Ten
Years’
Experience
C. Harrison Snyder, M.D.
Departments of Pediatrics, Oclisner Clinic and Tulane Unicersity Medical Sc/moo!
ADDRESS: Ochsner Clinic, 3503 Prytania Street, New Orleans 15, Louisiana.
VISCERAL
LARVA
MIGRANS
85
PEDIATRICS, July 1961
T
HE CONCEPT of visceral larva migranswas first formulated in 1950 when three
cases were encountered in New Orleans.1
These cases were studied in collaboration with Dr. Paul Beaver of the Department of
Parasitology, Tulane University. It was he who identified the nematode larva found in
the first patient’s liver. These patients were all small children who had hepatomegaly, anemia, and extreme eosinophilia, and gave a history of eating dirt. On laparotomy their livers were found to contain multiple eosinophilic granulomata, in some of which
could be found living larvae of the canine roundworm, Toxocara canis. It was postu-lated that the disease was caused by the
ingestion of dirt containing Toxocara ova that hatched in the human intestine, liberat-ing larvae that migrated to the liver, and tilere set up an inflammatory reaction. In
the dog the larvae would be expected to
pass to the lungs, up the trachea, and back
to the intestine where they would reach
maturity. In the human host, apparently,
the larvae were trapped by the inflamma-tory reaction in the liver and prevented from completing their normal life cycle.
During the 10 years since these patients were seen, we have continued to encounter
similar cases. At present at the Ochsner
Clinic we have records of 20 children in
Wilom the diagnosis of visceral larva mi-grans has been made. In 10 of them the
diagnosis was proven by liver biopsy. Tile rest were not sick enough to justify lapa-rotomy but were accepted as having visceral larva migrans because they satisfied
the criterion of hypereosmnophilia (over 30%) in children who ate dirt and had no other detectable cause for eosinophilia.
Table I presents a tabulation of the
clini-cal features of these 20 cases, and analysis of the data in this chart brings out certain
important clinical features of the disease. First of all, it becomes clear that this is a
disease of small children. The oldest was 48
months; the youngest was 16 months; the
median age was 24 months. Most of them
(75%) were boys. (Apparently little girls are
cleanlier in their habits!) All of them, with-out exception, gave a definite history of
pica. In all cases, the mothers definitely stated that they had been worried because
the children had an extraordinary craving
for dirt.
As for symptoms, 1 1 of 20 (55%) had fever.
This was usually recurrent and often mild, i)tmt in some cases bouts of fever as high as 104#{176}F (40#{176}C) were recorded. Pallor was
noted in eight (40%) and coughing or wheez-ing in four cases (20%). Other frequent symptoms were lassitude, anorexia and weight loss or failure to gain weight.
On physical examination hepatomegaly
was found in 17 of the 20 patients (85%). This was often moderate, but in some cases extreme, the liver edge reaching well below the umbilicus. Splenomegaly was frequent
(45%) but never of great degree.
Erythrocyte counts revealed anemia in
most cases. Hemoglobin concentrations
varied from 5.8 to 14 gm/100 ml, with less
than 11 gm/100 ml in 80% of the cases.
Leukocytosis was pronounced in all but the mildest cases. One patient had 120,000
leukocytes/mm3. Nearly half the patients (9 of 20) had over 40,000 leukocytes/mm3.
Eosinophilia of over 30% was considered essential for the diagnosis. It was over 50%
in most (60%) of the cases and reached 90%
in one case.
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ARTICLES 87
more severe cases. In only eight patients
was the protein concentration in serum
miieasmmrecl, l)tmt flyc of these had increased
ghobimhin levels. Patient 3 had 11.3 gm of
total Prtei1i/1(X) nil of seruni, of viiich 8.2
gin was globulin.
Pulmilonarv involvement was common,
(‘yen though only four patients had
respira-tory svniptonis. Roentgenograms of the
chest shloWe(1 pulmonary infiltrations in 7
of 17 patients (42). These findings may
represent actual migration of larvae
tllrotlgil the lung, simice studies of fatal
cases at neeropsv have shown larvae in the
I Hug.
There vere no deaths in this series.
Re-covers’ was complete in all but one case;
Patiemit 17 i)ecame blind in one eye.
CASE REPORTS
Certaiml of the cases deserve special
men-tiomi i)eedtmSe of their unusual features.
Case 5
Case 5 l)r(’selit(’(l, iii 1(lditiOll to the
usu al blood changes and iiepatomiiegaly,
(‘videllee of involvemllent of skill and I)One.
