Immune Serum in the Prophylaxis and Treatment of Virus Diseases

IMMUNE SERUM IN THE PROPHYLAXIS AND TREATMENT OF VIRUS DISEASES

SIDNEY O. LEVIN SON, M.D."" AND HOWARD J. SHAUGHNESSY, PH.D·t INTRODUCTION

PERIODIC critical examination of even well established concepts contributes to medical progress. Such re-evaluation is particularly justified in those fields under intensive study. Virus diseases have attracted increasing scientific attention, and many contributions have appeared in recent years which help materially to a better understanding of the nature of virus diseases. Since the physician is concerned with prevention and treatment of disease, it may be opportune to review specific serum prophylaxis and treatment of virus diseases in the light of our present knowledge and experience.:j: Viruses. (and rick~!!skt)__~!.ff~!:_K~~~~~ent~~~Lf~!!!J:2.:l:S~Ei~1!!..tbgt they are mtracellula~..Er_a~lJ~s, ThIS property has long been thought fiiIi1a"ketl1eTrifectlOus agent immune to therapeutic measures. In practically all other respects, however, virus infections and immunity to virus infections are comparable to bacterial infections and immunity. As Rivers! says, "There is nothing peculiar about immunity in virus diseases. Principles that hold in other fields operate also in the virus domain." A brief reconstruction of the probable behavior of the virus in the susceptible host may throw more light on what may be expected from specific treatment. The infectious agent enters the body through one or more portals of entry, usually the nasopharynx, intestinal tract or skin, and invades the body cells. Multiplication of virus in these body cells takes place. The virus, after a period of time, escapes from these cells and is transmitted through one or more pathways to other cells of the body. From the Samuel Deutsch Serum Center, Michael Reese Institute of Research, Chicago, and the Division of Laboratories, Illinois Department of Public Health. "Clinical Assistant Professor of Pediatrics, College of Medicine, University of Illinois; Director, Samuel Deutsch Serum Center, Michael Reese Hospital. t Chief, Division of Laboratories, lllinois Department of Public Health; Associate.Professor of Bacteriology and Public Health, College of Medicine, University of Illinois. :j: Joseph Stokes, Jr., proposes, with good reason, that the term "treatment" be applied to the use of immune bodies after exposure to infection, and "prophylaxis" only before exposure takes place. In this paper, however, the terms will be employed in the orthodox manner, that is, "prophylaxis" applies to treatment during the incubation period before the acute disease, and "therapy" is used after the active disease develops. 61

62

SIDNEY O. LEVINSON, HOWARD

J.

SHAUGHNESSY

The virus may invade adjacent cells, it may invade the blood and lymph stream, or it may extend along nerve fibers or by other means. The method of spread probably varies considerably in different infections and may play an important part in determining the efficacy of any specific therapy. Such continued spread and multiplication must be progressive until the infection reaches the maximum extent of cellular invasion. The infectious agent also leaves the cells and, in most diseases, is eliminated from the body through one or more portals of exit, such as the upper respiratory tract, the gastrointestinal tract, or the skin. There are certain salient facts which must be' reviewed briefly in order that specific prophylaxis or treatment can be judiciously considered. 1. Vjrus iIlfec:tions are followed by a variabl~_amount of antiviral substance in the . blood str~a_m. Therefore, convalescent serums Illay ~~ri5.ia~raoliin j)o-tency. - _.2. For a s~rum to be _.eff~£~iy~, itJDllst beJiciljpxiJ:al antibodies. 3. Immune serum can, I.leutralize ex.tr~cdlular yj.cusjn transit and at the sitc:~!..£ar~~t1zed ce!ls jn the bgdy. 4.1inm.un~rum surrounding susc;eptii:>J.eGells will probably pre. vent in(~cti.~n._9Ttl:1~~~c~lIs~E."Tius: 5. Il! some diseases, if the virus has invaded cells, the presence. of immune· serum subsequently·· will notpreyent the growth and. multip1icatlon 6r the virus in the cell. Therefore, the cardinal principles that should govern efforts to treat virus infections are: (1) t1;u:..llSfLQf se.r..llITl..Iich in immune bodies, (2) treatme~L!l!!i~it.llt~d e~rly in the illness before there is extensive celUnvl!~jQI1 J?y yir l1s. and (3) 1~r.K(! repe.ated .doses administered by a ro~hich will bring the immune bodies rapidly in contact with the tissue celIs-:'··· . .. .. Clinical and experimental investigation on the use of serum for virus infections is remarkably limited and tht:;,Jesults haye generally ~en can~<:
o

