Effective diagnostic tests and anthelmintic treatment for Strongyloides stercoralis make community...

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PNG Med J 2008 Sep-Dec;51(3-4):

Effective diagnostic tests and anthelmintic treatment for Strongyloides

stercoralis make community control feasible

JENNIFER M. SHIELD1

AND WENDY PAGE2

Aboriginal Resource and Development Services and Miwatj Health Aboriginal

Corporation, Nhulunbuy, Northern Territory, Australia

SUMMARY

Strongyloides stercoralis is endemic in tropical and subtropical countries, and isprevalent particularly in economically impoverished people. Although an estimated 30to 100 million people world-wide suffer from S. stercoralis infection and it is a life-longdisease, it remains a neglected tropical disease. Faecal testing for S. stercoralis is veryinsensitive. The prevalence of S. stercoralis in Indigenous Australians (up to 60%) ismuch higher than previously thought, and its prevalence in Papua New Guinea is likelyto be much higher than currently believed. When S. stercoralis and the HTLV-1 viruscoexist in the one person, both diseases progress more quickly than when either infectionis on its own. When people become infected with S. stercoralis, they develop acutestrongyloidiasis which may be life threatening. At any time during the course of thedisease, if the immune system is suppressed, most often by corticosteroid drugs, infectedpeople may develop hyperinfective strongyloidiasis and they will die unless the underlyingS. stercoralis infection is effectively treated. The use of serology for diagnosis, togetherwith ivermectin treatment, has revealed that it is possible to eradicate S. stercoralis fromthe patient, and serology can also define the effectiveness of treatment. The reservoir ofinfection is humans; the free-living stages are short-lived. Mass treatment may beeffective at eliminating S. stercoralis from a community. Safe water and effectivesanitation alone do not lead to elimination of S. stercoralis. Up-to-date knowledge of S.stercoralis has been revealed through the workshops of the National StrongyloidesWorking Group in Australia and is summarized here. Much of this information is nowavailable on the world wide web, and the addresses of relevant web sites are given.

1 Aboriginal Resource and Development Services, PO Box 1671, Nhulunbuy, Northern Territory 0881, Australiaand La Trobe University, PO Box 199, Bendigo, Victoria 3552, [email protected]

2 Miwatj Health Aboriginal Corporation, PO Box 519, Nhulunbuy, Northern Territory 0881, Australia

Introduction

Strongyloides stercoralis (Bavay 1876)Stiles and Hassal 1902 was first described inFrance by Bavay in 1876 as Anguillulastercoralis. The genus Anguillula waspreoccupied by an eel genus, so in 1879Grassi erected a new genus Strongyloidesfor roundworms previously known asAnguillula. In 1902, Stiles and Hassallshowed that the correct name isStrongyloides stercoralis (1). This species iswidespread particularly throughout tropicaland subtropical areas of the world. Estimatesof the number of people affected vary from

30 to 100 million (2). S. stercoralis occurs inPapua New Guinea (PNG) (3) but its extentis unknown. Surveys by Alan Kelly in the early1970s did not reveal S. stercoralis (4). Itspresence in Morobe Province was revealedin the early 1980s by using a filter paperculture technique (JMS, unpublished data).

S. stercoralis is a nematode tissue parasitethat causes a life-long disease unlesseradicated by treatment (5). It can cause anoverwhelming infection called hyperinfection,or disseminated strongyloidiasis, when aninfected person’s immune system issuppressed (6). Corticosteroids play an

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important role in triggering hyperinfection (7).Other drugs and conditions that suppress theimmune system also lead to hyperinfection,and in about 10% of the cases the cause isnot clear (8). Human T-cell leukaemia virustype 1 (HTLV-1) occurs in some parts of PNGand West Papua (9). Coinfection with S.stercoralis and HTLV-1 causes acceleratedprogression of both diseases (10) andresistance to anthelmintic treatment for S.stercoralis (11,12).

Although disease caused by S. stercoralisis now diagnosable and treatable (5), it hasbeen neglected. It is now classified by theWorld Health Organization as a neglectedtropical disease.

