Read at the Centennial Medical Convocation of the Children’s Hospital of Philadelphia, Jnne 2, 1955. Dr. Faber is Professor Emeritus of Pediatrics, Stanford University School of Medicine.
ADDRESS: 2351 Clay Street, San Francisco 15, California.
278
SPECIAL
ARTICLE
THE
EVOLUTION
OF
POLIOMYELITIC
INFECTION
By Harold K. Faber, M.D.
T
HE INVITATION with which you have honored me on this memorableocca-sion has given me a tempting opportunity
to discuss certain problems with which my
associates and I have been engaged for
nearly a quarter of a century, and to
cor-relate the results of some 25 separate
stud-ies on the various aspects of pathogenesis, published, mainly in the Journal of Experi-mental Medicine, during that time. Most of these have dealt with the beginnings and
evolution of the disease up to the onset of
paralysis, in search of answers to such
ques-tions as: How and where does the virus
enter the body? Where do the initial lesions occur? What are the sources of viral excre-tion? How is viremia produced? By what
routes is the central nervous system in-vaded? What is the explanation of silent
infections? What are the defenses, natural and artificial, against the disease? And,
finally, can a unitarian concept be sustained
of the pathogenesis of pobiomyelitis in terms
of the relation between host and virus? Before discussing these questions, cer-tain prefatory remarks are in order about
the host-cell affinities of poliomyelitis virus. While it is interesting and in various ways
very important that these can be radically
altered in vitro by Enders” methods of tis-sue culture, and in vivo by pretreating
ani-mals with cortisone or ACTH, as shown by
Schwartzmann and Aronson,2 nevertheless
such results should be applied with the
greatest caution to the pathogenesis of the human disease, in which cytopathic changes
in such extraneurab tissues as kidney, mus-cle, skin and testis, when they occur at all,
are exceptional and not part of the char-acteristic pathologic picture. In infected
animals without hormonal preparation they
are virtually never seen.’ On the other hand, lesions of the nervous system are
constant and characteristic. While I am
fully aware of the current popularity of
the dualistic view’ which regards the virus of poliomyelitis as primarily a parasite of extraneural tissues, particularly in the ali-mentary mucosa, with only secondary, mci-dental and perhaps exceptional invasion of
the nervous system, this concept-apart from tissue culture and the results of the
cortisone experiments-is, I suggest, based
on an erroneous identification of the
extra-cellular phases of tile virus in the
aiimen-tary lumen and in the blood, with true
in-fection of extraneural tissues. Extra- and
intracellular phases are common to all
vi-ruses, the former being responsible, as
Delbr#{252}ck has pointed out, for the
com-munication of infection and the latter, for the production of pathologic lesions.
Viewed in this bight, the paucity of
extra-neural lesions in vivo and the uniform
presence of neural lesions become highly significant and give special weight to the
following quotations from Dr. Howard Howe,5 dated 1952: “With the possible
exception of rabies, the causative agents of
poliomyelitis are more highly neuronotropic than are the other neurotropic viruses which
infect man”; and, again, “The chief locus
of activity for poliomyebitis virus is the
neuron.”
The first question to be discussed is how
and where the virus enters the body. Epi-demiologists are in general agreement that
poliomyelitis is not conveyed by biting
in-sects but mainly by person-to-person
con-tact. Exposures in school rooms and other
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
1)l1ces of congregation do not appear to
heighten the risk. Clinically, the disease is
iiot characterized by respiratory symptoms,
such as sneezing and coughing. These
van-oils features seem inharmonious with air-borne entry and so, in a rather paradoxical
way, does the following laboratory investi-gation.
In 1944 we published experiments on
in-fection by inhalation,’ in which the heads of
monkeys were placed in a chamber into
which atomized virus suspension was dis-charged in fine droplets. The following
l)Oints were noted. 1) Monkeys without preliminary blockade of the olfactory
mu-cosa regularly became infected by the
olfac-tory nerve route, as shown by typical lesions
in the olfactory bulbs. 2) Monkeys with
ol-factory blockade also came down, although
less frequently, and, with 2 exceptions, not
1)y the olfactory route. From these expeni-ments the following inferences can be
drawn. 1) Airborne virus readily causes
in-fection by tile olfactory route if infective
amounts of poliomyelitis virus are inhaled, but since the olfactory bulbs in human poliomyelitis are known to be only very
rarely involved,7 this mode and route of
infection in the human disease must be very exceptional, and probably negligible; hence, poliomyelitis virus must be only
ex-ceptionally air-borne in infective quantities. 2) Since, in the experiments the pharynx was
also directly exposed, and animals with olfactory blockade also became infected,
entry by the pharyngeal route remained a definite possibility, to which the presence of acute lesions in the trigeminab and other
ganglia gave positive testimony.
