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Occurrence of and risk factors for Strongyloides stercoralis infection in South-East Asia Fabian Schär a,b,∗ , Federica Giardina a,b , Virak Khieu a,b,c , Sinuon Muth c , Penelope Vounatsou a,b , Hanspeter Marti b,d , Peter Odermatt a,b a

Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland c National Center for Parasitology, Entomology and Malaria Control, Ministry of Health, Phnom Penh, Cambodia d Medical and Diagnostics Department, Swiss Tropical and Public Health Institute, Basel, Switzerland b

a r t i c l e

i n f o

Article history: Received 14 August 2014 Received in revised form 4 March 2015 Accepted 6 March 2015 Available online xxx Keywords: Strongyloides stercoralis South-East Asia Prevalence Risk factors

a b s t r a c t The soil-transmitted nematode, Strongyloides stercoralis is one of the most-neglected of all neglected tropical diseases. It is globally distributed, favouring the humid, wet climates of the tropics and subtropics. Inadequate sanitary conditions promote the spread of S. stercoralis infection. In South-East Asia, many countries provide the ideal ecological and economic setting for high S. stercoralis infection rates. Yet, in most of these countries, little is known about the actual prevalence and distribution of S. stercoralis. One reason for this lack of knowledge pertains to the time- and resource-intensive diagnostic methods used to detect S. stercoralis infection. The Koga Agar culture method and the Baermann method are considered to be the best coprological diagnostic methods for field settings today. Both detect the parasite with high sensitivity. This sensitivity can be increased further by examining stool samples for several consecutive days, thereby increasing the chances of detecting low-intensity chronic infections. Diagnostic challenges, however, lead to the omission of S. stercoralis in studies of soil-transmitted helminths and few studies focus on S. stercoralis, specifically. These factors lead to an underreporting of the nematode’s prevalence, not only in South-East Asia but worldwide. We have reviewed the scientific literature of the last 25 years and estimated country-wide prevalence rates for South-East Asia. We aim to summarise what is known today about the prevalence of S. stercoralis in South-East Asia, as well as to ascertain the risk factors and diagnostic methods most commonly applied. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Infection with Strongyloides stercoralis, the soil-transmitted nematode, is one of the most-neglected of all neglected tropical diseases (NTDs) (Olsen et al., 2009). It occurs world-wide, but higher infection rates occur in tropical climates where favourable ecological, socio-cultural and economic conditions (low sanitary standards and poor hygiene) prevail (Schär et al., 2013b). More than 50% of S. stercoralis infections are asymptomatic and most of them are chronic (Concha et al., 2005). Immunosuppressed hosts with disseminated hyperinfections have a very high mortality rate (Siddiqui and Berk, 2001). S. stercoralis infective larvae are found in faecally-polluted, moist soil. Larvae penetrate the intact human skin. Walking barefoot

∗ Corresponding author at: Swiss Tropical and Public Health Institute, Postfach, 4002 Basel, Switzerland. Tel.: +41 61 284 87 73. E-mail address: [email protected] (F. Schär).

and/or occupational exposure to soil (e.g. farming) are known risk factors for infection (Grove, 1989). A unique feature of S. stercoralis is autoinfection, which refers to the immediate re-infection of the host in the peri-anal skin area. Autoinfection may lead to persistent, long-lasting S. stercoralis infections of up to 75 years (Prendki et al., 2011). Today, control programmes for helminthic infections mainly target the three major soil-transmitted helminthic infections (STHs), namely Ascaris lumbricoides, Trichuris trichiura and the hookworms (Necator americanus and Ancylostoma duodenale). Unlike S. stercoralis, they are detected with the Kato Katz diagnostic method. For S. stercoralis, more time- and labour-intensive diagnostic methods are needed, such as copro-cultures (Koga Agar or Baermann method). There are also serological diagnostic methods available but applying distinct diagnostic antigens there can be a risk of cross-reactivity with other helminthic antigens and thus the prevalence may be over-reported. The more recently developed luciferase immunoprecipitation system (LIPS) assay using a recombinant antigen (NIE) appears species specific, yet needs to be tested

http://dx.doi.org/10.1016/j.actatropica.2015.03.008 0001-706X/© 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Schär, F., et al., Occurrence of and risk factors for Strongyloides stercoralis infection in South-East Asia. Acta Trop. (2015), http://dx.doi.org/10.1016/j.actatropica.2015.03.008

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on a larger scale (Krolewiecki et al., 2010; Ramanathan et al., 2008). Further there are molecular diagnostic methods available, mainly the polymerase chain reaction (PCR). The PCR showed good sensitivity in proven cases of S. stercoralis, yet feasibility of the use of PCR in field settings is still limited (Kramme et al., 2011; Schär et al., 2013a; Verweij et al., 2009). S. stercoralis is equally neglected in mass-drug administration (MDA) programmes that combat these infections. In South-East Asia (SEA), climatic, ecological and socioeconomic conditions are ideal for the transmission of S. stercoralis. Yet, information on its occurrence is relatively scarce (Schär et al., 2013b). The objective of this study is to review existing knowledge on the occurrence of and risk factors for S. stercoralis in SEA over the last 25 years.