11W first svmnptoni was the development of a soft swelling over the left parietal area.
Roentgenograms revealed a defect in the
skull (Fig. 1). At that time the leukocyte
count was 60,000/mm, \itll 60
#{128}osino-piiils. X-ray treatment was given, and the
k’siomi promptly (lisappeared ; complete
healing of tile defect was shown by
subse-(juemit roentgenographic studies. Tile
eosillo-I)ililia, however, 1)ersisted. Later the boy
developed many painful hemorrhagic and
necrotic lesions omi the skin of the buttocks
aIl(l thighs (Fig. 2). Biopsy of these lesions
ShlOWe(I Ilotiung specific, and fl() larvae
could i)e found; but at laparotomv the
en-larged liver was found studded with the
typical eosinophilic granulomata of visceral
larva migramls. It seems likely that the
de-structive lesions of skin and hone were due
to l)araSitic invasion, even though this could
riot ie pr(’(I.
Other atmtliors have rcl)orted cimtaiicotms
Fi;. 1. Case 5. Cranial defect in a child with
vis-ceral larva migrans. This lesion disappcare(l
follow-imig x-ray therapy.
involvement in visceral larva migrans, i)ut
the OSSeOuS lesion iii tiliS patient so far is
unique.
Case 17
Case 17 is of particular importance
be-cause of the sequel of ocular involvement with blindness. When first seen by us, this
little boy presented the no’ classic
se-quence of pica followed by fever and
anorexia and the development of
hepa-tomegaly and extreme eosinophilia. Liver
biopsy yielded larvae of T. canis. Treatment
Witil piperazine and diethylcarbamazine
(
Hetrazan) had no (lernonstrable effect, butthe child improved slowly vhemi dirt-eating
was I)re\Tente(1. After 10 months, he felt
well, but still had 22,700 leukocytes/mnmll1,
with 16% eosinophils. Four ‘ears later the
child returned complaining of visual
dis-turbance. At that time tile left eve showed a
dense grayish white membrane extending
from the superior one-third of the ciliary
body posteriorly to the retina. Since that
time the child has lost vision in this eye completely. Serial observation over a periO(l of 1 year showed no furtiler progression in
the size of the lesion, and for this reason
88 VISCERAL LARVA MICRANS
‘ ‘I. . 4
lIC. 2. Cas’ 5. 1 lcniorrimagic necrotic skimi lesions
imi chjld \vitll isccral larva migramis. All lesiomis
il(’11((l rapi(llv (hIring treatment vith
diethylcar-l)amuazimle.
Case 18
Case 18 is of sI)ecial interest because of
eXcej)tiollallV severe plillilollary illvolve-lilcIlt. This 24-miiontii-oid 1)Ov, a comifirmed
dirt eater. became ill with fever and
ta-Cil\’j)Ilea. Despite amltii)iotie therapy, his
COll(litiOn worsened and he had to he ad-nutted to th(’ hospital. His respiratory rate reached 80 P” niinute. The temperature
imlcreaSed to 104#{176}F(40#{176}C), a generalized macular eruption appeared, amid he become
cyanotic ali(l seemed critically ill. Roent-genograms of the chest showed diffuse
mnottiing of both lungs, the Pictlre
re-sembling the “Sm)w stOrmTl’ pattern of
I-n iliary tui)ereulosis. The leukocvte count
reached 120,000/mm. Under treatment
with oxygen, cortisone, and parenterally
given fluids, he slowly improved. There
were tvo relapses with fever aiid (lysj)nea,
again responding to cortisone, but finally the cilild made a eomnplete aild permanent
recovery.
It is of interest that this cilild, for a few
months prior to tile onset of his
pneu-nionitis, had suffered repeated mild seizures
clinically typical of petit mai epilepsy.
COMMENT
The etiology of visceral larva migrans
seems now to be rather clearly established.
Nearly all patients are dirt eaters and have
contact with dogs. Liver biopsies reveal
larvae in proportion to tile size of tile tissue
sI)ecimi1c11 1fl(l tile care vitii vhich it is
exanhmne(1. Randomii tissue sections seldom
SilO)\’ tiioi larva. hut (liiigemit stlm(h of serial
s#{128}’etiOlis is usimahiv re\\’or(lc(i vitii success.
Eemi i)etter is the studs’ of unfixed biopsy
specimens crimsiied i)ctwcen glass sI ides alldl
examililiedI for tiie still motile intact larvae.