Epidemiologic and some other considera-tions, which I have not time to describe in detail, have led to the present general belief
that entry, as a rule occurs by the oral
route. This has been confirmed experi-mentally by many observers,8 including ourselves,9 who have produced infection
readily by simple feeding and other atrau-matic methods of oral administration of the
virus. Some of these studies will be pres-ently discussed.
The second question concerns the initial lesions of polionlyelitis. Search for these may be logically directed to 2 main sites:
1) the alimentary mucosa itself, and 2) the peripheral ganglia which provide its nerve
supply. For obvious reasons, our data must
depend almost entirely on animal expeni-ment, with such confirmation as can be obtained from human autopsy. As regards
the non-neural tissues of the tract, Bodian,1#{176}
who is one of the principal proponents of
the theory of primary infection of the
in-testinal mucosa, remarked in 1949: “It is a
remarkable fact that even in those non-neural tissues from which tile virus of polio-myelitis may be isolated at autopsy, its effect is so subtle that as yet it cannot be demonstrated by histologic means”; and,
as recently as 1954, he has described 1 of
the 2 “principal places in which the virus
multiplies” as “certain unknown tissues in the upper and lower parts of the alimentary tract.” Our own occasional histologic
ex-aminations of the intestinal mucosa have
also failed to reveal lesions, nor do I know
of any other workers who have found them. In the face of such negative evidence, I
find it difficult indeed to assume on the sole basis of the presence of virus in the
ali-mentary tract that the latter must be the primary site of viral multiplication. On the
other hand, typical lesions are regularly
present in the peripheral ganglia supplying the alimentary tract, and especially its up-per portions, at a very early period after exposure, as will be presently shown.
The passage of poliomyelitis virus through the axons of nerves is one of its
fundamental characteristics, as it is of rabies virus and some others. This was shown most convincingly by Fairbrother and Hurst1’ in 1929 and in 1941 by Bodian and
Howe.12 One may therefore envision the
entry of virus from the mucosal surfaces,
perhaps aided by the minor friction
attend-ing mastication and swallowing, into the superficial telodendra of peripheral nerves,
followed by ascent into the supplying re-gional ganglia, such as the gasserian, vagal,
about 50 mm. a day, as measured by Bodian
and Howe,1’ and then attacking nerve cells.
Ill a series of human autopsies w&’
dis-covered ganglionic lesions in all cases, and
in the trigeminal ganglion most commonly.
This served as a point of reference and
de-parture for our animal experiments; ai-though it was not itself conclusive, the
pres-ence of lesions left open the possibility of centripetal nerve-borne spread in the
hu-man disease.
In our experinlents we investigated the
peripheral ganglia supplying the alimentary tract in cynomolgus monkeys after oro-pharyngeal exposures by 2 methods, gen-tle swabbing of the throat9a and feeding
virus mixed with the animal’s regular food.91’
The ganglia were examined histologically
by serial section and, in parallel series, by
subinocubation, both on successive days after exposure. In the swabbing
experi-ments, cotton swabs dipped in a virus
sus-pension were gently rolled, not rubbed,
over the fauces for periods of about 1 min-ute repeated at 5-minute intervals over a
total period of 2 hours. The animals were
under anesthesia. in the side-lying position,
and nearly all excess suspension ran out of
the mouth. The amount of friction probably
did not exceed that involved in mastication and swallowing, and was certainly bess than
that from the use of a toothbrush. In my opinion, this procedure was reasonably
comparable to natural conditions of
ex-posure when virus enters the mouth.
Neuro-nophagic lesions appeared as early as 2 days
after swabbing, reached a maximum at 5
days and progressively declined thereafter,
while virus was regularly demonstrable by subinoculation from 3 to 6 days inclusive,
and only once as late as the eighth day. The
gasserian ganglion was most regularly
af-fected, but the vagal (nodose) and sympa-thetic ganglia were also involved, including the celiac, which supplies the intestine.
