TOXOPLASMOSIS
By Harry A. Feldman, M.D.
Department of Preventive Medicine, State University of New York, Upstate Medical Center at Syracuse
Studies conducted in the author’s laboratory have been made possible principally by a series of grants
from the National Institutes of Health, Public Health Service.
ADDRESS: 766 Irving Avenue, Syracuse 10, New York.
REVIEW
ARTICLE
559
PEDIATRICS, September 1958
T
HAT toxoplasmosis represents aprob-lem of special interest to pediatricians
comes as no surprise, since the first in-stances of proven human infection were de-tected in newborn infants by Wolf, Cowen
and Paige.1 Although Toxoplasma gondii
was first recognized in 1908 by Nicolle and Manceaux2 in North Africa and by
Splen-dore3 in Brazil, and although there had
been sporadic reports of other encounters with this parasite, it aroused no great ex-citement until the afore-mentioned report1 of its unquestionable role in the encephalo-myelitis of infancy. In the years immedi-ately following this publication there was a flurry of interest in toxoplasmosis but this
was interrupted by the war years. Begin-fling with the descriptions of new, precise
serologic procedures in 1948, human and
animal toxoplasma infections have become of such world-wide concern that it is now almost impossible to remain abreast of the mushrooming list of publications which deal with the many facets of toxoplasmosis.
The recognized manifestations of human
and animal disease are so broad as to pique the curiosities not only of pediatricians but also of pathologists, ophthalmologists, in-ternists, epidemiologists, veterinarians and biologists. While toxoplasmosis represents a somewhat new disease, which of itself arouses excitement, much of its appeal is related to the causative agent’s character-istics : it is an intracellular parasite which is readily observed microscopically and has little concern for the kind of cell in which it multiplies; and there are serologic pro-cedures available for limited or broad-scale studies, such as are not possible with most other disease-producing agents. Another unusual aspect of the organism is that the
illnesses which it may initiate are similar in all hosts.
Because of the voluminous literature which now deals with toxoplasmosis, it is the objective of this review to summarize the present status of certain aspects of the problem, rather than to attempt a survey of the total bibliography.
BIOLOGY
Toxoplasma gondii is considered to be the only species of toxoplasma. The parasite usually has a crescentic appearance with one end being rounded and the other
some-what pointed, but it may appear ovoid in
tissues. The organism usually measures about 2 to 4 by 4 to 7 p. It stains best with
Giemsa or Wright stains, appearing as a
reddish nucleus in a pale, blue cytoplasm. Multiplication by binary fission can be ob-served in preparations made from rapidly growing parasites.
Toxoplasma have been found in all cells, except erythrocytes, of many mammals and birds, which probably makes it the most “unspecialized” parasite known at present. There have been some reports of its
pres-ence in reptiles but such infections have not been confirmed.4 Parasites have been injected into and recovered from lizards and turtles but there is insufficient evidence that active multiplication took place; there are indications that the parasite persisted for several weeks to a month in these hosts.
Aside from man, infections have been en-countered among gondi, mice, rats, rabbits, guinea pigs, squirrels, dogs, foxes, cats, mink, chinchillas, swine, sheep, cattle and various primates. Toxoplasma, also, have
560
been produced in other species of birds. In Iflost instances, yoiig animals have ha(l
more severe infections and higher death
rates than adult animals. There is good evidence that animals that have recovered from infections frequently continue to sup-port viable parasites in the tissues for
con-siderable periods of time, if not for life. That such “encysted” parasites break out to produce recurrent disease in the same host has been suggested but not
substanti-ated. There are many indications which
point to the existence of human
counter-parts for these animal experiences.
Aggregates of toxoplasma have been
noted in sections of brain, spinal cord, heart
and skeletal muscle of both humans and
animals. These are usually referred to as “pseudocysts” on the assumption that the “wall” which encircles the clump of para-sites is not derived from the toxoplasma but represents a contribution by the host. How-ever, Frenkel5 considers the parasites to be responsible for the “wall” and, therefore, that these structures are cysts. There is no real disagreement with the assumption that organisms thus contained remain viable for a long time, if not for the life of the host.
There is also some disagreement as to
whether such organisms or their products
may initiate recurrent illness by release into surrounding tissues from rupture of a “cyst” wall and induction of a local hypersensitiv-ity reaction to the antigenic material which escapes. This has been suggested to be the
mechanism whereby recurrent attacks of
human uveitis are 6
SEROLOGIC METHODS
The dye and complement-fixation tests
have been employed widely since 1948.
Briefly, the former7 consists of mixing con-stant amounts of fresh, live parasites
sus-pended in a fresh, normal, human serum
with similar quantities of varying dilutions of the inactivated test serum. Following in-cubation, freshly prepared alkaline methy-lene blue is added to each mixture and the relative number of stained and unstained parasites is determined by direct
micro-scopic count. Unaffected parasites are
stained blue, while those which have been exposed to antibody PIlls a heat-labile serum
component known as activator (supplied
by the normal serl.Illl in which the parasites
were suspended) remain unstained. That
dilution of test serum which contains 50% unstained parasites is considered to be the end-point or titer of the serum. The dye test is performed generally with fourfold dilutions of serum.
Recent have indicated that
“activator” is the properdmn system :‘#{176}
prop-erdin + hemolytic complement + magne-sium ion. Gr#{246}nroos8 believes that the C’-l component of hemolytic complement is not
required, that very high concentrations of properdin alone may induce positive dye
reactions. The author’s experience9 indicates
that all four components of hemolytic
com-plement are necessary; it has not been pos-sible in his laboratory to produce a positive
reaction with properdmn alone. Of consid-erable interest is the fact that the toxo-plasma system is the only one in which it
has been demonstrated that the activity of a specffic antibody depends upon the pres-ence of the properdin system, as it is cur-rently defined.
Normal human and mouse sera do not
yield positive dye tests, as do other animal
and fowl sera.7 This latter reaction is
non-specific in that it may be abolished by heat-ing the serum for 30 minutes at 56#{176}C,but
cannot be restored by the addition of fresh, human serum unless antibody is present.
This nonspecific, antitoxoplasma effect of
various normal animal sera also may be
removed by treating the fresh serum with
zymosan. It is evident that in order to
avoid such nonspecific reactions, all sera
should be inactivated prior to their titration.
This step has been discussed often12 and is
essential to the proper performance of the dye procedure. Unless it has been adhered
to, data on the nonspecificity of the test,
particularly with animal sera, must be
con-sidered to be inadequate. Cathie1
cor-roborated and extended these conclusions and demonstrated how failure to take this
phenomenon into account led to
toxoplasma and sarcosporidia.’ In the same report Cathie states that he was unable to confirm other findings of Awad regarding cross reactions between toxoplasma and
trichomonas, trypanosoma, malaria and
salmonella infections. The author has had similar experiences.
The inability of normal mouse serum to
function in the dye test can be explained by its deficiency in hemolytic complement,
but the reason for the difference in anti-toxoplasmic activity between fresh normal human and other animal sera is obscure.
The dye test is sensitive and specific, but technically demanding. Since it requires the use of live parasites (a real hazard), the test cannot be expected to be performed except in a limited number of suitably equipped laboratories. Antibodies may be detected with the dye test in about 2 weeks after onset of clinical symptoms. They persist in gradually diminishing titer for many years.
