NO 43 peter creticos allergy patfis.pdf

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 disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of immunotherapy on the underlying inflammatory component of allergic respiratory disease. The clinical relevance of these observations belies our understanding of allergic 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 symptoms. 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 respiratory 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 patient’s immune response and, in so doing, attenuate or eliminate the patient’s 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) sensitivity. 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 therapeutic 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 relevant 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 features of the disease bears out the critical role that seasonal aeroallergens (pollens, mold spores) play in triggering 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 diameter), 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 airways, readily induced both an immediate and a late asthmatic 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 protein (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 symptoms parallel the outdoor pollen count, asthma symptoms are more accurately correlated with total airborne allergenic activity, reflective of the presence of smaller airborne 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

1tKlO

1200

800

400

0

loo

7s

SC

25

0 4

3

2

1

0

s

s

4

2

. k-li!hJ

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 airborne 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 microenvironment 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 important 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 positive skin tests to cats and dogs. Fe1 d 1 is the major allergenic 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 saliva and dander. It does not cross-react with Fe1 d 1. In rodents (rat/mice) urinary protein appears to be the dominant source of allergen. In rabbits and guinea pigs, both saliva and urine are important sources of allergenic protein.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 allergen 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 sensitization and acute exacerbations of asthma and inner city asthma. Three major cockroach species appear to be relevant: 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 activation, 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 lymphocytes. 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 c U r Ml T 7 aAe lammation E Histamine

S Tryptase

.t Den, r TS

Allergen

Antibody

I- Basic proteins

1 LTs cylokims

rl LTs CjditlCS

C Ii R 0 N I

C

s Y M P T 0 M s

I N F L A M M A T I

0 N

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 inflammatory cascade, results in the development of a smoldering clinical process because of persistent exposure to a relevant 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 triggering 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 specimens to study severe grass-allergic rhinitis. Biopsy specimens 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 provocation. 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 responsiveness to not only specific allergic stimuli but also various 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 inflammatory mediators measurable in bronchial lavage fluids

9562 Creticos

l


AA l *

AA +c

1 T

160 , I

Cl00 E 2. =z 60

o 60

A l

TOW MS Ly N E Galr

84 AB+ Easophlls MasItX8 IndalermyIpIO

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 significant 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 al’s used a model of bronchial allergen challenge to provide evidence 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 presence 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 treated with immunotherapy, these lymphocytic responses were decreased, and an increased activity of antigen-specific 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 demonstrated 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 histamine required to produce a 20% fall in FEV, value. Kuna et al’? accentuated the clinical relevance of this observation by showing that in grass-immunized subjects, a significant 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 controlled by pharmacotherapy. Significant clinical improvement was observed with a reduction in clinical symptoms and a reduced need for supplemental “rescue” medications 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 lymphocytes 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 lymphocytes, macrophages. and eosinophils were observed. With in situ hybridization techniques, enhanced expression 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 primary 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 aI’s 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 allergen-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 findings 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 inflammatory 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 immediate-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 typical 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, significantly fewer patients demonstrated inflammatory mediator release in their nasal secretions or experienced clinical symptoms on nasal provocation. The actual absolute concentrations of inflammatory mediators measurable in their nasal secretions after allergen challenge was significantly lower in the immunized patient group when compared with the nonimmunized patients.

Subsequent studies by Iliopoulos et a129 further

demonstrated that ragweed immunotherapy not only influenced the immediate-phase reaction but also attenuated the late-phase inflammatory reaction in rdgweed- allergic patients, with a significant reduction in histamine, 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 fashion.

Majchel et alsi used histamine challenge of the nose to demonstrate the effects of immunotherapy on nonspecific 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 demonstrated by Sundin et aIs2 in patients with cat-allergic asthma; whereby immunotherapy not only ablated the specific allergen-induced bronchohyperresponsiveness (to cat) but also significantly attenuated hyperresponsiveness 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 nonspecific 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 demonstrated 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 immunizing 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 clinical 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 significant 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 followed 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 secretions.

NONSPECIFIC CHANGES

Tissue mast cells and circulating basophils are capable of releasing histamine on allergen challenge. The positive correlation has been shown between basophil sensitivity and symptom diary scores in patients with allergy. Lichtenstein et al43 have demonstrated that immunotherapy is associated with a decrease in both cellular sensitivity (the amount of allergen required to induce 50% basophil histamine release) and cellular reactivity (the ability of basophils to release 100% of their cellular histamine). Brunet et al4 observed that this cellular sensitivity 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 histamine-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 immunotherapy in patients with allergy with a component of

lower respiratory disease (asthma). In this context, studies 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 consistently result in clinical improvement.