Some of the lesions were obviously very
early ones, notably those with chromatoly-sis, and could not have been due to
infec-tion preceding exposure. Early lesions and virus recoveries were also observed in the
ganglia after simple feeding. The lesions themselves were as a rube more severe and
extensive after feeding than after swabbing,
probably due to the fact that the virus
dosage was at beast 4 times greater. The presence of well-developed lesions at 48
to 56 hours after exposure indicates that
they began to form at beast several hours
earlier and that the interval is too short
to permit primary extraneural alimentary
invasion, multiplication of virus, viremia, secondary invasion of ganglia from the
blood-stream and formation of lesions, a 5-step process, to run its full course.
Con-firmation of this assumption was obtained in negative results from histologic examina-tion of ganglia, such as the spinal, not
di-rectly connected with the alimentary tract, which would have been simultaneously and
equally exposed to any circulating virus present at the time.14
Our conclusion from these experiments
seems well substantiated, therefore, that ingested virus promptly reaches the regional ganglia by the neural route and infects
them, with the production of what may be
regarded as the primary lesions of
polio-myelitis.
It will be noted that both lesions and virus were found in the celiac ganglion as well as in the ganglia supplying the upper alimentary tract, although bess regularly. This has a bearing on the subsidiary
ques-tion, whether the pharynx or the gut is the preferential site of initial infection, a ques-tion of special interest because of the cur-rently widespread belief that poliomyeiitis
is primarily an intestinal infection. In 1944
and again in 1948 we performed some ex-periments15 on a total of 44 cynomolgus monkeys in which exposure was confined to
the stomach and intestines by means of fat-covered capsules containing virus,
intro-duced through a cannula directly into the esophagus. Only 1 of the 44 came down with paralysis; only in this animal was virus recovered from the stools after the
immedi-ate post-ingestionab period. By simple feed-ing of the same strains, 40 to 50 per cent of control animals became paralyzed. So
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
SPECIAL ARTICLE 281
far as these experiments go-and we should
like to have repeated them with a more
virulent strain-they indicate that the
pharynx is more vulnerable to infection
than is the bower portion of the alimentary
tract.
The third question to be discussed
con-cerns excretion of the virus. You will recall that in human patients excretion has been
found to begin ill both the throat and the intestine several days before the onset of
symptoms, to reach a peak during the acute
phase and to persist, in a gradually
declin-ing proportion of cases, for several weeks.’
While it has l)een stated that virus
disap-I)ears oner from the throat than from the
stools, I aili not at all sure that this is true.
The amounts of material that can be
ob-tamed from tile throat for testing are much
smaller tilan those from the intestine, in
spite of which positive results have been
obtained from throat swabs in patients with
poliomyelitis as follows : twice at 8-9 days after onset; 3 times, at 11-14 days; once at 17 days, and once at 4 months after onset.
I have commented on the absence of
lesions in the alimentary mucosa and on the presence of lesions in the regional
gan-glia very shortly after exposure. Identifica-tion of the ganglia as sources of excretion of virus into the upper and lower portions of
the alimentary canal was therefore a logical
subject for investigation. In order to avoid
initial contamination of the mucosa,
par-enteral inoculations were employed.16 Fecab
excretion after such inoculations was al-ready on record at the time we began our studies, notably in the study by Melnick’T
who had obtained a large number of positive results following intracutaneous and other injections. In our first experiments we ex-posed the central end of a divided
cutane-ous branch of the trigeminal nerve by dip-pmg it into a suspension of virus and there-after examined the nasopharyngeal wash-ings and stools at daily intervals. Excretion occurred in 3 instances as early as 2 days after exposure, in other instances on the third and fourth days, and usually in the
pharyngeal washings as well as in the stools.
Direct inoculation of the gasserian ganglion
gave positive tests on the fourth day.
Ex-cretion occurred after intrathalamic inocu-lation on the fourth and fifth days in 2 of 4 animals, but only in the pharyngeal
wash-ings. Inoculation of the celiac ganglion gave positive stool tests
(
pharyngeal sampleswere not collected) in 2 of 3 animals, be-ginning #{248}nthe fourth day. Massive intra-venous inoculations failed to produce
ex-cretion at 24 and at 48 hours.
