Advances in PARASITOLOGY
VOLUME 51
Editorial Board M. Coluzzi, Director, Istituto de Parassitologia, Università Degli Studi di Roma ‘La Sapienza’, P. le A. Moro 5, 00185 Roma, Italy C. Combes, Laboratoire de Biologie Animale, Université de Perpignan, Centre do Biologie et d’Ecologie Tropicale et Méditerranéenne, Avenue de Villeneuve, 66860 Perpignan Cedex, France D.D. Despommier, Division of Tropical Medicine and Environmental Sciences, Department of Microbiology, Columbia University, 630 West 168th Street, New York, NY 10032, USA J.J. Shaw, Instituto de Ciências Biomédicas, Universidade de São Paulo, av. Prof Lineu Prestes 1374, 05508-900, Cidade Universitária, São Paulo, SP, Brazil K. Tanabe, Laboratory of Biology, Osaka Institute of Technology, 5-16-1 Ohmiya Asahi-Ku, Osaka, 535, Japan P. Wenk, Falkenweg 69, D-72076 Tübingen, Germany
Advances in PARASITOLOGY Edited by
J.R. BAKER Royal Society of Tropical Medicine and Hygiene, London, England
R. MULLER London School of Hygiene and Tropical Medicine, London, England and
D. ROLLINSON The Natural History Museum, London, England VOLUME 51
Amsterdam Boston London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo
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Typeset by M Rules, London, UK Printed and bound in Great Britain by MPG Books, Bodmin, Cornwall 02 03 04 05 06 07 MP 9 8 7 6 5 4 3 2 1
CONTRIBUTORS TO VOLUME 51 B. FRIED, Department of Biology, Lafayette College, Easton, Pennsylvania 18042, USA A. HEMPHILL, Institute of Parasitology, University of Berne, LänggassStrasse 122, CH-3012 Berne, Switzerland. Email:
[email protected] K. KITA, Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1130033, Japan D.A. MAYER, Department of Surgery, New York Medical College, Valhalla, New York 10595, USA M. SILES-LUCAS, Unidad de Parasitologia, Facultad de Farmacia, Universidad de Salamanca, Avenida del Campo Charro sn, 37007, Salamanca, Spain. Email:
[email protected] S. TAKAMIYA, Department of Parasitology, School of Medicine, Juntendo University, Japan
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PREFACE
As this volume was going to press, we were saddened to hear of the death, at the age of 88, of Professor W. H. Russell Lumsden. Russell succeeded Ben Dawes, the founder, as senior editor of Advances in Parasitology in 1978 (Vol. 16), assisted by two of us (J. B. and R. M.), and continued in that role until 1982 (Vol. 20). He subsequently continued to serve as an editorial board member until prevented by illness a few years ago. Russell had a distinguished and varied scientific career. He qualified initially as a zoologist in Glasgow in 1935, and subsequently in medicine in 1938. He was awarded a DSc by the University of Glasgow in 1956 and an MD in 1975. Russell served in the British Army during the 1939–45 war, latterly as commanding officer of No. 3 Malaria Field Laboratory. Subsequently he specialized in virology, joining the staff of the Yellow Fever Research Institute (later the East African Virus Research Institute) at Entebbe, Uganda in 1947. He then transferred his interests to parasitic protozoa, becoming director of the East African Trypanosomiasis Research Organization in 1957 (where one of us, J. B., was working). From there he moved to the UK in 1963 and, after five years in the University of Edinburgh, he became Professor of Medical Protozoology in the University of London (at the London School of Hygiene and Tropical Medicine and Hygiene) in 1968. During that time he co-wrote (with W. J. Herbert and G. J. C. McNeillage) Techniques with Trypanosomes (Churchill Livingstone, 1973) and edited (with David Evans) the major two-volume reference work Biology of the Kinetoplastida (Academic Press, 1976–79). He retired from the Chair in 1979, becoming Professor Emeritus and returning to his native habitat (Scotland) to live in Edinburgh accompanied by his wife Pamela, who had supported him throughout his career and who survives him. Russell’s retirement was far from idle. He pursued a variety of interests until ill health forced him to relinquish many activities,
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including a study of the design and construction of Zambian arrowheads, a subject on which he published. The publisher’s announcement of Russell’s retirement from the editorship in Vol. 20 (p. vii) included the words ‘We . . . have found him always a delight to work with, constructive, helpful and responsive . . . .’ Those of us who were fortunate enough to work with Russell in this and other ways wholeheartedly support this assessment, wishing to add only a tribute to his, often slightly mischievous, sense of humour. We shall miss him greatly as colleague and friend. In the opening review of this volume, David Mayer of the New York Medical College and Bernard Fried of Lafayette College, Pennsylvania, USA have reviewed recent developments in the study of both protozoan and helminthic human parasitic diseases in which surgical intervention may be required. The introduction of minimally invasive surgery in the last ten years has revolutionized such interventions with much smaller incisions and consequent reductions in post-operative recovery times. The authors have also reviewed new information on other aspects of the infections such as epidemiology, pathogenesis, diagnosis, treatment and prevention. Kiyoshi Kita and Shinzaburo Takamiya (University of Tokyo, Japan) provide a detailed account of electron transfer complexes in the mitochondria of Ascaris and other parasitic worms in the second review. The authors point out that parasites have exploited unique energy metabolic pathways as adaptations to their habitats within the host. Respiratory systems of parasites tend to show a greater diversity in electron pathways than those of host animals. The review is timely as there have been recent developments in our understanding of the respiratory chain concerning both the molecular structure of the biochemical components and the changes that occur during the parasite’s life-cycle. A. suum could prove to be a useful model to study regulation of transcription by the oxygen level in the environment. And finally, Mar Siles-Lucas (University of Salamanca, Spain) and Andrew Hemphill (University of Berne, Switzerland) have provided an overview of the place of laboratory models, both in vivo and in vitro, in investigating the host–parasite relationships of cestodes. Most studies have involved genera of the greatest medical and veterinary importance, such as Echinococcus, Taenia and Spirometra, but there have also been models to maintain different lifecycle stages of Hymenolepis and Mesocestoides. These models have been used for many studies on the development, morphology and metabolism and gene expression of the cestodes, on drug screening against them, and on the pathology and immunology of the infections. John Baker Ralph Muller David Rollinson
CONTENTS CONTRIBUTORS TO VOLUME 51 . . . . . . . . . . . . . . . . . . . . . . v PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Aspects of Human Parasites in which Surgical Intervention May Be Important D.A. Meyer and B. Fried
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . Trypanosoma cruzi . . . . . . . . . . . . . . . . . . . . Entamoeba histolytica . . . . . . . . . . . . . . . . . . Leishmania donovani . . . . . . . . . . . . . . . . . . Strongyloides stercoralis . . . . . . . . . . . . . . . . . Taenia solium . . . . . . . . . . . . . . . . . . . . . . Schistosoma mansoni . . . . . . . . . . . . . . . . . . Paragonimus westermani . . . . . . . . . . . . . . . . Echinococcus granulosus . . . . . . . . . . . . . . . . Ascaris lumbricoides . . . . . . . . . . . . . . . . . . . Fasciola hepatica . . . . . . . . . . . . . . . . . . . . Surgical Treatment for Parasitic Infections Not Covered in the Text . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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3 3 5 11 17 24 29 36 48 53 62 70
. . . . . 76 . . . . . 79
Electron-transfer Complexes in Ascaris Mitochondria K. Kita and S.Takamiya
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
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2. 3. 4. 5. 6. 7. 8. 9.
Energy Metabolism of Parasitic Helminths . . . . . . . Developmental Changes in the Respiratory Chain . . . . NADH-Fumarate Reductase System . . . . . . . . . . . NADH-dependent 2-Methyl Branched-chain Enoyl-CoA Reductase System . . . . . . . . . . . . . . . . . . . . Role of Rhodoquinone in Anaerobic Respiration . . . . Evolution of the Parasite Electron-transport System . . Heterogeneity in Helminth Mitochondria . . . . . . . . Conclusions and Perspectives . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 97 . . . . . 100 . . . . . 107 . . . . . . .
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115 116 120 122 123 124 124
Cestode Parasites: Application of In Vivo and In Vitro Models for Studies on the Host–Parasite Relationship M. Siles-Lucas and A. Hemphill
Abstract . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . Laboratory Models for Studies on Echinococcus spp. . Laboratory Models for Studies on Taenia spp. . . . . Hymenolepis spp.: Versatile Cestode Parasite Models . Mesocestoides spp. As Experimental Models to Study Cestode Biology . . . . . . . . . . . . . . . . . . . . 6. Experimental Investigations on Spirometra spp. . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . 1. 2. 3. 4. 5.
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134 134 136 153 164
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180 186 193 194 194
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Aspects of Human Parasites in which Surgical Intervention May Be Important David A. Mayer1 and Bernard Fried2 1Department
of Surgery, New York Medical College, Valhalla, New York 10595, USA; 2Department of Biology, Lafayette College, Easton, Pennsylvania 18042, USA
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Trypanosoma cruzi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. American trypanosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Entamoeba histolytica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Amebiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Leishmania donovani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Strongyloides stercoralis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Strongyloidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADVANCES IN PARASITOLOGY VOL 51 0065–308X $30.00
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5.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Taenia solium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Taeniasis and cysticercosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schistosoma mansoni . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paragonimus westermani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Paragonimiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Echinococcus granulosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Echinococcosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ascaris lumbricoides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Ascariasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fasciola hepatica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1. Case report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. Fascioliasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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11.7. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 12. Surgical Treatment for Parasitic Infections Not Covered in the Text . . . . . 76 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
ABSTRACT
Until recently, physicians and surgeons in developed countries only occasionally encountered patients with parasitic protozoan and helminthic infections. High-speed travel, immigration and the popularity of the tropics as vacation areas have increased the number of people at risk for parasitic disease. This chapter examines the significant literature on a select number of protozoan and helminthic parasites for which surgical intervention is important in the diagnosis, treatment or cure of the disease. Although traditional surgical approaches are covered, emphasis is placed on recent advances in the areas of transplantation and minimally invasive surgery. Combining the disciplines of parasitology and surgery, this chapter covers three protozoan and seven helminthic parasites for which surgery is a valid treatment option based on the frequency of cases reported in the literature. Following coverage of the selected parasites, a table is included listing additional helminths for which surgery contributes to patient management. Physicians in the USA, UK, and Europe need to be more aware of the presentation and treatment of parasitic infections. It is our sincere hope that this review accomplishes that goal, and ultimately benefits the patients we serve.
1. INTRODUCTION
The purpose of this chapter is to examine a select number of protozoan and helminth parasites for which surgical intervention is important in the diagnosis, treatment, or cure of the parasite. The review originally started out with the title ‘Surgical Intervention in Parasitic Diseases’. As the text developed, we realized the need to include more information about the parasites covered, i.e., case history, parasite transmission, epidemiology, life cycle, pathogenesis, clinical manifestation, and treatment other than surgical. With the change in emphasis of the text for the parasites covered, evolved the new title, ‘Aspects of Human Parasites in which Surgical Intervention May Be Important.’ After completion of coverage of the selected parasites, we added a table at the end of the chapter listing additional helminths for which surgery is an option in diagnosis, treatment, or cure. Two biomedical scientists with diverse backgrounds have written this
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review. One (DAM) is a general and vascular surgeon, who developed an interest in clinical parasitology as a surgical resident at Cornell University from 1973 to 1978. The second (BF) is an experimental parasitologist, who became interested in medical parasitology during his tenure as a Louisiana State University Medical Fellow in the Central American tropics in 1967. Because numerous medical and surgical terms are used in the text, we have provided definitions (in parentheses) of some of the more esoteric terms the first time they are used. These definitions should help parasitologists not familiar with the nuances of medical and surgical terminology. Protozoan and helminthic infections are of enormous importance worldwide, and the number of people infected or at risk of infection is overwhelming. Until recently, most physicians and surgeons in developed countries only occasionally encountered patients with such infections. At present, with increased mobility of large segments of the world’s population, the popularity of the tropics as vacation areas, and the high speed of transportation, physicians in the USA, UK, and Europe need to be more aware of parasitic infections. The situation has also been exacerbated by the emergence of immunocompromise, whether by AIDS, helminthic or protozoan infections, chemotherapy, or immunosuppressive drugs. A main emphasis of this chapter is on surgical intervention in parasitic diseases. It is important to remember that during the past approximately 10 years, surgery has undergone a revolution. In most instances, the patient is no longer forced to undergo painful operations done through large, slow-healing incisions. The era of minimally invasive surgery is here. The surgeon works with small incisions using video imaging through scopes placed in body cavities. Patients usually have minimal postoperative discomfort, with relatively quick recovery time. In response to parasitic infections for which surgery is a treatment option, minimally invasive procedures such as laser photocoagulation, laparoscopy, thoracoscopy, endoscopy, and image-guided needle aspiration are being used to treat and cure parasitic infections. Our review considers ten parasites (protozoans and helminths) for which surgery is a valid treatment option based on the frequency of cases reported in the literature. Each section begins with a case report, followed by a discussion of parasite transmission, epidemiology, life cycle, pathogenesis, clinical manifestation, and treatment, especially surgical. Some topics that relate to surgical intervention include liver transplantation for alveolar echinococcosis, heart transplantation for chronic Chagas’ disease, endoscopic management of biliary liver flukes, laparoscopic treatment of ascariasis, and percutaneous drainage of amebic liver abscess. When we completed coverage of the ten selected parasites, we realized there were other parasites for which surgical management is a treatment option. Information on surgical treatment of these parasites is considered in Table 1 at the end of the chapter.
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2. TRYPANOSOMA CRUZI 2.1. Case report
A 44-year-old woman from Ecuador who immigrated to the USA at age 21, presented with a mild stroke caused by embolization of clot from an aneurysm of the left ventricle of the heart. She had depressed left ventricular function with marked cardiomegaly. No coronary artery disease was found on angiogram, and endomyocardial biopsies showed diffuse myocardial fibrosis. No parasites were observed on microscopic examination. The diagnosis of Chagas’ cardiomyopathy was confirmed by a positive immunoprecipitation and complement fixation test. The patient experienced progressive deterioration of cardiac function, accompanied by severe mitral and tricuspid valvular regurgitation. Refractory ventricular tachycardia and intractable congestive heart failure made heart transplantation her only chance for survival. Orthotopic heart transplantation was performed. In this method, the donor heart is sutured in place in the anatomic bed of the explanted heart, as opposed to the heterotopic transplant, in which the new heart is placed on top of the diseased heart, which is left in situ. The patient was immunosuppressed over the eight post-transplant months with a multidrug regimen consisting of cyclosporin, steroids, azathioprine and OKT3 (a monoclonal antibody against human CD3 T-cell antigen). The goal of immunosuppression is to allow proper healing while inducing tolerance to the allograft. Cyclosporin (2–8 mg kg–1 day–1) is the cornerstone of all regimens, acting by inhibiting production of interleukin-2 and attenuating cytotoxic Tlymphocytes. Steroids (methylprednisolone 0.15–0.2 mg kg–1 day–1) and azathioprine (2 mg kg–1), when added to cyclosporin, are known to increase cardiac transplant survival to 85–90% at 1 year (Gay, 1995). Additionally, OKT3 was administered at 5 mg day–1, both for immunosuppression and to enable the use of lower steroid dosages, thereby reducing side effects. Although no preoperative therapy for Chagas’ disease was given, nifurtimox (120 mg day–1 for 3 months, followed by 150 mg on alternating days) was administered postoperatively to suppress potential recurrence of Trypanosoma cruzi, with plans to continue the drug indefinitely. The patient was alive and well 6 years after transplant, and remained free of reactivation of Chagas’ disease. Pathology of the explanted heart revealed diffuse endocardial interstitial fibrosis. Lymphocytic, plasmocytic, and eosinophilic infiltrates of heart muscle indicated acute and chronic myocarditis. Again, no parasites were seen microscopically (Blanche et al., 1995).
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2.2. American Trypanosomiasis
Chagas’ disease, also called American trypanosomiasis to differentiate it from its African counterpart, is caused by infection with T. cruzi. This flagellate protozoan is an anthropozoonotic parasite infecting many vertebrates. Triatome or reduvid bugs are the vectors. In 1909, a Brazilian medical student, Carlos Chagas, discovered the etiology of the disease that now bears his name. Human infection starts with an acute phase of high parasitemia lasting several weeks, followed by a long chronic phase of positive serology and low parasitemia. The severity of the disease increases as one moves south from Texas to Brazil. Years after acute infection, 20–30% of patients develop chronic cardiomyopathy, 10% develop intestinal megasyndromes (pathologic dilatation of the esophagus or colon), and a small percentage develop peripheral nerve involvement. The polymorph T. cruzi has an indirect life cycle. The insect vectors, reduvid bugs, are obligate blood feeders measuring 5–45 mm in length. By ingesting blood from infected human or animal reservoirs, they become infected with circulating trypomastigotes. In the bug, these transform into flagellated epimastigotes, 20 µm long, with an anterior kinetoplast near the nucleus. In the midgut of the bug, they divide by binary fission. The daughter epimastigotes migrate to the hindgut to become metacyclic trypomastigotes. Humans are infected when the feeding triatome bug defecates metacyclic trypomastigotes onto the skin near the bite site. Often aided by scratching by the human victim, the trypomastigotes penetrate the slightest break in the cutaneous barrier to infect tissue histiocytes. Here, nests of intracellular oval amastigotes, 3 µm in diameter, multiply by binary fission. Daughter amastigotes form trypomastigotes, which are released upon rupture of the host cell to enter the bloodstream. The trypomastigotes are flagellated, 15–20 µm long, with a large posterior kinetoplast. Especially infective to muscle and nerve cells, they use receptors to attach and enter other host cells to again form pseudocysts of amastigotes. The time from penetration of a trypanomastigote into a host cell to the cell’s eventual rupture is approximately 5 days. The insect vector feeding on the blood of the infected vertebrate host completes the cycle (Magill and Reed, 2000).
2.3. Epidemiology
The majority of cases of human Chagas’ disease are reported from Brazil, but Bolivia has the highest (20%) seropositive rate. American trypanosomiasis is prevalent from the southwestern USA as far south as Argentina and Chile. Pathogenicity of T. cruzi isolates is greater in Brazil than in North or Central America, with megasyndromes (pathologic dilatation) of the gut and
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cardiomyopathy being more common. In Latin America, 16–18 million people are seropositive, or about 4–5% of the population. An estimated 100 000 seropositive persons are currently living in the USA. T. cruzi has been identified in more than 100 mammalian species, but the sylvatic cycle is an important facilitator of human infection by domestic animals such as dogs lying around the house at night, when reduvid bugs feed. Of the many vector species, Triatoma infestans is predominant due to its predilection for living in wall cracks in primitive housing and its preference for human blood. Although direct bug bites account for the majority of cases of Chagas’ disease, additional modes of transmission include contaminated blood transfusions, maternal to fetal infection, accidental ingestion of contaminated food, and laboratory accidents (Magill and Reed, 2000).
2.4. Pathogenesis
The acute phase of human infection is characterized by rapid parasite multiplication inside cells, with amastigotes having a predilection for the heart, brain, and liver. With advancing infection, inflammatory lymphocytes and plasma cells appear, and parasites are harder to find. The heart becomes enlarged and dilated, replete with nests of amastigotes encased in pseudocysts prior to rupture of myofibrils. Chagas’ disease is characterized by one of the most severe forms of myocarditis, and congestive heart failure leads to organ congestion and fluid retention. Focal myocardial inflammation and scarring can also destroy the cardiac conducting system. The brain and meninges can become inflamed, and lesions of the esophagus and gut occur in muscle layers and nerve plexi. Since the reduvid bugs have an affinity for biting the face, an early indication of acute infection is unilateral orbital edema from rubbing bug feces in the eye, known as Romana’s sign. In the chronic phase, the early severe myocarditis can cause Chagas’ cardiomyopathy. The organ becomes thin walled, lacking in tone, with fibrosis of the chambers and dilated valve rings. Electrocardiogram findings of extra ventricular beats and heart block often occur early, with eventual congestive heart failure, left ventricular aneurysms, and pulmonary or systemic emboli from intracardiac clot. Megasyndromes also occur late in the chronic phase consisting of a dilated esophagus or sigmoid colon. The cause is parasite destruction of the submucosal parasympathetic ganglion cells leading to difficulty swallowing (megaesophagus) or constipation (megacolon). Megaesophagus is graded according to degree of esophageal dilatation: grade 1: <4 cm, grade 2: 4–7 cm, grade 3: 7–10 cm, grade 4: >10 cm. Pressure at the gastroesophageal junction is increased, with no relaxation upon swallowing as normally occurs. Reflux of gastric secretions with their aspiration into the tracheobronchial tree often
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lead to secondary pneumonia, exacerbating wasting from malnutrition. Megacolon is evident with progressive constipation and abdominal distension. The sigmoid colon may twist, called a volvulus, resulting in a surgical emergency. Fecaloma, or impaction, may also acutely obstruct affected patients (Kirchoff, 1996).
2.5. Diagnosis
Parasites detected in tissues, or the presence of antibodies to T. cruzi in the blood, constitute a positive diagnosis. During the acute phase, fresh smears of unstained blood or buffy coat are examined for motile trypomastigotes. If unsuccessful, polymerase chain reaction (PCR) assays for T. cruzi nuclear and kinetoplast DNA can be tried. Xenodiagnosis, where uninfected laboratorybred reduvid bugs are fed on the patient, may be helpful. A month later, the bug feces should show flagellates if the patient is seropositive. In the chronic phase, serologic tests are preferable since parasitemia is low. Antibody detection is possible with indirect hemagglutination assay (IHA), immunofluorescence test (IF), complement fixation test (CF), and enzymelinked immunosorbent assay (ELISA). In all these methods, a lysate of culture-derived epimastigotes is the source of capture antigen. Negative seroconversion is believed to represent parasitologic cure (Markell et al., 1999b).