There are a number of reasons why S.stercoralis has been neglected. These areelaborated later. Briefly they are:

• The disease has been difficult todiagnose. The symptoms are non-specific and secondary infection oftenmasks the underlying cause of thedisease. Faecal testing is insensitive.Although the sensitivity of the specificIgG test is high, patients in the acuteor hyperinfective phase of the diseasemay not have the antibodies.Consequently there has been grossunderdiagnosis of the disease, as wellas gross underestimation of itsprevalence and its contribution tomorbidity and mortality. In aretrospective study in Queensland from1998 to 2002, of 120 hospitaladmission records of patients whotested positive for Strongyloides, only6 gave strongyloidiasis as the primarydiagnosis. The primary diagnosis ofthe remaining 114 was one of thefollowing: gastrointestinal disorder,respiratory disorder, failure to thrive,genitourinary disorder, skin disorder orsepsis (13). All these conditions arefeatures of S. stercoralis infection, andit is likely that the true primary causeof disease in these cases was in factS. stercoralis infection.

• The sensitivity of faecal testing is low.Until recently, practitioners have reliedon faecal testing for diagnosis. Thismeans that there has been anunderestimation of prevalence and anoverestimation of the efficacy ofanthelmintic drugs (14,15).

• The disease has been difficult to cure.There was a lack of effective drugs(until ivermectin became available). Inaddition, the ability of the worms tomultiply in the host means that all theworms must be eliminated in order toeffect a cure. So it is important to beable to determine whether a treatedperson has been effectively treated.The IgG diagnostic test has made thispossible (16).

• A mistaken belief that free-living stagesof S. stercoralis persist in theenvironment. In fact, the free-livingstages are short-lived (17,18).

As a result, health authorities have notseen the need to carry out mass treatmentto control S. stercoralis. Australia, in spite ofhaving an excellent health system, has notcome to grips with S. stercoralis in its midst.Although S. stercoralis is rare in mainstreamAustralia, it is hyperendemic throughouttropical and subtropical Indigenous Australia.Estimates of prevalence in variousIndigenous settlements are between 4.5%and 60% seropositive (19-25) and between2% and 41% positive by stool testing(19,26,27). In central Australia, it coexistswith HTLV-1 (28).

In 2001, a group of concernedprofessionals came together at a workshopin Nhulunbuy in the Northern Territory andformed the National Strongyloides WorkingGroup (NSWG) of the Australasian Collegeof Tropical Medicine to investigate S.stercoralis. Since then, the NSWG has heldbiennial National Workshops onStrongyloidiasis in order to share informationabout S. stercoralis and to makerecommendations on how to tackle thedisease. This has resulted in bringingtogether information about S. stercoralis,some of which would not otherwise haveentered the public arena.

What we now know gives us the tools toenable the disease to be controlled. Thispaper will summarize this information andrefer to more detailed material, much of whichis available on the world wide web on theAboriginal Resource and DevelopmentServices web site at http://www.ards.com.au/health_strong.htm or the James CookUniversity web site at http://www.jcu.edu.au/school/phtm/PHTM/ss/.

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Strongyloides stercoralis life cycle

The life cycle is represented schematicallyin Figure 1. It is described in detail by Speare(5) and is available at http://www.jcu.edu.au/school /phtm/PHTM/ss/acrrm-cd/CD-Index.pdf. A patient education flip chart aboutS. stercoralis, the life cycle, the disease, andhow to prevent and treat it, is available in plainEnglish at http://www.ards.com.au/StrongFront.pdf. Infective filariform larvaeare illustrated in Figure 2. There are a

number of features in the life cycle that haveimplications for the treatment of patients andcontrol of the disease.

The parasitic females actively burrowthrough the intestinal absorptive epitheliumcounteracting the movement of epithelial cellsas they migrate towards the tips of the villi(30), and filariform larvae can migrateanywhere in the body (31). Thus S. stercoralisis a tissue parasite in intimate association withthe host.

