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aaaaiflame.gif (170 bytes) Physician Reference Materials: Position Statement 14


Clinical Ecology

Approved by the Executive Committee of the American Academy of Allergy and Immunology

Background
Clinical ecology is an approach to medicine that ascribes a wide range of symptoms to exposure to numerous common substances in the environment. 1-7 Advocates of this practice describe themselves as ecologically oriented. Patients are said to be environmentally ill, or hypersensitive, or allergic to environmental factors such as food, water, chemicals, and pollutants.

It is suggested that this adverse host response and multiple symptomatology develop after prolonged environmental exposure. Once such sensitivity has occurred, individuals become sensitive to multiple other environmental exposures (foods, chemicals, etc.). Symptoms exhibited as a result of so-called ecologic disease are multiple. These include behavior disorders, depression, chronic fatigue, arthritis, hypertension, learning disabilities, schizophrenia, gastrointestinal symptoms, respiratory problems, and urinary complaints. There are very few symptoms that have not been considered to be related to such an etiology.

Theron Randolph, 1,3 a founder of the clinical ecology movement, believes that traditional allergy is restricted by definition. 1,5 In his view, each person exists in a dynamic equilibrium with his environment with an adaptation to the environment. When this adaptation becomes deranged, i.e. maladaptation, either acute or chronic illness results. He claims that the primary aim in clinical ecology is the demonstration of etiology, i.e., the cause-and-effect relationships between given environmental exposures and specifically susceptible persons.

Recently, it has been postulated that these chemical and food sensitivities are related to a malfunction of the immune system that has been termed immune system dysregulation. This concept has been described as follows 2 :

Immune system dysregulation can develop over a long period of time and is triggered by a single serious viral infection, major stress, fungi infection, particularly Candida albicans, and accumulative exposure to toxic chemicals, even at low levels found in our everyday environment or massive chemical exposure.

Immune system dysregulation often remains undiagnosed however, because many physicians faced with its incredible array of seemingly unrelated symptoms, and unfamiliar with the available diagnostic methods, misdiagnose it as stress, psychosomatic disease, or the like. The medications commonly prescribed for these problems may suppress the symptoms to some extent but often further aggravate the problem without dealing with the underlying disease process. When the immune system is malfunctioning, it causes a broad range of symptoms and reactions to a number of harmless or even beneficial substances entering the body. The malfunction commonly originates with the T cells. When the normal complement of T cells are reduced in number or when their ability to function is impaired, they can no longer adequately control B cell production of antibodies. Without this control, the B cells cannot distinguish harmless dust, pollen, animal dander, or vital and nutritious foods from toxic chemicals or life-threatening bacteria or viruses. The actual healing process from immune system dysregulation is long, slow, and punctuated by exasperating short-term setbacks. These setbacks are part of the healing process and invariably follow a roller coaster pattern. The frequency, duration, and severity of setbacks gradually diminish until symptoms are mild and occur only occasionally.

In establishing a diagnosis for ecologically related diseases, the testing techniques include serial end point titration and the use of subcutaneous and sublingual provocation and neutralization techniques in addition to RAST and paper radio immunosorbent tests. 2 Other modalities include fasting, except for water, and introduction of new foods in a cyclic manner. Multiple tests of the immune system are frequently done, including assays of B and T cells, complement, immune complexes, and lymphocyte function. Treatment usually requires major changes in the home environment and life-style. Diets are often highly restricted. Often foods are rotated in a cyclic manner in which a specific food is ingested every 3 or 4 days. Processed foods containing coloring or flavoring agents are often eliminated. At times, a total elimination diet, except for special spring waters, is prescribed initially, followed by simple oral challenges with less contaminated organic foods. At times, the patient is hospitalized in a comprehensive environmental control unit in a presumably chemically free environment. Home and working environments are restricted with recommendations for so-called safe rooms. These are special isolation rooms where the air is filtered and from which all synthetic materials have been removed. Social lives are often markedly restricted since most environments away from home are unsafe.

In addition to dietary and environmental restrictions, patients are frequently treated with solutions of allergens administered either by injection or sublingually. They are generally low in dosage and follow the provocation and neutralization technique. In addition to the conventional food, pollen, and mold allergens, immunization treatment may include chemicals, such as phenol, formaldehyde, histamine, and serotonin.

