Gwaltney
et aI,
J ALLERGY
CLIN IMMUNOL SEPTEMBER 1992
DISCUSSION
instilling culture?
Dr. Spector. I wonder if either of you or both would comment on the advantagesof culturing the mucosa obtained at the time of surgery. I only know of one study from
Dr. Gwaltney. If fluid cannot be obtained, we instill 1 ml of normal saline solution to obtain a specimen. Dr. Wald. Probably the single most important thing is getting the specimen to the laboratory as fast as possible
Finland some years ago. What I remember was that they showed in cases with chronic sinus disease a very high incidence of anerobic organisms that had never been suspected before. I wonder why more people do not do that. Dr. Gwaltney. The question is, are they of any importance in the etiology of the condition? Nobody really knows. Dr. Spector. Is there an advantage or disadvantage in
Environmental control allergic disease Richard
saline solution in the sinus when you do the
and then getting in on the right media I agree with Jack. I think that normal sinusesarebacteriafree; on the other hand, the idea that they might be transiently contaminated with great frequency holds much appeal. I think quantitation is important for us to assess whether the organism is truly there in high number or it is just passing through.
and immunotherapy
for
Evans III, MD, MPH Chicago, Ill.
Treatment for allergic disease can help prevent recurrent sinusitis. Removal of carpeting and feather bedding and use of acaricides can sig@cantly improve symptoms caused by house dust mites or animal dander. To kill mites, wash-water temperature must be at least 58” C. Patients with severe allergy should use an air-jiltering vacuum cleaner and an air cleaner with a HEPA jilter. Humidity should be kept at under 50%. If other measures fail, pets may have to be removed. Subcutaneous immunotherapy is effective for patients with anaphylactic reactions to insect stings, allergic rhinitis, and allergic asthma. It is ineffective for food allergy or nonallergic rhinitis or asthma. In children, immunotherapy is reserved for generalized life-threatening airway reactions. Relative indications for immunotherapy include inability to avoid the allergen and poor results or significant side efsectsfrom pharmacologic treatment. Eficacy depends on dosage, duration of treatment, and allergen selection. Low initial doses are increased at a set rate until the dose induces appropriate antibody response without signijcant reactions. Patients should be much improved or symptom-free for 1 to 2 years before immunotherapy is discontinued. Pollen, house dust mite, cat, and some mold spore extracts reduce symptoms and sensitivity to nasal or bronchial provocation. When used appropriately, immunotherapy is safe and effective. (J ALLERGYCLIN IMMVNOL 1992:90:462-B.) Key words: Allergy, animal, asthma, environment, extracts, house dust mite, immunotherapy, insect bites and stings, rhinitis
Because there is an apparent relationship between allergic rhinitis and sinusitis, it is likely that treatment for allergic disease will have the additional benefit of helping prevent recurrent sinusitis. Toward that end, patients with allergic rhinitis and recurrent sinusitis
From the Division of Allergy, Children’s Memorial Hospital, and Northwestern University Schooi of Medicine, Chicago, Ill. Reprint requests: Richard Evans III, MD, Allergy Division, Box 60, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. 1IO/38498
462
Abbreviations used Der p: Dermatophagoides pteronyssinus Der f: Dermatophagoides farinae
require an aggressive approach toward management of their allergic disease. Today, IgE-mediated diseases such as allergic asthma and allergic rhinitis are managed by one or all of three approaches: allergen avoidance, drug therapy, and/ or allergen-specific immunotherapy. Of the three,
VOLUME NUMBER
90 3, PART 2
allergen avoidance would seem to be the simplest, most effective, least expensive, and best tolerated form of treatment, and in many cases it is. For example. elimination of an offending food from the diet is generally straightforward and easily accomplished. However. the identification and elimination of airborne allergens can be much more difficult. Immunotherapy may be warranted in some cases that do not respond to other measures. Home. school, and work environments are obvious targets for identification and reduction of exposure to allergens. Most individuals spend approximately 50% of their lives at home,’ so the home is the logical place to begin removal of airborne allergens from the environment. Common aeroallergens in the home include those from house dust mites. pet dander, cockroaches. molds, and pollens.
HOUSE DUST MITES Worldwide, house dust mite is the most prevalent allergen. Studies of the inhabitants of the Eastern Highlands of Papua New Guinea, offer perhaps the most dramatic proof of the impact of the house dust mite on allergic disease. Before the arrival of the Europeans, who brought with them blankets and bedding, asthma was virtually unknown in this part of the world. Now the prevalence of asthma is 7311000 in adults. among the highest anywhere.* Researchers attribute this skyrocketing asthma prevalence to the moditication in traditional life-style, that is, the use of blankets and bedding that is infested with mites. Mites are relatives of ticks and spiders. They belong to the order Acaridae. The genus Dermatophagoides is the most important allergen source in house dust. Three species predominate in most homes: D. pteronyssinus, D. farinae, and D. microceras. Of these, D. pteronyssinus and D. farinae contribute more than 90% of the allergens in house dust.’ Mites thrive best at a humidity of 70% and a temperature of 70” F. Immunochemical techniques have isolated two major groups of allergens in mite insect parts and mite feces. These two groups are the Der I group and the Der II group. Both groups have been isolated from each of the three major species. The Der I group occurs in very high concentration in mite feces.’ It elutes rapidly from isolated fecal particles but very slowly from mite bodies. The Der II group appears to be concentrated in mite bodies. Culture extracts contain relatively more Der I than Der II because they contain large numbers of mite feces. The key value for excessive mite growth in the home is an absolute indoor humidity of approximately 7 gmikg.’ This is equivalent to a relative humidity of 60% at 70” F or a relative humidity of 75% at 60” F.
