Review article

Supported by a grant from AstraZeneca Pharmaceuticals

Nasal provocation testing: a review

Ludmila I. Litvyakova, MD, PhD* and James N. Baraniuk, MD†

Objective: This review focuses on the uses of nasal provocation testing (NPT) for effects. The possibility that an allergen
scientific investigations of the mechanisms of allergic and nonallergic rhinitis. It may cause a positive nasal response,
also describes the use of NPT as a diagnostic tool in clinical practice. The indica- but not be relevant to a subject’s
tions, contraindications, advantages, and limitations of different techniques for asthma must be considered.15 The
evaluation of nasal responses are reviewed. The paper familiarizes investigators same dilemma occurs with allergen
with particulars of different nasal delivery systems, provocation agents, nasal skin testing for prediction of bronchial
patency measurements, secretion collection, and nasal lavage techniques. responses to allergen. Despite these
Data Sources: Relevant publications obtained from a literature review. concerns NPT generally offers a safer
Study Selection: Relevant publications on the topics of NPT, allergic, and alternative to bronchial provocation
nonallergic rhinitis were critically evaluated. when evaluating the role of specific
Results and Conclusions: To date, NPT has been used primarily as a research allergens in a patients’ asthma. Indica-
tool for the investigation of allergic and nonallergic rhinitis with a wide variety of tions for scientific investigations have
techniques depending on the specific scientific purposes. NPT will continue to been described (Table 2) because NPT
provide useful information about the pathogenesis of airway diseases. Standardized allows ready access to respiratory mu-
nasal provocation testing has the potential to become a more frequently used clinical cosa for sampling of mediators, cells,
test in the diagnosis of allergic and occupational rhinitis and for determination of the and secretions.
appropriate and focused therapy.
Ann Allergy Asthma Immunol 2001;86:355–365. CONTRAINDICATIONS
Acute bacterial or viral mucosal in-
INTRODUCTION niques, the absence of standardization flammation is accompanied by rhinor-
Nasal provocation testing (NPT) has for methods and some reagents, and rhea, stuffy nose, and nonspecific hy-
been crucial for the scientific investi- lack of validated direct comparisons perreactivity, which preclude NPT
gation of the pathophysiology, immu- between methods. The absence of data (Table 3). In accordance to the general
nology, and pharmacotherapy of aller- regarding inter- and intra-subject vari- approach in allergy, generalized aller-
gic and nonallergic rhinitis. These ability needs to be addressed to stan- gic reactions, including anaphylactic
studies also offer insights into the dardize allergen NPT so that it may shock and severe bronchospasm and
pathophysiology of hyperreactivity in become a more widely accepted diag- status asthmaticus can occurr in pa-
lower airways because of the similarity nostic method.1,2 tients during the acute phase or exac-
of the response to allergen challenge of erbation of their allergic disease (rhi-
the upper and lower airways. Several INDICATIONS nitis, food allergy, drug allergy, insect
techniques of NPT have been used de- NPT is mainly used for scientific pur- allergy, urticaria) or in patients with
pending on purpose of the investiga- poses in the United States,3 but in sev- previous anaphylactic reactions to the
tion. Each method has its own advan- eral European countries, it is used for allergen of interest. NPT should not be
tages and disadvantages. Limitations clinical evaluation.4,5 conducted in patients with restricted
include the wide variety of test tech- Indications for NPT as an office pro- lung capacity. The danger of miscar-
cedure range from diagnosis of com- riage due to anaphylaxis prohibits NPT
plicated clinical cases to selection of during pregnancy. A wide variety of
optimal therapy (Table 1). Nasal aller- drugs can cause false-negative NPT
* International Center of Interdisciplinary Stud-
ies of Immunology, Georgetown University, gic reactions are thought to be predic- and should be withdrawn before test-
Washington, DC. tive of bronchial responses. This can ing (Table 4). Nasal congestion may
† Division of Rheumatology, Immunology, and occur only if both target organs are also result from oral contraceptives
Allergy, Georgetown University, Washington, DC. sensitized and responsive to the same and preparations containing sulfite pre-
Supported by PHS Award RO1 AI42403.
Received for publication May 12, 2000. allergen. Under this frequent circum- servatives such as bronchodilator solu-
Accepted for publication in revised form De- stance, nasal provocations will likely tions (metaproterenol, isoproterenol,
cember 30, 2000. be predictive of bronchial, asthmatic isoetharine), analgesics (meperidine),

VOLUME 86, APRIL, 2001 355

Table 1. Clinical Indications for NPT
1. To identify a role of an individual,
nonstandardized, novel, or unique
specific allergen in the nasal target
organ using allergen preparations.6
2. To confirm the role of a special
occupational agent, such as baker’s
yeast and dusts, carpenter’s saw dusts,
or latex.7,8
3. To confirm the clinical relevance of a
specific allergen in patients with
multiple positive allergy skin tests.6
4. To assess the role of allergens
implicated by a patient’s history when
allergy skin test and/or RAST are
negative or when the reactions of the
nasal mucosa to an allergen are more
pronounced than those of skin.9,10
5. To investigate food-induced
rhinorrhea.11
6. To determine if nasal application of
allergen can induce symptoms in the
conjunctiva, middle ear, sinus, and
lower respiratory airways.12–14
7. To confirm the allergic nature of
asthma, since positive nasal reactions
may be obtained when the
corresponding bronchial provocation
tests are negative15 or can not be safely
performed.