In a subsequent study’8 on centrifugal migration of virus in peripheral nerves
after intrasciatic and intrathabamic
inocu-lation we observed both pharyngeal and intestinal elimination of the virus, which was related to the advance of virus into the
distal nerve segments.
We have, therefore, convincing evidence of both pharyngeal and intestinal excretion
of virus originating in peripheral ganglia supplying the alimentary tract, together
with evidence that it is related to centrifu-gal spread through peripheral nerves. To
account for excretion, therefore, it is not necessary to postulate viral multiplication
in the mucosa itself, but rather inner, neural
foci of infection.
The chronology of fecal excretion throws
further light on the point at issue. In 1950 Howe, Bodian and Morgan8 studied
excre-tion in 50 chimpanzees fed various amounts of virus of types 1 and 2. For each type there was a total of 59 first feedings. Tests, often several, were made on each animal, usually on consecutive days. All tests were negative in 20, or 34 per cent of the
ani-mals, 1 of which became paralyzed. The peak for first positive tests was at 10 to 12
days (16 cases) after feeding, with 10 others
still later, and as bate as 20 to 21 days.
There are also human observations in the
61 children reported by Kaprowski and his associates,19 following oral administration of a nonparalyzing strain of type 2 virus.
Here the chronology of first excretion,
ex-cept for a somewhat earlier peak (8 days)
was similar. Thirty-two of the children (52 per cent) had negative tests throughout.
r
seems clear that excretion is a rather late phenomenon relative to the time of
ex-posure, is irregular and inconstant, and very
difficult to explain on the basis of primary infection of the alimentary mucosa.
There is another feature of excretion which has, I believe, considerable
patho-genetic importance in the evolution of
polio-myelitic infection. As the virus is excreted
into the pharynx and gut, ideal conditions
are created for successive reinvasions and for cumulative re-excretion of larger and
larger amounts of virus, a chain-reaction which presumably continues until the
im-munobogical defenses come into play. This
process may well have important sequelae
in regard to extension of infection and the
production of viremia.
What is the source of viremia? The exact
mechanism responsible for this feature of
poliomyelitis, discovered in 1952 by Horst-mann2#{176}and by Bodian2’ to be at least fairly frequent, which was contrary to previous
belief, is not known. Certain observations by Horstmann and by ourselves, however,
throw some bight on the matter and suggest a relationship with excretion. Horstmann2#{176} showed that after virus is fed to cynomolgus monkeys and to chimpanzees viremia
be-gins as a rule 4 to 6 days later and usually disappears before or soon after the onset of symptoms. In human patients it has been found during the early symptomatic stage,
as well as in asymptomatic cases, and is
accompanied by both fecal and
nasopharyn-geal excretion of virus. In some instances,
Horstmann noted vir#{235}mia 24 hours after feeding virus,22 which disappeared for a
few days and then returned. In our experi-ments,23 in which 80,000 PD,,, or more were fed, the blood was negative at 12 and 18 hours, but became positive at 36 hours. However, when only 500 PD5,, were
fed-an amount much nearer that involved in natural exposures-the blood was con-sistently negative until 5 days when, as well
as on the sixth day, it was positive. Virus
was recovered from the stools on each day.
From these various observations, I have
formulated an hypothesis which admittedly
awaits further proof. Under natural circum-stances, viremia begins after the initial phases of infection have proceeded to a point where virus is excreted into the
au-mentary lumen in considerable quantities,
roughly corresponding with those present immediately after massive feeding. From
the interval of about 36 hours between massive feeding and the onset of viremia
it may be inferred that virus is taken up by intermediate tissues, such as the tonsils and adenoids and the solitary and agminated follicles of the intestinal wall which after a short period discharge some part of their
viral content into the blood stream by way
of the lymphatics. Virus could also be taken up by the portal capillaries and temporarily held up by the reticuboendotheliab tissues of
the liver. Some corroboration of the batter process was found in the fact that in our animals the liver also gave a positive test for virus at 36 hours. Under natural condi-tions, viremia might then be regarded as due to uptake of virus from the alimentary
surfaces during the reinvasion-re-excretion
cycle, or chain-reaction, which I have
sug-gested as the cause of a continuous and
in-creasing output of virus into the lumen.