2.6. Treatment
The role of heart transplantation in end-stage Chagas’ cardiomyopathy is not well defined. There are relatively few publications regarding this controversial issue (Milei et al., 1992; Bocchi et al., 1994; Blanche et al., 1995; de Carvalho et al., 1996). The fear is that drugs used to prevent rejection, by suppressing the immune system, may lead to recurrence of T. cruzi infection with resultant damage to the allografted heart. The actual operation required to transplant a heart is well established, with centers reporting 1-year survival of over 90% and 5-year survival of over 80%. Generally, cardiac transplantation is limited to patients with terminal heart disease who cannot achieve palliation or prolongation of life with conventional medical or surgical therapy. Active infection has been considered a contraindication because of the probability of dissemination with immunosuppression (Gay, 1995). There may be 75 000 undiagnosed cases of Chagas’ cardiomyopathy in the USA today. Leiby et al. (2000) raised the concern that the emigration of several million people from T. cruzi endemic areas into the USA has caused this increased prevalence. In their study of 11 430 cardiac surgery patients, enzyme immunoassay and radioimmunoprecipitation analysis of postoperative blood
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samples showed six positive tests (0.05%). Overall, 2.7% of Hispanic patients tested positive. Interestingly the diagnosis of Chagas’ disease was not considered preoperatively in any of the six seropositive cases. Leiby et al. (2000) concluded that T. cruzi is an underdiagnosed cause of cardiac disease in North America, especially in regard to those patients born in endemic areas. In patients with Chagas’ cardiomyopathy, heart failure, left ventricular aneurysm, or global dysfunction (weak contraction of the entire heart muscle) are ominous signs. The life expectancy from the start of heart failure is 6–13 months. Therefore, the role of cardiac transplantation in this disease is an issue of great relevance (Milei et al., 1992). Libow et al. (1991) showed that T. cruzi replicates actively both in vitro and in vivo in the presence of immunosuppressive drugs. Therefore, organ transplantation in patients with Chagas’ disease would appear problematic, since the obligatory immunosuppressive agents might trigger a resurgence of the parasite. Nonetheless, the overall experience with kidney transplantation in Chagas’ disease is a positive one (Luders et al., 1992). Similarly, American trypanosomiasis is not considered an absolute contraindication to cardiac transplantation. Bocchi et al. (1994) reported heart transplantation in 18 patients in Brazil, with T. cruzi reactivation in 13 (72%). In another Brazilian study, de Carvalho et al. (1996) found a lower incidence, with parasitemia present in three of ten cases, yet no allograft involvement. Fever, subcutaneous nodules, and myocarditis of the transplanted hearts were common findings. Although all patients in these studies were successfully treated with benzonidazole (5–10 mg kg–1 day–1 for 30–60 days), this agent may have been responsible for increased incidence of lymphoproliferative disease. De Carvalho et al. (1996) presented recommendations not to use prophylactic drug therapy since they believe disease reactivation is not prevented. Blanche et al. (1995), in a USA study, continued nifurtimox therapy (8–10 mg kg–1 day–1) permanently posttransplant with no reactivation. Almeida et al. (1996) confirmed the efficacy of the less toxic anti-gout drug allopurinol in controlling post-transplant Chagas’ parasitemia and myocarditis. In addition, although clearly immunosuppression is needed for the survival of the allografted heart, there is evidence that reducing the dosage of ciclosporin may decrease T. cruzi disease recurrence and improve survival. The authors cited above confirm that heart transplantation is a reasonable option for terminal patients with advanced Chagas’ cardiomyopathy. Owing to small numbers of cases, there are no clear guidelines for postoperative drug prophylaxis against T. cruzi, but there is consensus that lower doses of immunosuppressives enhance survival in these patients. The available literature demonstrates encouraging survival of approximately 75% at 1 year, and up to 65% at 10 years after transplant. Chronic Chagas’ gastrointestinal disease or megasyndrome differs from T. cruzi cardiac involvement in that treatment algorithms are both well studied
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and standardized. Denervation in the gut underlies the pathology, and affects both sympathetic and parasympathetic pathways. A loss of neurons in the submucosal Meissner and myenteric Auerbach plexi occurs, together with preganglionic lesions in vagal innervation. In a study of 1600 patients, de Rezende (1979) found the lifetime risk of esophageal dysfunction in T. cruzi-infected persons is about 30%, megaesophagus usually occurring many years after initial infection. Esophageal dilatation and wall thickening make swallowing difficult. Manometry (pressure readings obtained using a swallowed intraesophageal probe) shows a failure to relax the lower esophageal sphincter, similar to the acquired disease achalasia (a similar but nonparasitic condition, in which a high-pressure lower esophageal zone leads to massive esophageal dilatation). In most cases of Chagas’ megaesophagus, initial treatment is by balloon dilatation of the lower esophageal sphincter. Surgery is reserved for those patients who fail repeated balloon dilatations. Pinotti et al. (1993) found good long-term results in 95% of 722 cases treated with surgery to incise the muscular lower esophageal wall at the narrowed area (cardiomyotomy). Recently this has been accomplished by laparoscopy, thus sparing the patient a major incision with its inherent slow recovery. Laparoscopic myotomy may become the procedure of choice for Chagastic megaesophagus. After the esophagus, the colon is next most often involved, especially the lower left side or rectosigmoid. As aganglionosis progresses, the entire colon can be involved, causing constipation, cramps, and abdominal distension. Early stages can be managed with high-fiber diets and laxatives, and even occasional manual disimpactions. Complications of toxic megacolon and twisting of the dilated sigmoid colon (volvulus) require emergency operations. Failures of conservative therapy may also need surgical treatment. Cutait and Cutait (1991) noted various surgical procedures that have been applied to Chagastic megacolon. All of them include resection of the sigmoid colon as well as a portion of the rectum. If a part of the rectum is not removed, the portion of proximal bowel brought down and sutured to the rectum may become dilated, leading to a recurrence of megacolon.
2.7. Prevention
Currently, in the absence of a vaccine or risk-free drug treatment, Chagas’ disease must be controlled by preventing transmission. Efforts include elimination of domiciliated reduvid bugs in housing, better screening of contaminated blood in blood banks, and closer monitoring of maternal transmission (Magill and Reed, 2000).
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3. ENTAMOEBA HISTOLYTICA 3.1. Case Report
A 44-year-old man presented with a 2-day history of difficulty in breathing. Hospital two-dimensional cardiac echo (ultrasound) revealed fluid in the pericardial sac. Cardiac tamponade (fluid compressing the heart and restricting normal cardiac filling and contractility) warranted emergency operative decompression by pericardiectomy (removal of a portion of the pericardium). Upon opening the pericardial sac, the surgeons found chocolate-colored sterile pus containing Entamoeba histolytica trophozoites. An abdominal computed tomography(CT) scan identified a hypodense liver abscess in the left lobe. The diagnosis of amebic liver abscess with perforation into the pericardium was confirmed by a high serum titer of antiamebic antibodies on hemagglutination testing. The patient was treated with 2 weeks of metronidazole therapy (500 mg intravenously every 6 h), and was subsequently discharged in good condition (Chao et al., 1998).
3.2. Amebiasis
Jackson and Gathiram (2000) defined amebiasis as an infection caused by the ameba E. histolytica, a tissue-invasive pathogen that grows at 37°C in vitro producing quadrinucleated cysts 10–15 µm in diameter. The disease in humans ranges from subclinical to deep tissue invasion. This spectrum includes patients with acute life-threatening amebic dysentery to chronic asymptomatic cystpassers, the latter group comprising some 90% of those infected. Symptomatic or asymptomatic intestinal infection may be followed by the sequelae of tissue invasion: amebic liver abscess, pulmonary amebiasis, amebic pericarditis, ameboma (a granulomatous mass lesion of the cecum or rectosigmoid often mistaken for colon cancer), or stricture of the bowel. Fedor Losch first discovered E. histolytica in 1875, describing motile trophozoites in the stool of a Russian worker with dysentery. Interestingly he did not implicate the amebae as causative agents in the patient’s infection, believing them to be simply facilitators of a primary bacterial inflammatory process. In 1928, Emile Brumpt theorized that E. histolytica consisted of two separate species, E. dispar and E. dysenteriae (Jackson and Gathiram, 2000). E. dispar was nonpathogenic and geographically confined mainly to the temperate zones, whereas E. dysenteriae was responsible for invasive amebiasis and was more prevalent in the tropics. Brumpt’s work was largely ignored over the subsequent 50 years, but its validity is now recognized. It is currently believed that the morphologically identical E. histolytica and E. dispar are two
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distinct species, with the latter being a nonpathogenic gut commensal. Isoenzyme analysis, especially phosphoglucomutase and hexokinase, allows consistent identification of these two species.
3.3. Epidemiology
The life cycle of E. histolytica has three stages: trophozoite, precyst, and cyst. The cysts, whether uninucleated or quadrinucleated, are the infectious agents. They must be orally ingested by the human host through fecal contamination of water, food, or fingers. The cysts pass into the small intestine, where excystation occurs releasing metacystic quadrinucleated amebae. Cytoplasmic division occurs, producing eight metacystic uninucleated trophozoites from each quadrinucleated ameba. The infective trophozoites are the actively growing and multiplying stage and contain pseudopodia. They make their way down the bowel until an area suitable for invasion is found. The cecum is frequently preferred, where the trophozoites rapidly multiply by binary fission, invading the bowel wall using lytic and physical means. The trophozoites may metastasize through the portal system to the liver and other sites. As stool passes to the left colon and rectum, trophozoites are carried along, and eliminate their food vacuoles and other inclusions to become precysts. After the cyst wall thickens, the uninucleated cysts become mature quadrinucleated cysts, which are passed rectally to await transmission to the next host. In instances of profuse diarrhea, trophozoites are shed rectally before encystation can occur. Maturation into cysts outside the body has been described under certain favorable circumstances (Jackson and Gathiram, 2000). Invasive infection and severe disease caused by E. histolytica is more prevalent in the tropics, but amebiasis is found worldwide. Poor sanitation and nutritional deficiencies aid spread. Walsh (1986) estimated that 10% of the world’s population harbors the parasite. Endemic areas include West and South Africa, Mexico, western South America, the Middle East, and Southeast Asia. The 3% figure used to estimate the number of people in the USA who pass amebic cysts or trophozoites in their stools is misleading in the sense that institutionalized patients, homosexuals and Native Americans on reservation land tend to have much higher infectivity. Amebic cysts are killed by boiling and exposure to temperatures over 40°C or under 5°C. The cysts are hardy, however, and are not affected by the chlorine levels present in the water supply. They may remain viable for up to a month in raw sewage and natural water at 4°C. Cysts can live up to 48 h on food products at 20–25°C. Although animals like monkeys, dogs and pigs can serve as animal reservoirs, they have little impact on human transmission. Infection mainly occurs
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through direct person-to-person contact, or through contaminated food or water. In areas where tainted water or sewage is used to grow or freshen vegetables, or where human excrement serves as fertilizer, the ingestion of leafy or root salads becomes hazardous. Although females are infected as frequently as males, invasive amebiasis is much more common in males. Host genetic factors appear to have less influence on infectivity than do socioeconomic ones (Jackson and Gathiram, 2000).
3.4. Pathogenesis
The number of amebae ingested is directly proportional to the frequency and severity of gut lesions. The process by which trophozoites of E. histolytica adhere to the large-bowel mucosa is mediated by a lectin that is inhibited by galactose-N-acetyl-galactosamine. Adherence occurs only under conditions of low oxygen tension, as produced by a normal enteric bacterial flora. Areas of necrosis and ulceration occur as the amebae secrete proteolytic enzymes and cytokines that induce cytolysis of host mucosal cells, aided by phagocytosis (Abd-Alla et al., 1993). Flask-shaped ulcers with undermined edges are typical of amebic lesions of the cecal area, but may be disseminated throughout the colon. The center of the ulcer crater contains gray necrotic material consisting of fibrin, trophozoites and cellular detritus. The amebae can invade the submucosa entering blood vessels. Vessel thrombosis often leads to transmural infarction (death) of entire segments of bowel, accompanied by secondary bacterial infection (Ravdin, 1988). Perforation is a frequent complication of transmural (involving the entire bowel wall) intestinal amebiasis. Presentation is that of a toxic, febrile patient with increasing abdominal pain and rigidity. Abdominal distension from ileus (peritonitis-induced paralysis and swelling of the intestines) is typical. A mass may be palpable, often in the right lower quadrant or cecal area, if the greater omentum has walled off the perforation. Free air may be seen under the hemidiaphragms on upright chest X-ray or on CT scans. Toxic megacolon (pathologic septic colonic dilatation) with rectal bleeding may result, usually after several weeks of cramps, tenesmus (spasm), fever and other evidence of amebic dysentery (Abbas et al., 2000). Amebic appendicitis has been reported. Difficult to differentiate clinically from bacterial acute appendicitis, amebic appendicitis has the gray slough and ulcerations characteristic of lesions of E. histolytica (Demartines et al., 1995). Amebomas are firm inflammatory masses of the bowel wall found in about 1% of cases of colonic amebiasis. These granulomas are most common in the cecal area, and consist of fibroblasts, collagen, inflammatory cells, eosinophils, and scant amebae. When found during colonoscopy or barium enema, amebomas can be mistaken for colon cancer. Following an attack of transmural
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colitis, the inflamed bowel may heal with a fibrous amebic stricture or narrowing. The rectum and sigmoid colon are most often involved, and signs of high- or low-grade intestinal obstruction may result in constipation and abdominal pain and distension (Adams and MacLeod, 1977). Amebic liver abscess, caused by trophozoites being carried to the liver via the portal venous circulation, is five times more frequent in the right hepatic lobe than the left. Liquefactive necrosis yields gray or yellow liquid material in the center, with a fibrinous periphery where trophozoites may be found. Twenty per cent of cases of amebic liver abscess will have E. histolytica found on microscopic stool examinations, but 70% will have positive stool cultures. Patients present with right upper quadrant abdominal and right chest pain, elevated right hemidiaphragm, pleuritic pain (on taking a deep breath), chills, and fever (Akgun et al., 1999). Liver abscesses, especially those in the left lobe, may extend through the diaphragm into the pleural space. When the lung and bronchial tree are involved, the patient may cough up copious amounts of abscess material. Amebic pericarditis, as described in our case report above, also results from direct extension from a hepatic amebic abscess (Mbaye et al., 1998).
3.5. Diagnosis
The finding of trophozoites of E. histolytica in the stool is consistent with invasive amebiasis. Although E. histolytica cysts can remain viable outside the body for up to a month in raw sewage and natural surface water, trophozoites usually disappear within 30 min of passage. Commercial kits are available which contain fixatives to preserve cysts and trophozoites until they can be examined microscopically with wet mounts or iodine-stained smears. Since microscopy does not differentiate between E. histolytica and the nonpathogenic commensal E. dispar, further studies using isoenzyme electrophoresis or monoclonal antibodies in antigen-capture ELISA may be useful. Between 70 and 90% of infections are diagnosed when stool specimens are collected over 3 days or longer. Laboratories experienced in stool culture can improve this diagnostic yield. If invasive amebiasis is still suspected after negative stool examinations, serologic testing can be performed. Serum antibody detection is possible using IF, IHA, the latex agglutination test, the gel diffusion precipitation test, counterimmunoelectrophoresis, and ELISA. Seropositivity is seen in 96% of patients with amebic liver abscess, and 85% of patients with amebic dysentery. Seronegativity virtually rules out an amebic origin for the patient’s illness. Antibodies may be found in the sera of patients 6 months to 3 years following acute infections with E. histolytica (Markell et al., 1999e).
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3.6. Treatment
Before discussing the surgical treatment of invasive amebiasis, it must be mentioned that antibiotic therapy alone is generally curative in the majority of patients with invasive colonic and extracolonic disease. Metronidazole is given 500 mg intravenously every 6 h for 5–10 days or orally at 750 mg thrice daily, also for 5–10 days. Although curative in 90% of cases of invasive E. histolytica infection, metronidazole can cause nausea, headache, metallic taste, confusion, and ataxia (unsteadiness). Most seriously, psychosis or seizures mandate stopping the drug. With severe invasive amebiasis, dehydroemetine, at 1–1.5 mg kg–1 day–1 intramuscularly for 5 days, may be given together with metronidazole for a more rapid antiamebic effect. Following treatment of invasive disease, a luminal agent is given to eradicate intestinal presence of the organism. Paromomycin (30 mg kg–1 day–1 orally for 7 days) or iodoquinol (650 mg orally thrice daily for 20 days) may be used (Li and Stanley, 1996). Further treatment is indicated for the management of complications of invasive amebiasis. In a patient with invasive amebic colitis and suspected transmural involvement, antibiotics effective against enteric bacteria should be added to the antiamebic regimen. If metronidazole therapy has been started, a quinolone such as levaquin can be administered (500 mg intravenously every 24 h) to provide this coverage. Nasogastric suction, along with liberal intravenous hydration, is also required. Although small perforations of the colon that are walled off early by the greater omentum may occasionally be treated conservatively without surgery, caution is necessary when utilizing this approach. Takahashi et al. (1997), in a study of 55 Mexican patients, demonstrated that the nonsurgical treatment of fulminant amebic colitis increased mortality. Indications for emergency surgery include: toxic megacolon, perforation of amebic intestinal ulcers, gangrene of segments of colon, massive hemorrhage from transmurally involved large bowel, and intra-abdominal abscess from a colonic leak (Dautov, 1997). The goal of surgical intervention is to treat infection and stop blood loss. This generally means resection of all of the non-viable transmurally inflamed or perforated colon. No attempt at an anastomosis (connection) between the ends of resected bowel is advisable at the time of emergency operation owing to the likelihood of poor healing in the presence of inflammation and infection. It may be necessary to excise the entire abdominal colon, leaving the ileum as a skin-level stoma (a small-bowel version of a colostomy) and a closed rectal pouch in the pelvis. Once the patient has recovered, the small bowel can be reconnected to the rectum using stapling instruments in a secondary elective procedure 3–6 months later (Abbas et al., 2000) The development of amebomas or late fibrous strictures of the colon are occasional indications for elective operations, usually to differentiate them from colon cancer or to treat varying degrees of obstruction. Unlike the
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surgical treatment of toxic transmural colitis, a primary anastomosis can generally be performed in the right or left colon in these situations without the need for a colostomy (Ito et al., 2000). Amebic liver abscess generally responds to metronidazole therapy alone. It has been reported by Li and Stanley (1996) that amebic liver abscesses resolve slowly. Even successfully treated ones may transiently enlarge over the first few weeks before regressing. Ultrasound is commonly used to follow resolution of amebic liver abscesses, and most will have disappeared within 6 months of successful treatment. Ten per cent of patients will have abnormal ultrasound findings more than a year post-therapy. Jackson and Gathiram (2000) reported that needle drainage under ultrasound radiologic guidance is appropriate for abscesses over 10 cm in diameter, which may potentially rupture. Left lobe liver abscesses should also be aspirated to prevent rupture into the pericardium. Although the majority of amebic liver abscesses under 10 cm usually respond to drug therapy alone, if pain and fever persist past 3–5 days, aspiration should be considered as an additional modality. Should the liver abscess extend into the chest, fluid in the pleural space should also be aspirated or drained with a chest tube. Pham et al. (1996) reported a study of 1512 patients with amebic liver abscess in Vietnam. Ultrasound-guided aspiration was performed in 1289 patients, with 24.9% requiring a second aspiration, and 9.4% a third. They recommended aspiration and antiamebic treatment as the standard therapy for abscesses 4–17 cm in size. Abscesses smaller than 4 cm usually resolved with drug treatment alone. Abscesses greater than 17 cm responded poorly to aspiration and were best dealt with surgically. Surgical drainage is appropriate for a large left lobe abscess that is inaccessible to percutaneous needle drainage. Abscesses complicated by rupture into the peritoneal cavity also require laparotomy (operative exploration of the peritoneal cavity) and surgical drainage, as may abscesses not responding to antiamebic therapy and needle aspiration. Moazam and Nazir (1998) noted that, unlike adults, children with complicated amebic liver abscess are best managed non-surgically. In all 48 of their patients, aged 3 weeks to 14.5 years, none required open surgical drainage. Metronidazole and ultrasound-guided needle aspiration obviated the need for surgery, even in malnourished children with ruptured amebic liver abscess. Mondragon-Sanchez et al. (1995) reported 50 consecutive patients with amebic liver abscess in Mexico City. Medical (drug) treatment alone controlled the disease in 24 patients, percutaneous drainage was necessary in 15, and surgery was needed to treat complications in 11. They concluded that multimodality treatment carried a low (2%) mortality rate. This is consistent with Akgun et al. (1999), who noted a 2.2% mortality rate for their 44 patients with amebic liver abscess similarly treated.
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3.7. Prevention
The prevention of amebic infection starts with the avoidance of fecally contaminated food and water. Visitors to endemic areas should eat only cooked foods and peeled fruit, and drink only bottled water. A prototype vaccine has raised hope that invasive amebiasis may some day be eradicated (Zhang et al., 1994). Recombinant amebic antigens have been bioengineered: 170-kDa galactose-inhibitable adhesin, serine-rich E. histolytica protein (SREHP), and 29-kDa antigen. Efficacy, in terms of protection, has been shown in experimental animal studies for a combination of SREHP and the 170-kDa antigen. Cieslak et al. (1993) reported progress in developing an oral combined typhoid fever–amebiasis vaccine, in which recombinant SREHP was inserted into avirulent Salmonella strains. Zhang and Stanley. (1995) induced IgA and IgG antiamebic antibodies in mice through oral vaccination with SREHP fused to a cholera toxin B subunit.
4. LEISHMANIA DONOVANI 4.1. Case Report
A 30-year-old Japanese woman was admitted to hospital with a fever of unknown origin. At age 28, she had been to Bangalore, India to do graduate research and had spent 2.5 years there. Soon after returning, she began to have chills and fevers up to 40°C. She had a workup at New England Medical Center in Boston, Massachusetts. Blood tests showed a mild pancytopenia (diminished erythrocytes, leukocytes and platelets), elevated liver enzymes (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase), and an elevated sedimentation rate (a nonspecific test for inflammation or infection). Physical examination revealed hepatosplenomegaly (enlarged liver and spleen), a finding confirmed on abdominal CT scan. Although an infectious etiology was suspected due to her recent stay in India, blood cultures and smears were negative. Liver biopsy and bone marrow aspiration showed infiltration of monocytes and plasma cells. Malignant lymphoma was suspected, and she underwent a splenectomy in an attempt to diagnose the condition. No evidence of malignancy was found on pathologic examination of the spleen, and steroids (methylprednisolone 120 mg day–1) were started. Her fever went down and she returned to Japan. She was admitted to the Tokyo Medical and Dental School of Medicine for further treatment. The liver remained enlarged; blood cultures were again negative; and blood smears showed no evidence of malarial or other parasites. With no proof of malignant lymphoma, steroids were stopped. Blood tests then
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showed progressive leukopenia (low white cell counts) and predominance of monocytes. A polyclonal hypergammaglobulinemia was also noted. A bone marrow biopsy was repeated, and smears finally showed monocytes filled with the rounded amastigotes of Leishmania donovani, each parasite with the characteristic nucleus and kinetoplast. The diagnosis of visceral leishmaniasis was confirmed by culturing peripheral blood in a medium of human leukocytes. Three days later, promastigotes were found moving actively in the medium. Antileishmanial therapy was started with pentamidine isetionate intravenously at 200 mg day–1. Three days later the fever broke. A month later, the white cell count was up to normal and the monocytosis disappeared. Pentavalent sodium stibogluconate was given intravenously at 500 mg day–1 for 20 days to prevent relapse. Bone marrow reaspiration was then negative for amastigotes, and serum gammaglobulin and liver function tests improved. The patient was discharged on no medications, and remained relapse-free at 2 years follow-up (Kawakami et al., 1996).
4.2. Leishmaniasis
Magill (2000) defined leishmaniasis as a group of diverse clinical syndromes caused by the protozoan parasites of the genus Leishmania. Vectors include sandflies from the genera Phlebotomus and Lutzomyia. In 1885, parasites from lesions of cutaneous leishmaniasis were first described by Cunningham. In 1903, Leishman found the causative organisms in the spleen of a soldier who was stationed in Dum Dum, India. He used the name ‘Dumdum fever’, but the disease also became known as kala-azar, Hindi for black sickness.
4.3. Epidemiology
Visceral leishmaniasis or kala-azar is caused by L. donovani. Infection is characterized by fever, weight loss, enlargement of the liver and spleen, pancytopenia, and hypergammaglobulinemia. Old World visceral leishmaniasis is transmitted by a sandfly vector from the genus Phlebotomus. Zijlstra et al. (1995) described major epidemic areas in southern Sudan and the Ganges river basin in India. Endemic areas also include the Mediterranean basin, the Middle East, Central Asia, and northwest China. New World visceral leishmaniasis is spread by a sandfly vector from the genus Lutzomyia. Abramson et al. (1995) noted American kala-azar in northeastern Brazil, Argentina, Bolivia, Colombia, Venezuela, Central America and Mexico. The worldwide incidence of visceral leishmaniasis is estimated to be 100 000 new cases annually.
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Cutaneous leishmaniasis infection is identified by nodular and ulcerative skin lesions. Similar to the visceral form, it is transmitted by sandfly vectors, and is prevalent in both the Old and New World geographic distributions. Human disease is a rural zoonosis. Inhabitants of villages near infected rodents have prevalence rates approaching 100%. Tourists, military personnel, hunters, and others entering endemic ecosystems are at risk for infection (Samady and Schwartz, 1997). The life cycle of Leishmania parasites starts when promastigotes in the proboscis of a female sandfly are introduced through the skin into a vertebrate host during blood feeding. Promastigotes measure 15–20 µm in length and have a single free flagellum. A large central nucleus and a kinetoplast are present. The promastigotes invade the reticuloendothelial system, and transform intracellularly into amastigotes. Amastigotes are round or oval, measure 2–5 µm in diameter, and contain a large nucleus and kinetoplast. They multiply within phagolysosomes by binary fission, and invade further reticuloendothelial cells. When sandflies feed on infected vertebrates, parasitized cells are ingested, and the amastigotes transform into promastigotes. The promastigotes multiply in the gut of the vector and migrate to the proboscis to complete the life cycle (Magill, 2000). Reservoir hosts include dogs, foxes and rodents such as rats and gerbils. The sandfly vectors are 1.5–2.5 mm in size, have V-shaped wings, and move with a characteristic hopping motion. Sandfly saliva has a strong vasodilatory peptide known as maxadilin, which correlates with the course of the disease in humans. Warburg et al. (1994) noted that Costa Rican sandflies have small amounts of salivary maxadilin. There, visceral leishmaniasis is rare, but cutaneous leishmaniasis is common. Costa Rican sandfly bites induce little erythema (redness), but enhance cutaneous proliferation of parasites. In contrast, Brazilian sandflies have high levels of salivary maxadilin. In Brazil, visceral leishmaniasis is prevalent, but the cutaneous form rare. Sandfly bites in Brazil produce marked erythema, but cutaneous infection is not facilitated.