Figure 1. Schematic representation of the life cycle of Strongyloides stercoralis. Updated and modified fromZaman (29).


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Figure 2. Infective filariform larvae of Strongyloides stercoralis in faeces. Photo: P. Caramello. URL http://www.cdfound.to.it

S. stercoralis has the ability to multiply inthe body by the autoinfective cycle. Somerhabditiform larvae develop into infectivefilariform larvae in the lower part of the gut,and enter the body proper through the side ofthe lower gut or the skin around the anus (5).As a consequence, S. stercoralis causes alife-long disease, and hyperinfection occursparticularly when type 2 immune responsesare suppressed (32). In addition, a person iscured only when treatment has eliminatedevery worm in the body. A single worm mayreestablish a patent infection by theautoinfective cycle.

The infective larvae can migrate anywherein the body (31). So larvae can causesymptoms anywhere in the body, and bacteriacarried by the larvae from the gut may seedsecondary infection anywhere in the body.

S. stercoralis does not persist in theenvironment. There is a maximum of onegeneration of free-living S. stercoralis (33) andthe infective larvae survive for only two weekseven in ideal conditions (34). They are alldead within 3 weeks of faecal contamination.The reservoir of infection is infected people.

Infective filariform larvae have narrowtolerance limits for survival. Their optimumtemperature range is 20 to 28 degrees

Celsius and they die in the refrigerator and inthe heat (5). They die within a few hours ondry soil in the sun and within 3 days on drysoil in the shade (17). So it is essential tostore faecal samples correctly and for as shorta time as possible, particularly when usingdiagnostic tests that depend on the presenceof viable larvae in the faeces.

Strongyloidiasis: progression of thedisease

The three phases of strongyloidiasis

The progression of the disease issummarized in Table 1. There are threephases of strongyloidiasis: acute, chronic andhyperinfective (disseminated).

Acute strongyloidiasis

In the 1950s, Tanaka infected himself withinfective filariform larvae through the skin and,27 days later, rhabditiform larvae firstappeared in the faeces (5). The wormsmultiply in the body, and as the numbersincrease, the symptoms become moreintense. This is acute strongyloidiasis. Inchildren, the infection sometimes causeswasting and hypokalaemia (36). In adults, itsometimes causes dysentery (35). Somemortality may occur at this stage. Eventually

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the immune system responds with type 2immunity (40) that attacks the females in thegut and the larvae migrating through thetissues. The effect on the females is markedreduction in the rate of reproduction (38,41).The immune response slows the migrationof larvae through the tissues, and probablykills some of the migrating larvae (42). Theoverall effect is a reduction of the worm load,but the immune system is not able to eliminatethe worms.

Chronic strongyloidiasis

The infection persists. This has beenshown by studies of World War 2 ex-prisonersof war who acquired S. stercoralis in prisoncamps during the war and had the infectionfor up to 57 years (37,43,44). This phase iscalled chronic strongyloidiasis. The personhas fewer worms, and intermittent symptoms.Infected people remain infected for the restof their life (5).

Hyperinfective strongyloidiasis

In some people, the number of wormscontinues to increase slowly, andhyperinfective strongyloidiasis develops withno obvious cause. Most cases ofhyperinfective strongyloidiasis are associatedwith suppression of the immune system,particularly type 2 immunity. This topic hasbeen reviewed by Keiser and Nutman (32).A study of fatal strongyloidiasis in the literatureshowed that the most common precipitatingfactor was the administration of corticosteroiddrugs (60%) (7,8). Some deaths were dueto other conditions and other drugs thatsuppress type 2 immunity (30%). There wasno obvious cause of hyperinfection in a fewcases (10%) (8). Unfortunately,corticosteroids are sometimes given topatients for respiratory symptoms that areactually due to S. stercoralis larvae migratingthrough the lungs (45,46). An endoscopic andhistopathological study of the duodenum inhyperinfection was published recently (47).

