Visceral and Cutaneous Larva MigransPAUL C. BEAVER, Ph.D.

AMONG ANIMALS in general there is a

II. wide variety of parasitic infections inwhich larval stages migrate through and some¬

times later reside in the tissues of the host with¬out developing into fully mature adults. Whensuch parasites are found in human hosts, theinfection may be referred to as larva migransalthough definition of this term is becomingincreasingly difficult. The organisms impli¬cated in infections of this type include certainspecies of arthropods, flatworms, and nema¬

todes, but more especially the nematodes.As generally used, the term larva migrans

refers particularly to the migration of dog andcat hookworm larvae in the human skin (cu¬taneous larva migrans or creeping eruption)and the migration of dog and cat ascarids inthe viscera (visceral larva migrans). In a stillmore restricted sense, the terms cutaneous larvamigrans and visceral larva migrans are some¬

times used to denote the formation, of lesionsdue to a particular species of larva known or

presumed to be the one most commonly in¬volved: Ancylostoma braziliense in the skin,and Toxocara canis in the viscera. This usageof the terms is incorrect, however, since, as pre¬viously emphasized, the character and locationof the lesions and the resultant symptoms are

unreliable clues in the specific identification ofthe causative organisms (1).

Development of ConceptsThe various groups and species of worms in¬

volved in the larva migrans type of infection,the clinical features of the diseases caused bythem, and certain biological aspects of the host-parasite relationships have been discussed ina number of recent reports and reviews (2-5).

In the development of our concepts of larvamigrans there have been four major steps. Thefirst, of course, was the discovery by Kirby-Smith and his associates some 30 years ago ofnematode larvae in the skin of patients withcreeping eruption in Jacksonville, Fla. (6).This was followed immediately by experi¬mental proof by numerous workers that thelarvae of A. braziliense readily penetrate thehuman skin and produce severe, typical creep¬ing eruption.From a practical point of view these demon¬

strations were perhaps too conclusive in thatthey encouraged the impression that A. brazil¬iense was the only cause of creeping eruption,and detracted from equally conclusive demon¬strations that other species of nematode larvaehave the ability to produce similarly the pro¬gressive linear lesions characteristic of creep¬ing eruption. While in the initial studies byKirby-Smith it was possible to demonstratelarvae in 10 percent of the skin biopsies from in¬dividuals with creeping eruption, no sponta¬neous case of cutaneous larva migrans has yetbeen given a specific etiological diagnosis; thatis, no larvae have been identified in human skin.For many years after it was shown that nema¬

tode larvae cause creeping eruption it was as¬

sumed that the apparently aimless migrationwas due to abnormal host-parasite relationshipsand that the larvae eventually perished and

Dr. Beaver is professor of parasitology, departmentof tropical medicine and public health, Tulane Uni¬versity School of Medicine, New Orleans, La. Thispaper was presented at the Communicable DiseaseCenter's Conference for Teachers of Veterinary Pub¬lic Health and Preventive Medicine, and PublicHealth Workers, Atlanta, Ga., June 12-18,1958.

328 Public Health Reports

were destroyed in the skin. Two significantearly observations argued against that view.Wright and Gold's finding of pulmonary infil¬trations during or following the active phaseof creeping eruption suggested that at leastsome of the larvae succeeded in making thenormal migration to the lungs (7). It was alsonoted, however, that the pulmonary infiltra¬tions could have resulted from the larvae with¬out their having left the skin. Evidence of a

more convincing nature was provided by the re¬

port of an authenticated intestinal infection ofA. braziliense in a boy in Texas (8). If adultscould be found in the intestine, the larvae musthave migrated from the skin through the lungsenroute to the intestine. That record is no

longer accepted, however, and the reports of in¬testinal infections of A. braziliense in man inother parts of the world have likewise been ren¬

dered doubtful by the observations that a mor¬

phologically very similar species, Ancylostomaceylonicum, formerly regarded as a synonym ofA. braziliense, is a valid species (9). An obser¬vation by Muhleisen was, therefore, of specialsignificance (10). For a period of 24 days hefound large numbers of larvae in the sputum ofa man with severe and extensive skin lesions,leaving no doubt about migration from the skinto the lungs. Unfortunately the larvae were

not identified, but it was determined withoutany doubt that a mature intestinal infection didnot develop in this case.

Second StepThe second major event in the study of larva

migrans came in 1952 with the discovery andidentification of T. canis larvae in liver biopsiesfrom children with a common disease which upto that time had been given a number of dif¬ferent names but was of unknown etiology(11). This was followed a year later by an

experimental demonstration of the etiologicalrole of T. canis (12) and by numerous confirm¬atory reports indicating that this common as-

carid of dogs is responsible for much illness inchildren here and in other parts of the worldand that it apparently is an occasional cause ofdeath (13).Biopsy and autopsy studies in children, and

various types of studies in experimental ani¬

mals have provided more interesting factsabout T. canis as a cause of the visceral type oflarva migrans than can be mentioned here.