Critique
The environment is very important in the lives of every human being. Environmental factors, such as chemicals and pollutants, have been demonstrated to influence health. The idea that the environment is responsible for a multitude of human health problems is most appealing. However, to present such ideas as facts, conclusions, or even likely mechanisms without adequate support, is poor medical practice.

The theoretical basis for ecologic illness in the present context has not been established as factual, nor is there satisfactory evidence to support the actual existence of immune system dysregulation or maladaptation. There is no clear evidence that many of the symptoms noted above are related to allergy, sensitivity, toxicity, or any other type of reaction from foods, water, chemicals, pollutants, viruses, and bacteria in the context presented. Properly controlled studies defining objective parameters of illness, properly controlled evaluation of the treatment modalities, and appropriate patient assessment have not been done. Anecdotal articles do not constitute sufficient evidence of a cause-and-effect relationship between symptoms and environmental exposure. The major techniques used by the clinical ecologists are controversial and unproven. The American Academy of Allergy, Asthma and Immunology has previously published position statements concerning subcutaneous and sublingual provocation neutralization procedures and found them to be unproven. 8 More recent review of new data submitted by a number of clinical ecologists to the Practice Standards Committee of the Academy has not changed that recommendation. There are no adequate studies of the cyclic diets, elimination diets, injection therapy with chemicals, or even the environmentally controlled units to substantiate their use. Many of the patients are reported to have a normal physical examination and normal laboratory tests.

There are no immunologic data to support the dogma of the clinical ecologists. To suggest that these patients lack suppressor T cell function has not been supported by published data. The suggestion that neutralization therapy can provide rapid relief within minutes or hours cannot be supported by controlled clinical studies or immunologic data.

There does remain the problem of the patient with multiple symptoms who does not clearly fit any disease category and whose illness fails to respond to conventional therapy. These patients are often labeled psychosomatic, a concept that many patients and physicians have trouble accepting and managing. That dilemma may lead the patient to seek out the clinical ecologist. As Brodsky 9 points out:

This medical subculture (clinical ecology) does not talk about cures; the health-care professionals neither promise nor give hope of eliminating the offending condition, and the patients do not seem to expect it. Like people with diabetes or with long-standing inflammatory bowel disease, they accept the inevitable. In contrast, however, patients seem content with their condition and the reassurance that their symptoms have a physical cause.

Summary
An objective evaluation of the diagnostic and therapeutic principles used to support the concept of clinical ecology indicates that it is an unproven and experimental methodology. It is time-consuming and places severe restrictions on the individual's life-style. Individuals who are being treated in this manner should be fully informed of its experimental nature. Advocates of this dogma should provide adequate clinical and immunologic studies supporting their concepts, which meet the usually accepted standards for scientific investigation.

Executive Committee: John A. Anderson; Hyman Chai; Henry N. Claman; Elliot F. Ellis; Jordan N. Fink; Allen P. Kaplan; Philip L. Lieberman; William E. Pierson; John E. Salvaggio; Albert L. Sheffer; Raymond G. Slavin

REFERENCES

  1. Randolph TG: The future of medicine in a monotonous polluted world. Bull Hum Ecol ResFound1980
  2. Position paper: A new medical specialty designed to identify and treat environmental illness,1983-84. Soc Clin Eco.
  3. Randolph TG: Graphic representation of clinical ecology. Clin Ecol 2:27, 1983.
  4. Randolph TG: Ecologic-orientation in medicine: comprehensive environmental control in diagnosis and therapy. Ann Allergy 23:7 1965.
  5. Rea WJ, Bell IR, Suits CW, et al: Food and chemical susceptibility after environmental chemical overexposure: case histories. Ann Allergy 41:101, 1978.
  6. Rea WJ: The environmental aspects of ear, nose, and throat disease. Part I. JCEORL Allergy 41:41, 1979.
  7. Mantel M, Conte AA: The role of allergy in arthritis, rheumatism, and polysymptomatic cerebral, visceral, and somatic disorders: a double-blind study. J Intern Acad Prev Med 7: 1982.
  8. Reisman RE: American Academy of Allergy, Asthma and Immunology: positionstatements-controversial techniques. J ALLERGY CLIN IMMUNOL 67:333, 1981.
  9. Brodsky CM: Allergic to everything : a medical subculture. Psychosomatics 24:731,1983.

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Candidiasis Hypersensitivity Syndrome
Approved by the Executive Committee of the American Academy of Allergy, Asthma andImmunology

This statement concerns what has been called candidiasis hypersensitivity syndrome.