Symptoms

A summary of the symptoms is given inTable 1. The symptoms of S. stercoralisinfection have been described in detail byGrove (37) and summarized by Speare (5).Briefly, the majority of symptoms are non-specific. This is a major impediment todiagnosis of the disease. The severity of thesymptoms varies according to the number of

worms in the body, and which organs areaffected depends on where the larvae havemigrated to. The most frequent symptomsare associated with the skin, digestive systemand lungs, but any other organ may beaffected, including the joints and centralnervous system. Fatigue is common.Secondary infection may make its presencefelt as pneumonia, septicaemia or meningitis,or abcesses in any organ or in the muscles.The only symptom that is pathognomonic forS. stercoralis infection is larva currens. Itconsists of itchy linear urticarial rashes (Figure3) that move at 2 to 10 cm per hour (37).

Immune regulation of S. stercoralisinfection

In chronic strongyloidiasis, the level ofinfection with S. stercoralis is regulated by thetype 2 component of the immune system.IgA, IgM, IgG and eosinophils are lower insevere strongyloidiasis than in mild ormoderate strongyloidiasis (39).

The effects of antibodies on filariformlarvae in the body have been investigated byexperimental work in mice. Both IgG and IgMare important in killing filariform larvae in thebody, but the role of eosinophils is not clear.Brigandi et al. (42) showed that eosinophilsare associated with IgG-mediated killing offilariform larvae in mice. IgM together withcomplement and neutrophils was protectiveagainst filariform larvae (48). Similarly, IgGtogether with complement and neutrophilswas protective against filariform larvae (40).

With respect to the stages in the gut, IgAand IgE play a role in modulating larval output(43), probably by reducing parasitic femalefecundity by impairing their ability to feed andexcrete. When stunted females that were notproducing larvae were taken from immunedogs and transplanted into naive dogs, theyrecovered and reproduced (38).

The level of IgG4 rises in people who havebeen infected with S. stercoralis for a longtime (49). Experimental evidence isconsistent with the hypothesis that IgG4blocks IgE-mediated immune responses (43).

Diagnostic tests

There are two main possibilities fordiagnosing S. stercoralis available inAustralia: examination of faeces forrhabditiform larvae or filariform larvae, and

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examination of the blood for specificantibodies to S. stercoralis. Sputum andduodenal fluid are sometimes examined forS. stercoralis larvae.

Tests are currently being developed in theUSA based on recognizing antigenic materialfrom S. stercoralis in the blood or faeces (50).This may overcome the problem of changingimmune status during the progression of thedisease.

Faecal testing

Faecal testing has high specificity but poorsensitivity. The most sensitive faecal test isthe agar plate culture.

The most common test used is the directsmear. This is a particularly insensitive testfor the early stage of acute strongyloidiasis,for chronic strongyloidiasis and for the earlystages of hyperinfective strongyloidiasis dueto the very low larval output in the faeces.Conway et al. (51) summarized the relativesensitivity of various faecal tests. In thesestudies, the estimated number of peopleinfected was the number positive by any oneof a number of faecal tests. The estimated

sensitivity of the direct smear (3 studies)varied between 0% and 52%, formalin-etherconcentration (3 studies) between 13% and55%, nutrient agar plate culture (5 studies)between 78% and 100%, Harada-Mori filterpaper culture (3 studies) between 7% and58%, and Baermann concentration (1 study)60%. The latter three tests require viablelarvae, and therefore correct handling ofspecimens.

However, the true sensitivity is probablyabout half these estimates, judging bysensitivity estimates in two studies on patientswho had a previous positive faecal test. In astudy using the Baermann technique, 35%were positive by the first examination (14).In a study using the agar plate test, 58% werepositive after one test (15).

People coinfected with HTLV-1 are morelikely to return a positive direct faecal smear.In a study in Japan, 61% of people with bothS. stercoralis and HTLV-1 had a positivedirect faecal smear whereas only 18% ofthose with S. stercoralis and no HTLV-1 hada positive direct faecal smear (52).

