VISCERAL LARVA MIGRANSBY

W. DICKSON and R. C. WOODCOCKFrom the Bolton District General Hospital, Farnworth, Lancashire

(RECEIVED FOR PUBLICATION JULY 15, 1958)

There are many causes of persistent eosinophiliain children, but Perlingiero and Gyorgy (1947)described a case in which there was also hepaticenlargement, anaemia and fever. Two years laterZuelzer and Apt (1949) described eight similar casesand suggested that they formed a definite syndrome.Since then several more have been reported and ithas been shown that this syndrome is frequentlycaused by invasion of the viscera by the larvae ofthe dog or cat ascarid. We would like to describea further case and review the progress that has beenmade in the study of this syndrome.

Case Report

Marjorie was admitted to hospital as an urgent caseon September 14, 1956, because she had had a severeconvulsion.

She was nearly 2 years of age, the third child ofhealthy parents. Her first year was free from illnessand she made good physical progress, sitting up at6 months of age and standing at 9 months. When shewas 11 months old she was allowed to crawl about inher grandmother's back yard and it was then observedthat she was a dirt eater. Shortly after her first birthdayshe developed an acute febrile illness with wheezyrespirations. She was treated with penicillin and inabout five days the fever subsided but the noisy respira-tions persisted for about one month. After this illnessher disposition began to change; she became irritable,miserable and unfriendly and would speak only to hermother and grandmother. Her appetite became poorand she failed to gain weight. These rather indefinitesymptoms were still present when she was admitted tohospital.No other member of the family had had convulsions

but the following additional history was obtained aboutMarjorie. Since the age of 1 month she had what hermother described as mild fits in which she would gounconscious for a few seconds and then lie limp forabout 15 minutes. She was then having about twoattacks a week but they had become more frequentrecently. When she was 6 months of age she had fourmajor convulsions in three days and since then she hashad three major attacks.

There was no family history of allergic disease. Thefamily had a cat and a dog; the dog was killed in anaccident the night after Marjortie's admission to hospital.

Examination on admission: she was pale, restless andmiserable. Her temperature was 1030 F. The onlyabnormal findings were injection of the throat, enlarge-ment of the tonsillar glands and a few moist sounds inher lungs. Her liver was enlarged three fingers belowthe costal margin and it was smooth and firm.

She was thought to have had a febrile convulsionfollowing an upper respiratory infection and furtherinvestigations were carried out to find the cause of theenlarged liver.The results of laboratory investigations were as follows:

Hb 8-5 g. %, R.B.C. 4,440,000 per c.mm., C.I. 0-68;W.B.C. 23,000 per c.mm.; eosinophils, 67%; platelets,272,000 per c.mm.; B.S.R., 31 mm. in the first hour,61 mm. in the second hour; serum proteins, 8- 6 g. %;albumin, 4 g. %; globulin, 4-6 g. %; electrophoresisy globulin fraction markedly increased. Liver functiontests showed serum alkaline phosphatase, 31 units(K.A.); serum bilirubin, within normal limits; thymolturbidity, 2 units; thymol flocculation, normal; zincturbidity, 9 units; serum cholesterol, 115 mg. %;urine, no abnormalities; W.R. and Kahn tests negative.

Radiographs of the skull were normal; in those of thechest there was mottling in both upper lobes. AMantoux test 1:1,000 was negative.No ova or parasites were seen on repeated examination

of the patient's stools, the cat's faeces or the dirt fromthe back yard.

Iliac marrow puncture showed an eosinophilia butmost of the cells were mature and the picture was notthat of an eosinophilic leukaemia.The blood of the father, mother and sibs was tested;

the W.B.C. and differential count were normal.

Liver Biopsy. At operation, the liver was enlargedand its appearance most striking. It was studded withfirm greyish nodules which varied slightly in size butwere all a few millimetres in diameter..A small, wedge-shaped fragment of liver tissue about

1 cm. in diameter, containing some of the nodules, wasremoved and fixed in formol saline.

Serial sections of all the tissues were made and theyshowed inflammatory foci separated by normal livertissue. In some fields the liver cells had been destroyed

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ARCHIVES OF DISEASE IN CHILDHOOD

FIG. 1.-Liver. An early lesion. The section shows a focus ofinflammatory infiltration consisting mainly of eosinophils. Theeosinophils permeate between the liver cells at the periphery of thelesion. In the right hand corner a heavy concentration of eosinophils

is shown infiltrating some amorphous debris.