MEASLES

Prophylaxis.-The literature on the value of measles serum in prophylaxis is very large. First reported by Weisbecker2 in 1894, the value

63

IMMUNE SERUM IN VIRUS DISEASES

of convalescent serum is now well established. There is reason to believe that the measles convalescent serum must be rich in antibodies, because small doses are effective. This is confirmed in a recent publication by G. A. Orlov3 who reports success in titrating immune serum by complement-fixation test against virus antigen obtained by oral washings from patients and emulsions of infected mouse lungs. Furthermore, this titration bears out the clinical experience that measles convalescent serum is much more potent than normal adult serum, fQr the author found convalescent serum to be approximately twenty

seWmJiQiU-adrili:s-.--- ---. - ..---

ti~oreacavetliaii

Measle;-~e~~~' prophylaxis demonstrates very nicely the time relationship of serum administration and the effect on the disease, or the TABLE I.-MEASLES CONVALESCENT SERUM PROPHYLAXIS, SHOWING RESULT IN RELATION TO TIME OF ADMINISTRATION I

Days Exposed Number before of Serum Cases Administration

1 2 3 4 5 6 7 8 9

and over Total

No Measles

Outcome Modified Measles

Typical Measles

Number Per Cent Number Per Cent Number Per Cent

166 268 345 427 408 230 151 51 50

130 197 235 246 213 105 65 16 7

-1,214

_ _"If:,

2,096 '

78 73 68 58 52 46 43 31 14

31 58 97 169 161 117 79 28 18

19 22 28 39 39.5 51 52 55 36

5 13 13 12 34 8 7 7 25

3 5 4 3 8.5 3 5 14 50

58

758

-36

124

--

--

6

-

serum inhibiting effect on the virus in the host. If the amount of serum is held constant, it will usually cause complete protection when given in the first four days of the incubation period, cause a seroa~edm.~;l§les if given between__g~eJo~E!h~I?-~eighth,-qays .ofthe ig.cubation period, but wIll be valueless thereafter. On the other hancrif -the-dose of serum is increased as the incubation period progresses, the disease can still be prevented, even when serum is given late in the incubation period. Although accurate comparative studies are not available, a study of the published results indicates that convalesc;.ent meask.~l!1, globulin from adult serum, an£l!n~g!?bulinJrQJ:!l~~D.taLt;Atr<:l~t ?_~ probably comparable in P9ten~Y. The dose generally recommended _ _ .___ ",,_...

,_,,"._,_~.--......."~~_

..

~.~""O>'

.,

64

SIDNEY

o.

LEVINSON, HOWARD

J.

SHAUGHNESSY

is 2 cc. fori1!f!lI).ts, 3 to Scc. for )'"oung~hildren up to the age of fiv~ ~~aiS;-'alid"S 1:0 ~O cC:Over-hve"y'ears and for older childrep. EX<;~Et fOrlE.t?Qt.Lin whom complete protectl()n is desirable, iI is preferable to give the serum on the fifth to seventh days of the incubation period in an attempTto"'piOdUCeasero-attenuated or'modified measles which is followed by an active immunity. . Treatment.-Measles is a disease which lends itself well to the study of the therapeutic value of a virus immune serum. First, measles convalescent serum is quite potent. Secondly, the disease can be accurately diagnosed and treatment instituted before it reaches its fastigium. It is astonishing that prior to 1936 it was believed almost universally that measles serum was without therapeutic value. Since then, several studies 4 have established that the intravenous administration of large doses of convalescent serum (20 to 50 cc.) during the pre-eruptive active stage would, in most instances, modify the disease. Such therapeutic effect has since been also demonstrated with the use of immune globulin by Stokes, Maris, and Gellis5 who also pointed out that such therapeutic modification was most clearly evident in those children in whom Koplik spots appeared earlier and, therefore, treatment was instituted earlier. They further report two instances of a temperature crisis and complete inhibition of the development of a rash despite the fact that, at the time of treatment, the disease was florid in character with severe cough and catarrhal signs. POLIOMYELITIS