Briefly, it has been established that infectionis acquired by ingesting soil previously con¬taminated by infected dogs. Eggs passed inthe feces, under favorable conditions in the soil,become infective in 2 to 3 weeks, containingsecond-stage larvae which, when taken into theintestine of a child, erupt from the egg, pene¬trate the intestinal wall, and soon reach theliver. A majority of the larvae may remain inthe liver but others pass on to the lungs and toother parts of the body. Larvae have beenfound in nearly all organs. It is of chief inter¬est that a high proportion of them invade thecentral nervous system and a considerable num¬ber have been found in the eye. The tragicconsequence of invasion of the eye is the devel¬opment of a lesion which by its resemblanceto retinoblastoma prompts the unnecessary re¬

moval of that vital organ.Although most of the larvae eventually come

to rest in one location and stimulate fibrous en¬

capsulation, there is a period of at least severalweeks during which they move about in the tis¬sues of the visceral organs in much the samemanner as hookworm larvae migrate in theskin, leaving in their wake long trails of in¬flammatory and eosinophilic granulomatous re¬actions.Thus in comparison with their microscopic

size the wandering larvae produce large and ex¬

tensive lesions that can be readily seen with theunaided eye in and on the surface of the liverand, at times, in other organs, especially thebrain. This is the type of infection now calledvisceral larva migrans. Its most prominentclinical feature is high, stable, and persistent,eosinophilia, not uncommonly reaching levelssuggestive of eosinophilic leukemia. Less out¬standing and less constant features are enlarge¬ment of the liver, hyperglobulinemia, intermit¬tent fever, infiltrations of the lungs, neurologi¬cal symptoms, and deviations in behavior.Thus far T. canis is the only species of larva

identified in cases of visceral larva migrans.However, there is a good experimental and epi¬demiological basis for suspecting other speciesto be similarly involved. Toxocara cati, as

common or more so in cats as T. canis is in

Vol. 74, No. 4, April 1959 329

dogs, should occasionally reach the tissues ofchildren. In one instance a larva in a child'sliver has been questionably identified as T.cati (H).

Greatest anticipation of early incriminationis with Ancylostoma caninum. This worm ismore common in dogs than T. canis, and occurs

in cats as well as dogs. Whereas T. canis isrelatively uncommon in older dogs and is es¬

pecially uncommon in sexually mature females,A. caninum is found in both dogs and cats at allages. Both parasites take full advantage ofprenatal infection in maintaining a high levelof endemicity and both are known to persistin the tissue of experimental animals for more

than a year. There is no apparent reason whythe larvae of A. caninum should not be foundin the tissues of children along with the Toxo¬cara species. However, further studies maybring to light an explanation which is pres¬ently not apparent. Larvae entering the bodythrough the skin are less apt to be found in theliver and it is probable that A. caninum larvaeare much less frequently ingested than the eggsof Toxocara and some of the other helminths.The searching of liver biopsies for Toxocara

larvae has in recent years uncovered three cases

of Capillaria hepatica which formerly was

found only at autopsy and was thought to berare in man. It is hoped that when nematodelarvae are encountered in the examination ofhuman tissues it will not be assumed on cir¬cumstantial evidence that they are any particu¬lar species but rather will be identified on thebasis of characteristic morphology.

Third StepThe third notable contribution to our knowl¬

edge of larva migrans came from a series ofstudies on the basic life cycle patterns amongthe ascarids. Sprent (15) summarized thesestudies and pointed out that while infectionsby some and perhaps most of those speciesadapted to carnivorous land mammals can betransferred from host to host in the same man¬

ner as Ascaris lumbricoides, that is, by inges¬tion of infective eggs in contaminated soil, theusual pattern under natural conditions, includesintermediate or transport hosts.

Originally our domesticated dogs and cats

may have acquired their ascarid and perhapssome of their hookworm infections not directlyfrom the soil but indirectly by eating othermammals which by feeding on the ground hadearlier picked up the infective stages, pre¬served or further incubated them in their tis¬sues, and passed them on to their predators.

Experimentally, T. canis, T. cati, and A. cani¬num can be transferred to their final host byfirst inoculating mice or other small mammalswhich are then after several days, weeks, or

months fed to dogs or cats. The significanceof such observations is immediately apparent.They point out that our previous interpreta¬tion of larva migrans caused by these specieswas essentially incorrect. The migration andpersistence without development in human tis¬sues are not, as we had supposed, basically dueto an abnormal host relationship. We may stillregard man as an abnormal host for the adultstage, and an unnatural host for the larvae inthat he provides no advantage for the parasiteas a species, but the behavior of the larvae inman being the same as in natural transporthosts apparently is not abnormal. It is thento be expected that any of the larval stages ofnematode parasites of wild or domesticatedcarnivorous animals adapted to the use ofmammalian intermediate or transport hosts maygrasp the opportunity to enter the tissues ofhuman hosts and await, unsuccessfully ofcourse, the transfer to a predator final host.

