The classic symptoms of rhinitis, asthma, and dermatitis may appear without any evidence of the presence of allergy. Acceptance of this concept is difficult for many parents and some physicians. It is necessary to understand that the basic tissue responses in allergen-mediated diseases are dependent to some degree on autonomic imbalance and underfunctioning of the /3-receptors, as Drs. Summers and Evans point out in the following article. The resulting tissue hyperactivity may be triggered not only by antigen-antibody interaction but by a number of other stimuli as well (see box.)
The diagnostic effort, therefore, may have to begin with a determination of whether or not allergy is present in a given person before one attempts to determine a specific causative allergen. The two efforts may well be interwoven, as noted in the previous article.
Diagnostic approaches to allergy in childhood are shown in Table 1. A brief discussion of some of these steps may be helpful.
TAKING THE HISTORY
As is customary, a good history remains of paramount importance. The inherited nature of allergy has long been established,1 though the exact mode of inheritance is not entirely clear, and there is evidence that the underlying autonomic dysfunction may also be familial.
In the presence of a bilateral family history of allergy, similar manifestations may appear in 65 per cent of the offspring, while with a unilateral history the incidence may drop to 35 per cent. This compares with an incidence of 10 per cent in the general population.2 When the family history is combined with a careful medical history of the proband, one may obtain considerable evidence to validate the presence of atopy. A logical next step is a complete physical examination, looking not only for the customary stigmata of allergic disease but also for any contributing or associated pathology.
Every pediatrician should have available at least a basic laboratory evaluation of the child suspected of having an allergic disorder and such studies as complete blood counts, and smears of appropriately obtained mucous secretions for the detection of eosinophilia, will be helpful. A blood eosinophilia above 6 per cent is suggestive of allergy, and in the author's experience the greater the eosinophilia the more likely the treatment will have a successful outcome.3
TRIGGER MECHANISMS IN TISSUE HYPERREACTIVITY
DIAGNOSTIC PROCEDURES IN CHILDHOOD ALLERGY
When staining mucous secretions, one may use a Hansel or Giemsa stain, but even a simple Wright's stain, as used for blood smears, will be adequate to determine eosinophilia. A proportion of 10 per cent or more can be considered highly suggestive of allergy, but less than that number does not necessarily eliminate allergy from consideration, since the proportion of eosinophils will vary with the stage of the allergic disease and the availability of appropriate samples for staining. Early in the course of allergic rhinitis, eosinophilia may be marked, but as symptoms and signs continue, the clear mucus may be replaced with thick, cloudy, or greenish-yellow secretions, loaded with polymorphonuclear neutrophils as well as bacteria.
If there is doubt - especially in young children - about the presence of allergy, a total IgE determination may be obtained from many laboratories by a paper immunosorbent test (PRIST). Infants in the first year of life have IgE levels of 0-10 international units (IU)/ml., and this level does not change significantly as the year progresses. Rapid changes or significant elevations above 20 IU in the first year have been associated with clinical manifestations of allergy or subsequent development of allergic symptoms. After the age of one year, IgE levels vary widely, but usually significant elevations are noted in allergic rhinitis, asthma, and atopic dermatitis, in an ascending order of magnitude.
When asthma is the presenting problem, initial evaluation should always include a tine test and a chest roentgenogram. If respiratory infection plays a major part in the child's illness - especially in the very young - one may obtain sweat electrolytes to rule out the possibility of cystic fibrosis.4 Most laboratories are now equipped to do quantitative immunoglobulin determinations if specific immune deficiencies are suspected.
Pulmonary function testing may be an office procedure for some physicians,5 but the minimal requirement is that a spirometer or a peak flowmeter be available for simple ventilatory studies. Measurements of vital capacity and first-second expiratory volume (FEVi)* will be most useful in the asymptomatic asthmatic and may give a clue to the degree of pulmonary embarrassment even in the absence of a wheeze. Reductions of more than 20 per cent from normal would be significant.
Similar information may be obtained from the peak flowmeter, and both measurements may be useful in demonstrating changes in the course of asthma during the period of treatment. More complete pulmonary function studies, involving measurements of lung volumes, and ventilation and perfusion determinations, may be desirable and can be obtained in a pulmonary-function laboratory.
HNDING THE SPECIFIC ALLERGEN
One must eventually come to grips with the diagnosis of the specific offending allergen, which normally requires direct skin testing. The prick test is widely used, and in most instances has replaced the scratch test. The technique requires only the placing of a drop of extract on a cleansed area of the skin (back or forearm) and introducing a needle into the upper layers of the epidermis. Just the tip of the needle should go in, deep enough so that lifting the point results in a slight but painless tug at the skin that can be felt both by the technician and the patient. Extracts for the prick test may be 1,000 times stronger than extracts used for intradermal testing.
