PASSIVE IMMUNIZATION

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PASSIVE

IMMUNIZATION

Geoffrey Edsall, M.D.

From the Institute of Laboratories Massachusetts Department of Public Health, Department of Applied Microbiology Harvard School of Public Health, and Commission on Immunization

Armed Forces Epklemiological Board

(Accepted for publication May 15, 1963.)

Based upon a talk presented at the 1962 Annual Meeting of American Academy of Pediatrics, Chicago,

illinois, October 31, 1962.

See also the Review Article entitled, “Active Immunization: Current Considerations,” by Dr.

Mar-garet H. D. Smith, Pznwnucs, 32:444, 1963.

ADDRESS: (G.E.) 375 South Street, Jamaica Plain, Massachusetts.

PEDIATRICS, October 1963

REVIEW

ARTICLE

599

P

ASS1VE IMMUNIZATION has existed for

over 70 years, ever since Von Behring and Kitasato demonstrated its effectiveness in neutralizing diphtheria toxin. In fact, at first glance one might think that there was

little new to say on this subject. However, the very fact that its concepts and practices have been so long accepted and-in the minds of many-have fallen into the pat-tern of purely routine procedures, is in it-self sufficient justification to re-examine the subject. In addition, moreover, there have been a number of changes in the range of diseases for which passive immunization

may be employed, the type of antiserum used, and the guiding principles for use of such preparations. Therefore, it may be

timely to deal with some of the present con-siderations that apply to passive immuniza-tion, its prospects, its scope, and its

limita-tions.

At the risk of repeating old and familiar cliches it appears desirable to summarize, at first, the guiding principles which apply to the effectiveness (or ineffectiveness) of pas-sive immunization. First of all, it is well established that some techniques of passive

immunization are highly effective-e.g., diphtheria prophylaxis with antitoxin; some are very useful but fall short of the ideal of routine success with the purpose in-tended-e.g., the use of gamma-globulin for

the modffication of measles; whereas others are of relatively uncertain value so that their usefulness in medical practice still continues to be debated-e.g., gas gangrene antitoxin.

The reasons for such great disparity in the efficacy of different antisera cannot easily be put into generalizations, but surely the varied pathogenesis of the diseases in ques-tion must be a major factor, as well as the fact that high antibody titers can readily be obtained for some such sera, whereas they are difficult or impossible to achieve with

others.

Secondly, the major feature of passive im-munization is its immediacy of action. Its

use as a rule is in a medical sense an emer-gency measure, of value either when it is too late to achieve active immunization, or where active immunization is not practical.

It

is well to bear in mind that in most instances, passive immunization is employed after exposure has occurred, and hence pre-sumably after infection has begun. (An out-standing exception is the use of gamma-globulin for the prevention of hepatitis in travelers.) It is well to bear in mind the limits of the “immediacy of action” of pas-sive immunization. In those rare instances where a serum is given intravenously, virtually immediate action can be taken for granted. However, in most instances, the route of administration is intramuscular, and by this route significant protective titers may not be achieved for several hours, and peak titers may in many instances not be reached for about 2 days (Fig. 1).

Third, the inexorable laws of metabolism guarantee that passive immunization is a relatively transient phenomenon. The half

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INTCRVAL AFTER INJECTION

w

a

0

0 so S

Heterologous

(BGG)

Homologous

(RGG)

Do,, S

600

PASSIVE

IMMUNIZATION

Fic. 1. Titers of circulating mouse-protective

antibody after intramuscular injection of 30,000

units of pneuinococcal type I antibody. Open and solid circles represent horse and rabbit serum recipients, respectively. (From Finland and Brown,

J. Immunol., 35:245,

1938.)

may vary from about 30 days, in the case of human gamma-globulin, to as little as perhaps one day or less in the case of horse serum administered to an individual already immunologically sensitized to horse pro-teins. Thus the duration of the protection gained will vary enormously with the

cir-cumstances of its application. Moreover the use of passive immunization in itself leaves unsolved the ultimate question of the

long-term protection of the patient against the disease in question. Sometimes, as in the

case of modified measles, natural infection

intervenes as passive immunization wanes,

thus establishing long-term immunity. In

other instances-e.g., tetanus-simultaneous active and passive immunization may be employed, with somewhat variable results. In the remaining situations, status quo is generally re-established after the serum has

been eliminated from the recipient.

