Strongyloidiasis – the most neglected of the neglected tropical diseases?

ARTICLE IN PRESS+ModelTRSTMH-1159; No. of Pages 6

Transactions of the Royal Society of Tropical Medicine and Hygiene (2009) xxx, xxx—xxx

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REVIEW

Strongyloidiasis — the most neglected of theneglected tropical diseases?

Annette Olsena,∗, Lisette van Lieshoutb, Hanspeter Marti c, Ton Poldermanb,Katja Polmand, Peter Steinmanne,f, Russell Stothardg, Søren Thyboh,Jaco J. Verweijb, Pascal Magnussena

a DBL-Centre for Health Research and Development, University of Copenhagen, Copenhagen, Denmarkb Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlandsc Department of Medical and Diagnostic Services, Swiss Tropical Institute, Basel, Switzerlandd Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgiume Department of Public Health and Epidemiology, Swiss Tropical Institute, Basel, Switzerlandf National Institute of Parasitic Diseases, China CDC, Shanghai, People’s Republic of Chinag Department of Zoology, Natural History Museum, London, UKh Department of Epidemiology, Rigshospitalet, Copenhagen, Denmark

Received 29 December 2008; received in revised form 17 February 2009; accepted 17 February 2009

KEYWORDSStrongyloidesstercoralis;Diagnosis;Morbidity;Treatment;Control;Neglected tropicaldisease

Summary Soil-transmitted helminths of the genus Strongyloides (S. fuelleborni and the moreprevalent S. stercoralis) are currently believed to infect an estimated 30—100 million peopleworldwide. The health consequences of S. stercoralis infections range from asymptomatic lightinfections to chronic symptomatic strongyloidiasis. Uncontrolled multiplication of the parasite(hyperinfection) and potentially life-threatening dissemination of larvae to all internal organsis found among individuals with compromised immune system functions. This paper providesan overview of the current state of the art in relation to diagnostic methods for detecting theinfection, the morbidity caused by the infection and the recommended treatment. It furtherdiscusses some of the reasons why this infection is so neglected and the consequence of thisfor the estimated global prevalence. The paper finally points to the gaps in our knowledge and

Please cite this article in press as: Olsen A, et al. StrongyloidiasTrans R Soc Trop Med Hyg (2009), doi:10.1016/j.trstmh.2009.0

future research needs related to this infection. As Strongyloides infections have the potential todevelop into severe disease in certain population subgroups, untreated infections could causeserious problems in the community. Therefore, we need to carefully investigate this parasitein order to develop and implement effective control programmes.© 2009 Royal Society of Tropicareserved.

∗ Corresponding author.E-mail address: [email protected] (A. Olsen).

0035-9203/$ — see front matter © 2009 Royal Society of Tropical Medicindoi:10.1016/j.trstmh.2009.02.013

is — the most neglected of the neglected tropical diseases?2.013

l Medicine and Hygiene. Published by Elsevier Ltd. All rights

e and Hygiene. Published by Elsevier Ltd. All rights reserved.

dx.doi.org/10.1016/j.trstmh.2009.02.013

mailto:[email protected]


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. Introduction

oil-transmitted helminths of the genus Strongyloidesurrently infect an estimated 30—100 million peopleorldwide.1 At least two species parasitize humans —. fuelleborni and the more prevalent S. stercoralis.2,3

trongyloides fuelleborni is a zoonosis that usually occurs inon-human primates, but human infections occur in Africand Southeast Asia. Strongyloides stercoralis is an intestinalematode that infects humans percutaneously. It is com-on in many areas where sanitary conditions are poor,4

nd where the climate is warm and humid. However, thearasite is also endemic in several subtropical and temper-te regions, e.g. southern areas of the USA, Europe andapan. The ability of S. stercoralis to replicate within theost (autoinfection) leads to persistent infections and canesult in chronic disease with a wide variation of clinicalanifestations. Uncontrolled multiplication of the parasite

hyperinfection) and potentially life-threatening dissemi-ation of larvae to all internal organs are found amongndividuals with compromised immune system functions.part from parasitizing the vertebrate intestine, the lifeycle of these nematodes can also include one or moredepending on the species) free-living generations, leadingo important epidemiological consequences.

