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Editorial
The Complex
World
of Adverse
Most adverse reactions to drugs are toxic. These reactions are predictable, may occur in anyone if the dose is high enough, and, fortunately, usually can be anticipated from animal testing. Clinical reactions may occur with (1) overdose, (2) impaired metabolism or excretion, (3) drug interaction, or (4) intolerance. The last is defined as the condition of some individuals who experience the usual toxic symptoms and signs at unusually low doses [1]. Allergic reactions are not predictable from animal testing and theoretically do not occur on first exposure. Clinical manifestations of acute reactions are limited to a few characteristic symptoms and signs, such as flushing urticaria angioedema nasal congestion bronchospasm, and hypovolemic shock. Whereas a toxic reaction may be prevented by modest reduction in the dose or rate of administration even minute doses can produce reactions in allergic patients. Acute allergic reactions are caused by one or more chemical mediators that are activated when an antigen reacts with a specific antibody. Thus histamine, anaphylactic slow-reacting substance, and perhaps bradykinin, among others, are released from mast cells and basophils sensitized with antibodies of the immunoglobulin E (IgE) class. Reactions involving IgG and 1gM antibodies activate complemont, and products of the third and fifth components of complement (C3a and C5a, the anaphylatoxins) can also release histamine. Vascular endothelial injury produced by antigen-antibody complexes and complement activates Hageman factor (factor XII), the starting point for three parallel series of reactions leading to blood coagulation, fibrinolysis, and plasma kinin (bradykinin) generation. Products of the first two, thrombin and plasmin, can also activate the complement system with anaphylatoxin production as a result [2]. All these systems include a series of enzymatic reactions that are associated with specific inhibitors that normally keep these reactions under control. One example is the inhibitor of the activated form of Cl This esterase inhibitor is also involved in the regulation of coagulation, fibrinolysis, and kinin generation. Its absence in man is associated with a potentially fatal form of angioedema. lodinated contrast media have the same potential for causing adverse reactions as do drugs. Most reactions, with nausea and vomiting heading the list, are clearly not allergic [3]. The allergic-type symptoms mentioned above occur with sufficient frequency, though, to be of concern to allergists and radiologists alike. These symptoms may be explosive and, if shock and/or airway angioedema develop, can be fatal. Despite the typical ,
,
,
symptoms, most of these reactions may not be truly allergic-, that is, antibody-mediated. Brasch and Caldwell [4] did find significantly more antibodylike activity (globulin binding of diatrizoate) in the sera of patients after severe reactions, compared with controls, but acknowledged that there was no proof that this had anything to do with the production of symptoms. Among other things, the occurrence of acute reactions in patients with no prior exposure and the development of a reaction
,
native
1979
one
occasion
but
not
the
next
in the
same
pathway
(bypassing
the
first
three
reacting
com-
ponents, Cl C4, and C2) according to some reports, while others have implicated both the classical (Cl activation) and alternative pathways [6]. As with histamine release, though, complement activation is insufficient to explain clinical reactions, for it also seems to occur to the same degree in patients who don’t react as in those who do [5]. It is possible that contrast agents affect complement indirectly, via Hageman factor (factor Xli) activation. If this is so, then such activation may be important in other ways. In this issue of the Journal is a report by Lasser et al. on the effect of intravenous meglumine iodipamide on blood coagulation in rabbits. They observed a reduction in factor XII levels and evidence for activation of the intrinsic and even the extrinsic coagulation systems. They again observed the reduction in complement activity that they had reported earlier. Mortality was not changed by prior depletion of the later reacting components of complement by cobra venom. This is not sun,
.
February
on
patient argue against allergic sensitization being responsible for these reactions. There are reasonable alternative explanations. Several drugs, including the opiates, release histamine from mast cells without antibody mediation in a predictable, dose-related fashion [l]-so do contrast agents, both in vitro and in vivo. However, a problem with the histamine release concept as an explanation for clinical reactions is that the plasma histamine has been found to increase just as much after injection of the contrast medium in patients who did not have a reaction as in those who did [5]. Contrast agents also activate complement via the alter-
,
AJR:132,
Reactions
pnising;
if
complement
activation
had
contributed
to
mortality, then cobra venom administration itself should produce more serious reactions than it does. The most significant observations were that mortality could be greatly reduced by either fibninogen depletion or hepanin treatment. This may have a clinical counterpart; a few human cases of disseminated intravascular coagulation have been recognized after injection of a contrast agent. 309
EDITORIAL
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310
Since the effect on the clotting mechanism appears to be universal in rabbits, could it also be a common and predictable finding in man? The answer seems to be ‘yes.’ In the same study in which histamine and complement levels were compared, fibninogen split products were found in the serum of almost half of the patients after a contrast study. Again, there was no difference between those who had reactions and those who did not [5]. Obviously the answers are not all in. The kinin generating system that is triggered by factor XII activation certainly deserves more consideration. The chemical actions of contrast media do seem to affect all patients more or less equally. Rather than reacting to excessive mediator activation, those who experience allergylike (anaphylactoid) reactions may have an unusual degree of reactivity to a usually innocuous level of one or more mediators. This could be tested. Lasser et al. have raised another interesting possibility in their paper. They suggested that those who have clinical reactions are deficient in some inhibitor, and they have taken the logical step of looking at the Cl esterase inhibitor. However, it should be kept in mind that subjects who have a proven deficiency of this inhibitor suffer only from edema, so such a suggestion might not be adequate to explain the ‘
AJR:132,
urticanial, actions
bronchospastic, to iodinated
and
contrast
other
‘
1979
anaphylactoid
re-
media.