Such antibodies are transferred passively to the fetusl5 in whose serum they decrease sig-nificantly by 3 to 4 months, and from which
they disappear in about 6 months.
Antigens1#{176} derived from either infected chorio-allantoic membranes of embryonated
eggs or mouse peritoneal exudates may be
employed to detect antibodies in any stand-ard complement-fixation procedure. These
antigens are cell-free and may be handled with safety in the serologic laboratory.
Com-plenlent-fixmg antibodies develop slowly
and are said to disappear or decrease
markedly iii about 2 years. Thus, it is
pos-sible to have a high titer in the dye test and negative complement-fixation test,
either early or late in the course of infec-tion. The solution for this question is to repeat both tests at intervals of at least 2 weeks.
Positive skill reactions17’ 18 are of the de-hived type and iiia’ he elicited with anti-gens SilYIIltl to those llst-’(1 in the
(‘Olliple-IlleIlt -fixat ion test. I’Ol egg alitigells ColitlOl
luaterial dali be lIlade fnln thit’
(.‘hlOFiO-allalitoic IlleIlll)laIles of tuinioculated
elfl-l)ryOS, while 1fl extract of muue spleen
generally is used as the control for antigens
produced from mouse peritoneal exudate.
There is no satisfactory way to standardize antigens for skin testing, and it is
question-able whether comparable data can be
ob-tamed with different lots or dilutions of antigen, even when they have been
manu-factured by the same method. Although
negative skin tests do occur in the presence of high titers in the dye test, the reverse is problematic. While the usefulness of the skin test is probably limited to epidemi-ologic surveys rather than as a diagnostic aid in a specific case, the author has become increasingly dissatisfied with it because of an inability to achieve reproducible activity
in different lots of material.
Jab recently described a new
hem-agglutination test which also employs a
cell-free antigen. The titers obtained by this method seem to parallel those arrived at with the dye test, except that discrepan-cies are not infrequent with sera which have a high titer by the latter procedure. Further reports of experiences with the hemaggluti-nation test are awaited with interest.
Another, new serologic procedure has
been reported by Goldman21 to be useful in screening sera for dye-test titration. This method measures antibody by its ability to inhibit a fluorescein-labelled antiserum from producing fluorescence in toxoplasma, previously prepared as dried films on slides.
While the principle is interesting and pro-vocative, the available data are insufficient to permit its usefulness as a diagnostic tool to be appraised.
HUMAN TOXOPLASMOSIS
Toxoplasma infections of humans
con-veniently may be classified as follows:
1. Congenital 2. Acquired
a) Encephalitis h) Lyrnphadenitis c) Systenlic
ti) tJveitis
e’) IIIdpF)LItI1l
A diffuse niaculopapular rash may i)t-’
noted Ill atty of thit:’ first three of tite
ac-(ftlire(I fornis. A Iti iough toxoplasnilt ILL V(’
been isolated from the emicleated eye2 of
TOXOPLASMOSIS
not possible to determine whether this was a manifestation of unrecognized diffuse dis-ease or an isolated, acquired toxoplasmic chorioretinitis. The existence of the latter is one of the principal questions currently un-der investigation throughout the world.
En-cephalitis, lymphadenitis and systemic dis-ease may occur in variable degrees during the same illness.
Other classifications of toxoplasmosis
have been suggestedll2o but it is the
writer’s belief that, in general, they suffer from being overly ambitious in scope.
Per-haps that proposed here may be judged
similarly, for basically the outline can be reduced to two groupings; congenital and
acquired (active or inapparent). Both the congenital and active, acquired forms have broad spectra of expression and it would seem pointless to categorize each
combina-lion of signs and symptoms as a clinical
en-tity. The classification already proposed in-dicates only predominant expressions of in-fection, rather than detailed signs and
symp-toms. The term “inapparent” is most
un-satisfactory because it is based entirely on serologic data and implies that there has been no clinical illness. It probably should be interpreted as a symbol of our made-quacies as clinical diagnosticians.
The terms “latent” and “chronic”
toxo-plasmosis were not included for all too
often they have been applied to conditions
such as hydrocephaly (as an example) which
represent residua of infections rather than active infectious processes. Latency, on the other hand, should mean that following in-fection, the host has retained the parasite in such a state that the parasite again could initiate an acute illness. This may be in-herent in diseases produced by intracellular organisms. The classic example of this is
R. prowazekii and epidemic typhus and
subsequent Brill’s disease. Although we
know that toxoplasma produce acute
dis-ease and that viable parasites then may persist in the host, we lack definite evidence
that such organisms are responsible for
active illness at a later date. Until this has
been settled, it would seem somewhat
pre-mature to speak of “latent” toxoplasmosis with confidence.
Congenital Toxoplasmosis
This form is of special interest to the pediatrician and was the first from which parasites were isolated from a human case.1 There is no proof that either asymptomatic
congenital infections occur or that more than one pregnancy in the same mother will
be complicated by toxoplasma infection.27
The mothers of infants so afflicted invari-ably have high titers in the dye test and of complement-fixing antibodies, which pro-vide strong evidence for the recent acquisi-tion of the maternal infection.
Many isolated case reports of congenital
toxoplasmosis have been published from
various countries throughout the world.
While it is not proposed to review each of these, certain ones seem to be helpful in furthering our understanding of the
patho-genesis and course of the disease and these will be discussed in some detail.
It is generally assumed that congenital
in-fection comes about as an accidental
com-plication (usually of an inapparent infec-tion) of parasitemia, in a woman who
hap-pens to be pregnant. Parasitemia occurs in the absence of significant clinical symptoms in experimental infections of animals, such as rats and monkeys, and probably also in humans, for afebrile lymphadenopathy has been demonstrated in the latter by Sum.28
During the parasitemia, an infected locus
may be produced in the placenta25 permit-ting parasites to cross into the fetal circula-tion. If development of the placental lesion is delayed, then the passively transferred antibodies resulting from the maternal re-sponse to infection might prevent seeding of the fetus by the parasite. In contrast, if
infection spreads rapidly or if passive im-munization of the fetus fails to occur, then
the fetus would become infected. It is also possible for the fetal circulation to lack the necessary heat-labile accessory substances,
a congential infection. If this is so, one
would not expect toxoplasma infections to play a very prominent role in the causation
of congenital anomalies; this has been true
in the author’s experience. One would ex-pect further that since the seeding of the fetus is by way of the bloodstream, its infec-tion would be diffuse and, furthermore, that each fetus would be involved during a mul-tiple pregnancy.
It is conceivable that when two placentae are present, one fetus might escape or its infection be delayed sufficiently so that it is protected by antibodies and therefore
dam-aged less severely. A number of cases of
congenital toxoplasmosis in which there were multiple births have been reported
and in each instance both infants were
affected, although not always to the same degree. In fact, we recently studied a family in which one twin died soon after birth while the other has survived with little dam-age apparent at this time. In the binovular twins reported by Farquhar,29 one child had, among other things, hydrocephalus, cerebral
calcifications and chorioretinitis and the other was entirely normal except for mini-ma! retinal changes. There is no information
as to whether infection may fail to occur in
a fetus if the mother acquired toxoplasma
during the latter two-thirds of pregnancy, nor is there any evidence that congenital infections may occur without leaving any residual damage.
