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Nasal provocation challenge

Howard Druce
Journal of Allergy and Clinical Immunology

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 Nasal provocation challenge
Report of the Committee on Upper Airway Allergy,* Howard M. Druce, MD,
and Michael J. Schumacher, MD St. Louis, Mo., and Tucson, Ariz.
Provocation of symptoms of acute allergic rhinitis
by nasal challenge with allergens has been used as a
diagnostic procedure for more than a century. ~ How-
ever, it has not been applied extensively in clinical
practice. Techniques for NPC, discussed in several
articles, 2-s are being applied with increasing frequency
to clinical evaluation and research studies of patients
with rhinitis. In addition, the accessibility of the nose
for clinical investigation allows use of NPC in studies
to model lower airway disease. As technology has
advanced, more sophisticated parameters of nasal re-
sponse, such as chemical mediator production,9 nasal
airway resistance, ~~ and nasal mucosal blood flow, J~
have been measured. A profusion of methods for nasal
challenge and for study of upper airway responses has
suggested the need for guidance on appropriate meth-
ods for clinical practice and identification of areas that
require more research.
In most cases of uncomplicated allergic rhinitis, a
detailed history and careful physical examination,
supplemented by correctly performed skin tests, are
sufficient to make a diagnosis that will permit rational
therapy. ~2In more complex or obscure cases, a variety
of procedures and laboratory tests may be selected to
confirm a diagnosis (Table I). ,3 Definition of the pre-
cise casual relationship between specific allergens and
symptoms may be important when skin test or in vitro
testing conflicts with the history and physical exam-
ination, but in routine clinical practice, this may be
necessary only when decisions about allergen avoid-
ance become a major issue or when immunotherapy
is contemplated. Documentation of specific allergenic
causes of symptoms can be important in the workplace
Reprint requests: Howard M. Druce, MD, Division of
Allergy/ImmunologySt. Louis University School of Medicine,
1402 S. Grand Blvd., St. Louis, MO 63104-0081.
*'Nasal ProvocationSubcommittee:Howard M. Druce, MD (Chair-
man), Eric P. Brestel, MD, Gerald A. Buchohz, MD, Philip
Fireman, MD, John W. Geo~itis, MD, Albert E. Hensel, Jr.,
MD, Lowell M. Jones, MD, Herbert C. Mansmann, Jr., MD,
Minoru Okuda, MD, William E. Pierson, MD, Richard Rosen-
thai, MD, FACP, Howard J. Schwartz, MD, Gail G. Shapiro,
MD, Peter Small, MD, and Robert G. Townley, MD.
1 / 1 / 22269
Abbreviation used
NPC: Nasal provocation challenge
if continued employment depends on continued ex-
posure to a suspected allergen.
Currently, there is no accepted standardized method
for NPC. For this reason, this Committee considers
that results of NPC should be interpreted with caution
until there are data that correlate results of a particular
method of NPC clearly and consistently with an ac-
curate diagnosis in individual patients.
DEFINITION
NPC may be defined as a means to reproduce the
responses of the upper airways to natural exposure to
allergens or irritants and to study the pathophysiology
of upper airway disease by testing responses to pu-
tative biochemical mediators. NPC may be used to
answer specific questions, such as whether or not a
patient is nasally sensitive to an antigen or irritant, to
determine the degree of nasal sensitivity, and to study
factors that infuence nasal sensitivity.
To simulate clinical effects, environmental agents,
such as pollens, pollen extracts, dusts, or cold air,
may be placed in the nose. Symptoms produced, such
as nasal obstruction, sneezing, or mucus hypersecre-
tion, may be assessed. These may be compared to
objective measurements, such as nasal airway resis-
tance, cellular influx, and mediator release.
APPLICATIONS OF NPC
There are certain circumstances under which NPC
might prove useful in confirming a clinical diagnosis,
for example, difficulties in interpretation of skin tests
and other IgE-mediated diagnostic tests, and study of
reactions to solutions or vapors containing chemical
irritants encountered in industrial exposure. If a par-
ticular component of an effector pathway is believed
to be causing symptoms or is under investigation,
synthetic analogs may be introduced. Examples in-
clude neurohormone analogs, such as methacholine
261
262 Druce and Schumacher
TABLE I. Adjunctive tests in diagnosis of
nasal disease
1 Nasal cytology
2 Total and specific IgE measurements
3 Radiographs
4 Fiberoptic rhinolaryngoscopy
5 Rhinomanometry
6 Nasal provocation challenge
or phenylephrine. Investigation of pathophysiologic
mechanisms may be conducted with the use of selec-
tive antagonists, such as antihistamines or anticholin-
ergics.