Dent et ai. have further facilitated the
study of biopsy specimens 1)\’ imitroducing
the tecilllique of digesting the biopsy tissue
vith 1)c’I)sin, thtms lil)erating tiic’ living
lar-vae. B’ combining this and the tissue press
techllique, tiie’ were aI)le ill OI1C case to
demonstrate niotile larvae to tile nunll)er of
60 gran of liver tissue, 5 p gram of
lililsele tissue, and 3 to 5 1r grani imi the brain.
Further fulfillment of Koch’s postulates
for visceral larva nligrans was provided
when Snlith an(l Beaver’ actually produced
the disease ill aninials alid later imi t\v()
‘voullg ilunlan subjo’cts I)V feeding tiit’ OVii
T. canis.
Nevertheless, it rnimst be reniemberecl that
at least one other 1)trtlsite is known to
cause tile syndrome of visceral lar’a
mi-grans. This is Capillaria hepatica, a site usually infecting rats and squirrels,
which may inva(Ie hunians ho ingest soil
contaminated by cats or other prc(lltorS.
It is true that hvpereosimiophiiia is
asso-ciated with a wide variety of ilclminth
ill-festations ill \Vhicil tissue invasion occimrs,
but the svndromiies associate(I \Vitil these
are usually clinicall’ distinct froni that of
visceral larva nhigrans.
The patilologic Pre’ss 1)rodllmced by T.
canis in the humiian host is now kmlown to be much more widesprea(I thro)ugil ti e
1)O)dly than was originally collceivedi. The liver, of course, remains the organ first
in-vacleci by the 1)arasite, after it leaves the
gastrointestinal tract, and in most cases the
pathologic changes are greatest in tills
or-gan. However, it is now known that an’
or-gan or tissue of the body may he inadec1
by the larvae. Iii the reniarkable eaSe of Dent et (Ii. nlotile larvae were found in
Sj)i-ARTICLES 89
nal cord, intestine and lymph nodes. The
kidneys, as vell as liver, lung and heart, were involved in the case of Brill et al.s
From the clinical standpoint, we do
some-times encounter symptoms referable to these other organs and tissues. Pulmonary involvement is, of course, common and was present in 42% of our cases as already noted.
Indeed it is clear that visceral larva migrans
must now he reckoned one of the causes of te so-called Loeffler syndrome
(pneumo-nitis with eosinophilia).
Cutaneous involvement, seen in our Cases 5 and 18, has also been reported by Dent and Carrera. Osseous lesions as seen in
our fifth case have not been reported by others. Neurologic signs and symptoms are apparently rare, although delirium and
coma preceded death in Dent’s3 fatal case
where the brain yielded 3 to 5 larvae per gram of tissue at necropsy. Of special
inter-est is the report of petit mal epilepsy in a patient of Dent and Carrera,2 as also in our
Case 18. It is likely that the petit mal
epi-lepsy was due to the parasite, since genetic
petit mal is exceedingly rare in children under the age of 4 years.
Of major importance to ophthalmologists
is the occurrence of ocular involvement due
to nematode larvae. This matter first came
to light in 1950 when it was reported by Wilder9 of the Armed Forces Institute of Pathology. Wilder, in the course of routine
pathologic studies of eyes removed because
of suspected retinoblastoma, found 46 spe-cimens that proved to he free of neoplasm, hut instead contained eosmophilic
granu-lomata. Most of these were from children, and 24 of them were found to contain
nem-atocle larvae. The larva, at first thought to
be hookworm, was later identified by
Nichols1#{176} as T. canis. Unfortunately clinical
histories of these patients were not
avail-able, and it is not known whether the chii-dren had eosinophilia or hepatic involve-ment.
A single case1’ occurred in a 4-year-old
boy without recorded or known eosinophilia
Or visceral involvement. This child had a
mass in the retina, resembling
retinoblas-toma. The eye was enucleated and was
found to contain a granuloma surrounding a larva of T. canis. No neoplasm was found. Four similar cases have been reported in
England.12 Patient 17, therefore, is the first child who has been followed through the initial stage of hepatic infestation with eosinophiiia, and later has been seen to de-velop ophthalmitis with blindness.