At the Third Global Meeting of the Partners for Parasiteontrol, held at WHO headquarters in November 2004, itas recommended that measures for the control of Strongy-

oides should be included in health packages targeting areashere the infection is endemic.5 Today, more than 4 years

ater, no action has been taken and no specific measuresave been implemented. One of the probable reasons is theack of even basic data on Strongyloides endemicity andpidemiology. We also do not know to what extent exist-ng soil-transmitted helminth and lymphatic filariasis controlrogrammes affect the epidemiology of Strongyloides, ashe demonstration of this parasite requires special detec-ion methods, which usually fall outside the scope of theserogrammes.

As Strongyloides infections have the potential to developnto severe disease in certain population subgroups,ntreated infections could cause serious problems in theommunity. We therefore feel that we have to take actionow and carefully investigate this parasite in order toevelop and implement effective control programmes.

. Presentation of the parasite

he genus Strongyloides contains more than 50 species withn almost equally wide range of hosts. At least two speciesre known to infect humans.

Strongyloides fuelleborni primarily infects various pri-ates in Africa and Southeast Asia but has also been found in

umans. Thus, the parasite is zoonotic or, at least, zoonoticn its origin.6 Strongyloides fuelleborni eggs can be foundn stool and although the question of autoinfection is still


ot resolved, it probably does not occur in persons withgg-passing infections.6

The cosmopolitan S. stercoralis occurs in over 70 subtrop-cal and tropical countries, but is also endemic in severalemperate countries where conditions are favourable. For

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PRESSA. Olsen et al.

xample, S. stercoralis infections are, together with hook-orm infections, the only officially recognized occupationalarasitic health hazard for miners in Germany.7 The para-ite infects humans, other primates and dogs. Strongyloidestercoralis has a complex life cycle including a direct, anutoinfective and a non-parasitic free-living developmen-al cycle (Figure 1). Only parasitic females are found inhe host where they are embedded in the submucosa ofhe duodenum and parthenogenetically produce dozens ofmbryonated eggs a day. These hatch in the gut lumen of theost and the first-stage larvae are passed out in faeces andither develop into infective third-stage larvae or into free-iving adult males and females. Alternatively, larvae mayevelop to the third stage still within the gastrointestinalract and penetrate the intestinal mucosa or perianal skin,estarting a new infection cycle without ever leaving theirost. The free-living adults reproduce sexually and the off-pring develop into infective third-stage larvae. There existsnly one free-living generation of S. stercoralis.8 Third-stagearvae are able to penetrate the skin of the human host,each the lungs via the blood circulation and enter the respi-atory pathways, from where they migrate upwards throughhe trachea to be swallowed and finally reach the smallntestine where they mature into adult egg-laying females.

. Diagnosis and global epidemiology oftrongyloides

tandard parasitological diagnostic methods for detecting S.tercoralis infection are concentration techniques or stoolulture methods.9 However, these methods are laborious,ime consuming, and, in the case of stool cultures, need wellrained technicians in order to differentiate S. stercoralisrom hookworm larvae. Several immunological tests, suchs ELISA, IFAT and Western blot, have also been describedor the diagnosis of strongyloidiasis.10,11 These assays showariable sensitivity and specificity depending on antigenreparation and immunoglobulin isotypes used, and on theopulation tested. In specific target populations, such asmmigrants to non-endemic regions, serology has proven toe a valuable tool for screening and for the evaluation ofherapies;12 however, serology seems to lack sufficient sen-itivity to diagnose recently acquired infections.13 Althougherology seems to have good negative predictive value ifsed in endemic areas,14 specificity appears to be moreroblematic as pronounced crossreactivity is observed withther helminths, especially filaria. Specific detection oftrongyloides DNA in human stool samples by real-time PCRas recently been suggested to be a promising alternativeiagnostic approach, but needs further exploration.

The current estimate of 30—100 million Strongyloidesnfections in humans1 is likely to be too low. To achieve aeliable estimate of the true prevalence of infection, sev-ral stool samples should be collected over consecutive daysnd tested by various diagnostic methods. In a population-ased study in China, combining diagnostic approaches and


epeated examinations resulted in an unexpectedly highrevalence of 11.7%.15 Using a similar approach, Strongy-oides was shown to be a very common parasite (prevalence0.6%) in northern Ghana.16 In a recent study in Mozambiqueunpublished data) careful examinations of direct smears


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Strongyloidiasis 3

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Figure 1 The life cycle of Strongyloid

and formol ether concentration sediments showed 9% and12% of the population to be infected, while a combination ofculture, Baermann concentration and PCR revealed a preva-lence of 48%.