Let us now consider the mechanisms re-sponsible for invasion of the central nervous
system. Until the discovery of viremia as a
fairly frequent event in the early phases
of poliomyelitis it was generally supposed that infection only reached the central nerv-ous system by axonal ascent through periph-eral nerves, a process that today is perhaps too widely discounted or minimized.
Actual-ly there is experimental evidence for both
routes, and the main question concerns their relative importance. I have described our experiments showing quite conclusively how early and with what regularity and ease infection reaches the regional
periph-eral ganglia after surface exposure. On the other hand, it has been a matter of sur-prise to find how seldom such infection can
be traced centripetally into the correspond-ing centers of the nervous system.9” In an intensive search for the earliest histologic
signs of this event, we have succeeded only
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
rons. In 3 of 4 animals inoculated by the carotid route, no symptoms were observed
and no significant lesions were discovered
in either the neural or the glial elements.
All 4 animals receiving inoculations into the vertebral arteries became infected. One
of them was found dead at 4 days, 2 were
sacrificed at 3 and 5 days, respectively, before symptoms appeared, and 1 deveb-oped spinal paralysis at 9 days without any bulbar signs. The histopathobogic picture
was typical and similar in all, with
maxi-mum involvement in the spinal cord,
chro-matolysis, neuron necrosis, neuronophagia and varying degrees of polymorphonucbear,
lymphocytic and microglial infiltration. In
the medulla and pons, lesions were usually present, although on the whole less
exten-sive and severe than in the cord. In 1
ani-mal sacrificed on the third day, no lesions
were present in the medulla. We were un-able to confirm Bodian’s theory that the
area postrema of the medulla constitutes
the point of entry, this structure being
un-involved in the present series, as well as in
others we have studied. On the contrary,
virus appeared to have passed directly from the blood into nerve cells with surprisingly
little evidence of opposition by the inter-vening barrier tissues. Comparison of the
carotid and vertebral artery inoculations gives the impression that the critical factor governing the localization of lesions in the
central nervous system from viremia is the
relative susceptibilities of the neurons
them-selves. Selectivity for certain cell types, is,
of course, one of the prime characteristics of pobiomyebitis virus.
Comparison of nerve-borne with viremic
invasion of the central nervous system in
our experiments suggests that the former should be more apt to cause initial signs
and symptoms referable to the brainstem (i.e., “bulbar” manifestations), including certain nonparalytic ones, while viremia
should be more likely to cause primary spinal manifestations, particularly paralysis.
Preparalytic clinical symptoms are com-monly suggestive of bulbar involvement:27
vomiting, stiffness, headache, etc., and for
a few tinies. You will recall that after
swab-bing, both lesions and virus appeared to
decline in the ganglia after the fifth day,
aild the virus to disappear after the sixth
or seventh day. It may be inferred that
ganglion infection tends to subside after a
brief period of viral multiplication, without
in many instances advancing further, or
merely sending such small quantities of
virus upward as to permit only slight,
local-ized and transient infections of the central
nervous system. In a few instances, after
swabbing the throat, the only central lesions
discovered on serial section were small
in-filtrates in and limited to the spinal
trigem-inal nuclei in the pons or medulla. Herein
we may have an explanation for some
asymptomatic infections and cases of the
so-cabled “minor illness.”
Viremia obviously poses a threat of
cen-tral nervous system invasion against which
the unimmunized individual can only
op-pose the blood-neuron barrier, the ecto- and
mesodermal giia, which has generally been
regarded, largely on the basis of Flexner
and Amoss’s early experiments,24 as of
con-siderable protective value. Comparing the
ease of inducing infection by various
intra-neural inoculations with its difficulty by
even massive intravenous inoculations, these
workers estimated that tile batter require
about 1250 times as many infective doses as
does inoculation directly into nervous
tis-sue. We, too, have found barge intravenous
inoculations frequently ineffective, a
phe-nomenon explained by Bodian’s recent
ob-servation25 that intravenously injected virus
is rapidly and completely removed from the
circulation.
To assure entry from the blood stream
into the central nervous system, we
inocu-lated virus directly into its arterial supply, the carotid and vertebral arteries.26 The carotid supplies the cerebral hemispheres,
the striatum and the uppermost parts of
the brainstem-those areas which in general
are at beast susceptible to poliomyelitis
virus-while the vertebral artery supplies
the lower brainstem and the spinal cord,
neu-this reason, among others, I believe that nerve-borne entry remains of considerable importance and could explain some failures of immunization to protect against paralytic
infection.