It is important to note that an estimate of

Figure 3. Larva currens is pathognomonic for Strongyloides stercoralis infection and consists of itchy linearurticarial rashes that move at 2 to 10 cm per hour. Photo: W. Page.


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sensitivity depends on the mix of patientsbeing tested. If they are mostly in the acuteor hyperinfective phase, then the sensitivityof faecal testing will be higher than if they aremostly in the chronic phase, because thelarval output is higher in severestrongyloidiasis (39). Also, if there are severallarvae per field in a direct smear, it indicatesthat the patient has, or is heading for, severedisease (5).

Implications of the insensitivity of faecaltesting

• The diagnosis of S. stercoralisinfection has frequently been missed.

• People who were considered ‘cured’still had the infection.

• The efficacy of drugs for S.stercoralis infection has beenoverestimated. The efficacy ofthiabendazole has been thought to behigh, but in fact the main effect of thedrug is to inhibit reproduction inparasitic females (53), resulting innegative faecal testing after treatment.

• Grove’s morbidity study (37)underestimated the extent ofsymptoms due to S. stercoralisinfection because some of the ‘control’group were later found to have S.stercoralis (D. Grove, personalcommunication).

• Estimations of the specificity ofserology have been underestimatedbecause false positives were definedas positive serology and negativefaecal testing.

Serum-specific IgG ELISA

The first application of the use of theenzyme-linked immunosorbent assay(ELISA) to detect antibodies to S. stercoraliswas carried out in France in 1978 (54). Thistest was further developed in Australia todetect IgG antibodies to S. stercoralis in 1981(55).

In Australia today, blood testing consistsof the determination of IgG antibodies toStrongyloides ratti antigen in the serum byELISA. It is now routinely available in fourmajor laboratories using a single source ofantigen for routine testing. The sensitivity of

the test is estimated to be 93% and thespecificity 95%. The specificity approaches100% in the mid to high positive range (20).

A commercial kit tests for specific IgGusing a preparation of S. stercoralis filariformlarvae as the antigen. It gives comparableresults (56). Some private laboratories offerthis test.

The sensitivity of the IgG test is probablymuch higher for people with chronicstrongyloidiasis (see Table 1). In a study thatcompared returned travellers with immigrantsfrom areas where S. stercoralis is endemic,the sensitivity of the IgG test was lower intravellers (73%) than in immigrants (98%)(57). The authors did not offer an explanationfor their results. It is likely that the travellershad contracted S. stercoralis recently andsome were still in the ‘window period’ beforedeveloping immunity and producing thespecific IgG antibodies, whereas most of theimmigrants probably had chronicstrongyloidiasis. This would account for thedifference in the two groups.

People with hyperinfection may be negativewith the IgG test, depending on how severelytheir type 2 immune responses aredepressed. In addition some elderly WorldWar 2 ex-prisoners of war with S. stercoralisinfection are negative by the IgG test (WP,unpublished observations).

There have been efforts to improve thespecificity of the test by using monoclonalantibodies. It appears that there is no singleantigen from S. stercoralis larvae that isuniversally recognized by immune sera (58).So perhaps the strength of the current test isthe number of antigenic components in thepreparation used for testing.

Studies in Japan suggest thatStrongyloides serology may be less sensitivein patients infected with HTLV-1. This impliesthat patients with borderline serology shouldbe treated, as is done in central Australia (L.Einsiedel, personal communication).

Strongyloides kellyi, a S. fuelleborni-likespecies of Strongyloides, is endemic only inparts of Papua New Guinea. S. kellyi doesnot have an autoinfective cycle. It is likelythat S. kellyi antibodies would cross-react inthis test (I. Sampson, personalcommunication), but S. kellyi infections arereadily identified by faecal testing. Past work

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on the IgG test indicated that Wuchereriabancrofti, Ascaris lumbricoides, Necatoramericanus and Toxocara canis are unlikelyto cross-react (55).

A major advantage of the IgG test is theopportunity to identify people with chronicstrongyloidiasis so that they can be treatedand relieved of their non-specific symptoms,and not become victims of hyperinfectivestrongyloidiasis at a later date.