Paul University
February
of Washington
P. VanArsdel,
School
Seattle,
Jr.
of Medicine
Washington
98195
REFERENCES PP Jr: Adverse drug reactions, in Allergy Principies and Practice, vol 2, chapter 61 edited by Middleton E Jr, Reed CE, Ellis EF, St. Louis, Mosby, 1978 2. Wells JV: Immune mechanisms in tissue damage, in Basic and Clinical Immunology, 2d ed, chapter 23, edited by Fudenberg HH, Stites OP, CaIdwell JL, Wells JV, Los Altos, 1.
VanArsdel
,
Calif., 3. Witten
Lange, 1978 DM: Reactions
231 :974-977, 1975 4. Brasch AC, CaIdwell
to urographic
JL: The allergic
contrast
theory
media.
JAMA
of radiocontrast
agent toxicity: demonstration of antibody activity in sera of patients suffering major radiocontrast agent reactions. Invest Radiol 1 1 : 347-356, 1976 5. Simon RA, Schatz M, Stevenson 00, Curry N, Yamamoto F,
Plow E, Ring H, Arroyave
CM: Radiographic
contrast
media
infusions: measurement of mediators and correlation with clinical parameters. J Allergy Clin Immunol 61 : 145, 1978 6. Lieberman P, Siegle AL, Taylor WW Jr: Anaphylactoid reactions to iodinated contrast material. J Allergy Clin Immunol 62:174-180, 1978
Editorial
The Complex
World
of Adverse
Most adverse reactions to drugs are toxic. These reactions are predictable, may occur in anyone if the dose is high enough, and, fortunately, usually can be anticipated from animal testing. Clinical reactions may occur with (1) overdose, (2) impaired metabolism or excretion, (3) drug interaction, or (4) intolerance. The last is defined as the condition of some individuals who experience the usual toxic symptoms and signs at unusually low doses [1]. Allergic reactions are not predictable from animal testing and theoretically do not occur on first exposure. Clinical manifestations of acute reactions are limited to a few characteristic symptoms and signs, such as flushing urticaria angioedema nasal congestion bronchospasm, and hypovolemic shock. Whereas a toxic reaction may be prevented by modest reduction in the dose or rate of administration even minute doses can produce reactions in allergic patients. Acute allergic reactions are caused by one or more chemical mediators that are activated when an antigen reacts with a specific antibody. Thus histamine, anaphylactic slow-reacting substance, and perhaps bradykinin, among others, are released from mast cells and basophils sensitized with antibodies of the immunoglobulin E (IgE) class. Reactions involving IgG and 1gM antibodies activate complemont, and products of the third and fifth components of complement (C3a and C5a, the anaphylatoxins) can also release histamine. Vascular endothelial injury produced by antigen-antibody complexes and complement activates Hageman factor (factor XII), the starting point for three parallel series of reactions leading to blood coagulation, fibrinolysis, and plasma kinin (bradykinin) generation. Products of the first two, thrombin and plasmin, can also activate the complement system with anaphylatoxin production as a result [2]. All these systems include a series of enzymatic reactions that are associated with specific inhibitors that normally keep these reactions under control. One example is the inhibitor of the activated form of Cl This esterase inhibitor is also involved in the regulation of coagulation, fibrinolysis, and kinin generation. Its absence in man is associated with a potentially fatal form of angioedema. lodinated contrast media have the same potential for causing adverse reactions as do drugs. Most reactions, with nausea and vomiting heading the list, are clearly not allergic [3]. The allergic-type symptoms mentioned above occur with sufficient frequency, though, to be of concern to allergists and radiologists alike. These symptoms may be explosive and, if shock and/or airway angioedema develop, can be fatal. Despite the typical ,
,
,
symptoms, most of these reactions may not be truly allergic-, that is, antibody-mediated. Brasch and Caldwell [4] did find significantly more antibodylike activity (globulin binding of diatrizoate) in the sera of patients after severe reactions, compared with controls, but acknowledged that there was no proof that this had anything to do with the production of symptoms. Among other things, the occurrence of acute reactions in patients with no prior exposure and the development of a reaction
,
native
1979
one
occasion
but
not
the
next
in the
same
pathway
(bypassing
the
first
three
reacting
com-
ponents, Cl C4, and C2) according to some reports, while others have implicated both the classical (Cl activation) and alternative pathways [6]. As with histamine release, though, complement activation is insufficient to explain clinical reactions, for it also seems to occur to the same degree in patients who don’t react as in those who do [5]. It is possible that contrast agents affect complement indirectly, via Hageman factor (factor Xli) activation. If this is so, then such activation may be important in other ways. In this issue of the Journal is a report by Lasser et al. on the effect of intravenous meglumine iodipamide on blood coagulation in rabbits. They observed a reduction in factor XII levels and evidence for activation of the intrinsic and even the extrinsic coagulation systems. They again observed the reduction in complement activity that they had reported earlier. Mortality was not changed by prior depletion of the later reacting components of complement by cobra venom. This is not sun,
.