From this experience two conclusions
may he drawn. The first is that all cases of
visceral larva migrans should be followed
closely for years with special attention to
tile ophthalmoscopic examination. The
see-ond is that enucleation of suspected
retino-blastoma should not be performed without consideration of the possibility of a benign lesion due to T. canis. In suitable cases one
may be justified in postponing surgical
in-tervention, where the circumstantial evi-dence (such as pica, eosinophilia, etc.) points to visceral larva migrans. Cortisone
therapy in such cases might be tried before resorting to enucleation.
As to the matter of diagnosis, we still lack a reliable clinical test for visceral larva mi-grans, short of biopsy. Heiner and Kevy’3
have pointed out that patients with visceral
larva migrans have elevated
isohemag-glutinin titers against the A and B
fac-tors of human blood and that this
agglu-tinin can be removed from the serum by absorption with emulsions of the bodies of
T. canis parasites. They also pointed out
that precipitin tests, using Toxocara anti-gen, may give positive results. However,
J
ung and Pachee&16 have workedexten-sively to develop serologic tests that might
demonstrate specific antibodies against T. canis in the blood of patients with sus-pected visceral larva migrans. They have
concluded that at Present the tests are only
helpful, not conclusive, and that they may
give a positive serologic reaction against
T. eanis that could result from a previous
VISCERAL LARVA MIGRANS
patient with hepatomegaly and hypereo-sinophilia. Open laparotomy is preferable
to percutaneous needle biopsy, because the latter may miss the lesions.
The question of therapy in visceral larva
migrans remains unsettled. Mild cases prob-ably do not require any treatment, other
than prevention of pica. For the moderately iii patients we have generally employed di-ethylcarbamazmne, giving the drug orally in
a dose of 120 mg three times daily for a month. This treatment has had no consistent demonstrable effect on the eosmnophilia, but
the other manifestations (fever, malaise, anemia, cough, hepatomegaly and skin ie-sions) have receded rapidly in the cases so treated. The apparent benefit was striking
in Patients 3, 4, 5, 6 and 7, who showed
complete subsidence of all signs and symp-toms (except eosinophilia) at the conclusion of therapy, even though they had been quite ill at the time of diagnosis. In
Pa-tients 2, 8, 10, 16 and 17 the improvement was not much more rapid than in the
un-treated patients, however, and Patient 17 became blind in one eye despite therapy. It is difficult to assess the value of
diethyl-carbamazine in our cases, since most of the
children received supportive treatment as well as the antiparasitic drug, and espe-cially since all were cautioned against
fur-ther dirt eating. We are left only with a clinical impression that many of our pa-tients improved more rapidly with diethyl-carbamazine than they would have without
it.
Recently, however, objective evidence of the efficacy of diethylcarbamazine was pro-vided by the experiments of Pike,’7 who
produced visceral larva migrans in mice and then treated them with diethylcarbamazine, oxophenarsine hydrochloride, and
pipera-zine citrate. The last two drugs had little or
no effect, but with diethylcarbamazine the number of larvae found at necropsy after treatment was reduced to 35% of those re-coverabie from the untreated control
ani-mals. Large doses of diethyicarbamazine (50 mg/kg/day for 14 days) had to be used to achieve this result, and some of the
fail-tires in human cases may therefore be at-tributable to inadequate doses.
Mention should also be made of the use
of adrenal corticosteroids for visceral larva
migrans. Steroid therapy is probably
war-ranted in very severe cases, particularly
those with extensive pneumonitis (such as
our Case 19) where its anti-inflammatory effect may at times prove lifesaving.
In the end, however, the most helpful
ad-vice the physician can give is that the child be prevented from eating dirt. If pica can be prevented, nearly all children with
vis-ceral larva migrans will recover.
The prognosis, however, is not always
good. There are records of these
fatali-8, iS in children with visceral larva
mi-grans. In two the deaths were apparently
due to severe pneumonitis, and in one the
child died apparently from serum hepatitis as a result of transfusions, rather than from
the disease itself. A nearly fatal case of myocarditis due to T. canis was reported by Friedman and Hervada.’ Tllose patients
who survive are generally well, but one must watch for sequelae in the form of endophthalmitis (as in Case 17).
SUMMARY
An analysis has been presented of the
clinical features of visceral larva migrans based on the study of 20 cases seen during
a 10-year period at the Ochsner Clinic. The disease is seen in small children who eat
dirt and WilO thus ingest the ova of the canine roundworm, Toxocara canis. Larvae of the parasite invade the liver, causing hepatomegaly with extreme eosinophilia, and usually fever and anemia.