Eosinophilia

Eosinophilia defined as >400/µl varies indifferent series between 60% and 90% (59).57% of patients with S. stercoralis at RoyalDarwin Hospital from mid-1991 to mid-1992had eosinophilia (60). Eosinophilia is alsopresent in people infected with otherhelminths, so it is not a reliable test for S.stercoralis.

Value of the IgG test in monitoring theeffectiveness of treatment

The value of the IgG test has been thesubject of debate among medicalpractitioners in Australia. It was mistakenlybelieved that a positive IgG test does notdistinguish between past and currentinfection. Though this is true for viralinfections, it is not true for parasitic infections.People treated with anthelmintic drugs oftenreturned a negative faecal test, and thepractitioner then erroneously assumed thatthe person was cured, and a positive IgG testwas assumed to be past infection rather thanfailure of treatment

The advent of the drug ivermectin enabledthe clarification of the value of the IgG test(16). An Australian Indigenous medical clinicinstituted a monitoring program based on theidentification of strongyloidiasis using the IgGtest followed by treatment with albendazolefor three days, and then retesting severalmonths later. They found that although thetest results showed lower IgG levels aftertreatment, most did not become negative(22). This result was disappointingly similarto earlier studies using thiabendazole (61-63)or albendazole (63,64) as the anthelmintic.Then they used ivermectin (200 ìg per kgbody weight) as the anthelmintic treatment.On retesting after six months, most of thepatients treated with ivermectin werenegative by the IgG test. Thus the value ofthe IgG test for diagnosis and the efficacy of

treatment with ivermectin were clarified at thesame time. In addition, the value of the IgGtest in monitoring the effectiveness oftreatment was established (16). Since thattime, these conclusions have been confirmedduring a community control program inanother Indigenous community (23).However, there are some patients who testnegative by the IgG test who may still have afew worms and later the symptoms recur(WP, unpublished observations).

Anthelmintic treatment

Effects of anthelmintics on S.stercoralis

David Grove and others conducted anumber of studies examining the effect ofanthelmintic drugs on migrating larvae andparasitic adults of S. ratti (53). The effects ofthe drugs on S. stercoralis in people are likelyto be similar. The results are summarized asfollows:

• Ivermectin: there is dose-dependenteradication of adults in the gut andlarvae in the tissues, and survivinglarvae do not mature.

• Albendazole: there is also dose-dependent eradication of adults in thegut and larvae in the tissues.

• Thiabendazole does not kill adultworms but reduces larval output; it hasno effect on larvae in the tissues.

• Cambendazole eliminates adults andlarvae.

• Mebendazole kills adults but notlarvae, and is between 100 and 1000times less effective thancambendazole.

Of these drugs, thiabendazole is no longercommonly used because of the side-effectsof nausea and neuropsychiatric symptoms.There were a number of trials ofcambendazole during the early 1980s, but itwas withdrawn from the market by themanufacturer because of rare severereactions in cattle (61). Mebendazole iscompletely unreliable (61). Albendazole 400mg for 3 days is commonly prescribed. Theestimated efficacy of this regimen was 38%compared with 83% for ivermectin (65). This


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is probably an overestimate for both drugsbecause it relied on faecal testing for definingcure. The estimate of Archibald et al. of theefficacy of albendazole at 400 mg twice dailyfor 3 days was 75% (66). Their definition ofcure was all of three criteria: negative faecaltest, negative IgG test and no symptoms. Inanother study, the efficacy of one dose ofivermectin at 200 ìg per kg body weight was68% and of ivermectin followed by a secondcourse of either ivermectin or albendazolewas 83%, using a negative IgG test alone asthe criterion for cure (16).

One of the problems of albendazoletherapy is that it must be taken on threeconsecutive days. This makes it difficult toensure that all the doses have been taken.An advantage of ivermectin is that a courseis one dose, so the health professional candirectly observe that the drug has beenswallowed.