Fourth, the use of heterologous (e.g., horse or rabbit) serums for passive prophy-laxis arouses the immunological defenses of the recipient-as noted above-so that

the serum may not only be eliminated more rapidly, but the undesirable reactions and

complications of serum sickness may also ensue. The pattern of elimination of a for-eign serum after injection into a host may in a general sense, be described as three-fold (Fig. 2). Although Figure 2 applies to

studies in rabbits, the same basic principles apply to man. First there is the period of

redistribution of the soluble protein into the body tissues (a phenomenon which applies to all injected serums, whether homologous or heterologous) which results in a notice-ably rapid drop in the peak titer if the

prep-aration has been introduced intravenously.

Following this there is a slower but steady drop

in

titer due to metabolism of the sub-stance injected. Third, in the case of foreign serums, the rate of disappearance is ac-celerated, beginning usually at about 7 to 10 days after injection of the foreign serum, at the time that antibodies against the serum appear in the circulation. For ob-vious reasons, the rate of accelerated elfin-ination of the serum in this third phase, as well as the time of its onset, will vary greatly in different individuals, starting ear-her in those subjects that have already been immunologically sensitized (knowingly or by some unknown mechanism) to the

for-0

a w

a

g

1

S I V S #{149} SO II

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TABLE II

MINOR, SPECIAL, OR UNPROVED Usra OF

PassIvE IMMUNIZATION

eign proteins in question. Hence the

re-curring dilemma concerning the dose and

schedule of tetanus antitoxin to be used in unimmunized individuals exposed to the risk of tetanus infection.

In view of the uncertanty of the action of heterologous serums, and the risk of rare but extremely serious serum reactions such as peripheral neuritis, anaphylactic shock, focal encephalitis, etc.,13

it

is natural that there has been a steady shift, during the past 15 years, towards the substitution of

human for animal serums in passive fin-munization, wherever this is practical.

Therefore, when one considers present day practices in passive immunization, one has to include not only a wide range of degrees of efficacy and applicability in the use of this procedure, but in some cases a choice of two or more different preparations to be used for the purpose. The following

dis-cussion will deal with the major uses of passive immunization, in the light of the above comments, and will include brief notes on some of the minor, specialized or debated uses of this general procedure. The reader will also find useful summaries,

es-pecially as regards human immune globulin

(“gamma-globulin”), in some recent

re-45

Little will be said in this paper regarding unprocessed convalescent serums, for there

are only a few instances (e.g., pertussis) where they warrant specffic consideration, and they always carry the risk of

trans-miffing serum hepatitis, a risk which does not arise with gamma globulin.6

The generally accepted, well-established uses of passive immunization are

sum-marized alphabetically in Table I. Other uses, which may or may not be widely

ac-TABLE I

ESTABLISHED Usra OF Pssivt IMMUNIZATION

Botulism Pertussis

Diphtheria Rabies

Infectious hepatitis Rubella

Measles Tetanus

Vaccinia

Burn “toxemia” Recurrent respiratory infectious

Gas gangrene Staphylococcus infections

Influenza Serum hepatitis

Malaria Smallpox

Mumps Varicella

Poliomyeitis Miscellaneous bacterial infections

cepted but which are either still experi-mental, or for which clear-cut evidence of their effectiveness has not been obtained, are listed in Table II. No two individuals,

of course, are likely to agree completely on the composition of these Tables. However, the reasons for placing certain of the border line of debatable entities in the respective tables will be discussed below.

BOTULISM

Despite the paucity of evidence that bo-tulinus antitoxin is effective in preventing or curing botulism, it is nevertheless ac-cepted that when exposure to this terrify-ing and highly fatal disease is recognized, antitoxin prophylaxis is imperative. It should be borne in mind that in most instances botulinus antitoxin is actually used as a therapeutic agent, in individuals who

al-ready present clinical signs of the disease. However, it is extremely important to re-member that more lives are likely to be saved by administration of prophylactic

an-titoxin to other exposed individuals who

have not yet manifested symptoms, than by heroic antitoxin therapy of established clinical cases. The usual prophylactic dose of botulinus antitoxin is 2-10,000 units each of types A and B antitoxin. There is good reason to advise that it be given intraven-ously- with all the indicated precautions-in order to check as rapidly as possible the relenfless progress of the absorption of toxin to the susceptible cells. Other than this, the most important point to bear in mind about

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in an emergency the delays in its

procure-ment could be serious.

