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Clinical and serologic study of ragweed hay fever patients treated with histamine azoprotein (Hapamine)
CLINICAL AND SEROLOGIC STUDY OF RAGWEED FEVER PATIENTS TREATED M71TH HISTAMINE (HAPA3IIKE ) “t $ AZOPROTEIN ~4BBREVIATED ~ELIAN
HEBALD,
HA‘I
REPORT
M.D., ROBERT A. COOKE:, &1.1).. AXD LII.LIA~S NEW \-OKK, N. Y.
31. I)owrrn‘c+.
A.H.
N A recent study Fell and his co-worker+ reported the preparation of histamine antigens by coupling diazotized p-anlillo-benzoyl-histanlinr~ to various proteins. They hyperimmunized animals with these compounds in an atleml)i to produce protection against excess histamine released by antigen-ant ihod> reactions in anaphylaxis and allerg)-. It was calaimed that antibodies w(‘re 1)ro duced which were partially specific for the histamine haptine, and animals so immunized displayed a marked degree of resistance to anaphylaxis. It \va> Fell’s theory that, histamine azoprotein produced antibody to histaminf~ ;ln(l SCI collerl illlll ne~~tralized the supposed histamine liberated in the allergic! reaction. Friedman’ reported specific precipitins for histamine in ljatients t,reatctl wit11 histamine azoprotein and in vitro neutralization oi’ histamine by their st’ra. as Thck well as protection of the skin against histamine introduced intradermally. immunologic H-substance then is tbe supposed basis of anaphylactic shock, itntl, by analogy, the allergic reactions in man as well. It was surmised that an anti histamine-ant,ibody might prevent the lil)cration ot’ intracellular histarnincl irh such reactions. This investigat~ion was undertaken to determine if constitutional reactions could hc prevented in ragweed hay fever patients immunized with histaminc~azoprotein, to evaluate clinical benefits in patients so immunized, and t(J sty ii the specificity of the precipitins produced by such immunization was sl~~~cifc~ for t lie histamine haptine. In eight patients having clinical ragweed hay fever, four wcro treated wit II whole ragwcrd exbract and four were treated wilh whole ragweed cstrac*t JJIIIX fraction 1. Fraction 1 is the fract,ion of ragweed pollen prccipitatcatl by 5i 1 per cent saturation with ammonium sulfate. 1111of these pat,ients had had (‘on stitutional reactions in the course of their treatment at, fairly definite ‘%cchiling ’ levels of dosage, beyond which we could not go without again producing dcfinitcb but mild constit’utional reactions. Histamine azoprotein in increasing ;~mount s was given to each patient at weekly injections, in addition to the ragweed cxstracr which was kept below the level of dosage that produced a constitutional react ~OII. The total dosage of histamine azoprotein ranged from 2.3 ml. to li’ 1111.t’01. each patient in this group. We did not. attcmljt to increase the dosaq of ray weed extract) to t,he point that had produced a constitutional reaction or KL’i, I
beyond it, until a dosage of 2 ml. of histamine azoprotein for one injection had been reached in those patients who could take this amount. We also attempted to reach a top dosage of 2 ml. of histamine azoprotein for one injection in all patients before blood specimens were taken for precipitin determinations. It was not always possible to give t,his large amount in one injection. In one patient, for instance, a very large local reaction with severe pain and swelling of the axillary glands occurred followin g an injection of 0.6 ml. of the histamine azoprotein. In this group of eight patients, constitutional reactions with laa,
*The Fell.
histamine
casein
was
obtained
from
Parke
Davis
& Co.