Prick tests rarely give as much wheal and erythema as intradermal tests except in very sensitive individuals and rarely are responsible for any systemic reaction. Prick testing is preferred by many allergists, who consider it a necessary preliminary to any subsequent intradermal testing. A fair number of allergists use only intradermal tests, reserving prick tests for special situations. Some observers feel that prick testing for foods is more sensitive and accurate than intradermal testing. For the physician doing casual testing, the prick test is preferred, since allergens will be more stable and will not require dilution. Screening tests for dusts and area molds and pollens may be done readily, and a great deal of information is obtained.
Intradermal testing requires the introduction of a small amount of extract, usually 0.02 ml., into the superficial layers of the skin, raising a small bleb of approximately 2-3 mm. in diameter. Reading of the test is done within 15 to 30 minutes, depending upon the speed of the reaction and the size of the response. Both wheal and erythema are measured and compared with those caused by a control (usually buffered saline diluent). Significant reactions show a wheal of at least 5-10 mm. in diameter and an associated erythema of 102 cm. Marked reactions may give larger wheals, with or without pseudopods, and erythema measuring 3-4 cm.6 Histamine is used if a positive control is needed.
End-point titration by intradermal testing is claimed to be more informative, since it allows determination of the weakest dilution that gives a significant 1 or 2+ reaction (see box). This is done automatically in patients with mild-to-moderate sensitivity, as one increases the testing strength in an attempt to elicit a positive reaction. In highly sensitive patients it is necessary to start with a much weaker concentration than one would otherwise use, and then increase the testing strength until a significant reaction occurs. The initial history usually will serve as a guide to the safest level where testing may begin.
CRITERIA USED TO READ SKIN TESTS
Provocation testing has been advocated by some7 who feel that the true significance of intradermal tests lies not merely in their ability to produce the wheal and erythema but also in their ability to provoke the symptoms that are assumed to be due to the allergen in question. In essence, provocation testing represents a systemic reaction to the allergen, and proponents state that the effects of these tests can be neutralized by the subcutaneous injection of a much lower concentration of the same extract (e.g., diluted six- to-ninefold.)
PASSIVE TRANSFER AND RAST TESTS
Passive transfer tests8 are seldom employed today since the dangers of transmitting hepatitis have become more real. The technique is useful in patients with extensive atopic dermatitis but is applicable only to those situations where intrafamily testing is feasible. This method has been replaced by the in vitro radioallergoabsorbent (RAST) test.
The RAST9 allows detection of specific IgE by radioimmunoassay and has a high degree of correlation with the direct intradermal skin test (which continues to be the standard). The RAST is quantitative and can be repeated. It is convenient, involves no risk to the patient, and may be useful in long-term follow-up. Currently, however, this test is expensive, and is limited by the number of allergens available. Radio-labeled anti-IgE antibody and a gamma counter are required, which limits performance to a relatively few laboratories. The RAST may have a significant role in standardization of extracts, as well as in following patients on immunotherapy, and will be a very useful research tool.
WHEN THERE IS INFECTION
Culture of appropriate secretions may be desirable if infection appears to play a significant role in the production of symptoms or is present as a complication.10 When a defect in delayed hypersensitivity (cell-mediated immunity) is thought to be present as a contributing factor, one may employ intradermal skin tests to antigens to which the child may have been exposed and which tend to give delayed, tuberculin-type skin-test reactions. A battery of such tests may include Candida albicans, tetanus toxoid, streptokinase-streptodornase, Trichophyton, mumps, and purified protein derivative. Appropriate responses to one or more of these antigens will be helpful in establishing the functional integrity of the T-cell system.11
In asthmatic patients who have a suggestive family history of emphysema and minimal evidence of allergy, measurement of «,-antitrypsin levels may be indicated. Significant decrease in the level of this protease inhibitor will allow the production of lung damage, which will eventually lead to chronic obstructive pulmonary disease. In the absence of secondary infection, asthma rarely if ever leads to chronic lung disease.
The role of a specific allergen in allergic disease often can be proved by direct challenge. This has been a common practice in food allergies, where elimination of one or more suspected foods from the diet for a period of three or four weeks is followed by evaluation of the degree of improvement. If significant, this is followed by reintroduction of the suspected foods into the diet one at a time, while observing the patient for recurrence of symptoms.
