to treat, sinonasal
polyps, allergic fungal rhinosinusitis, enlarged
adenoids and otitis media with effusion.
rhinitis. In long-standing allergic rhinitis,
a severe drug-resistant hypertrophy of
the inferior turbinates may develop, which
leads to constant nasal obstruction & watery
secretion due to an increase in glandular
structures. (Fig. 1)
Turbinoplasty induces scar tissue and
fibrosis within the submucosal layer, while
Inferior
Turbinate
excellent relief with regards to symptoms of
nasal obstruction but less satisfactory in
rhinorrhoea. Advances in technology has
resulted in new tools which can produce
fibrosis and shrinkage of the inferior turbinate
while helping preserve mucosa. Laser surgery
using CO2 laser, KTP 532 laser, or diode laser
is simple and effective surgical treatment
that can be used to reduce the size of the
swollen nasal turbinate while preserving the
surface epithelium and ciliary function.
(Fig. 3) Complications of laser treatment are
not common, but include crusting, synechiae
formation, and bony exposure of nasal
structures.
Fig.1: Hypertrophied inferior turbinate in AR
destroying glandular and vascular structures.
The surgical reduction of the inferior turbinate
body and mucosal surface, which should always
be limited, increases the cross-sectional area
of the nasal valve, reduces nasal resistance and
increases nasal airflow. Reduction in nasal
obstruction and secretions results in significant
symptom relief.
Traditionally, submucus diathermy of
inferior turbinate which involves passing a
probe just below the mucosal surface lining
of the turbinate bones and cauterizing using
heat energy was used to shrink the size of the
turbinates. (Fig.2)
Cryosurgery to freeze and debulk the
hypertrophied inferior turbinates has also
been used. Cryosurgery has shown to provide
Fig. 3: Laser surgery of the inferior turbinate
Radio Frequency ablation (RFA) utilizes a
probe that is inserted directly into the inferior
turbinate and is used to deliver a low-frequency
ionic energy causing shrinkage of the turbinate.
Coblation turbinoplasty uses RF energy
between electrodes in a saline medium to create
a field of ionized sodium molecules capable of
ablating turbinate tissue. (Fig.4)
Turbinate Hypertrophy
This is the commonest indication for surgery
in allergic rhinitis. Although no single modality
has evolved as the gold standard treatment
of allergic rhinitis, the mainstay of surgical
intervention targets the inferior turbinate.
The inferior turbinate, being the initial
deposit point for allergens, has proven to
be the most important contributor to nasal
obstruction and dynamic compliance of
the nasal cavity. This is due to vaso-reactive
engorgement of turbinate tissue and associated
inflammation of mucosal lining in allergic
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RespiMirror|Volume V, Issue III, July-August 2015|
Fig. 4: Coblation turbinoplasty
Fig.2: Submucus diathermy of the inferior
turbinate
RFA and coblation are well tolerated with
minimal adverse effects and coblation in
particular, is associated with less pain, which
may have expanded implications for the
pediatric population. Microdebrider-assisted
>>Continued on page 5
>>Continued from page 4 Management of Allergic Rhinitis
surgery has demonstrated superior results in
improving nasal volume and blockage.
Concha Bullosa
Concha Bullosa is essentially pneuma tization of the anterior aspect of the middle
turbinate. (Fig. 5) Surgical treatment of concha
bullosa gives good symptom relief in AR.
(Fig.6)
(CRS) continue to experience bothersome
symptoms despite adequate medical treatment.
This group represents a therapeutic challenge.
Functional Endoscopic Sinus Surgery allows
adequate ventilation and drainage of the
involved sinuses. Co-morbid allergy has to
be treated with pharmacotherapy in patients
with sinusitis. Treatment of the allergy before
surgery may improve the success of ESS.
Balloon Sinuplasty involves using a
balloon catheter device and is another
surgical treatment option available for allergic
rhinosinusitis. (Fig. 8) This system is based
on a flexible catheter and wire technology to
restructure the blocked ostium allowing the
return of normal sinus drainage and function
with little or no disruption of the mucosal
lining. (Fig. 9, 10)
Fig. 5: Left concha bullosa
Fig. 8: Pre-op CT scan showing left maxillary sinusitis in a patient with AR
adequate sinus aeration and assist with medical
and topical therapies. (Fig. 11) Microde
briders which are surgical shaver systems
have greatly enhanced the ease of surgical
management of polyps.
Fig. 11: Microdebrider surgery for nasal
polyposis in AR
Allergic fungal sinusitis is a cause of
chronic sinusitis. It is a noninvasive disease
caused by mucosal hypersensitivity directed
against fungal antigens deposited on sinus
mucosa. (Fig.12) The diagnostic criteria for
AFS include the presence of chronic sinusitis
usually with chronic mucosal thickening on
sinus radiographs, (Fig.13) the presence of
“allergic mucin” and fungal hyphae within
the allergic mucin with large numbers of
eosinophils. A positive fungal culture of the
allergic mucin helps to confirm the diagnosis.
Management comprises of endoscopic sinus
surgery with pharmacotherapy. Complete
removal of allergic mucin & fungal debris
(antigenic reduction), drainage and ventilation
of the sinuses with preservation of underlying
mucosa should be achieved. (Fig. 14, 15)
Fig.6: Laser surgery for concha bullosa
Sinusitis, Sinonasal polyposis and
Allergic fungal sinusitis
Endoscopic Sinus Surgery (ESS) is of
indirect benefit in allergic rhinitis patients
who present with concomitant chronic
rhinosinusitis (CRS), sinonasal polyposis,
or allergic fungal sinusitis. Nasal allergy
may cause recurrent sinusitis because of the
obstruction to the sinus ostia and sinusitis is
the most frequent comorbidity of uncontrolled
AR. (Fig. 7) A significant percentage of
patients with AR and chronic rhinosinusitis
Fig.9: Balloon Sinuplasty device
Fig 12: Endoscopic picture of a case of
AFRS with polyps and mucin
Fig 10: Balloon Sinuplasty – Intra-op
Fig.7: CT scans showing sinusitis in a patient
with AR
Nasal polyps are considered as a chronic
inflammatory disease of the sinonasal
mucosa, being part of the spectrum of chronic
sinus pathology and implicates an IgE type
hypersensitivity. The goal of endoscopic sinus
surgery is to remove diseased tissue, provide
Fig. 13: CT scans in Allergic Fungal Rhinosinusitis.
