- Email: [email protected]
Reactions to antipneumococcal rabbit serum
REACTIONS
TO ANTIPNEUMOCOCCAL
RABBIT
SERUMV
X. EFFECT
ON REVERSED PASSIVE ANAPHYLAXIS OF VARYING SPEED OF INJECTIONS OF CONSTANT SHOCKING DOSES OF ANTIPNEUMOCOCCAL RABBIT SERUM OSCAR SWIN&OR’ORD, JR., M.D., AND DONALD CHAR.L~TTESVILLE, VA.
T. FAULKNER,
M.D.
P
ROMPT anaphylactic reactions to therapeutic injections of antipneumococcal rabbit serum are common. Conventional anaphylaxis is the accepted mechanism for the reactions which occur when skin tests for sensitivity to serum are positive. However, tests for sensitivity were negative in nearly 80 per cent of a large series of reactions to antipneumococcal horse serum.l Evidence has been offered that reversed passive anaphylaxis mediates reactions to antiserum which occur when tests for sensitivity are negative.? This is one of a series of experiments,3-5 still in progress designed to clarif.1 some of the problems of reactions to theapeutic antisera. Experiment X was designed to determine the effect on reversed passive anaphylaxis of varying the speed of injection of constant shocking doses of antipneumococcal rabbit serum. Sensitizing doses of type specific polysaccharide and the interval between sensit,izing and shocking doses were constant. Medium sized guinea pigs were sensitized with intravenous injections of 1.0 mg. of type 8 pneumococcal polysaccharide. One hour later they were given shocking doses of 0.5 ml. of type 8 antipneumococcal rabbit serum, lot 418, 3,400 units ml. It had been shown earlier that 0.5 ml. was a uniformly effective dose. The speed of injection of shocking doses was varied. In different groups of pigs the injection time was fifteen, thirty, sixty, ninety, one hundred and eighty, and three hundred seconds, respectively. In the first two groups the shocking dose volume was 0.5 ml. An equal volume of saline was added in the last four groups to simplify the injection of the small amount over the longer time. No effect of this dilution to 1.0 ml. was noted. The results are shown in Table 1. It is obvious that all injections which took less than sixty seconds, and mqst of those which took ninety seconds, were In sharp contrast are the mild or followed by severe anaphylactic reactions. negative reactions when the injection times were one hundred and eighty and three hundred seconds, respectively. *From the Allergy and Arthritis Division, Department of Internal Medicine, UniverSitY of Virginia Medical School, Charlottesville. Va. tThis experiment was made possible by generous supplies of antipneumococcal rabbit serum by Wyeth Incorporated and of pneumococcal polysaccharide by Lederle Laboratories. Incorporated.
126
SWINEFORD,
JR.,
ET
AL. :
ANTIPNEUMOCOCCAL
RABBIT
SERUM
127
EFFECT OF VARYING SPEED OF INJECTIONS TABLE I. REVERSED PASSIVE ANAPH-S. CONSTANT SHOCKINQ DOSE (0.5 ML.= 1,700 UNITS) OF TYPE 8 ANTIPNEUMOCOCCAL RABBIT SERUM, WHEN SENSITIZING DOSE (1.0 YG. TYPE 8 PNEUMOCOCCAL POLY~ACCHARIDE) AND INTERVAL (ABOUT 1 HOUR) BETWEEN SENSITIZING AND SHOCKING DOSES vmm CONSTANT TIME 15 seconds 30 seconds 60 seconds 90 seconds 180 seconds 300 seconds
areas,
REACTIONS
1 * 26 ++ + + 0
* 26
* 16
CONTROLS
I * A’$ +A
26 AD
OF
tt
See Text
AD
tt AD tt AD AD tt tt 0 0 t t t 0 0 0 0 t t t = Slight anaphylactic reaction = r&led hair, sick, expiratory dyspnea. +t = Moderate to marked reaction = quite sick, convulsive movements, marked dyspnea. AD = Anaphylactic death, Necropsy = pale, ballooned lungs, scattered hemorrhagic bronchial exudate. 0 = No reaction. * = Died in 24-36 hours.
As controls, four pigs were given 0.5 ml. of type 2 antiserum in fifteen seconds. Type 8 polysaccharide was used as the sensitizing dose. There were no reactions. DISCUSSION
The conclusion is obvious, that small shocking doses of antiserum are highly effective in producing reversed passive anaphylaxis when given rapidly, whereas the same dose is essentially ineffective when given slowly. The quantitative results probably would be different if the doses of sensitizing polysaccharide or shocking antiserum were varied or if different batches of antiserum were used.3* 4 This experiment would seem to justify the recommendation that therapeutic antipneumococcal serum be given very slowly, in order to lessen the likelihood of reversed passive anaphylactic reactions, when tests for sensitivity are negative. Cecil and Sutliff5 noted that “allergic reactions have nearly always occurred after the first intravenous injection of 5 cc. or less of serum.” When tests for sensitivity were negative their arbitrary “rule was to devote five minutes to the injection of 5 cc. of serum.” A safe speed in man cannot be stated from present data. In the guinea pig it is dangerous to inject 0.5 ml. (1,700 units) of serum in less than one hundred and eighty seconds. SUMMARY
1. Evidence is presented that reversed passive anaphylactic reactions in guinea pigs vary with the speed of injection of shocking doses of specific antiserum, when other factors are constant. 2. Severe reactions occurred in most animals when the injection time was ninety seconds or less. Reactions were negligible or absent when the injection time was one hundred and eighty seconds or longer. 3. It is recommended that therapeutic antisera be injected very slowly if reversed anaphylactic reactions are to be avoided.