4. Morbidity caused by Strongyloides

The health consequences of S. stercoralis infections rangefrom asymptomatic light infections to chronic symptomaticstrongyloidiasis involving anything from mild gastrointesti-nal morbidity to severe life-threatening conditions. Thepathology due to chronic uncomplicated S. stercoralisinfections includes pruritus, skin eruptions, larva currens,abdominal pain, diarrhoea, nausea and weight loss.17

The most severe effects of Strongyloides infectionsoccur in patients receiving immunosuppressive therapy withcorticosteroids.18—21 In these patients, the immune systemis no longer able to keep the larvae emerging from the


autoinfective cycle under control, resulting in hyperinfec-tion affecting the proper functioning of the gastrointestinaltract or the dissemination of larvae to multiple organsincluding the brain. Such massive infections may leadto life-threatening conditions with pneumonia, meningitis,

ssiit

ercoralis. Drawing by A.M. Polderman.

epticaemia and intestinal obstruction.17 The mortality ratef disseminated infections has been estimated to be asigh as 87%.22 Immunosuppression with Cyclosporine A is notnown to have such devastating effects.23

In many parts of the world strongyloidiasis occursogether with HIV/AIDS, but co-infection has not been foundo be associated with higher S. stercoralis prevalence orhe development of hyperinfections.24 However, S. sterco-alis hyperinfection has been described in AIDS patients asart of the immune reconstitution syndrome after startingighly active antiretroviral therapy.25 In a study in Tanzanianvolving HIV-infected pregnant women, S. stercoralis infec-ion was associated with a higher risk of low birth weight,hich is the single most important factor for high infantortality.26 In contrast, human T cell lymphotropic virus

ype 1 infection is strongly associated with a higher S. ster-oralis prevalence as well as with an increased incidence ofyperinfection.27—29

Although there is a pronounced association between dis-


eminated strongyloidiasis and suppression of the immuneystem, there are also a significant number of fatal casesn the literature which could not be linked to any knownmpairment of the immune system.30 They have tenta-ively been explained by host factors of intestinal parasite


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ontrol which act at the interface between the host andhe parasite, i.e. the mucosa of the gastrointestinal tract,nd are mediated by some local control mechanisms. Inmpoverished populations where subclinical malnutrition isommon, profound morphological disruption of the smallntestinal mucosa is highly prevalent. These changes mayave functional repercussions on the hosts’ ability to fightff infections.31 This hypothesis might also explain whyevere complicated strongyloidiasis with no clinical evi-ence of immunosuppression is more frequently observed inersons living in developing countries. Malnutrition, one ofhe most important causes of immunodeficiency in devel-ping countries, was found to be associated with severetrongyloidiasis.30 Autoimmune diseases such as diabetesellitus may exacerbate complications and impact on the

everity of Strongyloides infection.32

. Treatment

he recommended treatment for strongyloidiasis is eithervermectin (200 �g/kg body weight in a single dose) or alben-azole (400 mg daily for 3 days).33,34 In a study in Zanzibar,he effect of the two regimens was compared. A cure ratef 82.9% was achieved for ivermectin while three doses oflbendazole cured 45.0% of the infected individuals.33

Most helminth control programmes employ mass drugdministration as their principal tool; hence, they offerreatment without prior diagnosis. For control of soil-ransmitted helminths, the target population is usuallychoolchildren, but regular (e.g. annual) mass treatmentf entire communities using one of the four common ante-elminthic compounds included in the WHO model list ofssential drugs is recommended wherever the prevalence is50%.35 In areas where schistosomiasis is co-endemic withoil-transmitted helminths, praziquantel (40 mg/kg bodyeight) is co-administered with albendazole (400 mg singleose) or mebendazole (500 mg single dose), again mainlyo schoolchildren. In areas targeted for lymphatic filaria-is control, albendazole (400 mg single dose) and ivermectin150 �g/kg body weight) or diethylcarbamazine (wherenchocerciasis is not endemic) are given to the entire popu-ation above 4 years old. To minimize costs, collaborationetween the programmes is encouraged and is currentlymplemented in many countries.36 Thus, in areas wherechistosomiasis and lymphatic filariasis are both endemic,lbendazole plus ivermectin followed by praziquantel 1eek later is the preferred regimen. Among all these reg-

mens, only the distribution of ivermectin in the frame ofymphatic filariasis control can be expected to result in aeaningful reduction of the prevalence of S. stercoralis. In

reas with strongyloidiasis, targeted chemotherapy of highisk groups should be considered. As a minimum, all patientscheduled to receive corticosteroids should be given preven-ive anthelminthic treatment if they live in or have travelledn potential endemic areas.21