2. Methods 2.1. Literature search and data extraction We conducted a systematic literature review of all peerreviewed research articles published over the last 25 years, i.e. between January 1989 and June 2014. Papers were identified in PubMed by using the search terms “Strongyloides” or “Strongyloides stercoralis” or “strongyloidiasis” and the country name (Brunei, Cambodia, China, Indonesia, Lao People’s Democratic Republic/Lao PDR/Laos, Malaysia, Myanmar/Burma, Philippines, Singapore, Thailand and Vietnam). Studies were included if they contained information on prevalence of and/or risk factors for S. stercoralis infection, either among the general population or among subgroups. We excluded articles that were not written in English, Spanish, Portuguese, French or German language; that referred to specific bio-molecular laboratory research aspects of S. stercoralis or to infection in animals; and that did not provide additional information on the prevalence and/or risk of S. stercoralis infection. For each article, the following information was recorded: country, exact location (if indicated), number of infected individuals, number of examined individuals, risk factors (specific risk group or control group), diagnostic procedures used (copro-diagnostic, serological methods, etc.) and year of study.

2.2. Statistical analysis S. stercoralis prevalence among the general population and among risk groups was analysed. A Bayesian model for metaanalysis that included the diagnostic-test sensitivity (Schär et al., 2013b) was formulated and implemented in WinBUGS 1.4 (Lunn et al., 2000). Model-based prevalence estimates for each country was plotted on a world map, using ArcGIS (version 9.3). The Bayesian models employed in this study estimated the disease prevalence together with the diagnostic sensitivity. Information about the sensitivity of the different diagnostic tools used was derived from the literature and was used to categorise diagnostic procedures into one of three sensitivity groups (Schär et al., 2013b). We assigned a range of sensitivity based on the lowest and the highest sensitivity reported. The three groups are as follows: (i) copro-diagnostic procedures with low sensitivity (12.9–68.9%); (ii) copro-diagnostic procedures with moderate sensitivity (47.1–96.8%); and (iii) serological diagnostic procedures with high sensitivity (68.0–98.2%). Beta prior distributions were specified for the different diagnostic-test group sensitivities. For each study, the diagnostic method used (sensitivity group) was included as a determining factor in the model. The model results yielded the estimated prevalence for each country, including all studies per country and taking into account the

sensitivity level of the diagnostic tool used. A more detailed description of the model can be found elsewhere (Schär et al., 2013b). 3. Results 3.1. Current situation in South-East Asia We found 79 studies published in the last 25 years that reported on S. stercoralis in SEA. Thailand had by far the most studies with 47 (59.5% studies, Table 1a). In the other countries, far less data could be obtained. Cambodia had 10 (12.7%) studies, Indonesia and Lao PDR had 7 (8.9%) studies each. No data was available for Brunei, Myanmar, Singapore and the Philippines (Table 1b). Altogether 22 (27.8%) of the studies focused on children, 17 (21.5%) included in- or out-patients from hospitals. Nine (11.4%) studies were conducted among ethnic minority groups. In China, three (75.0%) of four and in Malaysia two (66.7%) of three studies were conducted among ethnic minority groups, respectively. The only study from Vietnam was also conducted in minority communities. Six (12.8%) of the studies were conducted with HIV-positive individuals, all originating from Thailand. The highest estimated prevalence calculated with our model was found in Malaysia, with 35.9% (95% BCI: 28.0–44.4%), and the lowest in Vietnam, with 0.1% (95% BCI: 0.01–1.8%) (Table 2). 3.2. Thailand Almost two thirds (47, 59.5%) of all studies included were conducted in Thailand. Studies conducted in rural communities, applying the Koga Agar culture method, reported infection rates as high as 38.8% among the general population (Uparanukraw et al., 1999) in Amphoe Sanpatong, Chiang Mai province, and 28.9% (Sithithaworn et al., 2003) among villagers in the northeast of Thailand. Other helminth studies conducted with low sensitivity for S. stercoralis reported only low infection rates. For example, Warunee et al. (2007) reported S. stercoralis prevalence as low as 0.1% among schoolchildren in Phuttamonthon district, Nakhon Prathom province, a semi-urban area west of Bangkok. The study used the formalin-ethyl acetate concentration method for diagnosis. While ecological, socio-cultural and economic factors can contribute to differences in prevalence rates, they do not necessarily explain large discrepancies in the reported prevalence rates. This is especially true when comparing populations in similar settings. The reported differences are then more likely due to the use of different diagnostic methods (for detection of S. stercoralis). Two studies in Thailand compared different geographical areas and applied the same diagnostic method throughout the study. The hospital-based study by Nuchprayoon et al. (2002) reported prevalence rates of 6.1% among villagers from the Northeastern part and only 1.2% among residents in the Southern part of Thailand. As the study applied the direct smear technique and formalin-ether concentration technique consistently, the reported regional differences are likely to reflect true differences but the true infection rates are likely to be higher in both areas. The study by Jongsuksuntigul et al. (2003) reported prevalence rates for the provinces of Northeastern Thailand, and applied the Koga Agar culture for all samples. The prevalence ranged from as high as 61.0% in Kalasin province to as low as 13.3% in Chaiyaphum province. Their reported overall prevalence for all of the Northeastern provinces was 23.5%. 3.3. Other countries in South-East Asia Of the other countries in SEA, Cambodia had the most studies (10) reporting prevalence rates, two of which were hospital-based, while the remainder were community-based studies. Six of the studies reported prevalence rates higher than 20%. In all studies,

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Table 1a Thailand: studies reporting on the prevalence of S. stercoralis. Year

Reference

Region

Population

1989

Kasuya

Schoolchildren

1990

Egger

1990

Koga

1990

Pitisuttithum

Chiang Mai province Sakon Nakhon province Ban Pang Mai Dang primary school, Chiang Mai province Bangkok