Prophylaxis.-There are no clinical studies on the value of antiserum as a prophylactic measure. The low contagious incidence and the haphazard development of the recognizable disease makes such a study very difficult. However, there are sufficient laboratory studies to justify the belief that immune serum is effective prophylactically. Despite the difficulties in obtaining clear-cut evidence from experiments on monkeys, Schultz and Gebhardt's6 results are statistically significant indication of protection from the use of immune serum. Kramer,7 using the Lansing strain in mice and human convalescent serum, not only showed protection when serum was given up to two weeks before virus, but also demonstrated protection when serum was given after intracerebral virus infection, some protection being apparent even when given ninety-six hours later. He concluded that the protection appeared to be specific, due to absorbed circulating antibody and felt that there was some direct relationship between the amount of neutralizing antibody and the degree of protection. These results have been corroborated 8 with the use of gamma globulin from adult serum wherein some protection was observed, even when the gamma globulin was given as long as ninety-six hours after intracerebral injection of virus in mice. Treatment.-Laboratory studies to determine the value of immune

65

IMMUNE SERUM IN VIRUS DISEASES

antibodies in therapy are handicapped by the fact that such studies have not been done on animals in which the disease follows a course comparable to man. The necessity of producing the disease by intracerebral injection of the virus imposes a very critical test for the value of immune antibodies, particularly since hyperimmune antibody sources have not been developed. The inference may be drawn from the aforementioned work by Kramer and Stokes that there was therapeutic effect since protection was afforded to mice ninety-six hours after virus inoculation, for it is probable that after a ninety-six hour interval the injected virus had already invaded nervous tissue cells. However, none of the animals who showed symptoms or signs of active disease survived. Critical analysis of the numerous clinical studies compels one to discount them all, whether favorable or unfavorable. From the introducTABLE 2.·-TITRATION OF ANTIBODIES AGAINST THE LANSING STRAIN OF POLIOMYELITIS IN WHITE MICE

Dilutions of Serum in Saline*

Serum Tested

Human Convalescent Serum, Lot 115 Gamma Globulin Normal Adult Serum, Lot 37 Normal Adult Serum, Lot 38 Control (Saline)

1/10

1/25

1/50

1/100

1/250

1/500

0/6 0/7 4/6 0/8 8/8

2/7 0/8 4/7 5/5

2/5 5/7 7/7 6/6

3/8 2/7 8/8 6/6 8/8

4/8 7/8 7/8 3/3

6/6 7/7 6/6 4/4

...

.. .

. ..

. ..

* Numerator = number of mice dead Denominator = number of mice inoculated

tory considerations, it is apparent that therapeutic efficacy is possible only from treatment instituted early in the course of illness, the socalled early preparalytic stage. Even in outbreaks, early recognition is the exception rather than the rule. The course of the disease is variable and unpredictable, and statistically significant results would require rather large numbers of cases. Furthermore, there is no abundance of potent immune serum. The so-called "convalescent" serum is, in most instances, serum collected from any paralytic patient, regardless of the interval since the illness. If the virus antibody titer of pOliomyelitis blood behaves like that of other postinfectious antibodies, then most "convalescent poliomyelitis serum," used clinically, must have a relatively low titer of antibodies. In fact, some of the early titrations in monkeys, even though not too accurate, indicated that ordinary adult serum had as good a titer as the serum obtained from long-standing poliomyelitis patients. 9 Recently, we had occasion to

66

SIDNEY

o.

LEVINSON, HOWARD

J.