It is obvious from these remarks that detailedstudies on the life cycles of all worm parasitesof animals having contact with humans havegreat usefulness in the study of larva migransand other zoonotic helminthiases.

Fourth StepThe fourth major advance in larva migrans

research was Nichols' demonstration of thefeasibility of identifying nematode larvae inmicrosections of tissues (16,17). These classicmorphological studies, while limited to only ahalf dozen species considered most likely to beencountered in human tissues, left no doubt thatdescriptions of these and other species could besufficiently detailed to permit reliable identifica¬tion often when only fragments of the larvaeare available for study. The interpretation,

330 Public Health Reports

prevention, and effective control of any para¬sitic disease are, of course, dependent upon theaccurate identification of the organism whichcauses it. To make this possible, additionalstudies such as Nichols' are needed.

Research on Prevalence

Inasmuch as public health programs placestrong emphasis on the reliable determinationof disease prevalence and on the development ofpreventive measures, we should mention heretwo additional phases of research in which re¬cent studies show promise of providing im¬portant, useful information.Thus far it has not been possible to get a

clear picture of either the extent or the prev¬alence of visceral larva migrans. Originally,diagnosis was based on liver biopsies taken bylaparotomy. This procedure is too hazardousand expensive to be used routinely. Further¬more, no specific therapy is available, and usu¬

ally when additional infection can be prevented,the prognosis is favorable. It is understand¬able, therefore, that a clinical diagnosis, un¬

confirmed by actual identification of the causa¬tive organism, is relied upon in the managementof most cases. It is equally understandable thatunconfirmed clinical diagnoses are not reallysatisfactory.In view of these circumstances, it is of great

interest that promising and already somewhatuseful serologic techniques of diagnosis are

being developed by Sadun and associates (18),Kagan (19), and Jung and Pacheco (20). Thefault in serodiagnostic methods has been theirlack of specificity due to cross-reacting antigen-antibody systems among related worms. Byfractionation and purification of antigens, cross-

absorption of antibodies, and application of therecently developed hemagglutination and floc¬culation tests apparently reliable diagnoses arenow being obtained.With the recognition that dog and cat para¬

sites cause obscure, serious disease in humans,surveys to determine the geographic distribu¬tion and prevalence of individual species havetaken on new significance. Among the first torecognize this and to carry out a thorough andmeaningful survey of dog parasites were Don¬aldson and his associates (21) and Ehrenford(22).

Ehrenford has given at least a partial answerto one of the first and most significant questionsasked about T. cards. Kecognizing that pupsare more often infected than adult dogs thequestion is often raised as to the actual riskwith older dogs. Ehrenford's answer is thatthe risk depends upon the sex of the dog. Malesare about as frequently infected as pups but theincidence among females is lower at all agesand is markedly lower in the mature adult. InIndiana and adjacent States less than 5 percentof mature females were found to be infected,while almost a third of the mature males were

passing Toxocara eggs that might eventuallybe the cause of illness in children. These datawere obtained from stray, uncared for, un¬wanted dogs, as has been the case in almost allpublished surveys.

Studies in New Orleans indicate that al¬though the rate of infection among well caredfor dogs is relatively much lower, it still isdisturbingly high. Among 171 fresh dog stoolscollected along the sidewalks in front of housesof perhaps the most sanitation-minded, hy¬giene-conscious, and economically most favoredfamilies in the city, 7 percent contained T. camseggs; hookworm eggs were found in 51 percent,and Trichuris in 25 percent. Almost all of thesestools were judged to have come from adultdogs.Also in New Orleans, among 103 immature

and 222 mature dogs brought to veterinariansfor various services, all relatively expensive(indicating the owners' concern for their well-being) , Toxocara was found in approximately15 percent of the young dogs and 3 percent ofthe older ones (23). Kelatively few of thedogs of either age group were presented spe¬cifically for anthelmintic treatment. Nearlyhalf of them harbored hookworms and one-fifth had Trichuris infections.

Conclusion

There is much needed information to be de¬rived from good surveys and epidemiologicalstudies of intestinal parasites of dogs and cats.To be of greatest usefulness such studies should

.be carried out with the same careful prepara¬tion and epidemiological forethought and pur¬pose as would be acceptable in a study of hu-

Vol. 74, No. 4, April 1959 331

man disease. In fact such studies can beregarded as being directly concerned with hu-man disease. We are only beginning to appre-ciate the importance of including householdpets in the total picture of the family's andthe public's health.

