The consideration of immunotherapy in

the treatment of allergic asthma

Peter S. Creticos, MD Baltimore, Md
Immunotherapy has undergone rigorous trials to assess its
therapeutic benefit in the treatment of allergic respiratory dis-
ease. The tools of molecular biology have provided a frame-
work with which to begin to understand the mechanistic
effects of immunotherapy on the underlying inflammatory
component of allergic respiratory disease. The clinical rele-
vance of these observations belies our understanding of aller-
gic inflammation as the subsoil for the development of ahnor-
mal airway physiology, heightened bronchial reactivity, and
the development of chronic asthmatic symptoms. Immunother-
apy provides the potential to downregulate this inflammatory
cascade, reduce IgE antibody production, and attenuate symp-
toms. Conceptually, early intervention of allergic disease holds
the most promise as a therapeutic intervention capable of
arresting the progression of the disease, altering the severity of
the disease, and/or preventing the development of the respira-
tory disease process. (J Allergy Clin 1mmunol2000;105:S559-
74.)
Key words: Immunotherapy, asthma, nllergic respiratory disease,
aemallergem
Immunotherapy is a therapeutic intervention in which
the patient is administered increasing doses of an extract
comprised of the specific allergens to which the patient
has been demonstrated to be allergic. Its underlying con-
struct is to modulate the patients immune response and,
in so doing, attenuate or eliminate the patients symptoms
on exposure to the relevant allergen(s). Immunotherapy
has been successfully used for the treatment of allergic
rhinitis, allergic asthma, and insect sting (venom) sensi-
tivity. This article will focus on the indications for and
therapeutic benefit of immunotherapy in the treatment of
allergic respiratory disease.
Immunotherapy is considered an appropriate therapeu-
tic intervention in those patients with properly diagnosed
allergy: (1) patients who have experienced an inadequate
or only partial response to environmental control and/or
pharmacotherapy, (2) patients who have experienced side
effects related to medication therapy, (3) patients who
have persistent symptoms as a result of exposure to rele-
vant allergen(s) on a seasonal or perennial basis, (4)
patients in whom compliance with the use of daily med-
From the Division of Allergy and Clinical Immunology, Departmem of Med-
icine, The Johns Hopkins University School of Medicine.
Reprim requests: Peter S. Creticos. MD, Johns Hopkins Asthma and Allergy
Cemer. 5501 Hopkins Bayview Circle-Room 28.57. Baltimore. MD
21224.
Copyright 0 2OOO by Mosby. Inc.
009 I -6749/2WO $12.00 + 0 1/0/100090
Abbreviation used
HRF: Histamine-releasing factors
ications is a factor, and (5) patients in whom perennial
disease results in a cost burden related to environmental
measures and chronic medication use.1
RELEVANT ALLERGENS
Asthma reflects an oftentimes heterogeneous disease
process with multiple triggering factors. However,
insight into the epidemiologic and pathophysiologic fea-
tures of the disease bears out the critical role that sea-
sonal aeroallergens (pollens, mold spores) play in trig-
gering episodic and/or seasonal exacerbations and that
certain perennial aeroallergens (eg, dust mites, animals,
cockroaches) play in inducing persistent inflammation
and chronic disease (symptoms).
Whole, intact pollen grains (eg, ragweed, 23 pm diam-
eter), when blown directly into the nose, trigger a typical
allergic response with sneezing, rhinorrhea, and mediator
release in nasal secretions.2 However, Wilson et a13
demonstrated that particles more than 10 pm diameter
are too large to reach the lower airways; hence they do
not induce either a clinical or physiologic response. In
contrast, Rosenberg et a14 demonstrated that fragments of
ragweed pollen grains (approximately 7 pm), or an
extract of ragweed pollen, when blown into the lower air-
ways, readily induced both an immediate and a late asth-
matic response.
Aerobiologic studies by Agarwal et al5 indicate that a
significant amount of total allergenic activity in the air
during the ragweed pollen season is the result of pollen
fragments and microaerosol suspensions of pollen pro-
tein (Amb a 1; Fig 1). Similarly, these investigators
showed that total mold allergen levels reflect both intact
spores and mold fragments, mycelial elements, and solu-
ble mold protein (Ah 1).
Of clinical relevance is that although hay fever symp-
toms parallel the outdoor pollen count, asthma symptoms
are more accurately correlated with total airborne aller-
genic activity, reflective of the presence of smaller air-
borne particles (~10 pm) that can easily reach the lower
respiratory tract.
Tangential to this observation, the indoor environment
plays a critical role in terms of exposure to aeroallergens
capable of inducing perennial allergic disease. House
dust mites, animals, insects, and mold can induce chron-
s559
S560 Creticos
RW pollen
(count/m 3 ah)
SRW allergen
(RIUa/m3 air)
Antigen E
(ng/m3 air)
scores
2ooo
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1200
800
400
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FIG 1. Results of 24-hour samples from July 1 to Ott 1, 1980, for
atmospheric ragweed (RI&j pollen counts, short ragweed (.SR!&l
allergenic activity, antigen E content, and average symptom
scores of SRW-sensitive individuals (From Agarwal MK, Swanson
MC, Reed CE, Yunginger JW. lmmunochemical quantitation of air-
borne short ragweed, Alternaria, antigen E, and Alt-l allergens: a
two-year prospective study. J Allergy Clin lmmunol 1983;74:40-5.
By permission.)
ic, persistent (allergic) asthma. House dust mites have
been shown to be an important cause of allergic rhinitis,
atopic dermatitis, and asthma. Various species have been
shown to predominate dependent on the microenviron-
ment of the geographic locale. In North America, Der-
matophagoides farinae and D pteronyssinus and Euro-
goyphus maynei are common. Storage mites, including
Blomia, found in stored foods and grains, may also be an
important species.6
House dust mites thrive in damp, humid areas (70%-
80% relative humidity) and during warmer months.
Although their growth season occurs in late summer
through late fall, they are most problematic during the
indoor heating season, a result of the heat/ventilation sys-
tems dispersing their fecal matter and decaying body
parts throughout the indoor air.
House dust mites live off shed human skin. Hence, the
dust mite allergen load is most pronounced in mattresses,
pillows, carpeting, and upholstered furniture. An impor-
tant point is that, even during the coldest, driest periods
of the year, the indoor microenvironment (bed, covers)
may still be conducive to mite survival.
Methods to measure mite allergen levels in the indoor
environment have shown a correlation between the risk
for sensitization and the potential development of asthma
with mite levels (>2 pg of Der p 1 per gram of dust).7
Furthermore, asthma exacerbations have been correlated
with levels of more than 10 pg Der p 1 per gram of dust.*
J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
Mite particles can vary from 5 to 20 pm in diameter.
Hence, those particles 10 pm or less are more easily
capable of traversing to the lower respiratory tract and
triggering asthma.
Over 50% of homes in the United States have domes-
ticated pets. By their very nature, they tend to be in close
contact with household members, often sleeping in the
bedrooms, if not on the bed of a family member. Approx-
imately 15% to 30% of patients with allergy have posi-
tive skin tests to cats and dogs. Fe1 d 1 is the major aller-
genic protein in cats. It is produced in cat saliva and from
sebaceous glands of the skin (dander). Other potentially
important allergens (albumin proteins) are found in the
urine. In dogs, Can f 1 is the major allergen found in sali-
va and dander. It does not cross-react with Fe1 d 1. In
rodents (rat/mice) urinary protein appears to be the dom-
inant source of allergen. In rabbits and guinea pigs, both
saliva and urine are important sources of allergenic pro-
tein.9
An important factor with cat allergy is that a consider-
able portion of the allergen load is less than 5 pm in
diameter. Hence, it is easily capable of reaching the
lower respiratory tract. Furthermore, it is quite sticky and
easily carried on clothing from 1 house to another. In
fact, significant levels of cat allergen have been measured
in homes without pets. It is also quite buoyant, capable of
staying suspended in the air for up to 18 to 24 hours, as
contrasted to dust mite particles that are relatively heavy
and tend to fall to the ground within 1 to 2 hours.9
Cockroaches are an important source of indoor aller-
gen in certain parts of the United States. Semitropical
southern climates and overcrowded, older buildings in
the inner city are prime areas for cockroach infestation.