SHAUGHNESSY

compare the titers of pooled adult serum, pooled convalescent serum obtained from patients who had had an attack of poliomyelitis from one to three years previously, and gamma globulin. These titrations, carried out against the Lansing strain of virus in white mice, revealed some very significant differences. Table 2 represents one such titration. It appears from these titrations that the pooled serum from relatively recent patients is more potent than pooled adult serum and about equal in potency to gamma globulin. Clinical studies, therefore, in which relatively small doses (50 to 100 cc.) of probably low potency serum was employed must be discounted. The course of human poliomyelitis is another obstacle in attempts to establish the value of immune body therapy in this disease. When a diagnosis of early "nonparalytic" or "preparalytic" poliomyelitis is made, virus invasion of central nervous system cells has, in all probability, taken place. There is no way of knowing the extent of such involvement. If it is extensive at this time, obviously serum treatment cannot be very effective. The results of gamma globulin therapy8 in measles may serve as an analogy. The longer the interval between Koplik spots and rash (and, thus, immune therapy being instituted when fewer cells were involved) the more beneficial the effect. Our early diagnostic criteria for poliomyelitis are very limited and unsatisfactory. Until these criteria are improved, and until we establish a good method of making an early diagnosis before there is extensive nerve cell invasion, immune serum therapy in poliomyelitis will continue to lab or under a handicap. In a study* over a ten year period, comparatively large doses of convalescent serum (ranging from 100 to 800 cc. and averaging 250 cc.) have been administered to patients in the early acute stage without obvious clinical paralysis, the diagnosis being made after a careful history, physical and neuromuscular examination, and confirmed by positive spinal fluid findings. Attempts were made to secure this immune serum from as recent cases as possible, usually those occurring within one to five years. The serum was always administered intravenously, although in the first two years small amounts were also given intraspinally. The initial dose was 100 to 200 cc., depending on age and weight, and the same dose was repeated at twenty-four-hour intervals until convalescence set in. In this period of time, 298 patients were treated. The incidence of permanent paralysis was 2.3 per cent and the mortality was 1 per cent. Although there is no control group for comparison, it is felt that these results are clinically significant, because the clinical disease during this time was at least of average severity. From other reports,lOa, lOb it is reasonable to expect that 30 per cent of these early cases would have progressed to paralysis and that one third to one half of the 30 per * This study was conducted from the Samuel Deutsch Serum Center, Chicago, by Doctor Albert M. Wolf and one of the authors.

IMMUNE SERUM IN VIRUS DISEASES

67

cent,10b.10C or 10 to 15 per cent, of the total number would have permanent paralysis. Thus, even though this study lacks a control group, the results are strongly indicative, for a much larger ratio of patients than normally expected had a more benign form of the disease when they received large doses of convalescent serum. In this group of 298 preparalytic patients, thirty-two, or 11 per cent, subsequently developed definite signs of bulbar poliomyelitis. These patients were more acutely sick and consequently received more serum, the average therapeutic dose being 350 cc. Twenty of these patients at no time exhibited the fulminating and critical picture usually characteristic of bulbar poliomyelitis. Two of the thirty-two patients, in addition to bulbar paralysis, also had spinal paralysis, in one mild, in the other moderately -severe. There were two deaths in this group of patients with bulbar poliomyelitis, a significantly low fatality rate for this type of the disease. MUMPS

Prophylaxis.-Although the literature is not extensive, it is uniformly favorable on the prophylactic value of mumps convalescent serum. Since Hess l l first used convalescent serum for this purpose, there have been other studies,12 all reporting success with doses varying from 2 to 15 cc. In our experience, mumps convalescent serum confers protection on exposed susceptibles, but it does not appear to be a rich source of immune bodies. We believe that the minimum prophylactic dose should be 20 cc., and it would be wise to increase this amount to 40' cc. for adults. Treatment.-Mumps convalescent serum has been used in the treatment of acute, noncomplicated mumps in adults with the principal purpose of preventing extension of the disease, particularly to prevent orchitis in males. There are but few reports that merit consideration; those of De Lavergne and Florentin13 and Iverson14 are probably the best. Both these studies point to a reduced incidence of orchitis in patients who were given convalescent serum after the appearance of parotitis. De Lavergne and Florentin treated 113 patients with two doses totalling 30 cc. The contrast of 24 per cent orchitis in 107 untreated controls with 4 per cent in the treated patients is rather striking. Iverson administered 40 cc. of mumps convalescent serum to alternate cases in a group of soldiers with mumps. In the fifty-six serum-treated cases, 20 per cent developed orchitis, one bilateral, while in the fifty-six controls, 30 per cent developed orchitis of which three cases were bilateral. A recent study by Rambar15 yielded results comparable to those of Iverson. In view of the probable low immune body content of the serum (judging fi"om the amounts required for effec-' tive prophylaxis) it appears that all these authors employed minimal and possibly inadequate amounts of serum. It would be worthwhile to conduct a study in which larger amounts of concentrated convales-

68

SIDNEY O. LEVIN SON, HOWARD

J.