Safety and efficacy of therapeutic agents that can
be absorbed across the nasal mucosa may be assessed
by NPC experiments. Orally absorbed agents can be
evaluated by their effect on enhancing or inhibiting
an NPC experiment. For example, oral antihistamines
may be evaluated by studying their effects on inhib-
iting a standardized nasal challenge with histamine or
allergens. Methodology for evaluation of antihista-
mines will be recommended in another Position State-
ment of this Committee. Intranasal inoculation with
viruses is another specialized form of NPC and may
be used to study efficacy of vaccines or other antiviral
agents. Low levels of environmental pollutants, such
as ozone, SOz, and other irritant gases, have been
introduced into the nose to study both nasal and sys-
temic consequences.
NPC WITH ALLERGENS AS AN
OFFICE PROCEDURE
NPC with allergens differs from allergen broncho-
provocation in that it is generally a safe procedure for
patients with allergic rhinitis, provided that precau-
tions against severe allergic reactions are taken. Al-
though its safety for patients with rhinitis and stable
asthma has been suggested, 14 its safety for challenge
of patients with rhinitis and unstable asthma has not
been documented.
For NPC to be a reproducible procedure, allergen
delivery to the nose must be quantitative. Since de-
livery of small volumes (<2 ml) by droppermay result
in uneven and unpredictable distribution in the nasal
cavity, this method should not be used. Atomizers are
acceptable provided that they are calibrated for deliv-
ery within a range of +- 10% (or SD, __-4%)of volume
delivered. Paper disks are also acceptable, provided
that allergen is applied to the disk with an accurate
pipette that delivers in the 10 p.1 range. Concentrations
of allergens suitable for use in challenge tests vary
widely, depending on the potency of the allergen ex-
tract and the expected sensitivity of the patient. As
J. ALLERGY CLIN. IMMUNOL.
AUGUST 1990
an approximate guide, starting concentrations of
grass-pollen extract of 5 Ixg/ml dialyzed dry weight
(approximately equivalent to a 1:10,000 wt/vol of
extract) could be used in an atomizer-dosimeter that
delivers 0.1 ml per spray, increasing the dose in three-
fold to fivefold increments during the procedure. 8 For
the paper-disk method, 0.5 Izg / ml of grass-pollen ex-
tract could be applied in a 10 ixl dose to a 4 mm paper
disk. Lyophilized allergen extracts or pollen grains
mixed with lactose may also be suitable, but technical
difficulties involved in ensuring accurate delivery
place these techniques beyond the capabilities of most
allergists' offices at the present time. Delivery should
avoid deposition of allergen in the lower airways. The
spray method with atomizers must ensure delivery of
large droplets that are deposited in the nose after
breath holding at total lung capacity. This precaution
also applies to use of particulate allergen dispersed in
powders.
Baseline nasal function should be assessed in the
office for at least 20 minutes before the deposition of
any materials in the nose. Longer periods will be
required for persons who are allergic to aeroaller-
gens and are being studied during their symptomatic
season, particulary when NPC is done in an air-
conditioned environment. Problems of impaired base-
line nasal function and "priming" effects may preclude
NPC during the subject's symptomatic season. Re-
sponse to challenge with diluent must be measured
before testing with allergen. The specific response of
the active agent can then be calculated by subtraction
provided that the nonspecific response is only a small
fraction of the expected response to the specific agent.
It should be noted that some commonly used tech-
niques administer doses of antigen far in excess of
doses normally encountered during natural pollen ex-
posure. Challenge with a single dose of allergen is
not recommended because allergic subjects vary con-
siderably in the threshold amounts of allergen required
to induce symptoms and because quantitative infor-
mation on the degree of nasal sensitivity to allergen
may be as important as measurement of nasal reac-
tivity (the severity of the nasal response). A test with
a single concentration of allergen may not be more
informative than a simple skin test. For most purposes,
challenge with fivefold dilutions of allergen extracts
allows for convenient and safe determination of nasal
sensitivity? s Allergens used for challenge should be
standardized so that results of rechallenge of the same
patient may be compared with the initial study and
nasal sensitivity of all patients challenged by the same
method may be compared. In the absence of immu-
nologic standardization of the extract, a sufficiently
large single lot of lyophilized extract, divided into
small aliquots, can be used.~S
VOLUME86
NUMBER 2
Symptomatic responses to NPC include upper air-
way itching, sneezing, increase and alteration of nasal
secretions, and changes in nasal obstruction. Scoring
of the severity of each of these symptoms may be too
subjective to be clinically useful and should be sup-
plemented by an objective measurement technique.
