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Hypersensitivity reactions associated with botulinal antitoxin
Hypersensitivity Reactions Botulinal Antitoxin
ROBERT E. BLACK, ROBERT A. GUNN, Atlanta,
M.D.. M.P.H. M.D.,M.P.H.*
Georgia
From the Enteric Diseases Branch, Bacterial Diseases Division, Bureau of Epidemiology. Center for Disease Control, Atlanta, Georgia. Requests for reprints should be addressed to Dr. Robert E. Black, Center for Vaccine Development, University of Maryland School of Medicine, Bressler Building, Room 409. 29 South Greene Street, Baltimore, Maryland 21201. Manuscript accepted March 31.1980. * Present address: Florida Department of Health and Rehabilitative Services, 1317 Winewood Boulevard, Tallahassee, Florida 32301.
Associated
with
During an 11-year period (1967 through 1977) CDC monitored reactions of hypersensitivity to botulinal antitoxin of equine origin. Of 268 persons given botulinal antitoxin, 24 (9.8 percent) had nonfatal acute (5.3 percent) or delayed (3.7 percent) hypersensitivity reactions to a skin test or therapeutic dose. The over-all rate of reaction did not differ with the age or sex of the recipient or with the type (AB or ABE) of antitoxin administered. Serum sickness occurred significantly more frequently in persons who received more than 40 ml of serum antitoxin (p <0.02). The over-all reaction rate was higher than that associated with other equine serum products and probably cannot be substantially reduced. This risk, however, would be substantially reduced if not eliminated by using botulinal immune globulin obtained from hyperimmunized human donors. Botulism, a paralytic illness caused by the potent neurotoxins of Clostridium botulinum, has been reported with increasing frequency in the past several years [Y-S]. This increase is due to both more reported cases of foodborne botulism and the recent recognition of botulism in infants [4,5], Currently recognized therapy for botulism includes equine botulinal antitoxin and intensive supportive care [6]. This antitoxin is also given sometimes to patients with other neurologic illnesses before they can be differentiated from botulism and to non-ill persons known to have eaten food containing botulinal toxin. Like other biologic products made from equine serum, botulinal antitoxin has been associated with anaphylaxis, serum sickness and other reactions [I]. The incidence of such reactions and the recognition of many cases of botulism in infants have prompted suggestions that an antitoxin of human origin be prepared [7]. In assessing the need for human botulinal immune globulin, it is important to know the risk of hypersensitivity reactions that follow administration of currently available equine antitoxin. In 1967, the Center for Disease Control established a surveillance system for recording adverse reactions to botulinal antitoxin. We reviewed thcsc data for an II-year period (1967 through 1977) to define better the reaction rate and thus to help to determine whether or not production of human botulinal immune globulin is justified. METHODS The Center for Disease Control (CDC) is notified of suspected cases of botulism by private physicians, hospital personnel, state and local health departments, the Food and Drug Administration, the U.S. Department of Agriculture and Lederle Laboratories, the only private supplier of botulinal antitoxin (distribution stopped in November 1978).
October 1980 The American Journal of Medicine
Volume 69
567
HYPERSENSITIVITY
TABLE
I
REACTIONS
Hypersensitivity
120 21-30 31-40 >40 Unknown Total Figures
BOTULINAL
Reactions
Number Receiving Antitoxin
Aw (Yd
NOTE:
AND
ANTITOXIN-BLACK,
by Age of Person Receiving
Urticarla
Anaphylaxis
1 2 1 3
-
-
-
266
7 (2.6)
5 (1.9)
1 2 2 5
Hypersensitivity
Antitoxin Given
Number Rsceivino Antitoxih
110”ml 1 l-20 ml 21-40 ml >40 ml Unknown
40 102 55 63 6
Total
266
Reactions
by Amount
l
October
1960
-
-
3 (7.5) 5.(10.9) 5 (10.2) 11 (10.0) 0 (0.0)
10 (3.7)
2 (0.7)
24 (9.0)
1
The American
of Botulinal
Antitoxin
Given
Type of Reaction Urticaria
Anaphylaxis
2 2 1 2
2 3
Serum Sickness
-
-
-
7 (2.6)
5 (1.9)
10 (3.7)
2 (0.7)
24 (9.0)
Journal of Medicine
to skin test.