1990

Supanaranond

Bangkok

1991

Koga

1992

Boyajian

1994 1995

Sukhavat Sato

1996

Manatsathit

1996

Wilairatana

Ban Mae Pong primary school, Chiang Mai province Surin province, Cambodian border n.s. Chiang Mai province Bamrasnaradura Infectious Diseases Hospital, Nonthaburi, Bangkok region Bangkok

1998

Punpoowong

1999

Jongwutiwes

1999

Uparanukraw

2000

Anantaphruti

2001

Waree

2001

Waywa

2001

Wiwanitkit

2002

2002

Risk group

Remarks

Children, 3–8 years old, rural and urban Schoolchildren

General population, urban General population, all male

Volunteers for a cholera vaccine trial

Schoolchildren

Children General population General population, rural All

Refugees

HIV-+

All

Department of Tropical Pathology, Bangkok King Chulalongkorn Memorial Hospital Bangkok Amphoae Sanpatong, Chiang Mai province 4 primary schools, Muang District, Nakhon Si Thammarat province Phitsanulok province Siriraj Hospital, Bangkok, Bamrasnaradura Hospital, Nonthaburi Bangkok, King Chulalongkorn Memorial Hospital

All

Nacher

Nuchprayoon

Refugees

All workers seeking work abroad, mainly from northeast HIV-+

Diagnostic method

Total examined

Total positive

Prevalence (%)

DS, FECT, HM DS, FECT

491

55

11.2

343

87

25.4

KAP

148

23

15.5

DS, HM

189

18

9.5

n.s.

171

9

5.3

KAP

137

31

22.6

DS, FECT

958

227

23.7

KAP KAP

200 205

61 39

30.5 19.0

FECT

45

2

4.4

FECT

362

51

14.1

FECT

22

3

13.6

All

KAP

1085

241

22.2

All, rural

KAP

250

97

38.8

Schoolchildren

HM

945

14

1.5

All, rural

FECT

584

56

9.6

FECT

288

23

8.0

FECT

60

2

3.3

FECT

731

11

1.5

FECT

6231

186

3.0

All

HIV-+

All

HIV-+

Ratchaburi province, Suan Phung district

All, rural

Ethnic minority

Bangkok, Out Patient Department, King Chulalongkorn Memorial Hospital

All

HIVinfected patients who visited the Out Patient Department Thai citizens of Karen origin

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Reference

Region

Population

Risk group

Remarks

Diagnostic method

2002

Saksirisampant

Children 3 to 19 years, rural

Ethnic minority

Karen ethnicity

FECT

781

7

0.9

2002

Saksirisampant

Mae Chame district, Chiang Mai province Bangkok, Out-patients Department of the King Chulalongkorn Memorial Hospital

Thai workers seeking overseas employment

FECT

2213

26

1.2

2002

Waikagul

Children, rural

FECT

1010

9

0.9

2003

Nacher

FECT

911

85

9.3

2003

Jongsuksuntigul

1233

290

23.5

2003

Saksirisampant

Bo Klau district & Chalerm Prakiet district, Nan province Rajburi and Kanchanaburi provinces (close to the Thai–Burmese border), referred to the Hospital for Tropical Diseases, Bangkok for malaria treatment All provinces of northeastern Thailand Pathum Thani province

FECT

106

1

0.9

2003 2004

Sithithaworn Anantaphruti

KAP, ELISA KK, TC

120 529

57 12

47.5 2.3

2004

Tungtrongchitr

59

1

1.7

2005

Nontasut

KAP

697

114

16.4

2005

Pinlaor

KAP

156

20

12.8

2005

Sithtithaworn

459

178

38.8

2005

Wongjindanon

1.0

2005

Yaicharoen

2006

Khampitak

2006

Yaicharoen

2007

Tungtrongchitr

2008

Kitvatanachai

Northeast, 3 villages Thong Pha Phum District, Kanchanaburi province Bangkok, Out Patient DepartmentGeneral Practice Section Siriraj Hospital and Ramathibodi Hospital San Pa Tong District, Chiang Mai province Sirithorn and Srinagarind Hospitals in Khon Kaen

All

All, rural

Mon (47%), Thai (32%), Karen (12%) and Burmese (9%).

All, rural and semi-urban

KAP

Pre-school children (10–82 months old) All, rural Schoolchildren, rural

All

All children were orphans

Irritable Bowel Syndrome

34 IBS patients and 25 controls

All, rural

All

HIV-+

78 HIV-+ patients and 78 matched controls

FECT

Total examined

Total positive

Prevalence (%)

5 communities in Khon Kaen province, northeastern Thailand Samut Sakhon and Surin province Faculty of Medical Technology, Mahidol University

All, rural

KAP, ELISA

All, rural

DS

2104

20

DS

2230

2

Nam Phong District, Khon Kaen province 4 public schools in Phuttamonthon district, Nakhon Pathom province Ubon Ratchathani and Khon Kaen province

Children, 6–12 years old, rural Schoolchildren, 7 to 13 years old

KAP

212

55

25.9

FECT

814

1

0.1

1603

10

0.6

3 villages, suburban Simun subdistrict, Nakhon Ratchasima province

All, suburban

214

7

3.3

All

All, rural

Annual medical check-up (1999/2004)

All 10 cases detected in Ubon R. prov.