FIG. 2.-Liver. A late lesion-low power. A discrete granulomaconsisting ofepithelioid cells and giant cellswith a zone of lymphocytes

and plasma cells surrounding them.

FIG. 3.-Liver. A late lesion-high power. The foreign body giantcells surrounding a clump of amorphous debris are demonstrated.

and replaced almost exclusively by eosinophils. Theseareas varied in size, were irregular in shape and mergedinto the surrounding liver tissue. Several distinctclumps of eosinophils invading amorphous debris wereseen (Fig. 1) and the appearances strongly suggested thatthe debris was derived from degenerated fragments oflarvae.

There was an inflammatory reaction around andwithin the portal tracts. In some places most of thecells were eosinophils but in others there was a largeproportion of lymphocytes and plasma cells.

Several discrete granulomas were seen. They con-sisted of ephithelioid cells and giant cells of the foreignbody type with a zone of lymphocytes and plasma cellssurrounding them (Fig. 2). No foreign body was detectedin any of these lesions but some contained fragments ofunidentifiable necrotic debris (Fig. 3).

Other similar lesions were undergoing fibrosis and thegritty feel of some of the nodules at operation suggestedthat calcification may have occurred. This has beenreported in the literature in visceral larva migrans.Jung (personal communication) and his colleagues in

New Orleans have examined the sections and agree thatthe appearances are typical of visceral larva migrans.

Progress. Marjorie has now been observed fornine months and, apart from a course of oral and intra-muscular iron, she has had no treatment. The diseasehas followed a benign course. She has not had anyfurther convulsions or pulmonary symptoms. Herirritability and anorexia have gradually improved andnow she is back to normal health. Her eosinophil count