Environmental control and irnmmoth~:rapy
463
The D. furinae tends to predominate in areas in which there are 3 or more months of dry weather. whereas D. pteronyssinus predominates in more humid areas such as London, Atlanta, and the Pacific Northwest. ’ Investigators have proposed standards both for scnsitization to mites and for the expression irf allergic symptoms in atopic patients. An international workshop on dust mite allergy proposed that iJ level of 2 pg of Der p I and Der f L per gram (4 dust be considered a risk factor for sensitization and the development of allergic asthma. A level OC 10 p+ ~gtm of dust was proposed as a major risk t‘xtor for the development of acute asthma in mite-allergit. persons.’ In evaluating these standards, Wahn et al.’ conlirmed that the presence of 2 pg of Der p I per gram of house dust would increase the probability that a~ asthmatic patient would be mite allergic. The development of these standards give\ us a goal to aim for when using environmental control measures to reduce allergen exposure. It is possible to measure allergens in houst dust samples with the USAof monoclonal antibody assays. In fact, it is more pmctical to measure the level of the allergen in a house dust SUP ple than to count the number of mites. The:;e assays are available for use in patient care:.
ENVIRONMENTAL CONTROLS Environmental control can be effectrve. but to make it worthwhile, it must actually reduce allergen exposure. Numerous studies have shown that the measures must be uggressivc). Otherwise the effort is not worth the undertaking. The measures must also be practical and capable of accomplishment by an ordinary fatnily with other demands on time and energy. Families vary widely in their commitment to the project. personal and financial resource>, energy levels. and other factors that would make avoidance treatment successful or unsuccessful. Ideally, the physician should know something about the household. At a minimum, the physician should learn the number of occupants of the home. smoking habits, type of heating and air conditioning, pets, whether the home is located in an urban, suburban, or rural area. the family’s socioeconomic situation. and the family’s attitude toward the desirability of avoidance measures. Because the patient spends much time there, the bedroom is probably the most important room in which to reduce allergen exposure. .The bedroom should be made as easy to clean as ptas4blc. Hardwood or tile floors are much less likely to harbor mites than carpeting. If the family has carpeting, they may be reluctant to remove it. If they elect to keep the carpeting. they should be informed that mites cannot effectively be removed by vacuuming, Ii carpeting is
464
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CLIN IMMUNOL SEPTEMBER 1992
kept, it must be steam cleaned and treated frequently with acaricides.
tentially toxic. In any event, acaricides should not be used when children are in the room.
ACARICIDES
BEDDING
Acaricides marketed in the United States are most commonly based on either tannic acid or benzyl benzoate. Miller et al6 found that an application of 3% tannic acid solution reduced dust mite antigen levels in carpets and furniture. An untreated section of a couch had an initial total mite antigen level of 13.4; 24 hours later, the level was 9.5. In a treated section of the same couch, levels went from 17.9 to undetectable after treatment. Several very recent studies have reported good results with Acarosan, an acaricide based on benzyl benzoate. The product is available as an aerosol foam for furniture and beds and as a moist powder for carpets. In one study of 25 dust mite-allergic patients, Brown and Merrett’ found that patients had significant improvement in symptoms of asthma, eczema, and rhinitis. Many patients were able to reduce or stop medication. These benefits persisted for up to 1 year after one-time treatment of furniture and carpets with Acarosan. Another double-blind trial of Acarosan with mite-allergic rhinitis patients found that 8 of 10 subjects in the acaricidal cleaner treatment group improved more than the control subjects, who performed normal but intensive cleaning.* Subjective symptoms disappeared in three patients, and after 1 year, the daily symptoms median was 47%, total IgE was 38%, and exposure to dust and mite products was 53% better in the Acarosan group than in control subjects. Because this product is relatively new, there will undoubtedly be further trials to test its effectiveness. Another concern is the potential toxicity of this or any other acaricide . Another acaricide, pirimiphos methyl, has been found to both decrease mite numbers and prevent mite reinfestation3 but it is still being tested for domestic use. Paragerm, a hospital disinfectant, has some acaricidal activity, but it has a very unpleasant odor and is not as effective as other products.’ Natamycin is a fungicide that is marketed in Europe under the name Tymasil as a spray for mattresses. However, Reiser et al.” recently reported results of a double-blind, placebo-controlled trial in which they found no significant difference in levels of Der p I in mattress dust between the Tymasil group and control subjects. In the future, other effective acaricides may be developed, but it is still easier to eliminate havens for mites, such as carpeting and upholstered furniture, than to treat the problem after the fact. Furthermore, acaricides can be expensive, and some may be po-
Mattresses should be covered with plastic, because vacuuming offers only temporary improvement. The plastic should be wiped clean periodically. Most people will want to use a mattress pad over the plastic. This pad should be washed as frequently as the bedding. In England, Owen et al.” tested bedding constructed with a vapor-permeable waterproof fabric that is reportedly impermeable to Der p I mite antigen. The material, Ventflux, a polyurethane coating, was used to make a mattress cover, pillow, and duvet. After 12 weeks of use, Der p I levels per gram of mattress dust were 1% of the levels in control samples from mattresses cleaned conventionally. This is another new product that may merit further study. Feather pillows, a favorite haven for mites, should be abandoned in favor of polyester-filled pillows. Needless to say, feather beds and comforters pose the same problem as feather pillows. Pillows and other bedding should be washed regularly in hot water at temperatures of at least 58” C. Andersen and Roesen” washed mites to determine the effects of washing and water temperature. Although they found that most mites died of drowning, some mites survived at temperatures of less than 58” C. Besides being popular with mites, woolen blankets are not appropriate because they shrink when washed at high temperatures. Preshrunk cotton blankets, particularly those with a thermal weave, are warm enough even for cold winters, and cotton is easily washed. Laundry should be dried indoors, because pollens can cling to fabric dried outside. In general, the bedroom should be kept as clutter free as possible, so as to make thorough cleaning easier. Upholstered furniture is better kept to other rooms. Because woolen clothing is attractive to mites, it should be stored elsewhere. WHOLE-HOUSE
CLEANING