Correlations have been shown between cockroach sensi-
tization and acute exacerbations of asthma and inner city
asthma. Three major cockroach species appear to be rel-
evant: German (Blattela germanica), American (Peri-
planeta americana) and oriental (Blatta orientalis). The
allergen source appears to be present in decaying body
parts, fecal matter, and saliva.10
PATHOPHYSIOLOGIC FEATURES
Allergen exposure induces both humoral and cellular
events. The immediate (acute) allergic response (eg,
exposure to cat) results in IgE-dependent mast-cell acti-
vation, preformed mediator release (eg, histamine), and
newly generated synthesis of mediators from the arachi-
donic acid pathway (eg. leukotrienes and
prostaglandins). Coincident with this, allergen is also
taken up and processed by antigen-presenting cells (eg,
macrophages, dendritic cells, Langerhans cells) with the
presentation of specific peptide sequences to T lympho-
cytes. In the patient with allergy, costimulatory signals
result in clones of CD4+ T,,+-type T cells being induced
to express specific cytokine (IL-3, IL-4, IL-5) that can
have direct effects on a variety of inflammatory cells
(mast cells, basophils, eosinophils) and antibody-produc-
ing B cells, to further enhance cell-to-cell interactions,
J ALLERGY CLIN IMMUNOL Creticos S561
VOLUME 105, NUMBER 2. PART 2
Allergic Inf
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U
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T
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lammation
E Histamine
S
Tryptase
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Den, r TS
Allergen
Antibody
I-
Basic proteins
1
LTs
cylokims
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LTs
CjditlCS
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0
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s
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FIG 2. Schematic of allergic inflammation. LTs, Leukotrienes; Eos, eosinophil; Bas, basophil. (From Creticos
PS. Peptide downregulation of the immune response. In: Marone G, Austen KF, Holgate ST, Kay AE, Licht-
enstein LM, editors. Asthma and allergic diseases: physiology, immunopharmacology and treatment. San
Diego (CA): Academic Press; 1998. p. 407-15. By permission.)
antibody (IgE) production, and inflammatory responses
(Fig 2).11-3
This complex unfolding of cellular events leads, on the
1 hand, to acute clinical symptoms (such as occurs when
the patient with allergy is exposed to a cat) and, perhaps
of more relevance to the underlying allergic inflammato-
ry cascade, results in the development of a smoldering
clinical process because of persistent exposure to a rele-
vant allergen (eg, a cat in the home).
Hence, the IgE-mediated allergic cascade is a reflec-
tion of an immediate phase of reactivity, the subsequent
development of a late phase of clinical symptoms (the
result of cellular recruitment, mediator release, and
inflammation) and, in many patients, the development of
nonspecific airway hyperreactivity (whereby not only the
relevant allergen[s], but also nonspecific irritants [pollu-
tants, smoke. cold air] become factors capable of trigger-
ing symptoms).
Laboratory methods using skin, nasal, or bronchial
provocation provide the opportunity to characterize this
clinical allergic response and to further investigate the
underlying cellular and biochemical inflammatory
process. Vamey et aIt4 used skin and nasal biopsy speci-
mens to study severe grass-allergic rhinitis. Biopsy spec-
imens from these patients with allergen-induced late-
phase cutaneous responses demonstrated an infiltration
of CD4+ T lymphocytes; GM-CSF, IL-3, and T,*+-type
cytokines (IL-4, IL-5); and recruitment and activation of
eosinophils.
Various investigatorsz~ts~te have used ragweed nasal
provocation to induce both acute clinical symptoms (of
allergic rhinitis) on challenge and have shown that this
correlates with the appearance of various inflammatory
mediators (histamine, prostaglandins, leukotrienes,
kinins) in nasal secretions. In a significant percentage of
these patients with allergy, a recrudescence of symptoms
occurs approximately 6 to 11 hours after allergen provo-
cation. This late-phase response is characterized by a
secondary recruitment of certain inflammatory cells
(eosinophils, basophils), resulting in a secondary wave of
inflammatory mediators. This not only results in a per-
sistence of airway inflammation but appears to also play
a role in the development of a heightened airway respon-
siveness to not only specific allergic stimuli but also var-
ious nonspecific irritant stimuliI
Using bronchial provocation with ragweed, it is possi-
ble to demonstrate the same characteristic pattern of an
immediate allergen-induced response, followed by a late-
phase bronchial reaction with a similar profile of inflam-
matory mediators measurable in bronchial lavage fluids
9562 Creticos
l
J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
AA
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FIG 3. Late-phase cellular responses after segmental airway challenge with saline solution and antigen in
subjects with asthma. Control lavage was performed at the time of saline solution and antigen instillation
into separate airway segments. After 17 to 22 hours, bronchoalveolar lavage was performed in challenged
segments. Cells were enumerated by Giemsa-type and alcian blue stain, and total cells of each type were
calculated on the basis of total cells recovered and differential enumeration. Antigen challenge increased
total cell recovery (*PC .05), lymphocytes (Ly; l P < .Ol), eosinophils (0, alcian blue-positive cells (As+),
basophils. and indeterminate alcian blue-positive cells compared with control. A large neutrophil (IV)
response was observed in both saline solution-challenged and antigen-challenged sites but was not signif-
icant because of large individual variability. Macrophages (Mac) and bronchial epithelial cells (Br) did not
change. Increases in total lymphocytes, eosinophils, alcian blue-positive cells, basophils, and indeterminate
alcian blue-positive cells were observed after antigen challenge compared with saline solution-challenged
sites (AP < .05; MP< .Ol). The vast majority of alcian blue-positive cells (97%) were basophils. (From Liu
MC, Hubbard WC, Proud D, et al. Immediate and late inflammatory responses to ragweed antigen challenge
of the peripheral airways in allergic asthmatics. Am Rev Respir Dis 1991;144:51-8. 0 1991 American Lung
Association. Official Journal of the American Thoracic SocietY.)
of these subjects with allergic asthma. Casale et als used
a model of bronchial allergen challenge to provide evi-
dence for mast cell-derived mediator (histamine) as a
basis for antigen-induced bronchial constriction.
Liu et alI9 performed segmental allergen challenge
and demonstrated a significant increase in T cells,
basophils, and eosinophils in the lungs at 18 hours after
the challenge. This observation correlated with the pres-
ence of specific inflammatory mediators from these cells
in the bronchoalveolar lavage fluids (Fig 3).
MECHANISMS OF IMMUNOTHERAPY
As discussed, T cells appear to play a major role in
orchestrating the unfolding of the allergic inflammatory
response. Rocklin et alzu showed that the peripheral
blood of individuals with allergy underwent enhanced
proliferation and cytokine production when incubated
with allergen. However, when these subjects were treat-
ed with immunotherapy, these lymphocytic responses
were decreased, and an increased activity of antigen-spe-
cific suppresser cells was observed.
Certain cytokines, termed histamine-releasing factors
(HRF) have been demonstrated to induce mast-cell and
basophil histamine release.2t Iliopoulos et al22 demon-
strated a significant correlation between (IgE-dependent)
HRF-induced basophil histamine release and the severity
of symptoms observed during the late-phase nasal
response. Alam et al studied individuals with asthma
and demonstrated a correlation between the spontaneous
production of non-IgE-dependent HRF from peripheral
blood mononuclear cells and the concentration of hista-
mine required to produce a 20% fall in FEV, value. Kuna
et al? accentuated the clinical relevance of this observa-
tion by showing that in grass-immunized subjects, a sig-
nificant shift (decrease) in spontaneous HRF production
by mononuclear cells was observed and that this
appeared to parallel the improvement in histamine
(PD,(J after 2 years of grass immunotherapy.
Varney et alzs studied the effects of Timothy grass
immunotherapy in 40 adults with severe seasonal grass-
induced pollinosis whose condition had been poorly con-
trolled by pharmacotherapy. Significant clinical improve-
ment was observed with a reduction in clinical symptoms
and a reduced need for supplemental rescue medica-
tions for control of symptoms during the grass-pollen
season. Furthermore, using immunohistologic staining
techniques on skin biopsy tissue, the investigators
showed a reduction in the number of CD4+ T lympho-
cytes and in the number of activated eosinophils recruited
into the dermis after allergen stimulation in the immunized
group of patients. In contrast, in the placebo-injected
J ALLERGY CLIN IMMUNOL
Creticos S563
VOLUME 105. NUMBER 2, PART 2
group. significant increases in total leukocytes, T lym-
phocytes, macrophages. and eosinophils were observed.
With in situ hybridization techniques, enhanced expres-
sion of mRNA for T,,,-type cytokines (IFN-y, IL-2) was
observed in most of the patients studied. However, no
effect of immunotherapy was demonstrated on the
expression of Ta2+ inflammatory cytokines (IL-4, IL-5).
A similar series of findings was observed with nasal
biopsy specimens of patients participating in this grass
immunotherapy study. Again, a significant reduction in
allergen-induced CD4+ T cells, in total and activated
eosinophils, and a significant increase in the message for
IFN-y and IL- 12 were observed.26
Jute1 et a117 simulated peripheral blood mononuclear
cells from honeybee-allergic individuals with the prima-
ry allergen from honeybee venom, phospholipase A. In
venom-immunized patients, they observed a decreased
IL-4 and IL-5 secretion and an increased IFN-y secretion.
This is in contrast to the findings of Secrist et aIs who
likewise studied cultured peripheral blood mononuclear
cells from grass-allergic patients who were undergoing
maintenance allergen immunotherapy. Although these
investigators demonstrated a significant decrease in aller-
gen-induced IL-4 synthesis when patient cells were
exposed to allergen (in vitro), no demonstrable effect on
IL-2 or IFN-y synthesis was observed.
In conclusion, the clinical implications of these find-
ings suggest that immunotherapy appears to induce an
upregulation of specific benign T-cell processes, effected
through T,,-type helper cells, with a production of IFN-
y and IL-2-specific cytokines. Immunotherapy may also
directly downregulate the specific T,z-induced inflam-
matory mechanisms that otherwise would result in the
production of various inflammatory cytokines.
CELLULAR EVENTS
Both nasal and bronchial provocation models can be
used to study the effects of immunotherapy on the imme-
diate-phase reaction, the late-phase reaction, cellular
recruitment. and nonspecific airway reactivity. Creticos
et aI used nasal provocation (with ragweed) to study a
group of 12 ragweed-allergic patients who had been
receiving maintenance immunotherapy (median, 6 pg
ragweed Amb l/injection) for 3 to 5 years with a group
of 26 patients who had not been previously immunized.