8. To confirm nasal reactivity before
starting local nasal immunotherapy.16
and eye drops (sulfacetamide, pred-
nisolone, dexamethasone). Oral con-
traceptives may also influence NPT
since women taking these drugs show
squamous metaplasia, interepithelial
edema, glandular hyperplasia, histio-
cytic proliferation, and fibrous tissue
deposition similar to those patients
with chronic hypertrophic nonallergic
rhinitis.31 The need for withdrawal of
these medications before the nasal
challenge is not clear.
Recent rhinitis can result in nasal
priming to allergen or upregulation of
the mechanisms of nasal hyperreactiv-
ity.32 NPT should be performed at least
2 to 4 weeks after any acute allergic
episode or seasonal allergic rhinitis.
Differentiation of allergic perennial
rhinitis from nonallergic represents a
difficult problem because nonallergic
mechanisms may lead to chronic
changes in nasal reactivity and may
356
increase false-positive results. Viral in-
fections alter patterns of vascular per-
meability and mucus macromolecule
exocytosis and induce mucosal hyper-
responsiveness.33 NPT should be de-
layed to 2 to 4 weeks after an infection.
Nasal reactivity is also decreased for 4
to 8 weeks after nasal or sinus surgery
since atypical reactions may be in-
duced.21 Nasal pathology such as pol-
yps, atrophic rhinitis, and septal devi-
ation can give false-positive or false-
negative results in NPT depending on
their severity.34
TECHNIQUES
Rhinoscopic examination should pre-
cede any nasal provocation to inspect
the baseline condition of nasal mucosa
and evaluate structural pathology such
as polyps, septal deviation, atrophic
rhinitis or sinusitis. If significant
pathologic changes are found, NPT
may not be required. Subjects should
have previous skin tests or/and RAST
performed to evaluate the likely atopic
sensitivities.
For clinical purposes, the most prac-
tical method is simple, safe, and easily
repeatable (Fig 1).4,34 –36 Most of the
clinical protocols are consistent with
Table 2. Indications for the
Scientific Investigations
1. To investigate the spectrum of allergen-
induced immediate and late phase
responses and the dose dependent
nature of these reactions.17–19
2. To identify the morphological and
cellular responses to inhaled allergens
using nasal lavage, biopsy, and
brushing.20,21
3. To detect chemical mediators, markers
of glandular exocytosis, and vascular
permeability in nasal lavage following
allergen provocation.22,23
4. To assess the response of nasal airways
to allergens and nonallergic provocative
agents and following changes in
bronchial responsiveness.24–26
5. To examine the therapeutic effects of
drugs such as antihistamines,
corticosteroids, cromoglycate,
anticholinergic medications, and
vasoconstrictors on acute, late phase,
nonspecific, and other aspects of
airway diseases.27
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
European practice, but are not ac-
cepted for clinical use in the United
States. Testing should be performed by
well trained personnel in a well
equipped unit under standard condi-
tions4 to readily identify and limit non-
specific irritant effects, and treat aller-
gic side effects as soon as they appear.
The best time for NPT is in the morn-
ing, before lunch time because this
limits effects of daily-life stimuli
(fumes, cold air, spicy food, physical
exercise). After adaptation to room
temperature for 30 minutes, clinical
symptom score and basal nasal func-
tion should be evaluated. Basal nasal
function can be measured by nasal
peak expiratory flow rate [NPEFR], or
nasal peak inspiratory flow rate
[NPIFR], anterior or posterior rhino-
manometry, or acoustic rhinometry
(gives volume of nasal cavity). Method
of NPEFR is not accepted by experts in
the United States. These measures are
repeated three times and the mean
value is recorded. Each measurement
should differ from the mean by less
than 10% to 15%.35,37 Values within
15% of normal are recommended be-
cause preexisting nasal obstruction
may lead to false-negative results be-
cause further obstruction may not be
possible, measurable or significant.