4.4. Pathogenesis
Berman (1997) described the pathogenesis of leishmaniasis. For the visceral form, promastigotes inoculated by the sandfly bite enter reticuloendothelial cells, where multiplication takes place. A granuloma forms at the bite site, filled with amastigotes and inflammatory cells. Parasites spread first to lymph nodes, and then by hematogenous pathways to the liver, spleen and bone marrow. The subsequent course can be a granulomatous-cell-mediated immunity type, which results in mild, self-limited disease, or a more virulent course, leading to the visceral leishmaniasis syndrome. This latter group of
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patients develops splenomegaly from hyperplasia of reticuloendothelial cells filled with Leishmania. The liver is also enlarged, with Küpfer cells replete with amastigotes. Macrophages containing parasites are found in the bone marrow. The patient with visceral leishmaniasis is weak, febrile, emaciated, and has hepatosplenomegaly and prominent lymph nodes. Alvar et al. (1997) noted the association between human immunodeficiency virus (HIV) infection and leishmaniasis. Visceral leishmaniasis is a significant opportunistic infection in AIDS patients when CD4 T-lymphocyte counts fall below 50 cells mm–3. Involvement of the gastrointestinal tract is more common in these patients, with macrophages containing parasites being found from esophagus to rectum. High parasite burdens are also seen, often with negative serologic tests making diagnosis difficult. Treatment must not only be focused on eradicating the Leishmania, but also on increasing the CD4 T-lymphocyte count with highly active antiretroviral therapy (HAART). Visceral leishmaniasis is also found as an opportunistic infection with renal and heart transplantation, as well as in immunosuppressed patients undergoing cancer chemotherapy or chronic corticosteroid use. Ramesh and Mukherjee (1995) reviewed post-kala-azar dermal leishmaniasis, and noted that it was first discovered in India, where up to 20% of patients with visceral leishmaniasis developed the characteristic nodules around the mouth, face, trunk, and extremities. In Sudan, the incidence is over 50%. The skin lesions appear a few months to 10 years after apparent successful treatment of kala-azar. Histologically, the lesions are granulomas containing L. donovani and inflammatory cells. The skin lesions may persist for up to 20 years, and afflicted patients pose a public health problem as persistent reservoirs of infection. Magill (2000) described cutaneous leishmaniasis as nodular and ulcerative skin lesions caused by L. tropica, L. major, L. aethiopica and L. infantum in the Old World, and L. mexicana, and L. braziliensis in the New World. Some colorful names for cutaneous leishmaniasis include: oriental sore, Baghdad boil, Dehli boil, aleppo evil, chiclero ulcer, forest yaws, and bay sore. The condition results from a cell-mediated response at the inoculation site, where parasites enter macrophages. Lymphocytes, mononuclear cells and plasma cells surround the macrophages in a granulomatous reaction. Once the parasite count diminishes, epithelioid and giant cells appear. Tissue necrosis occurs next, and the lesions eventually heal by fibrosis. The incubation period for cutaneous leishmaniasis is 2–8 weeks, but may be up to 3 years in rare cases. Multiple lesions are common, and more than 100 may be seen on the same patient. Lesions are most commonly found on exposed skin surfaces: face, hands, arms, and legs. Lymphatic spread, seen with L. major, is evidenced by a linear array of skin nodules leading to groups of enlarged lymph nodes.
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Diffuse cutaneous leishmaniasis, a result of L. aethiopica, is a cell-mediated immune response to the parasites, leading to multiple, large plaque-like nodules covering the face, nose, limbs, and buttocks. The appearance has been likened to leprosy, and coexisting visceral disease is uncommon. Bomfin et al. (1996) noted low interferon gamma (IFN-γ) and interleukin-10 expression, explaining the inability of diffuse cutaneous leishmaniasis patients to mount an effective anti-Leishmania immune response that would lead to clinical improvement. Leishmaniasis recidivans, found primarily in Iraq and Iran, is another unusual chronic form of cutaneous leishmaniasis, which can persist for 20–40 years, with lesions beginning on the face and progressing relentlessly (Grevelink and Lerner, 1996). Three per cent of persons infected with L. braziliensis develop mucosal disease. Mucocutaneous leishmaniasis is more prevalent in the southern latitudes, often appearing months to years after the initial cutaneous infection. Progressive mutilating destruction of the nasal septum, followed by the palate, lips, pharynx, and larynx, can cause death from aspiration or malnutrition. Susceptibility to mucosal disease has been correlated with regulatory polymorphisms leading to high levels of tumor necrosis factor alpha (TNF-α) in Venezuelan patients (Marsden, 1986).
4.5. Diagnosis
In endemic areas, visceral leishmaniasis is reliably diagnosed on clinical grounds, and confirmed by response to antileishmanial therapy. Parasitologic diagnosis is always preferable, especially if the clinical picture is less certain. Splenic aspiration is the most definitive method of confirming the diagnosis. Chulay and Bryceson (1983) reported 3000 splenic aspirates in 400 cases, with three patients dying in shock within 24 h of aspiration, presumably from splenic laceration from the needle. Another four patients had intraabdominal bleeding which resolved spontaneously. Because of the risk of significant morbidity and mortality, splenic aspiration is not recommended for the soft spleen of acute disease, or for the patient with abnormal clotting parameters or low platelet count (<40 000 mm–3). The aspiration is performed with a 22-guage needle attached to a 5 ml syringe inserted into the middle of the spleen. Suction is applied as the needle is inserted and withdrawn. The small amount of blood and splenic material is processed as thin smears and cultures. Smears stained with Giemsa or Leishman’s stains show amastigotes in 98% of cases. Incubation at 25°C for 2–7 days in Schneider’s or Nicolle, Novy, MacNeal’s medium can demonstrate promastigotes. Bone marrow aspiration is often preferred due to the risks of splenic sampling. Amastigotes are found in 80–85% of infected cases. Antigen detection assays and PCR amplification of Leishmania DNA from blood are available,
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but have lower yields than splenic or bone marrow aspiration. Serologic tests include formol-gel for IgG and IgM, IFA, ELISA, and western blot using promastigote antigens. They are over 90% sensitive, but have lower specificities. The direct agglutination test (DAT) using binding of L. donovani-specific monoclonal antibodies was reported to be 92% sensitive and 100% specific in a study of 50 Sudanese patients with visceral disease (Meredith et al., 1995). An ELISA assay using rK39 recombinant antigen to detect antibodies in the sera of infected patients also appears promising, with a high sensitivity and specificity of 95–100% (Singh et al., 1995). Cutaneous leishmaniasis, also usually diagnosed on clinical grounds in endemic areas, may be confirmed by aspiration or scraping of fluid from the ulcerative lesions. Amastigotes within mononuclear cells can be seen on smears, or grown on cultures in Schneider’s medium. Aspirated material can be injected into hamsters’ noses to watch for nasal inflammation. The Montenegro skin test, performed by intradermal injection of a suspension of killed promastigotes, is positive in a high percentage of L. tropica and in over 95% of L. braziliensis infections (Markell et al., 1999c).
4.6. Treatment
It is important to realize that successful drug treatment of leishmaniasis can lead to clinical cure, but that does not imply that all parasites have been eliminated from the host. Years later, with immunosuppression for example, disease reactivation can occur. Lack of efficacy of antileishmanial therapy in AIDS patients demonstrates that an intact immune system is needed for resolution of the infection. Herwaldt (1999) notes that pentavalent antimony compounds have been the mainstays of therapy since the 1930s. Sodium stibogluconate (SSG) is given intravenously at 20 mg kg–1 day–1 over 20–40 days. Longer courses reduce the relapse rate. If given at the proper doses, SSG has a 98% cure rate. Side effects include arthragias (joint pains), bone marrow suppression, and electrocardiogram (EKG) changes, the latter occurring in more than half of patients treated. Meglumine antimoniate is a similar drug given at the same dosage schedule with the same side effects. Resistant cases have benefited from the administration of allopurinol and interferon gamma IFN-γ in combination with SSG. Berman (1997) stated that amphotericin B deoxycholate, originally used in cases resistant to pentavalent antimonials, is now considered for first-line therapy. It is administered by slow intravenous drip over 4–6 h until a total dose of 20 mg kg–1 has been reached. Cure rates approach 100%. Usage of this drug has been limited by the fever, chills, nausea and thrombophlebitis (clotting and inflammation of the peripheral veins) associated with its administration. Long-
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term side effects include renal insufficiency, anemia, and hypokalemia (low serum potassium level). Sudden death has also been reported in patients with EKG changes from SSG who later received amphotericin B. In an effort to limit side effects, lipid-associated preparations of amphotericin B (liposomal, lipid complex, and cholesterol dispersion forms) have been recently introduced. Magill (2000) noted that splenectomy was used to treat kala-azar at the turn of the century. Now the primary indication for surgical removal of the spleen is drug-resistant visceral leishmaniasis. Following splenectomy, the patient has a prompt rise in erythrocyte, leukocyte and platelet counts. Further drug therapy is still necessary to produce cure. Patients without spleens are at risk for overwhelming post-splenectomy infection (OPSI), often due to pneumococci and other encapsulated bacteria. They should receive anti-pneumococcal vaccine, as well as life-long anti-malarial prophylaxis if they live in endemic areas. Rees et al. (1984) reported a study of five Kenyan children who underwent splenectomy for drug-resistant kala-azar. All improved immediately, but one died of OPSI 2 months postoperatively, and another of an unrelated illness (lymphoma) 7 months later. Uzun et al. (1999) reported a study of 3074 cases of cutaneous leishmaniasis in the Cukurova region of Turkey. More than 80% of the 4394 lesions were located on exposed body surfaces, and diagnosis was made by smears of aspirated tissue fluid in 90%. Treatment consisting of intralesional injection of antimony compounds was carried out in 76%. Cryosurgery with liquid nitrogen was used in the remaining 24%. The overall cure rate was over 90%. Gurei et al. (2000) found that intralesional SSG injection was curative in 92%, while cryosurgery healed lesions in 78%. Although both methods were well tolerated, they suggested intralesional SSG injection was more effective than liquid nitrogen therapy. Sharquie et al. (1998) reported a 93% clearance of lesions over a 4- to 6-week period of treatment with direct-current electrical stimulation, a result similar to intralesional SSG. Babajev et al. (1991) used a carbon dioxide laser to treat lesions of cutaneous leishmaniasis. The CO2 laser focuses a parallel beam of laser light that, at different distances from the handpiece, is capable of producing different tissue responses. Energy at the focal point is highly concentrated, allowing for knife-like surgical excisions. In this study, the beam was defocused. Owing to this beam divergence, energy further from the focal point is much less concentrated, and produces superficial vaporization of lesions. Nearly all the laser energy is absorbed by cell water, limiting heat transmission and collateral tissue damage. Bleeding, post-treatment pain and scarring are reduced. In this study, 108 patients underwent laser vaporization of their local lesions. Compared with other available therapies, treatment time was shortened, all patients had satisfactory cosmetic outcomes, and there were no recurrences.
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4.7. Prevention
In endemic areas in which humans are the reservoir (India, Kenya, and the Sudan), identification and treatment of infected individuals may interrupt epidemics. Destruction of canine reservoir hosts was tried in Brazil with unchanged prevalence and seroconversion rates. During malaria eradication programs, vector control was achieved by spraying with DDT, and leishmaniasis virtually disappeared from India. This effect was transient, and prevalence is back to high levels (Magill, 2000). Transmission-blocking vaccines are under development. Preparations include killed promastigotes, parasite fractions, recombinant antigens, and genetically engineered avirulent live parasites. Tonui (1999) noted that liposphoglycan (LPG), formulated from raising immune sera in the BALB/c and hamster murine models against Leishmania-derived antigens, appears to be a promising vaccine candidate.
5. STRONGYLOIDES STERCORALIS 5.1. Case Report
A 74-year-old Filipino man presented to the emergency room after 3 days of nausea, cramping, abdominal pain, distension, and watery diarrhea. Personal history revealed he was a prisoner of war in Southeast Asia during World War II. Medications included steroids for chronic obstructive pulmonary disease. Although without fever, he had bilateral wheezing in his chest. His abdomen was distended with rebound tenderness and guarding (signs of an acute surgical abdomen). Rectal examination was positive for occult blood. Abdominal X-ray films showed signs of small-bowel obstruction. He was taken to surgery, where abdominal exploration showed grossly dilated and edematous small bowel without a site of mechanical obstruction. Postoperatively, the patient had persistent ileus (paralysis of the intestines) and abdominal pain. He required total parenteral nutrition (high caloric feeding in a large central vein). Stool for ova and parasite examination was negative. Although the white blood cell count was normal, increased eosinophils were present. Finally, upper gastrointestinal endoscopy (oral passage of a lighted fiberoptic scope to directly examine the esophagus, stomach and duodenum) revealed embedded adult female Strongyloides stercoralis in biopsies of the duodenal mucosa. Cultures of the bile and aspirates taken from the jejunum were also positive for the parasite. The patient was treated with thiabendazole 22 mg kg–1 twice daily for 5 days, which successfully eradicated the parasite (Bannon et al., 1995).
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5.2. Strongyloidiasis
Gilman (2000) described the nematode S. stercoralis or threadworm as being unusual among helminthic infections in the ability of the parasite to multiply within the human host, facilitating persistent chronic autoinfection. In 1876, Normand found larvae of S. stercoralis in the stools of French soldiers with diarrhea in Southeast Asia. The female adult worm is usually found embedded in the mucosa of the small intestine. Also unique, the complete life cycle can take place in a free-living soil stage, as well as in the host. Abdominal pain, diarrhea, and a creeping rash (larva currens) may occur many years after exposure. Through a hyperinfection syndrome, S. stercoralis has been known to overwhelm immunocompromised hosts.
5.3. Epidemiology
The life cycle of S. stercoralis is complex. Filariform larvae, 400–500 µm long by 15 µm wide, have straight intestinal tracts, no genital primordia and notched tails. Human infection occurs with exposure of skin to fecally contaminated soil. The larvae penetrate the skin, and make their way to the lungs via the venous system. In the lungs, they penetrate the alveoli and travel up the trachea to the glottis, where they are swallowed. Once in the small intestine, two molts occur. Adult females emerge, to burrow and live in the superficial mucosa of the duodenum and jejunum. The adult worms measure 2.2 mm long by 0.04 mm wide. A characteristic striated cuticula is present, along with an elongated esophagus, paired ovaries, oviducts and uteri. There is controversy regarding the existence of male worms, and it is believed that reproduction is parthenogenetic. After a month, the female worm lays oval embryonated eggs, 55 µm long by 32 µm wide, which rapidly hatch into noninfective rhabditiform larvae. These larvae are shed in the stool 3–5 weeks following initial infection. Rhabditiform larvae (200–250 µm long by 15–30 µm wide) are shorter and wider than filariform larvae, and have a visible genital primordium. In the direct, homogonic cycle, rhabditiform larvae passed into soil molt twice before transforming into infective filariform larvae, which can survive for several weeks under favorable moist conditions. In the indirect or free-living cycle, rhabditiform larvae in soil develop into male (0.75 mm in length) and female (1 mm in length) adult worms, each about half as large as its intestinal counterpart. In the free-living stage, sexual reproduction and meiosis are seen during this brief, singlegeneration phase. Eggs hatch into rhabditiform larvae, and subsequent filariform infectious forms. Internal autoinfection is possible through rapid transformation of rhabditiform into dwarf filariform larvae in the intestinal mucosa. The filariform forms
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penetrate the gut mucosa, and migrate to the lungs to maintain persistent infection. External autoinfection can occur when filariform larvae in the colorectal area penetrate the perianal skin, and travel through the subcutaneous tissues (larva currens) to the lungs, and ultimately the small bowel (Markell et al., 1999a; Gilman, 2000). Conservative estimates cite 50–100 million persons infected with strongyloidiasis worldwide. Distribution is mainly in the wet, warm tropical, subtropical, and temperate climates. Institutional outbreaks where sanitation is poor are seen, as are outbreaks in mine and tunnel workers. Endemic areas include Latin America, Asia, Africa, southern United States, and southern and eastern Europe. Infection is widespread geographically, but prevalence is typically low (<10%). Frequency of infection is higher in older human T-cell lymphotropic virus (HTLV)-1 positive patients in endemic areas such as Japan and the Caribbean. Because infection with S. stercoralis can be maintained for 40 years or more, persons such as military personnel who were in the South Pacific during World War II, the Korean or Vietnam Wars may remain infected with risk of overwhelming hyperinfection if they should become immunosuppressed (Gilman, 2000). The free-living life cycle is short, and close proximity with an infected individual increases probability of disease transmission. This explains the increased incidence found among groups of institutionalized patients. A study in rural Tennessee demonstrated S. stercoralis in 6.1% of 229 hospitalized patients and 2.6% of 346 nursing-home patients. A third of those infected had never traveled abroad (Berk et al., 1987). The parasite was also found in 3% of schoolchildren in a prospective study in Clay County, Kentucky (Walzer et al., 1982). Although S. stercoralis is found in dogs, cats and monkeys, humans remain the principal reservoir. The finding of Strongyloides larvae in breast milk in Africa has suggested, but not proved, vertical transmission (Brown and Giaradeay, 1977).
5.4. Pathogenesis
Gilman (2000) described infection with S. stercoralis as consisting of three phases. Skin penetration with filariform larvae is first, followed by pulmonary migration, and finally intestinal penetration by adult worms. It is estimated that up to a third of patients with S. stercoralis infections remain asymptomatic. The site of entry of the filariform larvae is characterized by larva currens, a migrating pruritic (itchy) rash in which the subcutaneous parasites can move up to 5–10 cm h–1. As the larvae pass through the lungs, Loeffler’s syndrome, consisting of fever, wheezing, cough, shortness of breath, transient pulmonary infiltrates (lung densities on chest X-ray), and eosinophilia, can be seen. When the adult female worms attach themselves to the mucosa of the small bowel,
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the patient may experience crampy abdominal pain, vomiting, diarrhea, weight loss, malabsorption, and steatorrhea (fatty stools). Friedenberg et al. (1999) reported duodenal obstruction as a complication of S. stercoralis infection in an HTLV-1 infected host. With massive parasite burdens, edema of the bowel wall with secondary ileus (intestinal motor paralysis) can present as intestinal obstruction. These findings of a tender distended abdomen can mimic an acute surgical emergency, and lead to an unnecessary laparotomy (operative exploration of the abdomen). Bhatt et al. (1990) described life-threatening, massive upper-gastrointestinal hemorrhage with fulminant Strongyloides infection. In fact, potentially fatal bleeding due to migrating larvae can occur not only in the gut but also in the lungs. The ability S. stercoralis has for recycling and autoinfection within the human host can lead to the hyperinfection syndrome. Heyworth (1996) described the process of enhanced production of filariform larvae leading to increasingly heavy worm burdens in the intestinal mucosa and lungs, and dissemination of the parasite to other sites such as the brain and cerebrospinal fluid. Husni et al. (1996), Graeff-Teixeira et al. (1997), and Palau and Pankey. (1997) reported the association of the hyperinfection syndrome with disturbance of the host–parasite relationship. This can occur with any drug or illness that compromises the host immune system. Recognized cases have been found in patients immunocompromised by malignancies (especially leukemia and lymphoma), corticosteroid use (for treatment of asthma, autoimmune disorders such as systemic lupus, ulcerative colitis and renal transplantation), malnutrition, chronic infections (leprosy, tuberculosis and syphilis), and treatment with cimetidine (a histamine-2 receptor acid-reducing anti-ulcer drug). The loss of intact cellular immunity facilitates conversion of rhabditiform to filariform larvae, followed by hematogenous dissemination of the infective larvae throughout the body to virtually all organs. Thymic T-lymphocytes are depleted, and eosinophilia is lost. The host cellular immune response to the migrating larvae is remarkably absent, allowing strongyloidiasis to disseminate. Meningitis, endocarditis (infection of the inner lining of the heart and heart valves), and secondary bacterial infection due to heavy larval travel through the intestinal tract are found in 45% of patients studied. The hyperinfection syndrome develops in only 0.5% of all S. stercoralis infections, but the mortality rate for this fulminant condition is as high as 60–86% (Bannon et al., 1995). Heyworth (1996) noted that IgG and IgA antibodies against filariform larvae antigens have been detected in the sera of infected patients, but whether they serve a protective role is unknown. There is at least indirect evidence that eosinophils play a major role in protecting the host against the hyperinfection syndrome. First is the observation that a low eosinophil count in the peripheral blood is associated with aggressive disseminated strongyloidiasis. Second, Weesner et al. (1988) noted that adult worms embedded in rat intestinal
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mucosa were surrounded by eosinophils. Finally, these same eosinophils were depleted by corticosteroid administration. Although immunosuppression has been implicated in the hyperinfection syndrome, corticosteroid use may be the more specific etiology (Genta, 1992). Corticosteroids have been shown to deplete eosinophils in vivo, and therefore eliminate any potential eosinophil-enhanced containment of S. stercoralis infection. They have also been implicated in triggering the molting of rhabditiform to filariform larvae, increasing both the number of parasites per host as well as the dissemination of strongyloidiasis.
5.5. Diagnosis
A high index of suspicion, based on history of exposure and characteristic skin, lung, and intestinal symptoms, is one of the most important factors in correctly diagnosing strongyloidiasis. Diligent examination of stool specimens is needed to identify rhabditiform larvae. Because Strongyloides larvae do not float in hypertonic saline, commonly used to concentrate other parasites, van der Feltz et al. (1999) recommended the Baermann funnel gauze method. This approach uses warm water to concentrate stool-specimen larvae in the neck of a funnel, yielding results four times better than the hypertonic saline technique. In vitro culture of fecal material yields filariform larvae that multiply by the heterogonic cycle. Damp charcoal or Harada-Mori mediums have been used, but nutrient agar plates that allow larval burrows are now the method of choice. Duodenal aspirates, as well as bronchial washings, can be directly examined in wet mounts for Strongyloides larvae. Histological examination of duodenal or jejunal biopsy specimens obtained by endoscopy can demonstrate S. stercoralis adult worms embedded in the mucosa. Eosinophilia, although not disease-specific, is present in uncomplicated strongyloidiasis, but is lost in fulminant hyperinfection (Heyworth, 1996). Van der Feltz et al. (1999) reported that the combination of the Baermann method of stool examination and serology is the best way to diagnose strongyloidiasis. ELISA and IF using whole worms can detect serum antibodies against Strongyloides antigens. For population screening in endemic areas, an ELISA for IgG anti-Strongyloides antibodies is effective.
5.6. Treatment
Gilman (2000) stated that all patients with S. stercoralis infection should be treated because of the chance of autoinfection causing chronic symptomatic infection or the hyperinfection syndrome. Thiabendazole at 25 mg kg–1 orally, twice daily for 2 or 3 days, is the standard regimen. Because of the 15%
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relapse rate, a 2-day course of the drug is often given a week following initial treatment. For the hyperinfection syndrome, treatment is extended over 5–14 days. Thiabendazole can cause nausea, dizziness and malodorous urine. Ivermectin, originally developed in France, has provided excellent cure rates with few side effects when administered at 200 µg kg–1. Surgery has no defined role in the treatment of strongyloidiasis. Most instances of abdominal exploratory surgery for intestinal S. stercoralis infection could have been avoided if the obstruction had been treated with thiabendazole administered via a nasogastric tube.
5.7. Prevention
Prevention of strongyloidiasis begins with improving sanitation and waste disposal facilities. Since proximity to infected individuals is crucial to transmission, treatment of those infected is effective for preventing the spread of disease. Since the hyperinfection syndrome is often seen in patients with long-standing chronic infection who are newly immunocompromised or given corticosteroids, early recognition and treatment of chronic cases can prevent them from becoming disseminated (Gilman, 2000).
6. TAENIA SOLIUM 6.1. Case Report
A 38-year-old woman presented with blurred vision lasting for 3 weeks. Fundoscopic examination showed a fluid-filled subretinal mass comprising several ovoid cystic structures. The diameter of the mass was seven times that of the optic disc. Single, white oval structures were seen in each cyst wall, and appeared to be moving slowly. Three months before her current symptoms began, the patient had been playing with a 6-month-old German Shepherd dog shortly before the dog passed a tapeworm. The patient was taken to the operating room, where the serous mass was excised using standard subretinal surgical techniques. A retinotomy was made at the apex of the retinal detachment caused by the mass, and extraction of the mass was accomplished with a soft silicone-tipped extraction cannula and air–fluid irrigation. Microscopic examination showed evidence of a mature protoscolex with hooklets, suggestive of a proliferating cysticercus of Taenia crassiceps, a tapeworm of canids rarely infective to humans via the oral–fecal route. Serologic studies confirmed the diagnosis by demonstrating serum antibodies to T. crassiceps vesicular fluid and recombinant KETc7 antigens. Postoperatively the patient
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received praziquantel at 50 mg kg–1 day–1, orally for 2 weeks. Three months later, the retina was healed and reattached, and visual acuity was 20/20 (Chuck et al., 1997).