The patients in a nonimmunized group experienced typi-
cal clinical symptoms and demonstrated mediator release
(histamine. TAME-esterase. prostaglandins, leukotrienes)
in their nasal secretions on ragweed nasal challenge.
However, in the immunized group of patients, signifi-
cantly fewer patients demonstrated inflammatory media-
tor release in their nasal secretions or experienced clini-
cal symptoms on nasal provocation. The actual absolute
concentrations of inflammatory mediators measurable in
their nasal secretions after allergen challenge was signif-
icantly lower in the immunized patient group when com-
pared with the nonimmunized patients.
Subsequent studies by Iliopoulos et a129 further
demonstrated that ragweed immunotherapy not only
influenced the immediate-phase reaction but also attenu-
ated the late-phase inflammatory reaction in rdgweed-
allergic patients, with a significant reduction in hista-
mine, TAME-esterase, and kinins in their late-phase
nasal secretions.
These findings are consistent with our understanding
of the late-phase reaction, which suggests that it is
dependent on the recruitment of various cell types into
the inflammatory site (eosinophils, basophils, neu-
trophils). Furin et a130 showed that immunotherapy
resulted in a decrease in antigen-induced eosinophil
migration into the nasal mucosa. Furthermore,
immunotherapy blunted the typical seasonal influx of
eosinophils into the nasal mucosa in a dose-related fash-
ion.
Majchel et alsi used histamine challenge of the nose to
demonstrate the effects of immunotherapy on nonspecif-
ic nasal reactivity. Their findings showed that
immunotherapy prevented the increased responsiveness
of the nasal mucosa to histamine during the peak of the
ragweed-pollen season. A similar effect has been demon-
strated by Sundin et aIs2 in patients with cat-allergic asth-
ma; whereby immunotherapy not only ablated the spe-
cific allergen-induced bronchohyperresponsiveness (to
cat) but also significantly attenuated hyperresponsive-
ness to a nonspecific irritant (histamine) in patients with
cat-allergic asthma.
These studies provide the framework to demonstrate
that immunotherapy has the potential to downregulate
the entire allergic cascade, as evidenced by a reduction in
the immediate-phase allergic reaction, late-phase allergic
reaction, specific allergen-induced sensitivity, and non-
specific airway reactivity, with resultant clinical
improvement.
ANTIBODY CHANGES
In 1921, Prausnitz and Kustner33 recognized that a
substance in the serum of a patient with allergy could
transfer the allergic wheal-and-flare reaction from a
patient with allergy to a nonsensitized individual. How-
ever, it was not until 1968 that Ishizaka et aIs4 demon-
strated that a separate class of serum immunoglobulin,
termed IgE, was the factor responsible for this passive
transfer phenomena.
Subsequent studies by Cooke et a135 and Loveless36
demonstrated that patients with allergy receiving allergen
immunotherapy had an induced antibody response. This
was subsequently shown to be an IgG antibody response,
which was capable of blocking the mentioned passive
transfer reaction.37 Lichtenstein et a138 further showed
that immunotherapy was capable of blunting the typical
seasonal rise in IgE antibody. This drop in IgE antibody
has been shown to be inversely correlated with the rise in
blocking (IgG) antibody that occurs with treatment.39
Although specific antibody titers do not necessarily
predict clinical success in individual patients, an immu-
nizing dose that fails to induce a significant increase in
S554 Creticos J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
IgG antibody will be unlikely to afford measurable clin-
ical relief.40
.
Detailed studies by Peng et a141 of the IgG subclass
response have shown that IgGt is the dominant
immunoglobulin response during the early course of
immunotherapy; whereas IgG4 begins to appear in sig-
nificant quantities only after prolonged immunization.
Platts-Mills et al42 have shown that immunotherapy is
associated with an increase in IgG and IgA antibodies in
nasal secretions of immunized patients. However, no
relationship has been demonstrated between clinical
improvement and appearance of these antibodies in nasal
secretions.
In summary, immunotherapy has been associated with
(1) a rise in serum IgG-blocking antibodies, (2) a sup-
pression of the usual seasonal rise in IgE antibodies fol-
lowed by a slow decline in the level of specific IgE
through the course of immunotherapy, and (3) an
increase in IgE and IgA antibody levels in nasal secre-
tions.
NONSPECIFIC CHANGES
Tissue mast cells and circulating basophils are capable
of releasing histamine on allergen challenge. The posi-
tive correlation has been shown between basophil sensi-
tivity and symptom diary scores in patients with allergy.
Lichtenstein et al43 have demonstrated that immunother-
apy is associated with a decrease in both cellular sensi-
tivity (the amount of allergen required to induce 50%
basophil histamine release) and cellular reactivity (the
ability of basophils to release 100% of their cellular his-
tamine). Brunet et al4 observed that this cellular sensi-
tivity and releasing ability of basophils is enhanced in
patients as they proceed through an allergen season.
These investigators subsequently showed that ragweed
immunotherapy resulted in a blunting of the basophil his-
tamine-releasing ability of patients during the pollen
season in ragweed-immunized patients as compared with
placebo-injected patients.
EFFECT OF DOSE
A variety of well-designed placebo-controlled clinical
studies have demonstrated the therapeutic benefits of
immunotherapy in animal-induced, dust mite-induced,
and pollen-induced asthma. The thread that underlies
successful immunization in these patients is the use of
well-characterized, standardized extracts. Successful
immunotherapy requires that an adequate therapeutic
dose of the relevant allergen be administered to the
patient for an appropriate length of time.
Emperic studies with immunotherapy have generally
pushed to a maximally tolerated dose as the endpoint for
clinical success. However, as the dose of immunotherapy
is advanced, there is a higher risk of systemic reactions.
This is particularly an issue when considering immuno-
therapy in patients with allergy with a component of
lower respiratory disease (asthma). In this context, stud-
ies using nasal and bronchial challenge have allowed us
to characterize the allergic response and, more impor-
tantly, to correlate the effects of dose with clinical relief.
Both the single dose given and the cumulative dose
received can be predictive of a dose that is likely to con-
sistently result in clinical improvement.
As previously cited, Creticos et a145 clearly demon-
strated that both the clinical and the underlying inflam-
matory mediator response to nasal allergen provocation
were significantly improved in ragweed-allergic subjects
who had been on maintenance immunotherapy (6 pg
Amb a l/injection) when compared with patients who
had never been immunized. Furthermore, in a double blind
prospective study of 27 patients with ragweed allergic
rhinitis, those patients randomized to a conventional
extract of ragweed demonstrated a distinct stepwise
attenuation (reduction) in nasal responsivity to ragweed
pollen challenge as the dose of immunotherapy was
increased from low dose (O-6 pg Amb a l/injection) to
moderate dose (12.4 pg Amb a l/injection) to high dose
(24.8 pg Amb a l/injection).
Similar dose-related findings have been demonstrated
in patients with ragweed-induced asthma. Bruce et a146
used a dose of 2 pg of Amb a l/injection and failed to
demonstrate clinical improvement in asthma symptoms
or rhinitis symptoms or on bronchial challenge. Howev-
er, Creticos et al47 demonstrated that a maintenance dose
of 10 pg of Amb a l/injection resulted in a significant
reduction in specific bronchial sensitivity to ragweed and
that this was paralleled by favorable effects on clinical
parameters (Fig 4).
Haugaard et al@ used bronchial provocation to study
patients with dust mite-allergic asthma. These investiga-
tors likewise demonstrated a significant dose-dependent
improvement on bronchial allergen challenge to an
extract of Der p 1 as the immunizing dose was increased
from 0.7 pg to 7 pg to 21 pg Der p l/injection. In con-
trast, there was no improvement in bronchial sensitivity
in the control group. However, the authors noticed a step-
wise increase in the systemic reaction rate (0.56%,
3.30%, and 7.10% respectively) as the immunizing dose
was increased from 0.7 to 7 to 21 pg/injection. Although
the higher dose regimens (7 and 21 pg Der p l/injection)
were demonstrated to be more effective as compared
with the 0.7 pg/injection regimen, the higher reaction
rate with the 21 pg/injection regimen made the authors
conclude that a maintenance of 7 pg Der p l/injection
was the appropriate target dose. These findings are con-
sistent with the results observed with ragweed
immunotherapy.
Studies of patients with cat-allergic asthma have used
both bronchial provocation and cat room exposure to
characterize the clinical response to immunotherapy. Van
Metre et al49 demonstrated that a maintenance dose of 8
to 12 pg Fe1 d 1 per injection resulted in a significant
reduction in airway reactivity on bronchial challenge
with cat extract. Hedlin et also demonstrated that the
J ALLERGY CLIN IMMUNOL
VOLUME 105. NUMBER 2, PART 2
Ragweed Placebo
Creticos S565
FIG 4. Allergen bronchial provocation with ragweed demonstrated a significant improvement in antigen
sensitivity in the ragweed immunized group versus the placebo-injected subjects (P= ,031. IT, immunother-
wv.
reduction in cat-induced bronchial sensitivity afforded by
an immunizing dose of 15 pg Fe1 d 1 per injection pro-
vided continued attenuation of bronchial hyperreactivity
3 years after immunotherapy was discontinued. These
studies suggest that a target dose range of 6 to 15 pg of
the major protein moiety per injection consistently
results in favorable effects on objective parameters (eg,
bronchial hyperresponsiveness) and that this is also par-
alleled by improvement in subjective clinical indices.