The heterogeneous density is pathognomonic
Adenoid hypertrophy
Nasal obstruction, secretions or rhinorrhoea
become bothersome in children with AR
and adenoid hypertrophy. The incidence of
>>Continued on page 11
|Volume V, Issue III, July-August 2015|RespiMirror 5
ALLERGIC RHINITIS AND IT’S IMPACT ON ASTHMA
Dr. Sitesh Roy
Dr Roy Health Solutions Clinic, Mumbai
Asthma and allergic rhinitis are both
diseases of airway inflammation and often
coexist as a spectrum of the same disease entity
i.e. one airway hypothesis or united airways
disease. Some experts even propose that it is
reasonable to consider patients with asthma as
a subgroup of the larger population of patients
with allergic rhinitis, since allergic rhinitis is
highly prevalent in patients with asthma.
Allergic rhinitis (AR) is defined clinically
by the symptoms caused by immunologically
mediated (most often IgE-dependent)
inflammation after the exposure of the nasal
mucous membranes to offending allergens to
which the individual is sensitised. Symptoms
of allergic rhinitis include rhinorrhea, nasal
obstruction or blockage, nasal itching,
sneezing, and postnasal drip that reverse
spontaneously or after treatment. Allergic
conjunctivitis often accompanies allergic
rhinitis.
Patients with perennial symptoms of AR,
which are often associated with sensitisation
to indoor allergens (eg, dust mites, pet dander,
fungi/mould), tend to have prominent nasal
congestion and posterior nasal drainage,
suggesting greater sinus involvement. Patients
with asthma are also more likely to have
rhinosinusitis, which describes disorders
affecting both the nasal passages and paranasal
sinuses causing nasal congestion, posterior
nasal drainage, facial pressure and pain,
headache, fatigue, and reduced sense of smell.
Allergic rhinitis was previously classified
into seasonal, perennial, and occupational.
Perennial allergic rhinitis is usually caused by
indoor allergens such as dust mites, moulds/
fungus, insects (cockroaches) and animal
dander. Seasonal allergic rhinitis is usually
related to a wide variety of outdoor allergens
such as tree, grass, weed pollens or moulds/
fungus. However, from a diagnostic and
therapeutic point of view, it is often difficult to
differentiate between seasonal and perennial
symptoms. Some seasonal allergens cause
perennial symptoms, while some perennial
allergens may cause seasonal symptoms
only, and the majority of patients in India
are polysensitized to seasonal and perennial
allergens.
Introduction
The incidence of allergic diseases such as
allergic rhinitis and asthma are increasing
rapidly (allergic rhinitis: 10-40%; and
asthma: 5-15%), both in the developed and
the developing world, leading to reduced
quality of life of the patients, reduced
productivity and increasing medical costs.
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Epidemiologically, up to 40% of
patients with allergic rhinitis also
have asthma, and up to 80% of
patients with asthma experience
nasal symptoms.
The rising evidence on the links between
allergic rhinitis and asthma comes from
epidemiological, immunological and clinical
studies. Furthermore, patients with allergic
rhinitis are at three times the risk of developing
asthma compared with those without allergic
rhinitis.
In children who develop rhinitis within the
first year of life, their chances of developing
asthma are twice as great as in those who
develop rhinitis later in life. There is also a
strong link between asthma and bacterial
rhinosinusitis, viral upper respiratory
infections (acute viral rhinosinusitis), and
nasal polyposis seen too. Indeed, rhinitis
frequently precedes asthma in the atopic
march, and treating allergic rhinitis with
pharmacotherapy and immunotherapy has
beneficial effects on asthma control, suggesting
that upper airway disease is closely linked
to and a risk factor for asthma. The WHO
Allergic Rhinitis and Its Impact on Asthma
(ARIA) guidelines suggested the currently
accepted classification for allergic rhinitis as
mild or moderate-severe and as intermittent
or persistent to mirror the now well-accepted
longer standing classification of asthma as
intermittent, mild, moderate or severe as per
several international guidelines.
Pathophysiological Links between
Allergic Rhinitis and Asthma
Interestingly, anatomically the respiratory
epithelium is substantially the same from the
nasal passage to the bronchioles. Also, the nose
and the bronchi share the same adrenergic
and cholinergic innervations. Both AR and
asthma cause airflow limitation as a key
feature. Bronchial inflammation evidenced
by increased eosinophils and increased
basement membrane thickness has been
seen in patients with isolated allergic rhinitis
compared to healthy controls. Allergic rhinitis
patients without asthma, who underwent
bronchoprovocation challenges in and out
of their sensitised pollen seasons, had a
significant lower PC20 values i.e. greater
bronchial hyperreactivity noted in-season
compared to out-of-season suggesting a link
between upper and lower airway inflammation
and reactivity. Similarly, the inflammatory cell
counts in the bronchi of these isolated allergic
rhinitis patients was greater in pollen season
vs. out-of-season. Allergic rhinitis patients also
tend to show greater forced expiratory value
in 1st second (FEV1) rise after bronchodilator
therapy compared to healthy controls, which
is a feature typically seen in asthma patients.
Two-thirds of allergic rhinitis patients in one
study demonstrated >12% increase in FEV1
after bronchodilator therapy without having
a pre-existing diagnosis of asthma.
Epidemiological Links for
Allergic Rhinitis with Asthma
Individuals with AR have a 3-fold risk
of developing asthma in the future. On the
basis of the WHO ARIA classification, a
retrospective study in 9 countries showed
that intermittent rhinitis was observed in less
than 20% of patients, whereas patients with
persistent rhinitis comprised approximately
80%. Although 25-30% of allergic rhinitis
patients had mild allergic rhinitis, 60-70%
had moderate-severe rhinitis. Furthermore,
approximately 40-60% of allergic rhinitis
patients had co-existent asthma, and
their asthma symptoms worsened in their
allergy season. In the Tasmanian Asthma
Study, childhood allergic rhinitis raised the
consequent risk of developing asthma between
7-12 years of age by 7-fold, between12-20 years
of age by 4-fold and between 20-44 years of age
by 2 fold compared to non-allergic children.