6.2. Taeniasis and Cysticercosis
Sciutto et al. (2000) noted that the tapeworms or Cestoda are a class of the phylum Platyhelminthes, along with the free-living Turbellaria and the parasitic Trematoda or flukes. Of the four major groups of cestodes, two orders directly affect humans. Tapeworms of the order Pseudophyllidea have a scolex or attachment organ with two sucking grooves. This order contains the genus Diphyllobothrium, which includes the fish tapeworm D. latum. The order Cyclophyllidea has a scolex and four suckers. Included in this order is the genus Taenia, with T. saginata or beef tapeworm, and T. solium or pork tapeworm. Tapeworms of importance to humans range in size from less than 1 cm in Echinococcus to up to 10 m in T. saginata. Tanowitz et al. (2001) stated that tapeworm infections are among the most ancient of human afflictions. T. solium is endemic to most developing countries, and is emerging as a health problem of global dimensions due to ease of travel and immigration. Study of the epidemiology and pathogenesis of T. solium is of particular interest due to the potentially serious human infection by the larval stage or cysticercus. This larval infection, or cysticercosis, is the most common parasitic condition of the brain (neurocysticercosis), and the most common cause of adult-onset epilepsy. Cysticerci can infect all tissues, but the brain and spinal cord, eye, voluntary muscles and skin are most commonly affected. Porcine infection is a cause of considerable economic loss to farmers.
6.3. Epidemiology
Schantz et al. (2000) described the life cycle of T. solium. Pigs acquire infection by ingesting cestode eggs in fecally contaminated barnyards or pastures. The hatched hexacanth embryos penetrate the mucosa of the intestine with the aid of their six hooklets, and enter the bloodstream. The larvae undergo encystment in porcine striated muscle, and within 7 to 12 weeks become infectious cysticerci. A cysticercus measures 1.5–3.5 mm in width by 2–9 mm in length, and is a bladder-like translucent cyst with an inverted scolex. When a human ingests raw or inadequately cooked cysticercotic pork, gastric juices and bile salts stimulate the scolex of the cysticercus to evaginate. The ‘armed’ scolex is a muscular 1 mm structure with four suckers and a double crown of hooks, which enables it to attach to the jejunal wall to become a mature tapeworm in 5–12 weeks . The scolex is followed by a chain of
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segments or proglottids known as a strobila. T. solium varies from 1.5 to 8 m, contains about 1000 proglottids, and can live up to 25 years. New proglottids produced immediately posterior to the scolex are immature, not yet possessing fully developed internal structures. Near the middle of the chain, mature segments are larger and contain sets of both male and female reproductive organs. Since cestodes lack a digestive tract, the body covering or tegument must serve both as a protective covering and a metabolically active layer capable of absorbing nutrients and excreting wastes. The terminal portion of the strobila has ripe or gravid proglottids with tens of thousands of 30–40 µm -sized eggs in their branched uteri. Eggs are shed in the stool, as are individual or short chains of motile, terminal gravid proglottids. The eggs are able to live in the dispersed feces for many months, remaining infectious until coprophagic swine ingest them to complete the life cycle. Cysticercosis is T. solium larval infection of human tissues. Evans et al. (2000) noted that larval cestode infections occur via the fecal–oral route. Should humans ingest T. solium eggs, they can develop cysticerci in their tissues in the same manner pigs do. In this circumstance, humans become an incidental intermediate host, and a dead-end for the parasite. The cysticerci can live for several years, eventually dying and becoming calcified. Persons harboring a T. solium adult worm in their small intestine can infect themselves with anus–hand–mouth contamination, or through unsanitary food preparation. Autoinfection may also occur, as eggs released in the small bowel hatch into invasive embryos, which penetrate the mucosa to develop into cysticerci in voluntary muscle, the central nervous system, and subcutaneous tissues. Kalra et al. (1994) reported that 5–40% of patients with cysticercosis have concurrent taeniasis. Additionally, virtually all T. solium carriers develop antibodies to larval antigens. Sciutto et al. (2000) noted that the prevalence of T. solium infection is related to local habits of eating raw or undercooked pork. Human fecal contamination of the environment is needed to sustain the life cycle of T. solium. The majority of the 5 million persons infected worldwide are located in Latin America, the Slavic countries, Southeast Asia, Africa, China, and India. Infection in northwestern Europe, Canada, and the USA is low, with most cases being imported. Rodriguez-Canul et al. (1999) studied the epidemiology of T. solium infection in a rural village in Yucatan state, Mexico. Taeniasis was present in 7 of 475 subjects examined (1.5%). Seroprevalence of human cysticercosis was 3.7%. Antibody testing for cysticercosis was positive in 26 of 75 pigs kept in the community (35%). Pigs allowed to roam free were far more likely to have cysticercosis than those kept in pens. Rodriguez-Canul et al. (1999) concluded that risk factors associated with human taeniasis and cysticercosis included eating infected pork and close proximity to a carrier of T. solium. The main risk factor for porcine cysticercosis was free-range husbandry, permitting access to human feces.
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The prevalence of cysticercosis varies according to the practices of sanitation, animal husbandry and diet. Evans et al. (2000) noted that in Third World countries, more than 10% of people have antibodies to T. solium. Autopsy studies have demonstrated a 0.1–3.5% rate of cysticercosis in Mexico. In Peru, 12% of patients with epilepsy are seropositive, as compared with 1% of the population at large. Immigration and travel to developing countries can lead to sporadic cases of cysticercosis in industrialized nations. Evans et al. (2000) also noted that the diagnosis of cysticercosis was confirmed in 2% of neurological admissions to hospitals in southern California. Schantz et al. (1992) reported an outbreak of neurocysticercosis in an Orthodox Jewish community in New York City. The infection was traced to immigrant cooks with tapeworms.
6.4. Pathogenesis
Schantz (1996) noted that Taenia species live within the intestinal lumen, producing little pathologic alteration other than local mucosal inflammation at the site of scolex attachment. The adult worms induce a moderate eosinophilia and IgE elevation. Rare complications have been reported if the proglottids migrate to unusual sites such as the appendix, bile or pancreatic ducts. Mild abdominal pain, nausea, and weight loss can accompany tapeworm infections. Most patients with T. solium adult worm infections are asymptomatic, and may only become aware of the problem if they pass proglottids in the feces, or if they feel spontaneous movement of segments of the strobila through the anus. Cysticercosis is a much more serious complication of T. solium infection. Evans et al. (2000) noted that cysticerci elicit little host inflammation, especially in the brain and eyes, where they can evade immune recognition by the host. Symptoms usually occur because of inflammation around dying cysticerci, accounting for the delay of several years between infection and clinically recognizable disease. Most cases of cysticercosis are asymptomatic, and it is not known what percentage of infected people will develop symptoms or will spontaneously recover. Garcia and Del Brutto (2000) reported two types of cysticerci in neurocysticercosis. Cysticerci in the brain parenchyma or in the ventricles are ovoid 5–10 mm structures with a scolex. A less common form, racemose or bunch of grapes, is found in the basal cisternal spaces and is often fatal. Epilepsy is the most common symptom of cysticercosis. Degenerating cysticerci within the brain can cause seizures, increased intracranial pressure or meningitis. Obstruction of cerebrospinal fluid drainage with dilated ventricles (hydrocephalus) can accompany intraventricular or basal cysticercosis. Massive infection of the brain is sometimes seen in children and young females, and can be associated with excessive immune reaction and brain swelling. The more
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numerous the intracranial cysticerci, the less likely the patient will respond to therapy. Those with fewer than 20 cysticerci located in the brain parenchyma have a better prognosis than those with basal or ventricular disease associated with hydrocephalus. Evans et al. (2000) described ophthalmic cysticercosis as most often involving the retina, but occasionally the vitreous or aqueous humors. Inflammation around the parasite can cause retinal detachments and threaten vision. Cardenas et al. (1989) described the use of T. crassiceps as an experimental model for intraocular cysticercosis (see case report). Since an adequate response to medical treatment had not been observed, they recommended surgical excision, where possible. Pea-like subcutaneous nodules, present in fewer than 5% of South American and more than 20% of Asian cysticercosis patients, are easily excised for biopsy and diagnosis. Massive cysticercal involvement of muscle occurs, with resultant muscle hypertrophy and weakness. The prognosis for these patients is poor, with frequent associated infection in brain, pleura, heart, and tongue.
6.5. Diagnosis
Schantz et al. (2000) noted that patients with T. saginata and T. solium infections often recognize individual or short chains of motile proglottids in their stool. It is always advisable to identify the species to ascertain the risk of cysticercosis, seen only with T. solium. Examination of gravid proglottids collected in water or saline solution allows counting of primary uterine branches. T. saginata has 15 or more, while T. solium has fewer than 10. The gravid proglottid is viewed as a wet mount between two slides, aided by injection of India ink into the lateral genital opening to further outline the uterine branches. Fecal examination using egg concentration methods is not specific since T. saginata and T. solium eggs appear identical by light microscopy. Coproantigen assays (CoAg), or detection of host Taenia-specific antigens in feces, appear to be the most sensitive diagnostic tests. They use capture-type ELISAs with polyclonal antisera against worm somatic or secretory–excretory antigens. The CoAg test detects 2.5 times as many cases of taeniasis as does microscopy. Wilkins et al. (1999) reported a serologic assay to detect T. solium carriers using immunoblot assay with secretory–excretory antigens collected from in vitro cultures. Antigens that reacted with antibodies in sera of patients with taeniasis alone, and not with sera of known cysticercosis cases, were identified. Since samples from T. saginata patients did not cross-react, the test was 100% specific, and was determined to be 95% sensitive. The immunoblot serologic assay has important implications in screening, prevention, and control of disease.
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Cysticercosis can cause a wide array of symptoms, and a high index of suspicion facilitates diagnosis. Recent travel to endemic areas should prompt questioning regarding prior taeniasis. Passage of tapeworm segments, even decades previously, can be significant due to the possibility of autoinfection. CoAg assays of stool specimens are useful. Any subcutaneous cysticerci should be excised and examined. Plain X-rays of the skull and extremities may reveal calcified cysticerci. CT scans can show living cysticerci as hypodense 5–10 mm structures with a scolex. Calcified cysticerci appear as hyperdense lesions. Magnetic resonance imaging (MRI) is also useful, especially for examination of the posterior fossa, but is not as sensitive for calcification as CT (Schantz et al., 2000). The diagnosis of cysticercosis should include imaging studies together with reliable serologic tests. Vaz et al. (1996) reported an ELISA for anticysticerci of T. solium antibodies in cerebrospinal fluid. Shiguekawa et al. (2000) used an enzyme-linked immunoelectrotransfer blot (EITB) yielding greater than 98% sensitivity and specificity for the detection of IgG antibodies against T. solium antigens in serum samples of human neurocysticercosis. With EITB having equal sensitivity for both serum and cerebrospinal fluid (CSF), it is no longer necessary to perform a lumbar puncture to make a serologic diagnosis.
6.6. Treatment
Markell et al. (1999d) described treatment of T. solium infections with praziquantel administered as a single dose of 10 mg kg–1 of body weight. Alternatively niclosamide can be given as a single dose of 1 g for children between 11 and 34 kg, or 1.5 g for those over 34 kg. Both drugs are safe and provide cure rates of 90–100%. Although praziquantel and niclosamide kill the worms, they do not kill the eggs. Autoinfection and cysticercosis from degenerating gravid proglottids and subsequent egg release is theoretically possible. This has led to the recommendation that a cathartic purge be given 2 h after treatment to ensure rectal passage of mature segments before eggs can be released. Cure can be confirmed if serial stool samples are negative for T. solium eggs after allowing 2 months to pass for possible worm regrowth. Evans et al. (2000) noted that the treatment of cysticercosis is controversial. Treatment with praziquantel at 50–75 mg kg–1 orally for 2 weeks, or albendazole at 15 mg kg–1 orally for 8–15 days, will kill cysticerci efficiently. There is controversy about whether this cysticercicidal effect is accompanied by clinical improvement. Carpio et al. (1995) noted that two controlled studies failed to demonstrate amelioration of the course of neurocysticercosis by cestocidal drugs. Nonetheless, most physicians treat diagnosed cases of cysticercosis with praziquantel or albendazole, the latter being preferred due to improved efficacy and lower cost. In neurocysticercosis, worsening of
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symptoms can occur between day 2 and day 5 of therapy due to death of larvae and resulting brain edema, a problem treated with coadministration of corticosteroids. Evans et al. (2000) noted that many cases of cysticerci infecting the brain resolve without symptoms, and an option is not to treat such patients unless symptoms develop. For epilepsy due to neurocysticercosis, anticonvulsant drugs are indicated, but the role of anthelmintic therapy is unclear. If imaging studies (CT, MRI) show degenerating cysticerci, cestocidal drugs appear to be of little benefit. Raised intracranial pressure is treated with corticosteroids. Hydrocephalus is an indication for a ventriculoperitoneal shunt, which establishes drainage of CSF into the peritoneal cavity using thin surgical tubing. Bergsneider (1999) and Cudlip et al. (1998) reported the technique of minimally invasive neurosurgery using endoscopy, without the standard large craniectomy (removal of a large bone flap to gain access to the brain), to remove cysticerci from the third and fourth ventricles. In one patient, excision of the T. solium larvae, followed by albendazole therapy, cured the hydrocephalus and permitted the removal of a previously placed ventriculoperitoneal shunt. Ophthalmic cysticercosis is best treated with combined surgical excision of the parasite and corticosteroids to reduce the inflammatory response. Sundaram et al. (1999) reported five consecutive patients with T. solium retinal cysticerci who underwent successful surgery to remove the entire cyst, with return of vision in all cases. Muscle and subcutaneous cysticerci can be left alone if asymptomatic, or surgically excised and treated with cestocidal drugs if producing symptoms.
6.7. Prevention
Markell et al. (1999d) noted that thorough cooking of pork kills the larvae and, if widely practiced, could eliminate infection in both pigs and humans. Additionally, freezing below –5°C for 4 days or below –20°C for 12 h kills cysticerci. Treatment of infected individuals reduces the source of soil and sewage contamination with Taenia eggs. Changes in sanitary and pig-raising practices are useful in reducing infection. Trials of community education coupled with drug treatment of tapeworm carriers have not demonstrated sustained reductions in control of cysticercosis. Mass simultaneous treatment of humans and pigs was reported in two villages in rural Guatemala by Allan et al. (1997). Niclosamide therapy lowered human T. solium taeniasis from 3.5 to 1%. Treatment also reduced the seroprevalence of anticysticercosal antibodies in pigs from 55 to 7%. In heavily endemic areas, development of an effective vaccine against porcine cysticercosis is a potentially effective measure for prevention and
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control. Evans et al. (1997) discussed the implications of immunotherapy in pigs in human disease prevention. Parasitized pigs were inoculated with membrane-enriched cysticercal antigens, crude cysticercal antigens, or Freund’s adjuvant alone in a blinded, randomized study. Immunotherapy caused 64% of the inoculated pigs to develop new antibody bands on EITB, compared with 7% of the control pigs. Treatment with crude cysticercal antigen caused an increase from 10 to 34% in the number of cysticerci that failed to evaginate, and were therefore not infectious to humans. Toledo et al. (1999) reported further progress towards a cysticercosis vaccine. T. crassiceps recombinant antigen KETc7 has been shown to be effective against murine cysticercosis. One 18-amino-acid fragment of this antigen, GK-1 peptide, has the ability to induce antibodies in mice against both T. crassiceps and T. solium. GK-1 can also stimulate the proliferation of CD8 and CD4 T-cells with high levels of IFN-γ and intracellular cytokines. This ability to induce an inflammatory response, as well as its reactivity against T. solium eggs, cysticerci and adult worms, make this peptide a strong candidate for an effective vaccine.
7. SCHISTOSOMA MANSONI 7.1. Case Report
A 14-year-old male traveled from his farm home in the interior of Brazil to the New York Weill Cornell Medical Center (USA) for treatment of his schistosomiasis by extracorporeal hemofiltration. He was pale, fatigued and had multiple episodes of dizziness. Abdominal examination showed a hard, enlarged liver 4 cm below the right costal margin, and a bulky spleen extending 12 cm below the left costal margin. Stool examination demonstrated eggs of Schistosoma mansoni at the rate of 100 eggs g–1 of stool day–1. The patient underwent abdominal surgical exploration confirming hepatosplenomegaly, as well as portal hypertension (elevated portal venous pressures due to the granulomatous reaction S. mansoni eggs elicit in the liver) and esophageal varices (large, thin-walled, friable veins resulting from portal hypertension). The spleen was removed and the splenic vein was dissected from the upper surface of the pancreas in preparation for cannulation. A cutdown in the left groin allowed exposure of the junction of the greater saphenous and deep femoral veins. Following administration of heparin (1 mg kg–1), an F20 catheter was advanced through the splenic vein until its tip was felt within the portal vein. An F18 catheter was passed into the saphenous vein, and advanced into the iliac vein. A closed system primed with heparinized saline solution was created using an open-heart surgical filter, with mesh orifices of 0.19 mm by 0.23 mm, and a hand-powered roller pump, which propelled blood drawn from the splenic
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vein catheter through the filter and back into the patient via the catheter in the iliac vein. Mobilization of schistosomes from the peripheral intestinal venules to the portal vein was accomplished by administering antimony potassium tartrate (3 mg kg–1). Filtration then commenced at 750 ml min–1, with adult worms becoming visible on the filter 7 min after the antimony compound was given. Filtration proceeded for 60 min, with occasional filter changes, as 799 parasites were trapped and removed by the process. After discontinuing the filtration, all catheters were removed, the splenic and saphenous veins were ligated, the anticoagulation was reversed with protamine sulfate (1 mg kg–1) and the abdomen was closed. The patient’s postoperative course was uneventful (Goldsmith et al., 1967).
7.2. Schistosomiasis
Strickland and Ramirez (2000) noted that Schistosoma is the only bisexual genus of the class Trematoda. It differs from other human parasitic flukes by living in blood vessels, having non-operculated eggs, and lacking an encysted metacercarial stage. More than 200 million people in 77 countries have contracted schistosomiasis, also known as ‘snail fever’ or bilharziasis. Globally, one in thirty people are infected. In 1851, Theodore Bilharz identified the blood fluke responsible for endemic hematuria during an autopsy of a patient in Cairo, Egypt. In the early 20th century, Sir Patrick Manson described the three major disease-causing species. Infection occurs when cercariae of S. mansoni, S. japonicum or S. haematobium are shed into fresh water by intermediate snail hosts, and penetrate the skin of a definitive human host. Following migration through multiple organs, the adult worms live in the intestinal and bladder venules. Human expression of disease results from a granulomatous reaction to parasite eggs. Adult worm pairs of S. mansoni reside in the venules of the inferior mesenteric vein that drain the colon, produce about 250 eggs day–1 and prefer the genus Biomphalaria as their intermediate snail hosts.
7.3. Epidemiology
Elliott (1996) noted that schistosome blood flukes have a complex life cycle requiring two hosts, and alternating between sexual (vertebrate host) and asexual (invertebrate host) generations. Snails infected with schistosome larvae release infectious cercariae in fresh water. Cercariae are fork-tailed and free swimming in search of a definitive host. They can last up to 48 h in the water, with infectivity diminishing after 4 h. When contact with human skin is made, the cercaria uses its oral sucker for attachment. Penetration glands enable
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cerceriae to pass through intact epidermis in as little as 5 min, upon which the forked tail and glycocalyx are shed. The transformed form is now called a schistosomulum, and has a double lipid bilayer tegument to shield it against immune attack from the host. Passage through the dermis into venules is possible through secretion of lytic enzymes, and the schistosomula are carried within days through the right heart into the lungs. The parasites then migrate through pulmonary capillaries into the left heart and systemic circulation. Aortic flow transports the schistosomula to mesenteric arteries, splanchnic capillaries and ultimately the portal venous system of the liver. Elliott (1996) noted that, unlike other trematodes, each schistosomulum is either male or female. As the schistosomula mature in the portal venous blood over the next 2–3 weeks, they pair off with worms of the opposite sex. The long thin female worm (14 by 0.2 mm) resides within the gynecophoric canal of the shorter male (10 by 1.1 mm). Schistosome worms have an average life span of 3–5 years. The male uses an oral sucker to attach to the endothelial wall of the blood vessel, and carries the female against portal venous flow into mesenteric venules. S. mansoni and S. japonicum prefer the mesenteric veins, while S. haematobium prefers the venules of the bladder plexus. After worm pairs mate, the female leaves the male, and lays eggs 4–6 weeks after initial cercarial penetration. The eggs of S. mansoni are 60 by 140 µm, and have a prominent lateral spine. Approximately half of the eggs are swept in the prograde portal venous flow to become lodged in the microvasculature of the liver and other organs. The remaining 50% attach and embed in the wall of the mesenteric vein. Adult worms do little damage to the human host. Damage is created by the eggs deposited by the schistosome parasite. Cordingley (1987) noted that the eggs lodge in host tissues and elicit a T-cell-mediated granulomatous response caused by the release of enzymes and antigenic macromolecules. The eggshell itself is a glycine-rich protein cross-linked by oxidized tyrosine, and is resistant to intense inflammatory attack. Through the secretion of proteases, and aided by host tissue granuloma formation, eggs are able to traverse the intestinal wall over an 8- to 12-day period. Some eggs fail to fully penetrate and become calcified in granulomas, while others are passed out in the stool (S. mansoni and S. japonicum) or urine (S. haematobium). Strickland and Ramirez (2000) noted that each mature egg reaching fresh water hatches into a single, ciliated miracidium. Once the appropriate intermediate host is found, the miracidium penetrates the snail, loses its cilia and becomes a sporocyst. Two generations of sporocysts ensue: a mother and daughter generation. The daughter sporocyst migrates to the digestive gland of the snail and gives rise to hundreds of fork-tailed cercariae. Three to five weeks are necessary for completion of the intermediate-host phase. Although only 0.2–2% of snails may be infected at any one time in an endemic area, a single snail may shed thousands of cercariae. Cercarial penetration of human
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skin completes the life cycle. Since adult worm pairs do not multiply within the human host, intensity of infection depends upon the degree of contact with cercariae. The increasing prevalence of schistosomiasis is due to greater contact with contaminated water. Inadequate control measures coupled with wider availability of irrigation for agricultural purposes places more people at risk. It is estimated that out of the 500 to 700 million people in 77 countries exposed to potential schistosomal infection, 200 million are actually infected (Strickland and Ramirez, 2000). The disease is confined to geographical areas where freshwater temperatures range from 25 to 30°C. S. mansoni infection is found in the Arabian peninsula, Africa, Brazil, Suriname, Venezuela, and scattered Caribbean islands. S. japonicum is prevalent in China, Indonesia, and the Philippines. S. haematobium infections are encountered in sub-Saharan and west Africa, the Mediterranean region, and Southwest Asia. Infection occurs in tropical and subtropical areas where people use the local irrigation canal, river or lake for bathing, swimming, defecation, and urination. N’Goran et al. (1997) noted that in central Côte d’Ivoire, the construction of two large hydroelectric dams increased the prevalence of S. haematobium infection among local schoolchildren from 14 to 53% around Lake Kossou and from 0 to 73% around Lake Taabo. In endemic regions, populations have a 30–50% rate of schistosome egg release at any given time, with 90% having infection at some time during their lives. Coutinho et al. (1997) noted that for S. mansoni infection, the majority of people infected have small worm burdens as determined by fecal egg counts. Whitty et al. (2000) reviewed 1107 consecutive cases of schistosomiasis in returning travelers and immigrants to the UK and noted that 50.4% were asymptomatic. Only a small proportion of infected individuals have large worm burdens. Abdominal ultrasound screening has confirmed that only a minority of those infected have severe hepatosplenic disease with resultant abdominal fluid (ascites) or vomiting of blood (hematemesis). Since the severity of schistosomiasis depends upon the worm burden, the majority of endemic populations are asymptomatic.