KK

KK, HM

0.09

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Table 1a (Continued) Year

Reference

Region

Population

2009

Leelayoova

Royal Thai Army Dog Center

All

2009 2009

Viriyavejakul Warunee

2012

Laodim

2012

Kaewpitoon

2013 2013

Boonjaraspinyo Anamnart

2014

Jongwutiwes

2014

Ruankham

8 schools in Phutthamonthon District, Nakhon Prathom province Srinagarind Hospital, Faculty of Medicine, Khon Kaen University All 17 districts of Surin province Khon Kaen province Moklan village, Nakhon Si Thammarat Province Siriraj Hospital, Bangkok

Nanglae Sub-District, Chiang Rai Province

Risk group

All Schoolchildren, 7–12 years old

HIV-+

All

B. hominis infection

Remarks

Diagnostic method

Military personnel working with military dogs

FECT

317

8

2.5

DS FECT

64 1920

2 1

3.1 0.05

FECT

114

65

57.0

KK

333

16

4.8

FECT mFECT, KAP

253 600

15 198

5.9 33.0

6022

149

2.5

263

1

0.4

In and Out patients

Elderly, 60 years or older, rural All, rural All, rural

All

All, rural

Patients which received Ova and Parasite examination

FECT

KK

Total examined

Total positive

Prevalence (%)

Abbreviations: BM: Baermann test; DS: direct smear; ELISA: enzyme-linked immunosorbent assay; (m)FECT: (modified) formalin-ether concentration technique; HM: Harada Mori filter paper technique; KAP: Koga Agar plate culture; KK: Kato-Katz technique; n.s.: not specified; PCR: polymerase chain reaction; TC: polyethylene tube culture. Only method with highest sensitivity for S. stercoralis is reported.

except for the two hospital-based studies, prevalence rates were higher than 10%. The highest infection rate was reported in a largescale, province-wide, community-based survey of all age groups, reporting an overall prevalence rate of 44.7% (Khieu et al., 2014a). The study used the Koga Agar culture and Baermann methods on two consecutive days. The study concluded that in most rural parts of Cambodia, infection with S. stercoralis is rampant. In our model, the estimated prevalence of S. stercoralis was 24.5% for Cambodia (95% BCI: 23.6%–25.6%) (Fig. 1, Table 2). In China, Wang et al. (2013) recently performed a meta-analysis of the strongyloidiasis-cases reported between 1973 and 2011. Most cases were found in the South- and South-Eastern provinces of China, namely Guangdong and Guangxi provinces, and mainly among people working as farmers or from ethnic minority groups. These findings were similar to those of Steinmann and colleagues, who reported S. stercoralis prevalence rates of 17.9% and 11.7% in farming communities in Yunnan province in the South of China. The team used a diagnostic approach with high sensitivity (Steinmann et al., 2007, 2008). In Lao PDR, we identified seven studies. The most recent one, conducted by Vonghachack and colleagues (Vonghachack et al., in this issue), reported a prevalence rate of 41.0% on the Mekong Islands in rural Champasack province, Southern Lao PDR. Three reports document the presence of S. stercoralis in Malaysia. A study of the Orang Asli minority community applied low sensitivity diagnostic methods and showed low prevalence rates of 1.2% (Rahmah et al., 1997). In a more recent study by Ahmad and colleagues in the same community of minorities, no S. stercoralis larvae were identified in 54 coprologically analysed stool samples. However, serological examination of the same individuals

revealed a prevalence of 31.5%. The authors explained this puzzling observation by citing the possibility of low-intensity chronic infections (Ahmad et al., 2013). However, further clarification of this observation is required. The study by Basuni et al. (2011) was undertaken in a hospital in Sarawak and examined patients reporting gastrointestinal symptoms. A pentaplex-PCR was used to screen for several STHs. The prevalence of S. stercoralis was reportedly 39.0%. We found seven studies from Indonesia. A recent study focusing on the association between carotid intima media (CIM)-thickness and helminth infections on Flores Island showed a prevalence of 1.1% for S. stercoralis, detected by PCR (Wiria et al., 2013). In Bali, a large-scale community-based survey using the Harada Mori concentration technique found a prevalence of S. stercoralis of 1.6% (Widjana and Sutisna, 2000). Another study, conducted on Irian Jaya island reported a prevalence lower than 1.0%, but had only applied low sensitivity diagnostic methods (Bangs et al., 1996). While these studies prove the presence of S. stercoralis in the country, the reported prevalence rates are low, especially compared to the reported prevalence rates of hookworm infection (5.4% vs. 75.8% (Mangali et al., 1994); 2.3% vs. 68.3% (Mangali et al., 1993); 1.2% vs. 63.7% (Hasegawa et al., 1992)). These reported differences could be due to the use of low-sensitivity diagnostic methods for S. stercoralis. In certain regions, differences could be due to the limited presence of S. stercoralis. We could only identify one community-based study from Vietnam, conducted by Le Hung et al. (2005). The study was conducted among children from an ethnic minority community in southern Vietnam and found no infection with S. stercoralis. Van der Hoek and colleagues summarised the prevalence of hookworm infection for

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Table 1b Studies reporting on the prevalence of S. stercoralis, stratified by country. Country/ year

Reference

Study area

Population

Cambodia 2004

Koga-Kita

All, semi-rural

KAP

2005

Longfils

Schoolchildren, rural

2006

Chhakda

Schoolchildren, rural

2010

Copelovitch

2012

Moore

3 villages in Prek Russey commune, Kandal province 2 schools in Chum Kiri and Dang Tung District, Kampot province Kampong Thom, Kampong Chnang, Pursat and Battambang province In- and Outpatient Departments of Angkor Hospital for Children, Siem Reap In- and Outpatient Departments of Angkor Hospital for Children, Siem Reap