An international survey called the ‘One
Airway Survey’ carried out in four Asian
countries in patients or parents of patients, a
significant proportion of the patients reported
that having allergic rhinitis with asthma had a
negative effect on their ability to enjoy social
activities (64%) and eight out of 10 patients
felt a disruption in daily activities including
their ability to get a good night’s sleep (84%),
participation in leisure and sports activities
(81%), and concentration at work or school
(80%). Thus the personal and social impact
of these two epidemiologically linked entities
together is really significant.
Immunological Links for
Allergic Rhinitis with Asthma
Both allergic rhinitis and asthma are
inflammatory respiratory diseases, and their
inflammatory mechanisms are similar in that
they are characterized by an inflammatory
infiltrate made up of eosinophils, T-cells,
and mast cells that release several mediators,
chemokines and cytokines, local and systemic
specific IgE synthesis, and a systemic link
via the bone marrow. A typical early phase
>>Continued on page 7
>>Continued from page 6 ALLERGIC RHINITIS AND IT’S IMPACT
and late phase response are also common
to both rhinitis and asthma. Several studies
have shown that patients with allergic rhinitis
exhibit bronchial hyperresponsiveness and an
increase in inflammatory cells in the lower
airway, and that nasal allergen challenge
further increases this hyperreactivity.
Similarly, isolated segmental bronchial allergen
challenges have been demonstrated to increase
nasal inflammatory markers within hours
suggesting an immunological cross-talk that
is intrinsically built into our upper and lower
airways. Eosinophils have been demonstrated
in the nasal mucosa of patients with asthma,
even in the absence of symptoms of rhinitis.
In addition, patients with allergic rhinitis have
increased numbers of inflammatory cells in
their bronchial mucosa. Also, in patients with
severe asthma, sinus mucosal thickening on
computed tomography correlates with the
severity of lower airway disease indicated
by sputum eosinophilia, exhaled nitrous
oxide, functional residual capacity, and
diffusing capacity.
Therapeutic links for Allergic
Rhinitis with Asthma
The therapeutic outcomes of treating
allergic rhinitis on asthma has shown that
allergic rhinitis treatment improves asthma
symptoms and lowers the overall costs and
even reduces emergency room visit and
hospitalizations. This parallel relationship
is influenced by many interactions between
the upper and the lower airways. One such
interaction is based on the fact that the
nasal passages play a major homeostatic
role by conditioning inhaled air, but other
and perhaps even more important is
the bidirectional cross-talk that results
from the systemic inflammation that is
produced after local allergic reactions in
the upper or lower airways. Even in the
1900’s ENT surgeons noted improvement in
asthma control after nasal and sinus surgery
in selected patients.
As allergic rhinitis severity increases in
those patients with co-morbid asthma, the
severity of asthma also is found to increase.
Difficult to control asthma might be associated
with moderate to severe allergic rhinitis in
some cases too. Several therapeutic strategies
that can treat both rhinitis and asthma are
either available in the market today or are in
development. Among them are leukotriene
receptor antagonists (LTRAs), anti-IgE
monoclonal antibodies (omalizumab),
immunotherapy, DNA vaccines, anti-IL-4R,
anti-IL-5, anti-VLA-4, anti-CCR antibodies.
The IgE antibody plays a central role in allergic
immune responses. Recent studies have also
shown the local production of IgE in allergic
airway diseases. Targeting IgE is therefore
an important strategy in the treatment of
allergic diseases. Omalizumab (a humanized
monoclonal antibody) has the ability to
Mechanisms by which Allergic
rhinitis may lead to Asthma
1. Vagal reflex/rhinobronchial reflex
2. Per continuum passage of allergic
inflammation from the nose to the
bronchi
3.
Irritant mechanis caused by
postnasal drip
4.The oral respiration caused by
nasal obstruction, which promotes
bronchial hyperresponsiveness as
dry and cold air penetrates into the
bronchi
5. The systemic release of mediators
and cytokines involving even the
bone marrow.
reduce circulating IgE and represents a
unique therapeutic approach for the treatment
of IgE-mediated allergic diseases. The
anti-IgE monoclonal antibody (omalizumab)
has demonstrated efficacy in attenuating
both the early and late-phase bronchial
responses to inhaled aeroallergens. Therapy
with omalizumab reduces the frequency
of asthma exacerbations and the need for
inhaled corticosteroids (ICS), improves
asthma symptoms, lung function, and quality
of life but also simultaneously for those
patients with allergic rhinitis too, their nasal
and ocular symptoms are also significantly
reduced, and their quality of life is significantly
improved. Anti-IgE therapy for concomitant
upper and lower airway allergic diseases
by targeting a central common component
driving the allergic inflammatory response
is another proof of concept for the “one
airway hypothesis”.Cysteinyl leukotrienes are
important mediators in the pathophysiology
of both asthma and allergic rhinitis, released
in both the early and late phase of the allergic
reaction, further linking the ‘one airway’
concept of upper and lower airway disease.
LTRAs, which block the actions of cysteinyl
leukotrienes, have proved to be effective and
well tolerated therapies in the treatment of
asthma and allergic rhinitis.Both histamine
and cysteinyl leukotrienes are elevated in
the nasal secretions of patients with allergic
rhinitis.
Histamine induces several of the responses
that typify allergic rhinitis (e.g. itching and
sneezing), but other mediators such as
cysteinyl leukotrienes are manifold more
potent than histamine in causing nasal
congestion. Both newer generation nonsedating anti-histamines and anti-leukotriene
therapies have been shown to have beneficial
effects on both allergic rhinitis and asthma
symptoms. In a study by Price et al. in patients
with asthma and co-morbid allergic rhinitis,
the use of montelukast with budesonide as a
combination therapy was shown to be superior
to doubling the dose of budesonide, both with
or without the use of concomitant allergic
rhinitis medications.