Absorption of anthelmintics

Both albendazole and ivermectin arelipophilic and are best taken with a fatty foodsuch as full-cream milk (67). Ivermectin maybe poorly absorbed in the fasted state in acritically ill patient (68).

Resistance to anthelmintic treatment

Two studies of patients who had beentreated by two courses of ivermectin and thenfollowed up indicated that 17% and 16%respectively were still IgG positive six monthsafter treatment (16,23). If still positive afterretreatment, they may be resistant totreatment and should be treated on a regularbasis (41,69).

Resistance of S. stercoralis to treatmentwith albendazole is associated with elevationof the S. stercoralis-specific IgG4 antibodytitre at the expense of IgG1 (70). IgG4 isthought to block IgE-mediated responses inhuman strongyloidiasis (43).

Patients who are immunosuppressed(71,72) as well as HTLV-1 patients(11,12,73,74) are frequently resistant totreatment.

Safety of ivermectin

Ivermectin affects gamma-aminobutyricacid (GABA)-mediated nerves. In manyinvertebrates including roundworms, muscle

contraction is controlled by GABA-mediatednerves, and ivermectin causes paralysis. Inmammals, such nerves occur only in thecentral nervous system, and the blood-brainbarrier prevents ivermectin from entering thebrain. People with conditions that maycompromise the blood-brain barrier may beat risk of an adverse reaction when treatedwith ivermectin (5).

In general, ivermectin is a very safe drug(75). Its safety for very young children andpregnant women has not been establishedconclusively, so it should not be used routinelyin these groups. If there is a clinical need touse ivermectin, it should be considered on acase-by-case basis. Data collected so farsuggest that it is safe. During theoncocerciasis trials in Africa, some pregnantwomen were treated inadvertently. When theoutcomes of these pregnancies werecompared with the outcomes in those whowere not treated, there was no significantdifference between the two groups (76).

Ivermectin should be used with caution inpeople who may be coinfected with the eyeworm Loa loa. This species is endemic inparts of Africa. Individuals with high densitiesof L. loa microfilariae have developed seriousadverse effects when treated with ivermectin,and some have died (77).

Coinfection with HTLV-1

The rate of S. stercoralis infection issignificantly higher in patients with HTLV-1infection than in patients without HTLV-1infection (74,78).

HTLV-1 is associated with an exacerbatedtype 1 immune response. Coinfection withS. stercoralis or Schistosoma mansonidecreases the activation of type 1 cells, whichmay influence the outcome of HTLV-1infection (79). Helminths including S.stercoralis induce a type 2 response. HTLV-1 decreases the type 2 immune response thatis effective against S. stercoralis (10), leadingto hyperinfective strongyloidiasis.

HTLV-1 causes decreased levels of IgEand eosinophils, both of which are importantin the immune response to S. stercoralis (74).The high production of IFN-ã observed inpatients coinfected with HTLV-1 and S.stercoralis (73,80) decreases the productionof IL-4, IL-5, IL-13 and IgE, molecules thatparticipate in the host defence mechanism

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against helminths (80). Although coinfectionwith HTLV-1 was associated with a decreasein levels of IgE and skin sensitivity, it did notaffect the levels of IgG (10).

HTLV-1 patients are frequently refractoryto anthelmintic treatment. Resistance totreatment with albendazole has beenassociated with high levels of serum IFN-ãand TGF-â-1 (73). Similarly, resistance totreatment with ivermectin by HTLV-1-positivepatients has been demonstrated (11). Thisis probably due to impairment of immunity toS. stercoralis in people coinfected with HTLV-1.

Transmission

Aspects of the life cycle and transmissionof S. stercoralis and also effective controlmeasures are well understood, and havebeen summarized by Feachem et al. (81),except that it is now known that there is amaximum of one free-living generation (33),and the stages in the soil are short-lived, about2 weeks (34). Galliard showed in the 1950sthat the worms die within a few hours in theopen, or 2 to 3 days in the shade if the soil isdry (17).

