POSTINOCULATION POLIOMYELITIS

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EDITORIAL

POSTINOCULATION POLIOMYELITIS

P

OLIOMYELITIS following immunizing injections of presumably sterile material has occasionally been reported since 1921,1-5 as well as after Jennerian v a c c i n a t i ~ n , ~ - ~ but until quite recently the occurrence has been considered so rare as to have little practical significance. The publication in 1950, however, of four papers, three from England

(London)@-'I and one from Australia,12 in which about 100 cases of this sort were re- ported, nearly all in young children, and of an editorial in the Iournal of the American Medical A s s o ~ i a t i o n ~ ~ has suddenly increased interest in the subject and made it a matter of general concern to practicing physicians, particularly pediatricians.

Martins of London in March 1950 recorded 17 cases occurring in the period 1944-49, all under 3 years of age, in which paralysis of the inoculated limb began, with one exception, between 8 and 2 8 days (average, 17 days; median 16 days), after injection. In April 1950, M ~ C l o s k e y ~ ~ of Melbourne, Australia, reported 29 cases in children of 1 to 15 years (25 under 5 years) of poliomyelitis beginning 4 to 32 days after inoculation (average 13 days; median 12 days), in 24 of which paralysis developed in the inoculated limb. In April 1950, Geffenlo reported. 30 cases from London in which paralysis of the inoculated limb began less than 29 days after inoculation; in the same area and year, 182 cases of poliomyelitis, presumably~including the 30 postinoculation cases, were reported. In July 1950, Hill and Knowelden11 reported, also from London, 40 cases in children under 5 years with paralysis beginning 8 to 28 days (80% of them,

8 to 17 days) after injection, of which 33 showed involvement of the inoculated limb. During the same period (1949) in the same area of notification and age group, a total of 410 cases of poliomyelitis were reported. This series probably includes part or most of Geffen's cases; both showed a startlingly high proportion of all poliomyelitis cases related to recent injections. In the four reports, the interval between injections and the onset of symptoms was less than five days in only three instances.

No one type of inoculum wbs exclusively implicated. While alum-precipitated diph- theria toxoid (APT), pertussis vaccine or mixtures of the two were used in most instances, similar effects have followed p e n i ~ i l l i n , ~ ~ ~ ~ ~ typhoid-paratyphoid vaccine (TAB),214*5 cholera vaccine1 and, as already mentioned, smallpox vaccination.

The diagnosis of poliomyelitis in the reported cases appears to have been reasonably certain. The clinical features, including early and residual flaccid paralysis, have been typical as have the examinations of cerebrospinal fluid. The absence of characteristic sensory symptoms and signs appears to rule out neuritis. The fatality rate seems to have been low, and no postmortem studies appear in the four reports, but MacCallumM reported recovery of poliomyelitis virus from the stools of five postinoculation cases, two of them with paralysis of the injected limb.

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that the trauma produced by the injected materials promoted both the conversion of latent into apparent infection and its localization in the inoculated limb. This theory was based largely on the reports of R ~ s s e l l ~ ~ ~ ~ ~ ~ and of Hargreaves16 in which severe physical activity tended to produce or to increase paralysis, sometimes in the limb subjected to the greatest stress (postexertional type). Another possible explanation suggested by McCloskey but regarded by him as improbable is that syringes or needles used for injections may have been accidentally contaminated with the virus, from the doctor's hands, the patient's skin, or from other patients on whom they had been used, assuming inadequate sterilization thereafter.

The practical importance of finding the correct explanation is obviously so great that further exploration of the subject is urgently needed. However, facts already established but not brought out or sufficiently emphasized in previous discussions may provide the means of clarifying the issue and bringing it near solution.