Description of Syndrome
This syndrome has been described and popularized by Truss 1-3 andCrook. 4 The symptoms aredescribed as wide ranging, involving multiple systems, and include fatigue, lethargy,depression, inability to concentrate, hyperactivity, headaches, skin problems, includingurticaria, gastrointestinal symptoms such as constipation, abdominal pain, diarrhea, gasand bloating, respiratory tract symptoms, and symptoms involving urinary tract andreproductive organs. Crook 4 recommends to patients:

Before assuming your symptoms are caused or triggered by the common yeast germ Candidaalbicans,go to your physician for a careful history and physical examination and appropriate laboratory studies ortests. An examination is important because many other disorders can cause similar symptoms.However, if a careful check-up doesn't reveal the cause for your symptoms and your medical history (asdescribed in this book) is typical, it is possible or even probable that your health problems are yeastconnected (page 11).

He further notes that tests do not help much because:

Candida germs live in every person's body especially on the mucous membranes. Accordingly,vaginaland other smears and cultures for Candida don't help. Therefore the diagnosis is suspected from thepatient's history and confirmed by his response to treatment 4 (pages 27, 28).

The alleged basis for the syndrome is described by Crook as follows:

Antibiotics, especially broad spectrum antibiotics, kill friendly germs while they'rekilling enemies. And when friendly germs are knocked out, yeast germs (Candida Albicans) multiply. Diets rich in carbohydrates and yeasts, birth control pills, cortisone and other drugs also stimulate yeastgrowth. Large numbers of yeasts weaken your immune system. Your immune system is also affectedadverselyby nutritional deficiencies, sugar consumption, and by exposure to environmental molds andchemicals(such as formaldehyde, petrochemicals, perfume, and tobacco). When your immune system iscompromisedand your resistance is lessened, you may feel bad all over and develop respiratory, digestive, and other symptoms. And you're apt to develop adverse reactions to additional foods, inhalants, andchemicals.As a part of these reactions, mucous membranes throughout your body swell, and you developinfectionscaused by bacteria and viruses that a strong immune system would ordinarily conquer. When youdevelop an infection, you're apt to be given broad spectrum antibiotics. Such antibiotics, while at times essential, promote the growth of Candida albicans which depress your immune system. And yourhealth problems continue until the vicious cycle is interrupted by a comprehensive treatment programdesigned to decrease the growth of Candida albicans and increase your resistance 4 (pages 15,16).

The recommended program for the candidiasis hypersensitivity syndrome includes:

  1. Continuing observation in order that concomitant diseases can be detected, accuratelydiagnosed, and specifically treated
  2. Exercise program
  3. Mental health program
  4. Avoidance of chemical pollutants
  5. Use of antioxidants
  6. Use of special laboratory tests
  1. Ratio of helper cells to suppressor cells
  2. Blood vitamin studies
  3. Mineral studies in hair, blood, and urine
  4. Amino acid studies in urine
  5. Essential fatty acid profile
  1. Special dietary program
  1. Diet nutritionally adequate with fresh foods from a variety of sources
  2. Diversified diet
  3. Avoidance of all refined carbohydrates, including sugar, corn syrup, dextrose, and fructose
  4. Avoid refined, processed, and fabricated foods
  5. Avoids fruits and milk initially. Later, try to rotate fruits back into the diet if they are tolerated
  6. Avoid all yeast and mold-containing foods initially. Ultimately, some of these may prove to be tolerated since a yeast-containing food does not make Candida albicans organisms grow
  7. Eat sugar-free yogurt
  8. Take nutritional supplements, including vitamins, minerals, and essential fatty acids
  1. Use of antifungal agents
  1. Nystatin
  2. Clotrimazole
  3. Ketoconazole (Nizoral; Janssen Pharmaceutica, Piscataway, N.J.)
  4. Amphotericin B.

    These agents may be used orally or topically in the vagina for months.
  1. Use of allergenic extracts of candida albicans for
    1. immunotherapy and/or
    2. provocation/neutralization

Dr. Crook emphasizes two points about his program for candidiasis hypersensitivitysyndrome that are of great importance:

  1. The disorder is very common and has multiple manifestations. Any physician who readshis book will recognize that patients with the complaints described are very commonindeed.
  2. The disorder can be diagnosed only by favorable response to his treatment program administered over a sufficient period of time. He emphasizes that treatment requires time, patience, persistence, and careful management of the multiple factors contributing to the illness.