Volume
69
1
Total Reactions
-
reaction
1 2 1 6
Other
6’ (15.0) 6 (5.9) 2 (3.6) 9 (14.3) l(12.5)
NOTE: Figures in parentheses are percents. Includes three persons with acute hypersensitivity
566
1
Total Reactions
antitoxin. Of these 268 persons, 26 were treated because of exposure to food thought to contain botulinal toxin, nine for wound botulism and 233 for suspected foodborne botulism. Of 233 persons initially wspected to have botulism, botulism was diagnosed in 162 (70 percent), Guillain-Bar& syndrome in 21(9 percent), carbon monoxide intoxication in seven (3 percent) and various other illnesses, predominantly neurologic, in the remainder. Twenty-four (9.0 percent] hypersensitivity reactions were reported to have followed the administration of botulinal antitoxin in a skin test (three) or as a therapeutic dose (21). Five (1.9 percent] persons had anaphylaxis within 10 minutes of receiving antitoxin, and seven (2.6 percent] persons had urticaria either within minutes or as long as 12 hours after an injection. Ten (3.7 percent) persons experienced serum sickness from six to 20 days after antitoxin therapy was begun. One person each had other reactions, including immediate generalized cutaneous erythema and lingual edema. None of the reactions was fatal. The rate of reactions in men (9.4 percent) was similar to that in women (8.5 percent] and was not different in any age group (Table I). The incidences of the three major types of reactions are shown in Table II according to the amount of serum received. Anaphylaxis occurred predominantly in persons who were given relatively small doses of serum, whereas serum sickness occurred most often in persons, given more than 40 ml of serum (p <0.02, Fisher’s exact
In the 11 year study period, information on hypersensitivity reactions was obtained for 268 (75 percent] of 333 persons known to have been treated with botulinal
Amouniot
Other
are percents.
RESULTS
II
Antitoxin
Serum Sickness
1 1 3
Botulinal antitoxins, which are extracted from enzymetreated equine serum, were produced by three pharmaceutical companies and were administered during the period of study reported herein. Connaught Medical Research Laboratories’ trivalent ABE antitoxin contained 7,500 IU of type A antitoxin, 5,500 IU of type B and 6,500 IU of type E per 10 ml vial. Connaught monovalent E antitoxin contained 5.000 IU/Z ml vial. Lederle Laboratories’ bivalent AB antitoxin contained 10,000 IU each of types A and B antitoxin per 10 ml vial. A limited amount of antitoxin produced by Statens Seruminstitut, Denmark, was used in 1967 and 1966. This preparation contained a total of 62.000 IU of types A, B, C, D, E and F antitoxin per 20 ml vial. A supply of Connaught antitoxin preparations is stored in U.S. Public Health Service Quarantine Stations in major cities and is provided by CDC on request for treatment of persons suspected of having botulism. Lederle antitoxin was formerly provided directly by the manufacturer on request. Data on reactions to botulinal antitoxin were obtained from physicians who had reported suspected cases of botulism and who had administered botulinal antitoxin to their patients. Each physician was sent a questionnaire from one to six months after reporting a case and was asked to report the type and dose of antitoxin used and the route by which it was administered. The physician was also asked to report any reactions and to classify them as anaphylaxis, urticaria, serum sickness or other [with a description of the reaction).
TABLE
Botulinal
Type of Reaction
40 46 49 110 23
in parentheses
GUNN
1
TABLE III
Hypersensitivity Reactions Botulinal Antltoxln AB
Acute Serum Total
reactions’ sickness
REACTIONS AND BOTULINAL
by Type of
antitoxin, five (3.5 percent) of 142 persons with a negative skin test, five (4.3 percent] of 117 persons without a skin test and none of nine persons with a positive skin test had serum sickness.