DIPHTHERIA

As mentioned earlier, diphtheria antitoxin

is the original, earliest passive immuniza-tion reagent. Nowadays, an indication for its use is generally a sign of failure, somewhere along the line, of the public health and medical program of the community. How-ever, occasions still arise now and then when an unimmunized child has been ex-posed to diphtheria and cannot be kept un-der adequate surveillance to watch for the possible development of the disease. In

such cases, prophylactic antitoxin is the only reliable means of preventing diphtheria and its damaging effects. Although most authori-ties have for many years recommended the use of 1,000 units of antitoxin in such a sit-uation, the American Academy of Pediatrics “Red Book”7 recommends the

administra-tion of

10,000

units. The reason for this

rec-ommendation, not clearly stated in the “Red Book,” is that in cases where the lack of adequate medical surveillance renders the administration of antitoxin necessary, it

must be assumed that the risk of diphtheria may persist for a longer period than would be covered by the traditional small dose of antitoxin.

INFECTIOUS

HEPATITIS

The classic observations of Stokes et al.,8

Hsia et al. and Drake and Ming1#{176}estab-lished the apparent very high efficacy of human gamma-globulin in the prevention of infectious hepatitis, mostly in children,

after clear-cut exposure. Indeed these studies indicated that as little as 0.01 ml per pound of gamma-globulin was suffi-cient to give at least 90% protection in such groups. The more recently reported

disap-pointing results of Krugman et al.h1 ydth such small doses have reopened the ques-tion of what is an adequate dose of gamma-globulin for this purpose. A recent review of the problem by Krugman and Ward’2 sets forth the major considerations in a manner that invites little disagreement. They

ad-vocate a minimal dose of 0.02 ml per pound for individuals subjected to intimate but short-term family or institutional exposure to infectious hepatitis. They believe that the evidence for the efficacy of such a dose in adults is less clear than it is for children. For patients exposed to serious risk (e.g.,

pregnant or postmenopausal females, or

those with already existing liver disease) their recommended dose is 0.06 ml per

pound. Their classic Wilowbrook studies indicate that this larger dose will provide an effective umbrella against clinical hepa-titis for approximately 6 months. During this period, if exposure is more or less con-tinuous, most such individuals will experi-ence subclinical infection and will presum-ably develop immunity thereafter, in a

manner somewhat parallel to the principle involved in modffied measles.

As a working rule of thumb,

it

has been rather widely agreed that the dose for travellers going to endemic areas may be

adjusted on the basis of 0.01 ml per pound per month of travel, up to a maximum of 0.06 ml per pound. If travel or residence in an endemic area is prolonged past 6 months,

a second dose of 0.06 ml per pound is recom-mended. Limited experience to date with certain groups handled this way has shown that this schedule of two large doses 6 months apart will apparently reduce very

strikingly the incidence of infectious hepa-titis in Americans living overseas.

Since gamma-globulin became known as an effective prophylactic for infectious

hep-atitis, there has been an increasing tendency to administer it indiscriminately to every-body who might possibly have been

ex-posed, following every conceivable expos-ure. Such extravagant use of

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in any given situation. Moreover, it is es-pecially important not to give excessive doses in cases of isolated single exposures, since over-dosage with gamma-globulin is probably a highly effective way to prevent the acquisition of long-term immunity

through combined passive immunization and infection, mentioned above. In this

connection, this writer believes that the

long-established dose of 0.01 ml per pound is adequate for short-term exposure, pro-vided the gamma-globulin employed has

been prepared by the Cohn alcohol

frac-tionation method, which yields a highly

stable product that retains its potency for a long period of time. A larger dose may be justified when

it

is not possible to estab-lish that the gamma-globulin at hand has

been made by this method.