2013

Khieu

2013

Schär

2014

Khieu

2014

Schär

2014

Khieu

China 2003

Tang and Luo

2007

Steinmann

2008

Steinmann

2013

4 schools in Kandal province 4 schools in Kandal province 60 villages in Preah Vihear province Dong village, Preah Vihear province 60 villages in Takeo province

Children

Risk group

Childhood Necrotic Syndrome

Children

Remarks

112 CNSchildren compared to 12,352 control samples Results from routinely submitted feacal samples from 2006 to 2011

Diagnostic method

Total examined

Total positive

Preva-lence (%)

3574

521

14.6

BM

162

19

11.7

BM

188

38

20.2

DS

12,464

321

2.6

DS

16,372

429

2.6

Schoolchildren

BM, KAP

458

112

24.4

Schoolchildren

BM, KAP, PCR BM, KAP

218

38

17.4

2396

1071

44.7

All, rural

All, rural

BM, KAP, PCR

218

53

24.3

All, rural and semi-rural

BM, KAP

2861

601

21.0

5 aeras of Beibei district, 4 rural and 1 urban Nongyang village, Yunnan province Nanweng village, Yunnan province

All, rural and urban

DS

2558

1

BM, KAP

180

21

11.7

BM

123

22

17.9

Yap

BM

194

6

3.1

Indonesia 1992

Hasegawa

1993

Mangali

1994

Mangali

1996

Bangs

All, rural

Ethnic minority

All, rural

Ethnic minority

5 schools in Bulangshan township, Yunnan province

Schoolchildren, 9–12 years old

Ethnic minority

5 villages in Likupang, Minahasa Peninsula, North Sulawesi 5 villages in Campalagian District, South Sulawesi 6 villages in Kao district, Halmahera Island, North Maluku Oksibil Valley, Irian Jaya

All, rural

KAP

419

5

1.2

All, rural

KAP

398

9

2.3

All, rural

HM, FECT

389

21

5.4

DS

478

4

0.8

All, rural

Ethnic minority

Bulang ethnic group Bulang ethnic group Bulang ethnic group

0.04

Indigenous highland community

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Table 1b (Continued) Country/ year

Reference

Study area

Population

1999

Toma

All, rural

KK, HM

654

7

1.1

2000

Widjana and Sutisna

All, rural

KK, HM

2394

39

1.6

2013

Wiria

4 villages in Barru district, South Sulawesi 4 villages in Bali, in 4 geoclimatic different areas semi urban area of Nangapanda, Flores Island

All, semi-urban

PCR

446

5

1.1

All, semi-rural

KK

137

3

2.2

All, rural

KAP

669

127

19.0

All, rural

FECT

434

47

10.8

All, rural

FECT

5107

71

1.4

FECT

232

24

10.3

All, rural

FECT

1358

121

8.9

All, rural

BM

729

299

41.0

FECT

84

1

1.2

Patients presenting with abdominal symptoms Orang Asli community

PCR

77

30

39.0

PCR, ELISA

54

17

31.5

Ethnic minority community in mountainous southern Vietnam

DS

1083

0

0.0

Lao PDR 1998

Chai & Hongvanthong

1998

Vannachone

2006

Sithithaworn

2008

Erlanger

2009

Sayasone

2012

Conlan

2014

Vonghachack

Malaysia 1997

Rahmah

2011

Basuni

2013

Vietnam 2005

Pakse area, Champassak province 3 villages in Khammouane province Xai Udom, rural fishing community, Nam Ngun reservoir Nakai plateau, Central Lao PDR Mahosot Hospital (Vientiane) and Savannakhet Provincial Hospital (Savannakhet) and Khamsida village (Champhone district, Savannakhet province), Thamouangkao village (Saravane district, Saravane province) Oudomxay, Luangprabang, Xiengkhuang and Huaphan province, 6 villages each Donlong, Donthan and Donglieng Islands, located in the Mekong River in Khong district, Champasack province, southern Laos

Risk group

Remarks

19 persons from hospitals, presenting hepatobiliary or intestinal symptoms were invited to participate

All aged 15 years or older, rural

6 villages in Post Brooke 2 district hospitals in Sarawak

Children, 1–12 years old, rural All

Ethnic minority

Ahmad

Orang Asli community in Kuala Pangsun, Hulu Langat, Selangor, Malaysia

General population

Ethnic minority

Le Hung

Phan Thien commune, Binh Thuan province

Children

Ethnic minority

Diagnostic method

Total examined

Total positive

Preva-lence (%)

Abbreviations: BM: Baermann test; DS: direct smear; ELISA: enzyme-linked immunosorbent assay; FECT: formalin-ether concentration technique; HM: Harada Mori filter paper technique; KAP: Koga Agar plate culture; KK: Kato Katz technique; PCR: polymerase chain reaction. Only method with highest sensitivity for S. stercoralis is reported.

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8 Table 2 Estimated prevalence per country. Country

# of studies

Estimated prevalence

95% BCI

Range of reported prevalence

Brunei Cambodia China Indonesia Lao PDR Malaysia Myanmar Philippines Singapore Thailand Vietnam

No data 10 4 7 7 3 No data No data No data 47 1

n.a. 24.5% 6.4% 5.2% 30.8% 35.9% n.a. n.a. n.a. 27.1% 0.1%

n.a. 23.6–25.6% 4.8–8.3% 4.2–6.3% 28.7–33.0% 28.0–44.4% n.a. n.a. n.a. 26.0–28.2% 0.01–1.8%

n.a. 2.6–44.7% 0.04–17.9% 0.8–5.4% 1.4–41.0% 1.2–39.0% n.a. n.a. n.a. 0.05–57.0% n.a.