12x
THE
JOURiXAL
OF
ALLERGY
REFhRENCES 1. Rutstein,
2. 3.
4.
.i.
D. D., Reed, E. A., Langmuir, A. I)., and Rogers, E. S.: Immediate Serum Reactions in Man. Classification and Analysis of Reactions to the Intravenous Administration of Antinneumococcus Horse Serum in Cases of Pneumonia, Arch. lnt. Med. 68: 25, 1941. _ Swineford, O., Jr., and Robinson, M. 1%: Reactions to Antipneumocoecal Rabbit Serum, J. ALLERGY, 16: 5, 1945. Pearsall, H. Rowland, Eversole, Staunton L., and Swineford, O., Jr.: Reactions to AntiIII. Effects of Varying Amounts of Pneumococcal pneumococcal Rabbit Serum. Polysaccharide on Reversed Passive Anaphylaxis in Guinea Pigs. IV. A Simple Roughly Quantitative Method of Measuring Circulating Polysaccharide, J. ALLERGY 17: 190, 1946. Swineford, O., Jr., Hodges, Emory F., and Nelson, Kenwyn, G.: Reactions to Antipneumococcal Rabbit Serum. VIII. Effect of Varying Shocking Doses of Antiserum on Reversed Passive Anaphylaxis When Sensitizing and Shocking Doses are Constant. IX. Comparison of Reversed Passive Anaphylactogenic Properties of Samples of Antipneumococcal Rabbit Serum, Types II, VII and VIII, J. ALLERGY 19: 122, 1948. The Treatment of Lobar Pneumonia with ConcenCecil? Russel L., and Sutiff, W. D. trated Antipneumococcus Serum. J. A. M. A. 91: 2035, 1928.
TO ANTIPNEUMOCOCCAL
RABBIT
SERUMV
X. EFFECT
ON REVERSED PASSIVE ANAPHYLAXIS OF VARYING SPEED OF INJECTIONS OF CONSTANT SHOCKING DOSES OF ANTIPNEUMOCOCCAL RABBIT SERUM OSCAR SWIN&OR’ORD, JR., M.D., AND DONALD CHAR.L~TTESVILLE, VA.
T. FAULKNER,
M.D.
P
ROMPT anaphylactic reactions to therapeutic injections of antipneumococcal rabbit serum are common. Conventional anaphylaxis is the accepted mechanism for the reactions which occur when skin tests for sensitivity to serum are positive. However, tests for sensitivity were negative in nearly 80 per cent of a large series of reactions to antipneumococcal horse serum.l Evidence has been offered that reversed passive anaphylaxis mediates reactions to antiserum which occur when tests for sensitivity are negative.? This is one of a series of experiments,3-5 still in progress designed to clarif.1 some of the problems of reactions to theapeutic antisera. Experiment X was designed to determine the effect on reversed passive anaphylaxis of varying the speed of injection of constant shocking doses of antipneumococcal rabbit serum. Sensitizing doses of type specific polysaccharide and the interval between sensit,izing and shocking doses were constant. Medium sized guinea pigs were sensitized with intravenous injections of 1.0 mg. of type 8 pneumococcal polysaccharide. One hour later they were given shocking doses of 0.5 ml. of type 8 antipneumococcal rabbit serum, lot 418, 3,400 units ml. It had been shown earlier that 0.5 ml. was a uniformly effective dose. The speed of injection of shocking doses was varied. In different groups of pigs the injection time was fifteen, thirty, sixty, ninety, one hundred and eighty, and three hundred seconds, respectively. In the first two groups the shocking dose volume was 0.5 ml. An equal volume of saline was added in the last four groups to simplify the injection of the small amount over the longer time. No effect of this dilution to 1.0 ml. was noted. The results are shown in Table 1. It is obvious that all injections which took less than sixty seconds, and mqst of those which took ninety seconds, were In sharp contrast are the mild or followed by severe anaphylactic reactions. negative reactions when the injection times were one hundred and eighty and three hundred seconds, respectively. *From the Allergy and Arthritis Division, Department of Internal Medicine, UniverSitY of Virginia Medical School, Charlottesville. Va. tThis experiment was made possible by generous supplies of antipneumococcal rabbit serum by Wyeth Incorporated and of pneumococcal polysaccharide by Lederle Laboratories. Incorporated.