through
the
courtesy
of
HEBALD
ET
AL.:
RAGWEED
HAY
FEVER
TREATED
WITII
HISTAMIKE
AZOPROTEIS
1:
In view of the fact that no precipitins were demonstrable in any serum to the histamine casein, precipitins to histamine azoprotein can only mean precipihat1 tins to the azoprotein or protein radiclc. If any histamine neutralization occurred with histamine azoprotein therapy, then precipitins to the histamine casein should have been demonstrated. Wc ww not ahlc to show this. SUMMARY
1. We were not able to raise the “ ceiling” dosage of ragweed extract i II six of eight patients with the additional treatment of histamine azoprotein. 2. In five patients with ragweed hay fever who had never been treated before, there appeared to be no clinical benefit resulting from treatment with histamine azoprotein. In the eight patients who were treated with ragweed extract and histamine azoprotein there appeared to be no difference in the clinical result over the preceding year when ragweed extract alone had been given. 3. Skin tests with histamine dilutions and histamine response by subcutaneous injection were the same before and after treatment with histamine azoprotein. 4. In no patients were precipitins specific for the histamine radicle demonstrable after histamine azoprotein injections. All the histamine casein react ions were negative. 5. Regardless of effect in experimPnta1 animals, histamine azoprotein did not give protection against constitutional reactions nor proteclion against cliuicnl allergy of hay fever types. REFERENCES 1. Fell,
N., Rodney, G., and Marshall, Immunological Investigation, 9. Cohen, M. B., and Friedman, H. 245, 1944.
D. E.: Histamine-Protein J. Immunol. 47: 237, J.: Immunity Bgainst
Complexes 1943. II-Substance,
; Synthesis
and
J.
15:
AI,I,EM;~
DISCUSSIOS DR. LEO CRIEP, Pittsburgh, Pa.-Some day we will look back on this see-saw type of discussion on the merits of various agents very much as we look back at similar discussion on the various agents for the treatment of pernicious anemia prior to liver extract. Dr. Cohen states he has had results with hay fever. He feels there is an expansive type of reaction and there is liberated a large amount of histamine in the atopic reaction. To my mind, the treatment of urticaria or severe reaction should be associated with as much liberation of histamine as possible. Dr. Hebald and his associates have tried to clarify the confusion that exists concerning azoprotein. My own clinical opinion agrees with the conclusions brought out by this group. I wish to cite the case of a patient who presented a reaction to orris root and gave a posiShe was treated over a long time with several courses of azoprotein. tive patch test with it. After this period of time not only did her clinical condition fail to improve, but the intrndermal tests were the same as before treatment was instituted.
HEBALD,
HA‘I
REPORT
M.D., ROBERT A. COOKE:, &1.1).. AXD LII.LIA~S NEW \-OKK, N. Y.
31. I)owrrn‘c+.
A.H.
N A recent study Fell and his co-worker+ reported the preparation of histamine antigens by coupling diazotized p-anlillo-benzoyl-histanlinr~ to various proteins. They hyperimmunized animals with these compounds in an atleml)i to produce protection against excess histamine released by antigen-ant ihod> reactions in anaphylaxis and allerg)-. It was calaimed that antibodies w(‘re 1)ro duced which were partially specific for the histamine haptine, and animals so immunized displayed a marked degree of resistance to anaphylaxis. It \va> Fell’s theory that, histamine azoprotein produced antibody to histaminf~ ;ln(l SCI collerl illlll ne~~tralized the supposed histamine liberated in the allergic! reaction. Friedman’ reported specific precipitins for histamine in ljatients t,reatctl wit11 histamine azoprotein and in vitro neutralization oi’ histamine by their st’ra. as Thck well as protection of the skin against histamine introduced intradermally. immunologic H-substance then is tbe supposed basis of anaphylactic shock, itntl, by analogy, the allergic reactions in man as well. It was surmised that an anti histamine-ant,ibody might prevent the lil)cration ot’ intracellular histarnincl irh such reactions. This investigat~ion was undertaken to determine if constitutional reactions could hc prevented in ragweed hay fever patients immunized with histaminc~azoprotein, to evaluate clinical benefits in patients so immunized, and t(J sty ii the specificity of the precipitins produced by such immunization was sl~~~cifc~ for t lie histamine haptine. In eight patients having clinical ragweed hay fever, four wcro treated wit II whole ragwcrd exbract and four were treated wilh whole ragweed cstrac*t JJIIIX fraction 1. Fraction 1 is the fract,ion of ragweed pollen prccipitatcatl by 5i 1 per cent saturation with ammonium sulfate. 