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Basically, poliomyelitis is a nerve-transmitted infection" and it has been abundantly proved that if the virus is introduced into peripheral nerve18*18 it will travel centripetally to the nerve cells of the latter and, reaching the central nervous system, infect the corresponding motor segment of the spinal cord or brainstem, producing a primary paralysis referable to that segment. W e have found20 this process to occur also after direct introduction of virus into voluntary muscle (face, arm), presumably because the exposed motor nerves afford a direct pathway for ascent of virus from the muscle to the regional motoneurons. It is noteworthy that in everyday practice, many and perhaps most immunizing and other injections (e.g., penicillin) into the arm, buttock or leg, are actually intramuscular, often intentionally so. Experimentally, it has been repeatedly21-26 shown that intra- and subcutaneous inoculations of poliomyelitis virus are also frequently, if irregularly, followed by paralytic poliomyelitis. While, unfortunately, none of the pub- lished experimental studies has specified the site of the initial paralysis and only one the site of inoculation, it is perhaps not unreasonable to anticipate the existence of a relationship between the two after exposure of the cutaneous nerves; indeed, certain human experiences, to be presently cited, corroborate the expectation.

TO see whether the mechanism just discussed furnishes a clue to the human problem of postinoculation poliomyelitis, it will be helpful to divide the reported cases following trauma and stress into two groups: Group I, those in which the disease has followed penetrating trauma; and Group 11, those in which it has followed simple physical stresses

uncomplicated by penetrating trauma. Scrutiny of the various case reports in the light of these criteria reveals significant differences between the two groups, particularly as regards the interval between the trauma or stress and the onset of symptoms and/or paralysis. Thus, in the four reports of postinoculation poliomyelitis, the intervals with . only exceptions fell within the recognized incubation period, 3 to 35 days,26 of polio-

myelitis in general, whereas in the reports of Russell and of Hargreaves the interval was generally less than four days, and in Horstmann'sZ7 more recent study, no effect of physical stresses in promoting paralysis appeared unless the patient already showed poliomyelitic symptoms. Another example of Group I is presented by post-tonsillectomy poliomyelitis in which paralysis is also usually segmental (bulbar) to the trauma and in which, as shown by Aycock'sZ' study, the incubation period is nearly always be- tween 6 and 30 days. It seems clear that in Group I, with rare exceptions,* there has

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been no evidence of poliomyelitic infection prior to the trauma, while in Group 11, the reverse is true. It is interesting to note that in Russell's last ~ a p e r , ~ J dealing mainly with Group 11, Group I is represented by two cases, one after typhoid vaccine and one after penicillin, both with segmental paralysis, in which incubation periods of 7 and 8 days, respectively, were noted, with paralysis 3 and 4 days later. T h e segmental localization of paralysis appears to be much more frequent and well-defined in Group I than in Group 11. Thus, in Hill and Knowelden's series with onset 30 days or less after inoculation, segmental paralysis occurred in 33, or 80% of cases. As regards Group 11, Horstmann was unable to state with certainty in her series whether localization actually occurred in relation to the region of maximum stress, while Russell45 notes such a relationship in only 9 of the 100 patients studied by h i m ; both authors stress the importance of severe exertion in favoring or increasing paralysis, rather than its localizing effects. Experimentally, Levinson, Milter and LewinZ9 were unable to localize paralysis by nonpenetrating trauma applied to monkeys during the preparalytic stage of infection.

From the facts just presented, the possibility must be seriously entertained that in cases of Group I, virus has been accidentally introduced by injection or other forms of penetrating trauma, presumably into superficial nerves. There is other evidence to support this view. O n the basis of a fairly uniform rate of progression of poliomyelitis through peripheral nerve-f2.4 r n m . / h ~ u r ~ ~ - t h e incubation period, which measures the time required for the virus to reach the central nervous system and produce symptoms, should be shorter for injections into the arm than into the leg. In the cases reported by McCloskey, this expectation is fulfilled to the extent that the average incubation period for arm injections was 11.2 days (median, 11 days), and for leg injections, 17.7 days (median, 14 days). The experimental reproduction of postinoculation poliomyelitis has already been cited. There is a human counterpart to this in the tragic results in 1935-36 of attempted immun~zation with active poliomyelitis virus, putatively attenuated with sodium ricino- leate.37 As reported by Leake,sz nine cases of poliomyelitis, all with segmental paralysis, followed cutaneous injections of this material ("vaccine A"), the median incubation period being 10 days after the first or only injection. Excepting for their high fatality rate, these cases appear to have been identical with those presently under consideration.