Stanton and Pinkerton30 studied a
26-year-old woman who had had
lymphade-nopathy for 7 weeks, at which time a
right-anterior cervical node was removed and
found to contain a toxoplasma “pseudocyst.” The patient’s serum had a high titer of
anti-body by the dye test. Thirty-six weeks later (43 weeks after onset of the lymphadenop-athy) the patient was delivered of a normal,
full-term infant.
Gard and Magnusson3’ observed a
23-year-old woman who noted the onset of
fever and lymphadenopathy 18 days after her last menstrual period. A node removed
about a month later was thought to contain toxoplasma, and there was serologic
evi-dence of recent infection with toxoplasma. A normal, 3,800-gm infant was delivered 236 days after the onset of the fever and lymphadenopathy.
Sum28 reported a case in which a pregnant female was found to have lymphadenopathy
without fever during the third month of
pregnancy. Antibodies detectable by both
the dye and complement-fixation tests were
present at the time. She was delivered at term of a congenitally infected infant. Beck-ett and Flynn25 described a case of con-genital toxoplasmosis in which the placenta was found to contain several structures which strongly resembled toxoplasma
“pseudocysts.” The mother had had a febrile illness during the third month of pregnancy, accompanied by tender, posterior-cervical lymph nodes which remained palpable for
about 3 months. This affected baby was
born in the thirty-third week of gestation. These cases (summarized in Table I) sup-port the previously offered hypothesis that infections acquired just before, and soon after, onset of pregnancy (onset of lymphad-enopathy) may not result in congenital infections, even though viable parasites
per-sist in the nodes. However, infections which
disseminate to the lymph nodes of the
mother subsequent to the third month of
pregnancy may also spread to the fetus.
Among the cases that we have studied27 (Table II), prematurity occurred in 27%, with a mortality rate of 20% as compared with 7% for the full-term infants.
Congenital toxoplasmosis may present it-self in a variety of forms,26, 27. 32 ranging
from stillbirth to apparent normalcy at birth.
The newborn infant may be obviously
ab-normal with such evidences of active infec-tion as hepatomegaly, splenomegaly, icterus and maculopapular rash. Chorioretinitis and cerebral calcffications, singly or together, may be noted at this time or they may not
be detected until some weeks later. But the
infant who appears to be normal at birth
may, after several weeks or months, be
in-TABLE I
SL-GGESTIVE TEMPORAL RELATION BETWEEN STAGE OF PREGNANCY IN WHICH TOXOPLASMA
WERE ACQUIRED BY MOTHER AND OCCURRENCE OF FETAL INFECTION
Case
. . .
Clinwal illness in
Mother
Interval from
Onset of
Ill-.
ness to Birth of infant
(weeks)
Status of infant .
at Birth is.emarks
Stanton and
Pinkerton30
Gard and
Mag-nusson3’
Sum28
Beckett and
Flynn25
Lymphadenopathy
Lymphadenopathy
and fever
Lymphadenopathy,
afebrile
Lymphadenopathy
and fever
43
34
‘24
23(?)
(33rd week of preg-nancy)
Normal, full-term Toxoplasma “pseudocyst’
found in niaternal lymph
node 7 weeks after onset.
Normal (3,800 gm) Toxoplasma seen in lymph
node 1 flloIIth after onset
of lymphadenopathy.
Congenital toxoplasmosis W’eeks of gestation cann3t be calculated.
Congenital toxoplasmosis; Toxoplasma “pseudocysts”
weight, 1,700 gm; infant seen in placenta.
died 13 hours after
deliv-ery
stances, no abnormalities have been noted until the onset of convulsive disease sev-eral years later. We have not found con-genital toxoplasmosis to be unduly frequent in children with cerebral palsy or epilepsy. Eichenwa1d observed one congenitally
infected infant until it succumbed to an
unrelated illness at 19 months of age, at which time he was able to isolate toxo-plasma from the brain. Somewhat similar experiences have been reported by others. It is probable that, as in the experimental
animal, the organisms remained alive in
“pseudocysts” in the brain tissue.
Experi-TABLE II
PREMATURE AND FULL-TERM BIItTIIS IN RELATION TO
SURVIVAL AMONG 141 CASES OF CONGENITAL ToxoPLASMoSIS
Births Dead Living
Type No. % No. % No. %
Prematnre
Full-term
41
100 26.3
73.5
8
7
19.3
7.0
33
93 HOJ
9l.()
‘I’otals 141 100 1.5 10.7 126 89.3
ences such as this suggest that live parasites persist for many years in humans.
In Table III are summarized the findings reported to us from 180 cases of congenital
toxoplasmosis which we have had an
op-portunity to study serologically. It is
ap-parent that few, if any, survivors escaped unscathed. These babies27 were born in all months of the year; 78% of the mothers were between 18 and 29 years of age, and few of the fathers whose sera were available were
found to have antibodies. These data
sug-gest that the frequency of toxoplasmosis is slightly, if at all, subject to seasonal
influ-ences in the Northern Hemisphere, that
there is probably no human to human trans-fer (except mother to fetus), and that the predominant youthfulness of the mothers points to an age group of greater suscepti-bility, lending support to the hypothesis that congenital toxoplasmosis occurs as an ac-cidental complication of an initial infec-tion.
Generally. the titers in the dye test of
IllOtilel 311(1 iIIftllt ti’e high at l)iltil, usually
Ill CXCCSS of I :1,000, l)LIt the lilaterlual
coin-1)lenlent-fixation titel lll\ be elevtte(l tlI(l the infant’s SCFUII1 lacking in this antibody.
transferred passively, should there be any question al)oult the diagnosis, it woul(l be well to repeat the examination of tile sera of both mother and infant when the latter is 4 months of age, for by this time passively transferred antibody will have been reduced markedly. The antibody titer with the dye test of cerebrospinal fluid is usually about 1/300 of that demonstrable in the
blood-stream, so that none will be detected in
cerebrospinal fluid unless the serum titer is very high or the cerebrospinal fluid is con-taminated by blood.
Parasites may be isolated from cerebro-spinal or ventricular fluids by centrifuging and injecting the sediments into laboratory-reared mice. These are the preferred
ani-mals for isolation studies because spon-taneous infections (such as may be encoun-tered frequently in guinea pigs) are almost
unheard of in such mice. A smear of the
sediment from the ventricular or cerebro-spinal fluid, stained with Giemsa or Wright stain, may reveal toxoplasma. Generally, the titers in the dye test of congenitally
in-fected infants will remain high for many
years, but there are isolated instances where these titers have declined to low values in a much shorter period of time. In the case re-ported by Eichenwald,3 the infant’s titer was above 1 : 1,000 at birth but had de-creased to 1 : 128 several weeks prior to death; the titer in the complement-fixation test had decreased from 1 :64 to 1 :4 during
TABLE III
FREQUENCY WITH WHICH VARIOUS MANIFESTATIONS
WERE REPORTED IN 180 CASES OF CONGENITAL TOXOPLASMOSIS27
. .
Manifeskazon Total
u.ases
Manifestation
Present
No. %
Chorioretinitis
Cerebral calcification Psychomotor retardation
Convulsions
Microphthalmia
Hydroeephaly
Microcephaly
150
158 14
131
135
147
150
141
93
64
51
48
3
31 94
59
45
39
36
21
the same interval. As Eichenwald points
out, it is of special interest that this
anti-body titer diminished despite the fact that
live parasites could be isolated from the infant’s brain.