Antitoxin Type ABE
Both
ANTITOXIN-BLACK,
GT~JNN
3 (5.3) l(1.8)
5 (2.8) 5 (2.8)
1 (3.6) 4 (14.3)
COMMENT
4 (7.0)
10 (5.7)
5 (17.9)
In this series, equine botulinal antitoxin was associated with a 2 percent rate of anaphylaxis and a 3 percent rate of other immediate hypersensitivity reactions. This rate of anaphylaxis is higher than that reported for most other equine products [&lo]. Use of equine antitoxin was associated with a 4 percent incidence of serum sickness, a rate comparable to that associated with other enzyme-treated equine preparations [ill. Since some people in all the age groups reported had anaphylaxis after receiving small quantities of serum of each of the antitoxin types, the risk of this serious reaction probably cannot be substantially reduced. However, because incidence of serum sickness was the highest for persons who received more than 40 ml of serum, the risk level for this reaction might be lowered by limiting the amount of equine serum given. Unfortunately, even with this measure, serum sickness would still occur, since 40 percent of the cases were observed in persons who received less than 40 ml of serum (Table II). Although an intradermal test with diluted antitoxin is recommended, its use is unlikely to lower the reaction rate substantially. Of the persons given skin tests, more than half of those who had acute reactions had had negative skin tests; and three persons had acute reactions to the skin test itself. Furthermore, the skin test does not provide a reliable basis for predicting which persons are at higher risk of having serum sickness. The risk of having both acute and delayed hypersensitivity reactions associated with equine botulinal antitoxin is substantial and probably cannot be reduced easily. This risk would probably be eliminated by using botulinal immune globulin obtained from hyperimmunized human donors. Such homologous antitoxin may have additional therapeutic benefit as it should persist longer in serum. This factor may be of particular benefit in treating botulism in infants in whom it is postulated that toxin, which has been identified in stool specimens obtained long after the onset of illness, is slowly absorbed after being produced continuously in the intestines [4,5,12]. A safe antitoxin with an extended serum half-life would appear to offer a distinct advantage in this illness as well as in treatment of foodborne and wound botulism.
NOTE: Figures in parentheses are percents. includes anaphylaxis, urticaria, erythema, l
HYPERSENSITIVITY
and lingual
edema,
test). The incidence of urticaria was not clearly age or dose specific. When the route of administration was known, anaphylaxis or urticaria occurred in 10 of 215 persons who received only intravenous or both intravenous and intramuscular therapy. Serum sickness was reported in four of 100 persons given antitoxin intravenously only and in five of 115 persons given antitoxin both intravenously and intramuscularly. In one of 24 persons given only intramuscular antitoxin serum sickness developed; in none did either anaphylaxis or urticaria develop. In two persons urticaria developed and in one erythema developed after they received a skin test with diluted botulinal antitoxin. Antitoxin from the Statens Seruminstitut was used to treat four persons, each of whom received more than 50 ml of serum: serum sickness occurred in two. Antitoxins produced by Lederle (AB) and Connaught (ABE) were associated with similar over-all rates of hypersensitivity reactions (excluding reactions related to skin tests) (Table III). An intradermal skin test was carried out in 151 persons before they were given antitoxin. The test was considered positive in nine persoiis, three of whom immediately had urticaria or cutaneous erythema. One of these three persons reacted to a skin test with the Lederle antitoxin but not to testing with the Connaught antitoxin, which was then administered without adverse effect. The other two persons who reacted to the skin test were also given antitoxin safely (one had desensitization). Of the six other persons whose skin test was positive, two had desensitization and were then given full doses of antitoxin without adverse effect: however, two of four persons not given desensitizing doses of antitoxin had anaphylaxis. Of 142 persons whose skin tests were negative and who received antitoxin, urticaria developed in three and anaphylaxis in another. Of 117 persons who did not have a skin test, uriticaria developed in three when they were given antitoxin. When given
REFERENCES 3. Cunn RA, Terranova WA: Botulism in the United States. 1977. Rev Infect Dis 1979; 1: 722. 4. Arnon SS, Midura TF, Clay SA, et al.: Infant botulism: epidemiologic, clinical and laboratory aspects. JAMA 1977;
1. Merson MH, Hughes JM, Dowel1 VR, et al.: Current trends in botulism in the United States. JAMA 1874; 229: 1305. 2. Black RE, Arnon SS: Botulism in the United States, 1976. J Infect Dis 1977; 136: 829.