The wider side of the nose is used for
challenge, but airway obstruction mea-
surements are performed on both sides
during NPT to identify nasal cycle ef-
fects.4
The nasal provocation begins with
administration of a known volume of a
diluent solution such as phosphate-
Table 3. Absolute Contraindications
1. Acute bacterial or viral rhinitis or
sinusitis
2. Acute period or exacerbation of allergic
disease (rhinitis, food allergy, drug
allergy, insect allergy, urticaria)
3. Previous anaphylactic reaction to an
allergen
4. Severe general diseases or acute
period of diseases, especially severe
asthma, obstructive bronchial diseases,
cardiopulmonary diseases with
restricted lung capacity
5. Pregnancy
buffered saline with 0.4% phenol, lac-
tated Ringer’s solution, or normal sa-
line into one or both nostrils using a
metered dose delivery device. This
challenge will detect nonspecific re-
sponses. Over the next 15 minutes,
sneezes are counted, nasal discharges
are collected, and pruritus, rhinorrhea,
nasal blockage, and ocular symptoms
are scored. Symptom scoring systems
including 10-cm linear analog scales,
4-point severity scales, and other ordi-
nal methods have been used. If there
are no clinical symptoms or significant
changes of rhinomanometric measure-
ments (reduction ⬍ 20% by baseline),
then allergen is deposited into the
nose. An approximate guide for the
starting dose is determined before NPT
(see “Outcomes”). During allergen ap-
plication the patient must hold his
breath to avoid inhaling allergen into
the larynx or lower airways. If the ini-
tial nasal allergen response is negative
after 15 minutes, then the extract con-
centration can be increased 3-fold.
These sequential increments can be
given at 15-minute intervals. Doses are
increased in step-wise fashion until a
positive result is obtained, a maximum
concentration is given without any sig-
nificant reaction, or concentrations of
1:500 wt/vol or higher are reached that
cause nonspecific irritant effects in
nonallergic control subjects, and espe-
cially at levels above 1:100 with house
dust and fungus extracts.35
OUTCOMES
Clinical symptoms of sneezing, itch-
ing, rhinorrhea, and obstructed nasal
airflow, and measures of nasal patency
are evaluated before administration of
each dose of allergen. NPT is stopped
when a positive response occurs. The
intensity of the response is evaluated
by dose of allergen given to patient and
by total system score. True positive
response occurs at an allergen concen-
tration causing at least two of the fol-
lowing three criteria: 5 sneezes, 50%
fall in NPEFR, or rhinorrhea.7 Other
symptom scoring systems have also
been used.4,38 For example, one previ-
ously validated system38 scores the
number of sneezes (0 to 2 ⫽ 0 points;
VOLUME 86, APRIL, 2001
3 to 4 ⫽ 1 point; 5 or more ⫽ 3
points), pruritus (nose, palate or ear ⫽
1 point each), rhinorrhea (0 to 3
points), blockage (1 to 3 points), and
ocular symptoms (1 point). The end-
point is the amount of antigen required
to produce a total symptom score of 5
of a maximum of 13. The severity of
each sensation can also be evaluated
by 10-cm linear visual analog scale:
mild, 1 to 3 cm; moderate, 4 to 7 cm;
and severe, 8 to 10 cm at the dose that
caused a positive response.38 Accord-
ing to German guidelines, positive test
criteria should include flow reduc-
tion ⬎ 40% and/or more than three
score points: secretion, 0 to 2 points
(moderate, 1 point; severe, 2 points);
sneezing, 0 to 2 points (0 to 2
sneezes ⫽ 0 point; 3 to 5 sneezes ⫽ 1
point; ⬎5 sneezes ⫽ 2 points); addi-
tional symptoms such as tearing, itch-
ing (eyes, throat) ⫽ 1 point; conjunc-
tivitis, cough, urticaria, and/or
dyspnea ⫽ 2 points.39 Another investi-
gators considered the positive NPT
with a decrease of 20% or more in
NEPFR and occurrence of nasal symp-
toms such as sneezes, rhinorrhea, nasal
Table 4. Relative Contraindications
1. Episodes of allergic or infectious rhinitis
(2 to 4 weeks)
2. Nasal surgery (6 to 8 weeks after nasal
surgery)
3. Nasal pathology such as polyps,
atrophic rhinitis, or a deviated nasal
septum.
4. Treatment with certain medications.
Recommended withdrawal periods for
drugs before NPT21,28–30
a. antihistamines (48 hours to 1 week)
b. astemizole (4 to 12 weeks)
c. ketotifen (2 weeks)
d. nasal corticosteroids (6 hours to 2 or
3–6 weeks)
e. sodium cromoglycate (1 or 3 weeks)
f. nasal ␣-adrenergic agonist (0 or 1
day)
g. oral corticosteroids ⬎10 mg (2 to 4
weeks)
h. nonsteroidal analgesics (1 week)
i. central nervous antihypertensives
such as reserpine, clonidine (3
weeks)
j. imipramines and related tricyclic
drugs (2 to 3 weeks)
blockage and itching.3,37 Changes in
the nasal temperature (using thermog-
raphy) and the pH of nasal secretions
have also been proposed as endpoints.