In a follow-up study of congenital
toxo-plasmosis, not yet completed, we have
found that both dye and complement-fixing antibodies persist for many years in a sig-nificant proportion of both mothers and chil-then.
Three interesting cases have been
re-ported by Bain et In each instance the
diagnosis of hemolytic disease of the
new-born was entertained but each was found to have congenital toxoplasmosis. None of
these infants survived, two were stillborn and the third died soon after birth.
Another unusual report is that of Wolfe
et al.36 which described a 19-year-old boy with pituitary dwarfism who, in addition,
was found to have multiple cerebral
calci-fications, chorioretinitis and a high titer of
dye-test antibodies for toxoplasma. His
mother also had antibodies, but the comple-ment-fixation tests were negative in both.
This, therefore, could have been an instance of congenital toxoplasmosis. The authors
at-tempted to relate congenital toxoplasmosis to the pituitary dwarfism, predicting that
the pituitary gland or hypothalamus had been damaged by the parasite.
Acquired Toxoplasmosis
This has been described in all age
groups,32 and there is no reason to believe
that any particular form (other than the
congenital) is a function of age. An acquired
infection may manifest itself primarily in
the guise of lymphadenopathy, which has been encountered by a number of authors, but the major contributions are those of Sum.28 He believes that in Denmark, at
least, the lymph-node type of the disease may be febrile or afebrile, with enlarged
nodes present for many months. Sum has
isolated toxoplasma from excised lymph
nodes even after the patient has become
afebrile and the antibody titers quite
have a relative lymphocytosis, the initial clinical impression not infrequently is that
they are suffering from infectious mononu-cleosis. The Paul-Bunnell reaction uniformly has been negative.
In the case of a 12-year-old girl who was
found to have lymphadenopathy in the
course of a routine physical examination, Sum was able to isolate toxoplasma from
an ingumnal node, excised about 3 weeks after she had been found to have a positive dye test but negative complement-fixation
test. Complement-fixing antibodies were present at the time of the inguinal node
biopsy. An axillary node was removed 4
months after the initial gland excision and parasites again were demonstrated.
Sum reports28 that the lymph nodes are
generally about the size of walnuts and
often tender during the acute illness, but
that later they become quite painless. The
nodes are firm, discreet, uniformly enlarged and not attached to the overlying skin. They do no seem to suppurate. Lymphadenop-athy is usually generalized and may involve the hilar nodes, but the spleen generally is not palpable. He states that the
lymphad-enopathy may persist for 12 months or
more, with rather pronounced fatigability in some patients, and that he was able to
isolate parasites from muscle obtained from one such patient. (A muscle biopsy also was a source of parasites in another case.7)
Lymphosarcoma developed subsequent to
lymph-node toxoplasmosis in a 3-year-old
female patient studied by Sum, but he
could not relate this to the initial disease. In one instance, he succeeded in isolating parasites from the tonsils of a child suffering from lymph-node toxoplasmosis. Of approxi-mately 100 patients in Sum’s series of the lymph-node form of the disease, one
de-veloped chorioretinitis but there is no proof that this was a causal relationship. He
be-lieves that the histologic picture of
toxo-plasmic lymphadenitis is typical,38 but this opinion is not shared by others. For various reasons, it should not be anticipated that the study of patients with lymphadenopathy
in other geographic locations will be as
re-warding in respect to toxoplasmosis as those
of Sum.
The difficulties and inadequacies of
classi-fications of acquired toxoplasmosis are ap-parent as one disposes of the lymph node
types. Except, perhaps, for uveitis, the other types appear to be oversimplifications,
based upon the most prominent clinical
feature of the case. A good illustration of the unlikelihood that this parasite infects only a single system or organ is provided
by acquired “toxoplasmic” encephalitis. If
one reviews Sabin’s original, thorough
re-port39 of two such cases, he finds that the first patient (a 6-year-old male) was found to have not only encephalitis but
general-ized lymphadenopathy and a palpable
spleen as well. The second child (8-year-old male) had, in addition to encephalitis, en-larged cervical and ingumnal lymph nodes. The former succumbed and the latter
sur-vived without sequelae. A 6-year-old boy
whom we observed during the course of
toxoplasmic encephalitis, at one stage had a generalized maculopapular rash.32 If lym-phadenopathy and rash are indicators of dif-fuse dissemination of the parasite in the host, then encephalitis must represent only a fraction of the total infection.
Further evidence for this is contained in
the report by Sexton et al.,#{176}in which is described a fatal, acquired infection in a laboratory worker. The principal clinical findings were those of encephalitis and a
diffuse, maculopapular rash. Toxoplasma
were isolated from whole blood and
cere-brospinal fluid inoculated into mice ante
mortem and from brain, liver and spleen
obtained post mortem. Parasites also were noted in sections of heart muscle. A number
of other fatal, acquired cases are analyzed in the same report, illustrating the common occurrence of widespread tissue infesta-tion.
Another form of acquired toxoplasmosis has been termed “spotted-fever-like” after
the original description by Pinkerton and
Henderson41 of two fatal cases. Each
pa-tient was an adult with a history of tick
in-volving the scalp, palms and soles (also noted in Sexton’s case40) and evidence of
pneumonia. Histologic examination
re-vealed widespread lesions in the lungs, heart and brain, and toxoplasma were seen in many areas.
The case reported by Kass ci is an-other good example of the extensive nature
of the systemic spread of toxoplasma in
the host. This is not too surprising in view of the organism’s remarkable ability to mu!-tiply in all cell types (except erythrocytes)
in mammalian hosts. The latter is prob-ably the key to the unusual similarity
be-tween human and animal infections, which is almost without parallel among infectious
diseases.
In both humans and animals, the younger the host, the more likely is the disease to be severe. Although we are unable to esti-mate the case fatality rate, it seems likely that most patients survive, probably with-out residua.
Ocular Toxoplasmosis
The early discovery that chorioretinitis was a frequent component of congenital toxoplasmosis stimulated ophthalmologists and others to attempt to relate toxoplasma to the disturbing problem of acquired uve-itis of childhood and adult life. This rela-tionship is still not clear, so that the
prob-lem of involvement of the eye retains a
major place among current investigations of the role of toxoplasma in human illness. Nonetheless, enough has been learned dur-ing the past several years to bring several
divergent points of view into somewhat closer harmony.
It appears that congenital toxoplasmosis usually is complicated by chorioretinitis. In our experience this has been bilateral in 82% of the cases,27 which is not surprising
if the bloodstream serves as the route of
dis-semination of the parasite. Eichenwald42 noted that only 80% of 140 cases of congeni-tal toxoplasmosis had chorioretinitis, and
he divided them into three groups, as fol-lows:
(1) A group of children with healed
chorio-retinitis who had been followed six to seven
years without recurrence of the ocular
inflam-mation.
(2) A second group of children with healed
lesions who relapsed at about the age of 4 years. These children usually showed
cere-bra! calcifications. One child in this group had four relapses.
(3) A third group of infants, with acute sys-temic toxoplasmosis which showed no initial evidence of ocular involvement.