SHAUGHNESSY

cent serum were used and to see if the complication rate could be consistently and significantly reduced. EQUINE ENCEPHALOMYELITIS

With improved and increased facilities for virus diagnosis, outbreaks of this disease are being recognized with increasing frequency. A large outbreak occurred in 1941, and 1080 cases in North Dakota alone were reported,16 with a mortality of 8.9 per cent. A smaller outbreakl7 in Massachusetts in 1938 was highly fatal and caused about thirty deaths. Prophylaxis.-There is good laboratory evidence on the prophylactic value of hyperimmune rabbit and horse serum. 18 , 19 Small amounts of such serum will protect against subsequent intracerebral injection of many times the minimal lethal dose of virus. Treatmelit.-The principal evidence on the value of serum treatment of Western equine encephalomyelitis has been contributed by Zichis and Shaughnessy19 who worked with experimentally infected mice, guinea pigs and monkeys. It is significant that these workers rigidly observed those cardinal principles previously enumerated. Employing a laborious and prolonged course of immunization, they prepared a potent hyperimmune rabbit serum. Treatment was instituted as soon as the experimental animals became visibly sick. They gave large and repeated injections of serum, both intraperitoneal and intracardiac. With this regimen, 67.3 per cent of fifty-five guinea pigs recovered while only one of forty-one control animals spontaneously recovered. Further evidence that the serum-treated -and recovered animals had passed through the active disease was subsequent resistance to lethal amounts of the live virus. Some of the recovered animals subsequently sacrificed showed histopathologic findings indicative of healing encephalomyelitis. EPIDEMIC INFLUENZA

Laidlaw, Smith, Andrewes and Dunkin,20 in 1935, reported experiments on the use of concentrated hyperimmune serum treatment in mice experimentally infected with influenza virus. Although treatment was instituted twenty-four and forty-eight hours after infection, only 35 per cent died, in contrast to 80 per cent fatality in control, untreated animals. Of the greatest significance was the observation that most of the treated survivors showed extensive lesions of the lungs when subsequently killed. This led these workers to state that this was "convincing evidence that the virus had reached and produced damage in the lungs, and that concentrated serum was powerful enough to arrest the pathological process." These results have since been confirmed by Henle, Stokes and Shaw. 21 Not only was death prevented in experimentally infected mice up to forty-eight hours after infection when the animal was ill

IMMUNE SERUM IN VIRUS DISEASES

69

with severe influenza, but Stokes8 states that serum treatment by the inhalation route required only about one-tenth that required by the intraperitoneal route for the same effect. This experience emphasizes the importance of having the immune antibodies at the site of infection. It also tends to confirm- the favorable results reported by Smorodintsev 22 who used convalescent serum treatment by inhalation of Type A epidemic influenza in man. ATYPICAL PNEUMONIA

So-called "atypical" or "virus" pneumonia is being seen with increasing frequency. Although this disease is classified as a clinical syndrome, viruses have been isolated which fall in the psittacosis or ornithosis group. Meyer and Eddie,23 in reviewing the literature, had expressed a favorable opinion on the value of convalescent serum in therapy of psittacosis, although they made the reservation that convalescent serum was of low potency and that better results should be expected from hyperimmune serum. Solomon 24 found an opportunity, during an outbreak of "atypical" pneumonia at a Naval Air Station, to treat ten unselected patients with convalescent serum. He administered 250 cc. intravenously within tht:ee days of onset of illness, and reported crisis within twelve to eighteen hours following serum treatment, rapid recovery from illness, and discharge to duty after an average of twenty-two days. The control, untreated patients usually recovered slowly, the temperature dropped by lysis, and they averaged thirty-nine days in the hospital before discharge to duty. MISCELLANEOUS AND RELATED CONDITIONS