Critique
The Practice Standards Committee finds multiple problems with the candiasishypersensitivity syndrome.

  1. The concept is speculative and unproven.
  1. The basic elements of the syndrome would apply to almost all sick patients atsometime. The complaints are essentially universal; the broad treatment program (seeDescription of syndrome, particularly elements 1, 2,3, and 7a) would produce remissionin most illnesses regardless of cause.
  2. There is no published proof that Candida albicans is responsible for the syndrome.
  3. There is no published proof that treatment of Candida albicans infection with specific antifungal agents (see Description 8) benefits the syndrome.
  4. There is no proof that immunotherapy or provocation and/or neutralization with Candida albicans allergenic extracts (see Desription 9) benefit the syndrome.
  5. There is no proof that the recommended special studies (see Description 6) are effective diagnostic tests for the purposes for which they are used.
  1. Elements of the proposed treatment program are potentially dangerous.
  1. Resistant species of Candida albicans and of other pathogenic fungi may be producedby long-term oral use of the major antifungal agents (see Description 8).
  2. Untoward effects from oral use of antifungal agents (see Description 8) are rare, but some inevitably will occur.

Recommendations
On the basis of the evidence so far reviewed and until appropriate published evidence tothe contrary is brought to its attention, the Practice Standards Committee recommends thatthe concept of the candidiasis hypersensitivity syndrome (see Description of Syndrome)is unproven. The diagnosis, the special laboratory tests (see Description of Syndrome 6),and the special aspects of treatment (see Description of Syndrome 8 and 9) should beconsidered experimental and reserved for use with informed consent in appropriatecontrolled trials that have been approved for scientific merit and safety by competentinstitutional review boards.

Executive Committee: John A. Anderson; Hyman Chai; Henry N. Claman; Elliot F. Ellis; Jordan N. Fink; Allen P. Kaplan; Philip L. Lieberman; William E. Pierson; John E. Salvaggio; Albert L. Sheffer; Raymond G. Slavin

REFERENCES

  1. Truss CO: Tissue injury induced by Candida Albicans: mental and neurologic manifestations. J Orthomolecular Psychiatry 7:17, 1978.
  2. Truss CO: Restoration of immunologic competence to Candida albicans. J Orthomolecular Psychiatry 9:287, 1980.
  3. Truss CO: The role of Candida albicans in human illness. J Orthomolecular Psychiatry 10:228,1981.
  4. Crook WG: The yeast connection: a medical breakthrough, ed 2. Jackson, Tenn., 1984, Professional Books.

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Carotid Body Resection
Approved by the Executive Committee of the American Academy of Allergy, Asthma & Immunology

Excision of the carotid body(ies) was first reported by Nakayama 1 in 1942. Initially,headvocated bilateral extirpation of carotid bodies, but later in 1961, both he andOverholt 2 reported that unilateral glomectomy was equally effective. During thenextdecade, thousands of patients with severe asthma were treated by carotid body excision.The theoretical basis for the operation was based on experimental investigations by Nadeland Widdicombe 3 who demonstrated that carotid body chemoreceptors mediatedairwayrestriction in response to hypoxemia or intra-arterial injections of nicotine.

Enthusiastic reports about the efficacy of this procedure subsequently appeared in bothAmerican and European medical literature, but most of these reports were based onsubjective rather than objective observations. In those centers where the procedure wasevaluated objectively, disappointing results were obtained. 4 Many of these reportsemphasized the fact that lasting benefits were not obtained.

In response to this controversy, a Glomectomy Study Group of the American Academy of Allergy, Asthma and Immunology was commissioned to evaluate the combined experiences withthis procedure among members of the American Academy of Allergy, Asthma and Immunology. Theresults of this retrospective survey were presented at the 1968 annual meeting of the American Academy of Allergy & Immunology. 5 This survey included 82 patients with aunilateral glomectomy and one patient with a bilateral procedure. Subjective improvement in these patients was disappointing. About 10% of the group experienced temporary relief; persistent clinical improvement was observed in approximately 10% of the patients. Only 5% of this group required less treatment after the procedure, and objective evidence of improvement was observed in only two cases. The mortality figures compiled in this analysis were disturbing. Five patients died as a result of an asthmatic episode after the operation; three of these deaths occurred within 48 hours after the operation. On the basis of this critical evaluation, the American Academy of Allergy, Asthma and Immunology Glomectomy Study Group could not justify unilateral glomectomy as an effective therapeutic measure for the treatment of asthma. It was recommended that prospective double-blind studies, including sham operations, would be essential for resolution of the glomectomy controversy.