Similar measures to those taken in the bedroom should be applied to the rest of the house, and in particular, to those rooms in which the allergic individual spends considerable time. For some this could be the living room, television room, playroom, or workshop depending on personal interests. Regular vacuuming to remove surface dust is important in these rooms and throughout the house. However, vacuuming temporarily increases exposure to airborne particles. Vacuum cleaners are available that have special filters to clean exhausted air. People who have
VOLUME YUMBER
90 3, PART 2
severe allergies might want to investigate these products. Target areas for molds include damp basement floors, bathrooms (including shower curtains), air conditioners and ducts, humidifiers and dehumidifiers, refrigerator drip pans, greenhouses, and indoor spas, or other areas with high localized humidity. All major appliances should be inspected and cleaned often, particularly before seasonal use. Filters should be changed frequently according to manufacturer’s directions. Areas that are unavoidably humid can be washed with Lysol or bleach to retard mold. Cockroaches are also found in damp areas and in areas that contain garbage or poorly stored food products. Scrupulous cleaning, proper food storage, and prompt garbage disposal should prevent this problem. Humidity should be kept at under 50% if possible. ’ Air conditioning and dehumidifiers can reduce indoor humidity during warmer months. Leaky pipes should be repaired. and areas where water seeps into the home should be waterproofed. Attics and crawl spaces should be ventilated to permit moisture to escape. Clothes driers should be vented to the outside. It is also wise to provide a fan in the bathroom that vents to the outside. AIR CLEANING/FILTRATION Another means of allergen control is by filtering the air in the home. Various air cleaning/filtering products are available. Broadly speaking, these devices either filter air mechanically or by electrical attraction. Mechanical filters are most effective on particles larger than 1 km. The larger the particle size, the more effective mechanical filters become. The simplest mechanical filters contain panels of woven matting that are sometimes coated with oil to increase particle retention. Panel filters have about a 75% efticiency with particles the size of pollens, but their efficiency is too low to be useful for tobacco smoke and some molds.” On the other end of the scale, the HEPA filter is the most efficient mechanical filter. HEPA filters must meet stringent standards: they must have a minimum particle-removal efficiency of 99.97% for particles of 0.3 km diameter. HEPA filters have higher efficiencies for both larger and smaller particles than do other mechanical filters. HEPA filters contain submicronic glass fibers. Their efficiency actually increases with use, and they require little maintenance. Filter life exceeds 1 year and may reach 5 years.14 With the increased emphasis on a cleaner environment Tnegative ion generators have become more popular. These are simple electronic air cleaners that work by delivering a negative charge to airborne particles.
Environmental
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and immlrn7c~rhcr,.py
465
If the unit has a positively charged collectic~n @ate. the particles gather there. However, some dwcc\ do not have such plates. In that case, particles c:tllect on any positively charged surface. The resuit may hz cleaner air at the expense of dirtier walls aad I’\miture. Two-stage electrostatic precipitator5 are rclativcl) efficient. The precipitator draws ionized pa&c& through a series of oppositely charged plates. Collec. tion efficiency is related to the area oi the ti~ll&ing plates. flow rate. and the strength ot the ;:lecrrical field.” Precipitators have high-efficiency ratev i’or p:,i titles as large as pollen and as small as tobacco S~YK&X Electrostatic precipitators can be attached t:) central heating and cooling units. However. precipitatori ha\,c a lower efficiency than HEPA filter\. and thcv require frequent cleaning. Air conditioning also helps to keep indoor arr- cican by keeping out outdoor air at the time of >h:ar when it is most likely to contain pollens. Mite ck*unts and mold spores are also reduced by air conditittning hccause indoor humidity is reduced. A recent survey found that approximately 6 millron Americans are allergic to cats, and of these. nearly 2 million have cats despite their allergic problems.“’ I7 Overall. 28R, of American households hi:: at least one cat. that equals at least 50 million cat\, “10 it is difficult for anyone to entirely avoid exposurt: tmediate results. Luczynska et al.” iounc! that the amount of airborne allergen was less depr:ndcni i)n the number of cats than on whether the cat was confined indoors and whether there was uphoillercd furniture. This same study found that aggresbuve cleaning. removal of soft furniture, and u.scot air ti!tration, especially a HEPA filter, could succcssfullq rcmovc airborne cat allergen even when thil c:ll r~~nai~xd m the household. IMMUNOTHERAPY In some cases, immunotherapy may be neces>,ary. Immunotherapy has a long history that dates back to 1911 when Leonard Noon treated patients with grasspollen hay fever by administering subcutaneous injections of grass extract.” We use a similar method
466
Evans
today-increasing subcutaneous injections of an extract of a substance to which a patient is known to be allergic. The treatment should only be used in patients with IgE-mediated disease. Immunotherapy is effective for patients who have had anaphylactic reactions to insect stings, for patients with allergic rhinitis, and for those with allergic asthma. It is not effective for food allergy or nonallergic rhinitis or asthma. It should not be used as a substitute for avoiding an allergen, such as allergy to cats. Before immunotherapy is considered, it is absolutely essential to establish the diagnosis through careful history and physical examination. Skin tests and in vitro studies are used to confirm the diagnosis and not to establish it. The diagnosis of IgE-mediated disease should be established by a physician experienced in allergy, who should also determine whether immunotherapy is appropriate. In addition to nonallergic disease and food allergy, allergen immunotherapy is not indicated for patients who have chronic bronchitis, emphysema, hives, headache, drug reactions** or for patients who have had good responses to allergen avoidance and medication. However, allergen immunotherapy often complements pharmacologic, treatment in patients who otherwise would not be satisfactorily symptom free. The only absolute indication for immunotherapy is for patients with life-threatening reactions to hymenoptera insect stings. The diagnosis of insect-sting allergy is based on the history of the reactions and confirmation by positive skin tests. In adults who also have positive skin tests, generalized or systemic reactions that would warrant immunotherapy include systemic reaction with urticaria, angioedema, and respiratory or cardiovascular symptoms. In children, immunotherapy is reserved for generalized life-threatening reactions involving the airways. In either adults or children, local reactions to insect stings and negative skin tests do not warrant immunotherapy. Relative indications for immunotherapy include patients with allergic asthma or allergic rhinitis who cannot avoid the allergen. Patients who have poor results from pharmacologic treatment or significant side effects from drugs may also be candidates for immunotherapy. Allergen immunotherapy is contraindicated in patients who have autoimmune disease and patients who become pregnant before the start of treatment. Those patients who become pregnant after receiving immunotherapy may continue with the treatment. Young children are not good candidates for immunotherapy. Patients with severe systemic disease (particularly those receiving B-blocking agents), those with coro-