7.4. Pathogenesis
Clinical manifestation of disease is mainly one of host foreign body reaction to the schistosome parasite. Although mild reaction to the migrating larvae occurs, the most intense reaction is the granulomatous response to schistosome eggs. Elliott (1996) divided infection into two phases: prepatent and patent. The prepatent phase begins with cercarial penetration and ends with egg production. The patent phase, which may be acute or chronic, coincides with egg deposition in various target organs.
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During the prepatent phase when schistosomulae migrate through the lungs and vasculature, the tegument of the worm changes or sheds to conceal surface antigens. There is evidence that the tegument is camouflaged with host histocompatibility antigens and glycolipids (Simpson et al., 1983). The tegument also has a 94-kDa protein that inhibits complement-mediated lysis (Parizade et al., 1994). By release of toxins such as lysophosphatidylcholine and immunosuppressive neuropeptides, cell-mediated macrophage and T-cell activity is impaired (Duvaux-Miret et al., 1992). The result of these protective mechanisms is that adult schistosome worms are effectively hidden from the immune system of the host, allowing them to survive in the bloodstream of infected patients for up to 30 years (Arnon, 1990). Schistosome eggs produce the pathology of schistosomiasis by secreting proteases and toxins, resulting in a severe inflammatory response aiding egg migration through host tissues. Acute schistosomiasis or Katayama fever is characterized by fever, malaise, joint and muscle tenderness, cough, and diarrhea. Marked eosinophilia appears in the peripheral blood. Symptoms are caused by deposition of circulating immune complexes (Hiatt et al., 1980), and fatality rates, especially with S. japonicum infection, may reach 25%. After several weeks, symptoms subside and the patients enter the chronic phase of daily parasite egg deposition with resultant granuloma formation and scarring. Chronic schistosomiasis is a disease of protean manifestations. Although hepatosplenic, intestinal, and urinary tract involvement are most significant, eggs can travel through enlarged esophageal, gastric, and rectal portacaval venous collaterals to the right heart, gaining access to the lungs, central nervous system, and other organs. For the purpose of this review, the more common presentations will be emphasized. Hepatosplenic schistosomiasis is caused by eggs swept up into the liver by the portal venous circulation. Cleva et al. (1997) noted that eggs lodged in portal venules of the liver elicit granulomas that heal to form fibrotic scars. The branches of the portal vein become fibrotic in a characteristic manner of scarring called Symmers’ pipestem fibrosis. To reach this advanced stage, patients typically harbor the parasite for a period of 5–15 years. Portal hypertension from presinusoidal fibrous obstruction of the portal flow leads to the classic presentation of an enlarged liver and spleen. Xien et al. (1997), in a review of 1102 patients hospitalized for schistosomiasis, reported that abdominal ascites, a result of long-standing portal venous obstruction, has a mortality of 54.2%. As collateral venous channels develop around the obstructed portal vein, esophageal varices can cause life-threatening hemorrhage. DoehringSchwertfeger et al. (1992) noted that hepatosplenic schistosomiasis might improve as worm pairs are killed by drug therapy, although healing and remodeling of the liver and clearing of portal hypertension may take several years. Once end-stage Symmers’ fibrosis with liver decompensation and variceal hemorrhage occurs, the hepatosplenic disease is effectively irreversible.
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Intestinal schistosomiasis results from eggs being released into the portal venous flow to become wedged in the intestinal submucosa. Elliott (1996) noted that bloody diarrhea is the most common symptom. Patients may have tenderness and cramping over the sigmoid colon, or may be asymptomatic presenting with only anemia and occult blood in the stool. S. mansoni infections can cause inflammatory colonic polyps, more common in the rectosigmoid area. Microscopic examination of these polyps shows a lamina propria infiltrated with eosinophils and mononuclear cells surrounding schistosome eggs. Gastric hemorrhage and pyloric obstruction from granuloma formation and resultant fibrosis is occasionally seen with S. japonicum, which can lay eggs in masses up to 1000. All schistosome species deposit eggs in the mesentery of the bowel, which may lead to a mass or pseudotumor. Strickland and Ramirez (2000) described urinary tract schistosomiasis as mucosal and submucosal granulomatous lesions of the ureters and bladder in response to eggs from S. haematobium worm pairs living in the venules of the vesicle plexus. The same hemorrhagic, polypoid and fibrotic processes seen in the hepatosplenic and intestinal forms of the disease apply here as well. Obstructive uropathy refers to blockage of the drainage of the ureters into the bladder by granulomatous lesions. Bladder granulomas can lead to squamous bladder cancer, with common spread to the para-aortic lymph nodes. Patients with S. mansoni and S. japonicum infections may present with renal failure from glomerulonephritis (inflammation of the glomeruli due to deposition of circulating immune complexes, leading to glomerulosclerosis and eventual end-stage renal disease).
7.5. Diagnosis
Engels et al. (1996) noted that schistosome egg identification is an effective means to establish proof of infection. The Kato thick smear technique examines a 50 mg sample of stool that is pressed through a steel sieve onto a glass slide. A cellophane coverslip impregnated with glycerine is applied, and the entire slide is inverted and pressed on a bed of filter paper. The slide is then turned right side up again and left for 24–48 h until the fecal matter clears. Using 100× light microscopy, the parasite eggs are identified and counted. The raw egg count is multiplied by 20 to yield the number of eggs per gram of stool. This quantitative diagnosis is of use in tracking schistosome infection for epidemiological purposes. A single stool specimen may miss 10–15% of infections, and serial measurements on different days are recommended. Mohamed et al. (2000) described histological diagnosis from endoscopic biopsies, especially useful when stool samples are negative or inaccurate in the presence of diarrhea. Rectal or bladder biopsies can be obtained during colonoscopy or cystoscopy. One to three small mucosal biopsies are taken of
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any inflamed or granulomatous lesions. The sample may be examined pressed between a slide and coverslip, or by paraffin sections. Biopsies from the small bowel obtained by upper gastrointestinal endoscopy can occasionally demonstrate S. mansoni or S. japonicum eggs. Strickland and Ramirez (2000) noted that S. haematobium eggs can be detected in the urine by centrifuge sedimentation or micropore filtration, and examination by light microscopy. Collecting 24-h samples of urine or stool, homogenizing them, and examining aliquots, allows quantification of infection. Schistosome egg counts of <100 eggs gm–1 is light infection, 100–400 moderate, and >400 heavy. Since eggs are passed in the urine and stool long after drug treatment of schistosomiasis is completed, egg viability tests are important in determining ongoing active infection. Under high-power microscopy, a living egg is clear and transparent. The moving organelles of the miracidium inside the egg may be visible. Attempts can also be made to hatch the eggs by exposing samples prepared in distilled water to light for 15–20 min with the hope of documenting the release of swimming miracidia. Tarp et al. (2000) stated that serologic antibody detection tests could be problematic for the diagnosis of schistosomiasis since they remain positive for prolonged periods in patients from endemic areas with a history of remote infection. Serology may be most useful in travelers from non-endemic countries with suspected infection. Tarp et al. (2000) performed the IF test on whole schistosome adults harvested from mice after 8 weeks. Fluorescence in the gut of the schistosome, called gut-associated antigen (GAA), and fluorescence of the surface of the worm, called membrane-bound antigen (MBA), were noted. Sixty-five patients were studied: 48 Danish patients from a nonendemic area, and 17 immigrants from endemic areas. Standard schistosome egg-count methods as well as IF were employed. Eggs were found in 44% of the Danish patients and in 76% of the immigrants. IF was positive in 48% of the patients. In non-endemic patients, the finding of antibodies against GAA was diagnostic. Optimal sensitivity in the endemic area group was reached only by measuring both GAA and MBA. Because the IF may remain positive for several years following treatment, De Clercq et al. (1997) recommended the circulating anodic (CAA) and cathodic (CCA) antigen detection assays to monitor the effect of therapy. A new dipstick anti-CCA ELISA on serum and urine samples can detect S. mansoni infection with a sensitivity of 92%. De Clercq et al. (1997) studied populations in two villages in Mali, West Africa, endemic for both S. haematobium and S. mansoni. Eight weeks after mass treatment with praziquantel (40 mg kg–1), CAA and CCA antigen detection assays were performed on serum and urine samples. Cure rates as determined by antigen detection were half the amount given by egg-counting methods. The reduction in intensity of infection correlated best with the serum CAA assay. They concluded that a single antigen detection assay gave a better assessment of the impact of antischistosomal
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drug therapy than did egg detection. The future of circulating antigen testing appears to lie in monitoring large-scale therapeutic and vaccination programs.
7.6. Treatment
Olds and Srinivasan (2000) noted that upon confirmation of active infection by viable egg release, treatment of schistosomiasis is appropriate. There are three chemotherapeutic agents currently in use: praziquantel, oxamniquine and metrifonate. Praziquantel is active against all schistosome species, causing a tetanic contraction of the helminth’s musculature a few minutes following administration. The drug also disrupts the integrity of the fluke’s surface membranes exposing 200-kDa glycoprotein and 27-kDa antigen to antibody attack. A single oral dose of 40 mg kg–1 cures 70–95% of S. mansoni and S. haematobium infections. Eradication of S. japonicum requires a higher dosage, 60 mg kg–1 given as two equal doses of 30 mg kg–1, 6–24 h apart. Side effects are few, and usually limited to transient nausea and vomiting. Oxamniquine is efficacious in the treatment of S. mansoni at 15–20 mg kg–1. Strains from North and East Africa are particularly resistant, sometimes requiring doses up to 60 mg kg–1. Side effects include drowsiness and dizziness in up to 15% of treated patients. Fever associated with worm death and relocation of worms to the liver may appear on days 3 to 4 following administration. Metrifonate is an anticholinesterase, and is effective only against S. haematobium. The paralyzed worms are swept from the vesicular plexus into the inferior vena cava, and on to the lungs, where they are destroyed by the immune system. The dose is 7.5–10 mg kg–1 given in three doses at 2-week intervals, producing cure rates of 70–80%. As with the other agents, if cure is not achieved, there is no contraindication to retreatment. Side effects include nausea, vomiting and bronchospasm. Two reports regarding the efficacy of cyclosporin A in the treatment of S. mansoni infection concurred that this immunosuppressive agent also has an antiparasitic effect. Gargione et al. (1998) demonstrated that cyclosporin A complemented the schistosomicidal action of oxamniquine in mice inoculated with S. mansoni cercariae. Elkerdany et al. (1998) reported that active immunization of mice with worm surface antigen prior to induced S. mansoni infection enhanced the curative effect of cyclosporin A, and allowed lower, less-toxic dosages to be used to produce the same reduction in worm and egg loads. Strickland and Ramirez (2000) noted that definitive parasitic cure is defined as complete absence of viable eggs from excreta for 6 months following treatment. Samples should be examined on three consecutive days to improve accuracy. If negative, rectal mucosal biopsy is the final conclusive step. With
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the newer, less-toxic drugs available, the prognosis of schistosomal infection is good, unless reinfection occurs or end-stage irreversible disease is present. Cleva et al. (1997) noted that hepatosplenic schistosomiasis is treated with praziquantel or oxamniquine. Ultrasonography is performed to establish the extent of disease. Symmers’ pipestem fibrosis can be seen on ultrasound, as can splenomegaly and an enlarged portal vein correlating with increased portal venous pressure. Ascites is treated with a low-salt diet and diuretics. Esophagoscopy can establish the diagnosis of varices. Rupture of esophageal varices with hemorrhage can be initially treated with splanchnic vasoconstrictors to reduce portal blood flow: vasopressin (0.05–0.4 iu min–1), somatostatin (9250 mg h–1 over 2–5 days) or octreotide (0.1–0.3 mg day–1 over 5–7 days). Contractor et al. (1996) reported 20 patients with variceal hemorrhage from hepatosplenic schistosomiases that were treated by emergency endoscopic injection of their varices with butyl cyanoacrylate. This sclerotherapy achieved control of bleeding in 17 cases, but only the combination of sclerotherapy and surgery provided encouraging long-term results. Gastroesophageal devascularization with splenectomy was performed in 13 patients in this series. Selzner et al. (2001) reported that the technique of extensive gastroesophageal devascularization in the treatment of bleeding esophageal varices is based on dividing the esophageal and gastric venous plexi from the portal venous system while preserving azygos systemic venous esophageal drainage. Splenectomy completes the procedure. Surgical shunts between the portal vein and the inferior vena cava (portacaval shunts), although effective in arresting hemorrhage, have been complicated by encephalopathy (an increase in blood ammonium concentration precipitating central nervous system dysfunction). Distal splenorenal shunts, which connect the end of the splenic vein to the side of the left renal vein, have a lower chance of encephalopathy than do direct portacaval shunts. The attraction of the Suguira procedure is the absence of encephalopathy, low mortality and low incidence of recurrent hemorrhage. Currently, gastroesophageal devascularization appears to be the operation of choice for hepatosplenic schistosomiasis. As described by Goldsmith et al. (1967), schistosomiasis patients undergoing surgery for splenectomy or portosystemic shunting can also have simultaneous hemofiltration of parasites directly from their portal veins. This method is now of historical interest only. Liver transplantation is an option for end-stage irreversible hepatic fibrosis, although Zhang et al. (2001) reported a promising technique of liver-targeted gene therapy using the hepatocyte as the recipient cell. IFN-γ is known to elicit antiproliferative and antifibrogenic activity in mesenchymal cells. To study this effect, normal mouse liver cell lines were transfected with murine IFN-γ in vitro, and transplanted into the spleens of S. japonicum-infected mice. S. japonicum infection produced a marked increase in hepatic collagen synthesis as measured by
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immunohistochemical analysis. This collagen synthesis rate was significantly decreased in the livers of infected mice 4 weeks after treatment with IFN-γ. Furthermore, a decreased expression of tumor growth factor β (TGF-β), a collagen synthesis stimulator, was also found in the livers of IFN-γ-treated mice. A decrease in messenger RNA expression paralled the fall in TGF-β. Zhang et al. (2001) concluded that intrasplenic transplantation of IFN-γ gene-modified hepatocytes deserves more study in the treatment of hepatic fibrosis. Strickland and Ramirez (2000) noted that gastrointestinal schistosomiasis is treated with either praziquantel or oxamniquine. Drug treatment usually shrinks associated colonic polyps. Colonoscopy is useful in the removal of pedunculated (having a stalk) polyps. Should permanent fibrotic strictures lead to bowel obstruction, surgical resection of the involved portion of intestine may be required. Abscesses and fistulas around the anorectal area are treated with surgical drainage and antibiotics. Atik et al. (1998) reported a case of a 25-year-old Brazilian man with a hard mass in the left lower abdomen and signs of peritonitis. At exploratory laparotomy, fecal material was present in the peritoneal cavity, and a perforation of the sigmoid colon was encountered. A left hemicolectomy was performed with colostomy and oversewing of the rectal pouch (Hartmann procedure). Specimen pathology revealed a thickened, narrowed segment of bowel containing polyps. Microscopically, chronic granulomatous colitis with S. mansoni eggs was seen. Elmasalme et al. (1997) reported a bilharzioma producing rectosigmoid colonic intestinal obstruction that was also managed surgically in a pediatric patient. Bilharziomas are localized masses of fibrous and inflammatory tissue containing many eggs produced by one or more schistosome worm pairs in a single site. Even in endemic areas, bilharziomas are quite uncommon in adults, but have been reported to cause intestinal obstruction in children. Confusion with malignant bowel tumors can occur, with the correct diagnosis being delayed until the excised surgical specimen is examined pathologically. Weber et al. (1998) noted a patient with schistosomiasis of the appendix. Although this entity is found occasionally in endemic areas, their case was in an Israeli traveler who presented with acute appendicitis 2 years after a trip to Africa. Rajiv et al. (1999) reported a 5-year-old boy who had immigrated to the UK from Tanzania, East Africa, 11 months earlier. He needed emergency exploratory surgery for abdominal pain. An inflamed Meckel’s diverticulum (an outpouching of the ileum usually within 60 cm of the ileocecal valve) was removed, which showed granulomatous S. mansoni infection on pathological examination. He was treated with praziquantel, as was the rest of his family, who all had positive Schistosoma serology. Strickland and Ramirez (2000) noted that cardiopulmonary schistosomiasis can be classified into three types. Larval pneumonitis is self-limited, and a short course of corticosteroids can alleviate respiratory distress. Reactionary pneumonitis is an eosinophilic infiltration of the lungs, which can be an indication
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to interrupt antischistosomal therapy until improvement occurs. Corticosteroids may also be of help if respiratory distress is present. Cor pulmonale is right heart failure caused by egg deposition in the lungs through portasystemic venous collaterals. Antischistosomal therapy is given to arrest further progression of disease. Strickland and Ramirez (2000) reviewed urinary schistosomiasis. Praziquantel or metrifonate can be used. Since obstructive disease is frequent, ultrasound or intravenous pyelogram should be performed. Urinary obstruction usually responds to drug therapy, but may require surgery if fibrous permanent obstructive lesions form. Antibiotics are used to treat bacterial urinary infection. Treatment of renal failure from end-stage disease may ultimately require dialysis or renal transplant. Radical surgery and cancer chemotherapy are indicated for associated bladder cancer, but are generally only palliative. Praziquantel therapy is indicated for central nervous system schistosomiasis. Corticosteroids are recommended to reduce inflammation around space-occupying masses. Ruberti and Saio (1999) reported a 20-year-old African man with an epidural bilharzioma from S. mansoni compressing the spinal cord at T12 resulting in paraplegia. Surgical removal of the bilharzioma with chemotherapy resulted in a complete functional recovery 1 year after surgery. Leite et al. (2000) also noted a similar case of a 2-year-old Brazilian boy with progressive lower-extremity paralysis and bowel and bladder dysfunction, caused by a spinal cord mass from the T9 to L1 levels. The mass was partially resected at surgery. Once pathology confirmed S. mansoni infection, praziquantel and oxamniquine were administered enabling the patient to make a partial recovery. Ropper et al. (2001) reported a 31-year-old man with a seizure and a mass in the right parietal lobe of the brain. The patient was a researcher who had participated in a field study in Uganda, East Africa, 18 months before admission to the Massachusetts General Hospital, USA. He developed uncontrollable flailing of his right arm and leg. An MRI scan with gadolinium contrast showed an irregular area of abnormal enhancement 3.5 cm in diameter in the right parietal lobe. Brain biopsy confirmed a necrotizing granuloma surrounding a refractile egg of S. mansoni. The patient received chemotherapy with corticosteroids and praziquantel and was asymptomatic 3 months following treatment.
7.7. Prevention
Strickland and Ramirez (2000) noted that control of schistosomiasis is twofold: control of population morbidity and control of transmission. Application of mass chemotherapy to targeted populations can cure at least 75% of those infected, with a single dose of praziquantel, and reduce egg release by 90–95%.
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Boisier et al. (1998) reported a 3-year study of 289 villagers in the central highlands of Madagascar, a hyperendemic area for S. mansoni infection. Mass praziquantel therapy reduced egg release from 65.9 to 19.3%. The incidence of bloody stools fell from 24.9 to 8.4%. Ultrasound examinations documented a reduction in hepatic fibrosis from 28 to 10.3%, indicating a reversibility of S. mansoni-associated liver morbidity. Dupre et al. (1999) reported a promising synergistic effect in the addition of S. mansoni 28-kDa glutathione S-transferase DNA vaccination to standard praziquantel therapy. The praziquantel induced the unmasking of native glutathione S-transferase at the surface of the worm, permitting neutralization by antibodies raised by the DNA immunization. Strickland and Ramirez (2000) noted that snail control is effective in interrupting transmission, but a sustained effort is needed to prevent snail repopulation and resumption of the life cycle. Niclosamide is the chemical most commonly used to kill infected snails, but since the snail population can re-establish itself 3 months after the use of the molluscicide, repeated applications are needed. Biologic control that introduces natural snail predators (ducks, fish, turtles) or snail parasites (fungi, bacteria, viruses) can also be employed. In Puerto Rico, introduction of a competing snail, Marisa cornuarietis, has reduced S. mansoni transmission. Modification of the environment to create conditions detrimental to the intermediate host is another means of snail control. This includes increasing the rate of water flow in irrigation canals, cementing over or enclosing canals, and burying snails while digging out irrigation ditches. Environmental modification works best when combined with reduction of contamination and water contact by humans, and improvement of the standard of living. Since schistosomiasis remains endemic in over 75 countries, vaccines are needed to complement the above control measures. Tendler et al. (1995) noted that studies of the molecular cloning of parasite antigenic preparations have suggested that worm fatty-acid-binding proteins form a protective immune cross reactivity that could enable a single vaccine to be effective against at least two trematode worms: F. hepatica and S. mansoni. Tarrab-Hazdai et al. (1999) described the proteosome delivery of a protective 9B-antigen against S. mansoni. The 9B-antigen is localized at the surface of schistosomula, and is also found in the flame cells and cytoplasmic tubules of the parasite. When the 9Bantigen is delivered with Freund’s adjuvant it can confer 40% protection against infection with S. mansoni. When the antigen was coupled to proteosomes derived from meningococcal outer membrane proteins, the protection level rose to 60%. Vaccinated mice exhibited high levels of complement-mediated cytotoxicicity towards the parasite. This work is encouraging, but as subsequent researchers (Yang et al., 2000; Schechtman et al., 2001) pointed out, although the recent rapid advances in molecular biology and immunology have improved the chances of finding an effective vaccine, the immune
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responses elicited by the current experimental defined antigens are inadequate for reliable human protection against infection.
8. PARAGONIMUS WESTERMANI 8.1. Case Report
A 41-year-old Korean man complained of headache and motor weakness of the left side of the body. MRI of the brain showed multiple ring-like enhancements in the temporal, occipital and frontal lobes of the right cerebral hemisphere. An intradermal skin test was positive for Paragonimus westermani. History revealed that the patient used to eat freshwater crayfish in his childhood, when he lived in an area endemic for paragonimiasis. Neurosurgeons performed a craniotomy to remove the brain nodules. Pathology confirmed calcified, necrotic lesions containing eggs of P. westermani. The chest X-ray was normal, as were searches for parasite eggs in the sputum and stool. It was presumed that the cerebral lesions were formed 30 years previously during the patient’s exposure to P. westermani (Kang et al., 2000).
8.2. Paragonimiasis
Bunnag et al. (2000b) defined paragonimiasis as infection with lung flukes from the genus Paragonimus. Of the 200 million people at risk for infection in endemic areas, an estimated 21 million harbor the parasite. The most prevalent is P. westermani, or oriental lung fluke. Trematodes belonging to the genus Paragonimus are identified by typical tegumentary spines, coffee-bean shape, oral and ventral suckers, chromosomes, eggs, and migration path through host tissues. Adult parasites are 7–16 mm long, 4–8 mm wide, and 2–5 mm thick. The flukes are reddish-brown with a broad anterior end. Their eggs measure 80–120 µm long by 50–65 µm wide, and are thick-shelled, golden-brown, ovoid structures with a flattened operculum. Blair et al. (1999) noted that adult flukes are usually encapsulated in cystic structures in the lungs adjacent to the bronchi. The life cycle of species of Paragonimus is complex, requiring two intermediate and one definitive host.
8.3. Epidemiology
Bunnag et al. (2000b) described the life cycle of P. westermani. Eggs laid by adult flukes living within pulmonary cysts are passed through tunnels to the
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bronchial tree. The eggs reach water by being expectorated, or swallowed and passed in the feces. After 3 weeks they embryonate, hatch and release miracidia that infect snails, the first intermediate host. The 20 species of susceptible snail hosts belong to the families Thiaridae, Pleuroceridae and Pomatiopsidae. In the snail tissues, the miracidia transform asexually into sporocysts and two generations of rediae. After 3–5 months, cercariae are shed that penetrate the crustacean second intermediate host. Crustacean hosts include freshwater crabs and crayfish, and to a lesser degree, freshwater shrimp. Crabs also acquire infection by direct consumption of infected snails. In 6–8 weeks, infectious metacercariae are present in crustacean tissues. Humans contract paragonimiasis by ingesting raw or poorly cooked crabs or crayfish containing the encysted metacercarial stage. In endemic areas of Japan, transmission also occurs through human consumption of paratenic hosts (rat, mouse, pig, and wild boar) that carry larval flukes in their tissues. Chung et al. (1995) noted that to infect definitive human or paratenic hosts, metacercariae of P. westermani must excyst in the duodenum. Optimal conditions for excystment are a pH of 8 to 9 and a temperature of 40°C. The process appears mediated by the secretion of cysteine protease by the metacercariae, which hydrolyzes collagen, fibronectin and myosin within 1 h. Excysted metacercariae then penetrate the intestinal wall, grow into immature flukes within the abdominal cavity, penetrate the diaphragm, and enter lung tissue, where they form a pseudocapsule. In 5–6 weeks, adult worms capable of producing eggs are present in the lungs. Flukes have been documented to survive for 20 years or more in humans. Eggs can be detected in the sputum or feces 8–10 weeks following infection of the definitive host. Bunnag et al. (2000b) noted that paragonimiasis is a zoonotic disease of carnivores with four main endemic foci: Asia, Africa, Central and South America. Factors important in transmission to humans include abundant reservoir hosts, large numbers of first and second intermediate hosts, and social customs in endemic areas. In Asia, infection occurs from eating ‘drunken crab’ (a delicacy of live crabs immersed in wine), raw crab sauce, raw shrimp salad, and crayfish curd. Crab or crayfish juice is also used for traditional oriental medicine in the treatment of diarrhea, rash, and measles. Contamination of kitchen utensils and food preparation areas can cause infection despite adequate cooking. In Africa, women consume raw crustaceans in the hope of improving fertility.