29 of the 61 provinces in Vietnam (van der Hoek et al., 2003). They found a prevalence of 28.6%. Similar to the situation in Indonesia as stated above, the common routes of transmission and ecological needs of hookworm and S. stercoralis could indicate that S. stercoralis is also present in Vietnam. More research focusing specifically on S. stercoralis is needed to document the existence of the parasite. We could not identify community-based surveys originating from Brunei, Myanmar, the Philippines and Singapore. 3.4. Risk factors for Strongyloides stercoralis infection Analysis of behavioural and environmental risk factors was not commonly conducted and, if it was, it most often focused on infection status with other helminthic infections. Large-scale community-based studies with a focus on S. stercoralis and

analysing risk factors for infections and document associations were scarce. Sex is a risk factor that has been reported by Conlan et al. (2012). In their study conducted in rural Lao PDR, they found that males had a higher risk of infection with an odds ratio (OR) of 2.76. The sex difference was also reported from Thailand, where Khampitak et al. (2006) reported a prevalence of 35.2% in boys and 16.8% in girls (p = 0.003); and in Cambodia, where Koga-Kita (2004) reported an odds ratio of 1.4 for infection with S. stercoralis for males (17% vs. 13% prevalence, p = 0.001) and Khieu et al. (2014b) reported a higher prevalence was found among males than among females, in all age groups (OR: 1.7; 95% CI: 1.4–2.0; p < 0.001). Several studies listed age as a risk factor. The study by Conlan et al. (2012) from Lao PDR reported significantly higher risks of infection among people older than 20 years (20–34 years, OR: 2.66;

Fig. 1. The estimated prevalence of S. stercoralis in South-East Asian countries.

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35–49 years, OR: 2.51; >50 years, OR: 2.19). A similar association was also found in Cambodia by Khieu et al. (2014b). They showed a gradual increase of the prevalence rate up to 20% in the first 20 years of age. While the prevalence among females did not further increase as they got older, the prevalence among males further increased up to almost 40% among the 50 year old group. Khieu et al. (2014a) found that individuals with a latrine at home were significantly less frequently infected with S stercoralis than those who did not. Calculation of the population attributable risk found that the number of strongyloidiasis cases would be reduced by 39% if all participants used a latrine for defecation. We could only find one study examining geo-climatic factors and infection risk from SEA. The study by Widjana and Sutisna (2000), conducted in Bali, Indonesia, reported S. stercoralis prevalence rates from 0.9% in the dry lowland areas up to 3.3% in the wet highland areas. Statistically significant differences between rural and urban settings have also been reported. For example, the study by Egger et al. (1990) reported an S. stercoralis prevalence of 13.8% among urban children, compared to 28.1% among rural children (p < 0.05). Copelovitch et al. (2010) reported an association between infection with S. stercoralis and childhood nephrotic syndrome (CNS) derived from a hospital-based study in Cambodia. While the prevalence of S. stercoralis in the control group was 1.8%, the prevalence among children presenting with CNS was 6.1% (p = 0.0088). In a study of Thai children, thiamine status was associated with S. stercoralis infection. For the children with a normal thiamine status, the prevalence was 21.5%, while among the children presenting with a thiamine deficiency, prevalence was as high as 40.0% (p = 0.03). In SEA, all studies focusing on HIV-patients originated from Thailand. Pinlaor et al. (2005) included age- and sex-matched HIVseropositive (n = 78) and HIV-seronegative (n = 78) patients from two hospitals in Khon Kaen province. They found a significant difference in the infection rates of S. stercoralis (17.9% seropositive vs. 7.7% seronegative) among HIV-seropositive individuals. A meta-analysis conducted by Schär and colleagues that included 16 case-control studies reported on OR of 2.17 (95% BCI: 1.18–4.01) for HIV-positive individuals compared to non-infected controls (Schär et al., 2013b). Other studies reported infection rates in HIVpositive individuals, reporting S. stercoralis prevalence rates from 3.1% (Viriyavejakul et al., 2009) up to 13.6% (Punpoowong et al., 1998). Additionally, we found reports on prisoners of war, who had been held captive in SEA during either the second world war or the Vietnam war. The infected soldiers sustained the infection by autoinfection for many years (Genta et al., 1987; Gill and Bell, 1987; Gill et al., 2004; Robson et al., 2009a,b). These soldiers, and especially the prisoners of war, like refugees, have often been exposed to risk factors due to poor or non-existent sanitary facilities and malnutrition.