J ALLERGY
CLIN IMMUNOL SEPTEMBER 1992
nary artery disease, or those with severe hypertension should not be placed on immunotherapy because these conditions can severely hamper treatment of a systemic allergic reaction. Patients who have repeated allergic reactions to immunotherapy should discontinue the treatment. Subcutaneous injections are the preferred mode of treatment. Intravenous delivery should be avoided, and oral and nasal routes of delivery have not yet been proved. The efficacy of allergen immunotherapy has improved over the years as better extracts have become available and diagnosis has become more precise. However, efficacy depends on the dosage, duration of treatment, and allergen selection.22 For example, clinical and immunologic studies of immunotherapy for ragweed hay fever have shown that low-dose maintenance immunotherapy is ineffective, that relapses may occur when effective treatment is discontinued, and that the therapeutic benefit is limited to the allergen administered .22 Another recent study related efficacy in part to effects on the late-phase reaction. Pienkowski et a1.23 found that immunotherapy was associated with the suppression of the skin late-phase reaction, and the magnitude of the late-phase reaction was correlated with the level of IgG antiragweed. (IgG is the “blocking antibody” induced by immunotherapy.24) As Creticos and Norman described,25 a favorable clinical response to immunotherapy results from an alteration in the balance between the protective immunologic responses mediated by IgG and the allergic immunologic responses mediated by IgE antibodies in conjunction with other incompletely defined mechanisms. An increase in IgG antibody is essential to the process. This is why an adequate dose is so important. Ideally the dose would induce an appropriate antibody response without producing significant reactions. Initial doses are set low to avoid risk of severe allergic reaction. Doses are usually increased at a set rate, perhaps doubled at each visit, until the dose nearly reaches the anticipated maximum, when it may be increased at a slower rate. If patients experience severe reactions at higher doses, doses may be cut back. The patient should not expect to see significant improvement for at least 6 months after the start of immunotherapy. 26 Delayed relief of symptoms reflects in part the time required to build up to an effective dose. If modified antigen preparations are used, the dose may be stepped-up more quickly, but it will still be several months before the patient sees an effect. It is important that patients be aware that they will not experience immediate relief. Otherwise their initial expectations may be too high.
VOLUME90 NUMBER 3.PART2
There is no absolute endpoint for immunotherapy when the patient is doing well on it. In general, patients should be much improved or symptom free for 1 to 2 years before immunotherapy is discontinued. Most patients receive immunotherapy for 3 to 5 years. Allergen extracts that have proved effective in ameliorating symptoms and/or in reducing the subject’s sensitivity to nasal or bronchial allergen provocation are pollen extracts (grasses,“‘, ” ragweed,29 mountain cedar, and birch trees”.“), house dust mite,” cat I?. 12.31and two common mold spores, Alternaria and Cladosporium. 22,id, ” Researchers have recently developed promising modifications of extracts. Some allergens are modified by polymerization. Another new group of extracts, allergoids, are treated with formaldehyde or glutaraldehyde. These extracts retain immunogenicity but have decreased side effects. Studies have found that patients treated with allergoids had significantly higher IgG antibody levels than patients treated with aqueous extracts, both initially and after several years of treatment.7h-‘X Another merit of allergoid extracts is that they can apparently be given less frequently. Norman et al.‘” reported that patients receiving allergoid injections every 3 months had similar symptom scores, IgG antibody levels, and rates of local and systemic reaction as did patients receiving injections every 6 weeks. Because the 3-month treated group had approximately half as many injections, the group also had half as many reactions. Other treatments for IgE-mediated disease are under investigation, but immunotherapy already has a record of clinical safety and efficacy that has endured for three quarters of a century. In the future we can expect more and improved standardized extracts. The World Health Organization has already authorized several international standard preparations and more are on the way. These developments will only add to the usefulness of this already well-established treatment. REFERENCES I. Hamilton RG, Chapman MD, Platts-Mills WE, et al. Aeroallergen measurements in clinical practice: a guide to allergenfree home and work environments. A monograph. Baltimore: Johns Hopkins University Asthma and Allergy Center, 1991 (publication no. 061). 2 Dowse GK, Turner KJ. Stewart GA, et al. The association between Devmatopha,goides mites and the increasing prevalence of asthma in village communities within the Papua New Guinea highlands. J ALLERCYCLIN IMMUNOL1985;75:75-83. 3. Platts-Mills TAE, Chapman MD. Dust mites: immunology, allergic disease, and environmental control. J ALLERGYCLIN hMCNOI. 1987;80:755-74. 4. Chapman MD, Heymann PW, Wilkins SR, et al. Monoclonal lmmunoassays for the major dust mite (Dermarophagoides) allergens. Der p I and Drrf I, and quantitative analysis of the
Environmental
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and immtinothe~apv
467
allergen content of mite and house dust extracts .I i\r !-I:K(~~ CLIN IW.IUNOL. 1987;SO:184-94.
5. Dust mite allergens and asthma-a worldwide problem J Ai LERGY CLIN IMMUNOL 1989;83:416-27. 6. Miller JD. Miller A, Luczynska C, et al. Effect oi tanmc acid spray on dust-mite antigen levels in carpet\ [Abstract] J AI LERGY CLIN
~MMUNOL 1989;83:262.
I. Brown HM, Merrett TG. Effectivenes\ oi an :%cticidc m management of house dust mite allerg) 4rtn Allergy 1991:67:25-31. 8. Kniest M, Young E, Van Praag MCG, et al. Clinical ebaluatmn of a double-blind dust-mite avoidance trial with mite-allergic rhinitis patients. Clin Exp Allergy 1991:2 I .3Y-47 9. Penaud A. Nourrit J, Timon-David P, et al. Rehults of a con“pp. in dwellmg trolled trial ofparagenn on Dermatophapnid~s houses. Ciin Allergy 1977:7:49-53. 10. Reiser J, Ingram D, Mitchell EB. et al House dust mite allergen levels and an anti-mite mattress spray cnatamycm) in the treatment of childhood asthma. t’lm I:rp Allergy L990;20:561-7. 11. Owen S, Morganstem M, Hepworth J, et al. Control of bou\c dust mite antigen in bedding. Lancet 1990~335.346-7 12. Andersen A, Roesen J. House dust mire. Drrrnuro~~lrcl~l,fd.s preronywinus, and its allergens: effect< of wa&ing Allergy 1989;44:396-400. 13. Nelson HS, Hirsch SR, Ohman JL Jr, et al. Recommendations for the use of residential air-cleaning devices in the treatment of allergic respiratory diseases. J Ar ! RR
et aI,
J ALLERGY
CLIN IMMUNOL SEPTEMBER 1992
DISCUSSION
instilling culture?