Unfortunately, the number of children in
each category is not stated. It is said,
though, that 20% of the 140 cases had no
evidence of chorioretinitis at the time when the diagnosis of congenital infection was
made. Most cases were diagnosed during
the first month of life, although he found one patient who still had no evidence of eye disease when 3 months old.
Among 339 patients with uveitis whose sera we have tested, only 38% were found to have definitely positive dye tests.43 These
patients were of all ages and resided in
many different places; most of them had
unilateral eye disease. One has to conclude that among these cases of uveitis, more than half were unrelated to toxoplasmosis.
The problem of involvement of the eye
would seem to revolve around the following three questions:
a) Does toxoplasmic chorioretinitis only accompany congenital toxoplasmosis with some of the patients (see Eichenwald42) fail-ing to have significant eye involvement early in infancy but manifesting this at some later date? If the interval were long enough, the clinical interpretation might be that the disorder had been acquired postnatally.
b) Is the acquired (?), acute uveitis of
childhood and adult life a recurrence (either allergic or by spread of infection23’ 43) of a congenital infection?
c) May postnatally acquired toxoplasmo-sis initiate chorioretinitis either by direct
infection of the eye or as a complication of
parasitemia or both?
answered with substantial assurance, par-ticularly since viable parasites may persist in the host for years (life?), their discussion
may be productive. That eye lesions are
common in congenital toxoplasmosis is
ac-cepted by all students of the subject. This
generally affects both eyes,27 presumably because the organism spreads via the blood-stream and, perhaps, because fetal tissues
are unusually susceptible to destructive
in-fection by the parasite. We have made the assumption previously that inapparent, e.g. maternal, or lymph-node, infections are
ac-companied by parasitemia. One might
ex-pect resultant eye lesions (infections?) to
be bilateral, if not always, then, in a sub-stantial proportion of cases. While the data available are insufficient to either affirm or deny this generalization, it is possible that postnatally acquired infections ordinarily
have such low grade parasitemias that
ocular lesions are unlikely accidents;
there-fore, unilateral involvement should be an-ticipated as a matter of chance.
Considerable impetus for renewed
inter-est in the investigation of toxoplasmic eye disease was provided by the 1952 report of Wilder44 that structures resembling toxo-plasmas had been found in sections of
hu-man eyes which had been enucleated
be-cause of painful granulomatous uveitis.
J
acobs, Cook and Wilder45 subsequently found that each of 21 of these patients, who could be located, had antibodies fortoxo-plasma. Wising46 reported that a
31-year-old woman who had an acute illness
ac-companied by lymphadenopathy, also de-veloped acute chorioretinitis. This patient was found to have both dye and
comple-ment-fixing toxoplasma antibodies, which
supported the diagnosis of acute toxoplas-mosis. In Sum’s experience,28 acute chorio-retinitis was detected in 1 of about 100 cases of acquired toxoplasmosis (lymph-node type).
Jacohsl2 recovered live toXOl)laSIlla froni
an eye enucleated from a 30-year-old mall
\VIR) ba(l hlit(l uveitis for nore than 8 years. This is the most definite example of an
adults abnormal eye being found to harbor
live toxoplasma. It is reasonable to assume
that this patient’s eye problem had been a continuing one, illustrating again the ability of the parasite to remain viable in tissues for many years.
Recently, there were published47 details of another case which represents a most important contribution to our understand-ing of the eye problem. In this instance, the patient, a 48-year-old female, was
hos-pitalized several months after the onset (?)
of toxoplasmosis. She had a high titer of dye-test antibodies, and parasites were
readily isolated from lymph nodes and
muscle tissue. Photophobia and blurring of vision had been noted in the left eye for about 3 months. This was diagnosed as an-tenor and posterior uveitis in the hospital and cleared during treatment for active toxoplasmosis (see section on treatment). Since parasites were isolated from other areas of this patient, it appears likely that the eye lesion was the result of unilateral ocular infection by toxoplasma.
There have been other discussions48 of acquired toxoplasmic eye disease but fre-quently the principal bases for the diag-noses are the presence of positive serologic
tests or the combination of these with a
good response to treatment-a precarious combination of criteria (to be discussed
un-der Treatment).
Two additional papers of interest have
been presented by O’Connor0 11 who uti-lized the agar diffusion technique to
demon-strate toxoplasmic precipitins in the sera and aqueous humors of patients with
sus-pected ocular toxoplasmosis. Some of these patients were found to have precipitins in
the aqueous humors at a time when none
could be found in the sera.
Experimentally induced toxoplasmic uve-itis has been studied by Beverley
et
al.,52among others, and appears worthy of
fur-ther investigations.
The entire eye problem has been
ex-aniined critically 1)V Sabin in a paper43 that shollld l)e reviewed by those eS)ecially
in-tereste(l ill this aspect of toxoplasmosis. #{176}
0 The following report appeared aftcr coiilpletioii
REVIEW ARTICLE
Epidemiology
There is ample serologic evidence that ill-fections with toxoplasma occur in all parts of the world, except. perhaps, in the Arctic
and Antarctic areas; one repOrt suggests
that they occur even above the Arctic
Circle. When a number of population
groups were surveyed with the dye test,54 it was found that the prevalence of positive reactors varied greatly from place to place. Persons living in Tahiti were found to have the greatest proportion of significant titers, some 16 times more than that observed in
Navajo Indians. Inhabitants of several
American cities, Haiti and Honduras
oc-cupied intermediate levels. Somewhat simi-lar results with the dye test have been
re-ported from 5 Finland,57
Ha-waii,58 Holland5#{176} and Guatemala.6#{176} The passive transfer of such antibodies must be taken into account when serologic data obtained in infants are evaluated.
A sample of the Trinidad population has
been examined with both the dye and
hemagglutmnation tests.#{176}’This is the first re-port of a survey conducted with the latter
procedure; the results obtained with the two methods were comparable. It is appar-ent from all of these experiences that before one can successfully relate infection with
toxoplasma to a specific clinical syndrome, it is necessary to have comparable informa-lion from a normal, control population re-siding in the same area. This has been true of skin-test studies as well.18, 23, 32, 6265
Dye-test antibodies have been detected
with equal frequency among males and
466 which fails to support the
con-clusion of some that females are more often infected. Human disease seems to follow no special seasonal pattern, but in Denmark wild hares appear to acquire parasites more often in the winter.67 This may be a
reflec-tion of “group-living” habits in cold weather.
The fact that husbands of women who have
given birth to congenitally infected infants frequently have no antibodies offers strong presumptive evidence that human to human
transfer, if it occurs at all, does so rarely. The exception would be transfer from
mother to fetus.
Cathie” described tile case of a
5-year-old boy who had had enlarged cervical
nodes for several weeks. Thirteen days after
the finding of high titers in the dlVC and
complement-fixation tests, sali ‘a from the patient was injected into mice; these
re-mained well for 1 month at which time
passage of their spleens into other mice re-sulted in the demonstration of toxoplasma.