October
1980
The American Journal of Medicine
Volume 69
569
HYPERSENSITIVITY
REACTIONS AND BO'KJLINAL
ANTITOXIN-BLACK,
237: 1946. 5. Pickett J, Berg B, Chaplin E, et al.: Syndrome of botulism in infancy: N Engl J Med 1976; 295: 770. 6. Donadio JA, Gangarosa EJ, Faith GA: Diagnosis and treatment of botulism. J Infect Dis 1971; 124: 108. 7. Metzger JF, Lewis GE: Human-derived immune globulin for the treatment of botulism. Rev Infect Dis 1979; 1: 639. 8. Moynihan NH: Serum sickness and local reactions in tetanus prophylaxis: a study of 400 cases. Lancet 1955; 2: 264.
570
October
1980
The American
Journal
of Medicine
GuNN
9. Kojis FG: Serum sickness and anaphylaxis. Am J Dis Child 1942; 64: 93. 10. Naiditch MJ, Bower AG: Diphtheria: a study of 1.433 cask observed durin a ten-year period at the Los Angeles County Hospita B Am J Med 1954; 17: 229. 11. Laurent LJM, Parish HJ: Serum reactions and serum scnsitivity tests. Br Med J 1952; 1: 1294. 12. Turner HO, Brett EM, Gilbert RJ. Ghosh AC, et al.: Infant botulism in England. Lancet 1978; 1: 1277.
Volume
69
ROBERT E. BLACK, ROBERT A. GUNN, Atlanta,
M.D.. M.P.H. M.D.,M.P.H.*
Georgia
From the Enteric Diseases Branch, Bacterial Diseases Division, Bureau of Epidemiology. Center for Disease Control, Atlanta, Georgia. Requests for reprints should be addressed to Dr. Robert E. Black, Center for Vaccine Development, University of Maryland School of Medicine, Bressler Building, Room 409. 29 South Greene Street, Baltimore, Maryland 21201. Manuscript accepted March 31.1980. * Present address: Florida Department of Health and Rehabilitative Services, 1317 Winewood Boulevard, Tallahassee, Florida 32301.
Associated
with
During an 11-year period (1967 through 1977) CDC monitored reactions of hypersensitivity to botulinal antitoxin of equine origin. Of 268 persons given botulinal antitoxin, 24 (9.8 percent) had nonfatal acute (5.3 percent) or delayed (3.7 percent) hypersensitivity reactions to a skin test or therapeutic dose. The over-all rate of reaction did not differ with the age or sex of the recipient or with the type (AB or ABE) of antitoxin administered. Serum sickness occurred significantly more frequently in persons who received more than 40 ml of serum antitoxin (p <0.02). The over-all reaction rate was higher than that associated with other equine serum products and probably cannot be substantially reduced. This risk, however, would be substantially reduced if not eliminated by using botulinal immune globulin obtained from hyperimmunized human donors. Botulism, a paralytic illness caused by the potent neurotoxins of Clostridium botulinum, has been reported with increasing frequency in the past several years [Y-S]. This increase is due to both more reported cases of foodborne botulism and the recent recognition of botulism in infants [4,5], Currently recognized therapy for botulism includes equine botulinal antitoxin and intensive supportive care [6]. This antitoxin is also given sometimes to patients with other neurologic illnesses before they can be differentiated from botulism and to non-ill persons known to have eaten food containing botulinal toxin. Like other biologic products made from equine serum, botulinal antitoxin has been associated with anaphylaxis, serum sickness and other reactions [I]. The incidence of such reactions and the recognition of many cases of botulism in infants have prompted suggestions that an antitoxin of human origin be prepared [7]. In assessing the need for human botulinal immune globulin, it is important to know the risk of hypersensitivity reactions that follow administration of currently available equine antitoxin. In 1967, the Center for Disease Control established a surveillance system for recording adverse reactions to botulinal antitoxin. We reviewed thcsc data for an II-year period (1967 through 1977) to define better the reaction rate and thus to help to determine whether or not production of human botulinal immune globulin is justified. METHODS The Center for Disease Control (CDC) is notified of suspected cases of botulism by private physicians, hospital personnel, state and local health departments, the Food and Drug Administration, the U.S. Department of Agriculture and Lederle Laboratories, the only private supplier of botulinal antitoxin (distribution stopped in November 1978).