A number of double-blinded or partially controlled studies concerning the efficacy of unilateral carotid body excision have been reported since 1964. 6-8 These studies revealed that transient subjective improvement was just as likely to occur in controlsubjects with sham operations as in glomectomized patients. None of these studies were able to discern significant objective improvement or reduction in drug therapy 6 months after the procedure. Investigators of one of these double-blind studies also reported long-term (4½ to 6 years) follow-up of patients receiving unilateral carotid body excision. 9 No differences in mortality, symptom severity, or objective clinical status were found between the unilateral glomectomy and groups with sham operations.

In 1968 the American Thoracic Society published a position statement that concluded that glomectomy had not proved to be an effective treatment for asthma. 10 Thus, before1970 there appeared to be a general consensus that unilateral carotid body excision was not an effective treatment for chronic asthma. Subsequently, the performance of unilateral glomectomy virtually disappeared from major medical centers in the United States.

As few individual surgeons still maintained that the procedure had merit not only for the treatment of asthma but also for other chronic obstructive pulmonary diseases. In 1971 one of the early adherents of unilateral carotid body excision agreed that this particular operation was inconsistent. He attributed the unpredictable results of the unilateral procedure to the fact that one carotid body might be physiologically dominant and that optimal clinical effects could only be obtained by bilateral carotid body excision. He further claimed that clinical benefit could be obtained in bronchospastic diseases without the occurrence of the sequelae of baroreceptor dysfunction by meticulously avoiding lateral nerve bundles at the carotid artery bifurcation, presumably because these bundles contain the lateral sinus nerve plexus, the major anatomic site of baroreceptor function. In a detailed report of this procedure, he discussed excellent results in 18 patients who received the bilateral operation. However, as far as can be determined from his report, these results were based on global assessment without objective documentation of long-term results. 11 Several of these same bilateral glomectomized patients were studied 6 years after surgery at an independent pulmonary physiology laboratory. 12 These patients demonstrated hypotensive responses on breathing 10% oxygen. One patient exhibited periodic breathing and hypoventilation as well as focal seizures. Moreover, these studies did not resolve pathogenetic uncertainties whether bilateral resection of carotid bodies improves underlying pulmonary disease in patients with asthma or the observed effects are secondary to reduction of ventilatory drive. Possible hazards of the latter effect were illustrated by a case report on an 11-year-old boy with asthma who experienced three life-threatening periods of cyanosis and disorientation without any prior feeling of discomfort or labored breathing. 13 Further studies on this child revealed that he had marked lack of ventilatory response to hypoxia. Similarly, another careful study of three patients who had bilateral glomectomy also revealed serious impairments in their abilities to respond to hypoventilation after breathing 10% oxygen. 14 These patients experienced adverse effects on blood pressure, dizziness,and headaches. It has also been suggested that such patients may lack hypoxic arousal responses during rapid eye movement (REM) sleep and that this could be potentially dangerous for patients with asthma with severe degrees of nocturnal lability. 15 Thus, although bilateral carotid resection may reduce ventilatory stress in patients with chronic obstructive airway disease, there is as yet no convincing evidence that this operation reverses chronic airflow limitation or causes long-term clinical improvement. These questions can only be satisfactorily resolved by double-blind clinical studies with sham operations. Furthermore, whether the risk/benefit ratio of this procedure is acceptable in patients with severe chronic asthma should only be decided by institutional human research committees. Because of these uncertainties about efficacy and safety, the American Academy of Allergy, Asthma and Immunology presently concludes that neither unilateral nor bilateral carotid body excision can be recommended as a routine clinical treatment for asthma. The treatment should be reserved for experimental use only in well designed prospective trials.