If postinoculation poliomyelitis results from introduction of virus at the time of injection, the source of virus might be one or both of those mentioned by McCloskey: (1)

the skin of the patient; ( 2 ) the syringe or needle, or possibly the container of the biologic material used, contaminated in one way o r another and not fully sterilized. T h e available data give no clue to which of these is the actual source. Most of the cases have occurred during epidemics when virus is presumably widely disseminated and could readily contaminate both persons and objects. Experiences with serum he pa ti ti^^^-^^ shows the dangers of transmission by needles and syringes incompletely sterilized and the considerable difficulty in practice of attaining complete sterilization of syringes and needles, for which autoclaving is now generally regarded as the safest method. T h e respective resistances to heat of the viruses of serum hepatitis and of poliomyelitis are,

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in fact, not too dissimilar. The former is said to withstand exposure to 56OC. for 60 minutes,37 while the latter, according to the recent study of Lawson and M e l n i ~ k , ~ ~ requires over 60°C. for 30 minutes for complete inactivation, and in protein-containing media higher and more prolonged exposures for both appear to be necessary (60°C. for 10 hours for hepatitis virus in albumin; 5 to lo0 extra for polio virus in milk). Since, in contrast to serum hepatitis, the virus of poliomyelitis is rarely present in the blood,39 it may be surmised that the source of infection in postinoculation poliomyelitis is not blood or its derivatives.

In summary, poliomyelitis following inoculations of immunizing materials of various sorts, with paralysis in the inoculated limb may be due to accidental introduction into peripheral nerves of virus from the patient's own skin (perhaps the more likely explanation), or from previously contaminated needles or syringes inadequately sterilized, rather than to exacerbation and localization of pre-existent infection. This conclusion is based on the following observations: (1) the onset of symptoms and paralysis has regularly occurred after an asymptomatic interval corresponding with the established incubation period of poliomyelitis; (2) the mean and median intervals appear to be longer for injections into the leg than into the arm in harmony with the greater length of peripheral nerve to be traversed by the virus; ( 3 ) the cases appear to be identical in essentials with those following immunizing injections of virus known to have been in active form; (4) the same picture has been experimentally reproduced in monkeys by inoculation into peripheral nerve, as well as into muscle.

The following practical suggestions emerge from the foregoing discussion as of poten- tial preventive value:

1. Syringes and needles used for injections of all sorts should be sterilized by autoclaving; or, if this is impractical, by boiling for 20 minutes.

2. A strong antiseptic should be used, preparatory to injections, both on the patient's skin and on the stopper of the vial. Alcohol or soap and water cannot be regarded as safe. Until more information is available as to the antiseptic of choice, 2 % tincture of iodine is suggested.

HAROLD

K.

FABER,

M.D.

Stanford Unit~ersify School of Medicine Sun Fra~cisco

1. de Teyssieu, M., Poliomyelite aigue condcutive i une injection de vaccin anticholCrique, J. de mCd. d e Bordeaux 92:77, 1921.

2. Mazel, P.. Meersseman, F., Camelin, A,, and Guibert, A., U n cas d e poliomyklitie c o n k u t i f h

une injection de vaccin associC (T.A.B. et anatoxine diphterique), Soc. de mCd. mil. franc, Bull mens. 33:314, 1939.

3. Cunning, D. S., Tonsillectomy-poliomyelitis survey-1947, Laryngoscope 58:503, 1948. 4. Cunning, D. S., Tonsillectomy-poliomyelitis survey-1947, Laryngoscope 59:441, 1949. 5. Russell, W. R., Paralytic poliomyelitis: Early symptoms and effect of physical activity on course

of disease, Brit. M . J. 1:465, 1949.

6. Jermulouicz, hl., Deux cas de poliomyelite en rapport avec la vaccination anti-variolique, Rev. ncurol. 37:92, 1930.

7. Bdntrjc.1, J . C.. Acute dntcrlor pol~orriyelitis following primary vaccination in infant, Indiana J. P t d ~ d t . 2: 177. 1935.

8. Verjaal, A. (Poliomyel~tis after vaccination and injury), Nederl. tijdsthr. v. pcncesk. 91:3137, 19.47.

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10. Geffen, D. H., Incidence of paralysis occurring in London children within four weeks after immmization, M. Officer 83: 137, 1950.

11. Hill, A. B., and Knowelden, J., Inoculation and poliomyelitis: Statistical investigation in Eng- land and Wales in 1949, Brit. M. J. 2:1, 1950.