Dr. Spector. I wonder if either of you or both would comment on the advantagesof culturing the mucosa obtained at the time of surgery. I only know of one study from
Dr. Gwaltney. If fluid cannot be obtained, we instill 1 ml of normal saline solution to obtain a specimen. Dr. Wald. Probably the single most important thing is getting the specimen to the laboratory as fast as possible
Finland some years ago. What I remember was that they showed in cases with chronic sinus disease a very high incidence of anerobic organisms that had never been suspected before. I wonder why more people do not do that. Dr. Gwaltney. The question is, are they of any importance in the etiology of the condition? Nobody really knows. Dr. Spector. Is there an advantage or disadvantage in
Environmental control allergic disease Richard
saline solution in the sinus when you do the
and then getting in on the right media I agree with Jack. I think that normal sinusesarebacteriafree; on the other hand, the idea that they might be transiently contaminated with great frequency holds much appeal. I think quantitation is important for us to assess whether the organism is truly there in high number or it is just passing through.
and immunotherapy
for
Evans III, MD, MPH Chicago, Ill.
Treatment for allergic disease can help prevent recurrent sinusitis. Removal of carpeting and feather bedding and use of acaricides can sig@cantly improve symptoms caused by house dust mites or animal dander. To kill mites, wash-water temperature must be at least 58” C. Patients with severe allergy should use an air-jiltering vacuum cleaner and an air cleaner with a HEPA jilter. Humidity should be kept at under 50%. If other measures fail, pets may have to be removed. Subcutaneous immunotherapy is effective for patients with anaphylactic reactions to insect stings, allergic rhinitis, and allergic asthma. It is ineffective for food allergy or nonallergic rhinitis or asthma. In children, immunotherapy is reserved for generalized life-threatening airway reactions. Relative indications for immunotherapy include inability to avoid the allergen and poor results or significant side efsectsfrom pharmacologic treatment. Eficacy depends on dosage, duration of treatment, and allergen selection. Low initial doses are increased at a set rate until the dose induces appropriate antibody response without signijcant reactions. Patients should be much improved or symptom-free for 1 to 2 years before immunotherapy is discontinued. Pollen, house dust mite, cat, and some mold spore extracts reduce symptoms and sensitivity to nasal or bronchial provocation. When used appropriately, immunotherapy is safe and effective. (J ALLERGYCLIN IMMVNOL 1992:90:462-B.) Key words: Allergy, animal, asthma, environment, extracts, house dust mite, immunotherapy, insect bites and stings, rhinitis
Because there is an apparent relationship between allergic rhinitis and sinusitis, it is likely that treatment for allergic disease will have the additional benefit of helping prevent recurrent sinusitis. Toward that end, patients with allergic rhinitis and recurrent sinusitis
From the Division of Allergy, Children’s Memorial Hospital, and Northwestern University Schooi of Medicine, Chicago, Ill. Reprint requests: Richard Evans III, MD, Allergy Division, Box 60, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. 1IO/38498
462
Abbreviations used Der p: Dermatophagoides pteronyssinus Der f: Dermatophagoides farinae
require an aggressive approach toward management of their allergic disease. Today, IgE-mediated diseases such as allergic asthma and allergic rhinitis are managed by one or all of three approaches: allergen avoidance, drug therapy, and/ or allergen-specific immunotherapy. Of the three,
VOLUME NUMBER
90 3, PART 2
allergen avoidance would seem to be the simplest, most effective, least expensive, and best tolerated form of treatment, and in many cases it is. For example. elimination of an offending food from the diet is generally straightforward and easily accomplished. However. the identification and elimination of airborne allergens can be much more difficult. Immunotherapy may be warranted in some cases that do not respond to other measures. Home. school, and work environments are obvious targets for identification and reduction of exposure to allergens. Most individuals spend approximately 50% of their lives at home,’ so the home is the logical place to begin removal of airborne allergens from the environment. Common aeroallergens in the home include those from house dust mites. pet dander, cockroaches. molds, and pollens.
HOUSE DUST MITES Worldwide, house dust mite is the most prevalent allergen. Studies of the inhabitants of the Eastern Highlands of Papua New Guinea, offer perhaps the most dramatic proof of the impact of the house dust mite on allergic disease. Before the arrival of the Europeans, who brought with them blankets and bedding, asthma was virtually unknown in this part of the world. Now the prevalence of asthma is 7311000 in adults. among the highest anywhere.* Researchers attribute this skyrocketing asthma prevalence to the moditication in traditional life-style, that is, the use of blankets and bedding that is infested with mites. Mites are relatives of ticks and spiders. They belong to the order Acaridae. The genus Dermatophagoides is the most important allergen source in house dust. Three species predominate in most homes: D. pteronyssinus, D. farinae, and D. microceras. Of these, D. pteronyssinus and D. farinae contribute more than 90% of the allergens in house dust.’ Mites thrive best at a humidity of 70% and a temperature of 70” F. Immunochemical techniques have isolated two major groups of allergens in mite insect parts and mite feces. These two groups are the Der I group and the Der II group. Both groups have been isolated from each of the three major species. The Der I group occurs in very high concentration in mite feces.’ It elutes rapidly from isolated fecal particles but very slowly from mite bodies. The Der II group appears to be concentrated in mite bodies. Culture extracts contain relatively more Der I than Der II because they contain large numbers of mite feces. The key value for excessive mite growth in the home is an absolute indoor humidity of approximately 7 gmikg.’ This is equivalent to a relative humidity of 60% at 70” F or a relative humidity of 75% at 60” F.