4. Discussion We have reviewed the scientific literature of the past 25 years on S. stercoralis in South-East Asia and summarised the reported prevalence rates and risk factor reported. We could demonstrate that information on S. stercoralis is scarce and that infection rates remain underreported. Further, we showed that most studies focusing on other STHs apply diagnostic methods that are inappropriate for detecting S. stercoralis. Information on risk factors associated with S. stercoralis infection is even rarer, since the parasite is often not the main focus of the studies conducted. Age (older age) and sex (male) are the best documented risk factors. Reports on S. stercoralis infection rates are hardly comparable. First, most studies focusing on helminth infections neglect

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Strongyloides altogether. Cases of S. stercoralis infection are therefore found “accidentally”, via sub-optimal diagnostic methods. The use of different diagnostic methods leads to a very heterogeneous picture of reported prevalence rates. In general, S. stercoralis is likely to be underreported. Furthermore studies conducted among possible risk groups or among hospital-based individuals makes it difficult to compare them to studies conducted among the general population. The studies from Thailand provide good examples of the problem of adequately estimating infection rates. More in-depth knowledge of age-/sex-related infection rates, for example, or of risk factors for S. stercoralis in general is even more uncommon. In other SEA countries, the situation is even more dire, as the number of studies reporting S. stercoralis infection rates are much fewer compared to Thailand. This lack of reports makes it difficult to draw a clear picture of the geographical distribution. One has to assume severe underreporting, especially in areas where lack of proper sanitation and behavioural and economic factors suggest high transmission of S. stercoralis. One such example is Indonesia, one of the most populous countries in the world with almost 240 million inhabitants. Most studies only focus on indigenous populations or minorities living in remote areas. We could not identify studies from the two main islands, Java and Sumatra, which account for almost 80% of the total population. Further, in Myanmar, we could not identify a published report, yet the study by Chaves et al. (2009) found a prevalence of 26% for S. stercoralis among Burmese refugees in Australia. In general, we argue that the absence of information might be because of a real lack of research or due to publication/language biases. As stated above, in the absence of a gold standard, the diagnostic methods applied in studies on STHs are the main contributor to underreported S. stercoralis infection. Parasitological diagnosis of S. stercoralis infection relies on identifying larvae in stool. Today, copro-culture methods, such as the Koga Agar culture method (Koga et al., 1991) and the Baermann method (Baermann, 1917), as well as the lesser known vermiculite stool culture (Polderman et al., 1991), are considered to be the diagnostic methods of choice for detecting S. stercoralis. They are considerably time- and labourintensive (Agrawal et al., 2009). All three methods are used in studies in SEA, although the Koga Agar culture is used more frequently. Studies focusing on other helminth infections deploy diagnostic methods suitable for those helminths (most notably the Kato-Katz method (Katz et al., 1972)), and therefore neglect possible Strongyloides infections. Only the inclusion of sensitive diagnostic methods can reveal the extent of infections and improve the accuracy of reported infection rates. Examining stool samples collected over a few days would also mitigate the risk of missing low-intensity infections. Although time- and resource-intensive, the ideal situation would include testing at least three stool samples per person on consecutive days with both the Koga Agar culture method and the Baermann method used in combination (Khieu et al., 2013; Knopp et al., 2008). Besides the coprological diagnostic methods, there are also serological and molecular methods available. However, these tools are more expensive and challenging to use in field settings. Furthermore, their specificity is often unknown as they may cross-react with other helminthic infections and yield an overestimation of S. stercoralis infection. Serological and molecular diagnostic methods must be validated through further studies to allow for better evaluation of these tools. Today, Ivermectin is the standard treatment for S. stercoralis infection. The most common dosage is a single oral dose of 200 ␮g/kg bodyweight. Other drugs have been used for treatment, including mebendazole, thiabendazole and albendazole. Several studies showed the efficacy of Ivermectin for treating S. stercoralis (Heukelbach et al., 2004; Igual-Adell et al., 2004; Khieu et al., 2013;

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Marti et al., 1996; Schär et al., 2014a; Suputtamongkol et al., 2011; Toma et al., 2000). The lack of information about the prevalence of S. stercoralis also makes it challenging to estimate the true disease burden and the attributable morbidity caused by strongyloidiasis. It is known that hyperinfection and disseminated strongyloidiasis can have a severe outcome, yet no data about the frequency in high risk populations is available. When considering S. stercoralis control, first evidence shows that animals play an important role in sustaining high transmission rates in rural communities. In Cambodia, for instance, research has focused on S. stercoralis in animals as well as in humans. Especially in rural farming communities, animals play an important role in the everyday-life of inhabitants and they often live in close contact with the villagers (Schär et al., 2014b). This opens up the possibilities for animal-human transmission of the parasite, a factor that needs to be taken into consideration when implementing control programmes. In rural Cambodia, around 10% of dogs harbour the same strain of S. stercoralis as do humans living in the same household (A. Streit, T. Gudeta, personal communication). Additionally, almost 50% of hookworm-infected humans harboured infection with Ancylostoma ceylanicum, the same species documented in 90% of hookworm-infected dogs (Inpankaew et al., 2014). In Lao PDR, Conlan et al. (2012) also analysed humans and animals for infection with STHs and documented that of the 105 dogs analysed, 94 (89.5%) were infected with hookworm, a nematode that exhibits the same transmission route as S. stercoralis. Azian et al. (2008) documented Strongyloides larvae in dogs and in the soil, differentiating between rural and urban dogs. All Strongyloides-infected dogs were found in the rural settings. While dogs, because of their close proximity to humans, can pose a serious threat for animalhuman transmission, S. stercoralis has also been documented in other animals in SEA. Orang-utans in Indonesia harbour S. stercoralis as well as S. fuelleborni fuelleborni (Labes et al., 2011). These findings suggest that control programmes take a “one health” approach, including the animals as well as humans. Of the studies on refugees or immigrants from SEA diagnosed with S. stercoralis, most were conducted in the USA, Canada and Australia (Boyajian, 1992; Buchwald et al., 1995; Goswami et al., 2009; Gyorkos et al., 1989, 1990; Lurio et al., 1991). These studies are further proof that S. stercoralis exists in SEA countries. Refugees are often exposed to very poor sanitary and nutritional conditions during their migration, possibly increasing the risk for infection with S. stercoralis. Other studies reported on soldiers/prisoners of war in SEA. There are case reports from veterans serving during the Vietnam war (Genta et al., 1987; Hakim and Genta, 1986; Pelletier and Gabre-Kidan, 1985) and from British soldiers that served in SEA (Myanmar/Burma) during World War II. Even though there is no confirmation that the infection was picked up in Myanmar rather than in the UK, climatic differences alone make it pretty safe to assume that this was in fact the case (Gill and Bell, 1987; Gill et al., 2004). One risk factor associated with S. stercoralis infection was infection with the human T-lymphotropic virus type I (HTLV-1) (Chieffi et al., 2000; Courouble et al., 2004; Einsiedel and Woodman, 2010; Hayashi et al., 1997; Marsh, 1996; Nera et al., 1989; Phelps, 1993; Robinson et al., 1994). Yet, HTLV-1 has a very specific global distribution. In SEA, the prevalence of HTLV-1 is very low or non-existant (Proietti et al., 2005), and therefore, HTLV-1 infection should not be considered a risk factor in SEA. However, HIV-infection might be a potential risk factor. In several reports, the prevalence of S. stercoralis infection was higher in HIV-infected individuals compared to HIV-negative controls. Further studies on this issue are warranted as HIV infection might be merely a confounding factor associated with a true determinant, such as low socioeconomic status and associated low hygiene and sanitation standards.