RISKS OF IMMUNOTHERAPY
Risk factors have been identified in both nonfatal and
fatal reactions to immunotherapysr~5z (Table I). Certain
precautions are mandated when immunotherapy is
administered. This becomes increasingly important when
considering immunotherapy in the patient with asthma.
As cited by Bousquet et al,53 increasing age (>50 years),
worsening lung function (c70%), and severity of asthma
were negative predictors of a successful outcome with
immunotherapy.
Time of onset
Asthma
Uncontrolled asthma
FEV, < 70%
Drug interactions
P-blocker therapy
High-dose therapy
Rush immunotherapy
Methods
Incorrect technique
Errors in dosage
Presence of symptomatic
asthma
High degree of allergen
sensitivity
Injections occurring during
seasonal exacerbations
Injections from new vials
Errors in dosage
Use of B-blockers
Careful attention must be given to a patients underly-
ing medical conditions, because certain systemic illness-
es could adversely impact a patients ability to survive a
systemic reaction from an injection. Significant cardio-
vascular disease (congestive heart failure, unstable angi-
na, recent myocardial infarction), uncontrolled hyperten-
sion, renal failure, and chronic lung disease, including
unstable or poorly controlled asthma, are recognized as
contraindications to immunotherapy. Communicative
disorders and noncompliance may be considered relative
contraindications to immunotherapy.54,55
phylaxis. Angiotensin-converting enzyme inhibitors may
induce cough (cough-variant asthma) or angioedema and
have been associated with anaphylaxis during venom
immunotherapy.56
Furthermore, beta-blocker therapy may interfere with
a patients ability to appropriately respond to epinephrine
when given as treatment for a reaction to an immunother-
apy injection. In this setting, beta-blocker therapy may
result in epinephrine having paradoxic unopposed a-ago-
nist activity and in inducing increased reflex vagal tone.
This may cause intense bronchoconstriction, increased
mediator release, atrioventricular (AV) nodal block,
bradycardia, and unopposed vasoconstriction of the coro-
nary artery bed.57
Certain medications may aggravate the condition of a
Immunotherapy should not be initiated in a pregnant
patient with asthma. Beta-blocker therapy may cause
patient or in a patient actively trying to become pregnant.
bronchospasm or result in more severe or protracted ana-
However, immunotherapy is not contraindicated in a
TABLE I. Risk factors in nonfatal and fatal reactions to
immunotherapy
Risk factors in nonfatal Risk factors in fatal reactions
reactions to immunotherapy to immunotherapy
S566 Creticos
PLACEBO
CG
SS
PD
DK
Do
-
BEFORE
TREATMENT am
CAT EXTRACT
FIG 5. Bronchial inhalation challenge with cat-pelt extract. PDZO in
FEVI is indicated on vertical axis (log scale). Mean PDZO-FEV, for
placebo-treated subjects was 294 and 56 breath units before and
after therapy, respectively. This was not significant. Mean PD,,-
FEV, for subjects who received cat-pelt earact was 51 and 2354
breath units before and after therapy (PC .Ol). (From Taylor WW,
Ohman JL Jr, Lowell FC. Immunotherapy in cat-induced asthma:
double-blind trial with evaluation of bronchial responses to cat
allergen and histamine. J Allergy Clin lmmunol 1978;61:283-7. By
permission.)
pregnant patient currently receiving maintenance thera-
py. In this regard, an assessment should be made of the
clinical response to immunotherapy at that point. In
patients who have experienced adverse reactions to their
injections, consideration should be given to reducing the
maintenance dose during the course of pregnancy.54.55
CLINICAL STUDIES OF IMMUNOTHERAPY
Animal-induced asthma
A number of investigators have studied cat- and/or
dog-allergic patients. Cat serves as a particularly good
model because the major allergenic moiety (Fe1 d 1) has
been characterized. The manufacturer of a standardized
extract, based on yg Fe1 d 1, has provided an excellent
source of material with which to immunize cat-allergic
patients.
Taylor et a158 evaluated 10 cat-allergic subjects with
positive skin tests and a history of cat-induced asthma.
All subjects demonstrated a significant bronchial chal-
lenge response to an extract of cat pelt on bronchial
provocation. The 10 subjects were randomized in a dou-
ble-blind fashion to receive either immunotherapy with a
cat-pelt extract (rich in cat allergen 1, Fe1 d 1 [approxi-
mately 32 pg Fe1 d 11) or placebo injections. The 5 place-
bo subjects showed no change in skin test reactivity, in
specific bronchial hyperresponsiveness to cat provoca-
tion, or in nonspecific airway reactivity. In contrast, after
only 4 months of treatment, the 5 cat-immunized patients
showed a reduction in skin prick test sensitivity to cat and
a lo- to loo-fold shift in specific (cat) allergen-induced
bronchial hyperresponsiveness (? cat PD,, FEV,; Fig 5).
J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
Ohman et a159 used a similar double-blind, placebo-
controlled study design to evaluate 10 patients with cat-
allergic asthma. These investigators likewise showed that
those patients randomized to active therapy (target dose,
approximately 16 pg Fe1 d 1) had a reduction in skin
prick test sensitivity, a significant increase in IgG anti-
body production, and a significant reduction in specific
(cat) allergen-induced bronchial hyperresponsiveness on
bronchial provocation to cat. Again, no shift in metha-
choline responsiveness was observed.
Symptom diaries showed a significant improvement in
ocular (P = .03) and pulmonary (P = .03) symptoms in
the cat-immunized group. Also. on cat chamber expo-
sure, the immunized patients demonstrated a significant
delay in the onset of ocular (P < .05) and pulmonary (P
< .05) symptoms (shift from symptoms occurring within
5-l 5 minutes to >90 minutes).
Sundin et al32 studied 41 subjects with allergic asthma
with positive skin tests and RAST tests to cat and/or dog
and a history of clinical asthma symptoms on cat or dog
exposure. All subjects also demonstrated positive
bronchial challenge sensitivity to cat or dog. In a 12-
month double-blind, placebo-controlled trial, patients
were divided to receive either active therapy (with cat or
dog) or placebo injections (target dose, 15 pg Fe1 d
l/injection).
In the cat-immunized patients, a reduction in skin
prick test sensitivity, specific sensitivity to bronchial
challenge provocation with cat, and nonspecific airway
reactivity (histamine) was observed. The cat-immunized
patients also demonstrated less pronounced symptoms on
cat exposure (Fig 6).
Hedlin et alSO continued to follow these patients for
several years after therapy had been discontinued. The
effect on bronchial hyperresponsiveness that had been
observed as a result of 3 years of active therapy was still
maintained 5 years after immunotherapy (to cat) had
been discontinued.
Valovirta et aleo evaluated 27 patients with asthma
who had positive skin prick tests and a positive conjunc-
tival and bronchial challenge response to dog extract.
The subjects were randomized in a double-blind fashion
to receive either active treatment with an aluminum
hydroxide-bound extract of dog dander (100,000 stan-
dardized quality units/ml) or to placebo injections. Of
the 15 patients who were receiving active therapy, 11
patients reached the projected maintenance dosage.
Active treatment resulted in a decreased skin prick test
sensitivity to dog and an increase in IgG antibody pro-
duction. Although a decreased sensitivity to dog on con-
junctival challenge was observed (P < .OOl), a nonsignif-
icant shift in bronchial challenge sensitivity to (dog)
allergen was noted. Both dog- and placebo-treated
patients subjectively appreciated a decrease in symptoms
on exposure to dog after completing the 1 -year treatment
period.
These studies demonstrate the ability to significantly
alter bronchial sensitivity to the relevant allergen. Also,
subjective symptom change was observed with either cat
J ALLERGY CLIN IMMUNOL
VOLUME 105. NUMBER 2, PART 2
Creticos S567
HEP
1.5
1.0
.5
0
-.5
-1 .o
-1.5
-2.0
-2.5
-3.0
CAT BRONCHO PROVOCATION
bg PC20 2.0
Years
HISTAMINE BRONCHO PROVOCATION
1.6
j:;
:0
:9
mg/ml j
-.2
-4
-.6
-.6
:::j
-1.
-1. t
-1.6
-2.0
i
Years 2
FIG 6. Changes in log PC,, for histamine in immunized and placebo-injected patients. (From Sundin 6, Lilja
G, Graff-Lonnevig V, et al. Immunotherapy with partially purified and standardized animal dander extracts.
I. Clinical results from a double-blind study on patients with animal dander asthma. J Allergy Clin lmmunol
1986;77:476-87. By permission.)
room exposure or with symptom diaries. However, none
of the patients studied had cats in their immediate envi-
ronment. Hence, this begs the question as to whether cat
immunotherapy can significantly alter the clinical
response in patients who are exposed to a relevant aller-
gen (cat) on a daily basis.
In clinical practice, allergy injections are often given
to cat-allergic patients who have cats in their home set-
ting. Although these studies have demonstrated the effi-
cacy of cat immunotherapy in improving either clinical
symptoms of cat-induced asthma or in reducing
bronchial sensitivity when patients have undergone
bronchial provocation to cat allergen, these protocols
have only studied patients with asthma who have spo-
radic or occasional exposure to cats and who do not have
cats in their immediate home environment. Therefore we
are currently involved in the study of patients with cat-
allergic asthma who have cats in their home. This should
provide a more meaningful mode1 to assess the therapeu-
tic effects of immunotherapy in a real-world situation,
that of an allergic stimulus (cat) that can induce persis-
tent inflammation and chronic symptoms. At issue, is
whether immunotherapy can alter this clinical presenta-
tion.