Environmental control and irnmmoth~:rapy
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The D. furinae tends to predominate in areas in which there are 3 or more months of dry weather. whereas D. pteronyssinus predominates in more humid areas such as London, Atlanta, and the Pacific Northwest. ’ Investigators have proposed standards both for scnsitization to mites and for the expression irf allergic symptoms in atopic patients. An international workshop on dust mite allergy proposed that iJ level of 2 pg of Der p I and Der f L per gram (4 dust be considered a risk factor for sensitization and the development of allergic asthma. A level OC 10 p+ ~gtm of dust was proposed as a major risk t‘xtor for the development of acute asthma in mite-allergit. persons.’ In evaluating these standards, Wahn et al.’ conlirmed that the presence of 2 pg of Der p I per gram of house dust would increase the probability that a~ asthmatic patient would be mite allergic. The development of these standards give\ us a goal to aim for when using environmental control measures to reduce allergen exposure. It is possible to measure allergens in houst dust samples with the USAof monoclonal antibody assays. In fact, it is more pmctical to measure the level of the allergen in a house dust SUP ple than to count the number of mites. The:;e assays are available for use in patient care:.
ENVIRONMENTAL CONTROLS Environmental control can be effectrve. but to make it worthwhile, it must actually reduce allergen exposure. Numerous studies have shown that the measures must be uggressivc). Otherwise the effort is not worth the undertaking. The measures must also be practical and capable of accomplishment by an ordinary fatnily with other demands on time and energy. Families vary widely in their commitment to the project. personal and financial resource>, energy levels. and other factors that would make avoidance treatment successful or unsuccessful. Ideally, the physician should know something about the household. At a minimum, the physician should learn the number of occupants of the home. smoking habits, type of heating and air conditioning, pets, whether the home is located in an urban, suburban, or rural area. the family’s socioeconomic situation. and the family’s attitude toward the desirability of avoidance measures. Because the patient spends much time there, the bedroom is probably the most important room in which to reduce allergen exposure. .The bedroom should be made as easy to clean as ptas4blc. Hardwood or tile floors are much less likely to harbor mites than carpeting. If the family has carpeting, they may be reluctant to remove it. If they elect to keep the carpeting. they should be informed that mites cannot effectively be removed by vacuuming, Ii carpeting is
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kept, it must be steam cleaned and treated frequently with acaricides.
tentially toxic. In any event, acaricides should not be used when children are in the room.
ACARICIDES
BEDDING
Acaricides marketed in the United States are most commonly based on either tannic acid or benzyl benzoate. Miller et al6 found that an application of 3% tannic acid solution reduced dust mite antigen levels in carpets and furniture. An untreated section of a couch had an initial total mite antigen level of 13.4; 24 hours later, the level was 9.5. In a treated section of the same couch, levels went from 17.9 to undetectable after treatment. Several very recent studies have reported good results with Acarosan, an acaricide based on benzyl benzoate. The product is available as an aerosol foam for furniture and beds and as a moist powder for carpets. In one study of 25 dust mite-allergic patients, Brown and Merrett’ found that patients had significant improvement in symptoms of asthma, eczema, and rhinitis. Many patients were able to reduce or stop medication. These benefits persisted for up to 1 year after one-time treatment of furniture and carpets with Acarosan. Another double-blind trial of Acarosan with mite-allergic rhinitis patients found that 8 of 10 subjects in the acaricidal cleaner treatment group improved more than the control subjects, who performed normal but intensive cleaning.* Subjective symptoms disappeared in three patients, and after 1 year, the daily symptoms median was 47%, total IgE was 38%, and exposure to dust and mite products was 53% better in the Acarosan group than in control subjects. Because this product is relatively new, there will undoubtedly be further trials to test its effectiveness. Another concern is the potential toxicity of this or any other acaricide . Another acaricide, pirimiphos methyl, has been found to both decrease mite numbers and prevent mite reinfestation3 but it is still being tested for domestic use. Paragerm, a hospital disinfectant, has some acaricidal activity, but it has a very unpleasant odor and is not as effective as other products.’ Natamycin is a fungicide that is marketed in Europe under the name Tymasil as a spray for mattresses. However, Reiser et al.” recently reported results of a double-blind, placebo-controlled trial in which they found no significant difference in levels of Der p I in mattress dust between the Tymasil group and control subjects. In the future, other effective acaricides may be developed, but it is still easier to eliminate havens for mites, such as carpeting and upholstered furniture, than to treat the problem after the fact. Furthermore, acaricides can be expensive, and some may be po-
Mattresses should be covered with plastic, because vacuuming offers only temporary improvement. The plastic should be wiped clean periodically. Most people will want to use a mattress pad over the plastic. This pad should be washed as frequently as the bedding. In England, Owen et al.” tested bedding constructed with a vapor-permeable waterproof fabric that is reportedly impermeable to Der p I mite antigen. The material, Ventflux, a polyurethane coating, was used to make a mattress cover, pillow, and duvet. After 12 weeks of use, Der p I levels per gram of mattress dust were 1% of the levels in control samples from mattresses cleaned conventionally. This is another new product that may merit further study. Feather pillows, a favorite haven for mites, should be abandoned in favor of polyester-filled pillows. Needless to say, feather beds and comforters pose the same problem as feather pillows. Pillows and other bedding should be washed regularly in hot water at temperatures of at least 58” C. Andersen and Roesen” washed mites to determine the effects of washing and water temperature. Although they found that most mites died of drowning, some mites survived at temperatures of less than 58” C. Besides being popular with mites, woolen blankets are not appropriate because they shrink when washed at high temperatures. Preshrunk cotton blankets, particularly those with a thermal weave, are warm enough even for cold winters, and cotton is easily washed. Laundry should be dried indoors, because pollens can cling to fabric dried outside. In general, the bedroom should be kept as clutter free as possible, so as to make thorough cleaning easier. Upholstered furniture is better kept to other rooms. Because woolen clothing is attractive to mites, it should be stored elsewhere. WHOLE-HOUSE
CLEANING
Similar measures to those taken in the bedroom should be applied to the rest of the house, and in particular, to those rooms in which the allergic individual spends considerable time. For some this could be the living room, television room, playroom, or workshop depending on personal interests. Regular vacuuming to remove surface dust is important in these rooms and throughout the house. However, vacuuming temporarily increases exposure to airborne particles. Vacuum cleaners are available that have special filters to clean exhausted air. People who have