8.4. Pathogenesis
The acute phase of invasion and migration of young flukes is characterized by fever, night sweats, abdominal pain, diarrhea, urticaria (hives), and eosinophilia. Kan et al. (1995) reported a 91% eosinophilia in a patient with P. westermani infection, but eosinophils typically comprise 10–30% of the total
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white blood cell count. Increases in the cytokine interleukin-5 (IL-5) appear to parallel the degree of eosinophilia. Taniguichi et al. (2001) confirmed that IL5 in the local inflammatory site is particularly important in mediating eosinophilia in both the peripheral blood and pleural fluid in patients with paragonimiasis. Shin and Lee (2000) studied the excretory–secretory product (ESP) of newly excysted metacercariae of P. westermani. The protease in ESP regulates IL-8 production, with the release of IL-8 being inversely proportional to eosinophil survival. Shin (2000) also demonstrated that ESP directly induces eosinophil apoptosis, as well as inhibiting IgG-induced superoxide production in granulocytes. These findings suggest that the ESP of metacercariae modulates both the recruitment and function of inflammatory cells in larval-infected lesions, thereby enhancing parasite survival. Mukae et al. (2001) studied new cases of pulmonary paragonimiasis in Kyushu, Japan and noted that 92% of patients had cough, hemoptysis (coughing up blood) or tenacious, rusty-brown sputum. Pleuritic chest pain (elicited by a deep breath) was found in 46%. Chest X-ray and CT scan showed pleural lesions in 62% and parenchymal lung lesions in 92%. Solitary pulmonary nodules mimicking lung cancer, tuberculosis or fungal infections were noted in 62%. The pulmonary worm cysts are usually 1–4 cm in size, containing one to four worms each. The total number of lung cysts is generally <20, with a predilection for the right lung. The wall of the cysts consists of granulation tissue and eosinophils, with burrows, tunnels and eggs present in the periphery. Chest X-ray may show cysts with ring- or crescent-shaped opacities, cavities, pleural thickening, or pleural fluid collections. Bunnag et al. (2000b) noted that flukes sometimes migrate from the lungs to almost any tissue or organ in the body. The parasites reach sexual maturity in the ectopic locations. Cysts, granulomas or abscesses can form around the worms and their eggs. Migratory subcutaneous nodules are present in 10% of P. westermani infections. Ectopic eosinophilic granulomas of muscle, pericardium, liver, intestine, other abdominal viscera, genitalia, and spinal cord have been reported. Immature flukes migrating from the lungs can pass through the carotid or jugular foramen of the skull-leading to infection of the temporal and occipital portions of the brain. Bunnag et al. (2000b) noted that cerebral invasion is prevalent in endemic areas of Asia, where 25% of all hospitalized cases of paragonimiasis are due to brain involvement. Cysts, usually up to 10 in number, are found in the temporal or occipital areas near the jugular foramina. Cysts may be a few millimeters to 10 cm in size, and can be imaged on CT scan. Symptoms may range from simple headache to paralysis, seizure and coma. Signs of increased intracranial pressure include nausea, vomiting, and papilledema (edema of the optic nerve). A high eosinophil count in the cerebrospinal fluid is pertinent. Death from fulminant cerebral infection can occur. Survivors, in remission after 1–2 months, face a risk of recurrence within 2 years.
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8.5. Diagnosis
Diagnosis of paragonimiasis may be confirmed by the detection of characteristic eggs in the sputum, stool, pleural or cerebrospinal fluid. An adult fluke found on pathology in subcutaneous nodules or other surgical specimens is also confirmatory. Immunodiagnosis is useful both in establishing the diagnosis, as well as in monitoring treatment, since most patients become seronegative 6 months after effective therapy is initiated. Ikeda et al. (1996) described an ELISA using worm-extract antigens from P. westermani, with good sensitivity in reacting to sera from patients with paragonimiasis, but high cross-reactivity to sera from most fascioliasis and some onchocerciasis and clonorchiasis patients. By fractionating cysteine proteases from the ESP of P. westermani, an ELISA using this enzyme preparation increased sensitivity and reduced cross-reactivity. Maleewong et al. (1998) developed an IHA using antigens purified by monoclonal antibody-affinity chromatography for the diagnosis of human paragonimiasis. This controlled study showed the sensitivity, specificity, and positive and negative predictive value of the IHA to be 100%. Kong et al. (1998) analyzed IgG and IgE by immunoblotting with 32- and 35-kDa proteins from adult worm extracts. The test was 100% specific. In 40 cases of confirmed paragonimiasis, IgG4 reaction was found in 83%, IgG1 in 73%, IgG3 in 50% and IgE in 83%. Both adult worm extracts were highly reliable for the serodiagnosis of human paragonimiasis. Kim et al. (2000b) cloned a gene encoding cysteine protease from P. westermani. After regions of the gene were amplified by PCR technique, an expressed protein with a molecular weight of 28.5 kDa was produced. This protein reacted with the sera of patients with paragonimiasis, but not with sera from persons infected by fascioliasis or clonorchiasis. Nakamura-Uchiyama et al. (2001) retrospectively analyzed 30 cases of P. westermani infection. Pleurisy (inflammation of the pleura), eosinophilia and dominant IgM antibody characterized early stage paragonimiasis. IgG antibody was dominant in later stages of infection. In addition to testing for parasite-specific IgG antibody, NakamuraUchiyama et al. (2001) recommended additional testing for IgM antibody in patients with pleurisy and suspected paragonimiasis.
8.6. Treatment
Praziquantel is the drug of choice for treatment of paragonimiasis. De et al. (2000) studied 1642 people from an endemic area of Lai Chau, Vietnam. The rate of infection for P. westermani was 6.4%. Cure was achieved with praziquantel therapy in 68.8% with a dosage of 25 mg kg–1 day–1 for 3 days, and in 75% with a dosage of 50 mg kg–1 day–1 for 3 days. Patients with heavy
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infections, not clearing with the first course of praziquantel, were successfully retreated. Responding cases had clearing of symptoms within a few months, and eggs disappeared from the feces in a few weeks . Radiologic evidence of pulmonary lesions took longer to resolve. Praziquantel side effects include headache and drowsiness, and are generally mild. In cerebral paragonimiasis, due to the risk of convulsion and coma, corticosteroids may be added to praziquantel to reduce intracranial pressure. Calvopina et al. (1998) studied the effect of triclabendazole in the treatment of paragonimiasis in the Ecuadorean Amazon region. Sixty-two patients with P. mexicanus infection were treated with one of three dosage regimens: 5 mg kg–1 day–1 for 3 days, 10 mg kg–1 twice in 24 h, and 10 mg kg–1 as a single dose. Praziquantel at 25 mg kg–1 thrice daily for 3 days was used as the control. Clinical tolerance, based upon side effects, was superior in the three triclabendazole regimens as compared with praziquantel. Symptoms resolved at a similar rate in all four treatment groups. A more rapid parasitologic response, as determined by reduction in the average number of parasite eggs in sputum, was achieved by triclabendazole. By day 90, 60 patients had no detectable eggs in their sputum, while two treated with a single dose of triclabendazole had a few eggs and were retreated. On day 365, none of the treated patients had evidence of persistent infection. Calvopina et al. (1998) concluded that triclabendazole is as effective as praziquantel in the treatment of paragonimiasis, and being better tolerated can be recommended as an alternative drug of choice. Tomita et al. (2000) reviewed cases of pulmonary paragonimiasis referred to the Department of Surgery at Miyazaki Medical Center, Japan. Of seven cases, six had mass lesions on chest X-ray that were indistinguishable from malignancy. Paragonimus eggs were found on specimen pathology from transbronchial lung biopsy in four patients. Sera from all seven cases were positive for Paragonimus-specific IgG antibody. One patient required decortication surgery for chronic pleural empyema (abscess). Decortication involves removal of the chronic fibrinous peel surrounding the empyema in the space between the lung and pleura, permitting the lung to expand normally. Potentially unnecessary surgery due to erroneous diagnosis was avoided in the six other cases. Tomita et al. (2000) emphasized that when a pulmonary mass lesion or empyema is found in a patient from an area where Paragonimus is prevalent, paragonimiasis should always be included in the differential diagnosis. Reports of ectopic paragonimiasis underscore the need for physicians to keep a high index of suspicion for unusual presentations of paragonimiasis in patients from endemic areas. Hahn et al. (1996) described a case of adrenal paragonimiasis simulating an adrenal tumor. The diagnosis was made only after surgical removal of the adrenal gland and pathological examination. Jeong et al. (1999) reported a case of retroperitoneal paragonimiasis presenting as periureteral masses. An abdominal CT scan showed retroperitoneal,
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clustered, ring-like enhancing lesions in a patient with pleuropulmonary disease suggestive of paragonimiasis. Kim et al. (1999) noted a patient with difficulty in voiding who presented with an oval-shaped cystic mass in the perirectal space on both transrectal ultrasound and MRI examination. Owing to a careful history of exposure, the diagnosis of paragonimiasis was appropriately included in the differential. Lee et al. (1997) reported a case of an elderly woman who had emigrated from mainland China to Taiwan 46 years previously. The patient had followed the custom of eating raw crabs from lakes in eastern China while residing in that country. During surgery for bleeding peptic ulcer, her omentum was found to contain numerous small nodules 2 cm in size. Pathological examination revealed eggs of P. westermani in the necrotic encapsulated nodules. Workup for pulmonary involvement, including chest X-ray and sputum examination, was negative. The patient remained asymptomatic following praziquantel therapy. Bunnag et al. (2000b) noted that pulmonary paragonimiasis is rarely fatal. Even if treatment is delayed or withheld, flukes eventually die and disappear within 10 to 20 years. Cerebral involvement carries considerable chronic morbidity from epilepsy and dementia, and 5% die from hemorrhage within 2 years.
8.7. Prevention
The best method of preventing human infection is to avoid eating raw or undercooked freshwater crab or crayfish. Ingrained dietary customs can only be changed with health education, with special targeting at children of early school age. Public education is the best line of attack, since elimination of snail and crustacean reservoir hosts is not practical at present. Ikuma et al. (1993) described the anthelmintic effect of bithionol. The drug competes with rhodoquinone for the electron transfer from NADH to fumarate. Mass treatment in some areas of Korea with bithionol has been effective in reducing the prevalence of paragonimiasis.
9. ECHINOCOCCUS GRANULOSUS 9.1. Case Report
A 56-year-old Turkish patient was hospitalized for chest pain suggesting acute myocardial infarction. Previously he had been in good health, and physical examination of the heart, lungs and abdomen was normal. EKG showed no
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signs of ischemia, and blood concentrations of myocardium-specific enzymes were not elevated (ruling out a heart attack). Echocardiography and MRI showed a rounded mass in the anterior wall of the heart. Noting the patient came from an area endemic for cystic hydatid disease, physicians ordered antibody titers for Echinococcus granulosus. Titers were 1:6400 (normal <1:100) and confirmed infection with E. granulosus. Emergency surgery was necessary due to acute cardiac tamponade. Under cardiopulmonary bypass, an intact hydatid cyst was resected. Drug treatment consisted of albendazole at 400 mg twice daily, and the patient recovered uneventfully (Vicol et al., 1998).
9.2. Echinococcosis
Moro et al. (2000) noted that of four species of Echinococcus, two are of particular importance in humans: E. granulosus and E. multilocularis. Echinococcosis is widely prevalent in areas of the world where dogs are used to care for flocks of sheep, and can be a lethal infection in humans. Cystic hydatid disease is caused by the larval stage of echinococcal tapeworms. The best chance for cure lies in early diagnosis and surgical resection. Recent improvements in treatment include improved liver resection techniques, laparoscopy, percutaneous aspiration–inactivation of hydatid cysts, and chemotherapy with benzimidazole-class drugs.
9.3. Epidemiology
Ammann and Eckert (1996) noted that the adult tapeworm lives in the small intestine of the definitive host: the dog, hyena, or dingo for E. granulosus, and the fox, wolf, coyote, or cat for E. multilocularis. Adult worms of E. granulosus are 2–11 mm long, and consist of three proglottids. Heavily infected definitive hosts can carry thousands of adult worms. Warren et al. (1995) examined echinococcal scolices using the scanning electron microscope. A double circle of hooklets, each 20–40 µm long, is inverted into the rostellum. The hooklets are used for anchorage and propulsion through fluid by the alternating invagination and evagination of the hooklet rows. The middle segment of the adult worm consists of a mature proglottid. The terminal segment is a gravid proglottid containing 100 to 1500 eggs. Eggs are spherical and range in size from 30 to 50 µm. Within the egg, the oncosphere is protected within a thick embryophore layer of keratin. Moro et al. (2000) indicated that once eggs are passed from the intestinal tract of the definitive host into the environment, infection of intermediate hosts can occur: ungulates such as sheep, pigs, cattle, and camels for E. granulosus, and rodents such as mice, voles, lemmings, and shrews for E. multilocularis.
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Once the intermediate host ingests infectious eggs, intestinal enzymes facilitate hatching of oncospheres. The oncospheres penetrate the intestinal wall and are carried via hematogenous and lymphatic spread to the liver and other organs, where they develop into another larval stage: the metacestode or hydatid cyst. When a fertile metacestode containing protoscolices is consumed by a definitive host, the life cycle is complete. Ammann and Eckert (1996) noted that although humans are considered accidental hosts for Echinococcus, they might serve as intermediate hosts in hyperendemic areas. All members of the genus Echinococcus require two mammalian hosts for the completion of their life cycle. Direct transmission from human to human is not possible. Humans may also not acquire infection by consuming raw viscera containing echinococcal metacestodes. Schantz et al. (1995) described the distribution of hydatid disease in humans. E. granulosus is endemic in South and Central America, Europe, the Middle East, Africa, Russia, China, and North America. Reported annual incidence rates are as follows: Greece (13/100 000), rural Uruguay (75/100 000), Rio Negro province of Argentina (143/100 000), Xinjiang province of China (197/100 000), and Turkana province of Kenya (220/100 000). Infection is fostered by the custom of feeding to dogs the viscera of slaughtered sheep or livestock containing hydatid cysts. Infected dogs contaminate the environment with Echinococcus eggs. Direct contact with dogs and the ingestion of water, vegetables, and food containing worm eggs are the chief means of transmission for human hydatidosis. Gilman and Lee (2000) noted that because E. multilocularis is harbored in a fox–rodent life cycle, hunters and fur traders are at higher risk of infection. Arctic villages can be endemic due to the prevalence of sled dogs, and the contamination of food with E. multilocularis eggs. The parasite is well suited to harsh arctic or alpine environments, surviving the winters in canid intestines or in cyst-form in hibernating rodents. Parasite eggs can resist the winter cold, and become infectious to rodents following the spring thaw. Within 2 to 4 months, 100 to 200 scolices develop per milligram of rodent cyst tissue. Consumption of these cysts by canids can lead to massive burdens of 100 000 to 160 000 worms per dog, also facilitating continued transmission.
9.4. Pathogenesis
Shalaby et al. (1999) described polyvisceral echinococcosis in humans and noted that metacestode cysts can involve virtually any anatomic site or organ. Parasitic spread of E. granulosus metacestodes can occur from primary to secondary areas via the bloodstream or lymphatic system, or by rupture of cysts into the peritoneal cavity, bronchial tree, pleura, or bile ducts. Iatrogenic (caused by the physician’s treatment of the patient) rupture of hydatid cysts
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with spillage of contents during invasive surgical procedures is another means of spread. Rupture of a hepatic cyst into the hepatic veins or inferior vena cava can allow parasitic membranes to pass through the right heart and lodge in the pulmonary arteries (causing a pulmonary embolism). Ammann and Eckert (1996) reported the sites of 1802 cysts from the Australian hydatid registry as follows: liver 63%, lungs 25%, muscles 5%, bones 3%, kidney 2%, brain 1%, spleen 1%, and heart, breast, prostate, parotid, and pancreas <1%. The right lobe of the liver is the most common site for a hydatid cyst. Ammann and Eckert (1996) reported a series of 369 patients from Kenya with echinococcal cysts. Solitary liver cysts were present in 72%, two cysts in 12% and three or more cysts in 16%. Most cysts were between 1 and 15 cm in diameter. Ultrasound has been used in Kenya to study the growth rate of cysts. Thirty per cent grew 1–5 mm year–1, 11% grew 6–15 mm year–1, and 11% grew an average of 31 mm year–1. Cyst collapse or lack of growth was found in 16%. Hydatid cysts are surrounded in host tissues by a pericyst that contains the metacestode endocyst. The endocyst comprises two layers: an outer acellular laminated layer, and an inner cellular germinal layer. Ten to twelve months are needed for protoscolices to form within a cyst. Larger cysts can contain smaller daughter cysts of varying size known as internal budding. Moro et al. (2000) reported that most cysts are asymptomatic, and only when they reach large dimensions do symptoms and complications occur. Secondary bacterial infection can cause liver abscess. Rupture of metacestodes into the peritoneal cavity can cause secondary formation of widespread peritoneal cysts. Additionally, rupture or leakage can sometimes cause a fatal allergic reaction (anaphylactic shock). Ferreira et al. (1995) proposed a possible explanation for anaphylaxis by demonstrating that E. granulosus sheep hydatid cyst fluid activated the complement pathway beyond the C5 step, producing potentially allergenic lytic complexes in vitro. Moro et al. (2000) noted that pulmonary cysts seldom cause symptoms, and are often found incidentally on routine chest X-ray. Rupture of a cyst into the bronchial tree can lead to expectoration of hydatid fluid and membranes. Secondary bacterial lung abscess may result. Rupture into the lung parenchyma can lead to allergic phenomena: itching, urticaria (hives), or anaphylaxis. Moro et al. (2000) stressed that if a hydatid cyst is identified in an unusual ectopic location, attempts to find coexisting liver or lung cysts must be made through the use of CT scanning, MRI, ultrasound, or chest X-ray. Gilman and Lee (2000) described the lesions of E. multilocularis. Unlike E. granulosus, the alveolar hydatid disease of E. multilocularis produces hard, yellow-grey, cancer-like masses that are primarily in the liver. The outer layer of the cyst lacks a restricting laminated membrane, resulting in diffuse spread into the host parenchyma in an alveolar pattern. Larval proliferation is apparent in the periphery of the lesions, with the center showing necrosis and liquefied abscess formation. Multilocular hydatid disease can spread by direct
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extension to adjacent structures, or pieces of germinal epithelium can metastasize in a cancer-like fashion to brain, lungs, and mediastinum via the blood or lymphatic systems. Pressure from the space-occupying alveolar cyst can cause portal vein obstruction, portal hypertension and bleeding esophageal varices, jaundice from bile duct invasion, or hepatic venous and inferior vena caval obstruction. Gilman and Lee (2000) noted that alveolar hydatid disease is fatal without treatment, with a 10-year survival of <10%. With early diagnosis and treatment, the 10-year survival rises to 90%.
9.5. Diagnosis
A patient from an endemic area presenting with a palpable fullness in the right upper quadrant of the abdomen, or a cannonball-appearing mass in the lung on chest X-ray, requires further workup to rule out cystic hydatid disease. Investigation may include CT, MRI or ultrasound examinations. Positive serology results are useful in providing immunologic confirmation of infection or prior exposure. Dottorini et al. (1985) reported the diagnosis of cystic hydatid disease in humans, using antigenic preparations from sheep hydatid fluid and scolices of E. granulosus salted out with ammonium sulfate. Sera from persons with hydatid disease and from controls were analyzed by IHA, ELISA, and complement fixation methods. Antigens from sheep hydatid fluid were diagnostically superior to those from scolices. Sensitivity was excellent for all antigens, but specificity was greatest for hydatid fluid extracts. Romia et al. (1992) reported 88.9% sensitivity and 96.9% specificity in detection of circulating echinococcal antibodies by dot-ELISA using hydatid cyst fluid antigens. Circulating antigens, as identified by reaction with hyperimmune rabbit sera, were detected with only 55.6% sensitivity. Romia et al. (1992) attributed this to difficulty in the detection of the small amounts of circulating immune antigenic complexes present in the serum of infected patients. Shambesh et al. (1995) studied the usefulness of 100- and 130-kDa antigens obtained from immunoblotting camel hydatid cyst fluid in the serodiagnosis of human cystic hydatid disease. Sensitivity among surgically confirmed cases was 94%, with no cross-reactivity to sera from human schistosomiasis or onchocerciasis patients (100% specificity). Traditionally, IHA and ELISA have been the two most effective immunologic methods for screening populations at risk for hydatid disease. Mistrello et al. (1995) reported the use of bovine liver hydatid antigen collected by immunoblotting, in a hydatid antigen dot immunobinding assay (HA-DIA). Sera from 17 patients with hydatid disease and control sera from 36 patients with other parasitic and nonparasitic diseases were tested with HA-DIA. Positive results were obtained in all sera of hydatid patients, and in none of the
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control sera (100% sensitivity and 100% specificity). Owing to the simplicity of the test, and the fact that it does not require laboratory instruments, Mistrello et al. (1995) concluded that HA-DIA is particularly suited for large-scale field screening. Guisantes et al. (1994) commented on antibody levels 1 year following surgery for cystic hydatid disease. One hundred and nine serum samples from 26 surgically confirmed cases of hydatid disease were analyzed. Eight of 26 patients had persistent cysts during the follow-up period. ELISA testing performed 1 year following surgery showed that total, or nonspecific, IgE levels returned to normal in 84.6% of the total patient pool, in 94.5% without remaining hydatid cysts, and in 62.5% with remaining cysts. Total IgE was considered a poor diagnostic marker for persistent hydatidosis. Levels of specific antiEchinococcus IgE were still evident in all patients 1 year after surgery, with a predominance of decreasing values in those without remaining cysts. Guisantes et al. (1994) concluded that specific IgE is more useful in serologic follow-up after hydatid surgery than is nonspecific IgE. Ito et al. (1995) described detection of antibody response against Em 18, a new E. multilocularis antigen. Fifteen patients from Alaska, USA with alveolar hydatid disease were studied. As determined by clinical, pathological, and immunological testing, the 15 were divided into 10 active and 5 inactive cases. Good correlation was found on ELISA testing between antibody IgG4 response against Em 18 and the presence of active lesions. Ito et al. (1995) concluded that detection of antibody response against Em 18 is useful in the differentiation of active from inactive cases of alveolar hydatid disease. Parija et al. (1997) presented the first report of the detection of hydatid antigen in the urine of patients with hydatid disease using countercurrent immunoelectrophoresis (CIEP). The antigen was found in 44% of patients with surgically confirmed hydatid disease, in 40% of ultrasound-proven hydatid disease, and in 57% of clinically diagnosed hydatid disease. No antigen was detected in any patients with parasitic diseases other than echinococcosis, but there were 8% false positives among healthy control samples. The results suggested the potential usefulness of CIEP as a rapid, noninvasive method of diagnosis for hydatid disease.