126
SWINEFORD,
JR.,
ET
AL. :
ANTIPNEUMOCOCCAL
RABBIT
SERUM
127
EFFECT OF VARYING SPEED OF INJECTIONS TABLE I. REVERSED PASSIVE ANAPH-S. CONSTANT SHOCKINQ DOSE (0.5 ML.= 1,700 UNITS) OF TYPE 8 ANTIPNEUMOCOCCAL RABBIT SERUM, WHEN SENSITIZING DOSE (1.0 YG. TYPE 8 PNEUMOCOCCAL POLY~ACCHARIDE) AND INTERVAL (ABOUT 1 HOUR) BETWEEN SENSITIZING AND SHOCKING DOSES vmm CONSTANT TIME 15 seconds 30 seconds 60 seconds 90 seconds 180 seconds 300 seconds
areas,
REACTIONS
1 * 26 ++ + + 0
* 26
* 16
CONTROLS
I * A’$ +A
26 AD
OF
tt
See Text
AD
tt AD tt AD AD tt tt 0 0 t t t 0 0 0 0 t t t = Slight anaphylactic reaction = r&led hair, sick, expiratory dyspnea. +t = Moderate to marked reaction = quite sick, convulsive movements, marked dyspnea. AD = Anaphylactic death, Necropsy = pale, ballooned lungs, scattered hemorrhagic bronchial exudate. 0 = No reaction. * = Died in 24-36 hours.
As controls, four pigs were given 0.5 ml. of type 2 antiserum in fifteen seconds. Type 8 polysaccharide was used as the sensitizing dose. There were no reactions. DISCUSSION
The conclusion is obvious, that small shocking doses of antiserum are highly effective in producing reversed passive anaphylaxis when given rapidly, whereas the same dose is essentially ineffective when given slowly. The quantitative results probably would be different if the doses of sensitizing polysaccharide or shocking antiserum were varied or if different batches of antiserum were used.3* 4 This experiment would seem to justify the recommendation that therapeutic antipneumococcal serum be given very slowly, in order to lessen the likelihood of reversed passive anaphylactic reactions, when tests for sensitivity are negative. Cecil and Sutliff5 noted that “allergic reactions have nearly always occurred after the first intravenous injection of 5 cc. or less of serum.” When tests for sensitivity were negative their arbitrary “rule was to devote five minutes to the injection of 5 cc. of serum.” A safe speed in man cannot be stated from present data. In the guinea pig it is dangerous to inject 0.5 ml. (1,700 units) of serum in less than one hundred and eighty seconds. SUMMARY
1. Evidence is presented that reversed passive anaphylactic reactions in guinea pigs vary with the speed of injection of shocking doses of specific antiserum, when other factors are constant. 2. Severe reactions occurred in most animals when the injection time was ninety seconds or less. Reactions were negligible or absent when the injection time was one hundred and eighty seconds or longer. 3. It is recommended that therapeutic antisera be injected very slowly if reversed anaphylactic reactions are to be avoided.
12x
THE
JOURiXAL
OF
ALLERGY
REFhRENCES 1. Rutstein,
2. 3.
4.
.i.
D. D., Reed, E. A., Langmuir, A. I)., and Rogers, E. S.: Immediate Serum Reactions in Man. Classification and Analysis of Reactions to the Intravenous Administration of Antinneumococcus Horse Serum in Cases of Pneumonia, Arch. lnt. Med. 68: 25, 1941. _ Swineford, O., Jr., and Robinson, M. 1%: Reactions to Antipneumocoecal Rabbit Serum, J. ALLERGY, 16: 5, 1945. Pearsall, H. Rowland, Eversole, Staunton L., and Swineford, O., Jr.: Reactions to AntiIII. Effects of Varying Amounts of Pneumococcal pneumococcal Rabbit Serum. Polysaccharide on Reversed Passive Anaphylaxis in Guinea Pigs. IV. A Simple Roughly Quantitative Method of Measuring Circulating Polysaccharide, J. ALLERGY 17: 190, 1946. Swineford, O., Jr., Hodges, Emory F., and Nelson, Kenwyn, G.: Reactions to Antipneumococcal Rabbit Serum. VIII. Effect of Varying Shocking Doses of Antiserum on Reversed Passive Anaphylaxis When Sensitizing and Shocking Doses are Constant. IX. Comparison of Reversed Passive Anaphylactogenic Properties of Samples of Antipneumococcal Rabbit Serum, Types II, VII and VIII, J. ALLERGY 19: 122, 1948. The Treatment of Lobar Pneumonia with ConcenCecil? Russel L., and Sutiff, W. D. trated Antipneumococcus Serum. J. A. M. A. 91: 2035, 1928.