Among the objective techniques for study of nasal
responses, rhinomanometry is the only accurate and
well-researched method currently available for office
practice. Rhinomanometry is preferred to nasal peak
flow measurements because the latter, being effort
dependent, are unreliable and poorly reproducible.
Anterior rhinomanometry is more convenient than
posterior rhinomanometry as an office procedure be-
cause of the difficulties many patients have in per-
forming posterior rhinomanometric maneuvers. How-
ever, left and right nasal resistances should both be
measured after bilateral nasal challenge to control for
changes from nasal cycling.
Rhinomanometry alone may be inadequate because
patients vary in the relative severity of obstruction,
sneezing, and mucus secretion during an allergen chal-
lenge. Measurement of nasal obstruction may be sup-
plemented with counts of sneezes and assessment of
the degree of nasal hypersecretion to produce a com-
posite score. Although the volume of excess nasal
secretions flowing through the anterior nares has been
measured during NPC, 16the total secretory rate is very
difficult to quantify precisely. Secretions may be an-
alyzed for proteins, chemical mediators, and cells, 6
but these methods are not yet applicable to routine
office procedures.
S U G G E S T I O N S FOR RESEARCH O N
NPC M E T H O D S
9A considerable body of information on the patho-
physiology of nasal disease is being accumulated
through use of a variety of methods for NPC and
evaluation of responses to challenge. Because indi-
vidual research objectives vary, this Committee does
not advocate the use of specific techniques. Use of
NPC with mediators, irritants, and hyperosmolar so-
lutions to measure nasal reactivity has begun 17-22 but
needs confirmation and extension before this type of
testing can be applied in the redefinition of a variety
of allergic and nonallergic rhinitic syndromes and for
clinical diagnosis.
The relevance of the available methods to clinical
practice remains controversial and should be defined
by the results of continued research. For example,
many protocols for NPC with allergens do not attempt
to reproduce the conditions of natural exposure to
allergens, partly because of inadequate availability of
reliable aerobiologic data. For NPC to be clinically
useful, it should have diagnostic sensitivity and spec-
Nasal provocation challenge 263
ificity for nasal disease, and nasal sensitivity to al-
lergens or air pollutants should correlate with the se-
verity of symptoms experienced on natural exposure
to those agents. There are occasional studies of use
of allergen NPC in parallel with symptom scoring for
study of efficacy of immunotherapy, z3' 24 However,
there is a need for additional studies specifically de-
signed to study seasonal changes in nasal sensitivity
measured by carefully performed NPC to test short-
term reproducibility of NPC within individual pa-
tients and to test relationships of NPC to clinical pa-
rameters and to other tests, for example, skin testing
and in vitro IgE antibody tests.
Since NPC is not yet used in many research labo-
ratories, there is a need for evaluation of the repro-
ducibility of NPC among different investigators in
several laboratories, applying a single method to de-
fined patient populations. The technique selected for
antigen delivery and response assessment should lend
itself to double-blind evaluation, and the study should
involve adequate numbers of patients and control sub-
jects. The results of repeated testing should be cor-
related with severity of clinical symptoms evaluated
for more than one season. There is also a need for
comparative studies of delivery methods, for example,
atomizers, paper disks, and whole pollen grains to
determine relationships between nasal sensitivity mea-
sured with different NPC methods in the same sub-
jects. Training for each challenge technique should be
standardized. Funding for such a project would have
to be obtained from a central source.
Although nasal blood flow has been demonstrated
to increase during NPC with allergen" and leukotriene
D4, 25 it does not correlate well with nasal airway re-
sistance, and its functional significance needs further
study. Since nasal hypersecretion is an almost invari-
able allergic response to allergen challenge, better
methods should be developed to quantify the total
nasal secretory rate and relate this to other variables,
such as mucociliary transport and mucus biochemis-
try. More research is needed to study the effects of
NPC on eustachian tube function, whereas the effects
of NPC on mucus secretion in paranasal sinuses awaits
investigation.
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