What is the pathogenesis of asyinpto-matic and mild, nonparalytic infections? These probably constitute a heavy majority
of all cases of human poliomyelitis, and are often accompanied by viral excretion. To
explain them, it is not necessary to postu-late extraneural infection. Neural involve-ment in the peripheral ganglia can subside,
as I have shown, without causing invasion of the central nervous system.
Comprehen-sive histologic examinations of asympto-matic cynomolgus monkeys,28 in which comparison of lesions in the ganglia
supply-ing the alimentary tract of newly received
animals with those in animals that had been
housed in our animal quarters for 2 or more weeks showed that a strikingly high
per-centage of the older animals had typical neuronophagic lesions while the new
ani-mals had none. No significant lesions were found in the central nervous system of any
of these animals. We have also observed. as have many other workers, asymptomatic
animals in which, after various types of inoculation, typical foci of limited extent
appeared in the central nervous system. Be-cause of these it is always necessary to examine the central nervous system before success or failure of inoculation can be decided. There can be little question that
asymptomatic infections of this kind also
occur in mall, and that mild, symptomatic
but nonparalytic cases are often due to central nervous system infection which sub-sides before irreversible damage has
oc-curred.
What are the natural and acquired de-fenses against poliomyelitic infection in both its primary and secondary aspects, and are these effective against nerve-borne
in-vasion? Unless already immune in some de-gree, the individual has little if any natural
defense against primary infection itself, but the chances favor asymptomatic or mildly symptomatic disease. The reasons
for this are obscure and may reside in the host, or in the particular strain of virus
involved. Individuals with a certain degree of immunity but still remaining susceptible
have an excellent chance of either escaping infection entirely or of acquiring it in
harmless form. Antibodies in the pharyngeal mucus, as demonstrated by Bell and
others,29 can neutralize ingested virus in the pharynx and thus block entry at that
point (apparently antibodies are not present in the intestine to perform a similar function there). If the individual acquires infection, antibodies in the blood, if in adequate titer,
can neutralize circulating virus and thus prevent viremic invasion of tile central
nervous system;1#{176} on the other hand,
hu-moral immunity probably has less value against nerve-borne invasion. Humoral im-munity, or possibly some other undefined
factor, can apparently check the spread of infection to a certain extent after neural
invasion ilas occurred and thus prevent or lessen the paralytic effects of central
nerv-ous system involvement. In the gamma globulin trials of 1952,31 there were several cases of paralytic poliomyelitis but these were less severe than those in the controls
and ended in recovery. In an experimental study of ours made in 1943,32 a series of
cynomolgus monkeys were subjected to
various nontraumatic exposures, such as swabbing of the tongue, enemas and naso-pharyngeal sprays. Five of the survivors
which never had shown signs of infection were then challenged by intracerebral
in-oculation with the same strain of virus. Four of the five which showed no symptoms were sacrificed and examined histologically for inapparent infection of the central nervous system. This was discovered in all 4, was
characterized by typical but mild lesions that had spread to only a limited extent from the point of inoculation to the brainstenl,
and had reached the spinal cord in only 1 instance. I mention this experiment mainly
because it contradicts the assumption that when virus has penetrated into the central nervous system or even into any nervous
structure, defensive mechanisms are
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
SPECIAL ARTICLE 285
able of preventing further spread. I feel
certain that this assumption is contrary to
the trutil, although the limitatiolls of such
prtectio11 are doubtless considerable.
In conclusion, if one surveys the whole picture of human poliomyelitis and
remem-l)ers tile striking and characteristic tendency
of the infection to halt spontaneously at
almost ally stage of its evolution it becomes
apparellt that on the basis of neurotropism the various clinical forms can be graded
simply by degrees of severity and
progres-sion and that tiley form a clinicopathologic
COlltillIIuIll. Thus, we see the asymptomatic case as OliC ill which infection is limited
to the peripheral ganglia or in some
in-stances perilaps has very lightly affected
the central nervous system but without
pro-(hieing clinical Illallifestations. In its
symp-tomatic fornis, infection has passed into the
central ller’VOIIS system, by either nerve- or
blood-borne entry, in sufficient degree to
1)rOdllce manifestations: in mild
nonpara-lytic cases, with little or no involvement of motoneurons; in mild paralytic forms, with
niotoneuronal involvement of minor degree, often reversible; in severe paralytic forms, with motoneurons, in Part at beast, irreversi-bly damaged.