. Why is Strongyloides infection soeglected?

he prevalence of S. stercoralis is thought to be severelynderestimated due to the low sensitivity of the currently

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vailable diagnostic tools and a dearth of specialized sur-eys. The most widely used method for the identificationf human intestinal helminth infections in developing coun-ries, i.e. the Kato-Katz technique, detects eggs in faecesut fails to demonstrate larvae. The performance of stan-ard procedures like formol-ether concentration methodss limited by the low concentration of larval stages in fae-al specimens in chronic strongyloidiasis. Parasite-specificoncentration methods like the Baermann technique andulture methods9 are much more sensitive, but even withhe use of these methods many light (chronic) infectionsre missed. Therefore, S. stercoralis infections are seldometected and many areas without information persist on thelobal S. stercoralis distribution map. Thus, the epidemio-ogical knowledge regarding this parasite is patchy at best.nly in patients with disseminated strongyloidiasis may largeumbers of larvae be demonstrated in faeces, sputum, urinend lung fluids as well as in organ biopsies. Chronic uncom-licated S. stercoralis infections also cause subtle pathology,hich is non-specific for this infection. Therefore, the infec-

ion often remains undiagnosed.

. Gaps in knowledge — future research needs

t is encouraging that the Partners for Parasite Control rec-mmend that Strongyloides infections should be includedn health packages wherever it is endemic.5 Today, thenfection is only targeted passively — and, presumably, notffectively — in the framework of integrated helminth con-rol programmes. The notion that an additional parasite cane controlled by these programmes may lead to a betterost-effectiveness rating of such programmes and, once thepidemiology and public health significance of strongyloidi-sis has been determined, to better acceptance. Thus, thepecific impact of these programmes on S. stercoralis awaitsareful evaluation. For example, we do not know how theurrently used drug regimes influence the course of infec-ion. The drug dosages are suboptimal especially in areashere lymphatic filariasis is not endemic and therefore iver-ectin is not used. One dose of albendazole will usually not

lear the infection. This is of particular concern becausehe parasite replicates within the host. The residual para-ites may represent a proportion of the population whichs more refractory to the drug. It is therefore possible thatesistance will develop and become established.

Many epidemiological aspects of Strongyloides infectionre unknown or only poorly understood. We do not known detail where Strongyloides is endemic, which prevalenceates and intensities can typically be expected in differentettings and populations, the zoonotic aspects, geographi-al variations, e.g. in transmission and clinical presentation,ost immunity and the risk factors for dissemination, andocial, cultural, ecological and environmental aspects.

Improvement and simplification is needed in the con-entional diagnostic methods, to facilitate epidemiologicaltudies of S. stercoralis in the field. There also is an urgent


eed to employ modern molecular methods to improve diag-osis and for the differentiation between species and strainsrom different hosts and geographical origin. It should alsoe established if we are dealing with a species complex orlearly defined biological species.


IN
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Strongyloidiasis

Little is known about the true clinical relevance ofStrongyloides infections, the symptoms associated withdifferent infection patterns, the association betweenStrongyloides and other infectious diseases, and of therelationship between severe infections and autoimmune dis-eases such as diabetes. The relevance of malnutrition forStrongyloides, especially among children, and the effectsof the resulting state on the clinical outcome of S. sterco-ralis infection as well as implications for pregnant womenstill need to be revealed.

It is uncommon for helminths to kill their host and inhealthy individuals, S. stercoralis usually causes little or‘only’ subtle pathology, allowing the infection to remainundiagnosed — and untreated — for years. Thus, the par-asite can persist in the host, perpetuating parasite dispersaland the risk of infection among the community. Given thetendency to develop severe disease in certain populationsubgroups, S. stercoralis is of major public health concern.Furthermore, since the use of immunosuppressive therapybecomes increasingly common in transition economies likeChina, India, Southeast Asia and Latin America, Strongy-loides could cause serious problems in the future if we donot take action now. We need to carefully investigate thisparasite, develop control programmes and implement themwhere appropriate.

Funding: None.

Conflicts of interest: None declared.

Ethical approval: Not required.

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Strongyloidiasis – the most neglected of the neglected tropical diseases?