Allergen challenge makes the pH more
alkaline, while the temperature in-
creases.40,41 These latter methods are
not widely used.
False-positive results can be caused
by preservatives in extracts such as
phenol, glycerol, benzalkonium chlo-
ride; extremes of extract pH, tempera-
ture, and osmolarity; evaluation within
2 to 4 weeks of allergic, viral or bac-
terial rhinitis; and when allergen ex-
tract concentrations reach 1:500 wt/vol
or higher.28,34,35 Appropriate vehicle
control solutions are essential to iden-
tify nonspecific irritant reactions and
prevent false-positive test results. Ex-
tracts should be used at room temper-
ature and pH of 5 to 8.28 The allergen
should be diluted in isoosmolar solu-
tion such as 0.9% saline or lactated
Ringer’s solution. These issues are es-
pecially important if the allergen ex-
tracts are prepared by the investigator.
Latex solution provides a good illus-
tration of these problems.42
The NPT is considered to be true
negative if the patient has no clinical
symptoms and no changes of nasal pa-
tency after receiving the 1:1,000 wt/
vol extract or maximum allergen
dose.35
False-negative NPT occur after the
use of contraindicated medications;
within 8 weeks of nasal surgery, in
patients with atrophic rhinitis, nasal
polyps, or occasionally after specific
immunotherapy. Subjects with chronic
sinusitis may also have abnormal re-
sults since they have high levels of
baseline mucous secretion, but do not
respond to secretagogues such as
methacholine.43
ALLERGEN DOSING
As a safety measure, it is recom-
mended to begin with a low allergen
concentration. For skin test-negative
patients, the initial dose of allergen
should be in the range of 1:10,000 to
1:5,000 wt/vol, or 50 to 100 PNU
(overall pollen protein concentra-
tion).35 If the initial allergen applica-
357

Figure 1. Protocol of NPT with allergens.
tion is negative, then the extract con-
centration can be increased in 3-fold
sequential increments at 15-minute in-
tervals (1:10,000, 1:3,000, 1:1,000 wt/
vol).34,35 For subjects with positive
scratch and puncture tests, skin titra-
tion is performed with 3-fold dilutions
of extracts. The concentration causing
a 3-mm wheal can be used for nasal
provocation.2 For intradermal tests, the
lowest concentration generating a
wheal can be determined, and a con-
centration 10 times more dilute used
for NPT.34 For atomizer-dosimeter, a
dose of 0.1 mL of allergen per spray
could be used, whereas for the paper-
358
disk method a 10-␮L dose and 4-mm
paper disk could be applied.44
A number of dosing regimens has
been used previously in NPT research
protocols that may be applied to diag-
nostic investigations.3 The dose de-
pends on the technique of delivery,
allergen preparation, and the purpose
of investigation. For the diagnosis of
dust mite allergy in childhood asthma,
10,000 AU/mL in one puff (0.01 to
0.05 mL) was sprayed into each nasal
cavity by a metered dose pump-spray
insufflator with a total dose of 800 to
1,000 AU for both nostrils.45 Nasal
sensitivity to Dermatophagoides pter
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
onyssinus was tested in patients with
mild and moderate skin reactions using
5, 50, 250, 500, and 1000 AU/mL ap-
plied in a fixed volume of 0.1 mL
aqueous solution per puff into each
nostril using metered dose pump
spray.10 Nasal immunotitration with 5,
10, 20, 40, 60, 80, 120, 160, and 240
AU was used before local immuno-
therapy with birch pollen aerosol and
powder methods. The initial treatment
dose was defined as the provocation
dose giving a positive reaction.46,47
Identification of a role of Blomia tropi-
calis as a cause of allergic rhinitis was
performed with concentrations of
1:125,000, 1:25,000, 1:5,000 vol/vol,
1:1,000, and 1:200 vol/vol.48 Compar-
isons of nasal reactions to house dust
and dust mite allergen extracts in skin
positive subjects with perennial rhinitis
were performed with 10, 100, 1,000,
and 2,000 PNU (house dust) and 5, 50,
and 500 PNU (dust mites). Allergic
patients varied considerably in nasal
sensitivity but all reacted to the final
dose.49 Identification of latex allergy
by NPT was performed with a
0.0005% latex solution.42 As can be
seen, the different methods of allergen
standardization such as allergy units
(AU) or biologic units (BU) and mea-
sures of overall pollen protein concen-
tration (PNU, wt/vol) make compari-
sons between studies difficult.