5. Conclusion In determining the current prevalence situation of S. stercoralis in SEA, many gaps remain. The information we have today only scratches the surface. In most countries in the region, the existence of S. stercoralis has been shown. Most often this is the only certainty, as detailed information about infections intensities, geographical differences and burden of disease remain undiscovered. Summarising the existing data for the region, we can make the following statements and recommendations: 1. S. stercoralis is likely to have a much higher burden than what is currently indicated by published study results. Large-scale community-based studies that apply high sensitivity diagnostic methods are needed in order to draw a clearer picture. 2. Studies that focus on other STHs should specifically include and test for S. stercoralis. 3. Ivermectin is a highly efficacious drug that has also been successfully applied in MDA-programmes. Countries with MDA-programmes targeting STHs should consider including Ivermectin. Further research efforts are needed to draw a more conclusive picture of the prevalence situation of S. stercoralis in SEA. Author’s contribution FS and PO conceived the study. FS conducted the literature review. FG conducted the meta-analysis. FG and FS prepared the maps. FS, FG, VK, SM, HM, PV and PO interpreted the results. FS wrote the manuscript. FS was supervised by PO in any aspect of this study. Conflict of interest The authors declare that there is no conflict of interest. Acknowledgement We thank Mrs Amena Briet for her efficient English editing. References Agrawal, V., Agarwal, T., Ghoshal, U.C., 2009. Intestinal strongyloidiasis: a diagnosis frequently missed in the tropics. Trans. R. Soc. Trop. Med. Hyg. 103, 242–246. Ahmad, A.F., Hadip, F., Ngui, R., Lim, Y.A., Mahmud, R., 2013. Serological and molecular detection of Strongyloides stercoralis infection among an Orang Asli community in Malaysia. Parasitol. Res. 112, 2811–2816. Azian, M.Y., Sakhone, L., Hakim, S.L., Yusri, M.Y., Nurulsyamzawaty, Y., Zuhaizam, A.H., Rodi, I.M., Maslawaty, M.N., 2008. Detection of helminth infections in dogs and soil contamination in rural and urban areas. Southeast Asian J. Trop. Med. Public Health 39, 205–212. Baermann, G., 1917. Eine einfache Methode zur Auffindung von Ankylostomum (Nematoden) Larven in Erdproben. Mededeel mit H. Geneesk. Laboratories Weltevreden Feestbundel, Batavia, pp. 41–47. Bangs, M.J., Purnomo Andersen, E.M., Anthony, R.L., 1996. Intestinal parasites of humans in a highland community of Irian Jaya, Indonesia. Ann. Trop. Med. Parasitol. 90, 49–53. Basuni, M., Muhi, J., Othman, N., Verweij, J.J., Ahmad, M., Miswan, N., Rahumatullah, A., Aziz, F.A., Zainudin, N.S., Noordin, R., 2011. A pentaplex real-time polymerase chain reaction assay for detection of four species of soil-transmitted helminths. Am. J. Trop. Med. Hyg. 84, 338–343. Boyajian, T., 1992. Strongyloidiasis on the Thai-Cambodian border. Trans. R. Soc. Trop. Med. Hyg. 86, 661–662. Buchwald, D., Lam, M., Hooton, T.M., 1995. Prevalence of intestinal parasites and association with symptoms in Southeast Asian refugees. J. Clin. Pharm. Ther. 20, 271–275. Chaves, N.J., Gibney, K.B., Leder, K., O’Brien, D.P., Marshall, C., Biggs, B.A., 2009. Screening practices for infectious diseases among Burmese refugees in Australia. Emerg. Infect. Dis. 15, 1769–1772. Chieffi, P.P., Chiattone, C.S., Feltrim, E.N., Alves, R.C., Paschoalotti, M.A., 2000. Coinfection by Strongyloides stercoralis in blood donors infected with human T-cell

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Please cite this article in press as: Schär, F., et al., Occurrence of and risk factors for Strongyloides stercoralis infection in South-East Asia. Acta Trop. (2015), http://dx.doi.org/10.1016/j.actatropica.2015.03.008