Dust mite-induced asthma
Early studies of immunotherapy in dust-allergic
patients used either poorly defined extracts or inadequate
therapeutic doses. Yet Bruun6r in a single-blind, placebo-
controlled 2-year study of dust injection therapy reported
that 74 of 95 patients (78%) who were receiving dust-
mite immunotherapy reported clinical improvement as
compared with 28 of 82 patients (34%) receiving place-
bo. Subsequently, Aas reported the results of a 3-year
double-blind, placebo-controlled study of 80 children
with asthma with positive skin test reactivity to an extract
of dust mite and positive bronchial challenge sensitivity
to this dust-mite extract. His results showed that those
patients immunized with the house dust-mite extract
demonstrated both subjective clinical improvement and a
decreased bronchial sensitivity on bronchial provocation
with an extract of dust mite as compared with the place-
bo group.
The primary allergens of the Derrnatophagoides
species of dust mites have been characterized on the
basis of both fecal (group I) or dust mite-body (group II)
allergens. Numerous studies have therefore used well-
characterized dust-mite extracts for immunotherapy.
S566 Creticos
1.280
660
320
160
80
SO
20
10
pto.665
BEFORE
IhWJNOfMLRAPY
J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
BEFOUE AFTER
I*L~uN~TI~ERAPY IhWUNOlHLRAPY
FIG 7. Evolution of the provocative dose (PD) eliciting a specific bronchial response before and after
immunotherapy in 20 patients who had a rush protocol with a standardized Dp extract. Statistical analysis
by Wilcoxon W-test. (From Bousquet J, Calvayrac P, Guerin B, et al. Immunotherapy with a standardized Der-
matophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J
Allergy Clin lmmunol 1985;76:73444. By permission.)
Srnith6s reported that subjective asthma diary scores
were significantly better for the group of dust mite-aller-
gic patients who had received a 4-month injection series.
In this study, symptoms of dust mite-induced rhinitis
were also improved. On analysis of medication require-
ments, 10 of 11 treated patients required no additional
medications for control of their asthma; whereas 6 of 11
control subjects required increased medication to control
their asthma symptoms.
DSouza et al@ studied 96 patients with a history of
perennial asthma and/or rhinitis and a positive skin prick
test to D pteronyssinus. After 3 months of treatment, a
significant improvement in asthma symptoms, medica-
tion use, and dust tolerance was observed in the dust
mite-treated group as compared with the group of
patients receiving placebo injections. In this study, no
improvement was noted in rhinitis symptoms, although a
significant decrease in nasal sensitivity to the dust-mite
extract was observed in the immunized group.
Warner et ales reported the results of a double-blind,
placebo-controlled study of immunotherapy with D
pteronyssinus. Eighty-five percent of immunized patients
reported clinical improvement in asthma symptoms. In
the actively treated group, approximately 50% of the
patients (12/22 patients) immunized with dust mites had
an ablation of their late-phase bronchial reactivity on
bronchial challenge.
Bousquet et al66 used a rush immunotherapy protocol
with a standardized dust-mite (D pteronyssinus) extract
to study 30 patients with dust-mite allergic asthma. In
this double-blind, placebo-controlled trial, the treated
group demonstrated a significant reduction in skin prick
test sensitivity and a significant increase in the provoca-
tive dose of allergen required to induce a 20% fall in
FEV, value (Fig 7).
Haugaard et al48 evaluated 74 dust mite-allergic
patients with positive skin tests and positive bronchial
challenge to a dust-mite extract (Der p 1). Over the 2
years of treatment, a dose-related increased tolerance to
Der p 1 and a decrease in medication/peak expiratory
flow scores were observed.
In summary, studies of patients with dust-mite allergic
asthma that have used well-characterized or standardized
allergens have demonstrated evidence of clinical benefit
as measured by subjective symptom diary scores and
objective evidence of improvement on bronchial provo-
cation with the specific dust-mite allergen. However,
Bousquet et al53 pointed out that care must be taken
when considering immunotherapy in patients with asth-
ma. In a controlled study of 215 patients with allergic
asthma, both a significant decrease in mean symptom
medication scores and a significant improvement in
FEV, values were observed after 1 year of treatment.
However, the study provided a number of predictive
J ALLERGY CLIN IMMUNOL
VOLUME 105. NUMBER 2, PART 2
Creticos S569
1200
VI
t
v)
5 1000
m
F:
E
?
p:
000
4
400
z
3
200
d
0
0
*..*.** ER Visits for Asthma/month
......... ER Visits for Rhinitis.:month
- Grass Pollen Counts/cm2
FIG 8. Total monthly emergency department (ER) visits for asthma and rhinitis to the David Grant Medical
Center compared with total monthly grass-pollen counts (GPCs) from Jan 1981 to Dee 1984. Asthma visits
correlated with GPC (r= 0.90 and P-z .OOl). Rhinitis visits correlated with GPC (r= 0.92 and P< .OOl). (From
Reid MJ, Moss RB, Hsu Y-P, et al. Seasonal asthma in northern California: allergic causes and efficacy of
immunotherapy. J Allergy Clin lmmunol 1986;78:590-600. By permission.)
I I I I 1
L........ .,,...,. u
I I I
JAN JUNE JAN JUNE JAN JUNE JAN JUNE
1981 1982 1983 1984
correlates to help determine likely candidates for im-
munotherapy. Increasing age (>50 years), worsening
lung function (<70%), and severity of asthma were neg-
atively correlated with the successful outcome with
immunotherapy. Furthermore, patients with perennial
allergen sensitivity, chronic sinus disease, and/or aspirin
intolerance were less likely to benefit from immunother-
apy.
Tree pollen-induced asthma
A variety of different tree species have been shown to
be important aeroallergens. Various investigators have
used either nasal, conjunctival, or bronchial provocation
models that demonstrate rhinoconjunctival or asthmatic
symptoms. However, many of the different tree species
have relatively short pollination seasons. This factor,
coupled with the prevalence of the relevant tree species,
are important considerations in determining whether a
course of immunotherapy should be considered. Of the
various tree species that have been studied, birch repre-
sents a primary model because it has been well charac-
terized with respect to its predominant allergens. It has
been standardized on the basis of its major protein moi-
ety (Bet v 1). Petersen et a167 studied 54 adults with tree
pollen-induced (birch, alder, and/or hazel tree) rhinitis (n
= 28) and/or asthma (n = 25). One group of patients was
randomized to treatment with birch immunotherapy
alone (n = 25), whereas the other 25 patients received an
extract comprised of each of the relevant trees to which
they were found to be sensitive (all received birch). Both
groups of patients noted a significant reduction in symp-
tom and medication usage scores. Furthermore, a signif-
icant improvement was also observed with skin prick
testing and on nasal provocation. Treatment with the
birch extract alone appeared to provide comparable clin-
ical improvement to that observed with the tree mix. This
suggests that these cross-reactive species (birch, alder,
hazel) may contain a common epitope.
Pence et a168 studied 40 patients with positive skin
tests to mountain cedar and a history of either allergic
rhinitis or asthma on exposure to this tree pollen. Thir-
teen of 17 patients receiving active therapy with the
mountain cedar extract, as compared with only 6 of 15
patients on placebo injections, noted improvement in
their rhinitis and/or asthma symptoms. A decrease in the
specific seasonal rise in IgE to mountain cedar was
inversely correlated with this improvement in clinical
symptoms.
Several other tree families (oak, maple, ash, elm) are
important pollen producers in the United States during
the spring through summer period. Further studies need
to be performed to characterize the relative efficacy of
immunotherapy with these and other tree pollens in tree-
allergic individuals.
Grass pollen-induced asthma
Grass pollen is a major cause of rhinoconjunctivitis
and asthma. Both an extended growth season for the
S570 Creticos J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
respective species of grass and the overlapping cross-
sensitivity of various grass species contribute to the rele-
vant importance of grass pollen as an allergen. In certain
areas, grass pollen may be airborne only during the late
spring through summer. However, in other parts of North
America, the grass-pollen season may actually extend for
8 to 10 months. Fortunately, the cross-reactivity of vari-
ous grass species works to our benefit when we consider
candidate grasses for immunotherapy. In this context, the
temperate grass family, which includes various species
from different yet chemically related genera (June [&XI],
rye [Lolium], fescue [Fesrula], orchard [Dactylis], and
Timothy [Phelum]) demonstrate distinct cross-reactivity.
However, Timothy pollen does appear to have certain
distinct proteins (epitopes) of its own that are not neces-
sarily shared or recognized by other members of the tem-
perate family. Hence this suggests that Timothy grass
alone may provide efficacy similar to a grass mix. This
certainly becomes practical when both cost and the
achievement of an optimal dose are considered. This
approach has been used successfully by Frostad et al@
and Bousquet et a170 in the treatment of grass-induced
rhinitis/conjunctivitis.