DELIVERY SYSTEMS
For clinical purposes the most accept-
able simple techniques with good re-
producibility involve delivering aque-
ous allergen extract by syringe, bottle
dropper, micropipette or pump action
nasal spray devices.14,35,50,51 Additional
techniques for research purposes in-
clude: a powder and pollen grain in-
sufflator52,53; a “nasal pool” device for
aqueous allergen extracts and soluble
agents54; saturated wads of cotton wool
that are placed under the medial con-
cha of the nose55; impregnated paper
discs placed on the inferior turbinate or
nasal septum with forceps24,56; and
modified airbrush techniques.57 Each
method has its own advantages and
limitations.
 The area of distribution of solutions
deposited via syringes and droppers
cannot be readily predicted. These
bulk application methods have the risk
that, in some cases, fluid may be aspi-
rated into the larynx, inducing cough,
laryngeal irritation, edema, or bron-
chospasm. These unwanted side ef-
fects are very rare if care is taken to
instruct the patient not to inhale force-
fully or bend their head backwards af-
ter the allergen is placed. Carriage of
the allergen posteriorly by mucociliary
clearance past the orifice of the Eusta-
chian tube and into the pharynx may
lead to nasopharyngeal swelling, itch,
or middle ear discomfort or dysfunc-
tion.56 The use of 5- to 10-␮L pipettes
allows the deposition of small, exact
volumes of the allergen directly onto
the turbinate under direct rhinoscopic
control.
Nasal pump spray devices improve
contact of the provocative agent with the
nasal mucosa by distributing it over the
exposed anterior nasal cavity surfaces.
Precise volumes on the order of 100 ␮L
are applied that generally do not lead to
bronchospastic reactions. Unfortunately,
the popular beclomethasone (Vancenase,
Schering-Plough, Kenilworth, NJ and
Beconase, Glaxo Wellcome, Research
Triangle Park, NC) spray bottles have
become difficult to obtain because these
products have been largely replaced in
the market place. Hand-held automizers
generate large-diameter particles, which
helps to avoid the delivery of allergens to
the lower airways. Volumes of 0.2 to 0.5
mL per nostril are arbitrarily but com-
monly used.58 The materials suspended
in the mist may be more readily ab-
sorbed by the mucosa than with the bulk
application methods mentioned previ-
ously. Allergen meter-dose pump spray
was recommended for clinical routine
and research in Europe.4
Pollen grain insufflations can be
used to imitate natural exposures. This
technique is simple and the dose of
pollen grains can be well controlled.59
However, most investigators prefer to
use aqueous extracts because of the
hydroscopic properties of pollen. Very
high doses of pollens are generally re-
quired to obtain large magnitude re-
VOLUME 86, APRIL, 2001
sponses in subjects who are studied out
of the pollen season. Hydration of
dried, defatted pollen grains leads to
the explosive release of a pollen eluate
with high osmolarity60 that may be suf-
ficient to cause irritation reactions in
patients with nonspecific nasal hyper-
reactivity. Similarly, some patients
may have nonspecific reactions to the
lactose that is used to pack the pollen
grains into inert capsules. Generally,
the dose of lactose is insufficient to
cause symptoms in lactose-intolerant
subjects.
The “nasal pool” device, a com-
pressible plastic container with a nasal
adapter, offers significant improve-
ments of provocation and lavage tech-
nique.54 The device can hold a soluble
agent of known volume and concentra-
tion. The adapter is pressed to the nos-
tril and the container compressed to
push the fluid into the nose for a pre-
cise time and in the defined space of
the anterior nasal cavity. The lavage
fluid is collected when the container is
re-expanded. Any soluble agent can be
tested. Even children can use the de-
vice correctly. A disadvantage of this
technique is the unknown dilutional ef-
fect of nasal secretions by lavage fluid.
The devices are no longer available in
the United States.
Topical application of allergenic ex-
tracts by means of cotton wool swabs
in the middle meatus under the medial
concha, impregnated paper discs, or a
modified airbrush technique for appli-
cation onto the inferior turbinate have
been used mostly for scientific inves-
tigations. The site of provocation is
relatively small, but changes in muco-
sal appearance can be observed at both
the local site and more distant mucosal
locations. Placing allergens in the mid-
dle meatus seems dangerous and po-
tentially could lead to sinusitis.
Filter paper discs (3-mm diameter)
impregnated with allergen solution can
be placed bilaterally by forceps on the
anterior part of the inferior turbinate or
nasal septum.61,62 Doses can be in-
creased in step-wise fashion, but the
concentrations used may need to be
individualized based upon the extract
potency.61 Larger discs (8-mm diame-
ter) that are dry can be placed to collect
small, undiluted samples of nasal fluid.