February
on
patient argue against allergic sensitization being responsible for these reactions. There are reasonable alternative explanations. Several drugs, including the opiates, release histamine from mast cells without antibody mediation in a predictable, dose-related fashion [l]-so do contrast agents, both in vitro and in vivo. However, a problem with the histamine release concept as an explanation for clinical reactions is that the plasma histamine has been found to increase just as much after injection of the contrast medium in patients who did not have a reaction as in those who did [5]. Contrast agents also activate complement via the alter-
,
AJR:132,
Reactions
pnising;
if
complement
activation
had
contributed
to
mortality, then cobra venom administration itself should produce more serious reactions than it does. The most significant observations were that mortality could be greatly reduced by either fibninogen depletion or hepanin treatment. This may have a clinical counterpart; a few human cases of disseminated intravascular coagulation have been recognized after injection of a contrast agent. 309
EDITORIAL
Downloaded from www.ajronline.org by Univ Of Connecticut Hlth Ctr on 10/16/15 from IP address 137.99.89.199. Copyright ARRS. For personal use only; all rights reserved
310
Since the effect on the clotting mechanism appears to be universal in rabbits, could it also be a common and predictable finding in man? The answer seems to be ‘yes.’ In the same study in which histamine and complement levels were compared, fibninogen split products were found in the serum of almost half of the patients after a contrast study. Again, there was no difference between those who had reactions and those who did not [5]. Obviously the answers are not all in. The kinin generating system that is triggered by factor XII activation certainly deserves more consideration. The chemical actions of contrast media do seem to affect all patients more or less equally. Rather than reacting to excessive mediator activation, those who experience allergylike (anaphylactoid) reactions may have an unusual degree of reactivity to a usually innocuous level of one or more mediators. This could be tested. Lasser et al. have raised another interesting possibility in their paper. They suggested that those who have clinical reactions are deficient in some inhibitor, and they have taken the logical step of looking at the Cl esterase inhibitor. However, it should be kept in mind that subjects who have a proven deficiency of this inhibitor suffer only from edema, so such a suggestion might not be adequate to explain the ‘
AJR:132,
urticanial, actions
bronchospastic, to iodinated
and
contrast
other
‘
1979
anaphylactoid
re-
media.
Paul University
February
of Washington
P. VanArsdel,
School
Seattle,
Jr.
of Medicine
Washington
98195
REFERENCES PP Jr: Adverse drug reactions, in Allergy Principies and Practice, vol 2, chapter 61 edited by Middleton E Jr, Reed CE, Ellis EF, St. Louis, Mosby, 1978 2. Wells JV: Immune mechanisms in tissue damage, in Basic and Clinical Immunology, 2d ed, chapter 23, edited by Fudenberg HH, Stites OP, CaIdwell JL, Wells JV, Los Altos, 1.
VanArsdel
,
Calif., 3. Witten
Lange, 1978 DM: Reactions
231 :974-977, 1975 4. Brasch AC, CaIdwell
to urographic
JL: The allergic
contrast
theory
media.
JAMA
of radiocontrast
agent toxicity: demonstration of antibody activity in sera of patients suffering major radiocontrast agent reactions. Invest Radiol 1 1 : 347-356, 1976 5. Simon RA, Schatz M, Stevenson 00, Curry N, Yamamoto F,
Plow E, Ring H, Arroyave
CM: Radiographic
contrast
media
infusions: measurement of mediators and correlation with clinical parameters. J Allergy Clin Immunol 61 : 145, 1978 6. Lieberman P, Siegle AL, Taylor WW Jr: Anaphylactoid reactions to iodinated contrast material. J Allergy Clin Immunol 62:174-180, 1978