1111of these pat,ients had had (‘on stitutional reactions in the course of their treatment at, fairly definite ‘%cchiling ’ levels of dosage, beyond which we could not go without again producing dcfinitcb but mild constit’utional reactions. Histamine azoprotein in increasing ;~mount s was given to each patient at weekly injections, in addition to the ragweed cxstracr which was kept below the level of dosage that produced a constitutional react ~OII. The total dosage of histamine azoprotein ranged from 2.3 ml. to li’ 1111.t’01. each patient in this group. We did not. attcmljt to increase the dosaq of ray weed extract) to t,he point that had produced a constitutional reaction or KL’i, I
beyond it, until a dosage of 2 ml. of histamine azoprotein for one injection had been reached in those patients who could take this amount. We also attempted to reach a top dosage of 2 ml. of histamine azoprotein for one injection in all patients before blood specimens were taken for precipitin determinations. It was not always possible to give t,his large amount in one injection. In one patient, for instance, a very large local reaction with severe pain and swelling of the axillary glands occurred followin g an injection of 0.6 ml. of the histamine azoprotein. In this group of eight patients, constitutional reactions with laa,
*The Fell.
histamine
casein
was
obtained
from
Parke
Davis
& Co.
through
the
courtesy
of
HEBALD
ET
AL.:
RAGWEED
HAY
FEVER
TREATED
WITII
HISTAMIKE
AZOPROTEIS
1:
In view of the fact that no precipitins were demonstrable in any serum to the histamine casein, precipitins to histamine azoprotein can only mean precipihat1 tins to the azoprotein or protein radiclc. If any histamine neutralization occurred with histamine azoprotein therapy, then precipitins to the histamine casein should have been demonstrated. Wc ww not ahlc to show this. SUMMARY
1. We were not able to raise the “ ceiling” dosage of ragweed extract i II six of eight patients with the additional treatment of histamine azoprotein. 2. In five patients with ragweed hay fever who had never been treated before, there appeared to be no clinical benefit resulting from treatment with histamine azoprotein. In the eight patients who were treated with ragweed extract and histamine azoprotein there appeared to be no difference in the clinical result over the preceding year when ragweed extract alone had been given. 3. Skin tests with histamine dilutions and histamine response by subcutaneous injection were the same before and after treatment with histamine azoprotein. 4. In no patients were precipitins specific for the histamine radicle demonstrable after histamine azoprotein injections. All the histamine casein react ions were negative. 5. Regardless of effect in experimPnta1 animals, histamine azoprotein did not give protection against constitutional reactions nor proteclion against cliuicnl allergy of hay fever types. REFERENCES 1. Fell,
N., Rodney, G., and Marshall, Immunological Investigation, 9. Cohen, M. B., and Friedman, H. 245, 1944.
D. E.: Histamine-Protein J. Immunol. 47: 237, J.: Immunity Bgainst
Complexes 1943. II-Substance,
; Synthesis
and
J.
15:
AI,I,EM;~
DISCUSSIOS DR. LEO CRIEP, Pittsburgh, Pa.-Some day we will look back on this see-saw type of discussion on the merits of various agents very much as we look back at similar discussion on the various agents for the treatment of pernicious anemia prior to liver extract. Dr. Cohen states he has had results with hay fever. He feels there is an expansive type of reaction and there is liberated a large amount of histamine in the atopic reaction. To my mind, the treatment of urticaria or severe reaction should be associated with as much liberation of histamine as possible. Dr. Hebald and his associates have tried to clarify the confusion that exists concerning azoprotein. My own clinical opinion agrees with the conclusions brought out by this group. I wish to cite the case of a patient who presented a reaction to orris root and gave a posiShe was treated over a long time with several courses of azoprotein. tive patch test with it. After this period of time not only did her clinical condition fail to improve, but the intrndermal tests were the same as before treatment was instituted.