For example, the osmolarity of the ab-
sorbed secretions was evaluated after
nasal provocation with cold dry air and
after stimulation with hypertonic saline
and mannitol solutions (800 to 1,000
mOsmol/kg H2O).63 The discs may
preferentially sample the sol phase of
the epithelial lining fluid, but may also
promote transepithelial exudation of
interstitial fluid from the upper lamina
propria.64
The option of using either unilateral
or bilateral challenges is a great advan-
tage over bronchial provocations. Af-
ter unilateral challenge, ipsilateral re-
sponses are due to local, direct effects
and recruited parasympathetic reflex
effects whereas responses in the con-
tralateral nostril represent “pure” para-
sympathetic reflex effects (Fig 2).65
NASAL PATENCY
MEASUREMENTS
Nasal patency is extremely dependent
on structures such as the septum and
nasal valve. The degree of swelling of
venous sinusoids deep in the mucosa
regulates mucosal thickness, air space
volume and nasal patency. Other fac-
tors that may also participate are mu-
cosal edema, cellular infiltration, and
the presence of luminal secretions.
Several methods are available to mea-
sure nasal airflow resistance: NPIFRs,
NPEFRs, nasal spirometry, passive an-
terior rhinomanometry, active anterior
rhinomanometry, active posterior rhi-
nomanometry, balloon method/intra-
nasal pressure measurements, and os-
cillometry.35,36 The nasal volume can
be measured by acoustic rhinometry.66
The nasal peak flow method is easy to
perform, inexpensive, and reasonably
well correlated with rhinomanometry,
but is less reproducible.36,67 Passive an-
terior rhinomanometry is a suitable
technique for recording air pressure
and airflow during breath-holding and
has been used in children, patients with
problematic dental prostheses, or with
an overactive gag reflex. In contrast,
this technique does not truly represent
the physiologic breathing process.68
Active anterior rhinomanometry eval-
359
uates the pressure/volume or pressure/
flow relationship for the nostril during
tidal breathing. It is the most widely
used technique. However, the active
inspirations cause significant changes
in the nasal valve, resulting in breath-
to-breath variability in measurements.
This technique cannot be used for pa-
tients with fragile and bleeding nasal
mucosa or with frequent sneezing, be-
cause the insertion of nasal adapter of
device can alter the nasal valve.
Changes in resistance may be limited
when there is severe occlusion of a
nostril by turbinate hypertrophy, pol-
yps, septal deviation, or severe rhinor-
rhea at the onset of the study.69 Active
posterior rhinomanometry also records
pressure, volume and flow rates during
tidal breathing. This technique is not
suitable for children, patients unable to
tolerate the close-fitting masks, and
patients who cannot satisfactorily co-
ordinate the required nasal, palate,
glottic, and breathing maneuvers.70
Acoustic rhinometry is a newer
technique that measures the cross-sec-
tional area of the nasal cavity.71 Pulsed
sounds are broadcast into the nose.
Signals are reflected from the mucosal
walls back to a microphone. After
spectral analysis, the cross-sectional
area is plotted as a function of distance
from the tip of the instrument. Changes
in the minimum cross-sectional area
and volume of the cavity can be deter-
mined.
Nasal microcirculation has been
used as an endpoint. Laser Doppler
velocimetry evaluates capillary blood
flow in the superficial mucosa.72 Ra-
dioactive xenon washout and clearance
of hydrogen (3H2) into exhaled nasal
air are limited to research institu-
tions.73 Colorimetric evaluation of mu-
cosal erythema has also been used.74
COLLECTION OF NASAL
SECRETIONS AND
LAVAGE FLUID
The amount, viscosity, and spinability
of the nasal mucous discharge, and
quantity of the mediators, cytokines,
plasma proteins, glandular secretory
products, extracellular matrix mole-
cules and cells in lavage fluids vary in
360
Figure 2. Nasal Provocation. Unilateral administration of allergen or other materials may lead to local,
ipsilateral responses, and parasympathetic reflex effects. Allergen leads to mast cell degranulation with
the release of histamine, LTC4/D4/E4, tryptase, and other mediators. Histamine acts upon H1-receptors
on endothelium to cause vascular permeability and exudation of an albumin-rich, watery discharge.
H1-receptors on nociceptive nerves lead to the sensation of itch. The neural mechanism leading to the
sensation of nasal congestion is not clearly understood. Nociceptive nerves may release neuropeptides
when activated (“axon response” mechanism). Substance P may cause glandular secretion, whereas
calcitonin gene-related peptide may cause vasodilation. Vasodilation with swelling of venous sinusoids
leads to thickening of the mucosa and obstruction to nasal airflow. Histamine, as well as other mediators
and cytokines, plays a key role in regulating cellular infiltration as seen in the late phase response and
clinical allergic rhinitis. Activation of nociceptive nerves recruits bilateral parasympathetic reflexes that
cause acetylcholine-mediated glandular exocytosis.
different forms of rhinitis and in re- anterior flexion of the head combined
sponse to different provocation agents with nasal exhalation. This method
and methods of collection. In clinical samples nasal and nasopharyngeal air-
practice, secretions may be collected ways. ␣-Adrenergic agonists have
by blowing directly onto a plastic film been used to improve fluid recovery.