Transmission may be indirect, by contactwith infective filariform larvae on damp soilor damp vegetation, or direct, by faecalcontamination of the skin. With rareexceptions, larvae in direct faecal smears arerhabditiform. Infective filariform larvae areobserved rarely (82,83), and these can bepassed on to others by faecal contamination.

There is evidence that transmission ofinfection occurs indoors. There have beenreports of high rates of infection with S.stercoralis in mental institutions in USA,Canada, USSR and Chile (18) and ofclustering of people infected with S. stercoralisin households in Jamaica (84) andBangladesh (85). Transmission in thesecircumstances could be either direct orindirect.

Community control

The reservoir of infection with S. stercoralisis infected people. Its free-living stages areshort-lived and sensitive to heat, cold anddrying. This means that treatment of peoplehas the potential to eliminate this species fromthe community. Prociv (26) found that, inchildren of an Australian Indigenous

community, prevalence of S. stercoralis wasreduced from 26% to below 6% six monthsafter thiabendazole treatment. This level wassustained for at least the ensuing three years.He concluded that sustained chemotherapywould have eliminated S. stercoralis from thecommunity without any change in livingconditions.

In situations where there is safe water,effective sanitation and good personalhygiene, an infected person does not passon the infection. This has been shown to betrue in a study of ex-prisoners of war infectedwith S. stercoralis during World War 2, noneof whom gave the infection to their wives (86).

Specific IgG testing is valuable inidentifying people with chronic strongyloidiasisin the communities where it is endemic,because in this situation most infected peoplehave the chronic form of the disease.

Community control should take place in theoverall context of other diseases that arepresent in the community. In Papua NewGuinea, other parasitic diseases includePlasmodium spp, Wuchereria bancrofti,Strongyloides kellyi, Necator americanus,Ascaris lumbricoides, Trichuris trichiura,Sarcoptes scabiei and enteric protozoa. Forexample, ivermectin treatment should beeffective against Strongyloides spp, W.bancrofti and Sarcoptes scabiei, andalbendazole for three days is effective againstA. lumbricoides, N. americanus and T.trichiura. Because A. lumbricoides and T.trichiura are persistent in the environment, on-going treatment would be required toeliminate these from the community.

Conclusion

It is now possible to diagnose and treatStrongyloides stercoralis infection. Thismeans that it is possible to identify peoplewith chronic strongyloidiasis and treat themso that they can be relieved of their non-specific symptoms and not become victimsof hyperinfective strongyloidiasis at a laterdate.

Recent studies have shown the value ofIgG ELISA serology for identifying people withStrongyloides infection and monitoring theeffectiveness of anthelmintic treatment. Theyhave also shown that past treatments havebeen ineffective and that ivermectin is themost effective and expedient treatment


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available, particularly when two courses aregiven.

Failed treatment can usually be identifiedby retesting with the serum IgG test sixmonths after treatment. Those who return atest that is not low or negative should beretreated. This process can be used toidentify people who are resistant to treatment.

Longer-term retesting perhaps at twoyears, or self-referral when the symptomsreturn, may be able to identify the few whoare negative six months after treatment butare still infected. For this reason, anyone whohas ever tested positive for S. stercoraliscould still have the disease. They shouldreceive prophylactic anthelmintic treatmentbefore being given corticosteroids or any othermedication that depresses the immunesystem.

HTLV-1 patients, those onimmunosuppressant drugs and others whoare resistant to treatment should receiveanthelmintic treatment on a regular basis.

Because the free-living stages are short-lived, it is possible to achieve communitycontrol by mass treatment with ivermectin.Safe water and good sanitation alone are notsufficient to eradicate S. stercoralis.

ACKNOWLEDGEMENTS

The National Strongyloides WorkingGroup and Professor Rick Speare havemade possible the collection of informationthat comprises this paper. We thank DrPietro Caramello, editor of the CD FoundParasitology Atlas 2000 web site, forpermission to use his photograph of S.stercoralis filariform larvae and Greg Stehleand Ella Fairbairn for preparing the life cyclediagram.

This paper is dedicated to the memory ofDr Helena Vrbova.

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