October 1980 The American Journal of Medicine
Volume 69
567
HYPERSENSITIVITY
TABLE
I
REACTIONS
Hypersensitivity
120 21-30 31-40 >40 Unknown Total Figures
BOTULINAL
Reactions
Number Receiving Antitoxin
Aw (Yd
NOTE:
AND
ANTITOXIN-BLACK,
by Age of Person Receiving
Urticarla
Anaphylaxis
1 2 1 3
-
-
-
266
7 (2.6)
5 (1.9)
1 2 2 5
Hypersensitivity
Antitoxin Given
Number Rsceivino Antitoxih
110”ml 1 l-20 ml 21-40 ml >40 ml Unknown
40 102 55 63 6
Total
266
Reactions
by Amount
l
October
1960
-
-
3 (7.5) 5.(10.9) 5 (10.2) 11 (10.0) 0 (0.0)
10 (3.7)
2 (0.7)
24 (9.0)
1
The American
of Botulinal
Antitoxin
Given
Type of Reaction Urticaria
Anaphylaxis
2 2 1 2
2 3
Serum Sickness
-
-
-
7 (2.6)
5 (1.9)
10 (3.7)
2 (0.7)
24 (9.0)
Journal of Medicine
to skin test.
Volume
69
1
Total Reactions
-
reaction
1 2 1 6
Other
6’ (15.0) 6 (5.9) 2 (3.6) 9 (14.3) l(12.5)
NOTE: Figures in parentheses are percents. Includes three persons with acute hypersensitivity
566
1
Total Reactions
antitoxin. Of these 268 persons, 26 were treated because of exposure to food thought to contain botulinal toxin, nine for wound botulism and 233 for suspected foodborne botulism. Of 233 persons initially wspected to have botulism, botulism was diagnosed in 162 (70 percent), Guillain-Bar& syndrome in 21(9 percent), carbon monoxide intoxication in seven (3 percent) and various other illnesses, predominantly neurologic, in the remainder. Twenty-four (9.0 percent] hypersensitivity reactions were reported to have followed the administration of botulinal antitoxin in a skin test (three) or as a therapeutic dose (21). Five (1.9 percent] persons had anaphylaxis within 10 minutes of receiving antitoxin, and seven (2.6 percent] persons had urticaria either within minutes or as long as 12 hours after an injection. Ten (3.7 percent) persons experienced serum sickness from six to 20 days after antitoxin therapy was begun. One person each had other reactions, including immediate generalized cutaneous erythema and lingual edema. None of the reactions was fatal. The rate of reactions in men (9.4 percent) was similar to that in women (8.5 percent] and was not different in any age group (Table I). The incidences of the three major types of reactions are shown in Table II according to the amount of serum received. Anaphylaxis occurred predominantly in persons who were given relatively small doses of serum, whereas serum sickness occurred most often in persons, given more than 40 ml of serum (p <0.02, Fisher’s exact
In the 11 year study period, information on hypersensitivity reactions was obtained for 268 (75 percent] of 333 persons known to have been treated with botulinal
Amouniot
Other
are percents.