Isolated reports on a variety of conditions contribute to a constantly accumulating literature, all bearing on the value of immune serum in the treatment of intracellular parasites. Thus, Habe12 5 recently presented experimental data indicative of protective value in antirabies serum. Evans, Slavin and Berry 26 administered specific hyperimmune rabbit serum to mice experimentally infected with herpes virus. They showed a statistically significant effect from the serum even when it was administered forty-eight hours after infection. They concluded that antibody administration retarded, and in some . cases arrested, progression of herpetic infection of the nervous system. In our laboratory,27 hyperimmune monkey serum was employed in the treatment of mice infected intracerebrally with a virulent lymphocytic choriomeningitis virus. There was definite protection when serum was given as late as forty-eight hours after infection with 50 per cent of the animals surviving, while the fatality rate in the controls was 100 per cent. Smorodintsev,28 in a review on spring-summer encephalitis, states that convalescent or hyperimmunized animal serum is effective dur-

70

SIDNEY O. LEVINSON, HOWARD

J.

SHAUGHNESSY

ing the incubation period provided the interval between injection of virus into mice and the inoculation of the serum was not greater than one to four days. Furthermore, he reports favorable results from use of the immune serum in treatment of the disease in man. He also stresses that, in order for therapy to be successful, the serum must be administered on the first or second day of the disease and followed by subsequent additional injections. He states unequivocably that "patients thus treated with repeated injections of convalescent serum showed a critical drop in temperature and a marked improvement of their general condition." T opping 29 has reported clear-cut evidence that an immune serum containing large amounts of protective antibodies will save a large majority of guinea pigs infected with Rocky Mountain spotted fever when the serum is lldministered after onset of symptoms of the active disease. He 30 has also used the immune rabbit serum in treating fiftytwo patients before the third day of rash. The fatality rate in this serum treated group was 3.8 per cent as compared to the expected rate of approximately 18.8 per cent. There have been several reports on hyperimmune typhus serum. Wyckoff and Bohnel,31 in a recent study, demonstrated that hyperimmune rabbit antiserum "has a positive therapeutic effect in guinea pigs diseased with epidemic typhus" even when the serum is administered as long as five days following infection. COMMENT

The chief aim in the presentation of material in this clinic is to open for review and reconsideration the value of immune bodies in the treatment of virus diseases, a topic which for long has been generally considered closed. The increasing knowledge on the behavior of viruses in the host and the accumulating favorable evidence justifies a reexamination of this subject and a possible reorientation of thinking. In the light of our present information, the earlier failures and resultant hopeless attitude become clear. The field of virus research is relatively new, and rapid progress is still impeded by many difficulties. tt;was fundamentally important. to useseruOls rich. it} amibQQjes. To produce such serums, potent antigens were necessary. It is only recently that any high-titered virus antigens have been prepared by isolating more virulent strains, by chick embryo technic, and by purification. The use of better antigens has made possible more potent serums which have been therapeutically successful where earlier efforts failed. A . very important qualifying factor in determining therapeutic efficacy of immune bodies is the extent of cell involvement at the time of therapy. ALth~J?gs.ent time, itJlP.Q~3:!sth!lt.c.~U~al!(!a~x..parasiti~ed ~.are--E£0bably. beyol1dany hf!Ip. ff9IILS.erum therapy~ ~gh cells may be invaded evenoefore demonstrable signs and symptoms of