MEASLES

Passive immunization to prevent or modify measles goes back many years, from the first use of convalescent serum for this purpose, up through the pioneer studies of

McKhann with “placental extract,”13 to

the era of the past 20 years during which the gamma-globulin found in serum or placental extract has been further purified, better standardized for potency, and ren-dered free of side reactions through the precise techniques developed by Cohn and his associates.14 Indeed it is through its use in the control of measles that “gamma-globulin” (officially known now as immune serum globulin, but in this form shortly

to be re-designated) has been universally established and accepted in medical prac-tice. It is generally recommended for use in prevention of measles in children under

3 years of age, and in susceptible older chil-dren or adults with complications such as pregnancy, tuberculosis, or other serious

infections, recent surgery or chronic illness. The administration of a large dose-0.1 ml

per pound up to a maximum of 15 ml-within 6 days of known exposure is mdi-cated in such cases, since the occurrence of

measles in such patients can be serious. In other individuals, lacking a history of

pre-vious measles, the disease may in most cases be modified by administering 0.02 ml per pound of body weight. The milder,

modified form of the disease with its longer incubation period and virtual lack of com-plications will be achieved with this dose in approximately two-thirds of the patients so handled, provided it is administered during the first 6 days after exposure. Perhaps 10% of such patients will develop full-blown measles regardless of the injection of gamma-globulin, and about 25% will con-tract no recognizable disease.14 This is far from a perfect score, but with present knowledge it is about the best that can be accomplished. However, with the imminent widespread use of measles vaccine, the occasions for passive prophylaxis or modifi-cation of measles will rapidly diminish in areas where measles vaccination becomes a general practice. Indeed

it

is to be hoped that the need for modffication of measles, in such areas, will virtually disappear.

Nevertheless, the occasional urgent need for complete prevention will continue to

arise.

PERTUSSIS

The prophylaxis of pertussis in young children and infants, and especially in in-fants under 6 months of age, can be a life-saving procedure. For this purpose three agents are available and the choice of

pref-erence is not a matter of general agreement.

Antipertussis serum prepared in rabbits has been used for a good many years, with re-ports of reasonably good success. Human hyperimmune serum is widely available and has the advantage of being homol-ogous so that it produces neither side re-actions nor accelerated elimination. Fur-thermore, in an emergency it can be

ad-ministered intravenously.

Third, a hyperimmune gamma-globulin

preparation has been on the market for several years and has the advantages of a

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PASSIVE

IMMUNIZATION

possible safely to administer gamma-globu-lin intravenously, since the incidence of rather alarming side reactions is signifi-cant when gamma-globulin is given by this route. Furthermore, the evidence for the

effectiveness of hyperimmune gamma-glob-ulin is not as solid as one would like.15 Therefore, although this writer’s preference would be for hyperimmune antipertussis gamma-globulin, there is still considerable divergence of views on this point, and each of the three preparations has been chosen as the agent of preference by experienced pediatricians. However, the problem of the prophylaxis of pertussis in young infants should, like diphtheria prophylaxis, become nonexistent in a well ordered community with a sound public health and medical program. The best protection an infant can have is to have vaccinated older siblings,

and no amount of emergency prophylaxis can take the place of a sound universal

per-tussis vaccination program.

RABIES

The use of rabies antiserum as an adju-vant to the post-exposure prophylaxis of this dreaded disease has come widely into favor during the past 6 to 8 years. The best guidance on this subject has been provided by the expert committee on rabies of the World Health Organization, whose fourth report in 1960 summarized the indications for the use of serum in conjunction with rabies vaccine.10 Since experience with this problem is constantly accumulating, van-ous changes have been made in the latest recommendations, and reference to prey-ous editions or reports of this committee is no longer acceptable. Antirabies serum should be given as early as possible after exposure to individuals who have suffered multiple bites, bites around the face, head, neck, and fingers or bites of wild animals under circumstances calling for rabies pro-phylaxis. The dose is 1,000 units per 40 lb, up to a maximum of 6,000 units. Where feasible, some of the serum should be in-filtrated around the bite. Whenever rabies serum has been given, and the risk of rabies

not subsequently excluded, it is imperative that a full-course of at least 14 doses of rabies vaccine be administered; less vaccine than this will be blanketed by the serum and will not immunize effectively. In addi-tion, it is now recommended that two sub-sequent doses of vaccine, preferably de-rived from non-nervous tissue, be

adminis-tered 10 and 20 days after completion of the regular course. Naturally, the above

recommendations may be modified in the light of special circumstances. It should be borne in mind that antirabies serum, like

other immune serums, is not an infallible panacea, but that all the available evidence indicates that when properly used it greatly

reduces the risk of contracting rabies.