Nasal steroids have been shown to reduce
the bronchial hyperresponsiveness of asthma
patients with seasonal allergic rhinitis. In
another case-control study evaluating data
on the risk of emergency room visits or
hospitalisations for asthma, those patients who
were on intranasal corticosteroids for their
AR, had a significantly reduced risk for both
the above mentioned outcomes. Therapeutic
strategies such as LTRAs or LTRAs plus
non-sedating anti-histamines, represent a
good option of therapy for the considerable
numbers of patients with mild asthma and coexisting allergic rhinitis by increasing patient
compliance and improving the quality of life.
Immunotherapy and its impact
on Allergic rhinitis and Asthma
Allergen exposure in clinically relevant
sensitised cases is a known trigger for both
allergic rhinitis and asthma symptoms. Those
patients with concomitant AR and asthma
show significant improvement in symptoms,
medication scores, and reduced exacerbations
for both conditions after appropriate AIT.
Carefully selected, 3-5 years of
allergen immunotherapy (AIT)
designed to de-sensitise the
patient to their major clinically
relevant aeroallergens is a wellestablished efficacious therapy
for such patients. Indeed timely
allergen immunotherapy utilising
standardized, reliable aeroallergen
extracts either sublingually or
subcutaneously can prevent the
future development of asthma in
several paediatric studies.
Conclusions
Much of the above epidemiological,
pathophysiological, immunological and
therapeutic evidences linking allergic rhinitis
and asthma in a variety of indisputable ways
have been summarised wonderfully by the
World Health Organization initiative Allergic
Rhinitis and its Impact on Asthma (ARIA).
Evaluating every patient with allergic rhinitis
for clinical or subclinical asthma via careful
history, spirometry and other investigative tools
as well as evaluating every patient with asthma
for evidence of allergen sensitisation with prick
skin testing or blood tests for specific IgE
towards selected aeroallergens would indeed
be worthwhile and highly recommended given
the strength of current clinical data relating
these two conditions. Thus, optimally comanaging allergic rhinitis and asthma, when
present in the same patient together using
allergen avoidance, pharmacotherapy and
immunotherapy ultimately leads to the best
clinical outcomes for our patients.
|Volume V, Issue III, July-August 2015|RespiMirror 7
Allergen Specific Immunotherapy
for Allergic Rhinitis
M T Krishna
Consultant Allergist and Immunologist and
Honorary Reader in Medicine
Heart of England NHS Foundation Trust Birmingham, UK
Dr. Anjali Ekbote
Consultant Immunologist,
Background
Allergic rhinitis (AR) is defined as presence
of at least two nasal symptoms (rhinorrhoea,
itching, sneezing or blockage) associated
with an IgE mediated immune response to
common aero-allergens such as pollens,
house dust mite, animal dander and rarely
moulds. Allergic rhinitis is the most common
form of non-infectious rhinitis and is usually
associated with conjunctivitis, i.e., allergic
rhinoconjunctivitis (ARC). The incidenceof
AR/ARC has been steadily increasing since
the 19th century and is estimated to affect
500 million individuals worldwide. Whilst the
physical symptoms of AR are well recognised,
its impact on health related quality of life
(HRQoL) is often underestimated. Diagnosis
of AR involves obtaining a detailed clinical
history in conjunction with demonstration
of sensitisation to relevant allergen(s) by skin
prick testing and/or serum specific IgE.
First line treatment for AR/ARC involves a
combination of H1-receptor antagonists(oral
and/or intranasal), intranasal corticosteroids,
leukotriene receptor antagonists and cromones
(nasal and ocular). Whilst most patients show
a good therapeutic response, some benefit only
partially. A common cause of treatment failure
is poor compliance and/or suboptimal nasal
spray technique. The Allergic Rhinitis and Its
Impact on Asthma (ARIA) guidelines defined
allergen specific immunotherapy (AIT) as “the
practice of administering gradually increasing
quantities of an allergen extract to an allergic
subject to ameliorate the symptoms associated
with the subsequent exposure to the causative
allergen”. Allergen specific immunotherapy
modulates the immunological response to
an allergen from an atopic T-helper 2 (Th2)
state to a tolerant T-helper 1 (Th1) or
T-regulatory (Treg) response thereby providing
lasting benefit.
Historical perspective
The allergy community worldwide
celebrated 100 years of AIT in 2011. In 1911,
Noon and his colleague Freeman from St.
Mary’s Hospital, London, UK described a
therapeutic process recognisable today as AIT.
Briefly, they reported that in subjects with
symptoms suggestive of grass pollen-related
AR/ARC, sensitisation was demonstrable
by conjunctival exposure to pollen extract.
Following subcutaneous (SC) injections of grass
pollen extract (referred to as pollen toxin in
1911) administered at incremental doses over
an initial (short interval between doses) and
8
RespiMirror|Volume V, Issue III, July-August 2015|
maintenance (longer interval between doses)
phase, subjects experienced clinical benefit.
Whilst the basic principles underpinning
AIT remains the unchanged after a century,
current vaccines are superior in terms of
their standardisation and immunogenicity
with several preparations available via
the subcutaneous (SC) and increasingly,
sublingual (SL) routes. Considerable evidence
demonstrating the efficacy and safety of these
modalities are available.
Current practice
Patient selection criteria
Robust patient selection criteria are
critical to the success of AIT. Candidates for
treatment display symptoms of AR which are
consistently attributable to allergen exposure.
Investigation to confirm IgE sensitisation to
the causative allergen is required. However, a
positive test alone does not make the diagnosis
of an allergy. Challenge testing can be used
to demonstrate an allergy but is impractical
and seldom used in routine clinical practice.