Executive Committee: John A. Anderson; Hyman Chai; Henry N. Claman; Elliot F. Ellis; Jordan N. Fink; Allen P. Kaplan; Philip L. Lieberman; William E. Pierson; John E. Salvaggio; Albert L. Sheffer; Raymond G. Slavin

REFERENCES

  1. Nakayama K: The surgical removal of the carotid body for asthma. Dis Chest 40:595,1961
  2. Overholt RH: Glomectomy for asthma. Dis Chest 40:605, 1961
  3. Nadel JA, Widdicombe JG: Effect of changes in blood gas tensions and carotid sinus pressure on tracheal volume and total lung resistance of airflow. J. Physiol (Lond) 163:13, 1962
  4. Segal MS, Dulfano, MJ: Glomectomy in the treatment of chronic bronchial asthma: a report of fifteen unsuccessful cases. N Engl J Med 272:57, 1965
  5. Bernstein IL, Argabrite JW, Etter RL, et al: Current status of glomectomy. J ALLERGY 41:89,1968 (abst)
  6. Curran WS, Oser JF, Longfield AN, et al: Glomectomy for severe bronchial asthma. Am RevRespir Dis 93:84, 1966
  7. Marschke G, Beall N, Stern WE, et al: Carotid-body removal in asthma. JAMA 91:397,1965
  8. O Rourke DA, O Rourke HM: Removal of the carotid body for asthma: an appraisal of results.Med J Aust 2:869, 1964
  9. Curran WS, Graham WG: Long-term effects of glomectomy. Am Rev Respir Dis 103:566,1971
  10. Busey JF, Fenger EPK, Hepper NG: Current status of the surgical treatment of pulmonaryemphysema and asthma: a statement of the Committee on Therapy. Am Rev Respir Dis 97:486, 1968
  11. Winter B: Bilateral carotid body resection for asthma and emphysema. Int Surg 57:458,1972
  12. Lugliani R, Whipp BJ, Seard C, et al: Effect of bilateral carotid body resection onventilatory control at rest and during exercise in man. N Engl J Med 285:1105, 1971
  13. Chang KC, Morrill CG, Chai H: Impaired response to hypoxia after bilateral carotid body resection for treatment of bronchial asthma. Chest 73:667, 1978
  14. Wood JB, Frankland AW, Eastcott HHG: Bilateral removal of carotid bodies for asthma. Thorax 20:570, 1965
  15. Sullivan CE: Bilateral carotid body resection in asthma: vulnerability to hypoxic death in sleep.Chest 78:354, 1980.

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Unproven Procedures for Diagnosis and Treatment of Allergic and Immunologic Diseases
Approved by the Executive Committee of the American Academy of Allergy, Asthma & Immunology

Definition of an Unproven Procedure
An unproven procedure for the diagnosis and treatment of allergic and immunologic diseases is defined as any specific procedure for these purposes that has not been proven effectiveby proper trial.

Recommended Policy for Processing an Unproven Procedure
All newly proposed procedures are unproven when they are first introduced. The future ofthe field of allergy and immunology and of the patient with allergic and immunologicdiseases will be strongly influenced by the care with which these unproven procedures aredeveloped and tested by those who initiate and sponsor them. 1 The unprovenprocedureshould be subjected to a fair trial to determine whether or not it is effective, thecircumstances under which it is effective, and its relative merit with reference to othereffective procedures for the same purpose. During the trial period, the procedure shouldbe considered experimental and reserved for use with informed consent in appropriatecontrolled trials that have been approved for safety and scientific merit by competentinstitutional review boards. The procedure should not be accepted for general use untilproof of effectiveness has been established and published in reputable refereed medicaljournals. Procedures that have not been proven effective may continue to be used on anexperimental basis as described above or discarded, but should not be sanctioned forroutine use. Unless a physician is concerned with the trial, a physician or a medicalfacility should have no obligation to use the procedure or to transmit knowledge of it.

An unproven procedure can be proven effective, since it is possible to prove a positive point. However, under most circumstances, it is not possible to prove that a procedure is ineffective, because one cannot prove a negative point. Therefore, the biomedical community should require proof of effectiveness of a procedure before the procedure is accepted for routine use but should not demand proof of ineffectiveness before discarding the unproven procedure.

The responsibility for testing the unproven procedure should rest with the proponent of the procedure, since the proponent understands and favors the procedure and can make sure that the trial is a proper one. The responsibility for reviewing the plans for and the results of the trial should reside with at least four groups of peers:

  1. physicians who work with and know the proponent,
  2. the institutional review board that reviews the trial protocol for safety and scientific merit,
  3. the editorial board and critics selected by the editorial board of the journal that considers for publication the manuscript that represents the recorded results of the trial, and
  4. appointed practice standards committees of allergy specialty societies such as the Practice Standards Committee of the American Academy of Allergy, Asthma and Immunology.