As previously cited, Creticos et a145 clearly demonstrated that both the clinical and the underlying inflammatory 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 investigators 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 contrast, there was no improvement in bronchial sensitivity in the control group. However, the authors noticed a stepwise 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 consistent 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 provided 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 paralleled 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 patient’s underlying medical conditions, because certain systemic illness- es could adversely impact a patient’s 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 patient’s ability to appropriately respond to epinephrine when given as treatment for a reaction to an immunotherapy 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 therapy. 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 challenge response to an extract of cat pelt on bronchial provocation. The 10 subjects were randomized in a double-blind fashion to receive either immunotherapy with a cat-pelt extract (rich in cat allergen 1, Fe1 d 1 [approximately 32 pg Fe1 d 11) or placebo injections. The 5 placebo subjects showed no change in skin test reactivity, in specific bronchial hyperresponsiveness to cat provocation, 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).


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 antibody production, and a significant reduction in specific (cat) allergen-induced bronchial hyperresponsiveness on bronchial provocation to cat. Again, no shift in methacholine 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 exposure, 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 conjunctival 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 standardized 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 production. Although a decreased sensitivity to dog on conjunctival 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


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 environment. Hence, this begs the question as to whether cat immunotherapy can significantly alter the clinical response in patients who are exposed to a relevant allergen (cat) on a daily basis.

In clinical practice, allergy injections are often given to cat-allergic patients who have cats in their home setting. Although these studies have demonstrated the efficacy 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 therapeutic effects of immunotherapy in a “real-world” situation, that of an allergic stimulus (cat) that can induce persistent inflammation and chronic symptoms. At issue, is whether immunotherapy can alter this clinical presentation.

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 placebo. 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 placebo 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


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-allergic 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 requirements, 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.

D’Souza 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, medication 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 provocative 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 provocation with the specific dust-mite allergen. However, Bousquet et al53 pointed out that care must be taken when considering immunotherapy in patients with asthma. 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


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 immunotherapy. 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 immunotherapy.

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 characterized with respect to its predominant allergens. It has been standardized on the basis of its major protein moiety (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 symptom and medication usage scores. Furthermore, a significant improvement was also observed with skin prick testing and on nasal provocation. Treatment with the birch extract alone appeared to provide comparable clinical 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


respective species of grass and the overlapping cross- sensitivity of various grass species contribute to the relevant 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 various 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 necessarily shared or recognized by other members of the temperate 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 immunotherapy (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 immunizing dose, a significant rise in total IgG antibody and IgG subclass antibodies to Timothy (antigen D) were observed. However, neither group of patients demonstrated 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 pollination. Over the 4-year period of observation, peak grass-pollen counts strongly correlated with emergency department visits and hospitalizations for asthma (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 significant 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 provocation 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 mechanisms 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 endpoints. 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 (median 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 demonstrate 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 ragweed-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 follow-up and the judicious use of anti-inflammatory medications 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 period of the ragweed season (P = .05) provide evidence for the specific benefit of immunotherapy.

With respect to clinical endpoints, the ragweed-immunized patients demonstrated an approximate 40% improvement in their asthma symptoms and had a measurable 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) measured in the morning before, during, and after the ragweed-pollination season. Measurements of peak expiratory 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 xanthine, 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 corticosteroid, 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. All rights reserved.)

ings, a measurement indicating a meaningful reduction in their underlying asthmatic inflammatory process. In contrast, the placebo-injected patients required approximately 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 during 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 ragweed-induced rhinitis (n = 175 patients) and asthma (n = 112 patients) and reported a significant reduction in both


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 immunotherapy with up to 7 relevant allergens. Both groups demonstrated a significant improvement in their P&a to methacholine. However, no significant differences were observed between groups for medication score, symptoms, 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 hyperresponsiveness, 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 demonstrated subjective relief (symptom and medication improvement), objective evidence for effkacy (improvement in physiologic parameters [pulmonary function]), provocation models (bronchial allergen challenge), and evidence for mechanism at the cellular level. Needed now are studies of effectiveness that better define the effect of immunotherapy on the severity of disease, quality of life, and health economics. Studies aimed at early intervention, 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 diseases: 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 allergic asthmatics. Am Rev Respir Dis 1991;144:51-8.

20. Rocklin RE. Sheffer AL, Greineder DK. Melmon KL. Generation of antigen-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 challenge [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 asthma. 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 double-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 uncontrolled 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 allergen: 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 season and immunotherapy. J Allergy Clin Immunol 1992;90:85-91.

32. Sundin B. Lilja G. GralT-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 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 immunity 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 measurements 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 subclass 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-ragweed 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 associated 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 systemic 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 immunotherapy. 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.


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. D’Souza 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 hyposensitization 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 standardized 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 hyposensitization 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 multiple-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 asthma: 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 single-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.

Date post:	21-Jul-2016
Category:	Documents
Upload:	lussievareta
View:	2 times
Download:	0 times

NO 43 peter creticos allergy patfis.pdf

Documents