Tile dichotomy inherent in the view that
the primary infection is extraneural and involvement of neural tissues is secondary,
incidental and perhaps exceptional, seems unnecessary, illogical and unwarranted by tile facts. On the other hand, as I have attempted to show, a monistic, unitarian concept, based on primary neurotropism of
tile virus seems to me to be fully warranted
by the various pathological, clinical and
perimental data bearing on the early, evolu-tionary aspects of the disease. True extra-neural infection, if it occurs at all in the
human disease, can properly he assigned
to the later stages when, under the stresses of advanced and severe infection and its
complications, pituitary or adrenocorticab hormones are produced and circulate in excess, which could account for the lesions
in lymph nodes, myocardium, etc. that are observed inconstantly in human tissues post
mortem, and correspond with those found
in the experimental disease only after hor-mone treatment. This process, if it does
oc-cur in man, can be regarded as the excep-tion that proves the rule of basic
neuro-tropism.#{176}
REFERENCES
1. Enders, J. F., Weller, T. H., and Robbiiis, F.C. : Cultivation of the Lansing straill
of poliomyelitis virus in cultures of
van-ous human embryonic tissues. Science,
109:85, 1949.
2. Schwartzman, C., and Anonson, S. M.: Alteration of Experimental Poliomyelitis
by Means of Cortisone with Reference
to Other Viruses. New York, Columbia Univ. Press, 1953.
3. Boclian, D. : (a) A reconsideration of tile pathogenesis of poliomelitis. Am. J. Hyg., 55:414, 1952; (b) Pathogenesis of poliomyelitis. Am. J. Pub. Health, 42: 1388, 1952.
4. Cold Spring Harbor Symposium on the Biological Nature of Viruses, reported
by Adams, NI. H. Science, 1 18:66, 1953.
5. Howe, H. A. : Poliomyelitis, in Viral and Rickettsial Infections of Man, 2nd Ed., T. I. Rivers, Editor. Philadelphia, Lip-pincott, 1952, p. 307.
6. Faber, H. K., Silverberg, R.
J.,
and Dong,L.: Poliomyelitis in the cynomolgus
mon-key. III. Infection by inhalation of drop-let nuclei and the nasopharyngeab portal
of entry, with a note on this mode of
infection in rhesus. J. Exper. Med., 80:
39, 1944.
7. Sabin, A. B.: The olfactory bulbs in human
poliomyelitis. Am. J. Dis. Child., 60: 1313, 1940.
8. Howe, H. A., Bodian, D., and Morgan, I. M.: Subclinical poliomyelitis in the chimpanzee and its relation to alimen-tary remfection. Am.
J.
Hyg., 51:85, 1950.9. Faber, H. K., Silverberg, R. J., and Dong,
L.: Studies on entry and egress of polio-myelitic infection. V. Entry after simple feeding: with notes on viremia. j. Exper. Med., 97:69, 1953.
10. Bodian, D.: Histopathobogical basis of clinical findings in poliomyelitis. Am. j. Med., 6:563, 1949.
* The diagrams and microphotographs shown on
lantern slides during this lecture, together with a fuller discussion of the various points at issue,
appear in a monograph by the writer on the
1 1. Fairbrother, R. W., and Hurst, E. W. : The
pathogenesis of, and propagation of the virus in, experimental poliomyebitis.
J.
Path. & Bact., 33:17, 1930.12. Bodian, D., and Howe, H. A. : The rate of
progression of poliomyelitis virus in nerves. Bull. Johns Hopkins Hosp., 69:
79, 1941.
13. Faber, H. K., and Sibverberg, R. J. : A
neuropathobogicab study of acute human
poliomyelitis with special reference to the initial lesion and to various potential portals of entry.
J.
Exper. Med., 83:329, 1946.14. Faber, H. K., Silverberg, R.
J.,
and Dong,L.: Unpublished data.
15. Faber, H. K., Silverberg, R.
J.,
and Dong, L. : Pobiomyelitis in the cynomolgusmonkey. IV. Further observations on
exposures confined to the stomach and
intestines, with notes on the fecal excre-tion of virus.
J.
Exper. Med., 88:65, 1948.16. Faber, H. K., Silverberg, R.