AIT is absolutely contraindicated in patients
with moderate-severe asthma and brittle
asthma. It should not be initiated in patients
with significant cardiac (e.g. ischaemic heart
disease, cardiac failure) or chronic respiratory
disease with poor respiratory reserve. Betablockers and ACE-inhibitors should be
discontinued prior to commencement of
AIT. It should not be initiated in pregnancy,
although can be continued after a careful
risk-benefit analysis provided treatment
has been well tolerated and in maintenance
phase. However, the general consensus is to
discontinue therapy as far as possible in view
of the rare but real possibility of anaphylaxis
that may potentially compromise the wellbeing of the foetus. Systemic autoimmune
conditions, immunodeficiency and concurrent
immunosuppressive or immunomodulatory
therapy are relative contraindications and
each patient is assessed on individual merits.
In the UK, patients selected for AIT typically
have markedly impaired HRQoL due to AR/
ARC with a sub-optimal response or those
In patients with co-existent mild
asthma and rhinitis, adequate control
of asthma must be documented by
spirometry and diary record of stable
peak expiratory flow rate (PEFR) prior
to enrolment into the AIT.
who have experienced an adverse reaction
to first line agent(s) (H1-antihistamines,
intranasal
corticosteroids,
leukotriene
receptor antagonists). In contrast, AIT may
be offered to patients with relatively milder
symptoms in other parts of the world. There
is some evidence in the literature that early
use of AIT in patients with house dust mite
related-AR (monosensitised) reduces the
risk of progression to asthma and onset of
newer sensitisation(s). This requires further
confirmation in larger clinical trials. Patient
selection criteria are identical regardless of the
AIT product employed.
Choice of treatments
Allergen
specific
immunotherapy
preparations used in the UK are standardised
for allergen content. Preparations may utilise
adjuvants, for example aluminium hydroxide is
used in some SC preparations to delay the release
of allergen and enhance immunogenicity.
Other preparations may use modified allergens
(termed “allergoids”) which are less allergenic
but maintain their immunogenicity thereby
theoretically reducing the risk of systemic
reactions.Whilst single AIT is used in the
UK, multiple allergen mixes are employed in
the USA based on the patient’s sensitisation
profile. However, evidence for the use of
multi-allergen mixesis lacking at the present
time.The two main modalities of AIT employed
in routine clinical practice are subcutaneous
injection immunotherapy and sublingual
immunotherapy as described in the following
sections.
Subcutaneous Immunotherapy (SCIT)
Standard SCIT protocols involve
administration of gradually increasing doses
of standardised allergen extract, usually
administered once a week until the target
maintenance dose is reached. The conventional
protocol involves a 12 week up dosing protocol
(induction phase). The maintenance dose is
then continued at 4-6 weekly intervals for
3-5 years. Accelerated induction protocols
have been described -“clustered”(7 weeks)
or “rush”(2-4 days) or “ultra-rush”(24 hrs)
have been employed, although the latter two
are associated with higher rate of systemic
allergic reactions. Dose modifications may be
required for missed injections, following large
local or systemic reactions and during pollen
season. All SCIT treatments are administered
in a hospital out-patients department setting.
>>Continued on page 9
Dr. Monica Barne
Chest Research Foundation, Pune
How to use The Nasal Spray
WHILE USING THE NASAL SPRAY
Using an INCS Spray:
1. Blow your nose until
your nostrils are clear.
2. Shake the bottle gently
and remove the dust
cover.
3. Hold the bottle firmly
with your forefinger
and middle finger on
either side of the spray
tip while supporting
the base of the bottle
with your thumb.
4. Hold one nostril closed
with your index finger.
5. Lean your head slightly
forward and carefully
put the tip of the nasal
applicator into your
open nostril keeping
the bottle upright.
1. If you are using
the pump for the first time,
point the bottle away from
your body and press down
and release the pump eight
times. If you have used
the pump before but not
within the last 4 days,
press down and release
the pump one time or until
you see a fine spray.
Caution
The nozzle should
not be pointed medially
towards the nasal septum
as this may damage the
Little’s area and cause
epistaxis. The nozzle
should be pointed slightly
laterally.
>>Continued from page 8 Allergen Specific Immunotherapy
Pre-SCIT injection checks include questions
relating to general health, adverse events,
changes in medication and PEFR. Patients
are monitored for an hour post-injection,
although delayed systemic reactions may rarely
occur. Common adverse reactions to SCIT
are swelling and itching at the ingestion site
and fatigue. Less commonly systemic reactions
ranging from rhinitis symptoms to anaphylaxis
may also occur. Long term efficacy up to 8-10
years following a 3 year course of treatment
has been reported in SCIT clinical trials for
grass pollen-related hay fever.
Sublingual Immunotherapy (SLIT)
Sublingual immunotherapy is available
as tablets (no up-dosing needed) and liquid
formulations (up-dosing is required). In
contrast to SCIT, SLIT is initiated under
medical supervision in the hospital setting
but continued daily by patients at home.
Regular 3-6 monthly follow-up in clinic helps
to ensure compliance with treatment, advice
regarding adverse events and dose adjustments
if required. Side effects include short-lived
local itching, irritation and swelling affecting
oropharyngeal mucosa. These reactions
typically reduce as patients become accustomed
to treatment. Less commonly heart burn,
abdominal discomfort, diarrhoea and systemic
reactions have been reported in clinical trials.
The optimal treatment duration in the UK is
three years. Recent studies have shown long
term efficacy with SLIT to grass pollen with
patients maintaining clinical benefit and
6.
Begin to breathe
through your nose.
7.
While
you
are
breathing in, use your
forefinger and middle
finger to press quickly
and firmly down on the
applicator and release
a spray. Continue to
breathe in.
8.Breathe out through
your mouth.
9. Repeat steps 4-8 for the
other nostril.
10.If you are advised to
take two squirts repeat
steps from 4-8.
11.Wipe the applicator tip
with a clean tissue and
replace the dust cover.
Image Courtesy : Cipla
sustained immunological responses at year 5
following a 3 year course of treatment. Further
data from long term follow up are awaited.
Practical aspects
Allergen specific immunotherapy must
only be undertaken by specialists with
adequate knowledge and experience in this
field. Due to the risk of an immediate systemic
allergic reaction including anaphylaxis,
particularly with SCIT, treatment should only
be administered in centres where facilities for
cardiopulmonary resuscitation are readily
available. Accelerated protocols are seldom
indicated for AR, but if undertaken, should
be administered in a high dependency unit
setting. Following SCIT injection (or initial
SLIT treatment), patients must be monitored
for 60 minutes.