or into a funnel, cup, or tube. However, Druce and Raphael58,76 began using
interpretation may be difficult if the pump spray devices and collected se-
fluid is viscous or swallowed, collec- cretions by placing a small, soft, red,
tions are incomplete, or the volumes of rubber 8F urethral catheter along the
secretions are small. Secretion of 0.5 floor of the nostril. Unilateral provoca-
mL (0.5 g) with 5 or more sneezes and tions could be performed with secre-
⬎20% decrease in peak flow is con- tions continuously collected from both
sidered a positive test.37 sides. As described above, the nasal
Introduction of nasal lavage fluid pool device is a further refinement for
promotes collection for biochemical challenge, lavage, and collection.54
analysis, but raises the problem of se- These techniques sample large sur-
cretion dilution. Naclerio75 pioneered face areas of mucosa, and can quantify
the method of instilling 4 to 5 mL of vascular, glandular, neuronal, and cel-
lavage fluid directly into the nose us- lular events simultaneously. Nasal la-
ing a pipette. Subjects are required to vages with isoosmolar saline can be
hyperextend their necks and obstruct performed repeatedly without causing
their posterior nasopharynx by palatal nasal mucosal irritation. The disadvan-
closure. Lavage fluid is recovered by tages of repeated nasal lavages are the
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
dilution of samples, the removal of im-
portant target cells such as adherent
eosinophils or metachromatic cells
during the initial provocations, and al-
terations in the dynamics of fluid flux
across the mucosal barrier. In each
method, the degree of dilution of the
original epithelial lining fluid cannot
be determined. However, the addition
of exogenous radiolabeled albumin or
lithium to the lavage fluid permits cal-
culation of the percentage of recovery
in research studies.77,78 These tech-
niques have provided useful informa-
tion about the amount of secretions,
but they do not define their source,
physical properties, or composition.
Measurement of urea in plasma and
lavage fluid provides an estimate of the
volume of epithelial lining fluid sam-
pled.79 These methods are impractical
for office practice. Dry filter paper
discs collect only small quantities of
undiluted secretions, limiting the num-
ber of analytes that can be assayed
with precision.
NASAL CYTOLOGY
Cellular changes during NPT can be
evaluated by nasal smear, blown secre-
tions, cotton swabs, imprints, nasal
scraping, nasal brushes, and biopsy.
Multiple methods of biochemical, his-
tochemical, immunochemical, and
electron micrographic can then be ap-
plied.80 Collection of cells with cotton
swabs is a simple but low reproducibil-
ity technique.81 The advantage of im-
prints and scrapings is that monocytes
and lymphocytes can be enumerat-
ed.82– 84 Nasal biopsy is rarely used for
diagnostic purposes in rhinitis, but it
has provided valuable information
about the ciliary dysfunction, role of
lymphocytes and cytokines in allergic
reactions. Biopsies are the only means
to study the structural elements. The
nature of cellular infiltrates can be
evaluated, but persistent bleeding may
follow the trauma of the biopsy.
LATE-PHASE RESPONSE
The immediate allergic response is
characterized by itch, sneezing, rhinor-
rhea, plasma exudation, and glandular
secretion attributable to the release of
VOLUME 86, APRIL, 2001
mast cell mediators. The clinical
symptoms of the late phase response
are limited to nasal congestion, poste-
rior drainage of secretions, and sinus
or facial pressure. Cell, mediators, cy-
tokines, and neurohormones in the na-
sal secretions of the late phase re-
sponse are different from those of
acute response.18,85,86 The clinical im-
plications of having a late phase re-
sponse after NPT are still debated. The
European Academy of Allergy and
Clinical Immunology’s recommenda-
tions for investigation of late-phase re-
actions entail assessments at 0.5, 10,
20, 30, 45, 60 minutes, then every hour
to 10 hours after provocation.2 If a
positive allergen response occurs, then
the subject should be challenged with
the diluent to determine whether it had
induced a false-positive response. The
times for evaluation after the vehicle
challenge should be exactly the same
as after the allergen. Both placebo re-
actors and subjects with nonspecific
hyperresponsiveness will be detected.