9.6. Treatment
The treatment of choice for cystic hydatid disease caused by E. granulosus is surgery. Sielaff et al. (2001) noted that local recurrence is rare following complete resection of intact cysts. The 10% overall recurrence rate is a result of spillage of cyst fluid, or the failure to surgically remove the entire germinal epithelium, daughter cysts, or protoscolices. To avoid intraoperative contamination with live parasitic material, the cyst is first aspirated, and then filled with
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hypertonic saline (20–30%), which acts as a scolicide. Other acceptable scolicides include hydrogen peroxide, povidone-iodine, silver nitrate, and ethanol. The hypertonic saline is left in the cyst for 5–10 min. The cyst is again aspirated and refilled with scolicide. Following repeat aspiration of cyst contents, the cyst is opened and parasitic membranes are removed. Because of the possibility of anaphylaxis if cyst contents are spilled, corticosteroids are administered. Completely calcified cysts are considered inactive and need not be treated. The mortality rate for surgical treatment of cystic hydatid disease is between 2 and 3%. Casado et al. (2001) studied 459 patients with 630 hepatic hydatid cysts operated on in two large hospitals in Madrid, Spain over a 22-year period. The patients were divided into two groups: group A undergoing surgery from 1974 to 1984, and group B from 1985 to 1996. There were no deaths related to surgical resection in any of the 459 cases. As expected from recent improvement in surgical technique, the morbidity was less for group B than for group A. Most notably, between 1990 and 1996 surgical mortality was 0%, and the incidence of complications was only 6% (biliary fistula in 2% and infection of the residual cavity in 4%). Only one of 459 patients had recurrence of their hydatid disease. Casado et al. (2001) concluded that the surgical treatment of hepatic hydatid cysts is safe, with an almost nil recurrence rate. Kir and Baran (1995) reported 23 cases of simultaneous removal of hydatid cysts of the liver and lung. In all cases, complete resection was possible in a single operation with no reported mortality. Karydakis et al. (1994) presented a series of 96 patients with ruptured hydatid cysts of the liver. Ruptures were into the biliary tree in 49, intrathoracic in 43, and freely ruptured into the peritoneal cavity in 4 cases. Intrabiliary rupture was treated by surgical drainage of the cyst cavity, and one of the following biliary decompression procedures: T-tube drainage of the common bile duct (insertion of a soft rubber drain with a flexible ‘T’ end), sphincteroplasty (cutting the muscular sphincter at the common bile duct’s entrance into the duodenum), or choledochoduodenostomy (anastomosing the common bile duct to the duodenum). Intrathoracic rupture was treated by resection of involved lung, repair of ruptured areas of diaphragm, and closure of openings into the bronchial tree. Intraperitoneal rupture required lavage (saline washout of the abdomen) and prolonged drainage of the hepatic cyst cavity. There were five deaths in the postoperative period: three from multiorgan failure, one from pulmonary embolism and one from suppurative cholangitis (ascending infection in the biliary tree). Khoury et al. (1994) reported the first laparoscopic resection of a hydatid cyst of the liver. The patient was a 27-year-old man with a 6-week history of right upper abdominal pain and ultrasound findings consistent with hydatidosis. The principles of open hydatid surgery, including repeat aspiration and injection of scolicide followed by complete evacuation of the cavity, were
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maintained during laparoscopic surgery. The minimally invasive surgical approach conferred the benefits of less pain, improved cosmesis, and rapid recovery and return to work. Khoury et al. (1998) reported the complication of anaphylactic shock from spillage of cyst fluid during laparoscopic treatment of a hydatid cyst of the liver. This led Ramachandran et al. (2001) to describe a technical improvement eliminating the risk of spillage of cyst contents. A 5-mm laparoscopic suction cannula was passed through a port in the abdominal wall and placed strategically near the site of the hydatid cyst puncture. As the cyst is sequentially aspirated and injected with scolicide, the 5-mm suction cannula removed any leaking fluid. Six patients had successful laparoscopic removal of their hepatic cyst contents, including all daughter cysts and germinal epithelium. Ramachandran et al. (2001) concluded that laparoscopy is a superior and viable alternative to the traditional open-surgical treatment of hepatic hydatid cysts. Gharaibeh (2001) reported successful laparoscopic total splenectomy for splenic hydatid cyst. Bickel et al. (2001) reported a study of 32 patients with hydatid cysts of the liver (49), spleen (10), and pelvis (2) that were operated laparoscopically with no recurrences during a mean follow-up of 49 months. Cyst puncture, parasite neutralization and cyst evacuation were facilitated by an operating instrument in which a constant vacuum enabled its tip to firmly adhere to the cyst wall throughout the procedure, thereby preventing spillage. Pelaez et al. (1999) treated 60 liver hydatid cysts in 38 patients with CT scan-guided percutaneous puncture–aspiration–injection–reaspiration (PAIR). Hypertonic saline was used as the scolicidal agent. Serial CT scans demonstrated a cyst mean volume reduction of 66%. Complications included two cases of urticaria, one case of anaphylaxis and one subcapsular hematoma (blood collection contained by the liver capsule). The low incidence of complications, together with the absence of mortality, suggested that PAIR is an effective alternative to the surgical treatment of hepatic hydatid cysts. Men et al. (1999) treated 168 hepatic hydatid cysts in 111 patients with ultrasoundguided PAIR. Cysts under 5 cm were treated with one-stage aspiration and injection with hypertonic saline. Larger cysts were treated an additional time with ethanol. Early complications were found in 28.8% of 111 patients: urticaria (7), fever (7), biliary fistula (7), infection of cyst (4), persistent serous drainage from cyst (2), leakage of cyst fluid into abdomen (2), pleural effusion (2), and fatal anaphylaxis (1). Late complications were found in 3.8% and included local recurrences (3) and intrabiliary cyst rupture (1). Ormeci et al. (2001) used CT scan and ultrasound-guided PAIR to treat 98 hydatid cysts of the liver in 87 patients, and presented their results after a follow-up of 33 months. Aside from one case of anaphylaxis, there were no major complications observed. The scolicides used were absolute alcohol and polidocanol 1%. Serial ultrasound examination demonstrated complete obliteration of the cyst
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cavity in 32 cases, two-thirds obliteration in 34, one-third obliteration in 23, and no obliteration in 8. Ormeci et al. (2001) concluded that PAIR is both effective and safe, and should be considered as the first treatment choice in patients with hydatid cysts of the liver. PAIR might be even more effective when combined with albendazole therapy at 10 mg kg–1 day–1 for 8 weeks. Muftuoglu et al. (2001) reported the successful surgical removal of a subretinal hydatid cyst in the right eye of a 34-year-old woman. After the cyst wall was excised, the retina was reattached with perfluorocarbon and silicone oil. Vision was 20/63 postoperatively, and there was no recurrence. Yaghan (1999) described a case of hydatid cyst of the breast. Diagnosis was made by fineneedle aspiration cytology allowing subsequent surgical removal. Chat et al. (2000) noted an extremely rare intradural spinal hydatid cyst found on CT and MRI in a 13-year-old girl, and described subsequent surgery. Soysal et al. (1997) described an unusual case of a right atrial cardiac hydatid cyst that embolized to both pulmonary arteries. The cyst was removed under cardiopulmonary bypass, and cyst material in the pulmonary arteries was extracted with balloon embolectomy catheters. The patient survived 3 months, only to die of pulmonary failure. Tejada et al. (2001) noted a 35-year-old man with a hydatid cyst in the interventricular septum of the heart, which presented with urticaria and chest pain. Echocardiography and MRI made the diagnosis, and the cyst was removed following sterilization with hypertonic glucose solution. Schoretsanitis et al. (1998) noted a patient with a primary adrenal hydatid cyst: only the ninth such case reported in the literature. Diagnosis of this entity is usually made pathologically after surgical excision. Singh and Khullar (1999) reported a hydatid cyst of the tail of the pancreas, treated by distal pancreatectomy. Singh et al. (2000) described a giant renal hydatid cyst managed by excision of the cyst alone, preserving the renal parenchyma. Hatipoglu et al. (2001) discussed two retroperitoneal hydatid cysts: one in the left psoas muscle and one in the pelvis. Both had the cyst walls successfully excised and oversewn. Postoperative albendazole therapy was continued for 10 weeks . Moro et al. (2000) noted that drug therapy for hydatid disease due to E. granulosus complements surgical treatment, but does not replace it. Even the small unilocular cysts that respond to albendazole do so only 30 to 40% of the time as a result of the formidable tissue barriers that need to be penetrated for the drug to reach the inner compartments of the metacestode. Albendazole is most commonly used for treatment of inoperable disease, and in pre- and postoperative treatment in order to reduce recurrence. Dosage is 400 mg twice daily administered in 3 to 12 cycles of 28 days with 14 days rest between cycles. Side effects include elevated liver enzymes, abdominal pain, headache, and hair loss. Gilman and Lee (2000) noted that surgical excision is also the treatment of choice for the alveolar hydatid cysts of E. multilocularis. Unlike the cysts of E.
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granulosus, alveolar cysts lack a fibrotic pericyst, and infiltrate organs in all directions. The impossibility of separating alveolar cysts from host tissue makes it imperative to diagnose them as early as possible. Early detection by serology and ultrasound screening increases surgical resectability from 20 to 80%. Long-term drug treatment with albendazole (10 mg kg–1 day–1) or mebendazole (40 mg kg–1 day–1) is recommended for nonresectable disease. Liver transplantation is an alternative treatment in cases of extensive liver involvement by the larval metacestode, providing survivals of 66% at 6 years. The overall 10-year survival rate of alveolar hydatid disease approaches 90% with long-term drug therapy.
9.7. Prevention
Moro et al. (2000) noted that effective measures in controlling echinococcosis include routine deworming of dogs with praziquantel every 6 weeks, avoiding feeding dogs with infected entrails, periodic inspection of abattoirs, and changing human behavior through education. Moreno et al. (2001) studied the chemoprophylactic efficacy of combined praziquantel and albendazole (PZ + ABZ) in a mouse model. PZ + ABZ pretreated mice did not develop hydatid cysts when injected with echinococcal protoscolices. The relevance of this work in human disease prevention remains to be established.
10. ASCARIS LUMBRICOIDES 10.1. Case Report
A 42-year-old female presented to her physicians in Cape Town, South Africa, with abdominal pain. Ultrasound showed an irregular, dense structure in the gallbladder. Subsequent CT scanning suggested a tumor of the gallbladder. Endoscopic retrograde cholangiopancreatogram (ERCP – endoscopically cannulating the duodenal papilla to inject contrast dye for radiographic outline of the bile and pancreatic ducts) was diagnostic for the presence of an Ascaris lumbricoides worm in the gallbladder. The patient was treated with piperazine resulting in the rectal passage of several additional worms. Owing to the persistence of biliary colic, laparoscopic cholecystectomy was necessary. The gallbladder containing a dead Ascaris worm was removed via the umbilical surgical port. The patient had an excellent recovery, and remained free of symptoms for 1 year following operation (Cullis et al., 1993).
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10.2. Ascariasis
Khuroo (1996) noted that ascariasis is a disease of humans caused by ingestion of embryonated eggs of A. lumbricoides, the largest of the intestinal nematodes. After the larvae migrate through the lungs, adult worms mature and reside in the small intestine. This roundworm was confused with the earthworm by the ancient Greeks and Romans, and named askaris (Greek for worm). Each female adult worm can release millions of eggs into the fecal stream. The eggs are resistant to drying and extreme temperatures. Crompton (2001) believed that eradication of ascariasis is not realistic in endemic areas, given the current shortage of sanitation. Since there is no effective vaccine available, periodic administration of anthelmintic drugs to schoolchildren appears to be a cost-effective means of controlling infection.
10.3. Epidemiology
Bundy and DeSilva (2000) described the life cycle of A. lumbricoides. The adult worm is pink or cream colored, and tapered at both ends. The male has a ventrally curved tail end, and numerous groups of pre-anal and post-anal papillae. Female worms are 20–49 cm long and 3–6 mm in diameter. Males are 15–30 cm long and 2–4 mm in diameter. Ascaris worms have an outer chitinous transversely striated layer, secreted by the underlying epithelium. Adult worms maintain their position in the gut of the definitive host by the activity of their longitudinal somatic muscle bands. The internal viscera, including the organs of the digestive, excretory, reproductive, and nervous systems, are suspended in the pseudocelom or false body cavity. A. lumbricoides lacks a circulatory system. The life span of adult worms is 6–18 months. Females produce up to 240 000 eggs day–1, which are deposited in the fecal stream of the human distal small intestine. The eggs have a thick hyaline shell, and measure 40 by 60 µm. Once released in the feces, the eggs are protected by a mamillated outer coat, promoting adherence of soil particles and preventing desiccation. Under warm, moist soil conditions, the embryo molts within the eggshell. The embryonated egg containing a second-stage larva is infective to humans. The entire soil stage takes between 2 weeks and several months, and eggs can remain viable and infective for up to 10 years. Human ingestion of embryonated eggs leads to infection. Children acquire ascariasis when playing on contaminated soil or by geophagia. Eggs can adhere to food and clothing or infect the water supply. Human feces used as fertilizer for growing vegetables spreads ascariasis. Airborne eggs in dry, windy climates can also lead to infection by inhalation. Boys tend to have more severe infection than do girls, a result of their behavior and affinity for outdoor activities.
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Ingested larvae hatch within the jejunum, penetrate the bowel wall, and enter the right heart by way of hepatic venules. Once in the pulmonary circulation, the larvae molt twice more in the alveolar spaces. These 1.5 mm larvae migrate up the trachea, and are swallowed. After a final molt, they mature into adult worms in the small intestine. Larvae reach the lungs 2 weeks following egg ingestion. Adult female worms begin egg production 10–12 weeks following initial ingestion. Khuroo (2001) noted that an estimated 1.4 billion people are infected with A. lumbricoides worldwide. Of those infected, 1.2 to 2 million people have heavy worm burdens (≥15 worms per patient or release of >10 000 eggs g–1 of stool), causing 20 000 ascariasis-related deaths per year. Endemic areas include China, India, Southeast Asia, Latin America, the Caribbean, and sub-Saharan Africa. Intensity of infection is highest in children under 10 years of age. Even moderate worm loads are associated with stunted growth in children. Ascariasis contributes to protein–calorie malnutrition in the host. Children with 13 to 40 worms lose about 4 g of protein day–1, and suffer from vitamin A and C deficiencies. Deworming programs result in significant improvement in childhood growth rates and performance on cognitive achievement tests. Kightlinger et al. (1995) presented an analysis of 1292 children from the Ranomafana rainforest of Madagascar, East Africa. The prevalence of ascariasis was 78%. Infection with A. lumbricoides was rapidly acquired during infancy, increasing to 100% prevalence by age 10. The mean worm burden was 19.2 worms per child. One year after mass mebendazole anthelmintic treatment, A. lumbricoides prevalence and intensity levels rebounded to pretreatment levels due to reinfection. Kightlinger et al. (1996) studied 663 children aged 4–10 years, living in the Ranomafana rainforest. Initial fecal egg counts documented a 93% infection rate for A. lumbricoides. Malnutrition among those infected was common, with growth stunting in 72%, low body weight in 61%, and wasting in 6%. Worm expulsion studies with pyrantel pamoate indicated that A. lumbricoides was not found exclusively in the most malnourished and immunosuppressed children, but in fact had a much wider prevalence.
10.4. Pathogenesis
Khuroo (1996) noted that Ascaris pneumonia is common in endemic areas. It typically lasts 2–3 weeks, and is due to migrating larvae in the bronchioles and alveoli. Common in children, Ascaris pneumonia is characterized by fever, coughing, wheezing, hemoptysis (coughing up blood), and substernal chest pain. Eosinophilia is present in the peripheral blood. Filariform larvae of A. lumbricoides can be found on examination of the sputum or gastric aspirate. Bundy and DeSilva (2000) described intestinal ascariasis. Many people
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with low worm loads have mild or no symptoms. Discovery of infection may occur with Ascaris eggs being found incidentally on stool examination, or by passage of a worm through the rectum, nose, or mouth. Worms may also appear as linear filling defects in the small bowel on barium meal X-ray examinations. Sharma et al. (2000) noted that chronic occult gastrointestinal bleeding is seen with roundworm infections. After presenting three cases of massive intestinal bleeding secondary to ascariasis, Sharma et al. (2000) suggested that endoscopic examination of the small bowel would lead to a more frequent correct diagnosis. In current medical practice, endoscopy is generally limited to the colon and upper gastrointestinal tract. Akgun (1996) noted that Ascaris-induced intestinal obstruction is common in endemic areas, comprising 35% of cases of intestinal blockage in such regions. Bolus obstruction occurs when aggregated masses of worms block the lumen of the bowel, most frequently in the terminal ileum. A mass may be felt through the right lower abdominal wall, and X-rays often show dilated loops of small bowel with air/fluid levels. Complicated obstruction is characterized by twisting (volvulus) or invagination of one segment of bowel into another (intussusception). Infarction and perforation may occur, and are life-threatening emergencies. With or without perforation, Ascaris worms can be found free in the peritoneal cavity, where they eventually die and elicit a granulomatous reaction. Worms may also enter the appendix and lead to appendicular gangrene and perforation. Khuroo (1996) stated that hepatobiliary and pancreatic ascariasis occur when worms enter the ampulla from the duodenum. The worms, noted for their propensity to explore small openings, may migrate further into the common and hepatic bile ducts, and even into the gallbladder or pancreatic duct. Ultrasound examinations have demonstrated that worms actively move in and out of the ductal system into the duodenum. If a worm remains in the duct for longer than 10 days, it can be presumed dead. Dead worms can act as a nidus for formation of stones and strictures of the bile duct. The clinical presentation of hepatobiliary ascariasis includes biliary colic, pancreatitis, acute cholecystitis, cholangitis (infection due to obstruction of the common bile duct), and hepatic abscess. Khuroo (1996) studied an area of India endemic for ascariasis. With ERCP as the diagnostic modality, A. lumbricoides was present in 36.7% of patients with biliary and pancreatic disease. Ascariasis was as common as gallstones as a cause of biliary disease. Fogaca et al. (2000) reported a rare case of liver pseudotumor caused by hepatic granuloma surrounding eggs of A. lumbricoides. Valentine et al. (2001) noted that in the USA, about 4 million people per year are infected with A. lumbricoides. A retrospective review of all patients with the diagnosis of ascariasis over a 6-year period at the Los Angeles County and University of Southern California Medical Centers was completed. The three most common presentations to the emergency room were: Ascaris-induced
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acute appendicitis, Ascaris pneumonia, and Ascaris-induced biliary disease. Quick et al. (2001) presented a patient who observed a 6-inch worm exiting his urethra while voiding. This was the first reported case of urinary ascariasis in North America. McSharry et al. (1999) found a group of children apparently immune to ascariasis in a hyperendemic region of Nigeria, West Africa. Immunity was associated with higher levels of serum ferritin, C-reactive protein and eosinophil cationic protein. These markers indicated ongoing acute-phase inflammation. Children susceptible to infection had little serologic evidence of inflammation despite high worm burdens. IgG antibodies to recombinant Ascaris antigens reflected the intensity of infection, but did not confer immunity. The immune group had significantly higher IgE responses than did the group susceptible to infection. McSharry et al. (1999) concluded that IgE antibody and inflammatory responses are both associated with natural immunity to ascariasis.
10.5. Diagnosis
Hall and Holland (2000) noted that the diagnosis of ascariasis is made through microscopy of nematode eggs in human feces. To increase the yield, Kato and Miura thick smears and sedimentation techniques may be applied. Ascaris larvae in sputum or gastric aspirate confirm pulmonary ascariasis. The finding of adult worms at surgery, or by spontaneous passage through the mouth or anus, is diagnostic. Ultrasound abdominal examination may reveal intestinal or biliary–pancreatic ascariasis. Mahmood et al. (2001) described the sonographic appearance of Ascaris worms in the small bowel. In longitudinal section, they appear as intraluminal masses with three or four linear echogenic interfaces. In cross-section, they are round, sometimes appearing as ‘target’ signs. Serpentine movements of the worms are sometimes seen on ultrasound. Larrubia et al. (1996) described sonography and its usefulness in detecting worms in the biliary tree. ERCP outlines the biliary and pancreatic ducts, can detect migrating worms, and is a means of worm extraction. Santra et al. (2001) reported an anti-Ascaris IgG ELISA antibody test and found it to be both a sensitive and specific marker for the diagnosis of ascariasis.
10.6. Treatment
Bundy and DeSilva (2000) reviewed the available effective drugs against A. lumbricoides. Pyrantel pamoate, mebendazole and albendazole all immobilize and kill the parasite, but clearance of the worms from the gastrointestinal tract
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may take up to 3 days. Pyrantel pamoate, a cyclic amide, is a depolarizing neuromuscular blocking agent that induces spastic paralysis of the worm. The drug is poorly absorbed and 50% is released in the feces. A single dose of 10 mg kg–1 up to a maximum 1 g is effective. Contraindications include pregnancy and hepatic disease. Mebendazole inhibits formation of the worm’s microtubules and blocks glucose uptake. Effective dosage regimens are 100 mg twice daily for 3 days, or a single 500 mg dose. It is also contraindicated in pregnancy, and can be associated with neutropenia (a reduction below normal of the number of neutrophils in the peripheral blood) and abnormal liver function tests. Albendazole has a similar mechanism of action against A. lumbricoides as mebendazole, but also inhibits helminth-specific fumarase reductase. A single 400 mg dose is effective, making albendazole useful in mass treatment programs. Side effects and contraindications are similar to mebendazole. Khuroo (1996) noted that piperazine paralyzes Ascaris worms by anticholinergic neuromuscular blockade. Recommended is a single dose of 75 mg kg–1, to a maximum 3.5 g for adults and children >12 years, and a maximum of 2.5 g for children between 2 and 12 years. The paralyzed worms are then evacuated by peristaltic action of the intestine. Occasional hypersensitivity and neurotoxic reactions have led to the drug being withdrawn from the market, in favor of the above-mentioned safer alternatives. A final drug, levamisole, is a fumarate reductase inhibitor that is nontoxic to humans and has an immunomodulating effect by activating macrophages. It is used as a single 150 mg dose for adults, or 5 mg kg–1 in children. Bundy and DeSilva (2000) noted that intestinal ascariasis can often be managed conservatively, provided the patient is stable and well hydrated. Nasogastric tube suction, intravenous fluids and antispasmodics treat the initial obstruction, followed by administration of anthelmintic drugs once the obstruction has ameliorated. If the drugs are given too early, they may paralyze a large mass of worms in the distal ileum precipitating complete bowel obstruction, a surgical emergency. Indications for surgical management of intestinal ascariasis, according to Khuroo (1996), include: (1) persistence of an abdominal mass for more than 24 h, (2) continued abdominal pain with a tender mass, and (3) toxemia and a rising pulse rate with disappearance of a mass (evidence of perforation). The most commonly indicated surgical procedure is manual advancement of the bundle of parasitic worms from the small bowel into the colon. If this fails, an opening can be made in the ileum (enterotomy) and the worms removed directly. Should gangrene or perforation of the bowel be encountered, resection of the involved segment is required. Villamizar et al. (1996) reported 87 children with Ascaris-induced intestinal obstruction, treated between 1984 and 1994. The mean age was 4.6 years, girls outnumbered boys (48 to 39), and half the patients had passed worms by
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mouth or anus. Most cases (73.5%) presented with a subacute clinical course, while 26.5% had acute symptoms such as severe abdominal pain, vomiting, fever, dehydration, and abdominal distension. Abdominal X-ray showing a whirlpool pattern of intraluminal worms confirmed the diagnosis in most cases. While the majority of patients were managed conservatively, 23 were operated upon. Eleven needed external milking of the obstructing bolus of worms from the ileum into the colon, six had intestinal resections with end-toend anastomoses, six had appendectomies (for Ascaris-induced appendicitis), and three had enterotomies to extract worms. There was no significant postoperative morbidity or mortality. Tondon et al. (1999) analyzed 250 cases of gastrointestinal ascariasis from the pediatric wards of Government Medical College, Jabalpur, India. Emphasis was placed on the use of hypertonic saline enemas as part of conservative treatment. Hypertonic saline passes through the ileocecal valve (which is incompetent in 80% of children) and acts on the worm bolus in the terminal ileum causing it to disintegrate. It also enhances intestinal motility, and therefore facilitates passage of worms into the colon. Tondon et al. (1999) reported a success rate of 95.6% with this hypertonic enema technique. Mukhopadhyay et al. (2001) presented 509 patients from Calcutta, India, all below the age of 10 years, treated for abdominal colic and the passage of roundworms in the stool or vomitus. Initial treatment was by antispasmodics and saline enemas, followed by anthelmintic drugs when the pain subsided. Of the 209 patients requiring hospitalization, 50% needed surgical intervention including manual advancement or extraction of worms, bowel resection with anastomosis, and appendectomy. Five patients died postoperatively, compared with no mortalities in the conservative management group. Mukhopadhyay et al. (2001) emphasized the importance of early recognition of ascariasis to prevent serious complications. Khuroo (2001) described hepatobiliary and pancreatic ascariasis as a disease of adult women (female to male ratio of 3:1). Obstruction of the bile or pancreatic ducts must be relieved surgically or endoscopically. Generally such intervention is indicated should the patient not respond to conservative treatment within the first few days of hospitalization, or should the worms not leave the ducts and return to the duodenum within 3 weeks . Biliary symptoms and pancreatitis usually resolve promptly following worm extraction. Rezaul (1991) managed 12 cases of biliary ascariasis from Chittagong, Bangladesh. Surgery with exploration of the common duct was required in all 12 instances, as all failed to improve with conservative therapy. De Andrade et al. (1992) presented a 25-year-old woman from Sao Paulo, Brazil, with surgical removal of 60 worms filling her common bile duct. Khuroo et al. (1993) reported 156 patients with hepatobiliary ascariasis, 32% of whom underwent endoscopic interventions. Worm extraction was successful in all 18 cases with worms located at the ampullary orifice, and in 89.5% with worms in the bile or
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pancreatic ducts. In five cases, a nasobiliary drain was placed to decompress pyogenic cholangitis. Following worm extraction and nasobiliary drainage, 91% had rapid relief of symptoms. There were three endoscopy-related complications. Misra and Dwivedi (1996) reported five cases of endoscopy-assisted emergency treatment of gastroduodenal and biliary ascariasis. Endoscopic worm removal was accomplished with a Dormia basket (a wire trap that can be tightened around the object to be extracted). Other procedures included insertion of a biliary stent and sphincterotomy. Following albendazole therapy, all five patients remained asymptomatic. Yoshihara et al. (2000) described successful laparoscopic cholecystectomy with extraction of a living Ascaris worm and associated stones from the common bile duct. Gonzalez et al. (2001) presented 69 patients from Ecuador, South America, with ultrasound-documented biliary ascariasis. The study supported the efficacy of non-surgical treatment. Initial therapy consisted of antispasmodics, analgesics, and albendazole 800 mg by mouth. In 97% of the patients, the worms disappeared with noninvasive therapy alone. Only those patients with persisting symptoms or high amylase levels in the blood underwent endoscopy. Endoscopy was performed in 42% of cases, with 14% having a worm found and extracted via the ampulla. All six cases with worms in the intrahepatic biliary tree cleared without requiring invasive procedures. Surgery was limited to one complicated case. Gonzalez et al. (2001) concluded that the treatment of A. lumbricoides migration into the biliary tree is mainly medical. Liangmin (1996) reported 50 cases using combined herbal medicine and acupuncture for treatment of infected biliary ascariasis. The herb used was An Hui Zhi Tong Decoction. The cure rate was 72%, with a total effective rate of 96%. The therapy had a good antipyretic effect, improved the symptoms quickly, and had a better therapeutic effect than did 42 control cases treated by conventional Western medicine.