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severe allergies might want to investigate these products. Target areas for molds include damp basement floors, bathrooms (including shower curtains), air conditioners and ducts, humidifiers and dehumidifiers, refrigerator drip pans, greenhouses, and indoor spas, or other areas with high localized humidity. All major appliances should be inspected and cleaned often, particularly before seasonal use. Filters should be changed frequently according to manufacturer’s directions. Areas that are unavoidably humid can be washed with Lysol or bleach to retard mold. Cockroaches are also found in damp areas and in areas that contain garbage or poorly stored food products. Scrupulous cleaning, proper food storage, and prompt garbage disposal should prevent this problem. Humidity should be kept at under 50% if possible. ’ Air conditioning and dehumidifiers can reduce indoor humidity during warmer months. Leaky pipes should be repaired. and areas where water seeps into the home should be waterproofed. Attics and crawl spaces should be ventilated to permit moisture to escape. Clothes driers should be vented to the outside. It is also wise to provide a fan in the bathroom that vents to the outside. AIR CLEANING/FILTRATION Another means of allergen control is by filtering the air in the home. Various air cleaning/filtering products are available. Broadly speaking, these devices either filter air mechanically or by electrical attraction. Mechanical filters are most effective on particles larger than 1 km. The larger the particle size, the more effective mechanical filters become. The simplest mechanical filters contain panels of woven matting that are sometimes coated with oil to increase particle retention. Panel filters have about a 75% efticiency with particles the size of pollens, but their efficiency is too low to be useful for tobacco smoke and some molds.” On the other end of the scale, the HEPA filter is the most efficient mechanical filter. HEPA filters must meet stringent standards: they must have a minimum particle-removal efficiency of 99.97% for particles of 0.3 km diameter. HEPA filters have higher efficiencies for both larger and smaller particles than do other mechanical filters. HEPA filters contain submicronic glass fibers. Their efficiency actually increases with use, and they require little maintenance. Filter life exceeds 1 year and may reach 5 years.14 With the increased emphasis on a cleaner environment Tnegative ion generators have become more popular. These are simple electronic air cleaners that work by delivering a negative charge to airborne particles.
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If the unit has a positively charged collectic~n @ate. the particles gather there. However, some dwcc\ do not have such plates. In that case, particles c:tllect on any positively charged surface. The resuit may hz cleaner air at the expense of dirtier walls aad I’\miture. Two-stage electrostatic precipitator5 are rclativcl) efficient. The precipitator draws ionized pa&c& through a series of oppositely charged plates. Collec. tion efficiency is related to the area oi the ti~ll&ing plates. flow rate. and the strength ot the ;:lecrrical field.” Precipitators have high-efficiency ratev i’or p:,i titles as large as pollen and as small as tobacco S~YK&X Electrostatic precipitators can be attached t:) central heating and cooling units. However. precipitatori ha\,c a lower efficiency than HEPA filter\. and thcv require frequent cleaning. Air conditioning also helps to keep indoor arr- cican by keeping out outdoor air at the time of >h:ar when it is most likely to contain pollens. Mite ck*unts and mold spores are also reduced by air conditittning hccause indoor humidity is reduced. A recent survey found that approximately 6 millron Americans are allergic to cats, and of these. nearly 2 million have cats despite their allergic problems.“’ I7 Overall. 28R, of American households hi:: at least one cat. that equals at least 50 million cat\, “10 it is difficult for anyone to entirely avoid exposurt: tmediate results. Luczynska et al.” iounc! that the amount of airborne allergen was less depr:ndcni i)n the number of cats than on whether the cat was confined indoors and whether there was uphoillercd furniture. This same study found that aggresbuve cleaning. removal of soft furniture, and u.scot air ti!tration, especially a HEPA filter, could succcssfullq rcmovc airborne cat allergen even when thil c:ll r~~nai~xd m the household. IMMUNOTHERAPY In some cases, immunotherapy may be neces>,ary. Immunotherapy has a long history that dates back to 1911 when Leonard Noon treated patients with grasspollen hay fever by administering subcutaneous injections of grass extract.” We use a similar method
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today-increasing subcutaneous injections of an extract of a substance to which a patient is known to be allergic. The treatment should only be used in patients with IgE-mediated disease. Immunotherapy is effective for patients who have had anaphylactic reactions to insect stings, for patients with allergic rhinitis, and for those with allergic asthma. It is not effective for food allergy or nonallergic rhinitis or asthma. It should not be used as a substitute for avoiding an allergen, such as allergy to cats. Before immunotherapy is considered, it is absolutely essential to establish the diagnosis through careful history and physical examination. Skin tests and in vitro studies are used to confirm the diagnosis and not to establish it. The diagnosis of IgE-mediated disease should be established by a physician experienced in allergy, who should also determine whether immunotherapy is appropriate. In addition to nonallergic disease and food allergy, allergen immunotherapy is not indicated for patients who have chronic bronchitis, emphysema, hives, headache, drug reactions** or for patients who have had good responses to allergen avoidance and medication. However, allergen immunotherapy often complements pharmacologic, treatment in patients who otherwise would not be satisfactorily symptom free. The only absolute indication for immunotherapy is for patients with life-threatening reactions to hymenoptera insect stings. The diagnosis of insect-sting allergy is based on the history of the reactions and confirmation by positive skin tests. In adults who also have positive skin tests, generalized or systemic reactions that would warrant immunotherapy include systemic reaction with urticaria, angioedema, and respiratory or cardiovascular symptoms. In children, immunotherapy is reserved for generalized life-threatening reactions involving the airways. In either adults or children, local reactions to insect stings and negative skin tests do not warrant immunotherapy. Relative indications for immunotherapy include patients with allergic asthma or allergic rhinitis who cannot avoid the allergen. Patients who have poor results from pharmacologic treatment or significant side effects from drugs may also be candidates for immunotherapy. Allergen immunotherapy is contraindicated in patients who have autoimmune disease and patients who become pregnant before the start of treatment. Those patients who become pregnant after receiving immunotherapy may continue with the treatment. Young children are not good candidates for immunotherapy. Patients with severe systemic disease (particularly those receiving B-blocking agents), those with coro-
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nary artery disease, or those with severe hypertension should not be placed on immunotherapy because these conditions can severely hamper treatment of a systemic allergic reaction. Patients who have repeated allergic reactions to immunotherapy should discontinue the treatment. Subcutaneous injections are the preferred mode of treatment. Intravenous delivery should be avoided, and oral and nasal routes of delivery have not yet been proved. The efficacy of allergen immunotherapy has improved over the years as better extracts have become available and diagnosis has become more precise. However, efficacy depends on the dosage, duration of treatment, and allergen selection.22 For example, clinical and immunologic studies of immunotherapy for ragweed hay fever have shown that low-dose maintenance immunotherapy is ineffective, that relapses may occur when effective treatment is discontinued, and that the therapeutic benefit is limited to the allergen administered .22 Another recent study related efficacy in part to effects on the late-phase reaction. Pienkowski et a1.23 found that immunotherapy was associated with the suppression of the skin late-phase reaction, and the magnitude of the late-phase reaction was correlated with the level of IgG antiragweed. (IgG is the “blocking antibody” induced by immunotherapy.24) As Creticos and Norman described,25 a favorable clinical response to immunotherapy results from an alteration in the balance between the protective immunologic responses mediated by IgG and the allergic immunologic responses mediated by IgE antibodies in conjunction with other incompletely defined mechanisms. An increase in IgG antibody is essential to the process. This is why an adequate dose is so important. Ideally the dose would induce an appropriate antibody response without producing significant reactions. Initial doses are set low to avoid risk of severe allergic reaction. Doses are usually increased at a set rate, perhaps doubled at each visit, until the dose nearly reaches the anticipated maximum, when it may be increased at a slower rate. If patients experience severe reactions at higher doses, doses may be cut back. The patient should not expect to see significant improvement for at least 6 months after the start of immunotherapy. 26 Delayed relief of symptoms reflects in part the time required to build up to an effective dose. If modified antigen preparations are used, the dose may be stepped-up more quickly, but it will still be several months before the patient sees an effect. It is important that patients be aware that they will not experience immediate relief. Otherwise their initial expectations may be too high.