Frankland and Augustin studied 200 patients with
grass-pollen hay fever (n = 200 patients) and/or asthma (n
= 57 patients). They reported that 79% of patients with
hay fever had either good or excellent results with
immunotherapy as contrasted with only 33% of patients
who had received inactive materials. Among patients with
asthma, 94% of patients receiving active therapy reported
good to excellent results as contrasted with only 30% of
patients who received inactive treatments (P = .OOl).
Ortolani et a172 studied the efficacy of grass immuno-
therapy (Timothy, velvet, vernal mix) in 15 patients with
grass-sensitive asthma. In this l-year, double-blind,
placebo-controlled trial, the grass-immunized patients
demonstrated a highly significant reduction in clinical
symptoms of both rhinoconjunctivitis and asthma as
compared with the placebo-treated patients (P < .OOl).
Consistent with having delivered an adequate immuniz-
ing dose, a significant rise in total IgG antibody and IgG
subclass antibodies to Timothy (antigen D) were
observed. However, neither group of patients demon-
strated a shift in their specific allergen-induced bronchial
hyperresponsiveness on bronchial provocation.
Reid et a173 studied 18 grass-sensitive asthmatic
military recruits stationed in northern California
(Sacramento basin), an area of intense grass pollina-
tion. Over the 4-year period of observation, peak
grass-pollen counts strongly correlated with emer-
gency department visits and hospitalizations for asth-
ma (Fig 8). In the group of patients (n = 9 patients)
randomized to receive a 7-grass mix (dose adjusted
based on rye grass group I units [micrograms]), a sig-
nificant reduction in asthma symptoms was observed
(P c .05). Somewhat surprising, a favorable but not
significant effect was observed on rhinitis symptoms
after the l-year treatment period.
Armentia-Medina et a171 conducted a double-blind,
placebo-controlled trial in 30 patients sensitive to
Bermuda grass pollen. Patients entered into the trial had
both positive skin prick test sensitivity and specific
bronchial hyperreactivity to an extract of Bermuda grass.
Immunized patients demonstrated a significant reduction
in bronchial hyperresponsiveness to bronchial provoca-
tion with Bermuda extract (P < .OOl), nonspecific
(methacholine) bronchial hyperresponsiveness (P < .05),
and a greater clinical improvement as contrasted with the
control subjects (P < ,001).
Ragweed pollen-induced asthma
Ragweed is a major cause of seasonal pollinosis and
asthma occurring during the autumn months in North
America. Its allergenic proteins have been carefully
characterized, and its major protein moiety has been
identified (Amb a 1 [antigen El). This has led to ragweed
being a primary model for understanding the mecha-
nisms of and studying the efficacy of immunotherapy.
Clinical trials of ragweed immunotherapy have incorpo-
rated both subjective (symptom diary data) and objective
criteria (nasal provocation) to define therapeutic end-
points. As noted, studies with ragweed immunotherapy
have consistently demonstrated significant clinical relief
in patients with rhinitis when patients received a single
maintenance dose of 6 to 12 pg Amb a l/injection (medi-
an cumulative dose, 30-70 pg Amb a 1).
Studies of ragweed-induced asthma likewise bear out
the importance of dose. A study by Bruce et a175 of 29
patients with ragweed-allergic asthma failed to demon-
strate improvement in either specific airway conductance
(PDlo specific airway conductance) or in chest or nasal
symptoms during the fall ragweed season. However,
patients received an immunizing dose of only 2 pg or less
Amb a l/injection. This low-dosing regimen failed to
ablate the seasonal rise in IgE. However, Creticos et al47
recently reported the results of a double-blind, placebo-
controlled study of 57 patients with ragweed-allergic
asthma. In this study, both placebo-injected and rag-
weed-immunized patients demonstrated significant
improvement in their asthmatic symptoms. However,
there were distinct differences underlying the basis for
the improvement seen in each group. Indeed, careful fol-
low-up and the judicious use of anti-inflammatory med-
ications and bronchodilator drugs resulted in meaningful
symptom improvement in the placebo group during the
2-year treatment period when compared with their pre-
treatment observation season. However, the protection
afforded the ragweed-immunized group against both
bronchial challenge (P = .03) and the improvement in
peak expiratory flow measurements during the peak peri-
od of the ragweed season (P = .05) provide evidence for
the specific benefit of immunotherapy.
With respect to clinical endpoints, the ragweed-immu-
nized patients demonstrated an approximate 40%
improvement in their asthma symptoms and had a mea-
surable increase (35-40 L/mm) in their peak flow read-
J ALLERGY CLIN IMMUNOL
VOLUME 105, NUMBER 2, PART 2
Creticos S571
12345670 12345676 12345676
Week
Obswval~on Phase Treatment Year 1 Treatment Year 2
Otswvabon Phase Trealmenl Year 1 Trealmenl Year 2
12345676 12345676 12345676 12345676 12345676 12345676
B Week C Week
FIG 9. Evaluations of Asthma. Data from Baltimore, Md, have been shifted by 1 week to make the times of
ragweed exposure coincide for the Baltimore, Md, and Rochester, Minn, areas. The brackets show the sig-
nificance of the difference between the placebo and the immunotherapy groups in daily measurements or
scores for the 3 weeks of the greatest pollen exposure, with the use of an analysis of variance to correct for
differences during the observation phase. A, The weekly mean (i SE) peak expiratory flow rate (PEFR) mea-
sured in the morning before, during, and after the ragweed-pollination season. Measurements of peak expi-
ratory flow were recorded (with a mini peak flow meter) as the highest of 3 successive readings of peak flow
when patients arose. B, The daily mean (i SE) medication scores for each week before, during, and after the
ragweed-pollination season. Each of the following actions was scored as 1 unit: 200 mg of short-acting xan-
thine, 100 mg of long-acting xanthine, 1 puff from a sympathomimetic inhaler, a 2-mg albuterol tablet, a 2.5-
mg terbutaline tablet, a lo-mg metaproterenol tablet, 1 puff of ipratropium, one half-puff of inhaled corti-
costeroid, 1 puff of a nasal corticosteroid, one half-puff of cromolyn, 0.5 mg of prednisone, and 0.4 mg of
methylprednisolone. An injection of a bronchodilator was scored as 4 units, and respiratory therapy with a
bronchodilator was scored as 4 units plus 1 unit for each 0.25 mL of medication. Antihistamines were not
scored. C, The daily mean (i SE) asthma-symptom scores. Symptoms were scored on a B-point scale: 0 =
none; 1 = trivial or doubtful; 2 = mild and causing little or no discomfort; 3 = annoying but causing no marked
discomfort; 4 = moderately severe and causing marked discomfort; 5 = severe and interfering with sleep or
activities but not incapacitating; and 6 = incapacitating. (From Creticos PS, Reed CE, Norman PS, et al. Rag-
weed immunotherapy in adult asthma. N Engl J Med 1996;334:501-6. Copyright 0 1996 Massachusetts Med-
ical Society. Al l rights reserved.)
ings, a measurement indicating a meaningful reduction in
their underlying asthmatic inflammatory process. In con-
trast, the placebo-injected patients required approximate-
ly a 3-fold increase in asthma medication requirements to
obtain a similar degree of asthma control. However, their
airway inflammation was still present, as indicated by
their peak flow measurements that continued to fall dur-
ing the peak of each ragweed season (Fig 9).
The findings from this study showed that, in carefully
selected patients with asthma, immunotherapy results in
positive clinical benefits that are comparable with that
achieved in studies with moderate-dose inhaled cortico-
steroids, and indeed, superior to that seen with other anti-
inflammatory drugs (cromolyn, nedocromil) or with
maintenance bronchodilator medications (theophylline,
salmeterol).
EARLY INTERVENTION
Johnstone immunized children with seasonal rag-
weed-induced rhinitis (n = 175 patients) and asthma (n =
112 patients) and reported a significant reduction in both
J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
S572 Creticos
TABLE II. The influence of treatment on the preyention or amelioration of pollen asthma
Children with pollen asthma Children with pollinosis without
before treatment pollen asthma before treatment
Asthma persisted No pollen Pollen asthma
Lost asthma in spite asthma after developed in spite
Total (n) on treatment of treatment Total (n) treatment of treatment
Group (total) n % n 96 n % n %
Highest tolerated dose
(1:200-1500) (n = 29) 22 15 68 7 32 7 7 100 0 0
I :5,000 (n = 26) 1.5 9 60 6 40 II 11 100 0 0
1:1o,ooo,ooo (n = 31) 21 4 19 17 81 10 4 40 6 60
Controls (n = 26) 14 I 7 13 93 12 7 58 5 42
Totals (n = 112) 72 29 40 43 60 40 29 73 II 27
From Johnstone DE. Study oftbe role of antigen dosage in the treatment of pollinosis and pollen asthma. Am J Dis Child 1957;94: l-5. Copyright 1957. Ameri-
can Medical Association.
rhinitis and asthma symptoms in 65% of patients who
were receiving active treatment as compared with only
14% of patients who were receiving placebo injections.
During the 3-year course of treatment, he made several
important observations. He noted that approximately two
thirds of children who had asthma on entry into the study
experienced a complete resolution of their asthma over
the course of active therapy. In contrast, only 7% of the
control group of patients lost their asthma. Further-
more, no patients who were receiving active
immunotherapy went on to experience the development
of asthma over the treatment period, as contrasted with
the 42% of the control patients and 60% of the subtbera-
peutic treatment group who experienced the development
of asthma (Table II). These observations raise important
questions considering when to consider immunotherapy.