RUBELLA

The incidence and the seriousness of con-genital malformations occurring in infants whose mothers contracted rubella during

the first trimester of pregnancy have been sufficiently great so that some clinicians have advocated routine abortion in preg-nant mothers who developed rubella

dur-ing this period. In the past several years there have been at least two studies which have supported the belief that large doses of normal adult gamma-globulin greatly re-duced the incidence of rubella if given

early in the incubation 718 The

Massachusetts Department of Public Health recommends the administration of

20 ml of immune serum globulin as

promptly as possible to women in the first trimester of pregnancy who have been ex-posed to rubella and have not previously been known to have the disease. However, until a method for titrating the antibody level of gamma-globulin against rubella

virus is developed to enable standardiza-lion of each preparation to a uniform level

of potency, some degree of variation in the results achieved must be expected. An

ap-proach to obtaining a better and more standardized preparation may be the use of convalescent gamma-globulin, if such

material could be obtained in sufficient

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TETANUS

A multitude of controversies continues to revolve about the subject of passive pro-phylaxis of tetanus. Although tetanus anti-toxin prepared in horses is as old as diph-theria antitoxin, argument concerning its effectiveness in prophylaxis of this disease has not abated. Data supporting the belief that it is effective were mostly assembled in the first 25 or 30 years of its use. Several recent studies in animals have suggested that it is not very effective in prevention of

experimental tetanus. At the same time, re-cent studies in man have confirmed and ex-tended the old observation that many in-dividuals eliminate tetanus antitoxin (or any other horse serum preparation) very rapidly, so that whatever protection may have been established at the time of the peak titer after injection is rapidly lost through immunological clearance.19 Thus

some advocate the use of extremely large doses of antitoxin (e.g.,

10,000

units) in all individuals with tetanus-prone injuries who lack a reliable history of previous

immuni-zation. Others advocate repeated small doses at 3 to 7 day intervals, if the risk of

tetanus infection is considered to be con-tinuing.2#{176} On the other hand, since tetanus antitoxin is probably the most widely used foreign serum protein injected into man,

the incidence of serious complications fol-lowing its injection is high enough and is widely publicized to have caused an in-creasing degree of alarm over its use. Hence, there are those who recommend the avoidance of any tetanus antitoxin at all ex-cept in instances where the likelihood of contamination of the injury with anerobic pathogens is overwhelming, reliance being placed on antibiotic prophylaxis, on de-bridement, and on active immunization with tetanus toxoid.21

Some of the above problems can presum-ably be side-stepped by the use of a tetanus hyperimmune gamma-globulin of human

origin, now on the market in limited

quanti-ties. Several studies2224have shown that hu-man antitoxin persists in the circulation fol-lowing its administration, for a longer time

and at a much more slowly falling level than is the case with equine antitoxin. Be-ing homologous in origin, the human

ma-terial of course does not arouse the im-munological clearance mechanism that

oc-curs in man after horse serum is injected. Therefore, it would appear in theory to be the ideal agent for passive tetanus prophy-laxis. However, the proper dose for such prophylaxis has not yet been established, except by analogy (current thinking favors 500 units or less for routine prophylaxis), and its effectiveness in the prevention of tetanus in man has not been established and conceivably never will be. Also the supply of this preparation is extremely lim-ited. Nevertheless, all available laboratory data indicate that it is the agent of choice, and it is very much to be hoped that the supply can be augmented through

commer-cial or public efforts, so that this prepara-tion can eventually replace equine antitoxin for those who need passive prophylaxis. Once again, it should be emphasized and reiterated that the necessity for using

anti-toxin for tetanus prophylaxis represents a failure in community or private medical practice, since universal tetanus toxoid im-munization is the most reliable way to pre-vent tetanus.