10.7. Prevention
Bundy and DeSilva (2000) noted that although uncomplicated ascariasis is relatively easy to treat, preventing reinfection is the key to controlling the disease. O’Lorcain and Holland (2000) reported that single-dose chemotherapy with mebendazole or albendazole is effective, safe and cost-effective, especially when targeted at school-aged children. Holland et al. (1996) analyzed the control of ascariasis in rural Nigeria, West Africa, and found that both mass and targeted levamisole chemotherapy were more effective than was selective therapy of only the most heavily infected individuals. Long-term control requires changes in human behavior as well as improved sanitation in order to prevent untreated human waste from reaching the soil.
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11. FASCIOLA HEPATICA 11.1. Case Report
A 29-year-old woman presented with acute abdominal pain in the 17th week of pregnancy. She had experienced two prior episodes of colic in the right upper abdomen within the last 6 months. This history, together with laboratory findings of leukocytosis and markedly elevated serum alkaline phosphatase and bilirubin, suggested the diagnosis of acute cholecystitis. A sonogram revealed dilated intra- and extrahepatic bile ducts containing two hyperechoic structures. The gallbladder was dilated with a thickened wall. ERCP was not possible due to the risk of X-ray exposure to her pregnancy. Open surgery was performed consisting of cholecystectomy and exploration of the common bile duct with a flexible choledochoscope. Two live adult Fasciola hepatica worms were removed from the bile duct. Fecal tests were positive for Fasciola eggs, and a T-tube common bile duct drain was left in for the remainder of her pregnancy. In the postpartum period, an ERCP with papillotomy (cutting the sphincter muscle at the entrance of the bile duct into the duodenum) was performed, and X-ray cholangiogram confirmed the absence of flukes in the biliary tree. Since fecal tests were now negative for parasite eggs, drug treatment was withheld. The patient has remained alive and well (Riedtmann et al., 1995).
11.2. Fascioliasis
Bunnag et al. (2000a) noted that flukes from three distomate families – Opisthorchiidae, Dicrocoelidae and Fasciolidae – infect the biliary tract of humans. F. hepatica and F. gigantica belong to the family Fasciolidae. Both parasites frequent the livers of sheep, the most common definitive host. Other herbivores, such as cattle, camels, hogs, horses, deer, goats, and rabbits, may harbor infection. Although humans are considered an occasional host for Fasciolidae, more than 2 million persons worldwide are infected with F. hepatica. Unlike F. gigantica, which has a tropical distribution, F. hepatica infection is found in temperate sheep-raising areas of North and South America, Europe, the former Soviet Union, Africa, Asia, and the Middle East. Human infection involves the liver and bile duct, as well as extrahepatic sites.
11.3. Epidemiology
Bunnag et al. (2000a) described the life cycle of F. hepatica. The adult fluke lives in the bile ducts of the definitive host. Adult flukes are up to 3 cm in
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length, 1.5 cm in width, with a characteristic cephalic cone. Eggs are passed in the feces as yellow-brown ovoid structures with an inconspicuous operculum. The eggs measure 130–150 µm by 60–90 µm. After 9–15 days in water at 22–26°C, miracidia develop and hatch. Graczyk and Fried (2001) noted that under optimal conditions, F. hepatica miracidia have up to 25 h to find a suitable intermediate host or die from glycogen depletion. Miracidia exhibit phototaxis, negative geotaxis and chemotaxis, which allows them to efficiently enter shallow-water-dwelling pulmonate snails of the family Lymneidae. Over the next 4–7 weeks, within the first intermediate snail host, the miracidia transform from sporocysts to rediae, rediae to daughter rediae, and finally daughter rediae to cercariae. Graczyk and Fried (2001) noted that shedding of F. hepatica cercariae from snails occurs during bright sunny days, and negative geotaxis accounts for their reaching the water’s surface. Sunlight also accelerates encystment of cercariae on aquatic vegetation. Metacercariae develop, and human infection occurs from ingestion of watercress grown in sheep-raising areas. Bunnag et al. (2000a) described the excystment of ingested metacercariae in the duodenum of the definitive host. The metacercariae migrate through the intestinal wall and enter the free peritoneal cavity. After penetrating Gleason’s capsule, they pass through the liver parenchyma to reach the bile ducts 3–4 months following initial ingestion. F. hepatica flukes can live in the biliary tree of humans as long as 9–13 years. Rondelaud et al. (2001) studied definitive and intermediate hosts of F. hepatica in natural watercress beds of central France. Field investigation over a 2-year period covered 52 watercress beds. Of 13 mammalian species studied, adult flukes were found in Lepus capensis (39% prevalence), Oryctolagus cuniculus (42%), and Sylvilagus floridanus (25%). Snails infected with F. hepatica were found in 14 watercress beds. Snail infection was detected in 1.1% of Lymnaea truncatula, and in 0.3% of L. glabra. The presence of hares and rabbits ensured continuation of the F. hepatica life cycle. Transmission to humans occurred when wild watercress was eaten. Esteban et al. (1997) noted a high prevalence of F. hepatica among children from four communities in northern Bolivia, South America. Single stool specimens from 559 children, aged 5–19 years, were collected and analyzed. Nineteen parasite species were found – 13 protozoans and 6 helminths. At least one parasite species was found in 98.7% of the children examined. F. hepatica, with a 27.6% prevalence, was the most common parasite. Intensity of F. hepatica eggs in stool specimens ranged from 24 to 5064 eggs g–1 of stool. This study found a positive association between coexisting infection with both F. hepatica and Giardia intestinalis. Esteban et al. (1997) noted that the prevalence of F. hepatica infection in the northern Bolivian altiplano region is higher than any other reported prevalence throughout the world.
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11.4. Pathogenesis
Bunnag et al. (2000a) indicated that migrating metacercariae of F. hepatica can result in local hepatic parenchymal necrosis, hemorrhage and abscess formation. Adult flukes elicit hyperplasia and dilation of the bile ducts. Proline production by the adult worms appears related to this bile duct fibrosis. Mannstadt et al. (2000) noted that fascioliasis belongs in the differential diagnosis of abdominal pain, especially when accompanied by eosinophilia. The acute phase of larval migration through the liver to the bile ducts is accompanied by fever, nausea, vomiting, right upper abdominal pain, hepatomegaly, urticaria, and marked eosinophilia. Once the migratory phase is over and flukes lodge in the bile ducts, symptoms can abate. However, adult worms obstructing the extrahepatic biliary tree can result in jaundice, elevated liver function tests and symptoms suggestive of gallstones. Involvement of ectopic sites such as lung, intestinal wall, brain, heart, and skin are commonly observed with F. hepatica infection. Perez et al. (2000) reported a case of eosinophilic panniculitis (inflammation of subcutaneous fat characterized by predominance of eosinophils on microscopic examination) in a patient with F. hepatica infection responsive to bithionol. In endemic areas, acute nasopharyngitis can occur with ingestion of raw infected sheep or goat liver. Flukes from contaminated liver attach to the pharyngeal mucosa producing irritation and edema. There has been recent interest in F. hepatica-induced host immune response. Jefferies et al. (1996) verified the immunomodulation of sheep and human lymphocytes by F. hepatica ESP. Uptake of triated thymidine by human lymphocyte cultures was progressively inhibited by increasing doses of ESP. Jefferies et al. (1997) confirmed the inhibitory effect of F. hepatica ESP on superoxide output of sheep and human neutrophils. Van Milligen et al. (1999) noted that protection against F. hepatica in the intestine depends upon eosinophil and IgG1 responses mounted against newly excysted juvenile flukes. Berasain et al. (2000) demonstrated that F. hepatica-secreted proteinases degrade all human IgG subclasses, producing immunoglobulin fragments potentially useful to the parasite in evading host defense mechanisms. O’Neill et al. (2000) noted that F. hepatica infection downregulates T-cell responses in mice, resulting in high levels of cytokines IL-4 and IL-5, and low levels of IFN-γ and IL-2.
11.5. Diagnosis
Definitive diagnosis of fascioliasis depends upon finding F. hepatica eggs in the feces or duodenal aspirate. Demonstration of adult flukes by liver biopsy, surgery or following anthelmintic therapy is confirmatory. Ultrasound and
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cholangiography may identify flukes in the biliary tree. Hammami et al. (1997) reported the diagnostic value of western blot assay in the serodiagnosis of fascioliasis. Eleven different F. hepatica-specific antigens were detected using sera from patients with fascioliasis, with major 57- and 29-kDa antigens having 100% specificity and 70 and 93% sensitivities respectively. Diaz et al. (1998) noted the usefulness of monoclonal antibody ES 78 in the recognition of F. hepatica ESP by a highly sensitive and specific ELISA. Cordova et al. (1999) described an ELISA using purified F. hepatica cysteine proteases with 95% sensitivity and 100% specificity with a 25-kDa antigen. Strauss et al. (1999) confirmed the accuracy of ELISA in the diagnosis of human fascioliasis based upon the detection of IgG4 antibodies raised against F. hepatica cysteine protease, and emphasized its usefulness in largescale epidemiological studies. Espino et al. (2000) noted that coproantigens in the stool are detectable using ES 78 monoclonal antibody, a finding of potential usefulness in the diagnosis of fascioliasis. Kim et al. (2000a) reported the molecular cloning and expression of cystosolic superoxide dismutase from F. hepatica flukes. The expressed protein reacted with the sera of bovine and human subjects with fascioliasis, but did not react with uninfected controls. Trueba et al. (2000) used the ELISA test to measure antibodies against F. hepatica ESP in a community screening program in the Ecuadorean Andes, South America. Six per cent (9 of 150) of the population tested positive. Fecal samples were positive for F. hepatica eggs in only two of the nine positive ELISA cases. Serologic testing was particularly useful in diagnosing ectopic disease, as well as in the early acute phase, when the flukes are young and eggs have not yet appeared in the stool.
11.6. Treatment
Bithionol has been recommended for treatment of fascioliasis at 30–50 mg kg–1 every other day for 10 to 15 doses. Unfortunately, its use is accompanied by frequent photosensitivity skin reactions, hives, abdominal pain, vomiting, and diarrhea. Moreau et al. (1995) studied the efficacy of praziquantel in the treatment of F. hepatica infection. Twenty-five patients with a definitive diagnosis of fascioliasis were followed for a mean of 18 months by clinical, biochemical and serologic criteria. All patients received praziquantel at 75 mg kg–1 day–1 orally for 5 days. In two cases, treatment was initiated following surgical or endoscopic removal of parasites from the biliary tract. Four patients needed a second course of praziquantel due to persistent symptoms, eosinophilia and positive serologic testing. The rate of normalized eosinophilia at 6, 9, and 12 months was 55, 65, and 75% respectively. The rate of seronegativity at 6, 9, and 12 months was 55, 70, and 100% respectively. There was complete recovery in 72% (18 patients). Importantly, there were no significant
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side effects from praziquantel therapy, aside from transient nausea in a few instances. Moreau et al. (1995) concluded that praziquantel is effective and well tolerated, and can therefore be recommended as the first option in the treatment of F. hepatica infection in humans. Millan et al. (2000) reported the efficacy of triclabendazole (TCZ) in Cuban patients with F. hepatica infection. Eighty-two patients with chronic or latent fascioliasis, refractory to prior anthelmintic therapy, were enrolled in this 60day trial. Patients received TCZ at 20 mg kg–1, administered in two doses, 12 h apart. Treatment efficacy was determined by stool microscopy, stool Fasciola ESP-antigen testing, and abdominal ultrasound examinations. Seventy-one (87%) of the patients treated had stools negative for Fasciola eggs at the end of the 60-day period. Efficacy of therapy was confirmed by both stool antigen and ultrasound results. Six patients required another TCZ dose at 60 days to achieve parasitologic cure. In 49% of patients, TCZ use was associated with colicky abdominal pain due to expulsion of dead or damaged flukes from the bile ducts, most commonly noted 3–7 days following TCZ administration. Millan et al. (2000) concluded that TCZ is an effective agent for the treatment of F. hepatica infection for patients failing to respond to other anthelmintic drugs. Wong et al. (1985) reported surgical treatment of a Thai patient with hemobilia (blood in the bile) and liver flukes. ERCP demonstrated gallstones, as well as crescent-shaped filling defects in the biliary system. Surgical treatment consisted of cholecystectomy and exploration of the common bile duct. Small elliptical flukes (Opisthorchis viverrini) were recovered from the bile duct, which was drained with a T-tube. The patient continued to have high fevers, and on postoperative day 53 passed a larger fluke (F. hepatica) down the T-tube drain. Bithionol administration achieved clinical resolution within 3 weeks. Dias et al. (1996) described the therapeutic value of ERCP in the treatment of biliary flukes. Danilewitz et al. (1996) reported the endoscopic diagnosis and management of biliary obstruction caused by F. hepatica in a 49-year-old merchant marine. The patient presented with jaundice and abdominal pain. Ultrasound examination showed a large number of noncalcified foci in the gallbladder. After contrast material was injected into the common bile duct, ERCP revealed an oval-shaped 2 cm filling defect. Endoscopic sphincterotomy permitted passage of a Dormia basket and retrieval of a 2 by 1 cm F. hepatica adult fluke. Bithionol was administered with both clinical resolution as well as subsequent negative stool testing for Fasciola eggs. Danilewitz et al. (1996) concluded that to diminish the chance of a physician missing the diagnosis of fascioliasis, a high index of suspicion must be maintained, and ERCP should be performed in cases of biliary colic or pancreatitis. Stain et al. (1995) updated the surgical treatment of recurrent pyogenic cholangitis (RPC). This chronic disease is characterized by intrahepatic biliary stones and strictures leading to recurrent abscess and infection, and eventually
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to hepatic dysfunction. Common in Asia, RPC is now seen with increased frequency in the West due to population migration and travel. Epidemiologic studies implicate infection with biliary helminths, particularly Ascaris and Opisthorchis, but also Fasciola, in the pathogenesis of RPC, with up to 25% of cases having stools positive for parasite eggs. Because RPC is a life-long progressive process, no one surgery results in definitive cure. Stain et al. (1995) proposed a high Roux-en-Y hepaticojejunostomy with a cutaneous jejunal stoma as the ideal surgical procedure. The operation creates an anastomosis between the bile duct, high up near the liver, with a jejunal bowel loop. One end of a divided jejunal loop is brought out to the skin as a stoma, the mid-portion is sutured to the bile duct, and the bottom portion anastomosed to the adjoining jejunum. The term ‘Roux-en-Y’ refers to the Y-shaped appearance of the surgically created bowel loop. The cutaneous jejunal stoma facilitates future instrumentation of the biliary tree for either diagnosis or treatment, a feature not offered by prior surgical approaches to RPC.
11.7. Prevention
Bunnag et al. (2000a) stated that human infection by F. hepatica is prevented by avoiding consumption of watercress salad and, for spurious infection, by thoroughly cooking ingested sheep and goat liver. Control measures include mollusciciding for eradication of snail intermediate hosts, and by anthelmintic treatment of herbivorous animal definitive hosts. Claxton et al. (1998) reported the strategic control of fascioliasis in the Andean Valley in Peru. Fascioliasis is an endemic problem among dairy cattle in this area. Cattle were given two doses of TCZ with the aim of reducing passage of F. hepatica eggs into the pasture environment. The molluscicide niclosamide was applied simultaneously. This double treatment program did not reduce overall parasite prevalence as measured with fecal egg counts. A degree of control was achieved, however, as evidenced by lowered eosinophil and liver enzyme levels in the treated animals, as well as a significant reduction in the number of snail intermediate hosts. Smooker et al. (1999) studied the humoral responses in mice following vaccination with DNA constructs of F. hepatica glutathione S-transferase. Intramuscular injection yielded an IgG2a dominant response, while intradermal injection yielded an IgG1/IgE reponse. Trudgett et al. (2000) noted that rats immunized with β-galactoside fusion protein, a major tegumental antigen of F. hepatica, showed enhanced resistance to challenge infections with the helminth.
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12. SURGICAL TREATMENT FOR PARASITIC INFECTIONS NOT COVERED IN THE TEXT
This section provides information on helminths not discussed in the body of the text. We have listed in Table 1, 23 entries (15 on nematodes, 5 on trematodes, and 3 on cestodes) for which surgery has been considered or used either for diagnosis, treatment, or cure of the disease. Where medical treatment has also been used, mention of this is made. Table 1
Surgical treatment of parasitic infections not covered in text.
Parasite
Disease
Surgical treatment
References
Abdominal angiostrongyliasis in children in the USA
At surgery, findings were thought to represent an atypical presentation of Meckel’s diverticulum
Hulbert et al. (1992)
Anisakis marina
Larval herring worm disease (anisakids) causing severe abdominal symptoms resembling acute appendicitis
Surgical removal of worms from esophagus and stomach
Kark and McAlpine (1994)
Anisakis simplex
Anisakiasis (also known as anasakidosis); a report of 25 cases and a review of the literature
Diagnosis made by gastroscopy, which allows removal of worms and cures the patients
Bouree et al. (1995)
Anisakis simplex
A study of 13 cases of anisakiasis in Spain
All patients with clinical onset as acute abdomen; patients required early surgery, in which a narrowing and inflammatory intestinal segment was observed and subsequently resected
Penas et al. (2000)
Anisakis simplex
A case of chronic anisakiasis as a mesenteric mass
A description of the computed tomographic appearance of a palpable mesenteric mass; first time this mesenteric mass was located by imaging prior to surgery
Cespedes et al. (2000)
Nematoda Angiostrongylus costaricensis
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Table 1 cont. Parasite
Disease
Surgical treatment
References
Capillaria hepatica
Hepatic capillariasis in children in Brazil
Diagnosis made by liver biopsy; surgical treatment not needed; capillariasis resolved by treatment with albendazole or thiabendazole
Sawamura et al. (1999)
Capillaria philippinensis
C. philippinensis causing severe diarrhea in patients in Egypt
Duodenal and jejunal biopsies used to help diagnose the cases; patients treated with mebendazole
Ahmed et al. (1999)
Dirofilaria immitis
Pulmonary dirofilariasis in a 36-year-old Balkan woman
Thoracic biopsy of a welldefined pulmonary mass; mass was thoracoscopically resected and shown to be due to D. immitis on histopathological examination
Narine et al. (1999)
Dirofilaria repens
Orbital dirofilariasis of patients in Italy
Worms removed surgically from ocular regions and identified positively as D. repens based on the PCR
Cancrini et al. (1998)
Dirofilaria repens
Mammary dirofilariasis in a 32-year-old Tunisian woman
Patient treated by surgical resection of the nodule from the breast
Mrad et al. (1999)
Gnathostoma doloresi
Colonic gnathostomiasis in Japan
Colonic resection removed the tumor; parasite found by postoperative histopathologic examination of the tumor
Seguchi et al. (1995)
Gnathostoma spinigerum
Ocular gnathostomiasis in Southeast Asia
Intraocular removal of G. spinigerum by vitrectomy
Biswas et al. (1994)
Oesophagostomum bifurcum
Esophagostomiasis (nodular worm disease) reported in humans from West and East Africa and Asia. Adult worms found in colon, especially cecum.
Surgery to resect region of colon may be necessary. Albendazole and pyrantel pamoate are efficient anthelmintics
Polderman and Blotkamp (1995)
78
D.A. MAYER AND B. FRIED
Table 1 cont. Parasite
Disease
Surgical treatment
References
Onchocerca cervicalis
Zoonotic Onchocerca that caused iritis of the right eye in a female patient in Colorado, USA
Surgical removal of O. cervicalis from the cornea; uneventful recovery with visual acuity, intraocular pressure and corneal edema resolved in 1 week after surgery
Burr et al. (1998)
Onchocerca volvulus
Onchocerciasis or river blindness in tropics
Use of modern surgery to effect cure when cataracts are involved; use of ivermectin for prophalyctic treatment
Narita and Taylor (1993)
Wuchereria bancrofti
Filariasis of a lymph node in a 15-year-old girl in Nepal
Surgical removal of an inguinal lymph node containing a W. bancrofti adult; patient also treated with diethylcarbamazine
Sah et al. (1999)
Patient in Saudi Arabia with acute gallstones and cholangiocarcinoma associated with C. sinensis infection
Surgical removal of common bile duct stones helped alleviate the condition
Alkarawi et al. (1993)
Clonorchis sinensis
Patients with chronic C. sinensis infection are prone to cholangiocarcinoma
Considerations are given for the treatment of primary sclerosing cholangitis to avoid predisposition to cholangiocarcinoma; article includes a discussion of the benefits and risks of the use of orthoptic liver transplantation in such cases
Harrison (1999)
Clonorchis sinensis
Solitary necrotic nodules of the liver in seven cases
Identification of C. sinensis following surgery in liver nodules
Tsui et al. (1992)
Trematoda Clonorchis sinensis
79
HUMAN PARASITES AND SURGICAL INTERVENTION
Table 1 cont. Parasite
Disease
Surgical treatment
References
Gymnophalloides seoi
Gymnophallid trematodiasis in Korea
Scheduled for pancreatectomy to cope with the severe symptoms caused by this parasite in the pancreas and pancreatic duct; problem resolved with praziquantel
Lee and Chai (2001)
Opisthorchis viverrini
Biliary parasites
Article considers situations of parasitic biliary infections from the standpoint of the surgeon; surgery is only indicated in complicated cases
Osman et al. (1998)
Sparganosis of brain and spinal cord in two cases in India
Surgical excision for both cerebral and spinal sparganosis as best treatment
Kudesia et al. (1998)
Spirometra mansoni
A case of intramuscular sparganosis in a Korean man
Surgical excision of the sparganum from a tumor in the sartorius muscle
Kim and Lee (2001)
Spirometra mansoni
A painless lump in the breast of a 47-year-old Chinese woman turns out to be sparganosis
Excision of the plerocereoid larva of S. mansoni from the breast
Chuenfung and Alagaratnam (1991)
Cestoda Spirometra mansoni
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