Previous surveys have shown that common
causes of near fatal or fatal anaphylaxis during
SCIT are related to misidentification of the
patient, administration of the incorrect
allergen, dosage errors and poorly controlled
asthma. However, with robust patient selection
criteria and stringent standard operating
protocols AIT remains a safe treatment. There
no reliable biomarkers that can accurately
predict treatment response. Efficacy is
evaluated in routine clinical practice using
HRQoL questionnaires pre and post AIT.
Allergen challenges are employed in a research
setting and these have shown that AIT induces
higher threshold for clinical reactivity and
reduces the area under the curve for early and
late phase allergic responses.
Future directions
Clinical trials involving new products and
novel routes of administration to improve
tolerability and efficacy of AIT are underway.
Allergoids or allergenic epitopes recognised by
T cells may be utilised to enhance Th1 reactivity.
Recombinant allergens also hold promise for
the future. New adjuvants such as bacterial
DNA and monophosphoryl lipid A (MPL)
enhance immunogenicity by potentiating the
Th1 response A recent study has shown that an
intralymphatic route of administration of grass
pollen extract is an effective and safe modality
of treatment for patients with seasonal allergic
rhinitis. There is also interest in intradermal
and epicutaneous routes of administration
of allergen but these need confirmation
in large randomised control trials (RCT).
Concurrent administration of monoclonal
anti-IgE antibody (omalizumab) with
SCIT has shown to enhance efficacy and
safety and this also requires large RCTs for
confirmation and investigation into health
economics.
Summary statement
In conclusion, AIT is a safe and effective
treatment for AR/ARC and alters the natural
course of the disease. It is a relatively expensive
and time consuming treatment and currently
offered only to patients with moderate-severe
disease not showing adequate therapeutic
response to first line pharmacotherapy. It is
likely that newer immunomodulatory therapies
will be available over the next decade for
treatment of AR/ARC.
|Volume V, Issue III, July-August 2015|RespiMirror 9
ADVANCES IN ALLERGIC RHINITIS
Dr. Mahesh PA,
Professor, Department of Pulmonary Medicine, JSS Medical College & University, Mysore
Epidemiology
Allergic Rhinitis is a very common disease
affecting a large proportion of patients across
the globe (10-30%) and is associated with severe
impairment of quality of Life. In the US, it is the
most common chronic condition in children and
in the top 6 chronic conditions in adulthood.
The cost of allergic rhinitis runs into billions of
dollars in direct and indirect health care costs.
The prevalence of allergic rhinitis continues to
increase in most countries in the world. Allergic
rhinitis can be classified as seasonal or perennial,
with symptoms being intermittent or persistent.
Intermittent allergic rhinitis is said to be present
when the frequency of the symptoms are <4 days/
week or <4 weeks/year. Persistent Allergic rhinitis
is said to be present when the frequency of >4
days/week and >4 weeks /year. Another term
has been introduced recently as Episodic allergic
rhinitis when the symptoms can occur due to an
individual’s exposure to an environment that is
not normally part of his environment; example,
exposed to a cat in a friend’s house. Rhinitis is
said to be mild when it has not affected the sleep
and the quality of life of the patient or moderatesevere when these are affected.
Recent advances in pathogenesis
Role of Dendritic Cells: Dendritic cells
along with the nasal epithelial cells are critical
players in the regulation of the immune system
in the nasal mucosa of patients with allergic
rhinitis. The Dendritic Cells and the Epithelial
cells have receptors called the pathogen
recognition receptors (PRR’s) that recognize
the various Pathogen Associated Molecular
Patterns (PAMP’s). At the time of the allergic
inflammation, Dendritic cells would be activated
by various cytokines such as Thymic Stromal
Lymphopoietin(TSLP), IL-1 and IL-33. Once
epithelial DCs are triggered, they are activated
and migrate to the draining lymph node via
lymphatics, controlled by CCR7. Activated DC’s
respond to various allergens as well as bacterial
products such as Staphylococcal super antigens.
Role of IL-33: Recently, studies have
demonstrated the role of cytokines such as IL33 in allergic inflammation. IL-33 is a nuclear
cytokine, which is expressed normally during
homeostasis but is not found extracellulary in
significant quantities. During tissue damage such
as an allergic reaction, these are released and
are potent mediators and immune stimulators
of the Th2 cells leading to large productions of
IL-5 and IL-13, important mediators of allergic
inflammation. IL-33 is very important in allergic
rhinitis as evidenced by studies on IL-33 deficient
mice.
Role of IL-32: A recent addition to the
cytokines that are important for allergic
10
RespiMirror|Volume V, Issue III, July-August 2015|
ARIA Guidelines :
Recommendations for Management
of Allergic Rhinitis
Mild
intermittent
Moderate
severe
intermittent
Mild
persistent
Moderate
severe
persistent
Intra-nasal steriod
Local cromone
Leukotriene receptor antagonists
Second-generation nonsedating H1 antihistamine
Intranasal decongestant (<10 days) or oral decongestant
Allergen and irritant avoidance
Immunotherapy
rhinitis is the IL-32, a cytokine produced
by immune cells, such as T lymphocytes,
natural killer cells, epithelial cells, mast cells,
keratinocytes, eosinophils. IL-32 contributes
to pro-inflammatory cytokine synthesis and is
involved in several inflammatory pathways such
as phosphatidylinositide 3-kinase (PI3K)/Akt
pathway, nuclear factor (NF)-κB/AP-1 pathway,
p38 mitogen-activated protein kinase (MAPK)
and caspase-1 pathways.
Role of TSLP: TSLP is an important regulator
of innate and adaptive immune responses
associated with the Th2 cytokine-mediated
inflammation, such as Allergic Rhinitis. IL-32
has been shown to significantly increase TSLP
production from monocytes. TSLP is expressed
in epithelial cells, fibroblasts, endothelial cells
and smooth muscle cells at nasal mucosa. TSLP
is also expressed in activated mast cells and
TSLP from filaggrin deficient keratinocytes in
patients with atopic dermatitis (AD) is critical
for the progression of AD to Allergic Rhinitis
and Asthma.