IMMUNE SERUM IN VIRUS DISEASES

71

disease are present,32 there is no basis for the belief that cell involvement is extensive and complete early in the disease. In fact, all clinical evidence points to the usual course of virus illness as a progressively extending cell invasion. Maximal cell involvement probably takes place well after the active illness has become manifest. The introduction of immune bodies into the host and their presence at the location of infection should protect the healthy cells from invasion by virus. This must be the mechanism of therapeutic efficacy which has been so clearly demonstrated in a number of virus infections. These considerations throw a sharp light on the great importance of early diagnosis of virus infections. At present, we are generally handicapped by vague diagnostic criteria. Differential diagnosis particularly is difficult. There are no specific laboratory tests to aid the clinicians to establish a definite early diagnosis. It is possible that this aspect of virus infections has been neglected because of the general attitude that therapy was worthless. We believe that an attitude of resignation is wrong. In fact, it is most important that a virus disease must be diagnosed at the earliest possible moment. Stokes8 has recently placed the greatest stress on the importance of earlier diagnosis. Clinicians and laboratory men should concentrate their efforts in establishing clear-cut diagnostic findings and laboratory tests. Even though a serum is potent, and a relatively early diagnosis is made, it is still important that the serum be administered by a route that brings the immune bodies most rapidly to the seat of infection . . The dose must also be adequate. Since the severity of many virus infections varies considerably, it would probably be a wise course to give maximal dosage rather than minimal. It would be too much to expect that all virus diseases are susceptible to antiserum therapy. Those diseases against which potent serums can be prepared and which can be treated early should respond. It would also be too much to expect all patients to be treated successfully. Some virus infections, such as poliomyelitis, are extremely variable, and those patients with a fulminating disease and early extensive cell involvemerit by virus will not be susceptible to therapy. The expression "too little and too late" can be aptly used to account for past failures in efforts to treat virus infections with immune serums. We should take cognizance of these mistakes in the future. We should renew our efforts to treat virus diseases in humans with immune bodies, following closely the cardinal principles of using p'0tent serums, treating the patient early, and using adequate dosage by a route which will most rapidly bring the antibodies to the seat of infection. REFERENCES

1. Rivers, Thomas M.: Immunity in Virus Infections. Science, 95:107-112 (Jan.

30) 1942. 2. Weisbecker, L.: Heilserum gegen Masern. Zeit. f. klin. Med., 30:312, 1896.

72

SIDNEY O. LEVINSON, HOWARD

J.

SHAUGHNESSY

3. Orlov, G. A.: Specific Titration of Anti-Measles Serum by Complement-Fixation. Am. Rev. Soviet Med., 2:531-536 (Aug.) 1945. 4. (a) Levinson, S. O. and Connor, J. A.: Human Convalescent Measles Serum; Its Uses in Prophylaxis and Therapy. Proc. Inst. Med., 2:128 (June 15) 1936.

L., Klein, I. F. and Schwarz, Herman: Treatment of Preeruptive Measles with Convalescent Serum. J.A.M.A., 111:2361-2364 (Dec. 24)

(b) Kohn, J.

1938.

(c) Levinson, S. O. and Connor, J. A.: The Treatment of Active Measles

with Buman Convalescent Serum. J. Pediat., 14:268 (Feb.) 1939. 5. Stokes, J., Maris, E. P. and Gellis, S. S.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. XI. The Use of Concentrated Normal Human Serum Gamma Globulin (Human Immune Serum Globulin) in the Prophylaxis and Treatment of Measles. J. Clin. Investigation, 23:531-540 (July) 1944. 6. Schultz, E. W. and Gebhardt, L. P.: Observations on the Prophylactic Value of Specific Immune Serum in Experimental Poliomyelitis. J. Pediat., 7:332351, 1935.

7. Kramer, S. D.: Protection in White Mice with Human Post-Convalescent Serum Against Infection with Poliomyelitis Virus (Armstrong Strain). n. J. Immuno!., 47(1):67-76 (July) 1943. 8. Stokes, Joseph, Jr.: The Use of Immune Bodies in the Treatment of Certain Infectious Diseases (Virus and Rickettsial Diseases) Caused by Intracellular Parasites. Yale J. Bio!. & Med., 16(5):463 (May) 1944. 9. Shaughnessy, B. J., Barmon, P. H. and Gordon, F. B.: The Neutralization of Poliomyelitis Virus by Human Serum. J. Prevent. Med., 4:463, 1930. 10. (a) Harmon, P. H.: Poliomyelitis. Am. J. Dis. Child., 47:1216-1255, 1934. (b) Province of Ontario Department of Health: Report on Poliomyelitis in Ontario, 1937. Monograph Published March, 1938. (c) Sherman, M. S.: The Natural Course of Poliomyelitis. J.A.M.A., 125:99102 (May 13) 1944. 11. Hess, A. F.: A Protective Therapy for Mumps. Am. J. Dis. Child., 10:99 (Aug.) 1915.