Adkinson et al77 studied the effects of immunotherapy
in multiply sensitive children with moderate-to-severe
perennial asthma. One hundred twenty-one children were
randomized to receive placebo injections or immunother-
apy with up to 7 relevant allergens. Both groups demon-
strated a significant improvement in their P&a to metha-
choline. However, no significant differences were
observed between groups for medication score, symp-
toms, peak flow, or methacholine reactivity. Subgroup
analysis did show that younger patients (18.5 years of
age) did report a positive benefit from immunotherapy.
FUTURE DIRECTIONS
Certainly these studies raise the important issue of
early intervention in terms of consideration for
immunotherapy. Tangential to this is recognition that the
atopic patient has inherited the unwanted ability to
experience the development of a respiratory disease
process. A variety of factors impact whether rhinitis or
asthma predominate in a given patient. Various genes
impact the development of atopy, bronchial hyperrespon-
siveness, and clinical asthma. Environmental influences
further shape the phenotypic expression of disease.
Implicit in these observations is that early therapeutic
intervention should afford the opportunity to effect the
severity of the disease, the chronicity of the disease, and
the cost of the disease. Furthermore, the interplay
between the upper and lower airways implies that, in
those patients capable of experiencing the development
of lower airway disease, aggressive therapy of the
rhinitic component of their process may prevent the
development of the asthmatic component.
Studies of immunotherapy in asthma have demonstrat-
ed subjective relief (symptom and medication improve-
ment), objective evidence for effkacy (improvement in
physiologic parameters [pulmonary function]), provoca-
tion models (bronchial allergen challenge), and evidence
for mechanism at the cellular level. Needed now are stud-
ies of effectiveness that better define the effect of
immunotherapy on the severity of disease, quality of life,
and health economics. Studies aimed at early interven-
tion, prevention of asthma, and positioning for
immunotherapy (overall immunopharmacotherapeutic
strategy) should better define our therapeutic paradigm
for management of respiratory disease.
REFERENCES
I. Creticos PS. Immunotherapy. In: Kaplan AP. editor. Allergy. 2nd edition.
Philadelphia: WB Saunders; 1997. p. 726.39.
2. Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, et al. Nasal challenge
with ragweed pollen in hay fever patients: effect of immunotherapy. J
Clin Invest 1985:76:2247-53.
3. Wilson AF, Novey HS. Berke RA, Surprenam EL. Deposition of inhaled
pollen and pollen extract in human airways. N Engl J Med
1973;288: 1056-S.
4. Rosenberg GL. Rosenthal RR, Norman PS. Inhalational challenge with
ragweed pollen in ragweed sensitive asthmatic [abstract]. J Allergy Clin
Immunol 1975:55: 126.
5. Agarwal MK. Swanson MC. Reed CE, Yunginger JW. lmmunochemical
quantitation of airborne short ragweed, Altemaria, antigen E. and Alt-l
allergens: a two-year prospeclive study. J Allergy Clin lmmtmol
1983;74:40-5.
6. Scinto JD. Bernstein DI. immunotherapy with dust mite allergens.
lmmunol Allergy Clin North Am 1992;12:53-67.
7. Plans-Mills T. Chapman M. Dust mites: immunology. allergic disease
and environmental control. J Allergy Clin lmmunol 1987;80:755-75.
8. Platts-Mills T, DeWeck AL. Dust mite allergens and asthma: a worldwide
problem (report of an international workshop). J Allergy Clin lmmunol
1989:03:416-27.
J ALLERGY CLIN IMMUNOL
VOLUME 105, NUMBER 2. PART 2
Creticos S573
9. Wood RA. Egg1e~t011 PA. Management of allergy to animal danders.
Immunol Allergy Clin Nonh Am 1992;12:69-84.
10. Chapman MD. Cockroach allergens: a common cause of asthma in North
American cities. Insights in Allergy 1993;8: l-8.
I 1. Creticos PS. Immunologic changes associated with immunotherapy:
immunotherapy of IgE-mediated disorders. lmmunol Allergy Clin North
Am 1992;12:13-37.
12.. Cousins DJ. Staynov DZ. Lee TH. Regulation of IL-4. IL-5 and GM-CSF in
T lymphocytes. In: Mamne G. Austen KF, Holgate ST, Kay AB, Lichtentein
LM. editors. Asthma and allergic diseases: physiology, immunopharmacolw
gy and treatment. San Diego, Calif: Academic Press: 1998: p.l93-203.
13. Kay AB. T lymphocytes in chronic asthma. In: Marone G. Austen KF.
Holgate ST. Kay AB, Lichtentein LM. editors. Asthma and allergic dis-
eases: physiology. immunopharmacology and treatment. San Diego,
Calif: Academic Press: 1998: p.207-21,
14. Vamey VA, Hamid QA. Gaga M. et al. Influence of grass pollen
immunotherapy on cellular infiltration and cytokine mRNA expression
during allergen-induced late-phase cutaneous responses. J CIin Invest
1993;92:644-5 I.
15. Creticos PS. Peters SP, Adkinson NF Jr. et al. Peptide leukotriene release
after antigen challenge in patients sensitive to ragweed. N Engl J Med
1984;3 10: 1626-30.
16. Naclerio RM. Meier HL. Kagey-Sohotka A. et al. Mediator release after
nasal challenge with allergen. Am Rev Respir Dis 1983;128:597-602.
17. Naclerio RM. Proud D. Togias AG. et al. Inflammatory mediators in late
antigen-induced rhinitis. N Engl J Med 1985:313:65-70.
18. Casale TB, Wood D. Richerson HB. et al. Direct evidence of a role for
mast cells in the pathogenesis of antigen-induced bronchoconstriction. J
Clin Invest 1987;80:1507-I I.
19. Liu MC, Hubbard WC. Proud D. et al. Immediate and late inflammatory
responses to ragweed antigen challenge of the peripheral airways in aller-
gic asthmatics. Am Rev Respir Dis 1991;144:51-8.
20. Rocklin RE. Sheffer AL, Greineder DK. Melmon KL. Generation of anti-
gen-specific suppressor cells during allergy desensitization. N Engl J
Med 1980:302:1213-9.
21. MacDonald SM. Kagey-Sobotka A. Proud D. et al. Histamine-releasing
factor release mechanism and responding population [abstract]. J Allergy
Clin Immunol 1987~791248.
22. Iliopoulos 0. Proud D. Lichtenstein LM. et al. Relationship between
early (ER). late (LPR) and rechalenge (RCR) responses to nasal chal-
lenge [abstract]. J Allergy Clin lmmunol 1987:79:253.
23. Alam R. Kuna P. Rozniecki J. et al. The magnitude of the spontaneous
production of histamine-releasing factor (HRF) by lymphocytes in vitro
corelates with the state of bronchial hyperractivity in patients with asth-
ma. J Allergy Clin Immunol 1987;79: 103-8.
24. Kuna P. Alam R. Kuzminska B. et al. The effect of preseasonal
immunotherapy on the production of histamine releasing factor (HRR by
mononuclear cells from patients with seasonal asthma: results of a dou-
ble-blind, placebo-controlled randomized study. J Allergy Clin lmmunol
1989:83:816-24.
25. Vamey VA, Gaga M. Frew AJ. Aber VR. Kay AB. Durham SR. Useful-
ness of immunotherapy in patients with severe summer hay fever uncon-
trolled by antiallergic drugs. Br Med J 1991;302:265-9.
26. Durham SR. Sun Ying. Vamey VA, et al. Grass pollen immunotherapy
inhibits allergen-induced infiltration of CD4+ T lymphocytes and
eosinophils in the nasal mucosa and increases the number of eels express-
ing messenger RNA for interferon-y. J Allergy Clin lmmunol
I996;97: 1356-65.
27. Jute1 M, Pilcher WJ, Skrbic D, et al. Bee venom immunotherapy results
in decrease of IL-4 and IL-5 and increase of IFNy secretion in specific
allergen-stimulated T cell cultures. J Immunol 1995:95:4188-94.
28. Secris~ H, Chelen CJ. Yan W. et al. Allergen immunotherapy decreases
interleukin 4 production in CD4+ T cells from allergic individuals. J Exp
Med 1993:178:2123-30.
29. lliopolous 0. Proud D. Adkinson NF Jr. el al. Effect of immunotherapy
O the early. late and rechallenge nasal reaction 10 provocation with aller-
gen: changes in inflammatory mediators and cells. J Allergy Clin
Immunol 1991;87:855-66.
30. Furin MJ, Norman PS. Creticos PS. Naclerio RM. Immunotherapy
decreases antigen-induced eosinophils migralion into the nz%d cavity. J
Allergy Clin Immunol 1991;88:27-32.
3 I. Majchel AM, Proud D, Freidhoff L. Creticos PS. N0m.m PS. Naclerio
RM. The nasal response IO histamine challenge: effect of the pollen sea-
son and immunotherapy. J Allergy Clin Immunol 1992;90:85-91.
32. Sundin B. Lilja G. GralT-Lonnevig V. et al. Immunotherapy with partial-
ly purified and standardized animal dander extracts. I. Clinical results
from a double-blind study on patients with animal dander asthma. J Aller-
gy Clin Immunol 1986:77:478-87.
33. Prausnitz C. Kustner H. Studies on supersensitivity. ZentmIbl Bakteriol
1921;86:160-9.