Role of Caspase 1 pathway: Caspase-1
is critical for innate immunity and plays an
important role in several important inflammatory
diseases. Activation of Caspase-1 pathway is
associated withnasal inflammation in mouse
models of AR with an increase in IL-1β, IL-18,
histamine and IgE. Important inflammatory
regulators such as IL-32 and TSLP are increased
by the activation of caspase-1 which also promotes
COX-2-dependent inflammation.
Clinical features
Clinicians should consider a diagnosis of
Allergic rhinitis, when patients present with a
history and clinical examination that is consistent
with an allergy and one or more of the symptoms
associated with allergic rhinitis: nasal congestion,
runny nose, itchy nose, or sneezing. Findings
of AR consistent with an allergic cause include,
but are not limited to, clear rhinorrhea, nasal
congestion, pale discoloration of the nasal
mucosa, and red and watery eyes.
Diagnosis:
Role of Allergy testing: Allergy testing is
recommended by the guidelines to identify the
causative allergen and to plan specific avoidance
measures. These data also helps to plan for
immunotherapy in selected patients who are
unable to avoid these allergens.
Role of Regular Sinonasal Imaging: Regular
CT scans are not recommended for all patients
with allergic rhinitis alone.
Role of Nasal Smears: Demonstration of high
eosinophilia in the nasal smears in the absence
of atopy can suggest Non-allergic rhinitis with
eosinophilia syndrome (NARES).
Management
Pharmacotherapy: Inhaled nasal steroids form
the cornerstone of the management of allergic
rhinitis especially moderate-severe persistent
allergic rhinitis. The myth that long-term use of
intra-nasal corticoids (INCS) can lead to mucosal
atrophy was evaluated in a systematic review,
which concluded that there is no evidence of
mucosal atrophy on long-term use of INCS. It may
be useful to use intranasal saline douching which
will help to remove the mucus and inflammatory
secretions and help in the absorption of INCS and
thus improve efficacy. In symptomatic patients
use of second generation non-sedating antihistamines are recommended. Clinicians may
offer intranasal anti-histamines such as azelastine
for patients with allergic rhinitis. Clinicians
should not offer leukotriene receptor antagonists
>>Continued on page 11
>>Continued from page 10 ADVANCES IN ALLERGIC RHINITIS
as a first line therapy for patients with allergic
rhinitis. Combinations of different pharmacotherapeutic agents can be given to patients
who do not respond to monotherapy.
Decongestants should not be used for children
less than 4 years.
Allergy Avoidance:
Environmental avoidance measures such as
removal of carpets from the living room and
bedroom, removal of pets that the patient is
sensitized to, exposure to strong sun for at least
3 hours twice a week for reduction of dust mites
in the bedding, pillow and blankets, house dust
mite allergen barrier bed and pillow covers and
air filtration systems are recommended. Though
many studies have demonstrated a reduction in
levels of allergens, studies that have evaluated the
correlation of reduced allergen levels to reduced
symptoms clinically are limited. It would probably
be useful to use more than one environmental
control measures for added benefit. It is also
advisable to avoid mosquito coils and burning
of incense sticks at home.
Immunotherapy:
Patients who do not respond adequately to
pharmacotherapy with or without environmental
controls should be referred for immunotherapy
either subcutaneous or sublingual. There is a large
body of evidence in the form of Randomized
Control Trials for both subcutaneous and
sublingual immunotherapy in the management
of allergic rhinitis and is given a Grade Level ‘A’.
The various benefits include an altered natural
history of allergic rhinitis and prevention of
progression, better symptom control, reduced
need for pharmacotherapy, improves asthma and
even prevents asthma or other comorbidities in
a significant proportion of patients, and may
prevent new sensitizations to other aeroallergens.
Cost-effective analysis has confirmed long-term
benefits in costs on use of immunotherapy.
Some of the problems associated with use of
subcutaneous immunotherapy include pain at
site of injection, local reactions, rarely systemic
reactions are noted and there is an increased
frequency of visits to the clinic/hospital for
injections and an increased initial cost. Most
of these are addressed by the use of Sublingual
immunotherapy, which is approved by the WHO
for home use.
Surgery:
Surgical reduction of the inferior turbinates’
in patients with allergic rhinitis who have nasal
obstruction that is not responding to medical
therapy is recommended. Surgery has been
shown to improve nasal airflow, quality of life,
better sleep and reduced medicine requirement
and better reach of the medicines into the nose
after the surgery.
Advances in Pharmacotherapy
There is a need for newer drugs in the
management of the allergic rhinitis. The current
armamentarium is sufficient in the management
of most cases with mild and intermittent allergic
rhinitis but is insufficient to manage severe
persistent rhinitis or refractory rhinitis. Studies
have continued on improving the delivery and
optimizing the dose of intranasal steroids. The
ideal dose of beclomethasone has been identified
as 320 microgram/day. A newer formulation of
ciclesonide dry powder nasal inhaler has been
approved in the USA. Ciclesonide is a pro-drug that
is activated by local esterases. The other prodrug
that is studied to have equal efficacy to other
inhaled steroids is rofleponidepalmitate. Antihistamines currently in development include
H3 receptor antagonists such as JNJ-39220675
and H4 receptor antagonists GSK835726 and H1/
H3 receptor antagonists GSK835726. Another
>>Continued on page 12
>>Continued from page 5 Management of Allergic Rhinitis
Fig. 16: Adenoid hypertrophy
Fig. 14: AFRS - Endoscopic sinus surgery
Fig. 18: Grommet in a patient with OME & AR
may be a useful adjunct when combined with
other procedures, such as turbinate reduction
or endoscopic surgery.