REFERENCES

(1) Beaver, P.: Larva migrans. A review. Exp.Parasitol. 5: 587 (1956).

(2) Beaver, P.: Parasitic diseases of animals andtheir relation to public health. Vet. Med. 49:199 (1954).

(8) Beaver, P.: Wandering nematodes as a cause ofdisability and diseases. Am. J. Trop. Med. &Hyg. 6: 433 (1957).

(4) Beaver, P.: Animal parasites and human dis-eases. Pediatrics 22: 380 (1958).

(5) Platou, R. V., and Beaver, P.: Visceral larvamigrans. Acta. Paediat. 46: 64 (1957).

(6) Kirby-Smith, J. L., Dove, W., and White, G. F.:Creeping eruption. Arch. Dermat. & Syph. 13:137 (1926).

(7) Wright, D. O., and Gold, E. M.: LUfflers syndromeassociated with creeping eruption (cutaneoushelminthiasis). Report of 26 cases. Arch.Int. Med. 78: 303 (1946).

(8) Dove, W. E.: An intestinal infection of Ancylos-toma brazilien8e in a boy and skin lesions pro-duced with larvae from this strain. J. Para-sitol. 15: 136 (1928).

(9) Beaver, P.: The record of Ancylostoma brazi-liense as an intestinal parasite of man in NorthAmerica. Am. J. Trop. Med. & Hyg. 5: 587(1956).

(10) Muhleisen, J. P.: Demonstration of pulmonarymigration of the causative organism of creep-ing eruption. Ann. Int. Med. 38: 395 (1953).

(11) Beaver, P., Snyder, H., Carrera, G., Dent, J., andLafferty, J.: Chronic eosinophilia due to vis-ceral larva migrans; report of three cases.Pediatrics 9: 7 (1952).

(12) Smith, M. H. D., and Beaver, P.: Persistence and

distribution of Tococoara larvae in the tissuesof children and mice. Pediatrics 12: 491(1953).

(13) Dent, J., Nichols, R., Beaver, P., Carrera, G., andStaggers, R.: Visceral larva migrans: with acase report. Am. J. Path. 32: 777 (1956).

(14) Karpinski, F. E:., Everts-Suarez, E. A., andSawitz, W. G.: Larval granulomatosis (viscerallarva migrans). Am. J. Dis. Child. 92: 34(1956).

(15) Sprent, J. F. A.: The life cycles of nematodesin the family Ascarididae Blanchard 1896. J.Parasitol. 40: 608 (1954).

(16) Nichols, R. L.: The etiology of visceral larva mi-grans. I. Diagnostic morphology of infectivesecond-stage Toxocara larvae. J. Parasitol.42: 349 (1956).

(17) Nichols, R. L.: The etiology of visceral larvamigrans. II. Comparative larval morphologyof Ascari8 lumbricoide8, Necator amerioanus,Strongyloides 8tercoralis and Aaneyo8tomacaninum. J. Parasitol. 42: 363 (1956).

(18) Sadun, E. H., Norman, L., and Allain, D.: Thedetection of antibodies to infection with thenematode, ToGcocara cani8, a causative agent ofvisceral larva migrans. Am. J. Trop. Med. &Hyg. 6: 562 (1957).

(19) Kagan, I. G.: Serum-agar double diffusion studieswith ascaris antigen. J. Infect. Dis. 101: 11(1957).

(20) Jung, R. C., and Pacheco, G.: Relationship ofclinical features to immunologic reactions invisceral larva migrans (abstract). Am. J.Trop. Med. & Hyg. 7: 256 (1958).

(21) Donaldson, A., Steele, J., and Scatterday, J.:Creeping eruption in the Southeastern UnitedStates. Am. Vet. M. A., Proc. 87th Ann. Meet.,p. 83, 1950.

(22) Ehrenford, F. A.: Canine ascariasis as a sourceof visceral larva migrans, a zoonosis. Am. J.Trop. Med. & Hyg. 6: 166 (1957).

(23) Vaughn, J. B.: The prevalence of Tococara canisinfection in dogs admitted to four veterinaryhospitals in New Orleans, Louisiana. Inpress.

Second National Conference on World Health

The Second National Conference on World Health will be held in Washing-ton, D.C., May 7-9, 1959, under the sponsorship of the National Citizens Com-mittee for the World Health Organization. Conference chairman will be Dr.Milton S. Eisenhower, president of the Johns Hopkins University. Topics in-clude prospects for the International Health Year; health and populationchanges; health and the American image abroad; and training and exchangeprograms for public health personnel.

332 Public Health Reports