VACCINIA

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606

PASSIVE

IMMUNIZATION

been inadvertently exposed to vaccinated

siblings, in infants who have been vacci-nated just before the occurrence of serious burns or other damage to large areas of skin, and in infants with eczema who are required to have smallpox vaccination prior to overseas travel. Large doses of VIG (0.06 to 1.2 mI/kg) are reported to have

pro-tected all such children from virus spread. In the Netherlands, where postvaccinal en-cephalitis has been a major complication of smallpox vaccination, especially in young adults, the Dutch army has recently com-pleted a study showing that the injection of 2 ml of VIG simultaneously with pri-mary vaccination has reduced the incidence of this serious complication about 75%#{149}26It

should be emphasized that these findings do not provide an indication for the use of

VIG

in American adults being vaccinated for the first time; postvaccinal encephalitis is-for unknown reasons-so rare in the

United States that it has virtually no bear-ing on routine smallpox vaccination policy

in this country.

When it appears that VIG is needed for

a specific patient, information concerning its procurement can be obtained from the

local Red Cross Chapter.

SPECIAL, UNPROVED, OR MINOR

INDICA-lIONS FOR PASSIVE IMMUNIZATION

In addition to the above uses, for which passive prophylaxis is generally very well founded, the possibilities listed in Table II deserve brief mention. Two that have been widely accepted in the past but are now

considered of relatively little importance are gas-gangrene antitoxin (equine in

on-gin) and human poliomyelitis immune glob-ulin. Although gas-gangrene antitoxin has been extremely widely used, it is almost

im-possible to find reliable evidence for its

efficacy.2? Many surgeons now consider that

the complications that may result from the administration of horse serum over-balance its doubtful clinical value, so that its use has greatly diminished. Poliomyelitis im-mune globulin, although shown to have

some definite value in reducing the

inci-dence of poliomyelitis if given in very large doses within about 5 days after recognition of the index case,28 is of little practical value at present. The determination of the time of actual exposure of the patients under

consideration, the transient nature of the protection, the very large dose required, and the universal availability of active vac-cination all contribute-nowadays-to the

vanishing importance of this product in the present scene.

A more complicated question concerns the usefulness of gamma-globulin in the prevention of serum hepatitis. Recent stud-ies suggest29 that two successive very large doses of gamma-globulin given to patients receiving multiple transfusions will cut down the incidence of post-transfusion

hep-atitis by perhaps 70 to 75%. However, it is not yet entirely clear how much of the hep-atitis actually prevented was truly “serum

hepatitis”; it is not yet clear why so little

post-transfusion hepatitis occurs, for

exam-pie, following exceedingly large numbers of transfusions, e.g., in cardiac surgery; and it is not yet known whether the dose used by the investigators cited above was

un-necessarily large or would be subject to other modifications. Finally, if the findings mentioned were put into practice, the sup-ply of gamma-globulin would be utterly

and completely inadequate to meet the de-mand. Therefore, it is recommended that

any use of gamma-globulin for this pur-pose be limited, at the present time, to par-ticulanly high risk individuals, especially

those 40 years of age or older. The pun-chase of gamma-globulin for such prophy-laxis will be an expensive item, since public health departments do not under any

or-dinary circumstances furnish it for this pun-pose, the supply being far too limited.

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1. Tyler, L. T., Kaplan, I. W., and Levy, R. W.:

Brachial plexus paralysis following

aciminis-for the prevention or modification of

van-cella would be totally unjustified at present. However, the serious complications of van-cella can be lethal in some individuals, par-ticularly those on steroid therapy.

There-fore the use of gamma-globulin for prophy-laxis of this disease in such patients is fully

warranted. In this connection, it is not sun-prising that beneficial results in the treat-ment of herpes zoster with gamma-globulin have also been reponted.hl

A

miscellaneous group of diseases or dis-ease categories is still under investigation as regards the usefulness of normal or hy-perimmune gamma-globulin for their con-trol. The toxemia and infection following burns have reportedly been mitigated by the administration of convalescent serum.32 Yet here, as in other instances mentioned in this section, the data ane not sufficient to warrant the use of this procedure in clini-cal practice. Numerous studies have been carried out on the use of gamma-globulin for the reduction or prevention of persistent or chronic respiratory infections, particu-laxly in small children.’3” The findings in this field appear to be in marked conflict at present. However, studies currently under way may provide a basis for defining the circumstances-if any-under which gamma globulin may be of real value in this field.