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VISCERAL LARVA MIGRANS

16.000

14.000

12.000

10.000

18.000

6,0005,0004.0003,0002,0001.000

SERUM GLOBULINS:21.9.56: 5-8 %4.12.56: 4 6 g9

303 57: 379 %20657: 349 100

~~~~~~9 o

7O0

9 10 12 M 2 3H 4 5 6 7MONTHS

FIG. 4.-Marjorie. Eosinophil count, serum globulins and haemo-globin levels in a case of visceral larva migrans.

has varied but has remained well above normal for morethan one year. Her haemoglobin and serum globulinhave very slowly returned to more normal levels(Fig. 4).

Review of Literature

Several reports of a syndrome like the one

described have appeared in the American literature.Zuelzer and Apt (1949) were the first to report a

group of eight cases which appeared to have a

common aetiology and demonstrate a syndrome.The syndrome occurs in young children and is

characterized by pica, pulmonary symptoms with a

low grade pyrexia, an enlarged liver studded witheosinophilic granulomas, chronic blood eosinophilia,anaemia and hyperglobulinaemia.The histology of the liver lesions suggested that

the inflammation had an allergic basis but theaetiology was obscure until nine years ago, whenMercer, Lund, Bloomfield and Caldwell (1950) foundthe larva of an ascarid in a liver lesion. LaterBehrer (1951) made a similar finding in another case.

They thought that the larvae were those of thehuman ascarid, but a year later Beaver, Snyder,Carrera, Dent and Lafferty (1952) described threecases and in one a larva was identified as that of thedog ascarid, Toxocara canis. They named thesyndrome 'visceral larva migrans' and consideredthat, like the commoner cutaneous larva migrans,it was due to the migration of nematode larvaethrough the tissues of an infected person.A year later Milburn and Ernst (1953) described

a further case in which the larva was identified.This case followed the typical benign course, but inthe same year Brill, Churg and Beaver (1953)described a fatal case in which granulomas were

found in the lungs, heart, liver and kidneys, and thetoxocara was again demonstrated. In 1956 Dent,Nichols, Beaver, Carrera and Staggers described the

post-mortem findings in a case which died fromhomologous serum jaundice. Again the character-istic lesions, some containing parasites, were widelyscattered in numerous organs, including the brain.It is interesting to note that Beautyman and Woolf(1951) found an encapsulated ascarid in the thalamusof a child dying of poliomyelitis. Further cases havebeen reported by Heiner and Kevy (1956) andGault and Webb (1957), writing from South India,described five cases and suggested that invasion ofthe liver and lungs by nematode larvae is the causeof tropical eosinophilia.

Discussion

(a) Pathogenesis. The human ascarid, Ascarislumbricoides, has a rather complicated life cycle.The adult worms live in the small intestine wherethey feed on its contents and lay eggs. After beingdischarged in the faeces, the eggs may remaindormant for several years or may embryonate indamp soil in two to four months. Infection is byingesting the embryonated eggs. The larvae escapefrom the eggs in the small intestine; they penetratethe wall and are carried to the liver in the portalblood stream. There they rest for a few days beforeresuming their journey through the right heart tothe lungs. During this period they grow consider-ably in size. After about eight days they are carriedup the trachea to the mouth and are swallowed a

second time. On this occasion they remain in thebowel and develop to maturity.The different species of ascarids only complete

their life cycles if they are in the correct hosts. Thefirst part of the cycle, that is the larval migration, isnot specific. Human ascarids migrate in mice andother animals but none reach sexual maturity.Similarly cat and dog ascarids will migrate in humanbeings but the larvae will be destroyed in the viscerabefore they can return to the gut. Thus no eggs willbe passed in the faeces as no adult worms are presentin the gut. The larvae are destroyed in the visceraof a foreign host and so may not be seen in liverbiopsies in all cases. In fact they have been foundonly in six cases. The inflammatory reaction willbe more severe than with the homologous ascaridand thus the signs and symptoms of the disease willbe more marked. Beaver et al. (1952) have sug-gested that patients who develop this syndrome havean allergic diathesis and this may enhance theresponse to the infection.

Salient Features. PICA. Infection of dogs andcats with toxocara is widespread. The animals mayeven be infected in utero. Examination of the soil

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ARCHIVES OF DISEASE IN CHILDHOODfrom places frequented by them often reveals largenumbers of ova.A history of pica was obtained in over 90% of

cases and ingestion of the ova of the toxocara in thedirt is the source of the infection.

AGE GROUP. The cases belong to a very definiteage group: 1 to 3 years.The reason for this may be that pica is uncommon

after 3 years of age or that, in older children, owingto the larger size of the liver capillaries, the toxocaramay pass more easily into the lungs. This mayaccount for some of the cases of Loeffler's syndrome,which belongs to an older group and is not associatedwith hepatomegaly.

PULMONARY SYMPTOMS. Pulmonary symptomscaused by invasion of the lungs by the larvae occurearly in the course of the disease and may precede,by a few months, the development of the eosinophiliaand hepatomegaly. Common symptoms are cough,coryza and frequently a wheezing type of breathing,often associated with pyrexia. They vary in severityand are often accompanied by radiological changesin the lungs which may resemble miliary tuber-culosis. Usually these lung changes are of shortduration.

CONVULSIONS. Convulsions and rather obscurecerebral symptoms have been reported in severalcases. Zuelzer and Apt (1949) thought that anencephalopathy due to vascular sensitization waspossibly part of the syndrome. However, it nowappears that infiltration of the brain by larvae maybe the cause of the symptoms, for larvae have beenfound in the brains of mice which have been fedwith toxocara ova.