Several requirements are necessary if challenge testing is to provide data useful for a sound evaluation:
1. There should be total elimination of the food or foods in question.
2. These foods should be eliminated for at least three or four weeks to allow ample time for the suspect substances to be eliminated from the system.
3. If a food is indeed the cause of the allergy, the patient should show significant improvement following the elimination of that substance from the diet.
4. Reintroduction of the suspected food should be in such a manner as to preclude its recognition by the patient. This is very difficult in children, especially if very young, but it can be attempted.
5. If a positive response is obtained and symptoms develop again within one to three days after the suspect food has been reintroduced into the diet, the experiment should be repeated at least once and preferably twice, to eliminate the possibility of coincidence.
Elimination diets are a tremendous challenge to a mother, especially when one suspects food allergy but has no specific leads. In such cases a hypoallergenic diet should be used. The pediatrician should spell out exactly what the child can have to eat and give the mother suggestions to help her understand how she and the child can survive on a diet that will contain no cereal grains, milk, or egg
With careful explanations, and much support, elimination diets can at times be extremely useful. Failure to improve on such restricted diets should be a signal to return to normal food intake, in order to avoid any nutritional deficiences. Even effective and successful diets, too long continued, may lead to adverse effects.
In asthma, bronchial challenge has been recommended as a method of obtaining cause-and-effect information on specific inhaled allergens.12 After establishing a baseline FEVi, the patient inhales a measured amount of an aerosolized antigen over a period of a few minutes. Subsequent serial determinations of the FEV1 at intervals after the challenge will be manifest by a drop of at least 20 per cent in the FEV1 if the challenge test is positive. Similar information may be obtained by using a peak flowmeter. Attacks of asthma, sometimes severe, may follow a positive bronchial challenge, and this technique is not recommended for general use.
Methacholine challenge has also been used to establish a diagnosis of asthma, regardless of whether allergy is a part of the etiology. The asthmatic chest is much more sensitive to methacholine challenge than is the normal, and a prompt decrease in FEV1 will follow inhalation challenge in the asthmatic individual. Again this procedure has significant but limited usefulness, and should be reserved for carefully controlled situations.
A number of more sophisticated laboratory procedures, such as histamine release and lymphokine studies, have been developed. They give insight into the nature of the immediate and delayed types of hypersensitivity, but are reserved for more complex situations, and have little place in the clinical approach to the allergies of infancy and childhood.
1. Wiener, A. S., Zieve, I., and Fries, ). H. The inheritance of allergic disease. Ann. Eugenics 7 (1935), 141.
2. Kantor, J. M. Incidence of allergy in childhood. In Speer, F., and Dockhom, R. J. (eds.). Allergy and Immunology in Children. Springfield, Dl.: Charles C Thomas, Publisher, 1973, p. 9.
3. Foung, S., and Glader, B. E. Eosinophilia in children. Pediatr. Ann. 8 (1979), 379-382.
4. Holsclaw, D. S., Jr. Recognition and management of patients with cystic fibrosis. Pediatr. Ann. 7 (1978), 4-14.
5. Polgar, G. Pulmonary function testing for pediatric chest diseases. Pediatr. Ann. 6 (1977), 526-539.
6. BuDock, J. D., et al. The skin window as a diagnostic tool in pediatric allergy. Ann. Allergy 26 (1968), 177.
7. May, J. C, Sih, J. T. C, Miller, J. R., and Seligmann, E. B., Jr. Optimization of parameters in protein nitrogen unit precipitation procedure for allergenic extracts. J. Allergy Gin. Immunol. 63 (1979), 87-97.
8. Prausnitz, C, and Kustner, H. Stuthen über Überempfindlichkeit. ZentraM. Bakteriol. 86 (1921), 160.
9. Arbesman. C. E., and Ito, K. New method for measuring IgE. J. Allergy 47 (1971), 85.
10. Howard, W. A. Infectious factors in allergy. In Speer, F., and Dockhom, R. J., supra.. 307-315.
11. Papageorgiou, P. S. Cell-mediated immunity mechanisms, significance, and evaluation. Pediatr. Ann. 5 (1976), 390-394.
12. Pepys, )., and Hutchcroft, B. ]. Bronchial provocation tests in the etiologk diagnosis and analysis of asthma. Am. Reo. Respir. Dis. 112 (1975). 829-859.
TRIGGER MECHANISMS IN TISSUE HYPERREACTIVITY
DIAGNOSTIC PROCEDURES IN CHILDHOOD ALLERGY
CRITERIA USED TO READ SKIN TESTS