1 2 . McCloskey, B. P., Relation of prophylactic inoculations to onset of poliomyelitis, Lancet 1:659, 1950.

13. Editorial, Poliomyelitis and prophylactic immunization, J.A.M.A. 144:240, 1950.

14. MacCallum, F. O., Clinical poliomyelitis in association with peripheral inoculation of prophy- lactics, 'Brit. M. J. 2:6, 1950.

15. Russell, W. R., Poliomyelitis: Preparalytic stage and effect of physical activity on severity of paralysis, Brit. M. J. 2: 1023, 1947.

16. Hargreaves, E. 'R., Poliomyelitis: Effect of excretion during pre-paralytic stage, Brit. M. J . 2: 1021, 1948.

17. Fairbrother, R. W., and Hurst, E. W., Pathogenesis of, and propagation of virus in, experimental poliomyelitis, J. 'Path. & Bact. 33:17, 1930.

18. Landsteiner, K., and Levaditi, C., La transmission de la paralysis infantile aux singes, Compt. rend. Soc. de biol. 67:592, 1909.

19. Hurst, E. W., Further contribution to pathogenesis of experimental poliomyelitis: Inoculation into sciatic nerve, J. 'Path. & Bact. 33: 1133, 1930.

20. Unpublished experiments.

21. Erber, B., and 'Pettit, A., A propos de la pluralit6 des souches de V ~ N S poliomy6litique, Compt. rend. Soc. de biol. 117: 1175, 1934.

22. Levaditi, C., Kling, C., and Haber, P. Est-il possible de vacciner I'homme contre la poliomyClite? Bull. Acad. de mCd., Paris 115:431, 1936.

23. Howitt, B. F., Recently isolated strain of poliomyelitic virus, Science 85:268, 1937. 24. Trask, J. D., and Paul, J. R., Skin infectivity of poliomyelitis vims, Science 87:44, 1938. 25. Stimpert, F. D., and Kessel, J. F., Infectivity and immunity resulting from injection of polio-

myelitis virus by intracutaneous route, J. Exper. Med. 71:645, 1940.

26. Horstmann, D. M., and Paul, J. R., Incubation period in human poliomyelitis and its implica- tions, J.A.M.A. 135:11, 1947.

27. Horstmann, D. M., Acute poliomyelitis: Relation of physical activity to course of disease, J.A.M.A. 142:236, 1950.

28. Aycock, W. L., Tonsillectomy and poliomyelitis. I. Epidemiologic considerations, Medicine 21: 65, 1942.

29. Levinson, S. O., Milzer, A,, and Lewin, P., Effect of fatigue, chilling and mechanical trauma on resistance to experimental poliomyelitis, Am. J. Hyg. 42:204, 1945.

30. Bodian, D., and Howe, H. A., Rate of progression of poliomyelitis virus in nerves, Bull. Johns Hopkins Hosp. 69:79, 1941.

31. Kolmer, J. A., Vaccination against acute anterior poliomyelitis, Am. J. Pub. Health 26:126, 1936.

32. Leake, J. P., Poliomyelitis following vaccination against this disease, J.A.M.A. 105:2152, 1935. 33. Darmody, E. M., and Hardwick, C., Syringe transmitted hepatitis, Lancet 2:106, 1945. 34. Neefe, J. R., Viral hepatitis: Consideration of certain aspects of current importance to practicing

physician, New England J. Med. 240:445, 1949.

35. Salomon, M. H., King, A. J., Williams, D. I., and Nicol, C. S., Prevention of jaundice resulting from antisyphilitic treatment, Lancet 2:7, 1944.

36. MacCallum, F. O., and Bauer, D. J., Homologous serum jaundice: Transmission experiments with human volunteers, Lancet 1: 622, 1944.

37. Havens, W. P., Jr., and Paul, J. R., Infectious hepatitis and serum hepatitis, in Rivers, T. M., Viral and Rickettsia1 Infections of Man, Philadelphia, J. B. Lippincott Company, 1948, chap. 11, p. 280.

38. Lawson, R. B., and Melnick, J. L., Inactivation of murine poliomyelitis viruses by heat, J. Infect. Dis. 80:210, 1947.

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1951;7;300

Pediatrics

HAROLD K. FABER