In our case, if the parents' observations are correctregarding the age of onset of the convulsions, it isunlikely that they were caused by the infection.Nevertheless, it is interesting that, as the child'sgeneral condition has improved, the convulsionshave ceased without treatment.

HEPATOMEGALY. This is a constant feature in allcases. The liver is usually firm, smooth and regularand may be enlarged as much as five fingers belowthe costal margin. It seems possible that theparenchymal damage may account for the anorexia,irritability and lassitude. The liver function testsare indicative of parenchymal damage in about 30%of cases.

ANAEMIA. This is also a fairly constant finding.It is of the iron deficiency type but it responds only

slowly to oral or intramuscular iron. The averagehaemoglobin at the height of the symptoms wasabout 8 g.

LEUCOCYTOSIS. Leucocytosis with a high per-centage of eosinophils was present in all cases atsome time in the illness. Counts as high as120,000 W.B.C. per c.mm. with 870% eosinophils inthe differential count have been recorded, but theaverage count is about 30,000 W.B.C. per cm. with50% eosinophils.These blood changes may not appear until two to

three months after the onset of the respiratorysymptoms. Behrer (1951) suggests that the cause ofthe eosinophilia is the keratin which the larva shedswhen it moults in passing through the various stagesof its life cycle. Keratin can be demonstrated in liversections and it is a very powerful eosinophilicstimulant.

HYPERGLOBULINAEMIA. A raised serum globulin,due to an increased gamma globulin, has been foundin all cases in which it was estimated. This suggeststhat foreign larvae stimulate a powerful antibodyresponse and that hypersensitivity or serologicalreactions may prove helpful in diagnosis. This isdesirable as the larvae can only be demonstratedwith difficulty in liver biopsies, which in childrenof this age are best obtained by laparotomy. Heinerand Kevy (1956) have'described an agar diffusionprecipitation reaction between the patient's serumand an antigen prepared from the toxocara larvae.The test gives promise of providing a specificdiagnosis in the near future.Jung (personal communication) and his associates

performed the test on our patient's serum one yearafter the onset of symptoms. The serum showedno significant titre of antibodies against toxocara orascaris, so it is possible that this patient may havebeen infected with a larval worm other than the twomentioned. Jung states that two groups of parasiteshave been shown in experimental animals to producesymptoms similar to visceral larva migrans: somehookworms and spirurids.

Liver Biopsies. Characteristic lesions have beenfound in the liver in all cases in which biopsy hasbeen performed. On naked eye examination thepresence of numerous small greyish white plaquesarranged indiscriminately is strongly suggestive ofthe diagnosis. Microscopic examination revealsnumerous inflammatory foci of varying ages whichhave been caused by migrating parasites. Theyounger lesions consist of aggregates, mainly ofeosinophils, which have replaced liver cells. The

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VISCERAL LARVA MIGRANS 67

more mature ones are granulomas consisting of,epithelioid cells and foreign body giant cells sur-rounded by a zone of lymphocytes and plasma cells.The oldest lesions are granulomas undergoingfibrosis or even calcification.

Larvae are rarely seen in the lesions but small andoften degenerate fragments are occasionally found.The very early lesions are most likely to contain aparasite. When they are present the opinion of anexpert parasitologist is necessary for their completeidentification. The important diagnostic featuresare as follows: (1) T. cati measures 350u in lengthand 17,u at its greatest diameter. T. canis is a littlelarger. (2) There is a simple oesophagus 12O0, longterminating distally in an elongated bulb 8,u indiameter, which contains a conspicuous nucleus 3p.in diameter. (3) In a cross-section larval crests oralae, I . long, may be seen.

Marjorie's progress is typical of the usual courseof the disease. The ultimate prognosis is good,although many of the children go through a longperiod of ill health. No form of treatment has anyeffect either on the duration of symptoms or thecourse of the disease.

SummaryA case of visceral larva migrans is described.The literature is reviewed and the important signs

and symptoms are discussed.

The disease may be an important cause of chroniceosinophilia in childhood and may account formany of the cases considered to be Loeffler'ssyndrome or tropical eosinophilia.The disease may be more common in this country

than is realized because of the high incidence oftoxocara infection in cats and dogs. It is suggestedthat other parasites of domestic pets, such as hook-worms, may produce this condition.

The authors would like to thank Dr. R. C. Jung forexamining the serum and sections, Professor W. F.Gaisford for his helpful advice and criticism and Mr.J. Parker. Mr. D. Hart and Miss E. Barton for technicaland secretarial assistance.

REFERENCES

Beautyman, W. and Woolf, A. L. (1951). J. Path. Bact., 63, 635.Beaver, P. C., Snyder, C. H., Carrera, G. M., Dent, J. H. and Lafferty,

J. W. (1952). Pediatrics, 9, 7.Behrer, M. R. (1951). J. Pediat., 38, 635.Brill, R., Churg, J. and Beaver, P. C. (1953). Amer. J. clin. Path.,

23, 1208.Dent, J. H., Nichols, R. L., Beaver, P. C., Carrera, G. M. and Staggers,

R. J. (1956). Amer. J. Path., 32, 777.Gault, E. W. and Webb, J. K. G. (1957). Lancet, 2, 471.Heiner, D. C. and Kevy, S. V. (1956). New Engl. J. Med., 254, 629.Jung, R. C. Personal communication.Mercer, R. D., Lund, H. Z., Bloomfield, R. A. and Caldwell, F. E.

(1950) Amer. J. Dis. Child., 80, 46.Milburn, C. L., Jr. and Ernst, K. F. (1953). Pediatrics, 11, 358.Perlingiero, J. G. and Gyorgy, P. (1947). Amer. J. Dis. Child., 73, 74.Zuelzer, W. W. and Apt, L. (1949). Ibid., 78, 153

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