RESULTS
II
Antitoxin
Serum Sickness
1 1 3
Botulinal antitoxins, which are extracted from enzymetreated equine serum, were produced by three pharmaceutical companies and were administered during the period of study reported herein. Connaught Medical Research Laboratories’ trivalent ABE antitoxin contained 7,500 IU of type A antitoxin, 5,500 IU of type B and 6,500 IU of type E per 10 ml vial. Connaught monovalent E antitoxin contained 5.000 IU/Z ml vial. Lederle Laboratories’ bivalent AB antitoxin contained 10,000 IU each of types A and B antitoxin per 10 ml vial. A limited amount of antitoxin produced by Statens Seruminstitut, Denmark, was used in 1967 and 1966. This preparation contained a total of 62.000 IU of types A, B, C, D, E and F antitoxin per 20 ml vial. A supply of Connaught antitoxin preparations is stored in U.S. Public Health Service Quarantine Stations in major cities and is provided by CDC on request for treatment of persons suspected of having botulism. Lederle antitoxin was formerly provided directly by the manufacturer on request. Data on reactions to botulinal antitoxin were obtained from physicians who had reported suspected cases of botulism and who had administered botulinal antitoxin to their patients. Each physician was sent a questionnaire from one to six months after reporting a case and was asked to report the type and dose of antitoxin used and the route by which it was administered. The physician was also asked to report any reactions and to classify them as anaphylaxis, urticaria, serum sickness or other [with a description of the reaction).
TABLE
Botulinal
Type of Reaction
40 46 49 110 23
in parentheses
GUNN
1
TABLE III
Hypersensitivity Reactions Botulinal Antltoxln AB
Acute Serum Total
reactions’ sickness
REACTIONS AND BOTULINAL
by Type of
antitoxin, five (3.5 percent) of 142 persons with a negative skin test, five (4.3 percent] of 117 persons without a skin test and none of nine persons with a positive skin test had serum sickness.
Antitoxin Type ABE
Both
ANTITOXIN-BLACK,
GT~JNN
3 (5.3) l(1.8)
5 (2.8) 5 (2.8)
1 (3.6) 4 (14.3)
COMMENT
4 (7.0)
10 (5.7)
5 (17.9)
In this series, equine botulinal antitoxin was associated with a 2 percent rate of anaphylaxis and a 3 percent rate of other immediate hypersensitivity reactions. This rate of anaphylaxis is higher than that reported for most other equine products [&lo]. Use of equine antitoxin was associated with a 4 percent incidence of serum sickness, a rate comparable to that associated with other enzyme-treated equine preparations [ill. Since some people in all the age groups reported had anaphylaxis after receiving small quantities of serum of each of the antitoxin types, the risk of this serious reaction probably cannot be substantially reduced. However, because incidence of serum sickness was the highest for persons who received more than 40 ml of serum, the risk level for this reaction might be lowered by limiting the amount of equine serum given. Unfortunately, even with this measure, serum sickness would still occur, since 40 percent of the cases were observed in persons who received less than 40 ml of serum (Table II). Although an intradermal test with diluted antitoxin is recommended, its use is unlikely to lower the reaction rate substantially. Of the persons given skin tests, more than half of those who had acute reactions had had negative skin tests; and three persons had acute reactions to the skin test itself. Furthermore, the skin test does not provide a reliable basis for predicting which persons are at higher risk of having serum sickness. The risk of having both acute and delayed hypersensitivity reactions associated with equine botulinal antitoxin is substantial and probably cannot be reduced easily. This risk would probably be eliminated by using botulinal immune globulin obtained from hyperimmunized human donors. Such homologous antitoxin may have additional therapeutic benefit as it should persist longer in serum. This factor may be of particular benefit in treating botulism in infants in whom it is postulated that toxin, which has been identified in stool specimens obtained long after the onset of illness, is slowly absorbed after being produced continuously in the intestines [4,5,12]. A safe antitoxin with an extended serum half-life would appear to offer a distinct advantage in this illness as well as in treatment of foodborne and wound botulism.