34. Ishizaka T. Hiram F, Ishizaka K. et al. Stimulation of phospholipid
methylation: Ca2+ influx, and histamine release by bridging of IgE recep-
tors on rat mast cells. Pox Nat1 Acad Sci USA 1980;77:1903-6.
35. Cooke RA, Barnard JH. Hebald S. Stull A. Serologic evidence of immu-
nity with coexisting sensitization in a type of human allergy (hay fever).
J Exp Med 1935;62:733-51.
36. Loveless MH. Immunological studies of pollinosis: IV. The relationship
between thermostale antibody in the circulation and clinical immunity. J
Immunol 1943;47:165-80.
37. Lichenstein LM, Holtzman NA, Burnett LS. A quantitative in vitro study
of the chromatographic distribution and immunoglobulin characteristics
of human blocking antibody. J Immunol 1968;101:317-24.
38. Lichtenstein LM, Ishizaka K, Norman PS. et al. IgE antibody measure-
ments in ragweed hay fever: relationship to clinical severity and the
results of immunotherapy. J Clin Invest 1973:52:472-82.
39. Yunginger JW. Gleich GJ. Seasonal changes in IgE antibodies and their
relationship to IgG antibodies during immunotherapy for ragweed hay
fever. J Clin Invest 1973;52:1268-75.
40. Creticos PS, Norman PS. Immunotherapy with allergens. JAMA.
1987;258:2874-80.
4 I. Peng 2. Naclerio RM. Norman PS, et al. Quantitative IgE and IgG sub-
class responses during and after long-term ragweed immunotherapy. J
Allergy Clin Immunol 1992;9:519-29.
42. Platts-Mills TAE, van Maw RK, Ishizaka K. et al. IgA and IgG anti-rag-
weed antibodies in nasal secretions. J Clin Invest 1976;57: 1041-50.
43. Lichtenstein LM. Nomxm PS, Winkenwerder WL, et al. In vitro studies
of human ragweed allergy: changes in cellular and humoral activity asso-
ciated with specific desensitization. J Clin Invest 1966;45:1126-36.
44. Brunet C. Bedard PM, Lavoie A. et al. Allergic rhinitis to ragweed pollen.
1. Reassessment of the effects of immunotherapy on cellular and hor-
monal responses. J Allergy Clin Immunol 1992;89:76-86.
45. Creticos PS. Marsh DG, Proud D. et al. Responses to ragweed pollen
nasal challenge before and after immunotherapy. J Allergy CIin Immunol
1989;84: 197-205.
46. Bruce AA, Norman P.S. Rosenthal RR, et al. The role of ragweed pollen
in autumnal asthma. J Allergy Clin Immunol 1977;59:449-59.
47. Creticos PS. Reed CE. Norman PS. et al. Ragweed immunotherapy in
adult asthma. N Engl J Med 1996:334:501-6.
48. Haugaard L. Dahl R, Jacobsen L. et al. A controlled dose-response study
of immunotherapy with standardized, partially purified extract of house
dust mite: clinical efficacy and side effects. J Allergy Clin Immunol
1993:91:709-22.
49. Van Meue TE Jr. Marsh DG. Adkinson NF Jr, et al. Immunotherapy for
cat asthma. J Allergy Clin Immunol 1988;82: 1055-68.
50. Hedlin G, Graff-Lonnevig V. Heilbom H, et al. Immunotherapy with cat-
and dog-dander extracts. II. In viva and in vitro immunologic effects
observed in a I-year double-blind placebo study. J Allergy Clin Immunol
1986;77:488-96.
51. Lackey RF. Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities
fromimmunolherapy (IT) and skin testing (ST). J Allergy Clin Immunol
1987;79:660-77.
52. Nelson BL. Bupont LA, Reid MJ. Prospective survey of local and sys-
temic reactions to immunotherapy with pollen extracts. Ann Allergy
1986;56:331-4.
53. Bousquet J. Hejjanoui A. Clauzel A-M, et al. Specific immunotherapy
with a standardized Dermatophagoides pteronyssinus extract. II. Predic-
tion of efficacy of immunotherapy. J Allergy Clin Immunol 1988;82:971.
54. Joint Task Force. Practice Parameters: representing the AAAAI. ACAAI
and JCAAI. J Allergy Clin Immunol 1996:98:1-I I.
55. Ownby DR. Indications and contraindications of allergen immunothera-
py. Manual sponsored by the American Academy of Allergy and
Immunology 1994. p. l-8.
56. Tunon-de-Lam JM. et al. ACE inhibitors and anaphylactoid reactions
during venom immunotherapy [letter]. Lance1 1992;340:908.
S574 Creticos J ALLERGY CLIN IMMUNOL
FEBRUARY 2000
57. Du Buske LM, Ling CJ. Sheffer A. Special problems regardipg allergen
immunotherapy. lmmunol Allergy Clin North Am 1992;12:145-75.
58. Taylor WW, Ohman JL Jr, Lowell FC. Immunothempy in cat-induced
asthma: double-blind trial with evaluation of bronchial responses to cat
allergen and histamine. J Allergy Clin lmmunol 1978;61:283-7.
59. Ohman JL, Findlay SR. Leitermann SB. Immunotherapy in cat-induced
asthma: double-blind trial with evaluation in viva and in vitro responses.
J Allergy Clin lmmunol 1984:74:230-9.
60. Valovirta E. Koivikko A, Vanto T. et al. Immunotherapy in allergy to dog:
a double-blind clinical study. Ann Allergy 1984:53:85-S.
61. Bruun E. Control examination of the specificity of specific desmsitiza-
tion in asthma. Acla Allergologia 1949;2: 122.
62. Aas K. Hyposensitiwtion in house dust allergy asthma. Acta Pnediatr
Stand I97 I :60:264-S.
63. Smith AP. Hypasensitization with Dennatophugoidesprerongssi,rus anti-
gen: trial in asthma induced by house dust. Br Med J 1971;4:204-6.
64. DSouza ME, Pepys J, Wells ID. et al. Hyposensitization with Der-
frlotophogoidespfero,r~~~iflus in house dust allergy: a controlled study of
clinical and immunological effects. Clin Allergy 1973;3: 177-93.
65. Warner JD. Price JF. Soothill JF, et al. Controlled trial of hyposensitiza-
tion to Dematophogoides premryssinus in children with asthma
[abstract]. Lancet 1978:2:912-5.
66. Bousquet J, Calvayrac P, Guerin B. et al. Immunotherapy with a stan-
dardized Demmtophogoides preron.wiws extract. 1. In viva and in vitro
parameters after a short course of treatment. J Allergy Clin lmmunol
1984:76:734-44.
67. Petersen BN. Janniche H, Munch EP, et al. Immunotherapy with panial-
ly purified and standardized tree pollen extracts. Allergy 1988;43:353-
62.
68. Pence HL, Mitchell DQ, Greely RL. et al. Immunotherapy for mountain
cedar pollinosis: a double-blind controlled study. J Allergy Clin Immunol
1976;58:39-50.
69. Frostad AB. Grimmer 0. Ssndvik L. et al. Clinical effects of hyposensi-
tization using a puritied allergen preparntion from Timothy pollen OS
compared to crude aqueous extracts from Timothy pollen and a fourgrass
pollen mixture respectively. Clin Allergy 1983;13:337-57.
70. Bousquet J. Becker WM. Hejjaoui A. et al. Differences in clinical nod
immunologic reactivity of patients allergic to grass pollens and to multi-
ple-pollen species. II. Efficacy of a double-blind, placebo-controlled.
specihc immunotherapy with standardized extracts. J Allergy Clin
lmmunol 1991:88:43-53.
71. Frankland AW. Augustin R. Prophylaxis of summer hay-fever and asth-
ma: B controlled trial comparing crude grass-pollen extracts with the iso-
lated main protein component. Lancct 1954;l: 1055-7.
72. Ortolani C. PastorelI E. Moss RB, et al. Grass pollen immunothempy: a sin-
gle-year double-blind. placebo-conrrolled study in patients with grass pollen-
induced asthma and rhinitis. J Allergy Clin lmmunol 1984:73:283-90.
73. Reid MJ, Moss RB. Hsu Y-P. et al. Seasonal asthma in northern Califor-
nia: allergic causes and efficacy of immunotherapy. J Allergy Clin
lmmunol 1986;78:590-600.
74. Armentia-Medina A. Blanco-Quiros A. Martin-Santos JM. et al. Rush
immunotherapy with a standardized Bermuda grass pollen extract. Ann
Allergy 1989;63:127-35.
75. Bruce AA, Norman PS. Rosenthal RR. et al. The role of ragweed pollen
in autumnal asthma. J Allergy Clin Immunol 1977;59:449-59.
76. Johnstone DE. Study of the role of antigen dosage in the treatment of
pollinosis and pollen asthma. Am J Dis Child 1957;94:1-5.
77. Adkinson NE Eggleston PA. Eney D. et al. A controlled trial of
immunotherapy for asthma in allergic children. N Engl J Med
1997;336:324-3 I.
78. Creticos PS. Peptide downregulation of the immune response. In: Marone
G, Ausren KF. Holgate ST. Kay AB. Lichtcnstein LM. editors. Asthma
and allergic diseases: physiology, immunopharmacology and treatment.
San Diego, Calif: Academic Press; 1998: p.407-15.