Each of these four groups of peers should on request by the proponent or other interested party provide a written critique of the recorded proposals for and accomplishments of the trial. Institutional review boards should have primary responsibility for proposals, editorial boards for unpublished reports of accomplishments, and practice standard committees for published reports of accomplishments.

Necessity for Proper Trials
There is considerable evidence that indicates that neither patient nor physician candistinguish between an effective and an ineffective procedure without performing a propertrial. For example, before controlled trials, for at least 40 years, low-doseimmunotherapy with ragweed-pollen extract was considered to be effective treatment forragweed hay fever. In recent years, a number of controlled trials have indicated thatlow-dose immunotherapy was no more effective than placebos, 2-5 whereasimmunotherapy withlarge doses of ragweed extract was effective, 3,5,6-10,11 was specific for ragweedhayfever, 3,9 and induced immunologic changes not induced by low-doseimmunotherapy or placebothat included an increase in protective IgG antibody to ragweed, 3,5,11,12-15 aninitialincrease in specific IgE antibody, 3, 5, 11, 12-14 a diminution of the expectedseasonal risein IgE antibody to ragweed, 3,5,11,10,12-14 and an ultimate decrease in ragweedIgE towardpretreatment levels. 3,12,14 Nevertheless, many patients who received low-doseimmunotherapyor placebos were of the opinion that they had received an effectivetreatment. 4,5,11

Before controlled trials, for more than 10 years, whole body extract of various Hymenoptera insects such as honeybees, yellow jackets, hornets, and wasps, were used to diagnose and treat anaphylactic reaction to their stings. Both patients and physicians were of the opinion that these extracts were effective for both diagnosis and therapy. 16 In recent years, a series of controlled trials comparing the effects of Hymenoptera venoms, Hymenoptera whole body extracts, and placebos have demonstrated that immunotherapy with whole body extracts was no more effective than placebos, whereas venoms were clearly effective. 16 Furthermore, the controlled trials demonstrated that skin tests with Hymenoptera venoms were effective for distinguishing patients with a history of anaphylactic reactions to hymenoptera stings from nonallergic patients, whereas skin tests with Hymenoptera whole body extracts were not effective for this purpose. 16

Proper Trials
A proper trial of an unproven procedure for diagnosis and therapy of allergic andimmunologic disease must deal effectively with problems that derive from the fact thatthe manifestations of these diseases in different patients run various courses that dependon a number of extrinsic factors that include allergens, emotional tension, irritants,infection and/or intrinsic factors such as the severity of the patient's sensitivity toallergens. The design of the trial should permit the investigator to separate the effectsof the procedure being tested from the effects of other factors. The hypothesis to betested should be stated clearly and related precisely to previously established fact andto its scientific basis. Reagents and procedures should be described and used in such away that they could be used in similar manner by subsequent investigators. They should notbe used in the trial until they are developed to a point where they elicit consistentresults under standard circumstances. The trial should concern a homogeneous group ofpatients whose characteristics are well described in order that similar patients couldbe found by a subsequent investigator. These patients should have the abnormality understudy, but otherwise be essentially well. Such patients may not be found easily in thepractices or allergy clinics of the investigators, and recruitment by advertisement inthe media may be necessary. These patients should be stratified with reference to riskfactors that might modify response, such as sensitivity to allergen. Then, by randomselection, they should be divided into groups of equal size in such a fashion thatpatients in each study group have comparable characteristics and risk factors. By randomselection, study groups should be assigned to test and control procedures. Results of theprocedure should be evaluated as objectively as possible and expressed in quantifiableterms. If evaluation depends on a patient's or physician's judgment, the trial should beconducted double-blind in order that neither patient nor evaluating physicians knowwhich patient received a specific test or control procedure. Appropriate statisticalmethods for evaluating the results of the study should be selected at the time of designof the study.

It is evident that before controlled trials were done, worthless procedures for diagnosis and therapy of allergic and immunologic diseases have been accepted as effective by both patient and physician. Therefore, proper trials are necessary, and an unproven procedure should be considered to be experimental and likely to be ineffective until proven to be effective.