Blood procured from the patient 3 weeks
after collection of the saliva was injected into mice. Ten days later, material from half
of these was passed to a second series of mice, resulting in infections in all of them. Both the saliva- and blood-inoculated mice
were “harvested” and “second-passaged” on
the same day, and parasites were demon-strated in the latter animals on the same day. Subsequent trials with blood and saliva were negative for parasites. Cathie suggests
that this experience indicates kissing may be a means for transferring toxoplasma
be-tween humans. Neither the child’s mother
nor three siblings ever developed
anti-bodies. The child’s father had a low titer in the dye test and a negative
complement-fixation test, when first examined. Neither the experiences of this family, nor that of
husbands of mothers of congenitally
in-fected offspring, lend strong support for this mode of spread of the infection.
Gibson69 failed to detect any difference between the titers in the dye test of
associ-ated urban and rural “normal” human
pop-ulations.
Many attempts have been made to relate human infections to animal contacts. It is always difficult to analyze such data for the
purpose of assigning responsibility for the
human infection, in view of the widespread
but varying prevalence of antibodies among
470
Deutsch and Horsley71 reported a case
of congenital toxoplasmosis in an infant born at term with hydrocephaly, exfoliating
dry skin, jaundice, hepatomegaly, sple-nomegaly and chorioretinitis. A positive dye test of 1 : 16,000 was observed after the
the serum continued to rise and tile infant died at 18 days of age. In a discussion of this paper, Gibson reported that toxoplasma were isolated from ventricular fluid, brain and heart muscle; the cerebrospinal fluid, spleen and liver were negative. The mother and infant both had elevated titers in the dye test and two siblings were also found to be positive. As usual, the father had no antibodies. All those with positive dye tests had positive complement-fixation tests. A
study72 of animals near the home of the family succeeded in isolation of toxoplasma
from cats, domesticated ducks, chickens,
pigeons, mice and a dog-found some four
blocks from the home. Parasites were not
demonstrated in either wild sparrows or
cardinals.
This case is of considerable interest from several points of view. Firstly, it is apparent
that toxoplasma were common to the
do-mesticated animals in the area in which this family resided. Secondly, the father did not have any antibodies and, therefore, must be presumed to have escaped infection. In contrast, the mother and her two children
seem to have been exposed to a common
source of infection, but whether this was one
of the domesticated animals cannot be
stated with certainty. It can only be con-cluded that the animals cannot be dismissed as a source of these infections and, if so, the
exposure took place for all members of the family except the father. Unfortunately, this
is the usual experience when we attempt to implicate an animal in the acquisition of in-fection by associated humans.7375
It has been suggested by Weinman and
Chandler76 that undercooked pork may be
a source of human infections. If this is so, it would probably function in isolated,
local-ized outbreaks rather than in the population
at large. Interestingly, the incidence of
anti-bodies to toxoplasma among orthodox
Jews77 is similar to that in the general pop-ulation.
Treatment
Sabin and Warren78 demonstrated that
certain of the sulfonamides could suppress
toxoplasma infections in animals. In the years that followed, many other substances were tested for their effect on the parasite but no satisfactory improvement on the sul-fonamide drugs was obtained until Eyles79 found that a combination of sulfadiazine and pyrimethammne was superior to either
one alone. A number of active human
in-fections have now been treated with this combination. It appears that the clinical course was affected favorably, but there is always the possibility that the infections
would have resolved spontaneously. Our
knowledge of the clinical course of active toxoplasmosis is too sparse to permit con-fident predictions of its outcome. Notice
should be taken that this combination is
adverse to other microorganisms and there-fore a good response to treatment does not prove that the patient had active toxoplas-mosis.
While other patients have received such treatment, the two reported by Kayhoe7 are especially important. Apparently both
had active toxoplasmosis and each was
treated with pyrimethamine and triple sul-fonamides with good clinical response.
However, one patient was found to have
lymphadenopathy slightly more than 2
months after finishing his course of treat-ment. A gland was removed and its histo-logic examination was interpreted as mdi-cating mild, reticulum-cell hyperplasia. No parasites were seen in the node nor were any recovered by inoculation into mice. In
the second patient, a newly enlarged
fem-oral lymph node was removed 66 days
after the completion of treatment; parasites
were demonstrated in it by subinoculation into animals. From this experience it would
appear that treatment with sulfonamides
and pyrimethammne may control clinical
symptoms, but not necessarily free the mdi-vidual of toxoplasma organisms. This leaves the problems in treatment to the usual ones involved in the elimination of intracellular
organisms.
The usual dosage of sulfadiazine (or
triple sulfonamides) is employed. The dose
ar-REVIEW ARTICLE
rived at somewhat arbitrarily.79 For adults and larger children 25 mg/day constitutes a maintenance dose. The dose is usually doubled during the first 2 days of treatment. Under a body weight of 60 lb (27 kg) the dose may be adjusted on the basis of 1 mgI kg. One month should be ample for a course of treatment, although if no improvement is noted during the first 2 weeks it is un-likely that anything startling will occur
sub-sequently. Pyrimethammne is a folic acid antagonist and severe leukopenia may ac-company its use in these doses. Leukocyte counts should be performed at frequent in-tervals and the drug withdrawn if a sig-nificant decrease is noted.
Perkins et al.80 conducted an interesting, controlled study in which pyrimethammne was added to the regular treatment regimen
of a number of patients with uveitis. Those who had antibodies for toxoplasma seemed to improve while those without antibodies
(presumably the uveitis was totally
un-related to toxoplasma) were unaffected by this additional treatment. Varying degrees of enthusiasm have been registered by other
ophthalmologists toward the value of the
sulfonamide-pyrimethamine combination in
the treatment of uveitis. It should be borne in mind that absence of antibodies probably eliminates toxoplasma as the cause, but the presence of antibody does not prove its eti-ology.
Whether infants with active disease
should receive such treatment is a matter of individual choice. It is unlikely that dam-aged tissues will revert to normal but chances for survival may be improved.
COMMENT
The past decade has witnessed the emer-gence of toxoplasmosis from a biologic and clinical curiosity to a subject of extensive re-search and clinical interest and importance. Experimentally, it is an excellent model for the study of intracellular parasitism and tis-sue specificity. Clinically, it poses an in-creasing challenge as a cause of congenital and acquired disease. Although widely
dis-tributed among man and animals, we do not
know how it is transmitted nor why it in-duces illness in some and no apparent dis-ease in most others.
REFERENCES
1. Wolf, A., Cowen, D., and Paige, B. H.: Human toxoplasmosis : Occurrence in in-fants as an encephalomyelitis; verifica-tion by transmission to animals. Science, 89:226, 1939.
2. Nicolle, C., and Manceaux, L. : Sur une in-fection
a
corps de Leishman (ou organis-mes voisins) du gondi. Compt. rend. Acad. sc, 147:763, 1908.3. Splendore, A. : Un nouvo protozoa parassita dei conigli. Incontrato nelle lesioni ana-tomiche d’una malattia che ricorda in molti punti il Kala-azar dell’uomo. Rev.
Soc. Sc., S#{227}oPaulo, 3:109, 1908.
4. Jacobs, L. : Propagation, morphology and biology of toxoplasma. Ann. New York Acad. Sc., 64:154, 1956.
5. Frenkel,
J.
K. : Pathogenesis of toxoplasmo-sis and of infections with organisms re-sembling toxoplasma. Ann. New York Acad. Sc., 64:215, 1956.6. Ryan, R. R., et al.: Diagnosis and treatment of toxoplasmic uveitis. Tr. Am. Acad. Ophth., 58:867, 1954.