Conclusion
Fig. 17: Coblation Adenoidectomy
Fig. 15: Post-op endoscopic picture in AFRS
adult adenoid hypertrophy is increasing
because of allergy. (Fig. 16) Surgery is indicated
in adenoids causing significant embarrassment
to the airway. (Fig. 17)
Otitis media with effusion (OME)
Observed prevalence of allergic rhinitis
in patients with chronic or recurrent OME
ranges from 24% to 89%. OME not responding
to medical management may require
myringotomy and insertion of ventilation
tube. (Fig. 18)
Deviated Nasal Septum
Anatomic deformities of the nasal septum,
such as bony spurs or cartilaginous deviation,
may affect laminar airflow and worsen
subjective nasal obstruction in allergic rhinitis
patients. Septoplasty may help in reducing
nasal obstructive complaints. Septoplasty
Allergic rhinitis can develop into chronic
rhinosinusitis or have associated complications,
such as nasal polyps, chronic sinusitis or
middle-ear disease. When allergen avoidance
and pharmacotherapy fail to control symptoms,
surgical intervention can be considered.
Although there is no gold standard surgical
treatment for allergic rhinitis, advancements
in technology and surgical technique have
made surgery safer and more effective. The
mainstay of surgery in AR is the conservative
reduction of the inferior turbinate. Septoplasty
and endoscopic sinus surgery alone have little
role in the treatment of allergic rhinitis, but
may be useful adjuncts when fixed anatomic
deformities, chronic rhinosinusitis, or sinonasal
polyposis are present. An understanding of the
underlying pathophysiology of allergic rhinitis
is crucial and a tailored approach is needed for
each individual patient.
|Volume V, Issue III, July-August 2015|RespiMirror 11
>>Continued from page 11 ADVANCES IN ALLERGIC RHINITIS
molecule under investigation is the R926112,
which is a mast cell inhibitor that prevents
release of histamine from mast cells and could
be useful in the management of allergic rhinitis.
Some of the most exciting work in newer drugs
in Allergic Rhinitis is in the development of
Toll-like receptor (TLR) agonists. The TLR’s are
present on the innate immune cells and recognize
various Pathogen Associated Molecular Patterns
(PAMP’s).
TLR-4 recognizes bacterial lipopolysaccharides
such as endotoxin, TLR-7 recognizes viral single
strand DNA and TLR-9 recognizes bacterial
DNA. Various TLR agonists are shown to be
useful in the treatment of allergic rhinitis. Already
in clinical trials are TLR-4 agonists called CRX675, which is used as an intranasal aqueous
preparation that can stimulate a Th1 immune
response. Studies are also being evaluated with
intranasal AZD8848, a TLR-7 agonist that is
likely to be useful in managing allergic rhinitis
by changing the immune balance towards Th1
from the Th2 immune profiles.
A TLR-8 agonist, VTX-1463, is being
evaluated in a randomized double blind
placebo controlled trial via intra-nasal route
and found to be clinically effective in reducing
nasal symptom scores. VTX – 1463 is a potent
drug that reduces the nasal inflammation by
regulating monocytes, macrophages and myeloid
dendritic cells. In patients with perennial allergic
rhinitis, CYT003-QbG10, a TLR-9 agonist is
used via injections, once a week for 6 weeks and
was found to reduce nasal symptom scores and
was found to be safe and well tolerated.Other
inflammatory mediators are also responsible for
the inflammation in allergic rhinitis. The CRTH2
is a receptor present on the Th2 cells, basophils
and eosinophils and is stimulated by PGD2.
CRTH2 antagonist, BI 671800 has been used as
a oral tablet at 200 mg twice daily and has been
found to be clinically useful. Another 5 CRTH2
antagonists are being evaluated at present.
Phosphoinositide 3-kinase (PI3K) is a key enzyme
in the signaling pathway in the intracellular
environment in various inflammatory cells such
as T and B-lymphocytes. It is important in cell
survival, response to stimuli such as antigens and
proliferation. The PI3K isoforms are of 4 classes;
PI3K a, PI3K b, PI3K g and PI3K l. P110d, the
isoform of PI3K l is an important regulator of
immune function. An oral P110d antagonist has
been tested in clinical trials and could be useful
in the management of allergic rhinitis.
Advances in Immunotherapy
Subcutaneous (SCIT): One of the key
important advances is the use of recombinant
allergens, which have been already produced for
house dust mites and a few pollens. They have
prepared whole allergens, which mimic the exact
wild type allergen, or only modified allergenic
epitopes that have higher immune-stimulatory
effects but reduced chance of eliciting a clinical
allergic reaction. Peptide fragment of allergenic
proteins 13-17 amino acids in length, either alone
or as a fusion protein attached to an unrelated
non-allergenic carriers have been developed
and are under investigation for improved safety
and efficacy as compared to conventional
immunotherapy. Sublingual (SLIT): A large
number of studies have been conducted on the
role of sublingual immunotherapy for clinical use.
The newer forms include Dissolvable sublingual
tablets (SLIT- tablet), sublingual aqueous
allergen extracts (SLIT-aqueous) and enteric
microencapsulated preparations.
Intralymphatic:
The other novel route being studied is
the intralymphatic route where the antigen
solutions are directly injected into the lymph
nodes. In both SCIT and SLIT the processing
of the antigens happens at the draining lymph
nodes. This route needs almost 1000 times
less antigens than SCIT and less frequent
injections and has been shown to have the same
efficacy as SCIT with less adverse events. More
studies are required before a final conclusion can
be drawn.
Epicutaneous:
This is recently being investigated and
involves the regular applications of antigens
in a base of petroleum jelly as a patch to the
skin. This is probably safer than SCIT but needs
a large number of studies before any conclusion
can be drawn.
Advances in Biologic therapy
Some studies are being conducted in subjects
with refractory allergic rhinitis to evaluate the
response to various biologic therapies that have
been found to be useful in the management of
asthma. Omalizumab, in the same dose as is used
in the management of asthma has been found
to be useful.
A IL-13 monoclonal antibody QAX576,
important in propagating the Th2 pathway
has been studied. Imatinib, a drug used in the
management of leukemia has been evaluated
in the management of allergic rhinitis. Its main
action is on c-kit an antigen on the surface of
the dendritic cells that is related to the activation
of the T cells. By inhibiting this c-kit axis,
inflammation mediated by both Th2 and Th17
can be controlled.
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RespiMirror|Volume V, Issue III, July-August 2015|