J.,
Luz, L. A.,and Dong, L.: Studies on entry and
egress of poliomyelitis infection. III. Ex-cretion of the virus during the presymp-tomatic period in parenteralby inoculated
monkeys.
J.
Exper. Med., 92:571, 1950.17. Melnick,
J.
L.: The recovery of poliomye-litis virus from the stools of experiment-ally infected monkeys and chimpanzees.J.
Immunob., 53:277, 1946.18. Faber, H. K., Sibverberg, R.
J.,
and Dong, L.: Studies on entry and egress of polio-myelitis infection. VI. Centrifugal spread of the virus into peripheral nerve: with notes on its possible implications.J.
Exper. Med., 97:455, 1953.19. Koprowski, H., Jervis, C. A., Norton, T.
W., and Nelsen, D.
J.:
Further studieson oral administration of living polio-myelitis virus to human subjects. Proc. Soc. Exper. Bioi. & Med., 82:277, 1953. 20. Horstmann, D. M.: Poliomyebitis virus in
blood of orally infected monkeys and chimpanzees. Proc. Soc. Exper. Biol. & Med., 79:417, 1952.
21. Bodian, D., and Paffenbarger, R. S.: Vir-emia and antibody response of abortive
poliomyelitis cases. Federation Proc.,
12:437, 1953,
22. Horstmann, D. M. : Viremia in
pobiomyc-litis. Bull. New York Acad. Med., 29:
736, 1953.
23. Faber, H. K. : The Pathogenesis of
Polio-myelitis. Springfield, Thomas, 1955.
24. Flexner, S., and Amoss, H. L. : Localiza-tion of the virus and pathogenesis of epidemic poliomyebitis. J. Exper. Med., 20:249, 1914.
25. Bodian, D. : Viremia in experimental
polio-myelitis. I. Ceneral aspects of infection after intravascular inoculation with
strains of high and of bow invasiveness.
Am.
J.
Hyg., 60:339, 1954.26. Faber, H. K., and Dong, L. : Studies on
entry and egress of poliomyelitic
infec-tion. VIII. The relation of viremia to invasion of the central nervous system.
J.
Exper. Med., 101:383, 1955.27. Faber, H. K. : Pathogenesis and onset
symptoms of poliomyebitis. PEDIATRICS,
6:488, 1950.
28. Faber, H. K., Silverberg, R. J., and Dong,
L. : Studies on the entry and egress of
poliomyelitis infection. I. Neurotropic
infection of peripheral ganglia in
ap-parently healthy monkeys following casual exposure.
J.
Exper. Med., 91 :417, 1950.29. Bell, E.
J.:
The relationship between theantipoliomyelitic properties of human
nasopharyngeal secretions and blood
serums. Am.
J.
Hyg., 47:351, 1948.30. Bodian, D.: Experimental studies on pas-sive immunization against pobiomyelitis. III. Passive-active immunization and pathogenesis after virus feeding in chim-panzees. Am.
J.
Hyg., 58:81, 1953.31. Hammon, W. MeD., Coriell, L. L., Wehrbe,
P. F., and Stokes, J., Jr.: Evaluation of Red Cross gamma globulin as a prophy-lactic agent for poliomyelitis. 4. Final report of results based in clinical
diag-nosis. J.A.M.A., 151:1272, 1953. 32. Faber, H. K., Sibverberg, R.
J.,
and Dong,L.: Poliomyelitis in the cynomolgus mon-key. II. Resistance to spread of infection
in the central nervous system following
exposures of the mucous membranes to virus, with comments on non-paralytic pobiomyelitis.
J.
Exper. Med., 78:519,1943.
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
1956;17;278
Pediatrics
Harold K. Faber
SPECIAL ARTICLE: THE EVOLUTION OF POLIOMYELITIC INFECTION
Services
Updated Information &
http://pediatrics.aappublications.org/content/17/2/278
including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or in its
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
1956;17;278
Pediatrics
Harold K. Faber
SPECIAL ARTICLE: THE EVOLUTION OF POLIOMYELITIC INFECTION
http://pediatrics.aappublications.org/content/17/2/278
the World Wide Web at:
The online version of this article, along with updated information and services, is located on
American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1956 by the
been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
at Viet Nam:AAP Sponsored on September 9, 2020 www.aappublications.org/news