OTHER PROVOCATION
AGENTS
Histamine produces the triple response
of nerves in the skin and causes an
analogous pattern in the nose: stimula-
tion of a population of H1-receptor
bearing type C neurons that mediate
itch that recruit cholinergic parasym-
pathetic reflexes that induce glandular
exocytosis; stimulation of plasma ex-
travasation with stimulation of endo-
thelial H1-receptors leads to exudation
of plasma into the lamina propria lead-
ing to edema with hydrostatically
driven exudation across the epithelium
into the nasal cavity to cause watery
rhinorrhea and vasodilatation of deep
venous sinusoids leading to mucosal
thickening, reduced nasal patency, and
obstruction to airflow. All of these
mechanisms are seen on the ipsilateral
side after unilateral histamine provoca-
tion, whereas only the reflex-induced
glandular secretion is seen in the con-
tralateral nonchallenged nasal cavi-
ty.87– 89 Methacholine induces glandu-
lar secretion only.90 Challenge with
histamine and methacholine have been
widely carried out for exploring of
nonspecific nasal hyperreactivity. Cap-
saicin stimulates nociceptive type C
fibers and neuropeptide release from
their sensory nerve endings. Capsaicin
provocations stimulate excessive glan-
dular secretion in a subset of vasomo-
tor rhinitis subjects.91 Capsaicin also
damages C fibers, and has been pro-
posed as a treatment for nonallergic
rhinitis.92 Bradykinin (BK) induces va-
sodilatation and vascular permeability
because of the stimulation of vascular
BK-B2 receptors.89,93 BK receptors on
sensory nerves are upregulated in se-
vere allergic rhinitis and lead to acti-
vation of cholinergic reflexes.94 Nico-
tine and serotonin also induce sensory
nerve stimulation with presumed axon
responses and cholinergic reflexes. Ir-
ritants such as ozone, sulfur dioxide,
formaldehyde, cigarette smoke, organ-
ic-solvent fumes, and cold air (or re-
warming after cold exposure) induce
nasal obstruction and rhinorrhea that
may be attributable to mast or epithe-
lial cell damage, the stimulation and
depolarization of trigeminal sensory
nerves, and the induction of axon re-
sponses and parasympathetic reflex-
es.65 Nasal and bronchial inhalations of
hypertonic solutions of saline, manni-
tol or other solutes have been used to
investigate nonspecific irritant and
neural sensitivity, and may offer in-
sights into exercise-induced asth-
ma.60,95–98 NPT with acetylsalicylic
acid and lysyl-acetylsalicylic acid is a
helpful procedure for diagnosis of as-
pirin-sensitive asthma, but is less sen-
sitive than oral challenge.99 Lysyl-ace-
tylsalicylic acid is not approved for use
in the United States.
CONCLUSION
As the methods of NPT become more
standardized, we anticipate that NPT
may become a more frequently used
clinical tool. Its place will be to define
the presence of allergic rhinitis when
the history is highly suggestive but
skin testing and RAST testing are neg-
ative, for the evaluation of unique or
occupational allergens, and to demon-
strate nonallergic, irritant, or nasal hy-
perresponsiveness mechanisms. In
these instances, the NPT responses
361
may lead to more appropriate and fo-
cused therapy. These tests may also be
useful to determine whether allergen-
specific IgE that can be detected in
nonallergic nasal polyp and sinusitis
subjects are relevant to the develop-
ment of these “nonatopic” diseases.
The nasal mucosa will also be of value
as a surrogate for bronchial testing,
and will continue to provide useful in-
formation about the pathogenesis of
airway diseases.
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Requests for reprints should be addressed to:
James N. Baraniuk, MD
Division of Rheumatology, Immunology, and
Allergy
Lower Level Gorman Building
3800 Reservoir Road, NW
Georgetown University, Washington, DC
20007-2197
E-mail: baraniuj@gunet.georgetown.edu
2. Which of the following is NOT an
absolute contraindication for
NPT?
a. Acute period of allergic rhinitis
b. Mild asthma in remission
c. Previous anaphylactic reaction
to an allergen
d. Acute viral or bacterial rhinitis
and sinusitis
e. Pregnancy
 3. Which of these statements is
false?
a. NPT can be done 4 weeks after
the episode of allergic or infec-
tious rhinitis
b. Polyps, atrophic rhinitis, and
deviated nasal septum are ab-
solute contraindications for
NPT
c. NPT can be done 6 weeks after
nasal or sinus surgery
d. Nasal congestion can result
from oral contraceptives and
preparations containing sulfite
preservatives
e. NPT should not be done in
VOLUME 86, APRIL, 2001
patients with restricted lung ca-
pacity (TLC ⬍60%)
4. A positive NPT is determined by:
a. The maximum allergen dose
that patient received
b. Self-report scoring of clinical
symptoms
c. 10-cm linear visual analog
scales of symptoms
d. Measures of nasal patency
e. The assessment of clinical
symptoms scores, nasal secre-
tion, and nasal patency mea-
surements
5. Which of these statements is
false?
Answers found on page 386.
a. NPT is a well standardized
method and is frequently used
in clinical practice in the
United States
b. NPT has shown promise for the
diagnosis of allergic and occu-
pational rhinits
c. The analysis of mechanisms of
NPT responses may lead to a
more appropriate and focused
therapy
d. There is a wide variety of NPT
test techniques for research
e. NPT provides useful informa-
tion about the pathogenesis of
airway diseases
365