VOLUME90 NUMBER 3.PART2
There is no absolute endpoint for immunotherapy when the patient is doing well on it. In general, patients should be much improved or symptom free for 1 to 2 years before immunotherapy is discontinued. Most patients receive immunotherapy for 3 to 5 years. Allergen extracts that have proved effective in ameliorating symptoms and/or in reducing the subject’s sensitivity to nasal or bronchial allergen provocation are pollen extracts (grasses,“‘, ” ragweed,29 mountain cedar, and birch trees”.“), house dust mite,” cat I?. 12.31and two common mold spores, Alternaria and Cladosporium. 22,id, ” Researchers have recently developed promising modifications of extracts. Some allergens are modified by polymerization. Another new group of extracts, allergoids, are treated with formaldehyde or glutaraldehyde. These extracts retain immunogenicity but have decreased side effects. Studies have found that patients treated with allergoids had significantly higher IgG antibody levels than patients treated with aqueous extracts, both initially and after several years of treatment.7h-‘X Another merit of allergoid extracts is that they can apparently be given less frequently. Norman et al.‘” reported that patients receiving allergoid injections every 3 months had similar symptom scores, IgG antibody levels, and rates of local and systemic reaction as did patients receiving injections every 6 weeks. Because the 3-month treated group had approximately half as many injections, the group also had half as many reactions. Other treatments for IgE-mediated disease are under investigation, but immunotherapy already has a record of clinical safety and efficacy that has endured for three quarters of a century. In the future we can expect more and improved standardized extracts. The World Health Organization has already authorized several international standard preparations and more are on the way. These developments will only add to the usefulness of this already well-established treatment. REFERENCES I. Hamilton RG, Chapman MD, Platts-Mills WE, et al. Aeroallergen measurements in clinical practice: a guide to allergenfree home and work environments. A monograph. Baltimore: Johns Hopkins University Asthma and Allergy Center, 1991 (publication no. 061). 2 Dowse GK, Turner KJ. Stewart GA, et al. The association between Devmatopha,goides mites and the increasing prevalence of asthma in village communities within the Papua New Guinea highlands. J ALLERCYCLIN IMMUNOL1985;75:75-83. 3. Platts-Mills TAE, Chapman MD. Dust mites: immunology, allergic disease, and environmental control. J ALLERGYCLIN hMCNOI. 1987;80:755-74. 4. Chapman MD, Heymann PW, Wilkins SR, et al. Monoclonal lmmunoassays for the major dust mite (Dermarophagoides) allergens. Der p I and Drrf I, and quantitative analysis of the
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allergen content of mite and house dust extracts .I i\r !-I:K(~~ CLIN IW.IUNOL. 1987;SO:184-94.
5. Dust mite allergens and asthma-a worldwide problem J Ai LERGY CLIN IMMUNOL 1989;83:416-27. 6. Miller JD. Miller A, Luczynska C, et al. Effect oi tanmc acid spray on dust-mite antigen levels in carpet\ [Abstract] J AI LERGY CLIN
~MMUNOL 1989;83:262.
I. Brown HM, Merrett TG. Effectivenes\ oi an :%cticidc m management of house dust mite allerg) 4rtn Allergy 1991:67:25-31. 8. Kniest M, Young E, Van Praag MCG, et al. Clinical ebaluatmn of a double-blind dust-mite avoidance trial with mite-allergic rhinitis patients. Clin Exp Allergy 1991:2 I .3Y-47 9. Penaud A. Nourrit J, Timon-David P, et al. Rehults of a con“pp. in dwellmg trolled trial ofparagenn on Dermatophapnid~s houses. Ciin Allergy 1977:7:49-53. 10. Reiser J, Ingram D, Mitchell EB. et al House dust mite allergen levels and an anti-mite mattress spray cnatamycm) in the treatment of childhood asthma. t’lm I:rp Allergy L990;20:561-7. 11. Owen S, Morganstem M, Hepworth J, et al. Control of bou\c dust mite antigen in bedding. Lancet 1990~335.346-7 12. Andersen A, Roesen J. House dust mire. Drrrnuro~~lrcl~l,fd.s preronywinus, and its allergens: effect< of wa&ing Allergy 1989;44:396-400. 13. Nelson HS, Hirsch SR, Ohman JL Jr, et al. Recommendations for the use of residential air-cleaning devices in the treatment of allergic respiratory diseases. J Ar ! RR