Much the same may be said for staphylo-coccus and other bacterial infections, cer-tam of which have long been attacked

(

rather unsuccessfully) with antitoxin, and which are now being approached by the use of human gamma-globulin, with as yet indifferent evidence of success. Finally, of

interest in certain parts of the world but

not important in the United States, is the recent finding36 that malaria in infants can be prevented by the administration of

gamma-globulin derived from adults raised in a highly malarious area.

Attempts to control or prevent influenza by the use of horse antiserum prepared as a dry powder and sprayed into the upper

res-piratory tract have been carried out by

several Soviet investigators. The hazard of

using horse serum in this manner, and the rather unimpressive results obtained, mill-tate against the likelihood that it would be of further interest.

Although one studyT (using gamma-globulin from convalescents) showed a marked reduction in the incidence of corn-plications of mumps, no clear-cut data have

emerged, to-date, to indicate the value of mumps immune globulin. Therefore, al-though this preparation is widely used, it must still be held in the “unproved” list for the present. A soundly designed, controlled study of its effectiveness is badly needed. It is of interest that the prevention of small-pox, unlike vanicella, can be readily achieved by the use of vaccinia immune globulin.38 As with malaria, this problem is not likely to arise in the United States, but it may be of some importance to mdi-viduals living overseas who have young infants exposed to the disease.

In conclusion, it is quite apparent that new uses for passive immunization are ap-peaing more rapidly than the olden ones are being discontinued. The development of human hypenimmune gamma-globulin is perhaps the most promising area for the future, and the use of plasmapheresis, as a means of greatly extending the amount of hyperimmune plasma available for this

purpose from human donors, may help in the transformation of this formerly limited procedure to a scale large enough to be of general value. Perhaps the most useful thing that all physicians can do, aside from the wise and judicious practice of passive immunization, is to lend their support to any and all efforts to develop extended sources of human normal or hypenimmune gamma-globulin, so that it may be possible not only to develop these preparations where their use is indicated, but to create supplies that will be adequate to meet the inevitably growing need.

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608 PASSIVE IMMUNIZATION

tration of tetanus antitoxin. Amer. J. Surg.,

95: 668, 1958.

2. Buff, H. B. : Fatal anaphylactic shock

follow-ing intradermal sldn test with dilute horse

serum tetanus antitoxin.

J.

A. M. A., 174:

1200, 1960.

3. Poser, C. M. : Focal encephalopathy after

ad-ministration of tetanus antitoxin. J. A. M. A.,

164:871, 1957.

4.

Gross, P. M., Gitlin, D., and Janeway, C. A.:

the gamma-globulins and their clinical

significance: IV. Therapeutic uses of

gamma-globulins. New EngI.

J.

Med., 260:170,

1959.

5. Levy, A. H. : The uses of gamma-globulins

in the prophylaxis of infection.

J.

Chron. Dis., 15:589, 1962.

6. Murray, R., and Ratner, F. : Safety of immune

serum globulin with respect to homologous serum hepatitis. Proc. Soc. Exp. Biol. Med.,

83:554, 1953.

7. Committee on the Control of Infectious

Dis-eases; Report of the Committee (“Red Book”). Evanston, Illinois; American

Acad-emy of Pediatrics, 1961.

8. Stokes, J., Jr. et al.: Infectious hepatitis:

length of protection by immune serum globulin (gamma globulin) during

epi-demics. J. A. M. A., 147:714, 1951.

9. Hsia, D. Y-Y., Lonsway, M., Jr., and Gellis,

S. S.: Gamma-globulin in prevention of infectious hepatitis : studies on uses of

small doses in family outbreaks. New Engl.

J. Med., 250:417, 1954.

10. Drake, M. E., and Ming, C.: Gamma-globulin

in epidemic hepatitis : comparative value

of two dosage levels, apparently near the minimal effective level. J. A. M. A., 155:

1302, 1954.

1 1. Krugman, S., et al.: Infectious hepatitis:

studies on the effect of gamma-globulin

and on the incidence of inapparent

infec-tion. J. A. M. A. 174:823, 1960.

12. Krugman, S., and Ward, R.: Infectious

hepa-titis : current status of prevention with

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1963;32;599

Pediatrics

Geoffrey Edsall