Migration of the larvae to other organs
may result in pneumonitis, encephalitis or
myocarditis. Lesions may also he seen in
skin, kidneys and possibly in bone. Proof of
diagnosis requires biopsy of liver or other
infected tissue. Treatment with
diethyl-carbamazine (Hetrazan) may 1)e helpful,
but even without treatment, once IJica is
stopped most patients recover.
lished.
CORRECTION
ARTICLES 91
blindness. These lesions, because they
re-SCllii)le retinoblastoma, have in the past led to unnecessary enucleation of the eye. Enu-cleation for suspected retinoblastoma, there-fore, silould not be performed withoimt due
consideration of the possibility of a benign granuloma caused by T. canis.
REFERENCES
1. Beaver, P. C., et a!.: Chronic eosinophihia due
to visceral larva niigrans. PEDIATRmCS, 9:7,
1952.
2. Demlt, J. H., and Carrera, C. M. : Eosinophilia
in childhood caused by visceral larva
mi-grans. J. Louisiana Med. Soc., 105:275, 1953.
3. I)ent, J. ii., et a!.: Visceral larva migrans-with
a case report. Amer. J. Path., 32:777, 1956.
4. Smith, I’I. H. D., and Beaver, P. C. :
Experi-mental visceral larva migrans. Amer.
J.
Dis.Child., 84:500, 1952.
5. McQuown, A. L. : Capillaria hepatica. A. J.
Ciin. Path., 24:448, 1954.
6. Ward, R. L., and Dent,
J.
H. : Capillariahe-patica infection in a child. Bull. Tulane Med.
Fac., 19:27, 1959.
7. Cochrane, J. C., and Skinstad, E. E. :Capillaria
hepatica in man. South African Med.
J.,
34:21, 1960.
8. Brill, H., Churg, J., and Beaver, P. C. : Allergic
granulomatosis associated with visceral larva
migrans. J. Chin. Path., 23: 1208, 1953.
9. \Viider, H. : Nematode Endophthalmitis. Trans.
Amer. Acad. Ophthal. Otolaryng., 55:99,
950.
10. Nichols, R. L. : Etiology of visceral larva
ml-grans : diagnostic morphology of infective
second stage toxocara larvae. J. Parasit., 42:
349, 1956.
1 1. Irvine, W. C., and Irvine, A. R., Jr. :
Nema-tode endophthalmitis. Amer. J. Oplithal., 47:
185, 1959.
12. Ashton, N. : Larval granulomatosis of the retina
due to toxocara. Brit.
J.
Ophthal., 44:129, 1960.1:3. Heiner, D. C., and Kevy, S. W. : Visceral larva
migrans: report of the syndrome in 3
sib-hugs. New Engl. J. Med., 254:629, 1956.
14. Jung, R. C., and Pacheco, C. : Use of a
heniag-glutination test in visceral larva migrans.
Amer. J. Trop. Med. Hyg., 9: 185, 1960.
15. Jung, R. C., amid Pacheco, C. : The Use of
intradermal and imidirect liemagg’utination
tests for the diagnosis of VLM-Proceedings
of the Sixth International Congress of
Tropi-cal Medicine amld Mahariology. To be
pimb-16. Jung, R. C., and Pacheco, C. : Tile relationship
of clinical features to immmmmiologic reactions
in visceral larva migrans. Amer. J. Med., 7:
256, 1958.
17. Pike, E. H. : Effect of diethylcarbamazine,
OX-ophenarsine iiy(irochlori(le, and piperazimme
citrate on Toxocara canis larvae in mice.
Exp. Parasit. 9:223, 1960.
18. Dent, J. H. : Visceral larva migrans. Sotmthern
Med. J. 53:616, 1960.
19. Friedman, S., and Hervada, A. R. : Severe
myocarditis with recovery in a child with
visceral larva migrans. J. Pediat., 56:91,
1960.
An error appeared in the article entitled “Renal
Tubular Dysfunction Complicating the Nephrotic
Syndrome,” by Stickler et a!., in PEDIATRICs, 26:75,
1960. In Figure 7, page 82, the fecah excretion
of phosphorus (hatched area) for Period 7 is plotted
incorrectly. The value should be 0.109 gm (not
0.6 as shown). The following statement in the text
on page 84 is correct: “In Case 2, after the
ad-ministration of vitamin D (Period 7), 63% of the
total intake of phosphorus was excreted in the
urine and only 10% of the phosphorus was excreted