Recommendations
The science of allergy and immunology has advanced to the point where effective proceduresfor diagnosis and treatment of allergic and immunologic diseases can be proven to beeffective. Currently available procedures of proven effectiveness are sufficientlysatisfactory for diagnosis and treatment of allergic and immunologic disease so thatprocedures of unproven effectiveness should not be used in routine fashion but rathershould be considered experimental and reserved for use with informed consent in controlledtrials that have been approved for safety and scientific merit by competent andinstitutional review boards.

Executive Committee: John A. Anderson; Hyman Chai; Henry N. Claman; Elliot F. Ellis; Jordan N. Fink; Allen P. Kaplan; Philip L. Lieberman; William E. Pierson; John E. Salvaggio; Albert L. Sheffer; Raymond G. Slavin

REFERENCES

  1. Lowell FC: Some untested diagnostic and therapeutic procedures in clinical allergy. J ALLERGY CLIN IMMUNOL 56:168, 1975
  2. Hirsch SR, Kalbfleisch JH, Golbert TM, et al: Rinkel injection therapy: a multicentercontrolledstudy. J ALLERGY CLIN IMMUNOL 68:133, 1981
  3. Norman PS: Immunotherapy. Prog Allergy 32:318, 1982
  4. Van Metre TE, Adkinson NF, Lichtenstein LM, Mardiney MR, Norman PS, Rosenberg GL,Sobotka AK, Valentine MD: A controlled study of the effectiveness of the Rinkel method of immunotherapy for ragweed pollen hay fever. J ALLERGY CLIN IMMUNOL 65:288, 1980
  5. Van Metre TE, Adkinson NF, Amodio FJ, Lichtenstein LM, Mardiney MR, Norman PS, Rosenberg GL, Sobotka AK, Valentine MD: A comparative study of the effectiveness of the Rinkel method and of the current standard method of immunotherapy for ragweed pollen hay fever. J ALLERGY CLIN IMMUNOL66:500,1980
  6. Franklin W, Lowell FC: Comparison of two dosages of ragweed extract in the treatment of pollenosis. JAMA 201:915, 1967
  7. Hirsch SR, Kalbfleisch JH, Cohen SH: Comparison of Rinkel injection therapy with standard immunotherapy. J ALLERGY CLIN IMMUNOL 70:183, 1982
  8. Lowell FC, Fraklin W: A double-blind study of treatment with aqueous allergenic extracts in cases of allergic rhinitis. J ALLERGY CLIN IMMUNOL 34:165, 1963
  9. Lowell FC, Fraklin W: A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl J Med 273:675, 1965
  10. Norman PS, Lichtenstein LM, Ishizaka K: Diagnostic tests in ragweed hay fever: acomparison of direct skin tests, IgE antibody measurements, and basophil histamine release. J ALLERGY CLIN IMMUNOL 52:210, 1973
  11. Van Metre TE, Adkinson, NF, Amodio FJ, Lichtenstein LM, Mardiney MR, Norman PS,Rosenberg GL, Sobotka AK, Valentine MD: A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. J ALERGY CLIN IMMUNOL 69:181, 1982
  12. Creticos PS, Van Metre TE, Mardiney MR, Rosenberg GL, Norman PS, Adkinson NF: Dose response of IgE and IgG antibodies during ragweed immunotherapy. J ALLERGY CLIN IMMUNOL 73:94,1984
  13. Gleich GH, Jacob GL, Yunginger JW, Hendersn LL: Measurement of the absolute levels of IgE antibodies in patients with ragweed hay fever: effect of immunotherapy on seasonal changes and relationship to IgG antibodies. J ALLERGY CLIN IMMUNOL 60:188, 1977
  14. Gleich GJ, Zimmerman EM, Henderson LL, Yunginger JW: Effect of immunotherapy onimmunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. J ALLERGY CLIN IMMUNOL 70:261, 1982
  15. Irons JS, Pruzansky JJ, Patterson R, Zeiss CR: Studies of perennial ragweed immunotherapy, associated changes in cellular responsiveness, total serum antigen-binding capacity, and specific IgE antibody concentrations. J ALLERGY CLIN IMMUNOL 59:190, 1977
  16. Lichtenstein LM, Valentine MD, Sobotka AK: Insect allergy: the state of the art. J ALLERGY CLIN IMMUNOL 64:5, 1979

Reviewed and considered current by the Practice Standards Committee 1992
JACI, St. Louis Vol. 78, no. 2, August, 1986, pp 269-277

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