7. Sabin, A. B., and Feldman, H. A. : Dyes as microchemical indicators of a new im-munity phenomenon affecting a proto-zoon parasite (toxoplasma). Science, 108: 660, 1948.
8. Gr#{246}nroos, P. : The action of properdin on Toxoplasma gondui. Ann. med. exper. et. biol. Fenniae, 33:310, 1955.
9. Feldman, H. A. : The relationship of toxo-plasma antibody activator to the serum-properdin system. Ann. New York Acad. Sc., 66:263, 1956.
10. Pillemer, L., at al.: The properdlin system and immunity: I. Demonstration and isolation of a new serum protein, proper-din, and its role in immune phenomena. Science, 120:279, 1954.
11. Feldman, H. A., and Miller, L. T. : To be published.
12. Feldman, H. A. : Laboratory methods in
current use for the study of toxoplas-mosis. Advances Ophth., 3: 1, 1954. 13. Cathie, I. A. B. : II. An appraisal of the
diagnostic value of the serological tests for toxoplasmosis. Tr. Roy. Soc. Trop. Med. & Hyg., 51:104, 1957.
Sarcocystis tenella spores. Tr. Roy. Soc. Trop. Med. & 11)7g., 48:337, 1954. 15. Sabin, A. B., and Feldman, H. A. :
Per-sistence of plaCentallv transmitted
toxo-plasuliC antibodies ill normal children
in relation to diagnosis of congenital
toxoplasmosis. PEDIATRICS, 4: 660, 1949. 16. Sabin, A. B. : Complement fixation test in
toxoplasmosis and persistence of antibody
ill human beings. PEDIATRICS, 4:443, 1949.
17. Frenkel, J. K. : Dermal hypersensitivity to toxoplasma antigens (toxoplasmins). Proc. Soc. Exper. Biol. & Med., 68:634, 1948. 18. Feldman, H. A., and Sabin, A. B. : Skin reactions to toxoplasmic antigen in people of different ages without known history of infection. PEDIATRICS, 4:798, 1949.
19. Jacobs, L., and Lunde, M. N. : Hemagglu-tination test for toxoplasmosis. Science,
125:1035, 1957.
20. Jacobs, L., and Lunde, M. N. : A hemag-glutination test for toxoplasmosis. J. Parasitol., 43:308, 1957.
21. Goldman, M. : Staining Toxoplasma gondii with fluorescein-labelled antibody. II. A new serologic test for antibodies to toxoplasma based upon inhibition of specific staining.
J.
Exper. Med., 105: 557, 1957.22. Jacobs, L., Fair,
J.
R., and Bickerton, J. H.: Adult ocular toxoplasmosis; report of a parasitologically proved case. Arch. Ophth., 52:63, 1954.23. Frenkel, J. K. : Pathogenesis, diagnosis and
treatment of human toxoplasmosis.
J.A.M.A., 140:369, 1949.
24. Sexton, R. C., Jr., Eyles, D. E., and Dill-man, R. E. : Adult toxoplasmosis. Am. J. Med., 14:366, 1953.
25. Beckett, R. S., and Flynn, F. J., Jr. : Toxo-plasmosis; report of two new cases, with a classification and with a demonstration of the organisms in the human placenta. New England
J.
Med., 249:345, 1953. 26. Eichenwald, H., and Levine, S. Z. :Toxo-plasmosis. Postgrad. Med., 15:282, 1954. 27. Feldman, H. A., and Miller, L. T. : Con-genital human toxoplasmosis. Ann. New York Acad. Sc., 64:180, 1956.
28. Sum,
J.
C. : Toxoplasmosis acquisita lym-phonodosa: Clinical and pathological as-pects. Ann. New York Acad. Sc., 64:185, 1956.29. Farquhar, H. G. : Congenital toxoplasmosis. Lancet, 2:562, 1950.
30. Stanton, M. F., and Pinkerton, H. : Benign
acquired toxoplasmosis with subsequent pregnancy. Am. J. Clin. Path., 23:1199,
1953.
:fl . Card, S., and Magriusson, J. H. : A
glandu-lar form of toxoplasmosis in connection
with pregnancy. Acta nied. scandinav.,
141:59, 1951.
32. Feldman, H. A. : The clinical manifesta-tions and laboratory diagnosis of toxo-plasmosis. Am. J. Trop. Med., 2:420, 1953.
33. Eichenwald, H. F. : The laboratory diag-nosis of toxoplasmosis. Ann. New York Acad. Sc., 64:207, 1956.
34. Feldman, H. A., and Miller, L. T. : Unpub-lished observations.
35. Bain, A. D., Bowie,
J.
H., Flint, W. F., Beverley,J.
K. A., and Beattie, C. P.: Congenital toxoplasmosis simulating haemolytic disease of the newborn. J. Obst. & Gynaec. Brit. Emp., 63:826, 1956.36. Wolfe, S. M., Sawitz, W. C., and Paschkis, K. E. : Pituitary dwarfism and toxoplas-mosis.
J.
Clin. Endocrinol., 15:745, 1955. 37. Kass, E. H., Andrus, S. B., Adams, R. D.,Turner, F. C., and Feldman, H. A.:
Toxoplasmosis in the human adult. Arch. Int. Med., 89:759, 1952.
38. Sum,
J.
C. : Acquired toxoplasmosis; report of seven cases with strongly positiveserologic reactions. J.A.M.A., 147:1641, 1951.
39. Sabin, A. B.: Toxoplasmic encephalitis in children. J.A.M.A., 116:801, 1941. 40. Sexton, R. C., Jr., Eyles, D. E., and
Dill-man, R. E. : Adult toxoplasmosis. Am.
J.
Med., 14:366, 1953.41. Pinkerton, H., and Henderson, R. G. : Adult toxoplasmosis. J.A.M.A., 116:807, 1941. 42. Hogan, M.
J.
: Ocular toxoplasmosis;cmi-cal and laboratory diagnosis; evaluation of immunologic tests; treatment. Arch. Ophth., 55:333, 1956.
43. Sabin, A. B. : Human toxoplasmosis; with special reference to intraocular inflamma-tion: A critical review. Am. J. Ophth., 41:600, 1956.
44. Wilder, H. C. : Toxoplasma chorioretinitis in adults; a preliminary study of forty-one cases diagnosed by microscopic examination. Arch. Ophth., 47:425, 1952.
lvmphadenopathi och chorioretinit. Nord. med., 47:563, 1952.
47. Kayhoe, D. E., Jacobs, L., Beye, H. K., and McCullough, N. B. : Acquired toxo-plasmosis; observations on two parasito-logically proved cases treated with pyrimethamine and triple sulfonamides. New England J. Med., 257:1247, 1957. 48. Woods, A. C., Jacobs, L., Wood, R. M..
and Cook, M. K. : A study of the role of toxoplasmosis in adult chorioretinitis. Am.
J.
Ophth., 37:163, 1954.49. Forbes, S. B.: Ocular toxoplasmosis; re-port of cases. Am. J. Ophth., 44:41,
1957.