NOTE: Figures in parentheses are percents. includes anaphylaxis, urticaria, erythema, l
HYPERSENSITIVITY
and lingual
edema,
test). The incidence of urticaria was not clearly age or dose specific. When the route of administration was known, anaphylaxis or urticaria occurred in 10 of 215 persons who received only intravenous or both intravenous and intramuscular therapy. Serum sickness was reported in four of 100 persons given antitoxin intravenously only and in five of 115 persons given antitoxin both intravenously and intramuscularly. In one of 24 persons given only intramuscular antitoxin serum sickness developed; in none did either anaphylaxis or urticaria develop. In two persons urticaria developed and in one erythema developed after they received a skin test with diluted botulinal antitoxin. Antitoxin from the Statens Seruminstitut was used to treat four persons, each of whom received more than 50 ml of serum: serum sickness occurred in two. Antitoxins produced by Lederle (AB) and Connaught (ABE) were associated with similar over-all rates of hypersensitivity reactions (excluding reactions related to skin tests) (Table III). An intradermal skin test was carried out in 151 persons before they were given antitoxin. The test was considered positive in nine persoiis, three of whom immediately had urticaria or cutaneous erythema. One of these three persons reacted to a skin test with the Lederle antitoxin but not to testing with the Connaught antitoxin, which was then administered without adverse effect. The other two persons who reacted to the skin test were also given antitoxin safely (one had desensitization). Of the six other persons whose skin test was positive, two had desensitization and were then given full doses of antitoxin without adverse effect: however, two of four persons not given desensitizing doses of antitoxin had anaphylaxis. Of 142 persons whose skin tests were negative and who received antitoxin, urticaria developed in three and anaphylaxis in another. Of 117 persons who did not have a skin test, uriticaria developed in three when they were given antitoxin. When given
REFERENCES 3. Cunn RA, Terranova WA: Botulism in the United States. 1977. Rev Infect Dis 1979; 1: 722. 4. Arnon SS, Midura TF, Clay SA, et al.: Infant botulism: epidemiologic, clinical and laboratory aspects. JAMA 1977;
1. Merson MH, Hughes JM, Dowel1 VR, et al.: Current trends in botulism in the United States. JAMA 1874; 229: 1305. 2. Black RE, Arnon SS: Botulism in the United States, 1976. J Infect Dis 1977; 136: 829.
October
1980
The American Journal of Medicine
Volume 69
569
HYPERSENSITIVITY
REACTIONS AND BO'KJLINAL
ANTITOXIN-BLACK,
237: 1946. 5. Pickett J, Berg B, Chaplin E, et al.: Syndrome of botulism in infancy: N Engl J Med 1976; 295: 770. 6. Donadio JA, Gangarosa EJ, Faith GA: Diagnosis and treatment of botulism. J Infect Dis 1971; 124: 108. 7. Metzger JF, Lewis GE: Human-derived immune globulin for the treatment of botulism. Rev Infect Dis 1979; 1: 639. 8. Moynihan NH: Serum sickness and local reactions in tetanus prophylaxis: a study of 400 cases. Lancet 1955; 2: 264.
570
October
1980
The American
Journal
of Medicine
GuNN
9. Kojis FG: Serum sickness and anaphylaxis. Am J Dis Child 1942; 64: 93. 10. Naiditch MJ, Bower AG: Diphtheria: a study of 1.433 cask observed durin a ten-year period at the Los Angeles County Hospita B Am J Med 1954; 17: 229. 11. Laurent LJM, Parish HJ: Serum reactions and serum scnsitivity tests. Br Med J 1952; 1: 1294. 12. Turner HO, Brett EM, Gilbert RJ. Ghosh AC, et al.: Infant botulism in England. Lancet 1978; 1: 1277.
Volume
69