12. (a) Regan, J. C.: Serum Prophylaxis of Epidemic Parotitis. J.A.MA., 84:279

(Jan. 24) 1925. L. H. and Ostroff, J.: Use of Human Blood in Protection Against Mumps. Am. J. Dis. Child., 42:1109, 1931. (c) Zeligs, M.: Convalescent Serum in the Prevention of Mumps. J. Pediat., 1:727 (Dec.) 1932. 13. De Lavergne, V. and Florentin, P.: Preventive Serotheraoy in Mumps. Bull. de l'Acad. de Med., Paris, 93:362 (March 31) 1925. Abstract in J.A.M.A., (b) Barenberg,

84:1701, 1925. . 14. Iversen, P.: Complications of Epidemic Parotitis and Experimental Treatment with Convalescent Serum. Ugeskrift f. laeger, 92:167, 1930. 15. Rambar, A. c.: To be published. 16. Leake, J. P.: Epidemic of Infectious Encephalitis. Pub. Health Rep., 56:19021905 (Sept. 26) 1941. 17. FothergiIl, L. D., Dingle, J. H., Farber, Sidney and Connerley, M. L.: Human

Encephalomyelitis Caused by the Virus of the Eastern Variety of Equine Encephalomyelitis. New England J. Med., 219:411 (Sept. 22) 1938. 18. Howitt, B. F.: Equine Encephalomyelitis. J.Infect. Dis., SJ:493-510 (Nov.Dec.) 1932. 19. (a) Zichis, Joseph and Shaughnessy, Howard J.: Experimental \Vestern Equine Encephalomyelitis. Successful Treatment with Hyperimmune Rabbit Serum. J.A.M.A., 115:1071-1078 (Sept. 28) 1940.

IMMUNE SERUM IN VIRUS DISEASES

73

(b) Zichis; Joseph and Shaughnessy, Howard J.: Successful Treatment of

20. 21. 22.

23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Experimental Western Equine Encephalomyelitis with Hyperimmune Rabbit Serum. Am. J. Pub. Health, 35 (8) :815-823 (August) 1945. Laidlaw, P. P., Smith, Wilson, Andrewes, C. H. and Dunkin, G. VV.: Influenza: The Preparation of Immune Serum in Horses. Brit. J. Exper. Path., 16:275-291 (June) 1935. Henle, W., Stokes, J., Jr. and Shaw, D. R.: Passive Immunization of Mice Against Human Influenza Virus by the Intranasal Route. J. ImmunoI., 40: 201-212 (Feb.) 1941. Smorodintsev, A. A.: Experimental and Clinical Investigation of the Specific Prophylaxis and Therapy of Influenza by Inhalation of Immune Serum. Third International Congress for Microbiology. Report of Proceedings, New York, 1940, p. 375. Meycr, K. F. and Eddie, B.: The Value of the Complement Fixation Test in the Diagnosis of Psittacosis. J. Infect. Dis., 65:225 (Nov.-Dec.) 1939. Solomon, Ernest M.: Human Serum Treatment of Atypical Pneumonia. J. Lab. & Clin. Med., 29(5) :493-499 (May) 1944. Habel, K.: Seroprophylaxis in Experimental Rabies. Pub. Health Rep., 60:545560 (May 18) 1945. Evans, C. A., Slavin, H. B. and Berry, G. P.: Effect of Specific Antibodies on Herpetic Infection of the Nervous System. J. Bact., 47:63 (May) 1944 (Abst.). Milzer, A. and Levinson, S. 0.: Unpublished studies. Smorodintsev, A. A.: Tick-Borne Encephalitis. Am. Rev. Soviet Med., 1 (5): 400-408 (June) 1944. Topping, Norman H.: Rocky Mountain Spotted Fever: Treatment of Infected Laboratory Animals with Immune Rabbit Serum. Pub. Health Rep., 55(2): 41-46 (Jan. 12) 1940. Topping, Norman H.: Rocky Mountain Spotted Fever. Further Experience in the Therapeutic Use of Immune Rabbit Serum. Pub. Health Rep., 58: 757-772 (May 14) 1943. Wyckoff, RaIph W. G. and Bohnel, E.: Therapeutic Effect in Guinea Pigs of Hyperimmune Epidemic Typhus Anti-Serum. Proc. Soc. Exper. BioI. & Med., 49:iI2-715, 1942. Faber, H. K. and Gebhardt. L. P.: Localization of the Virus of Poliomyelitis in the Central Nervous System during the Pre-paralytic Period, after Intranasal Instillation. J. Exper. Med., 57:933, 1933.