50. O’Connor, G. R. : Anti-toxoplasma precipi-tins in aqueous humor. Arch. Ophth., 57:52, 1957.
51. O’Connor, G. R. : Precipitating antibody to toxoplasma. Am. J. Ophth., 44 (Part II): 75, 1957.
52. Beverley, J. K. A., Beattie, C. P., and Fry, B. A. : Experimental toxoplasmosis of the uveal tract. Brit. J. Ophth., 38:489,
1954.
53. Harper, D. W., Ormsby, H. L., and Coc-keram, A. : A survey of skin and corn-plement-fixation tests for toxoplasmosis in the Toronto area. Am. J. Ophth., 43:470, 1957.
54. Feldman, H. A., and Miller, L. T. : Sero-logical study of toxoplasmosis prevalence.
Am. J. Hyg., 64:320, 1956.
55. Beverley, J. K. A., Beattie, C. P., and Rose-man, C. : Human toxoplasma infection. J. Hyg., 52:37, 1954.
56. Beattie, C. P. : Clinical and epidemiological aspects of toxoplasmosis. Tr. Roy. Soc. Trop. Med. & Hyg., 51:96, 1957. 57. Gronroos, P. : Studies on toxoplasma and
the serology of toxoplasmosis. Ann. med. exper. et biol. Fenniae, 33 : Suppl. 11, 1955.
58. Stitt, P. G., and Levine, M. : The possible existence of clinical toxoplasmosis in Hawaii. Hawaii M.
J.,
12:351, 1953. 59. Makstenieks, 0., and Verlinde, J. D. :Toxo-plasmosis in the Netherlands. Docum. med. geog. et trop., 9:213, 1957. 60. Gibson, C. L., and Coleman, N. :
Pre-liminary studies on toxoplasma anti-bodies in Guatemala and Costa Rica. Presented at the Annual Meeting, Am. Soc. Trop. Med. & Hyg., New Orleans, November, 1956.
61. Lunde, M. N., aIld Jacobs, L. : Results of dye and hemagglutination tests for
toxo-phismosis in a survey of Trinidad
na-tives. Presented at the Annual Meeting, Am. Soc. Trop Med. & Hyg., Philadel-phia, November, 1957.
62. Gard, S. : Laboratory diagnosis and epi-demiology of toxoplasmosis. Nord. med., 45:352, 1951.
63. Shusterman, M. : Toxoplasmosis in the To-ronto area. Tr. Canad. Ophth. Soc., 1951, p. 75.
64. Fisher, 0. D. : Toxoplasma infection in English children. Lancet, 2:904, 1951. 65. Hedqvist, T. : Toxoplasma infection at
dif-ferent ages, studied by the skin-test method.
J.
Hyg., 51:478, 1953.66. Gibson, C. L., Eyles, D. E., Coleman, N., and Smith, C. S.: Serological response of a rural Negro population to the Sabin-Feldman cytoplasm-modifying test for toxoplasmosis. Am.
J.
Trop. Med., 5:772, 1956.67. Christiansen, M., and Sum, J. C. : Toxo-plasmosis in hares in Denmark. Lancet,
1:1201, 1951.
68. Cathie, I. A. B. : Toxoplasma adenopathy in a child with isolation of the parasite. Lancet, 2:115, 1954.
69. Gibson, C. L. : Distribution of toxoplasma antibodies in comparable urban and rural groups. Pub. Health Rep., 71:1119, 1956.
70. Jones, F. E., Eyles, D. E., and Gibson, C. L. : The prevalence of toxoplasmosis in the domestic cat. Am.
J.
Trop. Med., 6:820, 1957.71. Deutsch, A. R., and Horsley, M. E. : Con-genital toxoplasmosis. Am. J. Ophth., 43:444, 1957.
72. Gibson, C. L., and Eyles, D. E. : Toxo-plasma infections in animals associated with a case of human congenital toxo-plasmosis. Am.
J.
Trop. Med., 6:990, 1957.73. Prior,
J.
A., Cole, C. R., Docton, F. L., Saslaw, S., and Chamberlain, D. M.: Toxoplasmosis. IV. Report of three cases with particular reference to asympto-matic toxoplasma parasitemia in a young woman. Arch. Tnt. Med., 92:314, 1953. 74. Cole, C. R., Prior,J.
A., Docton, F. L.,Chamberlain, D. M., and Saslaw, S.: Toxoplasmosis. III. Study of families ex-posed to their toxoplasma-infected pet dogs. Arch.
mt.
Med., 92:308, 1953. 75. Meier, H., Holzworth, J., and Griffiths,R. C. : Toxoplasmosis in the cat, fourteen
cases. J. A. Vet. M. A., 13L395, 1957. 76. Weinman, D., and Chandler, A. H. :
Recipro-cal oral infection and potential human hazard. Proc. Soc. Exper. Biol. & Med.,
87:211, 1954.
77. Jacobs, L., Cook, M. K., and Neumann, E.: Serological survey data on the prevalence of toxoplasmosis in the Jewish
popula-lion of New York (Research note). J.
Parasitol., 40:701, 1954.
78. Sabin, A. B., and Warren, J.: Therapeutic effectiveness of certain sulfonamides on
infection by an intracellular protozoon (toxoplasma). Proc. Soc. Exper. Biol. & Med., 51:19, 1942.
79. Eyles, D. E. : New knowledge of the chemotherapy of toxoplasmosis. Ann. New York Acad. Sc., 64:252, 1956. 80. Perkins, E. S., Smith, C. H., and Schofield,
P. B.: Treatment of uveitis with pyri-methamine (Daraprim). Brit. J. Ophth., 40:577, 1956.
INFECTION FOLLOWING SPLENECTOMY IN INFANTS AND CHiLDREN, C. C. Huntley.
(A.M.A. J. Dis. Child., 95:477, May, 1958.)
This paper presents an analysis of the experience at Duke Hospital in Durham, North Carolina, regarding the effect of splenectomy on susceptibility to infection. Of 46 patients who had been subjected to splenectomy, 7 developed serious infections
after the operation; 5 of these 7 patients were under 1 year of age at the time of splenectomy. It appeared that the younger patients were more susceptible to this
complication. Five of the seven patients had diseases which are known to be associ-ated with an increased susceptibility to infection. Therefore it appeared that the effect
of splenectomy on decrease of resistance to infection was more conspicuous in those
whose basic disease was associated with proneness to infections.
PROLONGED OBSTRUCTIVE JAUNDICE IN INFANCY, D. Y. Hsia et al. (A.M.A. J. Dis.
Child., 95:485, May, 1958.)
This paper is concerned with the syndrome of hepatitis and cirrhosis which has its onset in the first weeks of life and has been variously termed neonatal hepatitis, infan-tile hepatitis, giant-cell hepatitis and “the inspissated bile syndrome.” This form of
hepatitis in the newborn period has often been assumed to be due to the virus of
infectious hepatitis, transmitted from the mother to the infant in utero, but this etiol-ogy has not been proven. Because this form of neonatal hepatitis is sometimes seen in
several instances in the same family, an analysis of a possible hereditary component
in the pathogenesis of this disease was undertaken. The study included a total of 59 families in which one or more offspring were affected with neonatal hepatitis. Exclud-ing the index cases, there were 11 affected and 15 normal siblings in these families. The genetic analysis indicated the trait was consistent with an autosomal recessive mode of inheritance. In some families a number of normal children were born after the affected infant, and in other families women gave birth to affected and normal
